Rapid construction of tetralin, chromane and indane motifs via cyclization C-H / C-H coupling

Abstract

Disclosed herein are methods for achieving palladium-catalyzed cyclization C(sp 3 )‑H / C(sp 2 )‑H coupling reactions using natural, free carboxylic acids as directing groups, amino acid ligands, and oxidizing agents. The methods can be used to synthesize a range of biologically important parent nuclei, including tetralins, chromananes, and indanes.

Description

[0001] CLAIM OF PRIORITY

[0002] This application claims priority to U.S. Provisional Application No. 63 / 112,464, filed November 11, 2020, which is incorporated herein as if fully set forth.

[0003] GOVERNMENT SUPPORT

[0004] This invention was made with government support under Grant No. 2R01GM084019 awarded by the National Institutes of Health and Grant No. CHE-1700982 awarded by the National Science Foundation. The government has certain rights in the invention. BACKGROUND

[0005] Carbon-carbon (C-C) bond formation constitutes one of the most important classes of reactions in organic synthesis. Because such bond formation has the potential to shorten syntheses, the past two decades have witnessed rapid development in the use of C-H activation strategies to build C-C bonds. 1 While most coupling methods require pre-functionalized coupling partners (e.g., organoborons and organohalides), C-H / C-H coupling reactions offer a complementary strategy to build C-C bonds directly from two simple C-H bonds. 2 This green and atom-economic approach is highly attractive compared to traditional coupling methods because water can be the only stoichiometric byproduct of the process. Previous reports have focused on coupling two relatively reactive C(sp 2 )-H bonds for biaryl synthesis, 3 while only a few reactions for building the more challenging C(sp 3 )-C(sp 2 ) bond have been reported. Since these existing reaction protocols require an exogenous directing group (DG) to facilitate cyclometalation, additional steps are needed to install and remove the DG. 5，6 Furthermore, the reported methods suffer from practical limitations, such as stoichiometric use of expensive silver salts 4b，c，5，6b，c and harsh conditions 4b，c，5a，b，6 (with temperatures as high as 160 °C). In addition, current methods for C(sp 3 )-H / C(sp 3 )-H coupling initiated by C(sp 2 )-H activation are largely limited to the more reactive heterocyclic C(sp 2 )-H bonds. 5a，b，6 Therefore, there is a need for a C(sp3 )-H / C(sp 2 The development of -H coupling reactions remains a major challenge.

[0006] Recent advances in C-H functionalization provide chemical workers with creative and strategic retro-synthetic disconnections that would otherwise be difficult to achieve using traditional methods. 7 However, for C-H functionalization strategies to truly improve the overall efficiency of synthesis, three criteria should be met: (1) the ability to synthesize a wide variety of natural product families using a broad range of simple starting materials; (2) the use of natural functional groups as DGs; (3) the site selectivity of the C-H functionalization reaction should be precisely controllable. However, methods that can meet the above criteria are challenging and uncommon. 7a，8 SUMMARY

[0007] The present disclosure overcomes these challenges and additional challenges in various embodiments by providing a method for preparing a compound of formula (2):

[0008]

[0009] The method comprises contacting a compound of formula (1):

[0010]

[0011] with a ligand of formula (L):

[0012]

[0013]

[0014] The contacting occurs in the presence of a palladium (II) source and an oxidizing agent, thereby forming the compound of formula (2).

[0015] In the methods described herein:

[0016] X is CH2or O;

[0017] n is an integer selected from 0 and 1;

[0018] o and m are integers independently selected from 0, 1, and 2, wherein the sum of o and m is not greater than 4;

[0019] x and y are integers independently selected from 0 and 1;

[0020] z is an integer selected from 0, 1, and 2;

[0021] R 1 selected from H and C1-C6-alkyl;

[0022] each R 2 and R​3 independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, C1-C6-haloalkyl and (C6-C 10 -aryl)(C1-C6-alkyl)-;

[0023] or adjacent R 2 and R 3 together with the carbon atom to which they are bonded form a fused C5-C6-cycloalkyl or phenyl; and

[0024] each R 4 and R 5 are independently selected from the group consisting of H, C1-C6-alkyl and (C6-C 10 -aryl)(C1-C6-alkyl)-;

[0025] or, when z is 1, then R 4 and R 5 together with the carbon atom to which they are bonded form a 5- to 6-membered cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 to 2 substituents selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-alkoxy and C6-C 10 -aryl.

[0026] Further embodiments of the present disclosure are described in the drawings and the detailed description. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 . Natural products of biological interest include tetralin, chroman and indane frameworks.

[0028] Figure 2 . Ligand study in exemplary annulation C(sp 3 )-H / C(sp 2 )-H coupling reactions. Conditions: 1a (0.1 mmol), Pd(OAc)2(10 mol%), ligand (L) (10 mol%), LiOAc (1.0 equiv), Na2CO3·1.5H2O2(2.0 equiv), HFIP (1.0 mL), 60 °C, 12 h. Isolated yields were determined by crude product1H NMR analysis using CH2Br2as an internal standard. 1 H NMR analysis using CH2Br2as an internal standard. c Isolated yields.

[0029] Figure 3 . Ligand study in exemplary annulation C(sp 3 )-H / C(sp 2) substrate scope and isolated yield of the -H coupling reaction. Conditions A: 1 (0.1 mmol), Pd(OAc)2(10 mol%), L9 (10 mol%), LiOAc (1.0 equiv), Na2CO3-1.5H2O2(2.0 equiv), HFIP (1.0 mL), 60 °C, 12 h. c Conditions B: 1 (0.1 mmol), Pd(CH3CN)4(BF4)2(10 mol%), Ag2CO3(1.0 equiv), 1- fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (2.0 equiv), HFIP (1.0 mL), 90 °C, 12 h. Conditions B: 1 (0.1 mmol), Pd(CH3CN)4(BF4)2(10 mol%), Ag2CO3(1.0 equiv), 1- fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (2.0 equiv), HFIP (1.0 mL), 90 °C, 12 h.

[0030] Figure 4 Illudalane sesquiterpenes possess an indane core containing a quaternary center.

[0031] Figure 5 Full synthesis of (±)-russujaponol F. Conditions: (a) SOCl2, EtOH, reflux, overnight; I2(0.5 equiv), Selectfluor (0.5 equiv), CH3CN, 60 °C, 3 h. (b) Pd(OAc)2(10 mol%), L12 (10 mol%), pivalic acid (3.0 equiv), CsOAc (1.0 equiv), Ag2CO3(2.0 equiv), HFIP, 80 °C, 12 h. (c) Pd(CH3CN)4(BF4)2(10 mol%), Ag2CO3(1.0 equiv), 1-fluoro-2,4,6- trimethylpyridinium tetrafluoroborate (2.0 equiv), HFIP, 90 °C, 12 h. Conditions B: 1 (0.1 mmol), Pd(CH3CN)4(BF4)2(10 mol%), Ag2CO3(1.0 equiv), 1- fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (2.0 equiv), HFIP (1.0 mL), 90 °C, 12 h. DETAILED DESCRIPTION

[0032] The present disclosure relates, in part, to methods for cyclization C(sp 3 )-H / C(sp 2 )-H coupling reactions using natural free carboxylic acids as directing groups (DG). In exemplary embodiments, a cyclopentane-based mono-N-protected β-amino acid ligand and the practical and inexpensive oxidant sodium carbonate peroxide (Na2CO3-1.5H2O2) proved useful in the method. For example, tetrahydronaphthalene, chromane, and indane Figure 1) readily prepared by this method. The synthetic utility of this method was further demonstrated by the concise total synthesis of (+)-russujaponol F (the shortest and highest yielding to date) from readily available phenylacetic acid and pivalic acid in four steps via multiple C-H functionalizations (Scheme 1C), demonstrating the potential of C-H activation cleavage to improve the ideal state of synthesis 9 .

[0033] Definitions

[0034] “Ac” means an acetyl group having the formula -C(=0)-CH a .

[0035] “Alkyl” means a straight-chain or branched-chain hydrocarbon group containing from 1 to about 20 carbon atoms. For example, an alkyl group can have from 1 to 10 carbon atoms or from 1 to 6 carbon atoms. Exemplary alkyl groups include straight-chain alkyl groups such as methyl (“Me”), ethyl (“Et”), propyl, butyl (including tert-butyl (“tBu”)), pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like, and also include branched isomers of straight-chain alkyl groups such as, but not limited to, -CH(CH3)2, -CH(CH3)(CH2CH3), -CH(CH2CH3)2, -C(CH3)3, -C(CH2CH3)3, -CH2CH(CH3)2, -CH2CH(CH3)(CH2CH3), -CH2CH(CH2CH3)2, -CH2C(CH3)3, -CH2C(CH2CH3)3, -CH(CH3)CH(CH3)(CH2CH3), -CH2CH2CH(CH3)2, -CH2CH2CH(CH3)(CH2CH3), -CH2CH2CH(CH2CH3)2, -CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3, -CH(CH3)CH2CH(CH3)2, -CH(CH3)CH(CH3)CH(CH3)2, and the like. Thus, alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.

[0036] “Boc” means a tert-butyloxycarbonyl group having the formula (CH3)3C-0-C(=0)-.

[0037] “Bn” means a benzyl group having the formula -CH2-phenyl.

[0038] Each of the terms “halogen,” “halide,” and “halo” means -F or fluoro, -Cl or chloro, -Br or bromo, or -I or iodo.

[0039] The term "alkoxy" refers to -O-alkyl having the indicated number of carbon atoms. For example, (Ci-C6)-alkoxy includes -O-methyl, -O-ethyl, -O-propyl, -O- isopropyl, -O-butyl, -O-sec-butyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, -O-hexyl, -O- isohexyl, and -O-neohexyl.

[0040] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, tricyclic, or polycyclic 3- to 14-membered ring system, e.g., C3-C8-cycloalkyl. Cycloalkyl groups can be attached via any atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, the cycloalkyl group in the ligand of Formula (L) is substituted with, in addition to the -NHAc and -CO2H substituents as shown, one to two substituents selected from the group consisting of halogen, Ci-C6-alkyl, Ci-C6-alkoxy, and C6-Ci0-aryl. 10 - 1 to 2 substituents on the aryl group.

[0041] "Aryl" when used alone or as part of another term means a carbocyclic aromatic ring having the specified number of carbon atoms or up to 14 carbon atoms if no number is specified, whether or not fused, e.g., C6-Ci0-aryl. Representative aryl groups include phenyl, naphthyl, biphenyl, phenanthryl, naphthacenyl, and the like (see, e.g., Lang's Handbook of Chemistry (Dean, J. A. Ed.) 13th edition. Table 7-2

[1985] ). An exemplary aryl group is phenyl. The aryl group can be unsubstituted or optionally substituted with one or more substituents as described herein. 10 - 1 to 2 substituents on the aryl group. 14 - 1 to 2 substituents on the aryl group. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthryl, naphthacenyl, and the like (see, e.g., Lang's Handbook of Chemistry (Dean, J. A. Ed.) 13th edition. Table 7-2

[1985] ). An exemplary aryl group is phenyl. The aryl group can be unsubstituted or optionally substituted with one or more substituents as described herein.

