Functionalization of sulfoximines and applications thereof

Abstract

New routes for sulfoximine functionalization are described herein, including routes for N-alkylation and N-arylation of sulfoximines. Methods described herein employ benign and abundant starting materials, such as aliphatic alcohols, aryl halides, and aliphatic carboxylates, while delivering a broad range of differentially substituted, complex, functional sulfoximines in desirable yields. Further, methods described herein can accommodate sophisticated molecular scaffolds, such as existing and contemplated drug molecules, as the alkyl or aryl fragments, resulting in highly elaborate functionalized sulfoximine products.

Description

[0001] FUNCTIONALIZATION OF SULFOXIMINES AND APPLICATIONS THEREOF STATEMENT OF GOVERNMENT RIGHTS

[0002] This invention was made with government support under Grant No. GM 134897 awarded by the National Institutes of Health and Grant No. N00014-21-1-2138 awarded by the Office of Naval Research. The government has certain rights in the invention.

[0003] RELATED APPLICATION DATA

[0004] The present application claims priority pursuant to 35 U. S. C. § 119(e) to United States provisional patent application serial number 63 / 736,215 filed December 19, 2024, which is incorporated herein by reference in its entirety.

[0005] FIELD

[0006] The present application relates to the functionalization of sulfoximines and, in particular, to the N-alkylation and N-arylation of sulfoximines.

[0007] BACKGROUND

[0008] Sulfoximines, along with sulfondiimines, sulfonimidamides, and sulfondiimidamides, have increasingly attracted the interest of drug designers and medicinal chemists in recent years. Current technologies for N-H bond functionalization of sulfoximines primarily entail acylations. Moreover, existing methods for the arylation of these structural motifs rely on palladium-catalyzed cross-coupling reactions, which often suffer from low yields, particularly when complex aromatic structures or heterocycles, especially five-membered structures, are involved.

[0009] Additionally, the alkylation of sulfoximines represents a major challenge in sulfoximine functionalization. Existing methods often lack generality and functional group compatibility, and in some cases, require the use of explosive reagents (such as peroxides). To date, few examples exist in the literature that allow for the installation of secondary alkyl fragments, with primary alkyl groups mostly limited to methyl.

[0010] SUMMARY

[0011] In view of the foregoing disadvantages, new routes for sulfoximine functionalization are described herein, including routes for N-alkylation and N-arylation of sulfoximines. Methods described herein employ benign and abundant starting materials, such as aliphatic alcohols, aryl halides, and aliphatic carboxylates, while delivering a broad range of differentially substituted, complex, functional sulfoximines in desirable yields. Further, methods described herein can accommodate sophisticated molecular scaffolds, such as existing and contemplated drug molecules, as the alkyl or aryl fragments, resulting in highly elaborate functionalized sulfoximine products.

[0012] In some embodiments, a method of functionalizing a sulfoximine comprises coordinating the sulfoximine with a transition metal to provide a transition metal-sulfoximine complex, and capturing an alkyl radical with the transition metal-sulfoximine complex resulting in a higher valent intermediate, wherein the higher valent intermediate undergoes reductive elimination to yield aN-alkyl functionalized sulfoximine. As described further herein, the alkyl radical can be produced via various pathways. In some embodiments, the alkyl radical is generated from an N-heterocyclic carbene (NHC)-alcohol adduct. Alternatively, the alkyl radical, in some embodiments, is generated from a bicyclo[1.1.1]pentane (BCP) carboxylate which undergoes decarboxylation following reduction by a photocatalyst. In some embodiments, the alkyl radical is generated from halogen abstraction from an alkyl substrate.

[0013] These and other embodiments are further described in the following detailed description.

[0014] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 A illustrates a mechanism for the N-alkylation of sulfoximines according to some embodiments.

[0015] FIG. IB provides reaction conditions for the N-alkylation illustrated in FIG. 1 A, according to some embodiments.

[0016] FIG. 1C provides an example of sulfoximine N-alkylation according to some embodiments.

[0017] FIG. 2 illustrates N-alkylation of sulfoximines according to some embodiments.

[0018] FIG. 3 illustrates a mechanism for the N-alkylation of sulfoximines according to some embodiments.

[0019] FIG. 4 illustrates N-alkylation of sulfoximines according to some embodiments.

[0020] FIG. 5 illustrates modification of various small molecule substrates according to some embodiments. FIG. 6 illustrates modification of various drug and / or bioactive substrates according to some embodiments.

[0021] FIG. 7 illustrates a mechanism for the N-alkylation of sulfoximines according to some embodiments.

[0022] FIG. 8 illustrates N-alkylation of sulfoximines using BCP-carboxylic acids according to some embodiments.

[0023] FIG. 9 illustrates the tunability of pharmacological properties of compounds via biosteric replacement with methods described herein according to some embodiments.

[0024] FIGS. 10-11 provide non-limiting examples of N-arylation of sulfoximines according to some embodiments described herein.

[0025] FIG. 12A illustrates a mechanism for the N-arylation of sulfoximines according to some embodiments.

[0026] FIG. 12B provides reaction conditions for the N-arylation illustrated in FIG. 12A, according to some embodiments,

[0027] FIG. 12C provides an example of N-arylation of sulfoximines according to some embodiments.

[0028] DETAILED DESCRIPTION

[0029] Embodiments described herein can be understood more readily by reference to the following detailed description and examples and their previous and following descriptions. Elements, apparatus and methods described herein, however, are not limited to the specific embodiments presented in the detailed description and examples. It should be recognized that these embodiments are merely illustrative of the principles of the present invention. Numerous modifications and adaptations will be readily apparent to those of skill in the art without departing from the spirit and scope of the invention.

[0030] Definitions

[0031] The term “alkyl” as used herein, alone or in combination, refers to a straight or branched saturated hydrocarbon group optionally substituted with one or more substituents. For example, an alkyl can be Ci - C30 or Ci - Cis. The term “alkenyl” as used herein, alone or in combination, refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon double bond and optionally substituted with one or more substituents.

[0032] The term “alkynyl” as used herein, alone or in combination, refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond and optionally substituted with one or more substituents.

[0033] The term “aryl” as used herein, alone or in combination, refers to an aromatic monocyclic or multicyclic ring system optionally substituted with one or more ring substituents. Aryl includes fused and non-fused ring structures.

[0034] The term “heterocycle” as used herein, alone or in combination, refers to an mono- or multicyclic ring system in which one or more atoms of the ring system is an element other than carbon, such as boron, nitrogen, oxygen, sulfur, and / or phosphorus and wherein the ring system is optionally substituted with one or more ring substituents. The heterocyclic ring system may include aromatic and / or non-aromatic rings, including rings with one or more points of unsaturation. Heterocycle includes fused and non-fused ring structures.

[0035] The term “cycloalkyl” as used herein, alone or in combination, refers to a non-aromatic, mono- or multicyclic ring system optionally substituted with one or more ring substituents.

[0036] The term “heterocycloalkyl” as used herein, alone or in combination, refers to a non-aromatic, mono- or multicyclic ring system in which one or more of the atoms in the ring system is an element other than carbon, such as boron, nitrogen, oxygen, sulfur or phosphorus, alone or in combination, and wherein the ring system is optionally substituted with one or more ring substituents.

[0037] The term “alkoxy” as used herein, alone or in combination, refers to the moiety RO-, where R is alkyl, alkenyl, or aryl defined above.

[0038] The term “halo” as used herein, alone or in combination, refers to elements of Group VIIA of the Periodic Table (halogens). Depending on chemical environment, halo can be in a neutral or anionic state.

[0039] Terms not specifically defined herein are given their normal meaning in the art.

[0040] In one aspect, a method of functionalizing a sulfoximine comprises coordinating the sulfoximine with a transition metal to provide a transition metal-sulfoximine complex, and capturing an alkyl radical with the transition metal-sulfoximine complex resulting in a higher valent intermediate, wherein the higher valent intermediate undergoes reductive elimination to yield a N-alkyl functionalized sulfoximine. N-alkyl functionalized sulfoximines described herein can have the structure of Formula I:

[0041] O N-Alkyl

[0042] R1R2 (I),

[0043] wherein Ri and R2 are independently any desired moieties including, but not limited to, alkyl, alkenyl, aryl, heterocyclyl, cycloalkyl, -alkylene-aryl, -alkenylene-aryl, -alkylene-heterocyclyl, -alkenylene-heterocyclyl, and -alkylene-cycloalkyl. In some embodiments, Ri and R2 are the same. For example, in some embodiments, Ri and R2 are both alkyl, aryl or heterocyclyl.

[0044] Alternatively, Ri and R2 are different. In some embodiments, Ri is alkyl while R2 is aryl or heterocyclyl. Ri and R2, in some embodiments, combine to form one or more ring structures, including fused ring structures or spirocyclic structures. In some embodiments, at least one of Ri and R2 is a peptide. The peptide can have any desired number and identity of amino acids. In some embodiments, a peptide of Ri or R2 has at least three amino acids. A peptide of Ri or R2, in some embodiments, has 5-20 amino acids or greater than 20 amino acids. As described further herein, at least one of Ri or R2, in some embodiments, is a small molecule or pharmaceutical. Depending on specific identities of Ri and R2, the functionalized sulfoximines can present configurationally stable stereogenic centers.

[0045] In some embodiments, the Alkyl functionalizing the nitrogen of the sulfoximine in Formula I can be any desired alkyl, including linear alkyl, branched alkyl, cycloalkyl, spirocyclic structures, or heterocycloalkyl. The Alkyl can optionally be substituted with one or more substituents selected from the group consisting of halo, aryl, heterocyclyl, alkenyl, alkynyl, amine, amide, carboxy, and alkoxy. In some embodiments, for example, Alkyl substituting the sulfoximine nitrogen of Formula I is bicyclo[1.1.1]pentane (BCP) or a substituted BCP.

[0046] Any desired sulfoximine consistent with the technical objectives described herein can be functionalized. In some embodiments, the sulfoximine undergoing N-alkylation or N-arylation according to methods described herein can be an existing drug or drug precursor. Alternatively, the sulfoximine can exhibit any desired architecture for modifying existing or contemplated drugs / small molecules, wherein the drugs / small molecules serve as the molecular fragments participating in the sulfoximine functionalization. The versatility of methods described herein enable sulfoximines to play increasingly important roles in drug or small molecule design.

[0047] In the functionalization process, the sulfoximine is coordinated with a transition metal to provide a transition metal-sulfoximine complex. Any transition metal operable to undergo coordination with the sulfoximine and alkyl radical, followed by reductive elimination to yield the alkylated sulfoximine can be employed. In some embodiments, the transition metal is selected from Groups 10 and 11 of the Periodic Table. Moreover, the transition metal, in some embodiments, can be provided to the reaction mixture as a complex for coordination with the sufloximine. The transition metal complex, in some embodiments, comprises a salt, such as a transition metal acetate or transition metal halide. For example, copper acetate may be provided to the reaction mixture for amido complex formation and subsequent radical capture. In some embodiments, copper catalyst for use in sulfoximine alkylation and / or arylation described herein is selected from Table 1.

[0048] Table 1 - Copper Catalyst

[0049] _ CU(OAC)2 _

[0050] _ CuCl2_

[0051] _ CuBr2_

[0052] _ Cu(OTf>2_

[0053] _ Cu(acac>2 _

[0054] _ CU(TMHD)2_

[0055]

[0056] Cu(MeCN)4BF4

[0057] For N-alkylation of sulfoximines, an alkyl radical is captured by the transition metal-sulfoximine complex. Suitable alkyl radicals can be generated from several differing processes. In some embodiments, the alkyl radical is generated from an NHC-alcohol adduct. For example, an aliphatic alcohol can react with an NHC salt, such as a benzoxazolium salt, under mildly basic conditions, forming the NHC-alcohol adduct upon condensation. Any desired aliphatic alcohol can be employed to provide the NHC-alcohol adduct. Specific identity of the aliphatic alcohol can be dependent on the desired N-alkyl substitution the sulfoximine. The aliphatic alcohol can be a primary alcohol or a secondary alcohol, in some embodiments. The aliphatic alcohol can comprise a linear or branched structure. Alternatively, the aliphatic alcohol can be cyclic or spirocyclic, including cycloalkyl or hetercyclyl. The aliphatic alcohol can also be substituted with any desired moi eties to tailor the architecture / structure of the functionalized sufloximine. In some embodiments, the aliphatic alcohol comprises one or more moieties selected from the group consisting of aryl, aromatic heterocyclyl, non-aromatic heterocycle, cycloalkyl, alkenyl, alkynyl, alkoxy, halo, and protected amine. In some embodiments, the aliphatic alcohol has a more complex structure relative to the sulfoximine. In other embodiments, the sulfoximine has a more complex structure relative to the alcohol. Examples described herein provide non-limiting examples of sulfoximine functionalization via use of aliphatic alcohols according to some embodiments. In some embodiments, the sulfoximine can be an existing drug or a derivative thereof. The aliphatic alcohol, in some embodiments, can be the existing drug or a derivative thereof.

[0058] When generating the alkyl radical through an NHC-alcohol adduct, an a-oxy radical of the NHC-alcohol adduct is formed and undergoes P-scission of a C-0 bond to provide the alkyl radical and a carbamate byproduct. The a-oxy radical of the NHC-alcohol adduct can be generated by single electron transfer (SET) between the NHC-alcohol adduct and an excited state photocatalyst yielding reduced photocatalyst and a radical cation of the NHC-alcohol adduct, followed by deprotonation of the radical cation with base to provide the a-oxy radical. Any photocatalyst operable to participate in SET with the NHC-alcohol adduct can be employed. In some embodiments, the photocatalyst is an organic photocatalyst. For example, suitable organic photocatalyst can comprise l,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) or 4CzPN. Suitable photocatalyst may also comprise one or more transition metal complexes. The photocatalyst, in some embodiments, absorbs visible light to generate the photocatalyst excited state. It is also contemplated that the photocatalyst can absorb ultra-violet or infrared light to generate the excited state.

[0059] Any base consistent with the technical objectives described herein can be employed for deprotonation of the radical cation to provide the a-oxy radical. In some embodiments, suitable base is selected from Table 2.

[0060] Table 2 - Base for Radical Cation Deprotonation

[0061] BTMG: 2- / c77-biityl-1.1.3.3-tctramethylguanidine _

[0062] TMG: 1,1,3,3-tetramethylguanidine _

[0063] DBU: l,8-diazabicyclo(5,4.0)undec-7-ene: _

[0064] DBN: l,5-diazabicyclo(4.3.0)non-5-ene _

[0065] MTBD: 7-methyl-l,5,7-triazabicyclo(4.4,0)dec-5-ene

[0066]

[0067] BTTP: tert-buty 1 i m i no-tri (py rrol idi nojphosphorane Once generated, the alkyl radical is captured by the transition metal-sulfoximine complex resulting in a higher valent intermediate, wherein the higher valent intermediate undergoes reductive elimination to yield the N-alkyl functionalized sulfoximine. The higher valent intermediate refers to the increased oxidation state of the transition metal resulting from the capture of the alkyl radical. The oxidation state of the transition metal can increase by one or more resulting from capture of the alkyl radical. For example, copper of a sulfoximine complex can increase in oxidation state from +2 to +3 following capture of the alkyl radical.

[0068] FIG 1A illustrates a mechanism for the N-alkylation of sulfoximines according to some embodiments. For the NH-alkylation of FIG. 1A, the alkyl radical is generated as follows: first, an aliphatic alcohol reacts with an A-arylbenzoxazolium salt (NHC) under mildly basic conditions, forming an NHC-alcohol adduct upon condensation. Upon photoexcitation with visible light (450 nm), the photocatalyst 1,2, 3, 5- tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) is excited into its relatively long-lived triplet excited state. This photoexcited state is readily quenched by the NHC-alcohol adduct via SET, yielding the reduced radical anionic photocatalyst species and the radical cation of the NHC-adduct. The methine C-H bond in this radical cation is deprotonated by stoichiometric base, producing an a-oxy radical, which is prone to undergo P-scission of the C~O bond, affording an inert carbamate byproduct and the desired free alkyl radical.

[0069] The relatively nucleophilic NH sulfoximine is independently complexed with copper(II) acetate and stoichiometric base to produce a Cu(II)-sulfoximine complex. This complex intercepts the free alkyl radical at near-diffusion rates, generating a putative high-valent Cu(III) intermediate. The high-valent copper complex undergoes fast reductive elimination to produce the C(sp3)-N coupled product and a low-valent copper(I) species. Finally, the photocatalyst and copper-mediated cycle are turned over via the reaction of an oxidant with the reduced photocatalyst and the copper(I) complex. FIG. IB provides non-limiting reaction conditions for the N-alkylation illustrated in FIG. 1A while FIG. 1C provides another example of N-alkyl functionalization of sulfoximines according to some embodiments.

[0070] As described above, the photocatalyst and copper-mediated cycle are turned over via the reaction of an oxidant. Any oxidant consistent with the technical objectives described herein can be employed. In some embodiments, the oxidant is iodosomesitylene (MesIO). In other embodiments, suitable oxidant can be air, benzoyl peroxide (BZ2O2) or potassium persulfate (K2S2O8). Additionally, alkylation reactions described herein can be carried out in polar aprotic solvent. Suitable polar aprotic solvents are provided in Table 3.

