CH insertion process by geminal hydrogenation of internal alkynes

Abstract

The present invention relates to a CH insertion process by gem-hydrogenation of internal alkynes.

Description

[Technical field]

[0001] The present invention relates to a CH insertion process by gem-hydrogenation of internal alkynes. [Background technology]

[0002] The ability to transfer both H atoms of H2 to the same C atom of an internal alkyne is a fundamentally new reaction mode. This leads to the formation of metal carbenes flanked by methylene groups, which can react in various ways. Recently, during the application of hydrogen metathesis to the total synthesis of the marine natural product sinularone F, C-H insertion was observed as another possibility for the evolution of a transient carbene (Fig. 1A) (Peil, S. (2021). Anwendungen der geminalen Hydrierung von Alkinen; PhD Thesis, Technische Universitaet, Dortmund). However, such undesired side reactions are only violated when the carbene complex D, as in 1, bears adjacent ketone groups; even adjacent esters or amides are insufficient to increase the electrophilicity of the intermediate to the required degree; these compounds are simply reduced to alkenes or alkanes. On the other hand, certain piano stalled ruthenium carbenes generated by a completely different route, namely carbene / alkyne metathesis (CAM) (Fuerstner et al, J. Am. Chem. Soc. 2020, 142, 18541-18553), can be inserted in moderate to good yields into secondary or tertiary C-H bonds of appropriately placed acetals and ethers; insertion into primary C-H bonds has not been described. If putative E-type vinyl carbenes could be generated by gem-hydrogenation, the use of hazardous diazoalkanes could be avoided altogether. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Peil, S. (2021).Anwendungen der geminalen Hydrierung von Alkinen; PhD Thesis, Technische Universitaet, Dortmund [Non-Patent Document 2] Fuerstner et al, J. Am. Chem. Soc. 2020, 142, 18541-18553 [Non-Patent Document 3] DN Prada Gori et al,JOC 2018, 83, 12798-12805 [Non-Patent Document 4] BM Trost et al, JACS 2016, 138, 2981-2984 Summary of the Invention [Problem to be solved by the invention]

[0004] With such preliminary data, the chances were limited, and the goal of establishing a reasonably general hydrogenation-CH insertion protocol seemed (overly) ambitious. Furthermore, 1,3-eneynes were not readily accessible to [Cp * It is known that aryloxycarbonyl ethers bind very tightly to the [Ru]-fragment and have therefore proven problematic substrates in the past in various other reactions effected by such catalysts. Therefore, it was entirely unclear whether they could be suitably used in gem-hydrogenation reactions. Not only did this prove to be the case, but subsequent C-H insertion reactions turned out to be truly possible. Most notably, these reactions allowed access to (spirocyclic) building blocks of immediate relevance to medicinal chemistry. In parallel, the mechanistic information gleaned has brought the understanding of this type of transformation to a new level.

[0005] Based on these considerations, the present inventors have surprisingly succeeded in providing a process for the gem-hydrogenation of internal alkynes. The present inventors have found that in the case of 1,3-eneynes bearing propargyl-type steering substituents as substrates, the gem-hydrogenation reaction occurs regioselectively to give vinyl carbene complexes as reactive intermediates. The vinyl carbene complexes can be inserted into primary, secondary, or tertiary C-H bonds on the steering group itself or on other appropriately placed ether, acetal, orthoester, amide, sulfonamide, or carbamate substituents.

[0006] For example, structurally related products consisting of five-membered carbocycles or heterocycles bearing olefinic side chains have been prepared by mechanistically distinct routes, as described in DN Prada Gori et al, JOC 2018, 83, 12798-12805 and BM Trost et al, JACS 2016, 138, 2981-2984.

[0007] DN Prada Gori and co-workers describe the metathesis of enynes catalyzed by the classical Hoveyda-Grubbs catalyst, followed by partial reduction of the predominantly formed products. The transformation described by Gori is formally a reductive cyclization reaction, but it uses triethylsilane as the reducing agent, which differs from the hydrogenative CH functionalization reactions described herein, which always use hydrogen gas (or an isotope such as deuterium) but not silane. Thus, the process is not only mechanistically different, but also fundamentally mild and atom economical.

[0008] BM Trost et al. describe the reactions shown in Table 2, which require a diene substrate in which one of the alkene groups is part of an allyl chloride. The reaction described by BM Trost et al. is a classical "metallo-ene" reaction involving an allyl ruthenium intermediate formed by oxidative insertion of a catalyst into the allyl chloride, which acts as a leaving group, but is discarded because the leaving group is lost. In contrast, the transformation in the present patent application is proposed to involve a ruthenium carbene intermediate formed by a reductive step (hydrogenation) and is therefore mechanistically fundamentally different.

[0009] None of the processes disclosed in said prior art documents are relevant to the present application and no compounds as disclosed herein are prepared in said prior art documents. [Means for solving the problem]

[0010] More particularly, the present invention relates to a method for C-H insertion by gem-hydrogenation of internal alkynes, The compound of formula (I) is hydrogenated in the presence of a Ru catalyst in an organic solvent, thereby obtaining a compound of formula (II): [ka]

[0011] Here, in formulas (I) and (II), - R 1 and R 2 Each independently represents: Hydrogen, optionally with R 1 , R 2 at least one of is not hydrogen; 〇 Si(C1~C 12 Alkyl)3, C(=O)-O-(C1-C 12 alkyl), or 〇 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, Here, R 1 and R 2may form a ring system together via an alkyl or heteroalkyl; - R 3 and R 4 each independently represents: 〇 OSi(C1~C 12 Alkyl)3, C(=O)-O-(C1-C 12 alkyl); or 〇 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, Here, R 3 and R 4 may form a ring system together via an alkyl or heteroalkyl; - R 5 and R 6 each independently represents: Hydrogen, deuterium, 〇 O(C1~C 12 Alkyl), C(=O)-(C1-C 12 Alkyl), C(=O)-O-(C1-C 12 alkyl), 〇NR N1 R N2 , where R N1 is an arylsulfonyl group, (C1-C 12 ) alkylsulfonyl group, (C1-C 12 ) alkoxycarbonyl group, or -C(=O)-(C1-C 12 alkyl), R N2 C1~C 12 represents an alkyl group, or R N1 and R N2 are C1 to C 12 represents an alkyl group, or 〇 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, Here, R 5 and R 6 may form a ring system together via an alkyl or heteroalkyl; - where R1 and R2 do not form a ring system together, R2 and R 3 can form a ring system with each other, and / or, when R and R do not form a ring with each other, R 4 and R 5 can form a ring system with each other; - Here, Q is CH2, CH(C1-C 12 Alkyl), C(C1-C 12 alkyl)2, O or NR N where R N is an arylsulfonyl group, (C1-C 12 ) alkylsulfonyl group, (C1-C 12 ) alkoxycarbonyl group or -C(=O)-(C1-C 12 alkyl), - However, Q is CH2, CH(C1~C 12 alkyl), or C(C1-C 12 alkyl)2, R 4 and R 5 are each independently, (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, and O or NR N and R form a ring system. N is an arylsulfonyl group, (C1-C 12 ) alkylsulfonyl group, (C1-C 12 ) alkoxycarbonyl group or -C(=O)-(C1-C 12 alkyl), R 3 is (C1~C 12 )Alkyl, Hetero(C1-C 12 ) alkyl or OSi(C1-C 12 alkyl)3, R 6 is hydrogen, deuterium, (C1-C 12 ) alkyl or hetero(C1-C 12 ) alkyl, and R 1 , R 2 , each independently representing: Hydrogen, optionally with R 1 , R 2 at least one of is not hydrogen; 〇 Si(C1~C 12 Alkyl)3, C(=O)-O-(C1-C 12 alkyl), or 〇 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, Here, the Ru catalyst is represented by formula (III): [ka] Here, R cp1 ~R cp5 are each independently a C to C group which may be branched or linear. 15 Alkyl, C3-C5 cycloalkyl, OR H or NR H 2. C(=O)-O-(C1~C 12 Alkyl), C(=O)N(C1-C 12 alkyl)2, where X is Cl, Br, I, OTf, BF4, or PF 6, O(C1~C 12 alkyl), L represents a ligand or a dimer, trimer or tetramer thereof, such as [Cp * RuCl]4.

[0012] The ligand L of the Ru catalyst is COD, NBD, (C1-C 12 Alkyl)CN, or (C1-C 12 The ligand may be any of alkyl)O, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, substituted pyridines, η-arenes, H2, and the more common readily dissociating donor ligands known in the art.

[0013] Preferably, the Ru catalyst is [Cp * RuCl]4 (chloro(pentamethylcyclopentadienyl)ruthenium(II) tetramer). This and related catalysts can be used, for example, in the synthesis of [Cp *Ru(MeCN)3]PF6 can be generated in situ by reacting it with a suitable chloride source, such as tetra-n-butylammonium chloride. Alternatively, Ru(+3) precursors, such as the oligomeric complexes [Cp * RuCl2] n It can be generated in situ by reduction of

[0014] The hydrogen used in this method can be H2 and its isotopes, such as HD, or D2, or any combination of H, D, and T, including T2, where D represents deuterium and T represents tritium.