[0042] The term "optionally substituted" means optionally substituted (i.e., unsubstituted or substituted) with the indicated substituents.

[0043] The compounds described herein can exist in a variety of isomeric forms, including configurational, geometric, and conformational isomers, including, for example, cis or trans conformations. The compounds can also exist in one or more tautomeric forms, including both single tautomers as well as mixtures of tautomers. The term "isomers" is intended to encompass all isomeric forms of the compounds of the disclosure, including tautomeric forms of the compounds. The compounds of the disclosure can also exist in open-chain or cyclic forms. In some cases, one or more of the cyclic forms can result from the loss of water. The particular composition of the open-chain and cyclic forms can depend on how the compound is isolated, stored, or administered. For example, a compound can exist primarily in an open-chain form under acidic conditions, while cyclizing under neutral conditions. All forms are included in the disclosure.

[0044] Some of the compounds described herein can have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. The compounds as described herein can be in the form of an optical isomer or a diastereomer. Therefore, the present disclosure encompasses compounds as described herein in the form of their optical isomers, diastereomers, and mixtures thereof, including racemic mixtures. Optical isomers of the compounds of the present disclosure can be obtained by known techniques, such as asymmetric synthesis, chiral chromatography, simulated moving bed technology, or via chemical separation by employing optically active resolving agents of the stereoisomers.

[0045] The term "stereoisomers" means one stereoisomer of a compound, which is substantially free of other stereoisomers of the compound, unless otherwise indicated. Thus, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds include more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound, such as more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound, or more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound, or more than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomer of the compound. A stereoisomer as described above can be considered to comprise a composition of the two stereoisomers present in their respective weight percents as described herein.

[0046] If there is a discrepancy between an depicted structure and a given name for that structure, the depicted structure controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated by, for example, a dashed or solid line, then the structure or the portion of the structure is intended to encompass all possible stereochemistry. In some cases, however, when there is more than one chiral center, the structure and name can be represented as a single enantiomer to aid in describing the relative stereochemistry. One skilled in the art of organic synthesis will know from the methods used to make the compounds whether the compounds are made as single enantiomers.

[0047] In some embodiments of the methods described herein, X is CH2. In other embodiments, X is O.

[0048] In various embodiments, n is 0, while in other embodiments n is 1. In illustrative embodiments, the compound of formula (2) is selected from one of Table 1:

[0049] Table 1. Exemplary compounds of Formula (2).

[0050]

[0051]

[0052] In the ligand of Formula (L), according to various embodiments, z is 1. In other embodiments, z is 0 or 2.

[0053] In various embodiments, one of x and y is 0 and the other is 1. In further embodiments, R 4 and R 5 together with the carbon atom to which they are bound form a 5- to 6-membered cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 to 2 substituents selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-alkoxy and C6-C 10 -aryl, in addition to the -NHAc and -CO2H substituents as shown. For example, according to one embodiment, R 4 and R 5 together with the carbon atom to which they are bound form a 5-membered cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 to 2 substituents selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-alkoxy and C6-C 10 -aryl, in addition to the -NHAc and -CO2H substituents as shown. According to another embodiment, R 4 and R 5 together with the carbon atom to which they are bound form a 6-membered cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 to 2 substituents selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-alkoxy and C6-C 10 -aryl, in addition to the -NHAc and -CO2H substituents as shown. Exemplary ligands of Formula (L) are selected from one of Table 2.

[0054] Table 2: Exemplary ligands of Formula (L).

[0055]

[0056] For example, according to one embodiment, a useful ligand of Formula (L) is L9:

[0057]

[0058] In various embodiments, the ligand of formula (L) is present in an amount of about 1 mol% to about 15 mol% based on the amount of compound of formula (2). For example, the amount can range from about 7 mol% to about 12 mol%. In various embodiments, the amount of ligand (L) is about 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, or 15 mol%. In one illustrative embodiment, the amount is about 10 mol%.

[0059] In various embodiments, the compound of formula (1) is selected from one of Table 3.

[0060] Table 3: Exemplary compounds of formula (1).

[0061]

[0062]

[0063] In the methods described herein, the palladium catalyst is generated by the introduction of palladium (II) via a reagent known in the art or commercially available. According to one embodiment, a suitable source of palladium (II) is Pd(OAc)2. In another embodiment, the source is Pd(CH3CN)4(BF4)2.

[0064] The catalyst loading can vary depending on factors known to one skilled in the art, such as overall reaction kinetics. Thus, in various embodiments, the source of palladium (II) is present in an amount of about 1 mol% to about 15 mol% based on the amount of compound of formula (2). In other embodiments, the amount is about 7 mol% to about 12 mol%. Exemplary amounts include 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, and 15 mol%. In one embodiment, the amount is 10 mol%.

[0065] Various oxidizing agents known in the art can be used in the methods of the present disclosure. According to one embodiment, a suitable oxidizing agent is sodium percarbonate, as described in more detail herein.

[0066] In various embodiments, the contacting step of the methods described herein further occurs in the presence of LiOAc. In one embodiment, wherein the solvent available is hexafluoroisopropanol.

[0067] According to embodiments of this disclosure, the methods described herein can be performed at various temperatures. For example, temperatures of about 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, or 80°C. In one illustrative embodiment, the temperature is about 60°C.

[0068] In several embodiments, the ligand of formula (L) is (L9) present in an amount of approximately 10 mol%:

[0069]

[0070] The sum of o and m is 1 or 2; the palladium(II) source is Pd(OAc)2 in an amount of about 10 mol%; and the oxidant is sodium percarbonate.

[0071] Aliphatic carboxylic acids are ubiquitous and versatile motifs, and are generally inexpensive reagents in organic chemistry; therefore, they are preferred substrates for CH activation reactions. According to one embodiment of this disclosure, 10 Following the use of tert-butyl hydroperoxide (TBHP) as the sole oxidant for the β-C (sp) reaction of free carboxylic acids. 3 )-H lactonelation 10i and acyloxylation 10j The latest published information indicates that, by selecting TBHP as a bystanding oxidant and aliphatic acid 1a as a model substrate, research has begun on cyclized C(sp...) 3 )-H / C(sp 2 )-H coupling reaction. In the aforementioned β-acyloxylation reaction 10j Under optimal conditions, 50% can be obtained. 1 The desired product 2a is obtained in the 1H NMR yield without forming a competitive reductive elimination product, such as a β-lactone or β-hydroxy acid. Further studies on the bystander oxidant and substrate revealed that, in several embodiments, the combination of Na₂CO₃·1.5H₂O₂ and LiOAc increased the yield to 57% (see Examples). In some embodiments, sodium percarbonate (one of the cheapest and easiest-to-handle oxidants) is used. 11 This is an advantage that makes the method practical and scalable.

[0072] In light of recent advances in ligand-promoted Pd(II)-catalyzed CH activation, 12 The next step is to search for ligands that can significantly improve the reactivity of the catalyst. The C(sp) of the free carboxylic acid is achieved by using a mono-N-protected amino acid (MPAA) ligand. 3 Guided by the )-H activation reaction 10c，d，g，i，j, a series of commercially available MPAA ligands (L1 to L4) were tested: the β-amino acid ligand L4 exhibited superior reactivity (57% vs. 19% to 45%) relative to the a-amino acid ligands L1 to L3, which was also observed in other C(sp 3 )-H functionalization reactions via Pd(II) / Pd(IV) catalytic cycles 10d，i，j . Through systematic modification of the backbone of the β-amino acid ligand (L5 to L10; see Figure 2 ), it was surprisingly found that, in one embodiment, the cis-cyclopentane-based ligand L9 gave the best reactivity (78% isolated yield). Without being bound by any particular theory, the superior reactivity of L9 can be attributed to a more rigid conformation achieved by the cyclopentane linkage. Control experiments showed low yields (23% or 20%, respectively) in the absence of ligand or in the presence of a γ-amino acid ligand (L11).

[0073] Further, the scope of the annulative C(sp 3 )-H / C(sp 2 )-H coupling reaction was evaluated (Example 2) across multiple embodiments Figure 3 . A broad range of tertiary aliphatic acids bearing a single a-methyl group (1a to 1e and 1h) or a- geminal dimethyl groups (1f and 1g) were all compatible, giving medium to good yields (52% to 78%) of tetrahydronaphthalene products. The less reactive free carboxylic acids containing a- hydrogens (1i to 1l) also reacted with synthetically useful yields (35% to 65%). Among these, various functional groups on the aryl ring such as methyl (2b), methoxy (2j and 2k), fluoro (2c, 2g and 2l), and chloro (2d) as well as naphthyl (2e) were acceptable, with the halogen moiety (2d) serving as a synthetic handle useful for subsequent derivatization.

[0074] The methods of the present disclosure are also useful for the synthesis of biologically important chroman products. For example, according to multiple embodiments, β-phenoxy carboxylic acids containing a- geminal dimethyl groups (1m to 1r) or a-hydrogens (1s, from Roche ester) were all reactive substrates. While a series of electron-donating groups on the aryl ring (methoxy, t-butyl, cyclohexyl and benzyl) (2s and 2n to 2p) were all well-tolerated to give the desired products in good yields (70% to 85%), aliphatic acids containing electron-withdrawing groups (bromo and trifluoromethyl) (2q and 2r) exhibited relatively low reactivity (31% and 23%), which can be due to the slow nature of C(sp 2 )-H activation of electron-deficient arenes. Under the current conditions, the carboxylic acid 1t failed to provide the tetrahydroisoquinoline (THIQ) product 2t. This annulative C-H / C-H coupling reaction is also suitable for the synthesis of indane precursors (2u to 2w). For example, in one embodiment, the [F+ Oxidizing agent 3g，13 (1-Fluoro-2,4,6-trimethylpyridine) Tetrafluoroborate exhibits excellent reactivity (2v and 2w) to tertiary aliphatic acids containing α-gem-dimethyl groups.