[0071] Table 3 - Polar Aprotic Solvents

[0072] acetonitrile (MeCN) _

[0073] dimethyl sulfoxide (DMSO)

[0074] dimethyl carbonate (PMC)

[0075] 1,2-dimethoxyethane (DME)

[0076] ethyl acetate (EtOAc) _

[0077]

[0078] 1,4-dioxane

[0079] Moreover, one or more cosolvents may be used, in some embodiments. Suitable cosolvents can be selected from Table 4.

[0080] Table 4 - Cosolvents

[0081] methyl tert-butyl ether (MTBE)

[0082] Fluorobenzene (PhF) _

[0083] Trifluorotoluene (PhCF j _

[0084] Acetone _

[0085] ethyl acetate (EtOAc) _

[0086] 1,4-dioxane _

[0087]

[0088] dimethyl carbonate (PMC)

[0089] Owing to the versatility of the benzoxazolium reagent, a broad range of alcohols featuring diverse functional groups could be coupled to 5, -diphenylsulfoximine as the parent sulfoximine. Primary alcohols derived from chiral amino acids (4 and 5) provided the desired N-alkylated sulfoximines in high to excellent yields (67% and 86%). Moreover, sterically encumbered ^-quaternary alcohols, challenging substrates in traditional cross-coupling reactions, proved competent coupling partners (6, 60%), as did alcohols containing acid-labile acetal protecting groups, such as solketal 7 (58%).

[0090] Notably, methods described herein enable straightforward and efficient coupling of various secondary alkyl fragments with the parent sulfoximine. Seven-(8), six-(3, 9, 10), five-(11), and four-membered rings (12) were well tolerated, undergoing substitution at different ring positions in moderate to high yields (52-74%). Additionally, noncyclic secondary alcohols delivered the product in high yield (13, 75%). Compounds 4-13 are further illustrated in FIG. 2. In additional embodiments, the cyclopropyl moiety, due to the nature of its orbitals, is typically incompatible with S.vl or Sv2 conditions, necessitating alternative activation strategies. As a practical entry point for this motif, bromocyclopropane was employed in conjunction with adamantylaminosilane (AdNHSi(TMS)3) as a potent halogen atom abstraction (XAT) reagent, as set forth in the reaction mechanism of FIG. 3. This approach furnished A-cyclopropyl sulfoximine 14 (FIG. 2) in 73% yield, showcasing the complementary nature of methods described herein and their compatibility with diverse radical precursors and activation modes. As provided in FIG. 3, the alkyl radical is captured by the copper-sulfoximine complex and proceeds to the alkylated sulfoximine consistent with FIG. 1 A.

[0091] Methods described herein also permit coupling of enantiomerically pure sulfoximines with achiral alcohols with complete stereoretention, delivering product (15) in 81% yield and >99% ee. Furthermore, the introduction of a chiral alkyl fragment enabled construction of product 16 with three absolute stereogenic centers in a single step with high diastereoselectivity (58%, d.r. =17.5:1), exemplifying the power of methods described herein to generate stereochemical complexity.

[0092] Arene-alkyl sulfoximines were investigated and it was found that a wide array of (hetero)aryl groups at the sulfoximine scaffold were tolerated by methods described herein, including phenyl (17 and 18), pyridyl (19), and pyrazinyl (20) substituents, all delivering products in moderate to high yields (48-83%). The methodology was also applicable to various alkyl sulfoximines, including benzylic variants (21, 71%). For an electron-deficient S(VI)-CF3 derivative, changing the base to TMG and the ligand to neocuproine, afforded the desired product 22 in 57% yield. Cyclic sulfoximines also demonstrated high reactivity, including substrates derived from dibenzothiophene (23, 69%), tetrahydrothiophene (24, 66%), 1,4-oxathiane (25, 50%), thiomorpholine (26, 63%), and thiaazaspiro[3.5]nonane (27,

[0093] 82%). Encouragingly, the successful coupling of fully 5,5-alkyl-substituted sulfoximines was also extended to acyclic systems (28-30), with yields ranging from 55% to 67%. Compounds 15-30 are further illustrated in FIG. 4.

[0094] As described herein, complex alcohols and sulfoximines can be coupled according to the present methods, including those derived from naturally occurring biomolecules and scaffolds frequently found in pharmacologically active compounds. The broad availability of alcohols, combined with the straightforward synthesis of sulfoximines via oxidation / nitrene transfer from thioethers enabled access to products from structurally diverse and complex starting materials. A range of differently substituted hydroxypiperidines, including A-heterobenzoylated (31 and 32), / V-heteroarylated (33), and A-sulfonylated (34) alcohols were effectively employed as alkylating agents for sulfoximines bearing various substitution patterns, affording the desired products in high to very high yields (59-81%). Spirocyclic sulfoximines (35) and (36), featuring an exceptionally high degree of C(sp3) hybridization within their carbon skeleton in high yields (55% and 63%, respectively) were also obtained with methods described herein. Additionally, antiandrogen-derived 37 and an avanafil analog (38) were efficiently synthesized from the corresponding alcohols (61% and 54%, respectively).

[0095] In some embodiments, mild activation and radical generation enabled by the NHC -based reagent of methods described herein allow for the direct conversion of native sugar alcohols into alkyl radicals suitable for coupling. To demonstrate this utility, methods described herein were applied to a unnatural nucleoside (39), galactopyranose (40), and mannofuranose (41). In each case, the corresponding alkylated sulfoximines were obtained in high to very high yields (57-81%) with excellent diastereoselectivity (d.r. = 13:1 for 39 and d.r. > 20:1 for 41). Compounds 31-41 are further illustrated in FIG. 5.

[0096] Methods described herein can also permit late state installation of sulfoximine bioisosteres in pharmacologically active compounds and their derivatives bearing alcohol groups. FIG. 6 illustrates functionalization of pharmacologically active compounds with sulfoximine groups according to some embodiments. The sulfoximine group was readily incorporated into molecules derived from nateglinide (42), lonazolac (43), and linagliptin (45), affording the corresponding products in moderate to high yields (49-66%). Coupling with androsterone furnished sulfoximine (44) in 61% yield with a 1:1 diastereomeric ratio, providing access to both diastereomers for evaluation of potentially distinct biological activity or pharmacokinetic profiles. In addition, differently substituted complex sulfoximines were effective in the late-stage functionalization of alcohols derived from alogliptin (46) and metoprolol (47), delivering the desired products in high yields (66% and 63%, respectively), further underscoring the versatility of this methodology in connecting diverse and structurally complex building blocks.

[0097] This applicability was further demonstrated using racemic atuveciclib, a CDK inhibitor, as the sulfoximine coupling partner. By employing our optimized conditions with bromocyclopropane and AdNHSi(TMS)3, the corresponding N-cy cl opropanated atuveciclib derivative (48) was obtained in 56% yield. This result highlights the practicality of the alkylation strategy, as the parent compound can be directly engaged in the transformation without the need for extensive prior modification.

[0098] Apart from small molecules, the late-stage modification of peptides represents a powerful strategy in medicinal chemistry, enabling the precise and efficient diversification of complex peptide scaffolds without the need for lengthy de novo synthesis. By facilitating streamlined access to analogues, such methods significantly enhance the speed and precision of peptide-based drug development. To this end, a tripeptide model substrate was synthesized containing a Met-Phe-Leu sequence and subjected it to an oxidation protocol for converting thioethers into sulfoximines. Exposure of the resulting NH-sulfoximine peptide (MSO-Phe-Leu) to the alkylation methods described herein enabled the installation of an azetidine moiety in synthetically useful yield (49, 49%, d.r. = 1:1). Notably, this transformation would not have been feasible using traditional substitution techniques or previously reported metal-catalyzed methods. This methodology could prove useful in peptide library synthesis by converting native methionine residues into unnatural amino acids in a straightforward and versatile manner.

[0099] Methods described herein were also applied to synthesis of a lapatinib analogue (50), which was obtained in high yield (63%). In this case, compound (50) represents a direct bioisostere of the parent lapatinib, where the sulfone moiety, characterized by two hydrogen bond acceptors, was replaced by an alkylated sulfoximine that mimics these key acceptor features. Importantly, both bioisosteric compounds can be accessed from a common thioether precursor, thereby streamlining synthetic accessibility and enabling a late-stage divergence in the overall synthetic strategy. Compounds 42-50 are further illustrated in FIG. 6.

[0100] Methods described herein, in some embodiments, are employed for installation of bicyclo[l.l.l]pentane (BCP) moi eties in various sulfoximine compound architectures. In such embodiments, the alkyl radical is generated from a BCP-carboxylate which undergoes decarboxylation following reduction by a photocatalyst. FIG. 7 illustrates a mechanistic pathway employing BCP-carboxylates according some methods described herein. By altering reaction conditions and modifying the redox linchpins, including preactivating the BCP-carboxylic acids with iodomesitylene diacetate [MesI-(OAc)2] to generate diacetate 51 and using [Ir(dF(Me)- ppy)2(dtbbpy)]PF6 as the photocatalyst and Cu(acac)2 as the copper source, a variety of differently substituted sulfoximines were coupled with BCP-carboxylic acids (52-55) of FIG. 8 in moderate to excellent yields (55-93%). In some embodiments, iridium (Ir)-based photocatalyst for use with BCP-carboxylate embodiments is selected from Table 5.

[0101] Table 5 - Iridium Photocatalyst

[0102] Ir[dF(CF3)ppy]2(dtbbpy)PF6 _

[0103] Ir[F(Me)ppy]2(dtbbpy) PF6 _

[0104]

[0105] Ir(ppy)2(dtbbpy) PF6

[0106] As set forth in FIG. 7, no external oxidant is required as the system is based on a redox-neutral catalytic cycle. In situ formed Cu(I) complex VI (A’i / 2red[Cun(BPhen)2 / CuI(BPhen)2] = +0.08 Vvs. SCE in DMF, BPhen = 4,7-diphenyl-l,10-phenanthroline) possesses the ability to reductively quench the exited state of the Ir-based photocatalyst (E1 / 2red[* IrHI / Irn] = +0.99 V vs. SCE in MeCN), yielding the reduced Ir(II) photocatalyst as well as the required Cu(II)-sulfoximine complex IV. For the decarboxylative approach, it is proposed that iodomesitylene dicarboxylate (51), generated from carboxylic acid (56) with iodomesitylene diacetate [MesI(OAc)2], would undergo facile reduction by the Ir(II) species (E1 / 2red[Irni / Irn] = - 1.41 V vs. SCE in MeCN); EP[51 / 51*-] = -1.14 V vs. SCE in MeCN), leading to the formation of a carboxyl radical as well as the regeneration of the ground-state Ir(III) photocatalyst. Upon subsequent decarboxylation, the desired BCP-radical IX is obtained. In line with the mechanism for the deoxygenative approach, the higher valent Cu(III) intermediate X is formed upon coordination of radical IX to Cu(II) complex IV, which subsequently undergoes reductive elimination, furnishing the desired V-B CP sulfoximine (52).

[0107] Methods described herein can be employed in pharmaceutical compound design and modification of existing pharmaceuticals to improve or enhance pharmacokinetic properties. Sulfoximines, for example, are valuable functional groups for optimizing ADME profiles in drug development. To evaluate this potential, atuveciclib was selected, an established CDK inhibitor to assess whether the introduction of an alkyl group at the nitrogen atom of the sulfoximine would lead to improved pharmacological properties. Based on computational

[0108] docking studies, the alkylated derivative (57) was selected as a suitable candidate for our endeavor. Accordingly, the NHC -based methods described herein using cyclobutanol as the alkylating reagent, affording (57) directly from atuveciclib in 53% yield with full retention of stereochemical configuration.

[0109] Compound (57) was subsequently evaluated in HeLa human cervical carcinoma cells (CCL-2) to assess its cellular potency relative to the parent compound (FIG. 9). Gratifyingly, the IC50 value (0.7 «M) was comparable to atuveciclib (0.3 z / M), indicating that / V-alkylation does not compromise cellular activity. Encouraged by this result, it was examined whether N-alkylation improved the compound’s physicochemical properties in vivo. An increase in logD was observed, suggesting enhanced lipophilicity, which may contribute to improved membrane permeability. In parallel, kinetic solubility showed a notable improvement compared to atuveciclib (FIG. 9). Together, these properties are expected to increase the fraction absorbed (Fa) in vivo, potentially resulting in higher oral bioavailability. To further assess its ADME profile, we measured the permeability of compound (57) in Madin-Darby canine kidney (MDCK) cells, a model for epithelial absorption. Compound (57) exhibited enhanced permeability compared to the parent compound, suggesting improved oral bioavailability or tissue distribution. Together, these results underscore the potential of A-alkylated sulfoximines as valuable motifs for modulating both physicochemical and pharmacokinetic properties in drug development.

[0110] N-arylation of sulfoximines is now discussed. For N-ary lati on of sulfoximines, an aryl radical is captured by the amido complex formed between the transition metal and sulfoximine. Sulfoximines and transition metals forming the transition metal-sulfoximine complex can be any of the same described hereinabove for the N-alkylation of sulfoximines. Suitable aryl radicals can be generated from several differing processes. In some embodiments, the aryl radical is generated from halogen abstraction from an aryl halide. For example, bromine or chlorine can be abstracted from the aryl halide to provide the aryl radical. In some embodiments, an aminosilane radical is responsible for halogen abstraction. The aminosilane radical can be generated via SET between an aminosilane and an excited state photocatalyst yielding a reduced photocatalyst and the aminosilane radical. In some embodiments, the aminosilane radical is a an a-amino silicon-centered radical. Photocatalyst suitable for aminosilane radical generation can comprise photocatalyst described hereinabove for N-alkylation, in some embodiments.

[0111] Once generated, the aryl radical is captured by the transition metal-sulfoximine complex resulting in a higher valent intermediate, wherein the higher valent intermediate undergoes reductive elimination to yield the N-aryl functionalized sufloximine. FIGS. 10-11 provide nonlimiting examples of sulfoximine arylation according to some embodiments described herein. As illustrated in FIGS. 10-11, the aryl halide employed in the N-arylation can provide various structural motifs as desired. The aryl halide, in some embodiments, is a heteroaryl halide. In some embodiments, the aryl halide is optionally substituted one or more times with substituents selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocyclyl, alkoxy, sulfonyl, -alkylene-aryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl, -alkenylene-aryl, -alkenylene-heterocyclyl, and

[0112] -alkenylene-cycloalkyl.

[0113] FIG. 12A illustrates a mechanism for the N-arylation of sulfoximines according to some embodiments. For the NH-arylation of FIG. 12A, adamantyl aminosilane is used to quench the excited state of the photocatalyst, leading to the formation of an N-centered radical cation. Upon deprotonation with stoichiometric base, an N-centered radical is formed. Subsequent aza-Brook rearrangement results in the migration of a TMS group to the nitrogen atom, generating an electron-rich a-amino silicon-centered radical, which readily abstracts a bromine atom from an aryl bromide, furnishing the corresponding aryl radical. The relatively nucleophilic NH sulfoximine is independently complexed with copper(ll) acetate and stoichiometric base to produce a Cu(II) amido complex. This complex intercepts the free aryl radical at near-diffusion rates, generating the higher-valent Cu(III) intermediate. The higher-valent copper complex undergoes fast reductive elimination to produce the C(sp2)-N coupled product and a low-valent copper(I) species. Finally, the photocatalyst and copper-mediated cycle are turned over via the reaction of an exogenous stoichiometric oxidant (air) with the reduced photocatalyst and the copper(I) complex. FIG. 12B provides reaction conditions for the N-arylation illustrated in FIG.

[0114] 12A. FIG. 12C provides another example of N-arylation of sulfoximines according to some embodiments.

[0115] In another aspect, functionalized sulfoximine compounds are provided. The functionalized sulfoximine compounds can comprise any of the N-alkylated or N-arylated sulfoximine compounds described herein. In some embodiments, a functionalized sulfoximine is of the formula:

[0116] OxN-BCP

[0117] X

[0118] R1R2

[0119]

[0120] wherein BCP is bicyclo[l.l.l]pentane (BCP) or a substituted BCP, and wherein Ri and R2 are independently selected from the group consisting of alkyl, alkenyl, aryl, heterocyclyl, cycloalkyl, -alkylene-aryl, -alkenylene-aryl, -alkylene-heterocyclyl, -alkenylene-heterocyclyl, and -alkylene-cycloalkyl, and wherein Ri and R2 may optionally combine to form a substituted or unsubstituted cycloalkyl or heterocyclyl ring. In some embodiments, the BCP is substituted with one or more carboxy groups or alkoxy groups. Additionally, in some embodiments, Ri and R2 are independently selected from the group consisting of alkyl, aryl, and heterocyclyl, wherein the aryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, amine, amide, and alkoxy.

[0121] The following Examples are exemplary of methods and compounds described herein and should not be considered limiting unless expressly stated.

[0122] EXAMPLE 1

[0123] General Procedure A

[0124] In an oven-dried vial with an X-shaped stir bar, 4CzIPN (5 mol%), Cu(OAc)2 (15 mol%) and 1, 10-phenanthroline (17.5 mol%) were placed before the atmosphere was exchanged (3x) after which MeCN (5 mL) was added. The resulting suspension was sonicated for 1 minute to dissolve all components, during which a green disperse suspension was forming.