[0015] Any two R 1 ~R 6 When groups such as 1 ~R 6 It is intended that two of the R groups form a ring system with their respective R groups on the same carbon atom, or with an adjacent R group, or with a more distant R group, which ring may contain heteroatoms such as O, N or S or substituted or protected forms thereof in the ring system.

[0016] In one embodiment of the process of the present invention for the gem-hydrogenation of internal alkynes, a compound of formula (I) is hydrogenated in an organic solvent in the presence of a Ru catalyst, where R 3 and R 4 are each independently, (C1~C 12 ) alkyl or (hetero) (C1-C 12 ) alkyl, R 3 and R 4 are optionally joined together via an alkyl or heteroalkyl to form a ring system, and R 1 and R 2 each independently represents: Hydrogen, but optionally R 1 , R 2 at least one of is not hydrogen; 〇 Si(C1~C 12Alkyl)3, C(=O)-O-(C1-C 12 alkyl), or 〇 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, Here, R 1 , R 2 , alkyl or heteroalkyl may form a ring system together, R 5 and R 6 each independently represents: Hydrogen, deuterium, 〇 O(C1~C 12 Alkyl), C(=O)-(C1-C 12 Alkyl), C(=O)-O-(C1-C 12 alkyl), 〇NR N1 R N2 , where R N1 is an arylsulfonyl group, (C1-C 12 ) alkylsulfonyl group, (C1-C 12 ) alkoxycarbonyl group, or -C(=O)-(C1-C 12 alkyl), R N2 C1~C 12 Represents an alkyl group or R N1 and R N2 are C1 to C 12 represents an alkyl group, or 〇 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, Here, R 5 , R 6 , alkyl or heteroalkyl may form a ring system together, where Q is O or NR N where R N is an arylsulfonyl group, (C1-C 12 ) alkylsulfonyl group, (C1-C 12 ) alkoxycarbonyl group or -C(=O)-(C1-C 12 represents a protecting group selected from the group consisting of alkyl,

[0017] In another embodiment of the process of the present invention, the compound of formula (I) is hydrogenated in the presence of a Ru catalyst in an organic solvent to form R 3 and R 4 are each independently, (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, R 3 and R 4 are optionally joined together via an alkyl or heteroalkyl to form a ring system, Q represents O, and R 5 and R 6 are each independently hydrogen, deuterium, (C1-C 12 ) alkyl or hetero(C1-C 12 ) alkyl, where R 1 and R 2 each independently represents: Hydrogen, optionally with R 1 , R 2 at least one of is not hydrogen; 〇 Si(C1~C 12 Alkyl)3, C(=O)-O-(C1-C 12 alkyl), or 〇 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, Here, R 1 , R 2 , alkyl or heteroalkyl may be joined together to form a ring system.

[0018] In a further embodiment of the process of the invention, the compound of formula (I) is hydrogenated in an organic solvent in the presence of a Ru catalyst, where R 3 and R 4 Each is independently (C1 to C 12 ) alkyl or hetero(C1-C 12 ) alkyl, R 3 and R 4 are optionally joined together via an alkyl or heteroalkyl to form a ring system, Q represents O, and R 1represents hydrogen, and R 2 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, R 5 and R 6 Each independently represents the following: Hydrogen, deuterium, 〇 O(C1~C 12 Alkyl), C(=O)-(C1-C 12 Alkyl), C(=O)-O-(C1-C 12 alkyl), 〇NR N1 R N2 , where R N1 is an arylsulfonyl group, (C1-C 12 ) alkylsulfonyl group, alkoxycarbonyl group or -(C 12 alkyl), R N2 is C1~C 12 Represents an alkyl group or R N1 and R N2 are C1 to C 12 represents an alkyl group, or 〇 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, Here, R 5 , R 6 , alkyl or heteroalkyl may be joined together to form a ring system.

[0019] In yet another embodiment of the process of the present invention, the compound of formula (I) is hydrogenated in the presence of a Ru catalyst in an organic solvent, In formula (I), R 3 and R 4 are each independently, (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, R 3 and R 4 are optionally joined together via an alkyl or heteroalkyl to form a ring system, and Q is NR N where R N is an arylsulfonyl group, (C1-C12 ) alkylsulfonyl group, alkoxycarbonyl group or -C(=O)(C1-C 12 alkyl), and where R 1 and R 2 Each independently represents the following: Hydrogen, optionally with R 1 , R 2 at least one of is not hydrogen; 〇 Si(C1~C 12 Alkyl)3, C(=O)-O-(C1-C 12 alkyl), or 〇 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, Here, R 1 and R 2 may form a ring system with each other via an alkyl or heteroalkyl; R 5 and R 6 each independently represents: Hydrogen, deuterium, 〇 O(C1~C 12 Alkyl), C(=O)-(C1-C 12 Alkyl), C(=O)-O-(C1-C 12 alkyl), 〇NR N1 R N2 , where R N1 is an arylsulfonyl group, (C1-C 12 ) alkylsulfonyl group, alkoxycarbonyl group or -(C 12 alkyl), R N2 is C1~C 12 Represents an alkyl group or R N1 and R N2 are C1 to C 12 represents an alkyl group, or 〇 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, Here, R 5 , R 6, alkyl or heteroalkyl may be joined together to form a ring system.

[0020] In yet another embodiment of the process of the present invention, the compound of formula (I) is hydrogenated in the presence of a Ru catalyst in an organic solvent to give the compound of formula (I). - R 1 and R 2 each independently represents: Hydrogen, optionally with R 1 , R 2 at least one of is not hydrogen; 〇 Si(C1~C 12 Alkyl)3, C(=O)-O-(C1-C 12 alkyl), or 〇 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, Here, R 1 , R 2 , alkyl or heteroalkyl may form a ring system together, - R 3 and R 4 are each independently O(C1 to C 12 ) alkyl, - R 5 represents hydrogen, and R 6 is hydrogen or (C1-C 12 ) alkyl, and - Q stands for O.

[0021] In yet another embodiment of the process of the present invention, the compound of formula (I) is hydrogenated in an organic solvent in the presence of a Ru catalyst, wherein Q is CH2, CH(C1~C 12 alkyl), or C(C1-C 12 alkyl)2, R 4 and R 5 are each independently, (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl, and O or NR NTogether with R, they form a ring system. N is an arylsulfonyl group, (C1-C 12 ) alkylsulfonyl group, (C1-C 12 ) alkoxycarbonyl group or -C(=O)-(C1-C 12 alkyl), R 3 is (C1~C 12 )Alkyl, Hetero(C1-C 12 ) alkyl or OSi(C1-C 12 alkyl)3, R 6 is hydrogen, deuterium, (C1-C 12 ) alkyl, or hetero(C1-C 12 ) alkyl, and R 1 , R 2 , each independently representing: Hydrogen, optionally with R 1 , R 2 at least one of is not hydrogen; 〇 Si(C1~C 12 Alkyl)3, C(=O)-O-(C1-C 12 alkyl), or 〇 (C1~C 12 ) alkyl or hetero(C1-C 12 ) alkyl.

[0022] In the process of the present invention, the solvent for the gem-hydrogenation of the internal alkyne is preferably an organic solvent selected from aprotic non-polar organic solvents selected from dichloromethane, chloroform, 1,2-dichloroethane, tetrahydropyran, tetrahydrofuran, ethyl acetate, diethyl ether, di-n-propyl ether, tert-butyl methyl ether, acetone, or mixtures thereof.

[0023] In the process of the present invention, the compound of formula (I) is hydrogenated in an organic solvent in the presence of a Ru catalyst at a H2 partial pressure of 0.1-100 bar, preferably 0.5-5 bar, more preferably 0.8 bar-1.5 bar.

[0024] The compound of formula (I) is usually hydrogenated in an organic solvent in the presence of a Ru catalyst at a temperature range of 0°C to 150°C, preferably 60°C to 80°C.

[0025] The compound of formula (I) is usually hydrogenated in an organic solvent in the presence of 1 to 10 mol % of a Ru catalyst based on the molar amount of the compound of formula (I).

[0026] The reaction time in the method of the present invention is not particularly limited, and is usually in the range of 30 to 600 minutes, preferably 120 to 240 minutes.

[0027] In the context of the present aspects, the following definitions are of more general terms used throughout this application.

[0028] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 ” is C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It is.

[0029] The term "aliphatic" includes both saturated and unsaturated, straight-chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by those skilled in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term "alkyl" includes straight-chain, branched, and acyclic alkyl groups. A similar convention applies to other general terms, such as "alkenyl," "alkynyl," and the like. Furthermore, terms such as "alkyl," "alkenyl," and "alkynyl" encompass both substituted and unsubstituted groups. In certain embodiments, "lower alkyl" is used to refer to alkyl groups (acyclic, substituted, unsubstituted, branched, or unbranched) having 1 to 6 carbon atoms.