[0075] Another embodiment illustrates a method of this disclosure relating to iruane-type sesquiterpenes, which includes a large class of natural products: they are typically characterized by a dihydroindene core with a challenging full-carbon quaternary center (multiple oxidation states are possible) Figure 4 ). 14 Due to their promising biological activities, great efforts have been made to achieve the total synthesis of these targets. 15，16 Given the ability of this method to construct dihydroindene cores, the total synthesis of (±)-russujaponol F was initiated via multiple CH-functionalized processes. Figure 5 The first total synthesis of russujaponol F based on C(sp) was reported. 3 The )-H arylation strategy occurs in racemic and enantioselective forms in 13 steps (26% yield) and 15 steps (12% yield), respectively. 15 From commercially available or via ortho-CH methylation 17 The synthesis begins with phenylacetic acid 3, which is esterified and subsequently monoiodinated using I2 and a selective fluorine reagent. 18 Aryl iodide 4 was prepared in 79% yield. Studies on the CH arylation of neopentanoic acid showed that, in ligand L12... 10f ，19 Under these conditions, monoarylated product 5 can be obtained in 62% yield, and cyclized CH / CH coupling product 6 in 12% yield. The formation of 6 under these conditions can be attributed to a second arylation of 5 in the presence of another aryl iodide as a bystander oxidant. 20 Then use [F] under standard conditions + The oxidant was used for cyclization of CH / CH to give the desired product 6 in 41% yield. Finally, 6 was subjected to total reduction with LAH to give (±)-russujaponol F in 96% pure yield, thus completing the total synthesis in four steps and with an overall yield of 28%: the shortest and highest-yield total synthesis of russujaponol F to date.

[0076] The numbered references in the preceding section are as follows:

[0077] (1) For a review on C-H activation / C-C bond formation reactions, see: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Palladium(II)-catalyzed C-H activation / C-C cross-coupling reactions: versatility and practicality. Angew. Chem., Int. Ed. 2009, 48, 5094-5115. (b) Daugulis, O.; Roane, J; Tran, L. D. Bidentate, monoanionic auxiliary-directed functionalization of carbon-hydrogen bonds. Acc. Chem. Res. 2015, 48, 1053-1064 (c) He, G; Wang, B.; Nack, W. A; Chen, G. Syntheses and transformations of a-amino acids via palladium-catalyzed auxiliary directed sp 3 C-H Functionalization. Acc. Chem. Res. 2016, 49, 635-645.

[0078] (2) For a review on C-H / C-H coupling reactions, see: (a) Yeung, C. S.; Dong, V. M. Catalytic dehydrogenative cross-coupling: forming carbon-carbon bonds by oxidizing

[0079] two carbon-hydrogen bonds. Chem. Rev. 2011, III, 1215-1292. (b) Girard, S. A.; Knauber, T.; Li, C.-J. The cross-dehydrogenative coupling of C(sp 3)-H bonds: a versatile strategy for C-C bond formations. Angew. Chem., Int. Ed. 2014, 53, 74-100. (c) Liu, C.; Yuan, J.; Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A. Oxidative coupling between two hydrocarbons: an update of recent C-H functionalizations. Chem. Rev. 2015, 115, 12138-12204.

[0080] (3) Regarding C(sp 2 )-H / C(sp 2 For early examples of C-H / C(sp2)-H coupling reactions, see: (a) Stuart, D. R.; Fagnou, K. The catalytic cross-coupling of unactivated arenes. Science 2007, 316, 1172-1175. (b) Xia, J.-B.; You, S.-L. Carbon-carbon bond formation through double sp 2C-H Activations: synthesis of ferrocenyl oxazoline derivatives. Organometallics 2007, 26, 4869-4871. (e) Hull, K. L.; Sanford, M. S. Catalytic and highly regioselective cross-coupling of aromatic C-H substrates. J. Am. Chem. Soc. 2007, 129, 11904-11905. (d) Brasche, G.; Garcia-Fortanet, J.; Buchwald, S. L. Two fold C-H functionalization: palladium-catalyzed ortho arylation of anilides. Org. Lett. 2008, 10, 2207-2210. (e) Cho, S. H.; Hwang, S. J.; Chang, S. Palladium-catalyzed C-H functionalization of pyridine N-oxides: highly selective alkenylation and direct arylation with unactivated arenes. J. Am. Chem. Soc. 2008, 130, 9254-9256. (f) Zhao, X.; Yeung, C. S.; Dong, V. M. Palladium-catalyzed ortho-arylation of O-phenylcarbamates with simple arenes and sodium persulfate. J. Am. Chem. Soc. 2010, 132, 5837-5844. (g) Wang, X.; Leow, D.; Yu, J.-Q. Pd(II)-catalyzed para-selective C-H arylation of monosubstituted arenes. J. Am. Chem. Soc. 2011, 133,

[0081] (4) Pd-catalyzed C(sp 2 )-H activation initiated C(sp 3 )-H / C(sp 2 )-H coupling reactions,

[0082] Ref: (a) Liégault, B.; Fagnou, K. Palladium-catalyzed intramolecular coupling of arenes and unactivated alkanes in air. Organometallics 2008, 27, 4841-4843. (b) Pierre, C; Baudoin, O. Intramolecular Pd II -catalyzed dehydrogenative C(sp 3 )-C(sp 2 ) coupling: an alternative to Pd 0 -catalyzed C(sp 3 )-H arylation from aryl halides? Tetrahedron 2013, 69, 4473-4478. (c) Shi, J, -L.; Wang, D.; Zhang, X.-S.; Li, X.-L; Chen, Y.-Q.; Li, Y.-C.; Shi, Z.-j. Oxidative coupling of sp 2 and sp 3 carbon-hydrogen bonds to construct dihydrobenzofurans. Nat. Commun. 2017, 8, 238-244.

[0083] (5) Concerning Pd-catalyzed C(sp 3 )-H / C(sp 3 )-H coupling reactions initiated by C(sp 2 )-H activation,

[0084] Ref: (a) Jiang, Y.; Deng, G; Zhang, S.; Loh, T.-P. Directing group participated benzylic C(sp 3 )-H / C(sp 2)-H cross-dehydrogenative coupling (CDC): synthesis of azapoly cycles. Org. Lett. 2018, 20, 652-655. (b) Sun, W.-W.; Liu, J.-K.; Wu, B. Practical synthesis of polysubstituted unsymmetric 1,10-phenanthrolines by palladium catalyzed intramolecular oxidative cross coupling of C(sp 2 )-Hand C(sp 3 )-H bonds of carboxamides. Org. Chem. Front 2019, 6, 544-550. (c) Hao, H.-Y.; Mao, Y.-J.; Xu, Z.-Y.; Lou, S.-J; Xu, D.-Q. Selective cross-dehydrogenative C(sp 3 )-Harylation with arenes. Org. Lett. 2020, 22, 2396-2402.

[0085] (6) Regarding other metal enabled C(sp 3 )-H / C(sp 2 )-H coupling reactions, see: (a) Wu, X.; Zhao, Y.; Ge, H. Pyridine-enabled copper-promoted cross dehydrogenative coupling of C(sp 2 )-H and unactivated C(sp 3 )-H bonds Chem. Sci. 2015, 6, 5978-5983. (b) Tan, G.; You, J. Rhodium(III)-catalyzed oxidative cross-coupling of unreactive C(sp 3 )-Hbonds with C(sp 2)-H bonds. Org. Lett. 2017, 19, 4782-4785. (c) Wang, X.; Xie, P.; Qiu, R.; Zhu, L.; Liu, T.; Li, Y.; Iwasaki, T.; Au, C.-T.; Xu, X.; Xia, Y.; Yin, S.-F.; Kambe, N. Nickel-catalysed direct alkylation of thiophenes via double C(sp 3 )-H / C(sp 2 )-H bond cleavage: the importance of KH2PO4. Chem. Commun. 2017, 53, 8316-8319. (d) Tan, G.; Zhang, L.; Liao, X.; Shi, Y.; Wu, Y.; Yang, Y.; You, J. Copper-or nickel-enabled oxidative cross-coupling of unreactive C(sp 3 )-H bonds with azole C(sp 2 )-H bonds: rapid access to β-azolyl propanoic acid derivatives. Org. Lett. 2017, 19, 4830-4833.

[0086] (7) For reviews on C-H functionalization for natural product synthesis, see: (a) Baudoin, O. Multiple catalytic C-H bond functionalization for natural product synthesis. Angew. Chem., Int. Ed. 2020, 59, 17798-17809 (b) Lam, N. Y. S.; Wu, K.; Yu, J.-Q. Advancing the logic of chemical synthesis: C-H activation as strategic and tactical disconnections for C-C bond construction. Angew. Chem., Int. Ed. 2020, 59, DOI: 10.1002 / anie.202011901. (c) Gutekunst, W. R; Baran, P. S. C-H functionalization logic in total synthesis. Chem. Soc. Rev. 2011, 40, 1976-1991. (d) Abrams, D. J.; Provencher, P. A.; Sorensen, E. J. Recent applications of C-H functionalization in complex natural product synthesis. Chem. Soc. Rev. 2018, 47, 8925-8967.

[0087] (8) For selected examples of total synthesis using multiple C-H functionalizations, see:

[0088] (a) Wang, D.-H.; Yu, J.-Q. Highly convergent total synthesis of (+)-lithospermic acid via a late-stage intermolecular C-H olefination. J. Am. Chem. Soc. 2011, 133, 5767-5769. (b) Gutekunst, W. R.; Baran, P. S. Total synthesis and structural revision of the piperarborenines via sequential cyclobutane C-H arylation. J. Am. Chem. Soc. 2011, 133, 19076-19079. (c) Rosen, B. R.; Simke, L. R.; Thuy-Boun, P. S.; Dixon, D. D.; Yu, J.-Q.; Baran, P. S. C-H functionalization logic enables synthesis of (+)-hongoquercin A and related compounds. Angew. Chem., Int. Ed. 2013, 52, 7317-7320. (d) Hong, B.; Li, C.; Wang, Z.; Chen, J.; Li, H.; Lei, X. Enantioselective total synthesis of (-)-incarviatone A. J. Am. Chem. Soc. 2015, 137, 11946-11949. (e) Dailler, D.; Danoun, G.; Ourri, B.; Baudoin, O. Divergent synthesis of aeruginosins based on a C(sp 3)-H activation strategy. Chem. Eur. J. 2015, 21, 9370-9379. (f) Wu, F.; Zhang, J.; Song, F.; Wang, S.; Guo, H.; Wei, Q.; Dai, H.; Chen, X.; Xia, X.; Liu, X.; Zhang, L.; Yu, J.-Q.; Lei, X. Chrysomycin A derivatives for the treatment of multi-drug-resistant tuberculosis. ACS Cent. Sci. 2020, 6, 928-938.

[0089] (9) Gaich, T.; Baran, P. S. Aiming for the ideal synthesis. J. Org. Chem. 2010, 75, 4657-4673.