[0125] Subsequently, the corresponding NH-sulfoximine (0.5 mmol, 1.00 equiv.) was added followed by BTMG (2.0 equiv.). The resulting brown solution was stirred for 1 minute to ensure efficient complexation with the copper complex.

[0126] In parallel to an oven dried 40 mL vial charged with a X-shaped stir bar was added alcohol (2.00 equiv.) and NHC-H (2.2 equiv.). The vial was purged and backfilled with N2 once, then, dry MTBE (5 mL) was added via syringe against the flow of N2. The heterogeneous mixture was stirred vigorously for 2 minutes before pyridine (2.2 equiv.) was added in one portion. The mixture was stirred at room temperature for ~30 minutes during which the reaction mixture was regularly shaken by hand in addition to continuous stirring. Next, the MTBE suspension of activated alcohol was transferred to a syringe under air. A syringe filter was installed, and the suspension was filtered into a new 40 mL vial. Quantitative transfer of the activated alcohol was ensured by washing the condensation vial with ~0.1 mL of MTBE followed by filtration through the same syringe filter. With a new syringe needle, the solution was transferred to the sulfoximine solution. Next the vials were degassed for 15 min by bubbling N2 through the solution, followed by addition of iodosomesitylene (MesIO, 2.0 equiv.) against the flow of N2. The vial was subsequently sealed with melted parafilm, placed in the Ml PennOC or M2 PennOC integrated photoreactor and irradiated (450 nm LED module, 75% intensity, 750 rpm stirring, max fans) for 8 hours.

[0127] After the irradiation, the vials were opened to air and 1,3,5-trimethoxybenzene (TMB, 0.05 mmol) were added as an internal standard and aliquot (50 pL) were taken for analysis by NMR or UPLC. The solvent was subsequently removed under reduced pressure and directly subjected to purification.

[0128] General Procedure B

[0129] In an oven-dried vial with an X-shaped stir bar, 4CzIPN (2 mol%), Cu(OAc)2 (25 mol%) and 1, 10-phenanthroline (28 mol%) were placed before the atmosphere was exchanged (3x) after which MeCN (10 mL) was added. The resulting suspension was sonicated for 5 minutes to dissolve all components, during which a green disperse suspension was forming. Subsequently, the corresponding NH-sulfoximine (0.5 mmol, 1.00 equiv.) was added followed by bromocyclopropane (2.00 equiv.), AdNHSi(TMS)3 (2.2 equiv.) and 1, 1,3,3-tetramethylguanidine (TMG, 2.00 equiv.). The resulting green solution was stirred for 1 minute to ensure efficient complexation with the copper complex, was subsequently capped, and the septum pierced with a 16G needle. The vial was placed in the Ml PennOC or M2 PennOC integrated photoreactor with the needle pierced through the septum and irradiated (450 nm LED module, 10% intensity, 500 rpm stirring, max fans) for 12 hours.

[0130] After the irradiation, the vials were opened to air and 1,3,5-trimethoxybenzene (TMB, 0.05 mmol) were added as an internal standard and aliquot (50 pL) were taken for analysis by NMR or UPLC. The solvent was subsequently removed under reduced pressure and directly subjected to purification.

[0131] General Procedure C

[0132] The iodonium reagents were prepared according to a previously published procedure, lodonium (0.4 mmol, 1.0 equiv.), sulfoximine (0.8 mmol, 2.0 equiv ), Ir[dF(Me)ppy]2(4,4'-dtbbpy)PF6 (2 mol%), and Cu(acac)2 (50 mol%), were added to an oven-dried 40 mL vial equipped with an X-shaped stir bar and placed under an N2 atmosphere. Degassed 1,4-dioxane (0.33 M) was added followed by BTTP (0.4 mmol, 1.0 equiv.) and the vial was placed in the Ml PennOC or M2 PennOC integrated photoreactor (450 nm, 25% light intensity, 5000 rpm fans, 500 rpm stirring, single vial holder, 60 min). After the irradiation, the vials were opened to air and 1,3, 5 -trimethoxybenzene (TMB, 0.05 mmol) were added as an internal standard and aliquot (50 pL) were taken for analysis by NMR or UPLC. The solvent was subsequently removed under reduced pressure and directly subjected to purification.

[0133] Experimental and Characterization Data for N-Functionalized Products

[0134] Benzyl 4-((oxodiphenyl-λ6-sulfaneylidene)amino)piperidine-1-carboxylate (3)

[0135]

[0136] Prepared according to the general procedure A with S, S-diphenyl-sulfoximine (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), benzyl 4-hydroxypiperidine-l-carboxylate (235 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0137] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was loaded on a 25 g Biotage Sfar normal phase column and purified with eluents 0% to 70% EtOAc in hexanes. The resulting product fractions were concentrated to provide the product as a yellowish semi-solid (160.7 mg, 370 pmol, 74% yield).

[0138] 'H NMR (500 MHz, CDCh) 6 8.10 - 7.93 (m, 4H), 7.55 - 7.43 (m, 6H), 7.37 - 7.34 (m, 4H), 7.33 - 7.27 (m, 1H), 5.12 (s, 2H), 3.97 (d, J = 11.4 Hz, 2H), 3.29 (tt, J = 8.4, 3.9 Hz, 1H), 3.08 (ddd, J = 13.4, 9.7, 3.3 Hz, 2H), 1.81 (dq, J = 7.8, 4.1 Hz, 2H), 1.74 - 1.63 (m, 2H).

[0139] 13C NMR (126 MHz, CDCh) 5 155.49, 141.48, 137.18, 132.52, 129.27, 128.59, 128.06, 128.00, 127.90, 67.04, 51.05, 42.37, 35.41 (bs). Tert-butyl (R)-(1-((oxodiphenyl-λ6-sulfaneylidene)amino)-3-phenylpropan-2-yl)carbamate (4)

[0140] NHBoc

[0141] : Ph

[0142] Ph. /

[0143]

[0144] dPh

[0145] Prepared according to the general procedure A with S, S-diphenyl-sulfoximine (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1, 10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), tert-butyl / V-((S)-( l-benzyl-2-hydroxy-ethyl)carbamate (251 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0146] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 20% to 80% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and the product was obtained as a colorless solid (150.1 mg, 333 pmol, 67% yield).

[0147] 1H NMR (500 MHz, CDCh) 558.00 - 7.89 (m, 4H), 7.56 - 7.41 (m, 6H), 7.31 -7.23 (m, 4H), 7.20 - 7.14 (m, 1H), 5.33 - 4.86 (m, 1H), 4.05 - 3.76 (m, 1H), 3.14 - 2.86 (m, 4H), 1.42 (s, 9H).

[0148] 13C NMR (126 MHz, CDC13) 5 155.66, 140.86, 140.49, 139.09, 132.67, 132.62, 129.70, 129.32, 128.72, 128.64, 128.37, 126.19, 79.04, 52.80, 45.40, 38.70, 28.61.

[0149] Tert-butyl (S)-2-(((oxodiphenyl-λ6-sulfaneylidene)amino)methyl)pyrrolidine-1-carboxylate (5)

[0150]

[0151] Prepared according to the general procedure A with S, S-diphenyl-sulfoximine (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-l -carboxylate (201 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0152] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 70% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and the product was obtained as a colorless resin (171.4 mg, 428 pmol, 86% yield).

[0153] *H NMR (500 MHz, CDC13) 8 8.02 - 7.88 (m, 4H), 7.55 - 7.40 (m, 6H), 4.12 - 3.86 (m, 1H), 3.45 - 3.31 (m, 2H), 3.31 - 3.22 (m, 1H), 3.10 - 2.84 (m, 1H), 2.28 - 2.09 (m, 1H), 2.04 - 1.87 (m, 2H), 1.85 - 1.55 (m, 1H), 1.45 (s, 3H), 1.32 (s, 6H). (mixture of rotamers)

[0154] 13C NMR (126 MHz, CDCI3) 8 154.63, 141.21, 141.05, 140.79, 132.32, 129.17, 129.12, 128.69, 128.58, 128.42, 78.95, 78.71, 58.93, 58.65, 47.10, 46.69, 45.86, 45.46, 29.02, 28.49, 23.71, 22.85. (mixture of rotamers)

[0155] Tert-butyl (1-(((oxodiphenyl-λ6-sulfaneylidene)amino)methyl)cyclohexyl)carbamate (6)

[0156]

[0157] Prepared according to the general procedure A with S, S-diphenyl-sulfoximine (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv ), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), tert-butyl A-[l-(hydroxymethyl)cyclohexyl]carbamate (229 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL). After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was loaded on a 25 g Biotage Sfar normal phase column and purified with eluents 10% to 60% EtOAc in hexanes. The fractions containing product were concentrated and further purified by preparative HPLC (XB ridge BEH C18 OBD column, 30% to 95% MeCN in H2O with 0.1% NH40H) to provide the product as a colorless oil (128.1 mg, 299 pmol, 60% yield).

[0158] 'H NMR (500 MHz, CDC13) 57.96 (dd, J= 7.0, 2.9 Hz, 4H), 7.54 - 7.41 (m, 6H), 4.68 (br s, 1H), 3.15 (s, 2H), 2.16 - 2.08 (m, 2H), 1.56 - 1.46 (m, 7H), 1.45 (s, 9H), 1.34 - 1.23 (m, 2H).

[0159] 13C NMR (126 MHz, CDCI3) 5 155.05, 141.30, 132.36, 129.20, 128.72, 78.47, 55.90, 33.10, 28.70, 21.92.

[0160] (((2, 2-dimethyl-l, 3-dioxolan-4-yl)methyl)imim)diphenyl-X6-snlfanone (7)

[0161]

[0162] Prepared according to the general procedure A with S, S-diphenyl-sulfoximine (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), (2,2-dimethyl-l,3-dioxolan-4-yl)methanol (124 pL, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0163] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was loaded on a 25 g Biotage Sfar normal phase column and purified with eluents 10% to 60% EtOAc in hexanes. The fractions containing product were concentrated and further purified by preparative HPLC (XB ridge BEH C18 OBD column, 30% to 95% MeCN in H2O with 0.1% NH4OH) to provide the product as a colorless oil (96.8 mg, 292 pmol, 58% yield). > H NMR (500 MHz, CDCh) 8 8.00 - 7.92 (m, 4H), 7.54 - 7.42 (m, 6H), 4.33 (dtd,,7 = 7.6, 6.1, 5.1 Hz, 1H), 4.17 (dd, J= 8.3, 6.2 Hz, 1H), 3.92 (dd, J= 8.3, 6.1 Hz, 1H), 3.26 (dd, J = 12.2, 5.1 Hz, 1H), 3.09 (dd, J= 12.2, 7.6 Hz, 1H), 1.39 (s, 3H), 1.36 (s, 3H).

[0164] 13C NMR (126 MHz, CDCh) 8 140.60, 140.56, 132.64, 132.63, 129.31, 128.78, 128.67, 109.27, 68.44, 46.85, 27.01, 25.67.

[0165] Tert-butyl 4-((oxodipheuyl-A6-sulfaneylidene)amino)azepane-l -carboxylate (8)

[0166]

[0167] Bor;

[0168] Prepared according to the general procedure A with S, S-diphenyl-sulfoximine (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv ), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), terz-butyl 4-hydroxyazepane- 1 -carboxylate (215 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0169] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was loaded on a 25 g Biotage Sfar normal phase column and purified with eluents 0% to 60% EtOAc in hexanes. The resulting product fractions were concentrated to provide the product as a colorless solid (126.3 mg, 305 pmol, 61% yield).

[0170] 'H NMR (500 MHz, CDCh) 8 8.04 - 7.87 (m, 4H), 7.53 - 7.42 (m, 6H), 3.60 - 3.40 (m, 2H), 3.40 - 3.19 (m, 3H), 2.02 - 1.90 (m, 2H), 1.89 - 1.75 (m, 3H), 1.66 - 1.52 (m, 1H), 1.40 (s, 9H). (mixture of rotamers; major rotamer given)

[0171] 13C NMR (126 MHz, CDCh) 8 155.81, 141.53, 141.45, 141.36, 132.42, 132.38, 129.24, 129.20, 129.15, 128.72, 128.62, 128.59, 79.03, 79.00, 54.55, 54.02, 46.79, 46.15, 42.89, 42.42, 39.15, 38.46, 36.78, 36.43, 28.64, 28.52, 24.02, 23.78. (mixture of rotamers)

[0172] ((!-( 6-chloropyridazin-3-yl)piperidin-4-yl)imino)diphenyl-.6-siilfanone (9)

[0173]

[0174] Prepared according to the general procedure A with S, S-diphenyl-sulfoximine (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1, 10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), l-(6-chloropyridazin-3-yl)piperidin-4-ol (214 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0175] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 70% MeCN in water (0.1% NH4OH modifier). The resulting product fractions were concentrated to provide the product as a beige solid (113.7 mg, 275.6 pmol, 55% yield).

[0176] 'H NMR (500 MHz, CDCh) 5 8.09 - 7.90 (m, 4H), 7.55 - 7.42 (m, 6H), 7.14 (d, J = 9.6 Hz, 2H), 6.89 (d, J= 9.6 Hz, 2H), 4.13 (dt, J= 13.2, 4.7 Hz, 2H), 3.41 (tt, J= 8.4, 4.0 Hz, 1H), 3.26 (ddd, J= 13.1, 9.5, 3.3 Hz, 2H), 1.93 (ddt, J= 13.4, 6.7, 3.9 Hz, 2H), 1.81 (dtd, J = 13.1, 9.1, 3.8 Hz, 2H).

[0177] 13C NMR (126 MHz, CDC13) 5 159.06, 146.19, 141.39, 132.59, 129.32, 128.74, 128.59, 115.41, 50.98, 43.75, 35.03.

[0178] T ert-butyl -3-(( oxodiphenyl-X6-sulfaneylidene)amino)-8-azabicyclo[ 3.2.1 ]octane-8-carboxylate (10) Ph~~S=O

[0179] I

[0180]

[0181] Ph

[0182] Prepared according to the general procedure A with S, S-diphenyl-sulfoximine (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (227 mg, 1.00 mmol, 2.00 equiv ), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mb) and MTBE (5 mL).

[0183] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 15% to 70% MeCN in water (0.1% NH4OH modifier). The resulting product fractions were concentrated to provide the product as an orange solid (127.8 mg, 299.6 pmol, 60% yield, d.r. > 20:1).

[0184] 1H NMR (500 MHz, CDC13) 5 8.00 - 7.88 (m, 4H), 7.58 - 7.38 (m, 6H), 4.25 - 4.14 (m, 1H), 4.10 (s, 1H), 3.54 (tt, J = 10.8, 6.1 Hz, 1H), 2.89 (d, J = 22.2 Hz, 1H), 1.94 - 1.68 (m, 7H), 1.45 (s, 9H).

[0185] 13C NMR (126 MHz, CDCI3) 5 153.23, 141.51, 132.48, 129.21, 128.63, 79.13, 53.63, 52.87, 46.42, 42.27, 41.27, 29.96, 28.68.

[0186] Tert- / v / (j73-[[oxo(diphenyl)-sulfanylidene]amino]pyrrolidine-l-carboxylate (11)

[0187]

[0188] Prepared according to the general procedure A with S, S-diphenyl-sulfoximine (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 nmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv ), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), Z / 7-butyl 3 -hydroxypyrrolidine- 1-carboxylate (187 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0189] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar Cl 8 D reverse phase column, and purified with eluents 15% to 80% MeCN in water (0.1% NH4OH modifier). The resulting product fractions were concentrated to provide the product as a colorless solid (101.7 mg, 263 pmol, 53% yield).

[0190] XH NMR (500 MHz, CDC13) 6 8.04 - 7.88 (m, 4H), 7.56 - 7.43 (m, 6H), 3.72 (h, J= 6.2 Hz, 1H), 3.54 (dq, J= 15.3, 9.0 Hz, 2H), 3.27 (ddd, J= 26.0, 10.7, 7.1 Hz, 2H), 2.09 - 1.91 (m, 2H), 1.44 (s, 9H).

[0191] 13C NMR (126 MHz, CDCI3) 5 154.74, 140.87, 140.75, 132.75, 129.48, 129.38, 128.91, 128.68, 128.60, 128.48, 79.13, 54.04, 53.60, 53.45, 52.96, 44.77, 44.30, 35.53, 34.59, 28.69. (mixture of rotamers)

[0192] ((3, 3-difluorocyclobutyl)imino)diphenyl- 6-sulfanone (12)

[0193]

[0194] F

[0195] Prepared according to the general procedure A with S, S-diphenyl-sulfoximine (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), 3,3-difluorocyclobutanol (108 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0196] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar Cl 8 D reverse phase column, and purified with eluents 15% to 80% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and further purified by preparative HPLC (RediSep C18 column, 30% to 80% MeCN in H2O with 0.1% formic acid). The fraction containing product were carefully concentrated and the residual water phase extracted with EtOAc (3 x 50 mL). The dried combined organic extracts were concentrated under recued pressure to provide the product as a beige solid (80.4 mg, 262 pmol, 52% yield).