[0030] As used herein, "alkyl" refers to the radical of a linear, cyclic or branched saturated hydrocarbon group having 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2-6 "Alkyl"). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tert-amyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10 It is an alkyl.

[0031] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and zero heteroatoms provided to the aromatic ring system (see "C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0032] An alkyl, heteroalkyl, or aryl group is optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" heteroalkyl. In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that upon substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent.

[0033] Exemplary substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -O-alkyl, -N-dialkyl, -SH, -S.alkyl, -C(=O)alkyl, -CO2H, -CHO. Hetero substituents may be selected from O, N, S, or halogen.

[0034] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0035] R 1 ~R 6 represents hydrogen, its respective isotopes deuterium and tritium are also included in the above definition. The same applies to insertions into C-H bonds, and insertions into C-D or C-T bonds are also included in the above definition.

[0036] R 1 ~R 6 Any of the following is heterogeneous (C1 to C 12 When representing an alkyl group, the definition includes the fact that the heteroatom in the sense of oxygen or nitrogen is a hetero(C1-C 12 ) alkyl, and the heteroatom is bonded to a carbon atom having a hetero(C 12 ) is not directly attached to a carbon atom having an alkyl group (C1-C 12 ) alkyl group. These options include those where the heteroatom is included in the R 1 ~R 6 This also includes being part of a ring structure optionally formed by two of: [Brief description of the drawings]

[0037] The invention is further illustrated by the following figures and examples. Figure 1A: Hydrogenative metathesis of alkynones Figure 1B: Carbene / alkyne metathesis (CAM), Figure 2: Hydrogenation CH insertion Figure 3: Hydrogenation of acetals C-H insertion Figure 4: Structural diversity through site-selective CH insertion Figure 5: Generation of pyrrolidine derivatives by gem-hydrogenation Figure 6: Spirocyclic skeletons commonly used in medicinal chemistry FIG. 7: Exemplary downstream functionalization Reagents and conditions a)(i)O3,CH2Cl,2-78℃;(ii)Me2S,-78℃→RT,76%; b)Co(acac)3(25mol%),PhSiH3,O2,THF,69%; c) Fe(acacc)3, PhSiH3, methyl acrylate, 1,2-dichloroethane, ethylene glycol, 60°C, 74%; d)(i)O3,MeOH,-78℃;(ii)TEMPO,FeSO4·7H2O,-78℃→RT,63%; e) (i) O3, MeOH, -78 °C; (ii) TEMPO, FeSO4·7H2O, magnesium bis(monoperoxyphthalate) hexahydrate (MMPP), -78 °C → RT, 62%; f)(i)O3,MeOH,-78℃;(ii)PhSSPh,-78℃→0℃;FeSO7H4·2O; g) mCPBA, CH2Cl2, 45% (for both steps) Figure 8: Hydrogenation of orthoesters and CH insertion to form lactones DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] As shown in Figure 2, most of these enynes proved to be amenable to C-H insertion by hydrogenation under standard conditions. It is important to note that many of the products shown in Figure 2 are difficult - if not impossible - to obtain by known CAM-based routes. Another important point is that pre-assembly of the alkene in the substrate allowed compounds like 10 and 18 to be obtained in isomerically pure form. Such control of the configuration is usually not possible by CAM-based routes. A further important advantage is the fact that the new route is simple, safe and convenient, whereas the use of CAM for the synthesis of products 12-17 and 19-24 requires hazardous diazomethane as carbene precursor. For this very reason, the reaction scales up nicely, as shown in the preparation of 20, which was obtained in practically the same yield, independent of the fact that 23 mg (70%) and 1.53 g (72%) of product were produced. It goes without saying that this (and other) compounds can also be formed in partially or fully labeled forms. For example, by using perduteromethyl iodide and D2 as the cheapest deuterium source, we were able to make [D5]-20. Because labeled compounds are so important in medicinal chemistry and other fields, access to such convenient, flexible, and if necessary, scalable compounds is of great importance.

[0039] CAM is also challenging when using non-terminal alkynes, since the introduction of primary carbenes derived from diazo derivatives is generally regioselective. As Figure 2 amply shows, the new gem-hydrogenation approach has no problem accessing such products. Furthermore, compounds 7, 11 and 13, which contain a cyclic alkene moiety, are essentially inaccessible via CAM. In the present work, we have utilized the insertion of a methyl ether into the most challenging primary C-H bond, but (more activated) secondary and tertiary C-H bonds are also available for the reaction (11, 23, Schemes 4, 5).

[0040] As shown in Figure 3, a notable extension of gem-hydrogenation involves enynes where the steering substituent is part of an acetal rather than a simple ether. Figure 3 illustrates various ways to exploit the compliance of such substrates. Most important is the ability to form spiroketals from lactones, in two simple, high-yielding steps via enyne addition / alkylation followed by gem-hydrogenation C-H insertion (see compounds 33, 37). The inventors are not aware of any precedent for this approach. However, importantly, this concept is not limited to the formation of spirocycles, as bridging sequences such as 31 and 35 are possible as well.

[0041] As shown in Figure 4, these examples show that insertion into primary and secondary C-H bonds proceeds with similar efficiency. It was therefore interesting to investigate whether substrates consisting of more than one reactive site are amenable to regioselective C-H insertion. The gem-hydrogenation reaction of enyne 38 gave spirocycle 15 as the only detectable product (Scheme 7). This result is puzzling, since a transient ruthenium carbene was inserted into the C-H bond of the a priori less activated primary C-OMe group. In contrast, the similarly reactive intermediate derived from 39 readily participated in bond formation with the methylene group of the existing heterocycle, giving rise to bridged bicycle 40 in similar yield. This comparison suggests that the selectivity of the primary C-H bond is a kinetic one, which suggests that the actual C-H insertion step was initiated by the bulky auxiliary Cp * This means that there must be strong steric factors for the ligands. In any case, the ability to generate significantly different scaffolds from a single precursor by simply changing the protecting groups is considered a significant advantage. The scaffolds within reach of this new methodology feature prominently in modern medicinal chemistry, as evidenced by countless patents: the examples shown in Figure 6 are representative.

[0042] As shown in Figure 5, the scope of the reaction extends beyond propargyl ethers and acetals. In particular, tert-amide, -carbamate, and -sulfonamide derivatives such as 46 proved to be well-behaved, even though the nature of the amide group influences the yield of the resulting pyrrolidine derivative (compare 47 / 48). The exclusive formation of cis-configured compounds 49 and 50 is another notable feature. In fact, 49 can be seen as remotely related to kainic acid and related neurostimulants, and its structure has been compiled countless times. The hemiaminal 50 is a valuable N-sulfonylimnium ion surrogate. In the absence of an external nucleophile, it can be converted by catalytic HCl to the functionalized 1,3-diene block 51, which can then be used in the Diels-Alder cycloaddition reaction.

[0043] As illustrated by downstream functionalization in Figure 7, small ring systems in general and spirocyclic scaffolds in particular have emerged as a new type of building block in medicinal chemistry over the past decade. 3 The replacement of traditional flat (hetero)aromatic cores of drug candidates by arene-rich templates can be of great benefit: if properly selected, it guarantees optimal expression of binding functionality for interacting groups at the binding site of the targeted biological receptor. Moreover, they offer potential advantages in terms of metabolic stability, are usually less lipophilic compared to (hetero)arenes, and offer uncommon or unknown chemical space, providing many opportunities for chemical innovation and therapeutic advances. In this context, the ability to provide these building blocks by gem-hydrogenation in isotopically labeled form is considered to be a key advantage.

[0044] Given that gem-hydrogenation would allow such compounds to be readily accessible on a larger scale, we decided to explore downstream functionalizations in a schematic way. Compound 20 was chosen as a model substrate because its isopropenyl substituent provides a versatile handle (Figure 7). Although ozonolysis to open the double bond and generate 52 is clearly possible, some other transformations are more complex. Specifically, iron-catalyzed hydration affords the tertiary alcohol derivative 53. Rather than scavenging a transient radical with oxygen, intermediates of this type can also participate in 1,4-addition reactions, for example to ethyl acrylate, as shown by the generation of 54. Other entries show the possibility of iron-catalyzed dealkenylation with the formation of the valuable TEMPO-adduct 55 or directly ketone 56; sulfone 57 further illustrates the structural and functional diversity accessible from such a single platform. In this context, it should be noted that compound 56 is a commercially available but expensive building block, and this new route can be scaled up and provided in labeled form if desired. Extrapolation of the chemistry depicted in Figure 7 to other (spirocyclic) products bearing the isopropenyl (or related alkenyl) substituents mentioned above should provide a number of valuable scaffolds for medicinal chemistry and chemical biology.