[0090] (10) For β-C(sp 3 )-H functionalization reactions of free carboxylic acids, see: (a) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunder, L. B.; Yu, J.-Q. Palladium-catalyzed methylation and arylation of sp 2 and sp 3(b) Chen, G.; Zhuang, Z.; Li, G.-C; Saint-Denis, T. G.; Hsiao, Y.; Joe, C. L.; Yu, J.-Q. Ligand-enabled β-C-H arylation of α-amino acids without installing exogenous directing groups. Angew. Chem., Int. Ed. 2017, 56, 1506-1509. (c) Zhu, Y.; Chen, X.; Yuan, C.; Li, G.; Zhang, J.; Zhao, Y. Pd-catalysed ligabd-enabled carboxylate-directed highly regioselective arylation of aliphatic acids. Nat. Commun. 2017, 8, 14904. (d) Ghosh, K. K.; van Gemmeren, M. Pd-catalyzed β-C(sp 3 )-H arylation of propionic acid and related aliphatic acids. Chem. Eur. J. 2017, 23, 17697-17700. (e) Shen, P.-X.; Hu, L.; Shao, Q.; Hong, K.; Yu, J.-Q. Pd(II)-catalyzed enantioselective C(sp 3 )-H arylation of free carboxylic acids. J. Am. Chem. Soc. 2018, 140, 6545-6549. (f) Zhuabg, Z.; Yu, C.-B.; Chen, G.; Wu, Q.-F.; Hsiao, Y.; Joe, C. L.; Qiao, J. X.; Poss, M. A.; Yu, J.-Q. Ligabd-enabled β-C(sp 3)-Holefination of free carboxylic acids. J. Am. Chem. Soc. 2018, 140, 10363-10367. (g) Hu, L.; Shen, P.-X.; Shao, Q.; Hong, K.; Qiao, J. X.; Yu, J.-Q. Pd II -catalyzedenabtioselective C(sp 3 )-H activation / cross-coupling reactions of freecarboxylic acids. Angew. Chem., Int. Ed. 2019, 58, 2134-2138. (h) Ghosh, K. K.; Uttry, A.; Koldemir, A.; Ong, M.; van Gemmeren, M. Direct β-C(sp 3 )-H acetoxylation of aliphaticcarboxylic acids. Org. Lett. 2019, 21, 7154-7157. (i) Zhuang, Z.; Yu, J.-Q. Lactonization as a general route to β-C(sp 3 )-H functionalization. Nature 2020, 577, 656-659. (j) Zhuang, Z.; Herron, A. N.; Fan, Z.; Yu, J.-Q. Ligand-enabled monoselective β-C(sp 3 )-H acyloxylation of free carboxylic acids using apractical oxidant. J. Am. Chem. Soc. 2020, 142, 6769-6776. (k) Ghiringhelli, F.; Uttry, A.; Ghosh, K. K.; van Gemmeren, M. Direct β- and γ-C(sp 3 )-H alkynylation of freecarboxylic acids. Angew. Chem., Int. Ed. 2020, 59, DOI: 10.1002 / anie.202010784.

[0091] (11) (a) McKillop, A.; Sanderson, W. R. Sodium perborate and sodium percarbonate: Cheap, safe and versatile oxidising agents for organic synthesis. Tetrahedron Lett. 1995, 51, 6145 (b) Muzart, J. Sodium perborate and sodium percarbonate in organic synthesis. Synthesis 1995, 1325

[0092] (12) For reviews, see: (a) He, J.; Wasa, M; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Palladium-catalyzed transformations of alkyl C-H bonds. Chem. Rev. 2017, 117, 8754-8786. (b) Shao, Q.; Wu, K.; Zhuang, Z.; Qian, S; Yu, J.-Q. From Pd(OAc)2to chiral catalysts: the discovery and development of bifunctional mono-N-protected amino acid ligands for diverse C-H activation reactions. Acc. Chem. Res. 2020, 53, 833-851.

[0093] (13) Engle, K. M.; Mei, T-S.; Wang, X.; Yu, J.-Q. Bystanding F + oxidants enable selective reductive elimination from high-valent metal centers in catalysis. Angew. Chem., Int. Ed. 2011, 50, 1478-1491.

[0094] (14) (a) Yoshikawa, K.; Kaneko, A.; Matsumoto, Y.; Hama, H.; Arihara, S. Russujaponols A-F, illudoid sesquiterpenes from the fruiting body of Russula japonica. J. Nat. Prod. 2006, 69, 1267-1270. (b) Yoshikawa, K.; Matsumoto, Y.; Hama, H.; Tanaka, M.; Zhai, H.; Fukuyama, Y.; Arihara, S.; Hashimoto, T. Russujaponols G-L, illudoid sesquiterpenes, and their neurite outgrowth promoting activity from the fruit body of Russula japonica. Chem. Pharm. Bull. 2009, 57, 311-314. (c) Becker, U.; Erkel, G.; Anke, T.; Stemer, O. Puraquinonic acid, a novel inducer of differentiation of human HL-60 promyelocytic leukemia cells from Mycena pura (Pers. Ex Fr.). Nat. Prod. Lett. 1997, 9, 229-236. (d) Kuroyanagi, M.; Fukuoka, M.; Yoshihira, K.; Natori, S. The absolute configurations of pterosins, 1-indan nederivatives from bracken, Pteridium aquilinum var. latiusculum. Chem. Pharm. Bull. 1974, 22, 723-726. (e) Suzuki, S.; Murayama, T.; Shioho, Y. Echinolactones C and D: two illudalane sesquiterpenoids isolated from the cultured mycelia of the fungus Echinpdontium japonicum. Z.Naturforsch, B 2006, 61, 1295-1298.

[0095] (15) (a) Melot, R.; Craveiro, M.; Biiigi, T.; Baudoin, O. Divergent enantioselective synthesis of (nor)illudalane sesquiterpenes via Pd 0 -catalyzed asymmetric C(sp 3 )-H activation. Org. Lett. 2019, 21, 812-815. (b) Melot, R.; Craveiro, M. V.; Baudoin, O. Total synthesis of (nor)illudalane sesquiterpenes based on a C(sp 3 )-H activation strategy. J. Org. Chem, 2019, 84, 12933-12945.

[0096] (16) For recent examples, see: (a) Tiong, E. A.; Rivalti, D.; Williams, B. M.; Gleason, J. L. A concise total synthesis of (R)-puraquinonic acid. Angew. Chem., Int. Ed. 2013, 52, 3442-3445. (b) Elmehriki, A. A. H.; Gleason, J. L. A spiroalkylation method for the stereoselective construction of a-quatemary carbons and its application to the total synthesis of (R)-puraquinonic acid. Org. Lett. 2019, 21, 9729-9733. (c) Zeng, Z.; Zhao, Y.; Zhang, Y. Divergent total syntheses of five illudalane sesquiterpenes and assignment of the absolute configuration. Chem. Commun. 2019, 55, 4250-4253. (d) Xun, M. M.; Bai, Y.; Wang, Y.; Hu, Z.; Fu, K.; Ma, W.; Yuan, C. Synthesis of four illudalane sesquiterpenes utilizing a one-pot Diels-Alder / oxidative aromatization sequence. Org. Lett. 2019, 21, 6879-6883.

[0097] (17) Thuy-Boun, P. S.; Villa, G.; Dang, D.; Richardson, P.; Su, S.; Yu, J.-Q. Ligand-accelerated ortho-C-H alkylation of arylcarboxylic acids using alkylboron reagents. J. Am. Chem. Soc. 2013, 135, 17508-17513.

[0098] (18) Stavber, S.; Kralj, P.; Zupan, M. Selective and effective iodination of alky1- substituted benzenes with elemental iodine activated by Selectfluor TM F-TEDA-BF4. Synlett 2002, 598-600.

[0099] (19) For examples of C-H activation reactions using L12, see: (a) Le, K. K. A.; Nguyen, H.; Daugulis, O. 1-AminoPyridinium ylides as monodentate directing groups for sp 3 C-H bond functionalization. J. Am. Chem. Soc. 2019, 141, 14728-14735. (b) Zhuang, Z.; Yu, J.-Q. Pd(II)-catalyzed enantioselective γ-C(sp 3 )-H functionalizations of free cyclopropylmethylamines. J. Am. Chem. Soc. 2020, 142, 12015-12019.

[0100] (20) (a) Sun, W.-W.; Cao, P.; Mei, R-Q.; Li, Y.; Ma, Y.-L.; Wu, B. Palladium-catalyzed unactivated C(sp 3 )-H bond activation and intramolecular amination of carboxamides: a new approach to β-lactams. Org. Lett. 2014, 16, 480-483. (b) Zhang, S.-J.; Sun, W.-W.; Cao, P.; Dong, X.-P.; Liu, J.-K.; Wu, B. Stereoselective synthesis of diazabicyclic β-lactams through intramolecular amination of unactivated C(sp 3)-H bonds of carboxamides by palladium catalysis. J. Org. Chem. 2016, 81, 956-968. (c) Tong, H.-R.; Zheng, W.; Lv, X.; He, G.; Liu, P.; Chen, G. Asymmetric synthesis of β-lactam via palladium-catalyzed enantioselective intramolecular C(sp 3 )-H amidation. ACS Catal. 2020, 10, 114-120. (d) Zhou, T.; Jiang, M.-X.; Yang, X.; Yue, Q.; Han, Y.-Q.; Ding, Y.; Shi, B.-F. Synthesis of chiral β-lactams by Pd-catalyzed enantioselective amidation of methylene C(sp 3 )-H bonds. Chin. J. Chem. 2020, 38, 242-246.

[0101] (21) (a) Canty, A. J.; Jin, H.; Skelton, B. W.; White, A. H. Oxidation of complexes by (O2CPh)2and (ER)2(E = S, Se), including structures of Pd(CH2CH2CH2CH2)(SePh)2(bpy) (bpy = 2,2'-bipyridine) and MMe2(SePh)2(L2) (M = Pd, Pt; L2= bpy, 1,10-phenanthroline) and C...O and C...E bond formation at palladium(IV). Inorg. Chem. 1998, 37, 3975-3981. (b) Oloo, W.; Zavalij, P. Y.; Zhang, J; Khaskin, E.; Vedemikov, A. N. Preparation and C-X reductive eliminaion reactivity of monoaryl Pd IVX complexes in water (X = OH, OH2, Cl, Br) J. Am. Chem. Soc. 2010, 132, 14400-14402. (c) Abada, E.; Zavalij, P. Y.; Vedemikov, A. N. Reductive C(sp 2 -N elimination from isolated Pd(IV) amido aryl complexes prepared using H2O2 as oxidant J. Am. Chem. Soc. 2017, 139, 643-646.

[0102] Examples

[0103] Additional embodiments of the present disclosure are set forth in the following non-limiting examples.