[0197] > H NMR (500 MHz, CDC13) 87.94 (dd, J= 7.8, 1.8 Hz, 2H), 7.66 - 7.40 (m, 4H), 3.69 (tdt, J=10.7, 7.5, 3.8 Hz, 1H), 2.79 (dddt, J= 15.3, 11.5, 7.6, 3.9 Hz, 1H), 2.73 - 2.62 (m, 1H).

[0198] 13C NMR (126 MHz, CDC13) 8 140.61, 132.84, 129.41, 128.50, 119.47 (dd, J= 285.2, 266.9 Hz), 45.92 (dd, <7 = 22.6, 20.6 Hz), 38.84 (dd, J= 21.9, 4.0 Hz).

[0199] ((1 -phenoxypropan-2-yl)imino)diphenyl-X6-sulfanone (13)

[0200]

[0201] Prepared according to general procedure A with S, S-diphenyl-sulfoximine (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv ), l-phenoxypropan-2-ol (143 pL, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0202] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was loaded on a 25 g Biotage Sfar normal phase column and purified with eluents 10% to 60% EtOAc in hexanes. The fractions containing product were concentrated and further purified by preparative HPLC (RediSep C18 column, 30% to 80% MeCN in H2O with 0.1% formic acid) to provide the product as a colorless oil (132.3 mg, 376 pmol, 75% yield).

[0203] *H NMR (500 MHz, CDCh) 8 8.05 - 8.00 (m, 2H), 8.01 - 7.96 (m, 2H), 7.50 - 7.41 (m, 6H), 7.25 - 7.21 (m, 2H), 6.93 - 6.86 (m, 3H), 4.13 (dd, J= 9.3, 6.2 Hz, 1H), 3.86 (dd, J= 9.3, 6.9 Hz, 1H), 3.60 (h, <7= 6.4 Hz, 1H), 1.35 (d, J = 6.4 Hz, 3H).

[0204] 13C NMR (126 MHz, CDCh) 8 159.05, 141.25, 140.75, 132.58, 132.55, 129.53, 129.24, 129.06, 128.68, 120.59, 114.65, 74.03, 49.94, 21.81. Cyclopropylimino-oxo-diphenyl-sulfane (14)

[0205]

[0206] Prepared according to general procedure A with S, S-diphenyl-sulfoximine (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (12.4 mg, 10.0 pmol, 2 mol%), Cu(OAc)2 (22.7 mg, 125 pmol, 25 mol%), 1,10-phenanthroline (25.2 mg, 140 pmol, 28 mol%), bromocyclopropane (80 pL, 1.00 mmol, 2.00 equiv.), AdNHSi(TMS)3 (437 mg, 1.1 mmol, 2.2 equiv ), TMG (187 pL, 1.00 mmol, 2.00 equiv.), in MeCN (10 mL).

[0207] After irradiation for 12 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 15% to 70% MeCN in water (0.1% NH4OH modifier). The resulting product fractions were concentrated to provide the product as a colorless solid (93.1 mg, 362 pmol, 73% yield).

[0208] > H NMR (500 MHz, CDC13) 8 8.00 (dd, J = 7.1, 1.8 Hz, 4H), 7.57 - 7.42 (m, 6H), 2.50 (tt, J =7.2, 3.8 Hz, 1H), 0.68 - 0.58 (m, 2H), 0.51 (td, J = 6.9, 4.7 Hz, 2H).

[0209] 13C NMR (126 MHz, CDCI3) 8 140.68, 132.77, 129.33, 128.64, 26.45, 6.97.

[0210] Tert- / w j74-f [(methyl-oxo-phenyl-sulfanylidene)amino I methyl ]piper idine-1 -carboxylate (15)

[0211]

[0212] Prepared according to general procedure A with (X)-A'-methyl-X-phenylsultaximine (77.6 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), Zc / 7-butyl 4-(hydroxymethyl)piperidine-l -carboxylate (215 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mb) and MTBE (5 mL).

[0213] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 15% to 80% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a yellow oil (142.8 mg, 405 pmol, 81% yield, >99% ee).

[0214] 'H NMR (500 MHz, CDCh) 6 7.88 (dd, J= 8.1, 1.6 Hz, 2H), 7.64 - 7.59 (m, 1H), 7.56 (dd, J =8.4, 6.9 Hz, 2H), 4.19 - 3.97 (m, 2H), 3.08 (s, 3H), 2.84 (dd, J= 12.1, 6.4 Hz, 1H), 2.73 -2.65 (m, 2H), 2.62 (dd, J= 12.1, 7.2 Hz, 1H), 1.83 (d, J= 13.1 Hz, 1H), 1.74 (dt, J= 13.1, 2.8 Hz, 1H), 1.63 (dqd, J= 10.8, 6.9, 6.5, 2.8 Hz, 1H), 1.44 (s, 9H), 1.06 (qd, J= 12.4, 4.4 Hz, 2H).

[0215] 13C NMR (126 MHz, CDCh) 5 155.03, 139.63, 132.99, 129.56, 128.77, 79.24, 49.61, 45.25, 38.89, 30.38, 30.23, 28.58

[0216] T vcX-butyl ( YR, 2Rj-2-f ( )-methyl(oxo) (phenyl)-6-sulfaneylidene)amino)cyclohexyl) carbamate (16)

[0217]

[0218] Prepared according to general procedure A with (5)-5-methyl-5-phenylsulfoximine (77.6 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), Zc / 7-butyl ((lR,2R)-2-hydroxycyclohexyl)carbamate (215 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0219] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar Cl 8 D reverse phase column, and purified with eluents 20% to 70% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a yellow oil that slowly crystalized to a colorless solid (102.5 mg, 291 pmol, 58% yield, d.r.= 17.5:1).

[0220] XH NMR (500 MHz, CDC13) 67.99 - 7.93 (m, 2H), 7.62 - 7.57 (m, 1H), 7.57 - 7.51 (m, 2H), 5.18 (br s, 1H), 3.28 - 3.20 (m, 1H), 3.07 (s, 3H), 2.71 (ddd, J= 10.9, 9.7, 4.2 Hz, 1H), 2.26 - 2.20 (m, 1H), 1.66 (ddt, J= 12.9, 5.5, 2.6 Hz, 1H), 1.60 - 1.53 (m, 2H), 1.46 (s, 9H), 1.31 - 1.21 (m, 2H), 1.02 (ttd, J= 11.4, 9.0, 8.1, 5.2 Hz, 2H). (major diastereoisomer, d.r. = 17.5:1).

[0221] 13C NMR (126 MHz, CDCI3) 5 156.26, 141.53, 132.99, 129.37, 128.61, 78.67, 57.11, 56.48, 45.36, 35.58, 32.72, 30.01, 28.68, 28.49, 25.16, 24.67.

[0222] Methyl(phenyl) ( 4-phenylbutan-2-yl)imino)-6-sulfanone (17)

[0223]

[0224] Prepared according to general procedure A with 5-methyl-5-phenylsulfoximine (77.6 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), 4-phenylbutan-2-ol (76.7 pL, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0225] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 30% to 70% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a colorless oil (109.6 mg, 381 pmol, 76% yield, d.r.= 1:1).

[0226] 1H NMR (500 MHz, CDC13) 87.96 (d, J = 7.6 Hz, 2H), 7.90 (d, J = 7.7 Hz, 2H), 7.63 - 7.50 (m, 7H), 7.26 - 7.19 (m, 6H), 7.18 - 7.08 (m, 4H), 3.21 (h, J= 6.3 Hz, 1H), 3.2 (s, 3H), 3.10 (s, 3H),3.10 - 3.06 (m, 1H), 2.78 (ddd, J= 13.9, 10.5, 5.7 Hz, 1H), 2.74- 2.63 (m, 2H), 2.53 (ddd, J= 13.9, 10.4, 5.5 Hz, 1H), 1.91 - 1.82 (m, 1H), 1.78 (ddd, J= 10.8, 7.4, 5.5 Hz, 2H), 1.74 - 1.65 (m, 1H), 1.24 (d, J= 6.3 Hz, 3H), 1.09 (d, J= 6.3 Hz, 3H). (mixture of diastereoisomers).

[0227] 13C NMR (126 MHz, CDC13) 8 142.97, 142.67, 141.12, 140.25, 132.86, 132.81, 129.37, 129.36, 128.74, 128.62, 128.44, 128.37, 128.34, 128.31, 125.65, 125.57, 50.70, 50.05, 45.55, 45.28, 42.13, 41.71, 33.02, 32.80, 24.93, 23.97. (mixture of diastereoisomers)

[0228] ( 4-Fluorophenyl) (methyl) ( 3, 3, 3-trifluoropropyl)imino)-6-sulfanone (18)

[0229]

[0230] Prepared according to general procedure A with (4-fluorophenyl)-imino-methyl-oxo-sulfane (86.6 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), 3,3,3-trifluoropropan-l-ol (87.7 pL, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0231] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 20% to 80% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a colorless oil (64.9 mg, 241 pmol, 48% yield).

[0232] 'H NMR (500 MHz, CDCh) 67.93 - 7.87 (m, 2H), 7.28 - 7.21 (m, 2H)*, 3.18 (dt, J = 12.6, 7.4 Hz, 1H), 3.08 (s, 3H), 3.02 (dt, J= 12.6, 7.6 Hz, 1H), 2.43 - 2.38 (m, 1H), 2.38 -2.32 (m, 1H). * Signal overlaps with NMR solvent peak.

[0233] 13C NMR (126 MHz, CDCh) 8 165.74 (d, J= 255.6 Hz), 135.02 (d, J= 3.1 Hz), 131.50 (d, J= 9.4 Hz), 126.45 (q, J= 277.0 Hz), 117.01 (d, J= 22.5 Hz), 45.39, 37.20 (q, J= 3.9 Hz), 37.08 (q, J = 27.2 Hz).

[0234] Benzyl N-[2-[[methyl-oxo-(2-pyridyl)-sulfanylidene ] amino] ethyl] carbamate (19)

[0235] / — NHCbs

[0236]

[0237] Prepared according to general procedure A with imino-methyl-oxo-(2-pyridyl)-sulfane (78.1 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc) (13.6 mg, 75.0 pmol, 15 mol%), 1, 10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), benzyl N-(2-hydroxyethyl)carbamate (195 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0238] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 20% to 70% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and further purified by preparative HPLC (RediSep C18 column, 20% to 60% MeCN in H2O with 0.1% formic acid) to provide the product as a colorless oil (137.9 mg, 414 pmol, 83% yield).

[0239] 'H NMR (500 MHz, CDCh) 8 8.65 (d, J= 4.6 Hz, 1H), 8.08 (d, J= 7.8 Hz, 1H), 7.89 (td, J= 7.8, 1.7 Hz, 1H), 7.42 (dd, J= 7.7, 4.8 Hz, 1H), 7.38 - 7.29 (m, 5H), 5.68 (br s, 1H), 5.06 (s, 2H), 3.31 - 3.25 (m, 2H), 3.21 (s, 3H), 3.10 (dt, J= 12.7, 4.9 Hz, 1H), 2.90 (ddd, J = 12.3, 6.9, 4.4 Hz, 1H).13C NMR (126 MHz, CDC13) 5 157.38, 156.50, 150.64, 138.14, 136.99, 128.57, 128.23, 128.09, 126.82, 123.97, 66.50, 43.75, 42.79, 41.61.

[0240] Benzyl 4-((methyl(oxo)(pyrazin-2-yl)-l6-sidfaneylidene)amino)piperidine-l -carboxylate (20)

[0241]

[0242] Prepared according to general procedure A with imino-methyl-oxo-pyrazin-2-yl-sulfane (78.6 mg, 0.5 mmol, 1.00 equiv ), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1, 10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), benzyl 4-hydroxypiperidine-1 -carboxylate (235 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0243] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 60% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and further purified by preparative HPLC (RediSep C18 column, 20% to 80% MeCN in H2O with 0.1% formic acid) to provide the product as a colorless oil (92.0 mg, 246 pmol, 48% yield).

[0244] > H NMR (500 MHz, CDCI3) 89.32 (d, J= 1.4 Hz, 1H), 8.81 (d, J= 2.4 Hz, 1H), 8.72 (t, J= 1.9 Hz, 1H), 7.36 - 7.29 (m, 5H), 5.09 (s, 2H), 3.91 (d, J= 42.6 Hz, 2H), 3.24 (s, 3H), 3.19 (dq, J= 8.9, 4.4 Hz, 1H), 3.03 (ddd, J= 13.5, 10.1, 3.2 Hz, 1H), 2.95 - 2.86 (m, 2H), 1.86 - 1.77 (m, 1H), 1.65 - 1.56 (m, 1H), 1.48 - 1.32 (m, 2H).

[0245] 13C NMR (126 MHz, CDCI3) 8 155.38, 154.95, 147.55, 144.81, 144.30, 137.04, 128.58, 128.03, 127.91, 67.09, 51.26, 42.43, 42.34, 42.26, 35.69, 34.61. (mixture of conformers) T ert-b tyl 9-( (benzyl ( oxo) (phenyl ) -6-sulfaneylidene )amino) -3-azaspiro[ 5.5 ]undecane-3-carboxylate (21)

[0246]

[0247] Prepared according to general procedure A with benzyl-imino-oxo-phenyl-sulfane (116 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), Z / 7-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (269 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mb) and MTBE (5 mL).

[0248] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was loaded on a 25 g Biotage Sfar normal phase column and purified with eluents 10% to 70% EtOAc in hexanes. The fractions containing product were concentrated and further purified by preparative EfPLC (XB ridge BEH C18 OBD column, 30% to 80% MeCN in H2O with 0.1% NH4OEI) to provide the product as a beige solid (171.9 mg, 356 pmol, 71% yield).

[0249] ’H NMR (500 MHz, CDC13) 87.58 - 7.55 (m, 2H), 7.54 - 7.49 (m, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.28 - 7.22 (m, 1H), 7.20 - 7.13 (m, 2H), 7.00 - 6.94 (m, 2H), 4.36 (s, 2H), 3.36 -3.24 (m, 4H), 3.00 (ddd, J= 10.1, 7.8, 4.1 Hz, 1H), 1.77 - 1.70 (m, 1H), 1.66 - 1.48 (m, 7H), 1.44 (s, 9H), 1.22 (t, J = 5.8 Hz, 2H), 1.11 -0.98 (m, 2H).

[0250] 13C NMR (126 MHz, CDCI3) 8 155.17, 138.18, 132.80, 131.27, 129.84, 128.89, 128.87, 128.57, 128.28, 79.23, 63.52, 54.48, 40.12, 39.19, 34.68, 34.31, 32.33, 32.19, 31.29, 30.54, 28.61. Benzyl 4-(( oxo(phenyl) ( trifluoromethyl)- 6-sulfaneylidene )amino)piperidine-l -carboxylate (22)

[0251]

[0252] Prepared according to general procedure A with imino-methyl-oxo-pyrazin-2-yl-sulfane (78.6 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), neocuproine (18.7 mg, 87.5 pmol, 17.5 mol%), TMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), benzyl 4-hydroxypiperidine-1- carboxylate (235 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mb) and MTBE (5 mL).

[0253] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 20% to 90% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as an orange oil (121.0 mg, 284 pmol, 57% yield).

[0254] 'H NMR (500 MHz, CDCh) 8 8.08 (d, J= 7.9 Hz, 2H), 7.74 (t, J= 7.5 Hz, 1H), 7.61 (t, J= 7.8 Hz, 2H), 7.37 - 7.34 (m, 4H), 7.33 - 7.29 (m, 1H), 5.14 (s, 2H), 3.98 - 3.86 (m, 3H), 3.28 (tdd, J= 13.3, 9.0, 3.4 Hz, 2H), 1.91 - 1.84 (m, 2H), 1.71 - 1.65 (m, 2H).

[0255] 13C NMR (126 MHz, CDCh) 5 155.46, 137.04, 135.08, 132.70, 130.25, 129.46, 128.62, 128.08, 127.98, 121.84 (q, J= 339.7 Hz), 67.17, 50.58, 41.82, 41.73. Tert-butyl 6-((5-oxido-5A4-dibenzo[b,d]thiophen-5-ylidene)amino)-2-azaspiro[ 3.3 ]heptane-2-carboxylate (23)

[0256]

[0257] Prepared according to general procedure A with 5-iminodibenzothiophene 5-oxide (108 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), to7-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (213 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0258] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar Cl 8 D reverse phase column, and purified with eluents 30% to 70% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as colorless solid (140.7 mg, 343 pmol, 69% yield).

[0259] 'H NMR (500 MHz, CDCh) 57.82 - 7.74 (m, 4H), 7.60 (t, J = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 3.99 (p, J = 7.9 Hz, 1H), 3.91 (s, 2H), 3.81 (s, 2H), 2.50 (ddd, J = 12.4, 6.5, 2.8 Hz, 2H), 2.22 (td, J = 8.9, 3.2 Hz, 2H), 1.41 (s, 9H).

[0260] 13C NMR (126 MHz, CDCh) 5 156.32, 139.26, 133.21, 132.13, 130.32, 122.53, 121.75, 79.37, 44.52, 44.20, 32.40, 28.53.