[0045] Another notable extension of gem-hydrogenation involves enynes where the steering substituent is part of an orthoester rather than a simple ether or acetal, as shown in Figure 8. Upon hydrolysis, the corresponding lactone is obtained. EXAMPLES

[0046] Experimental Part All reactions were carried out under argon in flame-dried Schlenk glassware unless otherwise noted. Solvents were purified by distillation under argon over the indicated drying agents: THF, Et2O (Mg / anthracene), hexane (Na / K), EtOH, MeOH (Mg), 1,2-dichloroethane, CD2Cl2, CH2Cl2 (CaH2). DMF, DMSO, MeCN, Et3N were dried using an absorption solvent purification system with molecular sieves. 1,2-dichloroethane (DCE), CD2Cl2, and CH2Cl2 were degassed via freeze-pump-thaw cycles (3 times) and stored over molecular sieves. Flash chromatography: Merck Geduran silica gel 60 (40-63 μm). TLC was stained with KMnO4, anisaldehyde, or molybditol phosphate (5% in EtOH).

[0047] Hydrogen gas (N50, ≥99.999 vol%) was purchased from Air Liquide and used without further purification. Deuterium gas (99.8 atom % D, 99.995% purity) was purchased from Sigma Aldrich. Both H2 and D2 were handled using standard balloon techniques.

[0048] Unless otherwise stated, all commercially available compounds (abcr, Acros, TCI, Aldrich, Alfa Aesar) were used as received. * RuCl]4 was prepared according to the literature procedure. Organometallics 1990,9(6),1843-1852. The building blocks required for the synthesis of the different substrates were prepared according to the cited literature (see below).

[0049] Substrate preparation Non-Commercial Building Blocks [ka] The above building blocks were prepared according to literature procedures.

[0050] 4-(Cyclohexyl-1-en-1-yl)-2-methylbut-3-yn-2-ol (S10) [ka] n-BuLi (1.6M in hexane, 17.7mL, 28.3mmol) was slowly added to a solution of 1-ethynylcyclohexyl-1-ene (3.00g, 28.3mmol) in THF (180mL) at 0°C. The mixture was stirred at 0°C for 30 minutes before acetone (6.2mL, 84.8mmol) in THF (15mL) was slowly introduced. The mixture was stirred at 0°C for 10 minutes before saturated NH4Cl solution (50mL) and tert-butyl methyl ether (150mL) were added. The layers were separated and the aqueous layer was extracted with tert-butyl methyl ether (2x150mL). The combined organic layers were dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (silica, hexane / EtOAc, 10:1) to give the title compound as a colorless oil (4.12g, 89%).

[0051] 1-(3-Methylbut-3-en-1-yn-1-yl)cyclopentan-1-ol (S11) [ka] n-BuLi (1.6M in hexanes, 14.2mL, 22.7mmol) was slowly added to a solution of 2-methylbut-1-en-3-yne (1.50g, 22.7mmol) in THF (150mL) at 0°C. The mixture was stirred at 0°C for 30 minutes before a solution of cyclopentanone (3.0mL, 34.0mmol) in THF (7mL) was slowly introduced. The mixture was stirred at 0°C for 10 minutes before adding saturated NH4Cl solution (50mL) and tert-butyl methyl ether (100mL). The layers were separated and the aqueous layer was extracted with tert-butyl methyl ether (2x100mL). The combined organic layers were washed with MgSO4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (silica, hexanes / EtOAc, 10:1) to give the title compound as a colorless oil (2.47g, 73%).

[0052] tert-Butyl 3-hydroxy-3-(3-methylbut-3-en-1-yn-1-yl)azetidine-1-carboxylate (S12) [ka] n-BuLi (1.6 M in hexanes, 5.1 mL, 8.2 mmol) was added slowly to a solution of 2-methylbut-1-en-3-yne (630 mg, 9.5 mmol) in THF (60 mL) at -78 °C. The mixture was stirred at -78 °C for 15 min, then 1-Boc-3-azetidinone (1.00 g, 5.8 mmol) in THF (10 mL) was slowly introduced. Stirring was continued at -78 °C for 15 min, then the mixture was warmed to -20 °C over 60 min. Aqueous NH4Cl (40 mL) and EtOAc (40 mL) were added, the layers were separated, and the aqueous phase was extracted with EtOAc (2x40 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica, hexane / EtOAc, 4:1) to give the title compound as a white solid (1.15 g, 83%).

[0053] 4-(3-Methylbut-3-en-1-cin-1-yl)-1-tosylpiperidin-4-ol (S13) [ka] Prepared similarly from 1-tosylpiperidin-4-one (253 mg, 2.0 mmol); colorless oil (362 mg, 57%).

[0054] 4-(3-Methylbut-3-en-1-yn-1-yl)tetrahydro-2H-pyran-4-ol (S14) [ka] Prepared similarly from tetrahydro-4H-pyran-4-one (417 mg, 4.2 mg); colorless oil (481 mg, 70%).

[0055] 3-(3-Methylbut-3-en-1-yn-1-yl)tetrahydrofuran-3-ol (S15) [ka] Prepared similarly from tetrahydrofuran-3-one (230 mg, 2.7 mmol); colorless oil (391 mg, 96%).

[0056] 1-Cyclohexyl-4-methylpent-4-en-2-yn-1-one (S16) [ka] n-BuLi (1.6 M in hexane, 1.7 mL, 2.7 mmol) was added slowly to a solution of 2-methylbut-1-en-3-yne (200 mg, 3.0 mmol) in THF (10 mL) at -78 °C. The mixture was stirred at this temperature for 15 min, after which a solution of N-methoxy-N-methylcyclohexanecarboxamide (S9) (430 mg, 2.5 mmol) in THF (3 mL) was added slowly. Stirring was continued for 15 min at -78 °C and for 60 min at -20 °C. NH4Cl solution (20 mL) and tert-butyl methyl ether (20 mL) were added, the layers were separated and the aqueous phase was extracted with tert-butyl methyl ether (2x20 mL). After evaporation of the solvent, the crude product was purified by flash chromatography (silica, hexane / tert-butyl methyl ether, 98:2) to give the title compound as a pale yellow oil (377 mg, 85%).

[0057] tert-Butyl 3-ethynyl-3-methoxyazetidine-1-carboxylate (S17) [ka] tert-Butyl 3-ethynyl-3-methoxyazetidine-1-carboxylate (S17). A solution of alcohol S1 (3.05 g, 15.5 mmol) in THF (5 mL) was added slowly at room temperature to a suspension of NaH (334 mg, 13.9 mmol) in THF (60 mL) and DMF (10 mL). The mixture was stirred for 30 min, then a solution of MeI (1.1 mL, 17.0 mmol) in DMF (10 mL) was carefully added. After stirring for a further 10 min, a saturated NH4Cl solution (25 mL) and EtOAc (100 mL) were introduced and the layers were separated. The aqueous phase was extracted with EtOAc (2x100 mL) and the combined organic layers were washed with brine (2x15 mL) and dried over MgSO4. The solvent was evaporated and the residue was purified by flash chromatography (silica, hexane / EtOAc, 10:1 to 5:1) to give the title compound as a colorless oil (2.85 g, 97% (wrt. NaH)).

[0058] Sonogashira Coupling tert-Butyl (2,5-dimethylhexyl-5-en-3-yn-2-yl)carbamate (S18) [ka] NEt3 (0.57 mL, 4.1 mmol), CuI (52 mg, 0.27 mmol) and Pd(PPh3)4 (157 mg, 0.14 mmol) were added to a stirred solution of 2-bromoprop-1-ene (500 mg, 4.1 mmol) and tert-butyl (2-methylbut-3-yn-2-yl)carbamate (250 mg, 1.36 mmol) in DMF (7 mL). The mixture was stirred at room temperature for 2 h before introducing saturated NH4Cl solution (7 mL) and tert-butyl methyl ether (15 mL). The layers were separated and the aqueous phase was extracted with tert-butyl methyl ether (2x25 mL). The combined organic layers were washed with saturated NaCl solution (2x10 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica, hexane / EtOAc, 20:1 to 10:1) to give the title compound as a colorless oil (165 mg, 54%).

[0059] N-(2,5-dimethylhexyl-5-en-3-yn-2-yl)-4-methylbenzenesulfonamide (S19) [ka] Prepared similarly from propargylamine S6 (2.00 g, 8.43 mmol) as a pale yellow oil (1.85 g, 79%);

[0060] Substrates for gem-hydrogenation / CH insertion Via alkylation 1-(3-Methoxy-3-methylbut-1-yn-1-yl)cyclohex-1-ene (5) [ka] A solution of alcohol S10 (300 mg, 1.8 mmol) in THF (1 mL) was added to a stirred suspension of NaH (109 mg, 4.6 mmol) in THF (7 mL) at 0 °C. Stirring was continued at room temperature for 30 min before MeI (0.57 mL, 9.1 mmol) was introduced. After stirring for an additional 1 h, saturated NH4Cl solution (3 mL), water (6 mL) and tert-butyl methyl ether (30 mL) were added and the layers were separated. The aqueous phase was extracted with tert-butyl methyl ether (2x30 mL) and the combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / EtOAc, 1:0 to 40:1) to give the title compound as a colorless oil (210 mg, 64%).

[0061] (3-(Methoxy-[D])-3-methylbut-1-yn-1-yl)cyclohex-1-ene ([D1]-5) [ka] Prepared in a similar manner using mono-deutero-methyl iodide; colorless oil (287 mg, 88%).