[0104] General information. Pd(OAc)2, LiOAc, Ag2CO3, and sodium percarbonate (Na2CO3-1.5H2O2) were purchased from Sigma-Aldrich. Pd(CH3CN)4(BF4)2was purchased from Strem. 1-Fluoro-2,4,6-trimethylpyridinium hexafluorophosphate (TMSHFP) was purchased from TCI. Hexafluoroisopropanol (HFIP) was purchased from Oakwood. Unless otherwise noted, other reagents were purchased in the highest commercial quality and used without further purification. Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F254. Visualization was performed with short wave UV light or KMnO4and heat.1H NMR spectra were recorded on a Bruker DRX-600 instrument. tetrafluoroborate was purchased from TCI. Hexafluoroisopropanol (HFIP) was purchased from Oakwood. Unless otherwise noted, other reagents were purchased in the highest commercial quality and used without further purification. Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F254. Visualization was performed with short wave UV light or KMnO4and heat.1H NMR spectra were recorded on a Bruker DRX-600 instrument. 1 H NMR spectra. Chemical shifts are quoted in parts per million (ppm) with reference to 0.0 ppm for TMS. The following abbreviations (or combinations thereof) are used to designate multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Coupling constants J are reported in Hertz (Hz).1H NMR spectra were recorded on a Bruker DRX-600. 13C NMR spectra were fully decoupled by broadband proton decoupling. Chemical shifts were reported in ppm with reference to the center line of the triplet of CDCh at 77.16 ppm. Column chromatography was performed using E. Merck silica (60, particle size 0.043-0.063 mm) and preparative thin layer chromatography (pTLC) was performed on Merck silica plates (60 F-254). High-resolution mass spectra (HRMS) were recorded on an Agilent mass spectrometer using ESI-TOF (electrospray ionization-time of flight).

[0105] Preparation of aliphatic acids. Aliphatic carboxylic acids la to lw were obtained from commercial sources or synthesized according to literature procedures. 1-5

[0106] Preparation of mono-N-protected β-amino acid ligands. Ligands L5 to Ll 1 were commercially available or synthesized according to literature procedures. 6-9

[0107] General procedure for the cyclization C-H / C-H coupling reaction

[0108]

[0109] General procedure A: In a culture tube, Pd(OAc)2(10 mol%, 2.2 mg), ligand L9 (10 mol%, 1.7 mg), LiOAc (1.0 equiv, 6.6 mg), Na2C03-1.5 H20 (2.0 equiv, 31.4 mg) and 1 (0.1 mmol) were weighed in order in air and placed in a magnetic stir bar. Then HFIP (1.0 mL) was added. The reaction mixture was stirred at room temperature for 3 min and then heated to 60 °C for 12 h (600 rpm). After allowing it to cool to room temperature, the mixture was treated with HC02H (0.1 mL) and concentrated in vacuo. The crude mixture was purified by pTLC (hexane / EA and 1% AcOH) to give the product 2.

[0110] General procedure B: In a culture tube, Pd(CH3CN)4(BF4)2(10 mol%, 4.4 mg), Ag2C03(1.0 equiv, 27.4 mg), 1-fluoro-2,4,6-trimethylpyridine Tetrafluoroborate (2.0 eq, 45.4 mg), and 1 (0-1 mmol) and place in a magnetic stir bar. Then add HFIP (1.0 mL). Stir the reaction mixture at room temperature for 3 minutes, then heat to 90 °C for 12 hours (600 rpm). After allowing it to cool to room temperature, treat the mixture with HCO2H (0.1 mL), dilute with dichloromethane (DCM), filter through a plug of celite, and concentrate in vacuo. Purify the crude mixture by pTLC (hexanes / EA and 1% AcOH) to give product 2.

[0111] Example 1 : 2-Ethyl-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2a)

[0112]

[0113] Follow general procedure A on a 0.1 mmol scale. Purification by pTLC gave the title compound (colorless oil, 16.0 mg, 78% yield).

[0114] 1 H NMR (600 MHz, CDC13) δ 7.14 - 7.03 (m, 4H), 3.22 (d, J = 16.5 Hz, 1H), 2.92 - 2.83 (m, 1H), 2.83 - 2.75 (m, 1H), 2.67 (d, J = 16.5 Hz, 1H), 2.20 - 2.12 (m, 1H), 1.85 - 1.77 (m, 1H), 1.79 - 1.69 (m, 1H), 1.70 - 1.61 (m, 1H), 0.94 (t, J = 7.5 Hz, 3H).

[0115] 13 C NMR (150 MHz, CDC13) δ 182.5, 135.5, 134.9, 129.3, 128.8, 126.0, 125.9, 46.0, 36.6, 31.1, 30.1, 26.3, 8.9.

[0116] For C 13 H 15 O2 - [M-H] - HRMS (ESI-TOF) calcd for C12H13NO2: 203.1078; found: 203.1072.

[0117] Example 2: 2-Ethyl-7-methyl-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2b)

[0118]

[0119] Following general procedure A on 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 16.5 mg, 76% yield).

[0120] 1 H NMR (600 MHz, CDC13) δ 7.00 - 6.93 (m, 1H), 6.93 - 6.85 (m, 2H), 3.17 (d, J = 16.4 Hz, 1H), 2.87 - 2.78 (m, 1H), 2.78 - 2.70 (m, 1H), 2.63 (d, J = 16.4 Hz, 1H), 2.28 (s, 3H), 2.18 - 2.08 (m, 1H), 1.84 - 1.75 (m, 1H), 1.77 - 1.68 (m, 1H), 1.69 - 1.59 (m, 1H), 0.93 (t, J = 7.4 Hz, 3H).

[0121] 13 C NMR (150 MHz, CDC13) (major and minor rotamers) δ 182.8, 135.6, 135.6, 135.5, 134.8, 132.6, 132.0, 130.1, 129.6, 129.4, 128.9, 127.1, 127.0, 46.3, 46.2, 36.8, 36.5, 31.3, 31.3, 30.5, 30.3, 26.4, 26.1, 21.3, 9.1.

[0122] For C 14 H 17 O2 - [M-H] - HRMS (ESI-TOF) calcd for C12H13FNO2: 217.1234; found: 217.1232.

[0123] Example 3: 2-Ethyl-7-fluoro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2c)

[0124]

[0125] Following general procedure A on 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 16.5 mg, 76% yield).

[0126] 1H NMR (600 MHz, CDC13) δ 7.06 - 6.97 (m, 1H), 6.84 - 6.73 (m, 2H), 3.24 - 3.12 (m, 1H), 2.90 - 2.71 (m, 2H), 2.68 - 2.58 (m, 1H), 2.20 - 2.11 (m, 1H), 1.83 - 1.68 (m, 2H), 1.68 - 1.60 (m, 1H), 0.98 - 0.90 (m, 3H).

[0127] 13 C NMR (150 MHz, CDC13) (major rotamer) δ 182.2, 161.2 (d, J = 243.4 Hz), 136.9 (d, J = 7.2 Hz), 130.9 (d, J = 2.8 Hz), 130.1 (d, J = 8.2 Hz), 115.0 (d, J = 20.4 Hz), 113.1 (d, J = 21.3 Hz), 45.8, 36.6, 31.3, 30.3, 25.7, 8.9.

[0128] 13 C NMR (150 MHz, CDC13) (minor rotamer) δ 182.3, 161.2 (d, J = 243.4 Hz), 137.4 (d, J = 7.2 Hz), 130.5 (d, J = 7.8 Hz), 130.4 (d, J = 2.9 Hz), 115.4 (d, J = 20.8 Hz), 115.2 (d, J = 21.0 Hz), 46.1, 36.0, 31.2, 29.8, 26.5, 8.9.

[0129] For C 13 H 14 FO2 - [M-H] - HRMS (ESI-TOF) calcd for C7H7CIFNO2: 221.0983; found: 221.0990.

[0130] Example 4: 7-Chloro-2-ethyl-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2d)

[0131]

[0132] General procedure A was followed on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 14.5 mg, 61% yield).

[0133] 1H NMR (600 MHz, CDC13) δ 7.15 - 7.06 (m, 2H), 7.06 - 6.98 (m, 1H), 3.25 - 3.15 (m, 1H), 2.90 - 2.73 (m, 2H), 2.69 - 2.59 (m, 1H), 2.22 - 2.13 (m, 1H), 1.85 - 1.71 (m, 2H), 1.71 - 1.61 (m, 1H), 0.93 (t, J=7.5 Hz, 3H).

[0134] 13 C NMR (150 MHz, CDC13) (major and minor rotamers) δ 182.0, 182.0, 137.3, 136.8, 133.9, 133.4, 131.4, 131.4, 130.6, 130.1, 129.0, 128.6, 126.1, 126.1, 46.0, 45.8, 36.4, 36.1, 31.3, 31.3, 30.1, 29.9, 26.3, 25.8, 8.9.

[0135] For C 13 H 14 ClO2 - [M-H] - HRMS (ESI-TOF) calcd for CioH9NO2: 237.0688; found: 237.0684.

[0136] Example 5: 2-Ethyl-1,2,3,4-tetrahydrophenanthrene-2-carboxylic acid (2e)

[0137]

[0138] General procedure A was followed on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 13.3 mg, 52% yield).

[0139] 1 H NMR (600 MHz, CDC13) δ 7.92 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.45 - 7.40 (m, 1H), 7.20 (d, J=8.4 Hz, 1H), 3.35 (d, J=16.7 Hz, 1H), 3.23 - 3.12 (m, 2H), 2.82 (d, J=16.7 Hz, 1H), 2.36 - 2.29 (m, 1H), 1.99 - 1.91 (m, 1H), 1.83 - 1.74 (m, 1H), 1.74 - 1.66 (m, 1H), 0.97 (t, J=7.5 Hz, 3H).

[0140] 13 C NMR (151 MHz, CDCI3) δ 182.5, 132.3, 132.2, 132.1, 130.1, 128.6, 128.2, 126.3, 126.1, 125.0, 123.0, 45.7, 37.5, 30.9, 29.8, 23.2, 9.0.

[0141] For C 17 H 17 O2 - [M-H] - HRMS (ESI-TOF) calcd for C9H9FNO2: 189.0921 ; found: 189.0919.

[0142] Example 6: 2-Methyl-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2f)

[0143]

[0144] Following general procedure A on 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 12.5 mg, 66% yield).

[0145] 1 H NMR (600 MHz, CDCI3) δ 7.17-7.02 (m, 4H), 3.24 (d, J = 16.4 Hz, 1 H), 2.95-2.86 (m, 1 H), 287-2.78 (m, 1 H), 2.67 (d, J = 16.4 Hz, 1 H), 2.21 -2.13 (m, 1 H), 1.85-1.75 (m, 1 H), 1.32 (s, 3H).

[0146] 13 C NMR (150 MHz, CDCI3) δ 182.7, 135.1, 134.7, 129.4, 128.9, 126.0, 126.0, 41.6, 38.5, 31.8, 26.2, 24.4.

[0147] For C 12 H 13 O2 - [M-H] - HRMS (ESI-TOF) calcd for C9H9FNO2: 189.0921 ; found: 189.0919.