[0261] Benzyl 3-( l-oxidotetrahydro-l6-thiophen-l-ylidene)ammo)piperidine-l -carboxylate (24)

[0262]

[0263] Prepared according to general procedure A with 1 -iminothiolane 1 -oxide (60.0 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), benzyl 3-hydroxypiperidine-l-carboxylate (235 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0264] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar Cl 8 D reverse phase column, and purified with eluents 10% to 60% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and further purified by preparative HPLC (XBridge BEH C18 OBD column, 20% to 60% MeCN in H2O with 0.1% NH4OH) to provide the product as a colorless oil (110.7 mg, 329 pmol, 66% yield).

[0265] *H NMR (500 MHz, CDC13) 87.38 - 7.28 (m, 5H), 5.13 (s, 2H), 4.15 - 3.91 (m, 2H), 3.32 - 2.88 (m, 5H), 2.85 - 2.63 (m, 2H), 2.29 - 2.09 (m, 4H), 2.04 - 1.93 (m, 1H), 1.75 - 1.66 (m, 1H), 1.55 - 1.41 (m, 2H). (mixture of rotamers)

[0266] 13C NMR (126 MHz, CDCI3) 8 155.44, 137.11, 128.59, 128.03, 127.92, 67.10, 53.85, 53.47, 52.81, 52.19, 51.85, 44.24, 35.31, 35.02, 24.61, 24.28, 24.06, 23.70, 23.36.

[0267] (mixture of rotamers)

[0268] Benzyl 4-( ( 4-oxido-l, 4-6-oxathian-4-ylidene)ammo)piperidine- 1 -carboxylate (25)

[0269]

[0270] Prepared according to general procedure A with 4-imino-l,4-oxathiane 4-oxide (67.5 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), benzyl 4-hydroxypiperidine-l-carboxylate (235 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL). After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 60% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and further purified by preparative HPLC (XBridge BEH C18 OBD column, 20% to 60% MeCN in H2O with 0.1% NH4OH) to provide the product as a colorless oil (87.9 mg, 249 pmol, 50% yield).

[0271] > H NMR (500 MHz, CDC13) 57.38 - 7.27 (m, 5H), 5.12 (s, 2H), 4.10 (ddd, J = 12.6, 6.1, 3.7 Hz, 2H), 4.06 - 3.94 (m, 4H), 3.41 (td, J= 9.3, 4.5 Hz, 1H), 3.19 - 3.08 (m, 4H), 3.07 -2.99 (m, 2H), 1.83 - 1.71 (m, 2H), 1.60 - 1.48 (m, 2H).

[0272] 13C NMR (126 MHz, CDCI3) 5 155.41, 137.03, 128.60, 128.57, 128.03, 127.91, 67.10, 66.28, 52.91, 50.25, 42.54, 35.83.

[0273] Tert-butyl l-((l-(5-bromopyrimidin-2-yl)piperidin-4-yl)imino)-l6-thiomorpholine-4-carboxylate 1-oxide (26)

[0274]

[0275] Prepared according to general procedure A with / cvZ-butyl l-imino-l-oxo-1,4-thiazinane-4-carboxylate (117mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), CU(OAC)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), l-(5- bromopyrimidin-2-yl)piperidin-4-ol (258 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mb) and MTBE (5 mL).

[0276] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 60% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a beige solid (150.1 mg, 316 pmol, 63% yield).

[0277] 'H NMR (500 MHz, CDCh) 6 8.25 (s, 2H), 4.47 - 4.36 (m, 2H), 4.00 - 3.90 (m, 2H), 3.77 (ddd, J= 14.4, 8.0, 3.2 Hz, 2H), 3.50 (tt, J= 9.4, 4.0 Hz, 1H), 3.18 (ddd, J= 13.6, 10.7, 3.0 Hz, 2H), 3.09 - 2.98 (m, 4H), 1.85 (dt, J= 13.3, 3.9 Hz, 2H), 1.62 - 1.52 (m, 2H), 1.46 (s, 9H).

[0278] 13C NMR (126 MHz, CDCh) 5 159.97, 157.94, 153.90, 105.34, 81.43, 51.98, 50.77, 43.12, 42.80, 42.32, 35.83, 28.41.

[0279] Tert-butyl 7-((7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)imino)-77.6-thia-l-azaspir o[ 3.5] nonane- 1 -carboxy late 7 -oxide (27)

[0280]

[0281] Prepared according to general procedure A with / c / 7-butyl 7-imino-7-oxo-7thia-l-azaspiro[3.5]nonane-l-carboxylate (137 mg, 0.5 mmol, 1.00 equiv., d.r. = 1:1), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), / e / V-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (241 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0282] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 90% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as an orange solid (204.5 mg, 411 pmol, 82% yield). > H NMR (500 MHz, CDCh) 84.01 - 3.85 (m, 1H), 3.84 - 3.74 (m, 2H), 3.33 (q,,7 = 5.4 Hz, 2H), 3.25 (p, J= 2.9 Hz, 2H), 3.22 - 3.10 (m, 1H), 2.93 (td, J= 13.9, 6.4 Hz, 2H), 2.75 (ddd, J= 19.9, 15.9, 8.5 Hz, 2H), 2.27 - 2.18 (m, 2H), 2.17 - 1.98 (m, 4H), 1.84 - 1.70 (m, 2H), 1.57 - 1.39 (m, 23H). (mixture of diastereoisomers and rotamers)

[0283] 13C NMR (126 MHz, CDCI3) 8 154.73, 154.48, 80.12, 79.93, 79.34, 79.11, 78.97, 65.77, 65.69, 65.28, 65.15, 47.75, 46.91, 43.79, 43.40, 43.14, 42.84, 42.36, 40.49, 39.30, 35.78, 33.73, 33.40, 32.96, 32.51, 31.77, 28.46, 28.36, 28.27, 27.60, 26.38, 26.25. (mixture of diastereoisomers and rotamers; broadening of signals)

[0284] T exX-butyl 5-( (dimethyl(oxo)-6-sulfaneylidene)amino)-2-azaspiro[ 3.3 ]heptane-2-carboxylate (28)

[0285]

[0286] Prepared according to general procedure A with imino-dimethyl-oxo-sulfane (46.5 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), tert-butyl 7-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (107 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mb) and MTBE (5 mL).

[0287] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 50% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as an orange solid (97.1 mg, 337 pmol, 67% yield).

[0288] *H NMR (500 MHz, CDCI3) 84.41 (q, J= 7.6 Hz, 1H), 3.81 - 3.61 (m, 4H), 3.00 (m, 6H), 2.13 - 2.04 (m, 1H), 1.95 - 1.86 (m, 1H), 1.84 - 1.72 (m, 1H), 1.71 - 1.63 (m, 1H), 1.43 - 1.36 (m, 9H). (mixture of rotamers)

[0289] 13C NMR (126 MHz, CDCh) 8 156.65, 79.10, 58.77, 57.71, 56.57, 55.26, 53.86, 43.92, 43.54, 42.97, 28.54, 27.47. (mixture of rotamers) Tert-butyl 3-(S-methyl-N-(2-(pyridin-2-yl)ethyl)sulfonimidoyl)pyrrolidine-l -carboxylate (29)

[0290]

[0291] Prepared according to general procedure A with / cvZ-butyl 3-(methylsulfonimidoyl)pyrrolidine-l -carboxylate (124 mg, 0.5 mmol, 1.00 equiv., d.r = 1:1), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), 2-(2- pyridyl)ethanol (112 pL, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 ml) and MTBE (5 mL).

[0292] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 15% to 50% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and further purified by preparative HPLC (XBridge BEH C18 OBD column, 30% to 80% MeCN in H2O with 0.1% NH4OH) to provide the product as an orange oil (96.5 mg, 253 pmol, 55% yield, d.r = 1: 1).

[0293] Hi NMR (500 MHz, CDC13) 88.51 (dd, J = 5.0, 1.8 Hz, 1H), 7.57 (td, J = 7.6, 1.8 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.09 (dd, J = 7.5, 4.9 Hz, 1H), 3.75 - 3.51 (m, 4H), 3.52 - 3.45 (m, 2H), 3.40 - 3.32 (m, 1H), 3.06 - 2.95 (m, 2H), 2.72 (d, J = 5.8 Hz, 3H), 2.46 - 2.06 (m, 2H), 1.51 - 1.42 (m, 9H). (mixture of diastereoisomers)

[0294] 13C NMR (126 MHz, CDCI3) 8 160.38, 160.35, 154.06, 149.20, 136.29, 124.05, 123.98, 121.36, 80.13, 62.03, 46.06, 45.05, 45.02, 43.30, 43.25, 41.60, 41.55, 37.83, 28.54, 28.52, 26.36. (mixture of diastereoisomers) Benzyl 4-(((4-methoxy-4-oxobutyl)(methyl)(oxo)- 6-sulfaneylidene)ammo)piperidme-l-carboxylate (30)

[0295]

[0296] MeOOC

[0297] Prepared according to general procedure A with methyl 4-(methylsulfonimidoyl)butanoate (89.6 mg, 0.5 mmol, 1.00 equiv ), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), CU(OAC)2 (13.6 mg, 75.0 pmol, 15 mol%), 1, 10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), benzyl 4-hydroxypiperidine-l -carboxylate (235 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0298] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar Cl 8 D reverse phase column, and purified with eluents 20% to 80% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a yellow oil (122.7 mg, 309 pmol, 62% yield).

[0299] > H NMR (500 MHz, CDC13) 57.37 - 7.33 (m, 4H), 7.32 - 7.28 (m, 1H), 5.11 (s, 2H), 4.02 - 3.92 (m, 2H), 3.69 (s, 3H), 3.38 (tt, J= 9.2, 4.0 Hz, 1H), 3.21 - 3.01 (m, 4H), 2.92 (s, 3H), 2.51 (t, J= 1.5 Hz, 2H), 2.12 (tt, J= 8.3, 6.8 Hz, 2H), 1.81 - 1.70 (m, 2H), 1.58 - 1.46 (m, 2H).

[0300] 13C NMR (126 MHz, CDCI3) 5 172.80, 155.43, 137.07, 128.57, 128.01, 127.90, 67.07, 54.00, 51.98, 50.59, 42.56, 42.52, 35.78, 32.14, 29.94. ( (!-( 2-Chloro-6-methoxynicotinoyl)piperidin-4-yl)imino)(4-methoxyphenyl) (methyl)- 6-sulfanone (31)

[0301]

[0302] Prepared according to general procedure A with imino-(4-methoxyphenyl)-methyl-oxo-sulfane (92.6 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1, 10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), (2-chloro-6-methoxy-3-pyridyl)-(4-hydroxy-l-piperidyl)methanone (271 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0303] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 15% to 70% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and further purified by preparative HPLC (XBridge BEH C18 OBD column, 20% to 80% MeCN in H2O with 0.1% NH4OH) to provide the product as colorless solid (145.9 mg, 333 pmol, 67% yield).

[0304] > H NMR (500 MHz, CDC13) 87.84 - 7.76 (m, 2H), 7.55 - 7.37 (m, 1H), 7.04 - 6.96 (m, 2H), 6.74 - 6.60 (m, 1H), 4.42 - 4.30 (m, 1H), 3.94 - 3.89 (m, 3H), 3.88 - 3.84 (m, 3H), 3.53 - 3.34 (m, 1H), 3.20 - 3.11 (m, 1H), 3.12 -2.83 (m, 5H), 1.95 - 1.31 (m, 4H). (mixture of rotamers)

[0305] 13C NMR (126 MHz, CDCI3) 8 165.62, 165.54, 165.50, 163.67, 163.64, 163.59, 163.58, 163.44, 163.40, 163.39, 163.34, 144.45, 144.42, 144.30, 139.29, 139.21, 139.19, 131.66, 131.65, 131.56, 131.30, 131.19, 130.76, 130.70, 124.75, 124.69, 124.67, 124.61, 114.82, 114.78, 114.76, 114.72, 109.96, 109.81, 55.79, 55.78, 54.36, 51.15, 51.13, 51.05, 46.21, 46.17, 46.07, 45.96, 45.75, 45.69, 45.44, 45.39, 40.41, 40.36, 36.57, 36.50, 35.72, 35.62, 35.42, 35.33, 34.67, 34.46. (mixture of rotamers) (((1 -(5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoyl)piperidin-3-yl)methyl)imino)diphenyl-X6-sulfanone (32)

[0306] Me

[0307]

[0308] Prepared according to general procedure A with imino-oxo-diphenyl-sulfane (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), [3-(hydroxymethyl)-l-piperidyl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone (300 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0309] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 20% to 70% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and further purified by preparative HPLC (XBridge BEH C18 OBD column, 30% to 80% MeCN in H2O with 0.1% NH4OH) to provide the product as a colorless solid (147.9 mg, 296 pmol, 59% yield).

[0310] 'H NMR (500 MHz, CDCh) 5 8.03 - 7.95 (m, 6H), 7.91 (d, J= 8.3 Hz, 2H), 7.86 -7.73 (m, 11H), 7.69 (ddt, J= 9.7, 7.2, 1.4 Hz, 4H), 7.54 - 7.45 (m, 12H), 7.44 - 7.37 (m, 8H), 7.36 - 7.29 (m, 4H), 7.21 (dd, J= 7.8, 2.0 Hz, 1H), 7.12 (d, J= 2.0 Hz, 1H), 4.75 - 4.66 (m, 2H), 4.53 (dd, J= 13.0, 3.8 Hz, 1H), 4.50 - 4.45 (m, 1H), 3.79 (dq, J= 13.2, 3.8 Hz, 1H), 3.65 (dt, J = 13.3, 1.9 Hz, 1H), 3.30 (ddt, J= 21.6, 13.4, 4.2 Hz, 2H), 3.05 (dd,,7= 12.3, 6.5 Hz, 1H), 3.01 -2.89 (m, 4H), 2.86 (dd, J= 12.4, 5.3 Hz, 1H), 2.81 - 2.72 (m, 2H), 2.68 - 2.49 (m, 4H), 2.42 (s, 3H), 2.40 (s, 3H), 2.40 (s, 3H), 2.36 (s, 3H), 2.19 (t, J = 13.1 Hz, 1H), 1.99 - 1.66 (m, 5H), 1.57 (dddd, J= 33.6, 16.9, 8.1, 3.8 Hz, 2H), 1.45 - 0.86 (m, 7H). (mixture of 4 rotamers, smallest integral normed to 1)13C NMR (126 MHz, CDC13) 5 168.88, 168.83, 168.51, 168.41, 162.99, 140.71, 140.67, 140.64, 140.59, 140.57, 140.40, 140.29, 138.64, 138.62, 138.60, 135.82, 135.80, 135.77, 135.68, 134.12, 134.06, 133.93, 132.66, 132.63, 132.60, 132.58, 132.54, 130.62, 130.59, 130.43, 130.40, 129.40, 129.38, 129.35, 129.32, 129.24, 129.21, 129.17, 129.15, 129.14, 129.11, 128.93, 128.81, 128.79, 128.75, 128.69, 128.67, 128.64, 128.59, 128.57, 128.49, 128.35, 122.38, 122.09, 122.00, 121.84, 51.68, 51.55, 48.11, 47.57, 46.85, 46.58, 46.53, 46.22, 46.05, 45.97, 42.86, 42.59, 39.46, 38.45, 37.77, 37.25, 29.13, 28.78, 28.75, 28.70, 24.94, 24.82, 23.87, 23.81, 21.16, 21.13, 21.09. (mixture of 4 rotamers)

[0311] ((!-( 6-Chloropyridazin-3-yl)piperidin-4-yl)imino) ( ( 6-chloropyridin-3-yl)methyl)(methyl)- / ' -sulfcinone (33)

[0312]

[0313] Prepared according to general procedure A with (6-chloro-2-pyridyl)methyl-imino-methyl-oxosulfane (102 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), 1-(6-chloropyridazin-3-yl)piperidin-4-ol (214 mg, 1.00 mmol, 2.00 equiv ), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0314] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar Cl 8 D reverse phase column, and purified with eluents 10% to 60% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and further purified by preparative HPLC (XBridge BEH C18 OBD column, 10% to 50% MeCN in H2O with 0.1% NH4OH) to provide the product as a colorless solid (140.4 mg, 351 pmol, 70% yield).

[0315] 'H NMR (500 MHz, CDCh) 5 8.39 (d, J= 2.5 Hz, 1H), 7.79 (dd, J= 8.2, 2.5 Hz, 1H), 7.37 (d, <7= 8.2 Hz, 1H), 7.16 (d, J= 9.5 Hz, 1H), 6.89 (d, <7= 9.6 Hz, 1H), 4.32 (d, <7= 13.8 Hz, 1H), 4.24 (d, <7 = 13.9 Hz, 1H), 4.06 (dq, <7= 13.2, 4.1 Hz, 2H), 3.51 (dt,<7= 8.9, 4.7 Hz, 1H), 3.23 (dddd,,7 = 15.2, 13.3, 9.9, 3.2 Hz, 2H), 2.83 (s, 3H), 1.86 (ddddd,.7 = 16.7, 13.1, 5.4, 3.5, 1.6 Hz, 2H), 1.67 - 1.55 (m, 2H).