[0062] 1-(3-(methoxy-[D2])-3-methylbut-1-yn-1-yl)cyclohex-1-ene ([D2]-5) [ka] Prepared in a similar manner using dideuteromethyl iodide; colorless oil (282 mg, 86%).

[0063] 1-(3-([D3]-methoxy)-3-methylbut-1-yn-1-yl)cyclohex-1-ene ([D3]-5) [ka] Prepared in a similar manner using CD3I: Colorless oil (250 mg, 76%).

[0064] 1-Methoxy-1-(3-methylbut-3-en-1-yn-1-yl)cyclopentane (S20) [ka] A solution of alcohol S11 (280 mg, 1.9 mmol) in THF (1 mL) was added to a stirred suspension of NaH (112 mg, 4.7 mmol) in THF (7 mL) at 0 °C. The mixture was stirred at room temperature for 30 min before MeI (0.58 mL, 9.3 mmol) was introduced. After stirring at room temperature for 1 h, saturated NH4Cl solution (3 mL), water (6 mL) and tert-butyl methyl ether (30 mL) were added and the layers were separated. The aqueous phase was extracted with tert-butyl methyl ether (2x30 mL) and the combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / EtOAc, 1:0 to 40:1) to give the title compound as a colorless oil (225 mg, 73%).

[0065] 1-((1-Methoxycyclobutyl)ethynyl)cyclohex-1-ene (S21) [ka] Prepared in a similar manner from cyclobutanone and 1-ethynylcyclohex-1-ene; colorless oil (230 mg, 94%).

[0066] (1S,2S,5R)-2-isopropyl-1-methoxy-5-methyl-1-(3-methylbut-3-en-1-yn-1-yl)cyclohexane (S22) [ka] A solution of alcohol S5 (175 mg, 0.79 mmol) in DMF (1 mL) was added to a stirred suspension of NaH (48 mg, 2.0 mmol) in DMF (4 mL) at room temperature. The mixture was stirred for 20 min before MeI (0.25 mL, 1.6 mmol) was introduced. After stirring for a further 2 h, saturated NH4Cl solution (6 mL), water (3 mL) and tert-butyl methyl ether (15 mL) were added and the layers were separated. The aqueous phase was extracted with tert-butyl methyl ether (2x30 mL) and the combined organic layers were washed with brine (3x10 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / EtOAc, 1:0-100:1) to give the title compound as a colorless oil (25.9 mg, 14%).

[0067] (3-Methoxy-3-methylbut-1-yn-1-yl)cyclohexane (60) [ka] A solution of alcohol S3 (300 mg, 1.80 mmol) in THF (1 mL) was added to a stirred suspension of NaH (108 mg, 4.51 mmol) in THF (7 mL) at 0 °C. The mixture was stirred at room temperature for 30 min before MeI (0.56 mL, 9.0 mmol) was introduced. After stirring for an additional 1 h, saturated NH4Cl solution (3 mL), water (6 mL) and tert-butyl methyl ether (30 mL) were added and the layers were separated. The aqueous phase was extracted with tert-butyl methyl ether (2x30 mL) and the combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / EtOAc, 1:0 to 40:1) to give the title compound as a colorless oil (268 mg, 82%).

[0068] 1-(3-(methoxymethoxy)-3-methylbut-1-yn-1-yl)cyclohex-1-ene (S23) [ka] A solution of alcohol S10 (300 mg, 1.8 mmol) in THF (1 mL) was added to a stirred suspension of NaH (88 mg, 3.7 mmol) in THF (7 mL) at 0 °C. The mixture was stirred at room temperature for 30 min, then MOMCl (0.28 mL, 3.7 mmol) was slowly introduced at 0 °C. After stirring at room temperature for 18 h, saturated NH4Cl solution (3 mL), water (6 mL) and tert-butyl methyl ether (30 mL) were added and the layers were separated. The aqueous phase was extracted with tert-butyl methyl ether (2x30 mL) and the combined organic layers were washed with brine and dried over MgSO4. The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / EtOAc, 1:0 to 30:1) to give the title compound as a colorless oil (169 mg, 44%).

[0069] tert-Butyl 3-(2-(tert-butoxy)-2-oxoethoxy)-3-(3-methylbut-3-en-1-yn-1-yl)azetidine-1-carboxylate (S24) [ka] A solution of alcohol S12 (200 mg, 0.84 mmol) in DMF (1 mL) was added to a stirred suspension of NaH (51 mg, 2.1 mmol) in DMF (4 mL) at room temperature. The mixture was stirred for 20 min before tert-butyl 2-bromoacetate (0.31 mL, 2.1 mmol) was introduced. After stirring for 15 min at room temperature, saturated NH4Cl solution (3 mL), water (3 mL) and EtOAc (15 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2x15 mL) and the combined organic layers were washed with brine (2x10 mL) and dried over MgSO4. The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / EtOAc, 10:1) to give the title compound as a colorless oil (271 mg, 91%).

[0070] Via one-pot alkynylation / O-alkylation tert-Butyl 3-methoxy-3-(3-methylbut-3-en-1-yn-1-yl)azetidine-1-carboxylate (S25) [ka] n-BuLi (1.6M in hexanes, 1.07 mL, 1.72 mmol) was added to a stirred solution of 2-methyl-1-buten-3-yne (122 mg, 1.84 mmol) in THF (7.4 mL) at -78 °C under argon and the resulting mixture was stirred at that temperature for 15 min. A solution of 1-Boc-3-azetidinone (210 mg, 1.23 mmol) in THF (2.0 mL) was added slowly and the mixture was stirred for 15 min and then warmed to -20 °C over 1 h. A solution of MeI (0.31 mL, 4.91 mmol) in DMSO (4.8 mL) was added and the mixture was allowed to reach room temperature within 1 h. NH4Cl solution (6 mL) and water (6 mL) were added and the biphasic mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine (2x10 mL), dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica, hexane / EtOAc, 20:1 to 10:1) to give the title compound as a colorless oil (270 mg, 88%). When performed on a larger scale, the product yield was even higher (2.16 g, 92%).

[0071] tert-Butyl 3-(methoxy-[D3])-3-(3-methylbut-3-en-1-yn-1-yl)azetidine-1-carboxylate ([D3]-S25) [ka] Prepared similarly from 1-Boc-3-azetidinone and CD3I; colorless oil (276 mg, 88%).

[0072] 4-Methoxy-4-(3-methylbut-3-en-1-yn-1-yl)-1-tosylpiperidine (S26) [ka] Prepared in a similar manner from 1-tosylpiperidin-4-one; colourless solid (332 mg, 79%).

[0073] 4-Methoxy-4-(3-methylbut-3-en-1-yn-1-yl)tetrahydro-2H-pyran (38) [ka] Prepared in a similar manner from tetrahydro-4H-pyran-4-one; colourless oil (164 mg, 73%).

[0074] 5-Methoxy-2,2-dimethyl-5-(3-methylbut-3-en-1-yn-1-yl)-1,3-dioxane (S27) [ka] Prepared in a similar manner from 2,2-dimethyl-1,3-dioxan-5-one; pale yellow oil (198 mg, 76%).

[0075] tert-Butyl 6-methoxy-6-(3-methylbut-3-en-1-yn-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (S28) [ka] Prepared in a similar manner from the corresponding spiroketone; pale yellow oil (336 mg, 93%).

[0076] tert-Butyl (E)-3-(5-((tert-butyldimethylsilyl)oxy)pent-3-en-1-yn-1-yl)-3-methoxyazetidine-1-carboxylate (S29) [ka] Prepared in a similar manner from 1-Boc-3-azetidinone and (E)-tert-butyldimethyl(pent-2-en-4-yn-1-yloxy)silane (S7); colorless oil (400 mg, 89%).

[0077] Preparation of tert-butyl 3-methoxy-3-(3-methylbut-3-en-1-yn-1-yl)pyrrolidine-1-carboxylate (S30) [ka] Prepared in a similar manner from N-Boc-3-pyrrolidinone (185 mg, 1.0 mmol); colorless oil (127 mg, 48%).

[0078] 3-Methoxy-3-(3-methylbut-3-en-1-yn-1-yl)tetrahydrofuran (S31) [ka] Prepared in a similar manner from tetrahydrofuran-3-one (225 mg, 2.6 mmol); colorless oil (329 mg, 76%).