[0148] Example 7: 7-Fluoro-2-methyl-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2g)

[0149]

[0150] Following general procedure A on 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 11.0 mg, 53% yield).

[0151] 1 H NMR (600 MHz, CDC13) δ 7.06 - 6.99 (m, 1H), 6.84 - 6.74 (m, 2H), 3.26 - 3.14 (m, 1H), 2.93 - 2.74 (m, 2H), 2.67 - 2.57 (m, 1H), 2.22 - 2.12 (m, 1H), 1.81 - 1.72 (m, 1H), 1.31 (s, 3H).

[0152] 13 C NMR (150 MHz, CDC13) (major rotamer) δ 183.1, 161.2 (d, J = 243.6 Hz), 136.7 (d, J = 7.3 Hz), 130.5 (d, J = 1.8 Hz), 130.2 (d, J = 7.8 Hz), 115.4 (d, J = 20.8 Hz), 113.2 (d, J = 21.1 Hz), 41.5, 38.5, 31.9, 25.6, 24.5.

[0153] 13 C NMR (150 MHz, CDC13) (minor rotamer) δ 183.2, 161.2 (d, J = 243.6 Hz), 137.0 (d, J = 7.2 Hz), 130.6 (d, J = 6.2 Hz), 130.2 (d, J = 3.1 Hz), 115.0 (d, J = 20.5 Hz), 113.1 (d, J = 21.3 Hz), 41.7, 37.8, 31.5, 26.5, 24.5.

[0154] For C 12 H 12 FO2 - [M-H] - HRMS (ESI-TOF) calcd for C7H7FNO2: 207.0827; found: 207.0825.

[0155] Example 8: 2-Butyl-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2h)

[0156]

[0157] Following general procedure A on 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 11.0 mg, 53% yield).

[0158] 1 H NMR (600 MHz, CDC13) δ 7.13 - 7.03 (m, 4H), 3.22 (d, J = 16.4 Hz, 1H), 2.91 - 2.82 (m, 1H), 2.82 - 2.74 (m, 1H), 2.69 (d, J = 16.4 Hz, 1H), 2.20 - 2.10 (m, 1H), 1.87 - 1.77 (m, 1H), 1.73 - 1.63 (m, 1H), 1.63 - 1.55 (m, 1H), 1.35 - 1.23 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H).

[0159] 13 C NMR (150 MHz, CDC13) δ 181.4, 135.3, 134.7, 129.1, 128.6, 125.7, 125.7, 45.3, 37.9, 37.0, 30.2, 26.5, 26.1, 23.0, 13.9.

[0160] For C 15 H 19 O2 - [M-H] - HRMS (ESI-TOF) calcd for C12H15NO2: 205.1150; found: 205.1150.

[0161] Example 9: 1,2,3,4-Tetrahydronaphthalene-2-carboxylic acid (2i)

[0162]

[0163] General Procedure A was followed on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 11.5 mg, 65% yield).

[0164] 1 H NMR (600 MHz, CDC13) δ 7.17 - 7.03 (m, 4H), 3.11 - 2.97 (m, 2H), 2.95 - 2.84 (m, 2H), 2.84 - 2.75 (m, 1H), 2.29 - 2.20 (m, 1H), 1.96 - 1.83 (m, 1H)

[0165] 13 C NMR (150 MHz, CDC13) δ 181.7, 135.7, 134.7, 129.2, 129.0, 126.2, 126.0, 39.9, 31.5, 28.5, 25.8.

[0166] For C 11 H11 O2 - [M-H] - HRMS (ESI-TOF) calcd for C9H9NO2: 165.0701 ; found: 165.0707.

[0167] NMR data were in agreement with reported data 11

[0168] Example 10: 6-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2j)

[0169]

[0170] General procedure A was followed on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 12.0 mg, 58% yield).

[0171] 1 H NMR (600 MHz, CDC13) δ 7.02 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.63 (s, 1H), 3.77 (s, 3H), 3.05-2.93 (m, 2H), 2.91-2.83 (m, 2H), 2.82-2.73 (m, 1H), 2.29-2.19 (m, 1H), 1.94-1.82 (m, 1H).

[0172] 13 C NMR (150 MHz, CDC13) δ 181.2, 157.9, 136.8, 130.1, 126.8, 113.6, 112.4, 554, 40.1, 30.7, 28.8, 25.7.

[0173] For C 12 H 13 O3 - [M-H] - HRMS (ESI-TOF) calcd for C9H9NO2: 165.0701 ; found: 165.0707.

[0174] Example 11 : 5-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2k)

[0175]

[0176] General procedure A was followed on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 12.0 mg, 58% yield).

[0177] 1 ​H NMR (600 MHz, CDC13) δ 7.10 (t, J = 7.9 Hz, 1H), 6.72 (d, J = 7.7 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 3.82 (s, 3H), 318-3.08 (m, 1H), 2.93-2.80 (m, 2H), 2.79-2.70 (m, 2H), 2.25-2.18 (m, 1H), 1.92-1.78 (m, 1H).

[0178] 13 C NMR (150 MHz, CDC13) δ 179.1, 157.5, 137.1, 126.4, 123.7, 121.1, 107.2, 55.4, 39.4, 28.7, 25.6, 25.4.

[0179] For C 12 H 13 O3 - [M-H] - HRMS (ESI-TOF) calcd for C9H10FNO2: 205.0870; found: 205.0869.

[0180] Example 12: 7-Fluoro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (21)

[0181]

[0182] Following general procedure A on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 10.9 mg, 56% yield).

[0183] 1 H NMR (600 MHz, CDC13) δ 7.11-7.03 (m, 1H), 691-6.78 (m, 2H), 3.12-2.96 (m, 2H), 2.95-2.88 (m, 1H), 2.87-2.76 (m, 2H), 2.33-2.21 (m, 1H), 1.97-1.87 (m, 1H).

[0184] 13 C NMR (150 MHz, CDC13) (major rotamer) δ 180.7, 161.2 (d, J = 243.7 Hz), 139.6 (d, J = 7.4 Hz), 131.2 (d, J = 2.7 Hz), 130.3 (d, J = 8.2 Hz), 115.3 (d, J = 20.6 Hz), 113.3 (d, J = 21.4 Hz), 39.5, 31.4, 27.8, 25.8.

[0185] 13 C NMR (150 MHz, CDC13) δ 180.8, 161.3 (d, J = 244.2 Hz), 137.6 (d, J = 73 Hz), 130.5 (d, J = 7.8 Hz), 130.2 (d, J = 2.8 Hz), 115.1 (d, J = 20.7 Hz), 113.2 (d, J = 21.1 Hz), 39.7, 30.8, 28.6, 25.4.

[0186] For C 11 H 10 FO2 - [M-H] - HRMS (ESI-TOF) calcd for C7H7FNO2 [M-H]: 163.0502; found: 163.0502.

[0187] Example 13: 3-methylchromane-3-carboxylic acid (2m)

[0188]

[0189] The title compound was obtained as colorless oil (13.0 mg, 68% yield) following General Procedure A on 0.1 mmol scale. Purification by pTLC.

[0190] 1 H NMR (600 MHz, CDC13) δ 7.15 - 7.08 (m, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.91 - 6.85 (m, 1H), 6.83 (d, J = 8.2 Hz, 1H), 4.31 (dd, J = 10.8, 1.4 Hz, 1H), 3.95 (d, J = 10.8 Hz, 1H), 3.27 (d, J = 16.4 Hz, 1H), 2.70 (d, J = 16.4 Hz, 1H), 1.34 (s, 3H).

[0191] 13 C NMR (150 MHz, CDC13) δ 180.7, 153.5, 130.0, 127.7, 121.1, 120.1, 116.8, 71.0, 40.8, 34.5, 21.1.

[0192] For C 11 H 11 O3 - [M-H] - HRMS (ESI-TOF) calcd for C7H7FNO2 [M-H]: 163.0502; found: 163.0502.

[0193] NMR data were in agreement with reported data. 12 ​

[0194] Example 14: 7-(tert-butyl)-3-methylchromane-3-carboxylic acid (2n)

[0195]

[0196] General procedure A was followed on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 20.0 mg, 80% yield, 2n / 2n’ = 3 / 1).

[0197] 1 H NMR (600 MHz, CDC13) δ 6.99 (d, J = 8.0 Hz, 1H), 6.92 (dd, J = 8.0, 2.0 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 4.29 (dd, J = 10.8, 1.4 Hz, 1H), 3.93 (dd, J = 10.8, 1.4 Hz, 1H), 3.24 (d, J = 16.3 Hz, 1H), 2.66 (d, J = 16.3 Hz, 1H), 1.34 (s, 3H), 1.28 (s, 9H).

[0198] 13 C NMR (150 MHz, CDC13) δ 180.8, 153.0, 151.2, 129.4, 118.4, 117.0, 113.7, 71.0, 40.9, 34.6, 34.1, 31.4, 21.2.

[0199] For C 15 H 19 O3 - [M-H] - HRMS (ESI-TOF) calcd for C15H21NO3: 247.1340; found: 247.1339.

[0200] Example 15: 5-(tert-butyl)-3-methylchromane-3-carboxylic acid (2n’)

[0201]

[0202] 1 H NMR (600 MHz, CDC13) δ 7.05 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 4.37 (d, J = 10.5 Hz, 1H), 3.91 (d,.J = 10.5 Hz, 1H), 3.51 (d, J = 16.0 Hz, 1H), 2.90 (d, J = 16.0 Hz, 1H), 1.42 (s, 9H), 1.35 (s, 3H).

[0203] 13 C NMR (150 MHz, CDC13) δ 181.2, 151.1, 136.7, 126.5, 125.4, 121.6, 116.2, 70.9, 40.7, 34.5, 29.6, 23.1, 23.0, 22.9, 21.1.

[0204] For C 15 H 19 O3 - [M-H] - HRMS (ESI-TOF) calcd for C9H9NO2 [M-H]: 165.0647; found: 165.0647.

[0205] Example 16: 3-Methyl-3,4,7,8,9,10-hexahydro-2H-benzo[h]chromene-3-carboxylic acid (2o)

[0206]

[0207] Following general procedure A on 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 21.0 mg, 85% yield).

[0208] 1 H NMR (600 MHz, CDC13) δ 6.81 (d, J = 7.8 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 4.29 (d, J = 10.8 Hz, 1H), 3.96 (d, J = 10.8 Hz, 1H), 3.23 (d, J = 16.3 Hz, 1H), 2.70 (t, J = 5.8 Hz, 2H), 2.65 (d, J = 16.3 Hz, 1H), 2.64-2.58 (m, 2H), 1.80-1.69 (m, 4H), 1.33 (s, 3H).

[0209] 13 C NMR (150 MHz, CDC13) δ 181.2, 151.1, 136.7, 126.5, 125.4, 121.6, 116.2, 70.9, 40.7, 34.5, 29.6, 23.1, 23.0, 22.9, 21.1.