[0316] 13C NMR (126 MHz, CDC13) 5 159.08, 152.34, 151.14, 146.44, 140.88, 128.77, 124.87, 124.65, 115.42, 58.29, 50.77, 43.80, 43.72, 40.32, 35.13.

[0317] Tert-butyl 4-( 4-bromo- -( ( l-( ( 1, 3, 5 -trimethyl- lH-pyrazol-4-yl) sulf onyl)piperidin-4-yl)methyl)phenylsulfommidoyl)piperidine-l -carboxylate (34)

[0318]

[0319] Prepared according to general procedure A with Zc / V-butyl 4-[(4-bromophenyl)sulfonimidoyl]piperidine-l -carboxylate (202 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), [l-(l,3,5-trimethylpyrazol-4-yl)sulfonyl-4-piperidyl]methanol (287 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0320] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar Cl 8 D reverse phase column, and purified with eluents 10% to 70% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a beige solid (272.1 mg, 404 pmol, 81% yield).

[0321] 'H NMR (500 MHz, CDCh) 87.59 - 7.53 (m, 2H), 7.51 - 7.44 (m, 2H), 4.17 - 3.93 (m, 2H), 3.67 - 3.50 (m, 5H), 2.93 (tt, J = 12.2, 3.6 Hz, 1H), 2.85 -2.39 (m, 5H), 2.31 (d, J = 5.1 Hz, 3H), 2.28 - 2.19 (m, 5H), 2.08 - 1.93 (m, 1H), 1.81 - 1.75 (m, 1H), 1.72- 1.61 (m, 2H), 1.49 - 1.36 (m, 2H), 1.33 - 1.25 (m, 9H), 1.15 (dqt, J = 17.6, 9.2, 4.4 Hz, 2H).13C NMR (126 MHz, CDC13) 5 154.04, 147.64, 147.61, 141.88, 135.05, 132.45, 131.51, 128.14, 128.12, 112.01, 111.98, 79.69, 79.67, 61.73, 61.70, 48.22, 45.47, 45.42, 42.50, 37.88, 36.22, 29.26, 29.18, 28.11, 25.30, 24.75, 13.28, 10.79.

[0322] Tert-butyl 6-( (4-(( tert-butoxycarbonyl)ammo)-9-oxido-2-oxa-96-thiaspiro[ 5.5 ]undecan-9-ylidene)amino)-2-azaspiro[3.3]heptane-2-carboxylate (35)

[0323] BacHN

[0324]

[0325] Prepared according to general procedure A with tert-butyl (9-imino-9-oxido-2-oxa-9X6-thiaspiro[5.5]undecan-4-yl)carbamate (159 mg, 0.5 mmol, 1.00 equiv., mixture of diastereoisomers), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1, 10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), / ert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (213 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0326] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar Cl 8 D reverse phase column, and purified with eluents 20% to 80% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and further purified by preparative HPLC (XBridge BEH C18 OBD column, 30% to 80% MeCN in H2O with 0.1% NH4OH) to provide the product as a beige solid (141.2 mg, 275 pmol, 55% yield, d.r. = 1:1 from starting material).

[0327] 'H NMR (500 MHz, CDCh) 84.43 (br s, 1H), 3.92 - 3.86 (m, 2H), 3.84 - 3.63 (m, 5H), 3.49 (qd, J= 12.5, 2.2 Hz, 1H), 3.37 - 3.24 (m, 1H), 3.09 - 2.80 (m, 3H), 2.57 - 2.40 (m, 3H), 2.17 - 1.99 (m, 4H), 1.96 - 1.75 (m, 4H), 1.44- 1.37 (m, 18H), 1.36 - 1.09 (m, 1H).

[0328] (mixture of diastereoisomers)

[0329] 13C NMR (126 MHz, CDCh) 8 156.27, 155.14, 155.10, 79.78, 79.33, 79.31, 70.35, 70.17, 61.99, 60.37, 60.29, 47.02, 46.45, 45.22, 44.58, 44.49, 44.39, 43.70, 43.63, 43.10, 42.34, 38.25, 36.51, 33.10, 32.95, 32.18, 32.13, 28.47, 28.46, 27.84, 26.22. (mixture of diastereoisomers)

[0330] Tert-butyl 2-(((4S,5R)-4-((iQp.-biitoxycarbonyl)amino)-5-(2,5-difliiorophenyl)tetrahydro-2H-pyran-2-yl)imino)-26-thia-6-azaspiro[ 3.3 ]heptane-6-carboxylate 2-oxide (36)

[0331]

[0332] Prepared according to general procedure A with / c / 7-butyl 2-imino-2-oxo-2thia-6- azaspiro[3.3]heptane-6-carboxylate (123 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), / c77-butyl A-[(2A,3 )-2-(2,5-difluorophenyl)-5-hydroxy-tetrahydropyran-3-yl]carbamate (329 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0333] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 80% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a beige solid (176.4 mg, 316 pmol, 63% yield, d.r. = 1.6:1). The diastereomeric ratio was determined 1H-NMR analysis of the crude reaction mixture.

[0334] 1H NMR (500 MHz, CDCh) 67.25 - 7.14 (m, 1H+1H*), 7.00 - 6.88 (m, 3H+3H*), 4.61 - 4.04 (m, 8H+8H*), 3.98 (ddd, J= 13.9, 7.6, 3.5 Hz, 1H), 3.77 - 3.68 (m, 1H*), 3.64 - 3.53 (m, 1H+1H*), 3.49 (td, J= 12.0, 2.4 Hz, 1H), 3.27 (t, J= 10.8 Hz, 1H), 2.38 - 2.31 (m, 1H), 2.23 -2.16 (m, 1H+1H*), 1.92 - 1.79 (m, 1H), 1.74 (d, J= 12.6 Hz, 1H), 1.59 - 1.45 (m, 1H+2H*), 1.43 (s, 9H), 1.27 - 1.22 (m, 9H+18H*). (mixture of diastereoisomers; *minor diastereoisomer)

[0335] 13C NMR (126 MHz, CDCh) 5 159.96 (d, J= 243.3 Hz), 158.66 (d, J= 242.0 Hz), 157.26, 156.23 (d, J = 241.9 Hz), 155.92, 155.81, 155.35, 154.75, 154.73, 154.66, 129.08 - 128.85 (m), 128.61 - 128.50 (m), 128.51 - 128.09 (m), 127.94, 127.67, 115.94 (dd,, 7= 22.4, 8.8 Hz), 115.66 (d, J= 8.8 Hz), 115.25 (dd, J= 24.8, 4.5 Hz), 114.99, 80.49, 80.31, 79.62, 79.51, 79.31, 76.33, 75.64, 75.49, 74.10, 73.74, 73.19, 72.97, 68.50, 61.35, 59.36, 52.13, 51.50, 50.38, 50.03, 47.98, 41.41, 38.42, 28.37, 28.18, 26.53, 26.48, 25.84. (mixture of diastereoisomers)

[0336] 4-(5,5-dimethyl-2,4-dioxo-3-(4-((oxodiphenyl-6-sulfaneylidene)ammo)butyl)imidazolidin-l-yl)-2-(trifluoromethyl)benzonitrde (37)

[0337]

[0338] Prepared according to general procedure A with imino-oxo-diphenyl-sulfane (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-l-yl]-2-(trifluoromethyl)benzonitrile (369 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0339] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was loaded on a 25 g Biotage Sfar normal phase column and purified with eluents 10% to 80% EtOAc in hexanes. The fractions containing product were concentrated and further purified by preparative HPLC (XB ridge BEH C18 OBD column, 30% to 90% MeCN in H2O with 0.1% NH4OH) to provide the product as a beige solid (172.2 mg, 284 pmol, 61% yield).

[0340] 'H NMR (500 MHz, CDCh) 8 8.16 (d, J = 2.0 Hz, 1H), 8.01 (dd, J = 8.5, 2.1 Hz, 1H), 7.96 (dt, J= 6.9, 1.5 Hz, 4H), 7.90 (d, J= 8.4 Hz, 1H), 7.54 - 7.45 (m, 6H), 3.45 - 3.37 (m, 2H), 3.11 (t, J= 6.5 Hz, 2H), 1.88 (tt, J= 8.0, 6.1 Hz, 2H), 1.73 (p, J= 6.8 Hz, 2H), 1.52 (s, 6H).

[0341] 13C NMR (126 MHz, CDCh) 5 174.84, 152.73, 140.75, 136.62, 135.23, 133.57 (q, J = 33.2 Hz), 132.51, 129.23, 128.49, 127.88, 123.00 (q, J= 5.0 Hz), 122.91 (d, J= 274.2 Hz), 115.10, 108.10 (q, J= 2.0 Hz), 61.93, 43.16, 40.27, 30.05, 27.08, 23.49. Ethyl ( )-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(((oxodiphenyl- 6-sulfaneylidene) amino)methyl)pyrrolidin-l-yl)pyrimidine-5 -carboxylate (38)

[0342]

[0343] Prepared according to general procedure A with imino-oxo-diphenyl-sulfane (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), ethyl 4-[(3-chloro-4-methoxy-phenyl)methylamino]-2- [(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]pyrimidine-5-carboxylate (421 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0344] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was loaded on a 25 g Biotage Sfar normal phase column and purified with eluents 10% to 80% EtOAc in hexanes. The fractions containing product were concentrated and further purified by preparative HPLC (XB ridge BEH C18 OBD column, 20% to 70% MeCN in H2O with 0.1% NH4OH) to provide the product as a colorless solid (168.1 mg, 271 pmol, 54% yield).

[0345] *H NMR (500 MHz, CDCh) 5 8.70 - 8.45 (m, 1H), 8.37 (bs, 1H), 7.98 - 7.86 (m, 2H), 7.81 -7.75 (m, 1H), 7.50 - 7.26 (m, 8H), 7.23 - 7.11 (m, 1H), 6.89 - 6.81 (m, 1H), 4.63 -4.31 (m, 2H), 4.30-4.20 (m, 3H), 3.95 - 3.81 (m, 3H), 3.77- 3.53 (m, 2H), 3.47 - 3.32 (m, 1H), 3.24 -3.10 (m, 1H), 2.43 - 2.30 (m, 1H), 2.23 - 1.99 (m, 2H), 1.98 - 1.87 (m, 1H), 1.33 (t, J= 7.1 Hz, 3H). (mixture of rotamers)

[0346] 13C NMR (126 MHz, CDCh) 5 167.48, 167.32, 161.40, 160.91, 160.23, 160.12, 159.97, 159.86, 154.01, 153.95, 141.07, 140.79, 140.69, 140.58, 132.77, 132.36, 132.30, 132.26, 132.14, 129.76, 129.63, 129.03, 129.02, 128.94, 128.88, 128.58, 128.56, 128.52, 128.23, 127.18, 127.02, 122.24, 122.16, 112.06, 111.98, 95.63, 95.20, 60.01, 59.85, 59.64, 59.00, 56.15, 56.11, 47.91, 47.87, 45.24, 44.59, 43.09, 43.02, 40.81, 28.74, 28.66, 23.53, 23.07, 14.38, 14.34.

[0347] (mixture of rotamers).

[0348] Benzyl ( 3aS, -R, 6S, 6aR)-2, 2-dimethyl-6-((oxodiphenyl- / .6-sulfaneylidene)amino)tetrahydro -4H-cyclopenta[d] [ 1, 3 ]dioxol-4-yl)carbamate (39)

[0349]

[0350] Prepared according to general procedure A with imino-oxo-diphenyl-sulfane (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), benzyl N-[(4S,6R)-4-hydroxy-2,2-dimethyl-4,5,6,6atetrahydro-3aH-cyclopenta[d][l,3]dioxol-6-yl]carbamate (307 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0351] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 70% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as an orange oil (172.5 mg, 341 pmol, 68% yield, d.r. = 13:1).

[0352] 'H NMR (500 MHz, CDCh) 57.94 - 7.90 (m, 2H), 7.90 - 7.84 (m, 2H), 7.53 - 7.42 (m, 5H), 7.38 (t, J= 7.8 Hz, 2H), 7.36 - 7.28 (m, 5H), 6.72 (d, J= 9.5 Hz, 1H), 5.12 (d, J= 12.4 Hz, 1H), 5.07 (d, J= 12.5 Hz, 1H), 4.71 (dd, J= 5.4, 1.4 Hz, 1H), 4.65 (dd, J= 5.4, 1.5 Hz, 1H), 4.22 (dd, 7 = 9.5, 6.2 Hz, 1H), 3.67 (d, J= 4.7 Hz, 1H), 2.30 - 2.23 (m, 1H), 1.76 (d, J= 13.5 Hz, 1H), 1.36 (s, 3H), 1.25 (s, 3H). (mixture of diastereoisomers obtained; only major diastereoisomer given)

[0353] 13C NMR (126 MHz, CDC13) 5 155.63, 140.54, 139.94, 137.06, 132.86, 129.51, 129.42, 128.78, 128.49, 128.22, 127.94, 109.96, 87.66, 86.60, 66.38, 60.56, 57.87, 36.59, 26.25, 23.98. (mixture of diastereoisomers obtained; only major diastereoisomer given)

[0354] Diphenyl( ((( 3aR.5R, 5aS, 8aS, 8b\kj-2, 2, 7, 7-tetramethyltetrahydro-5]l-bis([ 1, 3 ]dioxolo)[ 4, 5-b:4',5'-d]pyran-5-yl)methyl)imino)-X6-sulfanone (40)

[0355]

[0356] Prepared according to general procedure A with imino-oxo-diphenyl-sulfane (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), ((3aR, 5R,5aS,8aS, 8bR)-2, 2,7,7-tetramethyltetrahydro-5H-bis([l,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methanol (260 mg, 1.00 mmol, 2.00 equiv.), NHCH (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0357] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 70% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and further purified by preparative HPLC (XBridge BEH C18 OBD column, 30% to 70% MeCN in H2O with 0.1% NH4OH) to provide the product as a colorless resin (130.2 mg, 283 pmol, 57% yield).

[0358] > H NMR (500 MHz, CDCI3) 5 8.10 - 7.84 (m, 4H), 7.56 - 7.35 (m, 6H), 5.51 (d, J = 4.9 Hz, 1H), 4.64 (dd, J= 8.0, 2.3 Hz, 1H), 4.56 (dd, J= 8.0, 1.8 Hz, 1H), 4.29 (dd, J= 5.0, 2.3 Hz, 1H), 4.03 (ddd, J= 8.0, 6.1, 1.8 Hz, 1H), 3.39 - 3.15 (m, 2H), 1.57 (s, 3H), 1.39 (s, 3H), 1.38 (s, 3H), 1.32 (s, 3H).

[0359] 13C NMR (126 MHz, CDC13) 5 140.89, 140.31, 132.41, 129.10, 129.06, 129.02, 128.65, 108.97, 108.59, 96.55, 71.16, 70.97, 70.83, 69.05, 43.73, 26.20, 26.10, 25.13, 24.68.

[0360] ( ((3aS, 4S, 6R, 6aS)-6-( (R)-2, 2-dimethyl-l, 3-dioxolan-4-yl)-2, 2-di methyl tetrahydrofurol 3, 4-d][l, 3 ]dioxol-4-yl)hnino)diphenyl-X6-sulfanone (41)

[0361] hte Me

[0362]

[0363] Prepared according to general procedure A with imino-oxo-diphenyl-sulfane (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), (3aS,4R,6R,6aS)-6-((5)-2,2-dimethyl-l,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-ol (260 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0364] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 70% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a colorless resin (186.6 mg, 406 pmol, 81% yield, d r. >20:1).

[0365] *H NMR (500 MHz, CDCI3) 57.99 - 7.89 (m, 4H), 7.56 - 7.42 (m, 6H), 5.25 (s, 1H), 4.91 (dd, J= 5.8, 3.7 Hz, 1H), 4.82 (d, J= 5.8 Hz, 1H), 4.34 (ddd, J= 8.2, 6.3, 4.5 Hz, 1H), 4.22 (dd, J= 8.3, 3.7 Hz, 1H), 4.00 (dd, J= 8.6, 6.3 Hz, 1H), 3.83 (dd, J= 8.6, 4.5 Hz, 1H), 1.45 (s, 3H), 1.42 (s, 3H), 1.37 (s, 3H), 1.32 (s, 3H).13C NMR (126 MHz, CDC13) 5 141.19, 140.29, 132.78, 129.38, 129.28, 128.71, 128.25, 112.26, 109.28, 90.78, 88.52, 80.46, 80.24, 73.34, 67.20, 27.12, 25.99, 25.44, 24.67.

[0366]

[0367] (k, 4R)-4-Isopropyl-N-( (oxodiphenyl-k-sulfaneylidene)amino)-3-phenylpropan-2-yl)cyclohexanek -carboxamide (42)

[0368]

[0369] Prepared according to general procedure A with imino-oxo-diphenyl-sulfane (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), 4-isopropyl-A-[(17?)-l-benzyl-2- hydroxyethyl] cyclohexanecarboxamide (303 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mb) and MTBE (5 mL).

[0370] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was loaded on a 25 g Biotage Sfar normal phase column and purified with eluents 10% to 80% EtOAc in hexanes. The fractions containing product were concentrated and further purified by preparative HPLC (XBridge BEH C18 OBD column, 30% to 100% MeCN in H2O with 0.1% NH4OH) to provide the product as a beige solid (140.6 mg, 280 pmol, 56% yield).