[0079] 1-Methoxy-1-(prop-2-yn-1-yl)cyclohexane (9) [ka] Oxirane S2 (1.29 g, 11.5 mmol) was added slowly to a stirred suspension of lithium acetylide ethylenediamine complex (1.38 g, 15.0 mmol) in DMSO (12 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirring was continued for 5 days, after which saturated NH4Cl solution (20 mL) and tert-butyl methyl ether (50 mL) were added. The aqueous phase was extracted with tert-butyl methyl ether (2x100 mL) and the combined organic layers were washed with HCl (2 M, 25 mL), saturated CuSO4 solution (25 mL) and brine, and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / EtOAc, 20:1 to 10:1) to give the corresponding homopropargyl alcohol (861 mg, 54%). A solution of this homopropargyl alcohol (409 mg, 2.96 mmol) in THF (1 mL) was added to a stirred suspension of NaH (63 mg, 2.66 mmol) in THF (4 mL) at 0 °C. The mixture was stirred at room temperature for 30 min before MeI (0.20 mL, 3.25 mmol) was introduced. After stirring at room temperature for a further 2 h, saturated NH4Cl solution (3 mL), water (3 mL) and tert-butyl methyl ether (30 mL) were introduced and the layers were separated. The aqueous phase was extracted with tert-butyl methyl ether (2x30 mL) and the combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / EtOAc, 1:0 to 50:1) to give the title compound as a colorless oil (196 mg, 48%).

[0080] Via Sonogashira Coupling (E)-(4-(1-methoxycyclohexyl)but-1-en-3-en-1-yl)trimethylsilane (8) [ka] i-Pr2NEt (0.97 mL, 5.6 mmol), CuI (106 mg, 0.56 mmol) and Pd(PPh3)2Cl2 (196 mg, 0.28 mmol) were added to a stirred solution of (E)-(2-bromovinyl)trimethylsilane (500 mg, 2.79 mmol) and alkyne S4 (500 mg, 3.63 mmol) in DMF (14 mL). The mixture was stirred at room temperature for 1 h, after which saturated NH4Cl solution (15 mL) and tert-butyl methyl ether (30 mL) were introduced. The layers were separated and the aqueous phase was extracted with tert-butyl methyl ether (2x50 mL). The combined organic layers were washed with saturated NaCl solution (3x10 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica, hexane / EtOAc, 1:0 to 100:1-50:1) to give the title compound as a pale orange oil (288 mg, 44%).

[0081] Ethyl (E)-5-(1-methoxycyclohexyl)pent-2-en-4-ynoate (S32) [ka] i-Pr2NEt (0.92 mL, 5.3 mmol), CuI (101 mg, 0.53 mmol) and Pd(PPh3)2Cl2 (185 mg, 0.26 mmol) were added to a stirred solution of ethyl (E)-3-bromoacrylate (500 mg, 2.64 mmol) and alkyne S4 (434 mg, 3.14 mmol) in DMF (13 mL). The mixture was stirred at room temperature for 1 h, after which saturated NH4Cl solution (15 mL) and tert-butyl methyl ether (30 mL) were introduced. The layers were separated and the aqueous phase was extracted with tert-butyl methyl ether (2x50 mL). The combined organic layers were washed with saturated NaCl solution (3x10 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica, hexane / EtOAc, 1:0 to 40:1) to give the title compound as a colorless oil (376 mg, 60%).

[0082] (4-(1-Methoxycyclohexyl)but-1-en-3-yn-2-yl)trimethylsilane (S33) [ka] i-Pr2NEt (0.97 mL, 5.6 mmol), CuI (106 mg, 0.56 mmol) and Pd(PPh3)2Cl2 (196 mg, 0.28 mmol).28 mmol) were added to a stirred solution of (1-bromovinyl)trimethylsilane (500 mg, 2.79 mmol) and alkyne S4 (500 mg, 3.63 mmol) in DMF (14 mL). The mixture was stirred at room temperature for 1 h, after which saturated NH4Cl solution (15 mL) and tert-butyl methyl ether (30 mL) were introduced. The layers were separated and the aqueous phase was extracted with tert-butyl methyl ether (2x50 mL). The combined organic layers were washed with saturated NaCl solution (3x10 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica, hexane / EtOAc, 1:0-100:1 to 50:1) and HPLC to give the title compound as a colorless oil (120 mg, 18%).

[0083] tert-Butyl 3-(3-(diethoxymethyl)but-3-en-1-yn-1-yl)-3-methoxyazetidine-1-carboxylate (S34) [ka] Prepared in a similar manner from tert-butyl 3-ethynyl-3-methoxyazetidine-1-carboxylate (211 mg, 1.0 mmol) (S17) and 2-bromopropenal diethyl acetal (250 mg, 1.3 mmol) to give a colorless oil (69.2 mg, 22%).

[0084] tert-Butyl 3-(5-((tert-butyldimethylsilyl)oxy)-3-methylenepent-1-yn-1-yl)-3-methoxyazetidine-1-carboxylate (S35) [ka] A solution of tert-butyl 3-ethynyl-3-methoxyazetidine-1-carboxylate (S17) (220 mg, 1.1 mmol) and ((3-bromobut-3-en-1-yl)oxy)(tert-butyl)dimethylsilane (S8) (325 mg, 1.2 mmol) in THF (2.0 mmol) was added to a solution of CuI (4.9 mg, 0.03 mmol) and Pd(PPh3)4 (3.6 mg, 0.003 mmol) in NEt3 (0.5 mL). The mixture was stirred at ambient temperature until TLC showed complete conversion. The mixture was filtered through a plug of Florisil and eluted with tert-butyl methyl ether. The combined filtrate was washed successively with HCl (0.1 M, 15 mL) and NaHCO3 (15 mL), dried over MgSO4 and evaporated. The crude product was purified by flash chromatography (silica, hexane / tert-butyl methyl ether, 85:15) to give the title compound as a colorless oil (76.7 mg, 19%).

[0085] tert-Butyl 3-methoxy-3-(3-(trifluoromethyl)but-3-en-1-yn-1-yl)azetidine-1-carboxylate (S36) [ka] Prepared in a similar manner from alkyne S17 (211 mg, 1.0 mmol) and 2-bromo-3,3,3-trifluoro-1-propene (227.0 mg, 1.3 mmol); pale yellow oil (217 mg, 72%).

[0086] tert-Butyl 4-((1-(tert-butoxycarbonyl)-3-methoxyazetidin-3-yl)ethynyl)-3,6-dihydropyridine-1(2H)-carboxylate (S37) [ka] Prepared in a similar manner from alkyne S17 (217 mg, 1.0 mmol) and N-Boc-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine (398.0 mg, 1.2 mmol); colorless oil (400.0 mg, 99%).

[0087] tert-Butyl 3-methoxy-3-((5-oxo-2,5-dihydrofuran-3-yl)ethynyl)azetidine-1-carboxylate (S38) [ka] Prepared in a similar manner from alkyne S17 (209 mg, 0.099 mmol) and 4-bromofuran-2(5H)-one (209.5 mg, 1.3 mmol); colorless oil (255 mg, 80%).

[0088] tert-Butyl 3-methoxy-3-(3-((trimethylsilyl)methyl)but-3-en-1-yn-1-yl)azetidine-1-carboxylate (S39) [ka] Prepared in a similar manner from alkyne S17 (209 mg, 1.0 mmol) and 2-bromo-allyl-trimethylsilane (272 mg, 1.3 mmol); colorless oil (255 mg, 80%).

[0089] Acetal Series 2-cyclohexyl-2-(3-methylbut-3-en-1-yn-1-yl)-1,3-dioxane 1-cyclohexyl (30) [ka] Trimethyl orthoformate (0.11 mL, 1.0 mmol) and p-TsOH-H2O (6.0 mg, 0.08 mmol) were added to a solution of 4-methylpent-4-en-2-yn-1-one (S16) (150 mg, 0.85 mmol) in 1,3-propanediol (4.0 mL). After stirring the mixture for 24 h, the reaction was quenched with saturated NaHCO3 (15 mL) and tert-butyl methyl ether (15 mL). The aqueous phase was extracted with tert-butyl methyl ether (2x15 mL) and the combined organic layers were washed with brine (10 mL) and dried over MgSO4. The solvent was removed under reduced pressure to give the title compound as a pale yellow oil (169 mg, 85%).

[0090] (1,1-dimethoxy-4-methylpent-4-en-2-yn-1-yl)cyclohexane (S40) [ka] To a solution of 1-cyclohexyl-4-methylpent-4-en-2-yn-1-one (S16) (150 mg, 0.85 mmol) in MeOH (3.0 mL) was added trimethyl orthoformate (0.47 mL, 4.3 mmol) at 0° C., followed by p-TsOH-H2O (6.0 mg, 0.08 mmol). After GC / MS showed complete conversion, saturated NaHCO3 (15 mL) and tert-butyl methyl ether (15 mL) were introduced, the aqueous phase was extracted with tert-butyl methyl ether (2×15 mL), and the combined organic phase was washed with brine (10 mL) and dried over MgSO4. The solvent was evaporated under reduced pressure to give the title compound as a pale yellow oil (189 mg, quantitative).

[0091] 2-Cyclohexyl-2-(3-methylbut-3-en-1-yn-1-yl)-1,3-dioxolane (S41) [ka] Trimethyl orthoformate (0.11 mL, 1.0 mmol) and p-TsOH-H2O (6.0 mg, 0.08 mmol) were added to a solution of 1-cyclohexyl-4-methylpent-4-en-2-yn-1-one (S16) (150 mg, 0.85 mmol) in ethylene glycol (4.0 mL). The mixture was stirred for 24 h, after which NaHCO3 (15 mL) and tert-butyl methyl ether (15 mL) were added. The layers were separated, the aqueous phase was extracted with tert-butyl methyl ether (2x15 mL) and the combined organic layers were washed with brine (10 mL) and dried over MgSO4. The solvent was removed under reduced pressure to give the title compound as a pale yellow oil (167 mg, 89%).