[0210] For C 15 H 17 O3 - [M-H] - HRMS (ESI-TOF) calcd for C9H9NO2 [M-H]: 165.0647; found: 165.0647.

[0211] Example 17: 8-benzyl-3-methylchromane-3-carboxylic acid (2p)

[0212]

[0213] Following General Procedure A on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 20.0 mg, 70% yield).

[0214] 1 H NMR (600 MHz, CDC13) δ 7.27-7.20 (m, 2H), 7.19 (d, J = 7.5 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 7.4 Hz, 1H), 6.80 (t, J = 7.5 Hz, 1H), 4.31 (d, J = 10.7 Hz, 1H), 4.03-3.88 (m, 3H), 3.28 (d, J = 16.4 Hz, 1H), 2.71 (d, J = 16.4 Hz, 1H), 1.34 (s, 3H).

[0215] 13 C NMR (150 MHz, CDC13) δ 180.5, 151.2, 141.1, 129.1, 129.0, 128.5, 128.4, 128.1, 125.9, 120.7, 119.9, 71.0, 40.7, 35.7, 34.7, 21.0.

[0216] For C 18 H 17 O3 - [M-H] - HRMS (ESI-TOF) calcd for C17H17NO3: 281.1183; found: 281.1184.

[0217] Example 18: 8-bromo-3-methylchromane-3-carboxylic acid (2q)

[0218]

[0219] Following General Procedure A on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 8.5 mg, 31% yield).

[0220] 1H NMR (600 MHz, CDC13) δ 7.36 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.76 (t, J = 7.8 Hz, 1H), 4.41 (d, J = 10.8 Hz, 1H), 4.07 (d, J = 10.8 Hz, 1H), 3.29 (d, J = 16.4 Hz, 1H), 2.72 (d, J = 16.4 Hz, 1H), 1.36 (s, 3H).

[0221] 13 C NMR (151 MHz, CDC13) δ 179.8, 150.1, 131.5, 129.2, 121.9, 110.9, 71.7, 40.7, 34.6, 21.0 (one carbon signal not assigned due to overlap).

[0222] For C 11 H 10 BrO3 - [M-H] - HRMS (ESI-TOF) calcd for C7H7BrNO3: 268.9819; found: 268.9820.

[0223] Example 19: 3-Methyl-8-(trifluoromethyl)xanthane-3-carboxylic acid (2r)

[0224]

[0225] Following general procedure A on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 6.0 mg, 23% yield).

[0226] 1 H NMR (600 MHz, CDC13) δ 7.36 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.76 (t, J = 7.8 Hz, 1H), 4.41 (d, J = 10.8 Hz, 1H), 4.07 (d, J = 10.8 Hz, 1H), 3.29 (d, J = 16.4 Hz, 1H), 2.72 (d, J = 16.4 Hz, 1H), 1.36 (s, 3H).

[0227] 13 C NMR (150 MHz, CDC13) δ 179.5, 151.6, 133.8, 125.4 (q, J = 5.4 Hz), 123.7 (q, J = 272.3 Hz), 121.6, 120.2, 118.2 (q, J = 30.9 Hz), 71.2, 40.3, 34.3, 21.0.

[0228] For C 12 H 10 F3O3 - [M-H] - HRMS (ESI-TOF) calcd for C9H9F3O3: 207.0663; found: 207.0660.

[0229] Example 20: (R)-7-methoxychromane-3-carboxylic acid (2s)

[0230]

[0231] General Procedure A was followed on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 15.0 mg, 72% yield).

[0232] 1 H NMR (600 MHz, CDC13) δ 6.98 (d, J = 8.4 Hz, 1H), 6.49 (dd, J = 8.4, 2.6 Hz, 1H), 6.39 (d, J = 2.6 Hz, 1H), 4.47-4.40 (m, 1H), 4.21-4.14 (m, 1H), 3.75 (s, 3H), 3.10-3.04 (m, 1H), 3.03-2.96 (m, 2H),

[0233] 13 C NMR (150 MHz, CDC13) δ 176.8, 159.4, 154.8, 130.3, 112.1, 108.1, 101.7, 66.3, 55.5, 38.4, 26.8.

[0234] For C 11 H 11 O4 - [M-H] - HRMS (ESI-TOF) calcd for C9H9F3O3: 207.0663; found: 207.0660.

[0235] Example 21: 2-ethyl-2,3-dihydro-lH-indene-2-carboxylic acid (2u)

[0236]

[0237] General Procedure A was followed on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 15.0 mg, 72% yield).

[0238] 1H NMR (600 MHz, CDC13) δ 7.21 - 7.16 (m, 2H), 7.16 - 7.11 (m, 2H), 3.48 (d, J = 16.2 Hz, 2H), 2.92 (d, J = 16.2 Hz, 2H), 1.83 (q, J = 7.2 Hz, 2H), 0.94 (t, J = 7.2 Hz, 3H).

[0239] 13 C NMR (150 MHz, CDC13) δ 182.3, 141.4, 126.7, 124.6, 54.7, 41.8, 31.5, 10.0.

[0240] For C 12 H 13 O2 - [M-H] - HRMS (ESI-TOF) calcd for C9H10NO2: 159.0748; found: 159.0748.

[0241] Example 22: 2,4-Dimethyl-2,3-dihydro-lH-indene-2-carboxylic acid (2v)

[0242]

[0243] General Procedure B was followed on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 11.5 mg, 61% yield).

[0244] 1 H NMR (600 MHz, CDC13) δ 7.08 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 3.53 (d, J = 15.9 Hz, 1H), 3.43 (d, J = 16.0 Hz, 1H), 2.86 (d, J = 15.9 Hz, 1H), 2.80 (d, J = 16.0 Hz, 1H), 2.24 (s, 3H), 1.41 (s, 3H).

[0245] 13 C NMR (150 MHz, CDC13) δ 184.2, 141.0, 140.0, 134.2, 127.6, 127.0, 122.1, 49.0, 44.2, 42.8, 25.4, 19.2.

[0246] For C 12 H 13 O2 - [M-H] -HRMS (ESI-TOF) calcd for C9H9NO2S: 205.0478; found: 205.0479.

[0247] Example 23: 2-Methyl-2,3-dihydro-lH-indene-2-carboxylic acid (2w)

[0248]

[0249] Following general procedure B on a 0.1 mmol scale. Purification by pTLC afforded the title compound (colorless oil, 8.0 mg, 48% yield).

[0250] 1 H NMR (600 MHz, CDC13) δ 7.23 - 7.18 (m, 2H), 7.18 - 7.14 (m, 2H), 3.52 (d, J=15.8 Hz, 2H), 2.85 (d, J=15.8 Hz, 2H), 1.41 (s, 3H).

[0251] 13 C NMR (150 MHz, CDC13) δ 182.5, 141.2, 126.8, 124.8, 49.5, 44.0, 25.0.

[0252] For C 11 H 11 O2 - [M-H] - HRMS (ESI-TOF) calcd for C9H9NO2S: 205.0478; found: 205.0479.

[0253] NMR data were in agreement with reported data. 13

[0254] Example 24: Total synthesis of (±)-russujaponol F

[0255]

[0256] To a solution of 3 (1.0 mmol, 164 mg) in EtOH (5.0 mL) was added SOCl2(2.0 eq, 0.15 mL) at 0 °C, then the mixture was stirred at reflux overnight. After allowing it to cool to room temperature, the mixture was concentrated under vacuum to give the corresponding ethyl ester. Following literature procedure 10 ​To a solution of the ethyl ester in CH3CN (10.0 mL) was added I2(0.5 equiv, 127 mg) and the selected fluorinating reagent (0.5 equiv, 177 mg) with slight modification and the mixture was stirred at 60 °C for 3 h. After allowing it to cool to room temperature, the mixture was diluted with EA, washed with saturated Na2S203, and concentrated in vacuo. The crude mixture was purified by column chromatography to give the iodinated product 4 (250 mg, 79% yield).

[0257] 2-(3-iodo-2,6-dimethylphenyl)ethyl acetate (4)

[0258]

[0259] 1 H NMR (600 MHz, CDC13) δ 7.65 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.75 (s, 2H), 2.48 (s, 3H), 2.29 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H),

[0260] 13 C NMR (150 MHz, CDC13) δ 171.0, 139.9, 138.1, 137.8, 133.0, 129.8, 99.7, 61.1, 37.1, 26.0, 20.5, 14.3.

[0261] For C 12 H 16 IO2 + [M+H] + HRMS (ESI-TOF) calcd for C12H13IO2: 319.0189; found: 319.0196.

[0262]

[0263] In a culture tube, Pd(OAc)2(10 mol%, 2.2 mg), ligand L12(10 mol%, 2.0 mg), CsOAc (1.0 equiv, 19.2 mg), Ag2CO3(2.0 equiv, 55.1 mg), pivalic acid (3.0 equiv, 30.6 mg), and 4 (0.1 mmol, 31.8 mg) were weighed in sequence in air and placed in a magnetic stir bar. HFIP (1.0 mL) was then added. The reaction mixture was stirred at room temperature for 3 min and then heated to 80 °C for 12 h (600 rpm). After allowing it to cool to room temperature, the mixture was treated with HCO2H (0.1 mL), diluted with DCM, filtered through a plug of celite, and concentrated in vacuo. The crude mixture was purified by pTLC (hexanes / EA) to give the arylation product 5 (18.0 mg, 62% yield) and product 6 (3.5 mg, 12% yield).

[0264] 3-(3-(2-ethoxy-2-oxoethyl)-2,4-dimethylphenyl)-2,2-dimethylpropanoic acid (5)

[0265]

[0266] 1 H NMR (600 MHz, CDC13) δ 6.99 (d, J = 7.9 Hz, 1H) 6.96 (d, J = 7.9 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.70 (s, 2H), 2.99 (s, 2H), 2.30 (s, 3H), 226 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H), 1.19 (s, 6H).

[0267] 13 C NMR (150 MHz, CDC13) δ 183.1, 171.6, 136.5, 135.7, 134.0, 132.5, 130.1, 127.5, 60.9, 44.1, 42.3, 36.2, 27.3, 24.7, 20.7, 17.0, 14.4.

[0268] For C 17 H 23 O4 - [M-H] - HRMS (ESI-TOF) calcd for C21H27NO4: 355.2081; found: 355.2083.

[0269]

[0270] In a culture tube, Pd(CH3CN)4(BF4)2(10 mol%, 2.2 mg), Ag2CO3(1.0 equiv, 13.8 mg), 1-fluoro-2,4,6-trimethylpyridinium Tetrafluoroborate (2.0 equiv, 22.7 mg) and 5 (0.05 mmol, 14.6 mg) were added in order and a magnetic stir bar was added. HFIP (0.5 mL) was then added. The reaction mixture was stirred at room temperature for 3 minutes and then heated to 90 °C for 12 hours (600 rpm). After allowing it to cool to room temperature, the mixture was treated with HCO2H (0.05 mL), diluted with DCM, filtered through a plug of celite, and concentrated in vacuo. The crude mixture was purified by pTLC (hexanes / EA) to give product 6 (6.0 mg, 41% yield).