[0371] 'H NMR (500 MHz, CDCI3) 8 8.05 - 8.01 (m, 2H), 7.89 - 7.84 (m, 2H), 7.56 - 7.48 (m, 4H), 7.48 - 7.42 (m, 2H), 7.33 - 7.29 (m, 2H), 7.28 - 7.23 (m, 2H), 7.20 - 7.15 (m, 1H), 6.33 (d, J= 8.5 Hz, 1H), 4.29 (dddd, J= 12.0, 8.2, 6.5, 3.7 Hz, 1H), 3.07 (qd, J= 12.7, 3.7 Hz, 2H), 3.02 -2.95 (m, 2H), 2.00 (tt,. / = 12.1, 3.5 Hz, 1H), 1.87 (ddq,.7= 17.1, 12.5, 2.8 Hz, 2H), 1.81 - 1.71 (m, 2H), 1.47 - 1.34 (m, 3H), 1.10 - 0.92 (m, 3H), 0.86 (d, J= 6.8 Hz, 6H).

[0372] 13C NMR (126 MHz, CDC13) 5 175.75, 140.99, 140.16, 139.05, 132.75, 132.71, 129.70, 129.42, 129.32, 128.79, 128.52, 128.35, 126.21, 50.74, 46.05, 45.71, 43.42, 38.24, 32.97, 29.97, 29.72, 29.24, 29.17, 19.90.

[0373] ((2-(3-(4-chlorophenyl)-l -phenyl- llA-pyrazol-4-yl)ethyl)imino)diphenyl-6-sulfanone (43)

[0374]

[0375] Prepared according to general procedure A with imino-oxo-diphenyl-sulfane (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), 2-[3-(4-chlorophenyl)-l-phenyl-pyrazol-4-yl]ethanol (299 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0376] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was loaded on a 25 g Biotage Sfar normal phase column and purified with eluents 10% to 70% EtOAc in hexanes. The fractions containing product were concentrated to provide the product as a yellow solid (127.3 mg, 256 pmol, 51% yield).

[0377] *H NMR (500 MHz, CDCI3) 87.94 - 7.83 (m, 5H), 7.76 - 7.68 (m, 4H), 7.51 - 7.46 (m, 2H), 7.45 - 7.40 (m, 7H), 7.39 - 7.34 (m, 2H), 7.28 - 7.23 (m, 1H)*, 3.32 (t, J= 7.3 Hz, 2H), 3.06 (t, J= 7.3 Hz, 2H). * Signal overlaps with NMR solvent signal.13C NMR (126 MHz, CDC13) 5 150.67, 140.65, 140.09, 133.57, 132.53, 132.39, 129.46, 129.41, 129.32, 129.26, 129.23, 128.73, 128.70, 128.57, 128.54, 127.19, 126.21, 119.67, 118.77, 44.79, 28.28.

[0378] Diphenyl( (73S / R, 5S.5R, 9R, 70S, 73S,14S)-8,10, 13-trimethyl-l 7-oxohexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)imino)-X6-sulfanone (44)

[0379]

[0380] Prepared according to general procedure A with imino-oxo-diphenyl-sulfane (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), androsterone (291 mg, 1.00 mmol, 2.00 equiv.), NHCH (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0381] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was loaded on a 25 g Biotage Sfar normal phase column and purified with eluents 10% to 70% EtOAc in hexanes. The fractions containing product were concentrated to provide the product as a colorless solid (148.4 mg, 303 pmol, 61% yield, d.r. = 1:1).

[0382] ’H NMR (500 MHz, CDCh) 8 8.02 - 7.93 (m, 4H), 7.53 - 7.40 (m, 6H), 3.06 - 2.96 (m, 1H), 2.45 - 2.35 (m, 1H), 2.09 - 1.97 (m, 1H), 1.93 - 1.84 (m, 1H), 1.82 - 1.71 (m, 4H), 1.71 - 1.64 (m, 1H), 1.62 - 1.55 (m, 3H), 1.54 - 1.43 (m, 2H), 1.32- 1.13 (m, 6H), 1.09 - 0.99 (m, 1H), 0.84 (s, 3H), 0.83 (s, 3H), 0.65 - 0.56 (m, 1H). (mixture of diastereomers).

[0383] 13C NMR (126 MHz, CDCh) 8221.57, 141.57, 141.52, 132.34, 129.24, 129.20, 129.18, 128.71, 128.59, 54.80, 54.69, 51.59, 47.92, 45.73, 39.59, 37.85, 35.96, 35.71, 35.16, 32.77, 31.70, 31.04, 28.45, 21.86, 21.16, 20.43, 13.92, 12.47. (mixture of diastereomers)

[0384] 7-(But-2-yn-l-yl)-3-methyl-l-((4-methylquinazolm-2-yl)methyl)-8-(3-((oxodiphenyl- 6-sulfaneylidene)amino)piperidin-l-yl)-3, 7 -dihydro- lH-purine-2, 6-dione (45)

[0385]

[0386] Prepared according to general procedure A with imino-oxo-diphenyl-sulfane (109 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG(200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), 7-but-2-ynyl-8-(3-hydroxy-l-piperidyl)-3-methyl-l-[(4-methylquinazolin-2-yl)methyl]purine-2, 6-dione (474 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0387] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 80% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a colorless resin (163.8 mg, 243 pmol, 49% yield).

[0388] *11 NMR (500 MHz, CDCh) 5 8.07 - 7.97 (m, 4H), 7.87 (d, J = 8.3 Hz, 1H), 7.78 -7.71 (m, 2H), 7.58 - 7.43 (m, 8H), 5.56 (s, 2H), 4.88 - 4.78 (m, 2H), 3.86 (dd, J = 12.5, 4.0 Hz, 1H), 3.67 (dq, J = 12.7, 4.3 Hz, 1H), 3.50 (s, 3H), 3.41 (tt, J = 9.1, 4.0 Hz, 1H), 3.21 (dd, J = 12.5, 9.3 Hz, 1H), 3.11 (ddd, J = 13.0, 11.0, 2.8 Hz, 1H), 2.97- 2.90 (m, 2H), 2.88 (s, 3H), 2.09 (dt, J = 13.8, 4.5 Hz, 1H), 1.95 - 1.84 (m, 1H), 1.46 (s, 3H).

[0389] 13C NMR (126 MHz, CDCh) 5 168.55, 161.42, 156.31, 154.49, 152.08, 150.16, 148.35, 141.33, 141.07, 133.25, 132.68, 129.42, 129.31, 129.14, 128.70, 128.53, 126.73, 124.94, 123.30, 104.49, 81.30, 73.48, 57.91, 51.23, 50.07, 46.42, 36.01, 34.86, 29.99, 29.83, 24.18, 21.93, 3.83. 2-((6-((3'&)-3-(((4-Fluorophenyl)(methyl)(oxo)- 6-sulfaneylidene)ammo)piperidin-l-yl)-3-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-l(2H)-yl)methyl)benzonitrde (46)

[0390]

[0391] Prepared according to general procedure A with (4-fluorophenyl)-imino-methyl-oxo-sulfane (86.6 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), 2-[[6-(3-hydroxy-l-piperidyl)-3 -methyl-2, 4-dioxo-pyrimi din- l-yl]methyl]benzonitrile (340 mg, 1.00 mmol, 2.00 equiv.), NHCH (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0392] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 80% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a colorless solid (163.9 mg, 331 pmol, 66% yield, d r. = 1:1).

[0393] 'll NMR (500 MHz, CDC13) 57.91 - 7.85 (m, 2H), 7.80 (dd, J= 8.4, 5.0 Hz, 2H), 7.63 - 7.58 (m, 2H), 7.55 - 7.45 (m, 2H), 7.37 - 7.29 (m, 2H), 7.25 - 7.18 (m, 4H), 7.08 (d, J = 7.9 Hz, 1H), 7.04 (d, J= 7.9 Hz, 1H), 5.35 (s, 1H), 5.32 (s, 1H), 5.27 - 5.18 (m, 4H), 3.27 (s, 3 H), 3.26 (s, 3H), 3.18 - 3.11 (m, 1H), 3.10 - 3.07 (m, 1H), 3.06 (s, 3H), 3.03 (s, 3H), 3.02 -2.98 (m, 1H), 2.94- 2.85 (m, 3H), 2.75 - 2.50 (m, 4H), 1.99 (s, 6H), 1.91 - 1.67 (m, 4H), 1.61 -1.35 (m, 4H). (1:1 mixture of diastereoisomers)

[0394] 13C NMR (126 MHz, CDCI3) 5 166.51 (d, J= 6.2 Hz), 164.48 (d, J= 6.2 Hz), 163.14, 159.77, 159.63, 152.56, 152.52, 141.08, 140.88, 135.81 (d, J= 3.1 Hz), 135.58 (d, J = 3.2 Hz), 133.16, 133.09, 133.06, 133.02, 131.28, 131.21, 131.16, 131.08, 127.71, 127.69, 127.25 (d, J= 159.6 Hz), 126.52, 126.43, 124.53 (d, J= 269.2 Hz), 117.07, 116.95, 116.88, 116.77, 116.70, 110.71, 110.69, 90.29, 90.06, 59.53, 58.76, 51.55, 51.34, 50.71, 50.57, 46.31, 45.62, 45.50, 34.11, 33.39, 27.87 (d, J= 1.7 Hz), 23.56, 23.01. (1:1 mixture of diastereoisomers)

[0395] Tert-butyl (S)-2-( (l-(( tert-butoxycarbonyl) ( isopropyl)amino)-3-( 4-( 2-methoxyethyl)phenoxy)propan-2-yl)imino)-2 6-thia-6-azaspiro[ 3.3 ]heptane-6-carboxylate 2-oxide (47)

[0396]

[0397] Prepared according to general procedure A with Zc / 7-butyl 2-imino-2-oxo-2thia-6-azaspiro[3.3]heptane-6-carboxylate (123 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), Cu(OAc)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), Ze / 7-butyl A-[2-hydroxy-3-[4-(2-methoxyethyl)phenoxy]propyl]-N-isopropylcarbamate (367 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0398] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 60% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a yellow oil (187.4 mg, 315 pmol, 63% yield).

[0399] 'H NMR (500 MHz, CDCh) 87.15 - 7.10 (m, 2H), 6.83 - 6.78 (m, 2H), 4.25 (d, J = 13.5 Hz, 1H), 4.21 (s, 2H), 4.17 - 4.05 (m, 5H), 4.05 - 3.98 (m, 2H), 3.96 - 3.88 (m, 1H), 3.85 -3.78 (m, 1H), 3.56 (t, J= 7.1 Hz, 2H), 3.51 - 3.36 (m, 1H), 3.34 (s, 3H), 3.04 (dd, J= 14.4, 5.4 Hz, 1H), 2.81 (t, J= 6.9Hz, 2H), 1.47 (s, 9H), 1.40 (s, 9H), 1.19 (d, J= 6.9 Hz, 3H), 1.15 (d, J = 6.6 Hz, 3H).13C NMR (126 MHz, CDC13) 5 157.01, 156.31, 155.82, 131.41, 130.00, 114.28, 80.23, 79.72, 76.62, 74.69, 73.85, 71.62, 60.64, 58.71, 54.10, 48.12, 35.33, 28.62, 28.58, 28.54, 28.35, 25.87, 21.26, 20.79.

[0400] ( Cyclopropylimino)(3-( 4-(4-fluoro-2-methoxyphenyl)-l, 3, 5-triazin-2-yl)amino)benzyl)(methyl)-6-sulfanone (48)

[0401]

[0402] Prepared according to general procedure A with rac-atuveciclib (194 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (12.4 mg, 10.0 pmol, 2 mol%), Cu(OAc)2 (22.7 mg, 125 pmol, 25 mol%), 1,10-phenanthroline (25.2 mg, 140 pmol, 28 mol%), bromocyclopropane (80 pL, 1.00 mmol, 2.00 equiv.), AdNHSi(TMS)3 (437 mg, 1.1 mmol, 2.2 equiv.), TMG(200 pL, 1.00 mmol, 2.00 equiv.), in MeCN (10 mb).

[0403] After irradiation for 12 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 15% to 70% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and further purified by preparative HPLC (XBridge BEH C18 OBD column, 30% to 100% MeCN in H2O with 0.1% NH4OH) to provide the product as a colorless solid (120.3 mg, 281 pmol, 56% yield).

[0404] 'H NMR (500 MHz, CDCI3) 5 8.79 (s, 1H), 8.16 (s, 1H), 7.92 (s, 1H), 7.80 - 7.56 (m, 2H), 7.34 (t, J= 7.9 Hz, 1H), 7.12 (d, J= 7.6 Hz, 1H), 6.78 - 6.68 (m, 2H), 4.44 (d, J= 13.9 Hz, 1H), 4.29 (d, J= 13.9 Hz, 1H), 3.89 (s, 3H), 2.75 (s, 3H), 2.63 (tt, J= 7.3, 3.9 Hz, 1H), 0.62 - 0.46 (m, 4H).

[0405] 13C NMR (126 MHz, CDCI3) 5 172.00, 166.65, 166.38, 164.65, 163.65, 160.34, 138.62, 133.78, 130.61, 129.59, 126.10, 122.64, 122.13, 122.10, 120.82, 107.70, 107.53, 100.37, 100.17, 60.35, 56.34, 38.46, 26.08, 7.04. Tert-butyl 3-( ( ( (S)-3-( ( tert-butoxycarbonyl)amino)-4-( (( )-!-(( (S)-l-methoxy-4-methyl-l-oxopentan-2-yl)amino)-l -oxo-3-phenylpropan-2-yl)amino)-4-oxobutyl)(methyl)(oxo)-l.6-sulfaneylidene)ammo)azetidine-l-carboxylate (49)

[0406] <>

[0407] Me

[0408]

[0409] Prepared according to general procedure A with / c / 7-butyl 3-((((5)-3- (( / cv7b utoxy carbonyl )am i no)-4-((fS')- 1 -(((5)- 1 -methoxy-4-m ethyl- 1 -oxopentan-2-yl)amino)- 1 -oxo-3-phenylpropan-2-yl)amino)-4-oxobutyl)(methyl)(oxo)-X6-sulfaneylidene)amino)azetidine-1-carboxylate (277 mg, 0.5 mmol, 1.00 equiv., d.r. = 1:1), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), CU(OAC)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), tert-butyl 3 -hydroxyazetidine- 1-carboxylate (173 mg, 1.00 mmol, 2.00 equiv.), NHC-H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mb) and MTBE (5 mL).

[0410] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 80% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a yellow oil (174.6 mg, 246 pmol, 49% yield, d.r. = 1:1).

[0411] *H NMR (500 MHz, CDC13) 57.41 - 7.27 (m, 2H), 7.25 - 7.18 (m, 33H), 6.55 - 6.15 (m, 2H), 4.72-4.61 (m, 1H), 4.56 - 4.47 (m, 1H), 4.35 - 4.28 (m, 1H), 4.25 - 4.19 (m, 1H), 4.19 - 4.09 (m, 2H), 3.89 - 3.76 (m, 2H), 3.72 - 3.64 (m, 3H), 3.43 - 3.15 (m, 1H), 3.15 -2.97 (m, 3H), 2.97-2.86 (m, 3H), 2.33 - 2.04 (m, 2H), 1.60- 1.45 (m, 3H), 1.42 - 1.32 (m, 18H), 0.94 - 0.82 (m, 6H). (mixture of diastereomers and rotamers)

[0412] 13C NMR (126 MHz, CDC13) 5 172.91, 172.82, 170.93, 170.77, 170.63, 170.51, 156.23, 156.03, 155.82, 136.47, 136.26, 129.38, 128.85, 128.80, 127.28, 127.16, 80.61, 80.51, 79.46, 59.14, 54.57, 54.47, 52.96, 52.68, 52.35, 51.39, 51.22, 50.99, 42.68, 41.30, 41.24, 40.33, 40.15, 37.86, 28.48, 28.43, 28.40, 24.74, 24.71, 22.84, 21.93, 21.92. (mixture of diastereomers and rotamers)

[0413] T ext-butyl ( 3R)-3-( ((( 2-( ( tert-butoxycarbonyl) ((5-(4-(( 3-chloro-4-( (3-fluorobenzyl)oxy)phenyl)amino)qumazolin-6-yl)furan-2-yl)methyl)aniino)ethyl)(methyl)(oxo)-6- sulfaneylidene)amino)methyl)piperidine-l -carboxylate (50)

[0414]

[0415] Prepared according to general procedure A with / < / 7-butyl ((5-(4-((3-chloro-4-((3- fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)furan-2-yl)methyl)(2-(S-methylsulfonimidoyl)- ethyl)carbamate (340 mg, 0.5 mmol, 1.00 equiv.), 4CzIPN (19.7 mg, 25.0 pmol, 5 mol%), CU(OAC)2 (13.6 mg, 75.0 pmol, 15 mol%), 1,10-phenanthroline (15.8 mg, 87.5 pmol, 17.5 mol%), BTMG (200 pL, 1.00 mmol, 2.00 equiv.), MesIO (262 mg, 1.00 mmol, 2.00 equiv.), tertbutyl (3 S)-3-(hydroxymethyl)piperidine-l -carboxylate (215 mg, 1.00 mmol, 2.00 equiv.), NHC- H (435 mg, 1.10 mmol, 2.2 equiv.), pyridine (89 pL, 1.10 mmol, 2.2 equiv.) in MeCN (5 mL) and MTBE (5 mL).