[0092] 2-Methoxy-2-(3-methylbut-3-en-1-yn-1-yl)tetrahydrofuran (32) [ka] n-BuLi (1.6M in hexanes, 4.25 mL, 6.81 mmol) was added to a stirred solution of 2-methyl-1-buten-3-yne (500 mg, 7.56 mmol) in THF (30 mL) under argon at -78 °C and stirred at that temperature for 30 min. BF3-OEt2 (1M in Et2O, 8.3 mL, 8.3 mmol) was added and the mixture was stirred at -78 °C for 30 min, after which γ-butyrolactone (0.70 mL, 9.1 mmol) was slowly introduced. The mixture was allowed to warm to room temperature and stirring was continued for 18 h. NH4Cl solution (6 mL) and water (6 mL) were added at 0 °C. The biphasic mixture was extracted with EtOAc (3x75 mL) and the combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / EtOAc, 2:1 to 3:2 to 1:1) to give a mixture of the corresponding γ-hydroxyketone, its lactol and its butyrate (692 mg, ∼60%). This mixture (200 mg, ∼1.3 mmol) was dissolved in MeOH (5 mL) and p-TsOH-H2O (25 mg, 0.13 mmol) was added at room temperature. The mixture was stirred for 18 h, after which a saturated NaHCO3 solution (3 mL) was introduced. The mixture was extracted with tert-butyl methyl ether (3×20 mL) and the combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / EtOAc, 20:1) to give the title compound as a colorless oil (126 mg, 58%).

[0093] 2-Isopropoxy-2-(3-methylbut-3-en-1-yn-1-yl)tetrahydrofuran (S42) [ka] Prepared in a similar manner using iPrOH instead of MeOH (101 mg, 34%).

[0094] 2-((4-(cyclohex-1-en-1-yl)-2-methylbut-3-yn-2-yl)oxy)tetrahydro-2H-pyran (S43) [ka] 3,4-Dihydro-2H-pyran (0.14 mL, 1.6 mmol) and toluenesulfonic acid monohydrate (11 mg, 0.06 mmol) were added to a solution of 4-(cyclohex-1-en-1-yl)-2-methylbut-3-yn-2-ol (200 mg, 1.2 mmol) (S10) in CHCl (2.5 mL) at 0° C., and the resulting mixture was stirred at this temperature overnight. Saturated NaHCO (15 mL) and tert-butyl methyl ether (15 mL) were introduced, the layers were separated, the aqueous phase was extracted with tert-butyl methyl ether (2×15 mL), and the combined organic layers were washed with brine (10 mL) and dried over MgSO. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography (silica, hexane / tert-butyl methyl ether, 98:2) to give the title compound as a colourless oil (90.2 mg, 30%).

[0095] Silyl Ether Derivatives Trimethyl((4-(3-methylbut-3-en-1-yn-1-yl)tetrahydro-2H-pyran-4-yl)oxy)silane (39) [ka] To a solution of 4-(3-methylbut-3-en-1-yn-1-yl)tetrahydro-2H-pyran-4-ol (S14) (150 mg, 0.90 mmol) in CHCl (3.0 mL) was added 1H-imidazole (70 mg, 1.0 mmol) in one portion and the resulting mixture was stirred for 15 min. TMSCl (0.12 mL, 0.96 mmol) was added and stirring was continued for 2 h. The reaction was quenched with water (20 mL) and the mixture was diluted with tert-butyl methyl ether (20 mL). The layers were separated and the aqueous phase was extracted with tert-butyl methyl ether (2x20 mL). The combined organic layers were washed with brine, dried over MgSO4, the solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / Et2O, 98:2) to give the title compound as a colorless oil (211 mg, 92%).

[0096] 4-(3-Methylbut-3-en-1-yn-1-yl)-1-tosyl-4-((trimethylsilyl)oxy)piperidine (S44) [ka] Prepared in a similar manner from 4-(3-methylbut-3-en-1-yn-1-yl)-1-tosylpiperidin-4-ol (S13) (200 mg, 0.63 mmol); colorless oil (245 mg, 99%).

[0097] Trimethyl((3-(3-methylbut-3-en-1-yn-1-yl)tetrahydrofuran-3-yl)oxy)silane (S45) [ka] Prepared in a similar manner from 3-(3-methylbut-3-en-1-yn-1-yl)tetrahydrofuran-3-ol (S15) (200 mg, 1.31 mmol); colorless oil (200 mg, 68%).

[0098] tert-Butyl 3-(3-methylbut-3-en-1-yn-1-yl)-3-((trimethylsilyl)oxy)pyrrolidine-1-carboxylate (S46) [ka] n-BuLi (1.6M in hexanes, 0.88 mL, 1.4 mmol) was added slowly to a solution of 2-methylbut-1-en-3-yne (153 mg, 1.6 mmol) in THF (6.0 mL) at -78 °C. The mixture was stirred at -78 °C for 15 min, then a solution of N-Boc-3-pyrrolidinone (190 mg, 1.0 mmol) in THF (2.0 mL) was added slowly. The mixture was stirred at -78 °C for 15 min, then warmed to -20 °C over 60 min. NH4Cl solution (40 mL) and EtOAc (40 mL) were introduced, the layers were separated, and the aqueous phase was extracted with EtOAc (2x40 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica, hexane / EtOAc, 4:1) to give the corresponding tert-alcohol in slightly impure form (200 mg, ~70%). To a solution of this compound (200 mg, ~0.72 mmol) in CHCl (3.0 mL) was added 1H-imidazole (63 mg, 0.93 mmol). After stirring for 15 min, TMSCl (0.11 mL, 0.86 mmol) was introduced and the resulting mixture was stirred for 2 h. The reaction was quenched with water (20 mL) and tert-butyl methyl ether (20 mL), the layers were separated and the aqueous phase was extracted with tert-butyl methyl ether (2x20 mL). The combined organic layers were washed with brine and dried over MgSO. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography (silica, hexane / tert-butyl methyl ether, 98:2) to give the title compound as a colourless oil (150 mg, 65%).

[0099] Propargylamine Derivatives tert-Butyl (2,5-dimethylhexyl-5-en-3-yn-2-yl) (methyl)carbamate (S47) [ka] A solution of carbamate S18 (160 mg, 0.72 mmol) in DMF (1 mL) was added to a stirred suspension of NaH (26 mg, 1.1 mmol) in DMF (3 mL) at room temperature. The mixture was stirred for 30 min before MeI (0.10 mL, 1.6 mmol) was introduced. After stirring at room temperature for 1 h, saturated NH4Cl solution (3 mL), water (3 mL) and tert-butyl methyl ether (15 mL) were added and the layers were separated. The aqueous phase was extracted with tert-butyl methyl ether (2x15 mL) and the combined organic layers were washed with brine (3x10 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / EtOAc, 40:1 to 20:1) to give the title compound as a colorless oil (148 mg, 87%).

[0100] N-(2,5-dimethylhexyl-5-en-3-yn-2-yl)-N,4-dimethylbenzenesulfonamide (46) [ka] Prepared in a similar manner from enyne S19 (300 mg, 1.08 mmol) as a colorless oil (270 mg, 86%).

[0101] tert-Butyl N-(2,5-dimethylhexyl-5-en-3-yn-2-yl)-N-tosylglycinate (S48) [ka] Sodium hydride (26.0 mg, 1.1 mmol) was added to a solution of enyne S19 (200 mg, 0.72 mmol) in DMF (1.0 mL) and the resulting mixture was stirred at ambient temperature for 15 min. tert-Butyl bromoacetate (0.16 mL, 1.1 mmol) was introduced and the solution was stirred for 4 h. The reaction was quenched with saturated NH4Cl solution (5 mL) and the aqueous phase was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (2x10 mL), dried over MgSO4 and evaporated. The crude product was purified by flash chromatography (silica, hexane / EtOAc, 80:20) to give the title compound as a white solid (230.0 mg, 82%).

[0102] N-(2,5-dimethylhex-5-en-3-yn-2-yl)-N-(methoxymethyl)-4-methylbenzenesulfonamide (S49) [ka] A solution of the enyne S19 (300 mg, 1.08 mmol) in DMF (1 mL) was slowly added at room temperature to a stirred suspension of NaH (39 mg, 1.6 mmol) in DMF (5 mL). The mixture was stirred for 30 min before MOMCl (0.18 mL, 2.4 mmol) was introduced. After stirring for 30 min at room temperature, saturated NH4Cl solution (5 mL), water (5 mL) and tert-butyl methyl ether (30 mL) were added and the layers were separated. The aqueous phase was extracted with tert-butyl methyl ether (2x30 mL) and the combined organic layers were washed with brine (3x10 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, hexane / EtOAc, 20:1 to 10:1) to give the title compound as a colorless oil (290 mg, 83%).