[0271] 5-(2-ethoxy-2-oxoethyl)-2,4,6-trimethyl-2,3-dihydro-1H-indene-2-carboxylic acid (6)

[0272]

[0273] 1 H NMR (600 MHz, CDC13) δ 6.90 (s, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.66 (s, 2H), 3.49 (d, J = 16.0 Hz, 1H), 3.44 (d, J = 16.0 Hz, 1H), 2.81 (d, J = 16.0 Hz, 1H), 2.80 (d, J = 16.0 Hz, 1H), 2.30 (s, 3H), 2.21 (s, 3H), 1.41 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0274] 13 C NMR (150 MHz, CDC13) δ 181.9, 171.7, 139.7, 138.3, 136.0, 133.3, 130.0, 124.1, 60.9, 48.8, 44.2, 43.5, 35.4, 25.5, 20.8, 16.5, 14.4.

[0275] For C 17 H 21 O4 - [M-H] - HRMS (ESI-TOF) calcd for C17H21NO4: 289.1445; found: 289.1447.

[0276]

[0277] In a culture tube, LAH (3.0 equivalents, 1.0 M in THF, 0.06 mL) was added to a solution of 6 (0.02 mmol, 6.0 mg) of THF (1.0 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight at room temperature. The mixture was diluted with diethyl ether, washed with saturated NH4Cl, and concentrated under vacuum. The crude mixture was purified by pTLC (hexane / EA) to give (±)-russujaponol F (4.5 mg, 96% yield). NMR data are consistent with reported data. 14，15 Consistent.

[0278]

[0279] 1 H NMR (600MHz, CDCl3) δ6.87 (s, 1H), 3.74 (t, J=7.4Hz, 2H), 3.52 (s, 2H), 2.95 (t, J=7.5Hz, 2H), δ2.88 (d, J=15.9Hz, 1 H), 2.84 (d, J=15.9Hz, 1H), 2.63 (d, J=15.9Hz, 1H), 2.59 (d, J=15.9Hz, 1H), 2.32 (s, 3H), 2.22 (s, 3H), 1.18 (s, 3H).

[0280] 13 C NMR (150MHz, CDCl3) δ140.3, 139.8, 135.4, 133.2, 132.3, 124.4, 71.1, 62.1, 44.3, 43.1, 42.4, 32.9, 24.6, 20.6, 16.3.

[0281] For C 15 H 21 O2 - [MH] - The calculated HRMS (ESI-TOF) value is 233.1547; the measured value is 233.1544.

[0282] The references numbered throughout the above embodiments are as follows:

[0283] 1. Park, H.; Chekshin, N.; Shen, P.-X.; Yu, J.-Q. Ligand-enabled, palladium-catalyzedβ-C(sp3)-Harylation of weinreb amides. ACS Catal. 2018, 8, 9292-9297.

[0284] 2. Shen, P.-x.; Hu, L.; Shao, Q.; Hong, K.; Yu, J.-Q. Pd(II)-catalyzed enantioselective C(sp3)-H arylation of free carboxylic acids. J. Am. Chem. Soc. 2018, 140, 6545-6549.

[0285] 3. Fillion, E; Dumas, A. Synthesis of fused 4,5-disubstituted indole ring systems by intramolecular Friedel-Crafts acylation of 4-substituted indoles, J. Org. Chem. 2008, 73, 2920-2923.

[0286] 4. Quach, T. D.; Batey, R. A. Copper(II)-catalyzed ether synthesis from aliphatic alcohols and potassium organotrifluoroborate salts. Org. Lett. 2003, 5, 1381-1384.

[0287] 5. Ikeda, K.; Achiwa, K.; Sekiya, M. Trifluoromethanesulfonic acid-promoted reaction or hexahydro-1,3,5-triazines. Introduction of a secondary aminomethyl group into carboxylates at the a-position through ketene silyl acetals. Chem. Pharm. Bull. 1986, 34, 1579-1583.

[0288] 6. Hong, K.; Park, H; Yu, J.-Q. Methylene C(sp3)-H arylation of aliphatic ketones using a transient directing group. ACS Catal. 2017, 7, 6938-6941.

[0289] 7. Naturale, G.; Lamblin, M.; Commandeur, C; Felpin, F.-X.; Dessolin, J. Direct C-H alkylation of naphthoquinones with amino acids through a revisited Kochi-Anderson radical decarboxylation; trends in reactivity and applications. Eur. J. Org, Chem. 2012, 5774-5788.

[0290] 8. Dener, J. M.; Fantauzzi,. P. P.; Kshirsagar, T. A.; Kelly, D. E.; Wolfe, A. B. Large-scale syntheses of FMOC-protected non-proteogenic amino acids; useful building blocks for combinatorial libraries. Org. Process Res. Dev. 2001, 54, 445-449.

[0291] 9. F. M. Palko, J, Kaman, L. Lazar, R, Synthesis of all fourenantiomers of 1-aminoindane-2-carboxylic acid, a new cispentacin benzologue. Tetrahedron: Asymmetry 2000, 11, 4179-4187.

[0292] 10. Stavber, S.; Kralj, P.; Zupan, M. Selective and effective iodination of alkyl-substituted benzenes with elemental iodine activated by Selectfluor™ F-TEDA-BF4. Synlett 2002, 598-600.

[0293] 11. Seo, H.; Liu, A.; Jamison, T. F. Direct β-selective hydrocarboxylation of styrenes with CO2 enabled by continuous flow photoredox catalysis. J. Am. Chem. Soc. 2017, 139, 13969-13972,

[0294] 12. Feng, Y. et al. Benzopyrans and analogs as Rho kinase inhibitors and their preparation and use in the treatment of Rho kinase-mediated diseases. pCT Int. Appl., 2009079008, 25 Jun 2009.

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[0296] 14. Melot, R.; Craveiro, M.; Bϋrgi, T.; Baudoin, O. Divergent enantioselective synthesis of (nor)illudalabe sesquiterpenes via Pd0-catalyzed asymmetric C(sp3)-H activation. Org. Lett. 2019, 21, 812-815.

[0297] 15. Melot, R.; Craveiro, M. V.; Baudoin, O. Total synthesis of (nor)illudalane sesquiterpenes based on a C(sp3)-H activation strategy. J. Org. Chem. 2019, 84, 12933-12945.

Claims

1. A method for preparing a compound of Formula (2): comprising contacting a compound of Formula (1): with a ligand of Formula (L): in the presence of a palladium (II) source and an oxidizing agent, thereby forming the compound of Formula (2), wherein: X is CH2or O; n is an integer selected from 0 and 1; o and m are integers independently selected from 0, 1, and 2, wherein the sum of o and m is not greater than 4; x and y are integers independently selected from 0 and 1; z is an integer selected from 0, 1, and 2; R 1 selected from H and C1-C6-alkyl; Each R 2 and R 3 Independently selected from C1-C6-alkyl, C1-C6-alkoxy, halogen, C1-C6-haloalkyl and (C6-C 10 -aryl)(C1-C6-alkyl)-; or adjacent R 2 and R 3 together with the carbon atom to which they are bonded form a fused C5-C6-cycloalkyl or phenyl; and Each R 4 and R 5 Independently selected from H, C1-C6-alkyl and (C6-C 10 -aryl)(C1-C6-alkyl)-; or, when z is 1, then R 4 and R 5 together with the carbon atom to which they are bonded form a 5- to 6-membered cycloalkyl, wherein said cycloalkyl is optionally substituted with 1 to 2 substituents selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-alkoxy and C6-C 10 -aryl.

2. The method of claim 1, wherein X is CH2.

3. The method of claim 1, wherein X is O.

4. The method of any one of claims 1 to 3, wherein n is 0.

5. The method of any one of claims 1 to 3, wherein n is 1.

6. The method of claim 1, wherein the compound of Formula (2) is selected from one of the following tables:

7. The method of any one of claims 1 to 6, wherein z is 1.

8. The method of any one of claims 1 to 7, wherein one of x and y is 0 and the other is 1.

9. The method of any one of claims 1 to 7, wherein R 4 and R 5 together with the carbon atom to which they are bound form a 5- to 6-membered cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 to 2 substituents selected from the group consisting of halogen, Ci-C6-alkyl, Ci-C6-alkoxy and C6-Ci4-aryl, in addition to the shown -NHAc and -CO2H substituents. 10 - 1 to 2 substituents in the aryl group.

10. The method of any one of claims 1 to 7 and 9, wherein R 4 and R 5 together with the carbon atom to which they are bound form a 5-membered cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 to 2 substituents selected from the group consisting of halogen, Ci-C6-alkyl, Ci-C6-alkoxy and C6-Ci4-aryl in addition to the shown -NHAc and -CO2H substituents. 10 -aryl.

11. The method of any one of claims 1 to 7, wherein the ligand of Formula (L) is selected from one of the following tables:

12. The method of claim 11, wherein the ligand of Formula (L) is L9:

13. The method of any one of claims 1 to 12, wherein the ligand of Formula (L) is present in an amount of about 1 mol% to about 15 mol%, based on the amount of compound of Formula (2).

14. The method of any one of claims 1 to 13, wherein the ligand of Formula (L) is present in an amount of about 7 mol% to about 12 mol%.

15. The method of any one of claims 1 to 14, wherein the ligand of Formula (L) is present in an amount of about 10 mol%.

16. The method of any one of claims 1 to 15, wherein the palladium (II) source is selected from Pd(OAc)2and Pd(CH3CN)4(BF4)2.

17. The method of any one of claims 1 to 16, wherein the palladium (II) source is present in an amount of about 1 mol% to about 15 mol%, based on the amount of compound of Formula (2).

18. The method of any one of claims 1 to 17, wherein the palladium (II) source is present in an amount of about 7 mol% to about 12 mol%.

19. The method of any one of claims 1 to 18, wherein the palladium (II) source is present in an amount of about 10 mol%.

20. The method of any one of claims 1 to 19, wherein the oxidizing agent is sodium percarbonate.

21. The method of any one of claims 1 to 20, further comprising performing the contacting in the presence of LiOAc.

22. The method of any one of claims 1 to 21, further comprising performing the contacting in the presence of hexafluoroisopropanol.

23. The method of claim 1, wherein the ligand of Formula (L) is (L9) present in an amount of about 10 mol%. ​ the sum of o and m is 1 or 2; the source of palladium (II) is Pd(OAc)2 in an amount of about 10 mol %; and the oxidizing agent is sodium percarbonate.

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