[0416] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 80% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated and loaded on a 25 g Biotage Sfar normal phase column and purified with eluents 0% to 10% MeOH in CH2C12. The fractions containing product were concentrated to provide the product as a yellow foam (275.3 mg, 314 pmol, 63% yield). > H NMR (500 MHz, CDCh) 88.90 (d, J = 18.4 Hz, 1H), 8.68 (s, 1H), 8.52 (s, 1H), 7.96 (dt, J = 8.7, 2.3 Hz, 1H), 7.86 (t, J = 7.9 Hz, 2H), 7.78 (s, 1H), 7.36 (td, J = 7.9, 5.7 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.06 -6.96 (m, 2H), 6.74 (t, J = 3.1 Hz, 1H), 6.41 (d, J = 50.7 Hz, 1H), 5.17 (s, 2H), 4.65- 4.43 (m, 2H), 4.06 (q, J = 9.9 Hz, 1H), 3.97 (ddt, J = 14.4, 9.7, 4.4 Hz, 1H), 3.92 -3.68 (m, 1H), 3.48 - 3.13 (m, 2H), 2.86 (s, 3H), 2.78 -2.63 (m, 2H), 2.63 - 2.47 (m, 1H), 2.44 -2.22 (m, 1H), 1.58 - 1.52 (m, 1H), 1.50 (s, 9H), 1.47 - 1.41 (m, 3H), 1.40 (s, 9H), 0.85 (qd, J = 11.3, 3.7 Hz, 1H). (mixture of diastereomers and rotamers)

[0417] 13C NMR (126 MHz, CDCh) 8 163.12 (d, J = 246.2 Hz), 162.70, 158.23, 155.10, 155.04, 154.86, 154.74, 152.98, 150.96, 149.28, 139.32 (d, J= 7.3 Hz), 132.97, 130.28 (d, J = 8.2 Hz), 129.05, 128.87, 128.46, 125.12, 123.24, 122.56 (d, J= 3.0 Hz), 115.78, 114.99 (d, J= 21.0 Hz), 114.24 (d, J= 15.6 Hz), 111.54, 110.87, 107.54, 85.28, 81.27, 79.34, 79.27, 70.53, 70.51, 56.09, 52.09, 50.88, 48.13, 47.51, 46.32, 46.28, 46.20, 46.14, 45.21, 43.90, 43.24, 42.61, 40.19, 38.16, 35.53, 28.60, 28.58, 28.53, 28.15, 24.64. (mixture of diastereomers and rotamers; due to hindered rotation many signals appear broadened and low in intensity)

[0418] Methyl 3-((oxodiphenyl-k6-sulfaneylidene)amino)bicyclo[ 1.1.1 ]pentane-l -carboxylate (52)

[0419]

[0420] Prepared according to general procedure C with corresponding iodonium (234 mg, 0.4 mmol, 1.0 equiv ), S,5-diphenylsulfoximine (174 mmol, 0.8 mmol, 2.0 equiv.), Ir[dF(Me)ppy]2(4,4'-dtbbpy)PF6 (8.11 mg, 8.0 pmol, 2 mol%), Cu(acac)2 (51.7 mg, 200 pmol, 50 mol%) and BTTP (169 pL, 0.4 mmol, 1 equiv.) in 1,4-dioxane (5 mL) and MTBE (1.2 mL).

[0421] After irradiation for 1 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar Cl 8 D reverse phase column, and purified with eluents 10% to 90% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a yellow oil (124 mg, 363 pmol, 91% yield). > H NMR (700 MHz, CDCh) 8 8.00-7.96 (m, 4H), 7.54-7.50 (m, 2H), 7.49-7.45 (m, 4H), 3.60 (s, 3H), 2.10 (s, 6H).

[0422] 13C NMR (176 MHz, CDCh) 8 170.76, 141.71, 132.77, 129.29, 128.42, 56.64, 51.75, 49.50, 35.65.

[0423] ((3-Methylbicyclo[ 1.1.1 ]pentan-l-yl)imino)diphenyl-X6-sulfanone (53)

[0424]

[0425] Prepared according to general procedure C with corresponding iodonium (199 mg, 0.4 mmol, 1.0 equiv), S, S-diphenylsulfoximine (174 mmol, 0.8 mmol, 2.0 equiv.), Ir[dF(Me)ppy]2(4,4'-dtbbpy)PF6 (8.11 mg, 8.0 pmol, 2 mol%), Cu(acac)2 (51.7 mg, 200 pmol, 50 mol%) and BTTP (169 pL, 0.4 mmol, 1 equiv.) in 1,4-dioxane (5 mL) and MTBE (1.2 mL).

[0426] After irradiation for 1 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar Cl 8 D reverse phase column, and purified with eluents 10% to 90% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as an orange solid (111 mg, 373 pmol, 93% yield).

[0427] > H NMR (500 MHz, CDCh) 8 8.01-7.97 (m, 4H), 7.52-7.49 (m, 2H), 7.48-7.39 (m, 4H), 1.71 (s, 6H), 1.09 (s, 3H).

[0428] 13C NMR (120 MHz, CDCh) 8 142.19, 132.40, 129.07, 128.50, 56.93, 48.89, 33.46, 16.63. 3-((Methyl(oxo)(p-tolyl)-X6-snlfaneylidene)amino)bicyclo[ I. I. l]pentane-l -carbonitrile (54)

[0429] Me

[0430]

[0431] Prepared according to general procedure C with corresponding iodonium (207 mg, 0.4 mmol, 1.0 equiv), imino-methyl-oxo-( / ?-tolyl)-sulfane (135 mmol, 0.8 mmol, 2.0 equiv ), Ir[dF(Me)ppy]2(4,4'-dtbbpy)PF6 (8.11 mg, 8.0 pmol, 2 mol%), Cu(acac)2 (51.7 mg, 200 pmol, 50 mol%) and BTTP (169 pL, 0.4 mmol, 1 equiv.) in 1,4-dioxane (5 mL) and MTBE (1.2 mL).

[0432] After irradiation for 1 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar Cl 8 D reverse phase column, and purified with eluents 10% to 90% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as an off-white solid (57.4 mg, 220 pmol, 55% yield).

[0433] 'H NMR (700 MHz, CDC13) 87.78 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 3.06 (s, 3H), 2.47 (s, 3H), 2.18 (m, 6H).

[0434] 13C NMR (176 MHz, CDC13) 5 144.79, 137.33, 130.40, 128.53, 117.93, 58.78, 52.05, 45.99, 21.71, 21.05.

[0435] ( 4-Chlorophenyl) (methyl)(( 3-methylbicyclo[ 1.1.1 ] pentan- 1-y I) imino) -6-sulfanone (55)

[0436]

[0437] Prepared according to general procedure C with corresponding iodonium (199 mg, 0.4 mmol, 1.0 equiv ), imino-methyl-oxo-(p-chloro)-sulfane (152 mmol, 0.8 mmol, 2.0 equiv ), Ir[dF(Me)ppy]2(4,4'-dtbbpy)PF6 (8.11 mg, 8.0 pmol, 2 mol%), Cu(acac)2 (51.7 mg, 200 pmol, 50 mol%) and BTTP (169 pL, 0.4 mmol, 1 equiv.) in 1,4-dioxane (5 mL) and MTBE (1.2 mL).

[0438] After irradiation for 1 hours, the solvent was removed under reduced pressure. The crude residue was dissolved in a minimal amount of DMSO, loaded on a 30 g Biotage Sfar C18 D reverse phase column, and purified with eluents 10% to 90% MeCN in water (0.1% NH4OH modifier). The fractions containing product were concentrated to provide the product as a yellow oil (94 mg, 348 pmol, 87% yield).

[0439] 1H NMR (700 MHz, CDCh) 67.88 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 3.06 (s, 3H), 1.66 (d, J = 9.6 Hz, 3H), 1.61 (d, J = 9.6 Hz, 3H), 1.07 (s, 3H).

[0440] 13C NMR (176 MHz, CDCh) 5 139.90, 139.75, 130.26, 129.64, 56.66, 48.70, 46.05, 33.42, 16.55.

[0441] (^)-(cyclobutylimmo)(3-((4-(4-fliioro-2-methoxyphetiyl)-l,3,5-triazin-2-yl)amino)benzyl)-(methyl)-k6-sulfanone (57)

[0442]

[0443] Prepared according to general procedure A with atuveciclib (130 mg, 0.34 mmol, 1.00 equiv.), 4CzIPN (16.6 mg, 13.4 pmol, 4 mol%), Cu(OAc)2 (9.14 mg, 50.3 pmol, 15 mol%), 1, 10-phenanthroline (10.3 mg, 57.0 pmol, 17.5 mol%), BTMG (135 pL, 0.67 mmol, 2.00 equiv.), MesIO (175 mg, 0.68 mmol, 2.00 equiv.), cyclobutanol (48 mg, 0.68 mmol, 2.00 equiv.), NHC-H (292 mg, 0.74 mmol, 2.2 equiv.), pyridine (60 pL, 0.74 mmol, 2.2 equiv.) in MeCN (3.3 mL) and MTBE (3.3 mL).

[0444] After irradiation for 8 hours, the solvent was removed under reduced pressure. The crude product was dissolved in a minimal amount of DMSO and subsequently purified by preparative HPLC (XBridge BEH C18 OBD column, 30% to 100% MeCN in H2O with 0.1% NH4OH) to provide the product as a colorless solid (78.3 mg, 177 pmol, 53% yield).

[0445] > H NMR (500 MHz, CDCh) 58.80 (s, 1H), 7.94 (s, 1H), 7.90 - 7.76 (m, 1H), 7.72 (s, 1H), 7.40 - 7.33 (m, 1H), 7.12 (d,. / - 7.6 Hz, 1H), 6.80- 6.71 (m, 2H), 4.34 - 4.23 (m, 2H), 3.97 (p,,7= 8.0 Hz, 1H), 3.91 (s, 3H), 2.72 (s, 3H), 2.24 (dt,.7 = 13.1, 6.9 Hz, 2H), 2.03 (p, J = 9.3 Hz, 2H), 1.93 (br s, 1H), 1.74- 1.66 (m, 1H), 1.66 - 1.56 (m, 1H).

[0446] 13C NMR (126 MHz, CDC13) 5 172.07, 166.72 (d, J= 251.1 Hz), 166.43, 163.68, 138.57, 130.77, 129.68, 126.15, 122.55, 122.13 (d, J= 3.2 Hz), 120.78, 107.69 (d, J= 21.5 Hz), 100.35 (d, J= 25.7 Hz), 61.30, 56.41, 49.18, 39.43, 34.17 (d, J= 5.2 Hz), 15.77.

[0447] EXAMPLE 2 - Arylation of NH-Sulfoximine

[0448] An oven-dried 20 mL vial was charged with 4CzIPN (4 mol%), CuBr2 (25 mol%), phenanthroline (28 mol%) and a cross magnetic stir bar. Acetonitrile (10 mL) was added, and the contents were sonicated for 1 minute and subsequently stirred for 5 minutes. A fine homogenous suspension was obtained. The V-nucleophile (0.5 mmol, 1 equiv) and the aryl bromide (2.0 equiv.) were added, and stirring was continued for 2 minutes, followed by the addition of (TMS)3SiNHAd (2.2 equiv.). Subsequently, 1,3,3- tetramethylguanidine (TMG) (3.0 equiv) was added to the reaction vial, which was subsequently capped, and the septum pierced with a 18G needle. The reaction was placed in the integrated photoreactor (short stack vial holder, 50% light intensity, max fan speed, 750 rpm stir rate, and 10 hours reaction time). After 10 hours of irradiation, the reaction was diluted with EtOAc (5 mL) and filtered through a pad of celite. The filtrate was concentrated in vacuo and purified by flash column chromatography.

[0449] Various embodiments of the invention have been described in fulfillment of the various objectives of the invention. It should be recognized that these embodiments are merely illustrative of the principles of the present invention. Numerous modifications and adaptations thereof will be readily apparent to those skilled in the art without departing from the spirit and scope of the invention.

Claims

1. CLAIMS1. A method of functionalizing a sulfoximine comprising:3.coordinating the sulfoximine with a transition metal to provide a transition metal-sulfoximine complex; and4.capturing an alkyl radical with the transition metal-sulfoximine complex resulting in a higher valent intermediate, wherein the higher valent intermediate undergoes reductive elimination to yield an N-alkyl functionalized sulfoximine.

2. The method of claim 1, wherein the alkyl radical is a secondary radical.

3. The method of claim 1, wherein the alkyl radical is generated from an N-heterocyclic carbene (NHC)-alcohol adduct.

4. The method of claim 3, wherein an a-oxy radical of the NHC-alcohol adduct undergoes P-scission of a C-0 bond to provide the alkyl radical and a carbamate byproduct.

5. The method of claim 4, wherein the a-oxy radical of the NHC-alcohol adduct is generated by single electron transfer between the NHC-alcohol adduct and an excited state photocatalyst yielding reduced photocatalyst and a radical cation of the NHC-alcohol adduct, followed by deprotonation of the radical cation with base to provide the a-oxy radical.

6. The method of claim 5, wherein the photocatalyst is an organic photocatalyst.

7. The method of claim 5 or 6, wherein the photocatalyst absorbs visible light to provide the excited state.

8. The method of claim 1, wherein the alkyl radical is generated from a12.bicyclofl. l.l]pentane (BCP) carboxylate.

9. The method of claim 8, wherein the BCP-carboxylate undergoes decarboxylation following reduction by a photocatalyst.

10. The method of claim 9, wherein the photocatalyst is a transition metal complex.

11. The method of claim 10, wherein the transition metal complex absorbs light in the visible region of the electromagnetic spectrum.

12. The method of claim 1, wherein the alkyl radical is generated from halogen abstraction from an alkyl halide.

13. The method of claim 12, wherein an aminosilane radical abstracts the halogen from the alkyl halide.

14. The method of claim 12, wherein the aminosilane radical is generated via single electron transfer between an aminosilane and an excited state photocatalyst yielding a reduced photocatalyst and the aminosilane radical.

15. The method of claim 14, wherein the photocatalyst is an organic photocatalyst.

16. The method of claim 14, wherein the photocatalyst absorbs visible light to provide the excited state.

17. The method of claim 1, wherein the transition metal is selected from Groups 10 and 11 of the Periodic Table.

18. The method of claim 17, wherein the transition metal is copper.

19. The method of claim 1, wherein the alkyl functionlized sulfoximine is C(sp3)-N coupled.

20. The method of claim 2, wherein the secondary radical is a cyclic or heterocyclic.

21. The method of claim 20, wherein the secondary radical is spirocylic.

22. The method of claim 3, wherein the alcohol forming the NCH-alcohol adduct is a primary alcohol.

23. The method of claim 3, wherein the alcohol forming the NCH-alcohol adduct is a secondary alcohol.

24. The method of claim 23, wherein the secondary alcohol is cyclic or heterocyclic.

25. The method of claim 23, wherein the secondary alcohol is spirocyclic.

26. The method of claim 1, wherein the sulfoximine is a pharmaceutical.

27. The method of claim 12, wherein the halogen is bromine or chlorine.

28. The method of claim 1, wherein the transition metal is part of a transition metal complex.

29. The method of claim 3, wherein the sulfoximine, transition metal, NHC-alcohol adduct and photocatalyst are present in a single reaction mixture.

30. The method of claim 29, wherein the single reaction mixture further comprises an oxidant.

31. The method of claim 14, wherein the sulfoximine, transition metal, aminosilane, and photocatalyst are present in a single reaction mixture.

32. The method of claim 31, wherein the single reaction mixture further comprises an oxidant.

33. A sulfoximine of the formula:36.OxN-BCP37.X39.

40. wherein BCP is bicyclo[l.l.l]pentane (BCP) or a substituted BCP, and wherein Ri and R2 are independently selected from the group consisting of alkyl, alkenyl, aryl, heterocyclyl, cycloalkyl, -alkylene-aryl, -alkenylene-aryl, -alkylene-heterocyclyl, -alkenylene-heterocyclyl, and -alkylene-cycloalkyl, and wherein Ri and R2 may optionally combine to form a substituted or unsubstituted cycloalkyl or heterocyclyl ring.

34. The sulfoximine of claim 33, wherein the BCP is substituted with one or more carboxy groups.

35. The sulfoximine of claim 33, wherein Ri and R2 are independently selected from the group consisting of alkyl, aryl, and heterocyclyl, wherein the aryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, amine, amide, and alkoxy.

36. A method of functionalizing a sulfoximine comprising:44.coordinating the sulfoximine with a transition metal to provide a transition metal-sulfoximine complex; and45.capturing an aryl radical with the transition metal-sulfoximine complex resulting in a higher valent intermediate, wherein the higher valent intermediate undergoes reductive elimination to yield an N-aryl functionalized sufloximine.

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