[0103] Hydrogenation CH insertion reaction Representative Procedure Preparation of 4-(cyclohex-1-en-1-yl)-2,2-dimethyltetrahydrofuran (7) [ka] [Cp * [RuCl]4 (2.3 mg, 2 mol%) was added to a stirred solution of enyne 5 (19.0 mg, 0.11 mmol) in 1,2-dichloroethane (1.1 mL, 0.1 M) in a flame-dried Schlenk tube under an argon atmosphere. While maintaining an atmosphere of H2 (ambient pressure, balloon filled with H2), H2 was bubbled through the mixture for 2 min before immersing the flask in a preheated oil bath (70 °C). After stirring at 70 °C for 3 h, the mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica, pentane / Et2O, 1:0 to 40:1) to give the title compound as a colorless oil (17.4 mg, 89%).

[0104] 4-(Cyclohex-1-en-1-yl)-2,2-dimethyltetrahydrofuran-3,3-[D2] ([D2]-7) [ka] Prepared according to the representative procedure from enyne 5 using D2 instead of H2 gas (19.1 mg, 0.11 mmol); colorless oil (15.9 mg, 81%).

[0105] 4-(Cyclohex-1-en-1-yl)-2,2-dimethyltetrahydrofuran-4,5,5-[D3] ([D3]-7) [ka] Prepared according to the representative procedure from enyne[D3]-5 (24.3 mg, 0.13 mmol); colorless oil (19.0 mg, 77%).

[0106] Gram-scale reaction, preparation of tert-butyl 7-(prop-1-en-2-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (20) [ka] In a flame-dried two-neck round-bottom flask, add [Cp *RuCl]4 (183 mg, 0.17 mmol) was charged. The flask was evacuated and backfilled with H2 (by attaching a hydrogen-filled balloon via a needle and septum). A solution of the enyne S25 (2.12 g, 8.43 mmol) in 1,2-dichloroethane (85 mL) was introduced while maintaining a static H2 atmosphere (ambient pressure, balloon filled with H2) before immersing the flask in a preheated oil bath (70 °C). After stirring at 70 °C for 3 h, the mixture was cooled to room temperature, the flask was evacuated, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica, hexane / EtOAc, 20:1 to 10:1) to give the title compound as a pale yellow oil (1.53 g, 72%).

[0107] (E)-(2-(1-oxaspiro[4.5]decan-3-yl)vinyl)trimethylsilane (10) [ka] The representative procedure was followed from enyne 8 (26.9 mg, 0.11 mmol); a colorless oil (22.3 mg, 92%) was obtained.

[0108] 4-(Cyclohex-1-en-1-yl)-5-methoxy-2,2-dimethyltetrahydrofuran (11) [ka] The representative procedure was followed starting with enyne S23 (32.2 mg, 0.15 mmol); a colorless oil (26.8 mg, 82%, mixture of diastereomers ∼2:1) was obtained.

[0109] 3-(Prop-1-en-2-yl)-1-oxaspiro[4.4]nonane (12) [ka] The representative procedure was followed from enyne S20 (32.2 mg, 0.20 mmol); a colorless oil (22.9 mg, 70%) was obtained.

[0110] 7-(Cyclohex-1-en-1-yl)-5-oxaspiro[3.4]octane (13) [ka] The representative procedure was followed from enyne S21 (18.6 mg, 0.10 mmol); a colorless oil (9.7 mg, 52%, 75% NMR) was obtained.

[0111] 3-(Prop-1-en-2-yl)-8-tosyl-1-oxa-8-azaspiro[4.5]decane (14) [ka] The representative procedure was followed from enyne S26 (37.1 mg, 0.11 mmol); a colorless oil (30.2 mg, 81%) was obtained. Single crystals suitable for X-ray analysis were obtained by slow evaporation of a concentrated solution in CH2Cl2 / pentane (1:1).

[0112] 3-(Prop-1-en-2-yl)-1,8-dioxaspiro[4.5]decane (15) [ka] The representative procedure was followed from enyne 38 (21.5 mg, 0.12 mmol); a colorless oil (14.9 mg, 67%) was obtained.

[0113] 8,8-Dimethyl-3-(prop-1-en-2-yl)-1,7,9-trioxaspiro[4.5]decane (16) [ka] The representative procedure was followed from enyne S27 (22.7 mg, 0.11 mmol); a colorless oil (18.0 mg, 79%) was obtained.

[0114] (5R,6S,9R)-6-isopropyl-9-methyl-3-(prop-1-en-2-yl)-1-oxaspiro[4.5]decane (17) [ka] The representative procedure was followed from enyne S22 (21.3 mg, 0.09 mmol); a colorless oil (7.8 mg, 36%; single isomer, isopropenyl stereochemistry unknown) was obtained.

[0115] Ethyl (E)-3-(1-oxaspiro[4.5]decan-3-yl)acrylate (18) [ka] The representative procedure was followed from enyne S32 (28.2 mg, 0.12 mmol); a colorless oil (18.2 mg, 64%) was obtained.

[0116] (1-(1-oxaspiro[4.5]decan-3-yl)vinyl)trimethylsilane (19) [ka] The representative procedure was followed from enyne S33 (25.5 mg, 0.11 mmol); a colorless oil (21.4 mg, 83%) was obtained.

[0117] tert-Butyl 7-(prop-1-en-2-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate-6,6,7,8,8-[D5] ([D5]-20) [ka] The representative procedure was followed from enyne[D3]-S25 (33.6 mg, 0.13 mmol) except that D2 was used instead of H2 gas; a colorless oil (23.5 mg, 69%) was obtained.

[0118] tert-Butyl 7-(3,3-diethoxyprop-1-en-2-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (21) [ka] Prepared in a similar manner from enyne S34 (30.7 mg, 0.090 mmol); a colorless oil (27.3 mg, 88%) was obtained.

[0119] tert-Butyl 7-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (22) [ka] Prepared in a similar manner from enyne S35 (36.0 mg, 0.091 mmol); yielding a colorless oil (26.0 mg, 72%).

[0120] Di-tert-butyl (6S * ,7R * )-7-(prop-1-en-2-yl)-5-oxa-2-azaspiro[3.4]octane-2,6-dicarboxylate (23) [ka] The representative procedure was followed from enyne S24 (44.2 mg, 0.13 mmol); a colorless oil was obtained (36.1 mg, contained 10% trans-hydrogenated product, 73%). An aliquot (26.4 mg) was purified by HPLC to give an analytically pure sample (19.8 mg).

[0121] tert-Butyl 9-(prop-1-en-2-yl)-7-oxa-2-azadispiro[3.1.4 6 .1 4 ]Undecane-2-carboxylate (24) [ka] The representative procedure was followed from enyne S28 (36.0 mg, 0.12 mmol); a colorless oil (27.7 mg, 76%) was obtained.

[0122] tert-Butyl (E)-7-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (25) [ka] Prepared in a similar manner from enyne S29 (39.7 mg, 0.10 mmol); colorless oil (18.0 mg, 45%).

[0123] tert-Butyl 7-(3,3,3-trifluoroprop-1-en-2-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (26) [ka] Prepared in a similar manner from enyne S36 (32.7 mg, 0.11 mmol); pale yellow oil (11.0 mg, 36%).

[0124] 1-Cyclohexyl-6-(prop-1-en-2-yl)-2,8-dioxabicyclo[3.2.1]octane (31) [ka] Prepared similarly from enyne 30 (26.4 mg, 0.11 mmol); a colorless oil (21.8 mg, 82%, mixture of diastereoisomers ∼2.5:1).

[0125] (3S * ,5R * )-3-(prop-1-en-2-yl)-1,6-dioxaspiro[4.4]nonane (33) [ka] Representative procedure B was followed from enyne 32 (34.4 mg, 0.21 mmol); a colorless oil (26.2 mg, 75%) was obtained.

[0126] (2R * ,4R *)-2-cyclohexyl-2-methoxy-4-(prop-1-en-2-yl)tetrahydrofuran (34) [ka] Prepared in a similar manner from enyne S40 (30.7 mg, 0.14 mmol); a colorless, very acid-labile oil (21.2 mg, 68%).

[0127] (1R * ,4R * ,5R * )-1-Dicyclohexyl-5-(prop-1-en-2-yl)-2,7-dioxabicyclo[2.2.1]heptane (35) [ka] Prepared in a similar manner from enyne S41 (22.0 mg, 0.10 mmol); a colorless, acid-sensitive oil (11.0 mg, 49%).

[0128] (4S * ,5S * )-4-(cyclohex-1-en-1-yl)-2,2-dimethyl-1,6-dioxaspiro[4.5]decane (36a) and (4S * ,5R * )-4-(cyclohex-1-en-1-yl)-2,2-dimethyl-1,6-dioxaspiro[4.5]decane (36b) Prepared in a similar manner from enyne S43 (30.7 mg, 0.090 mmol); flash chromatography (silica, hexane: tert-butyl methyl ether, 98:2) allowed the isolation of the diastereoisomers in analytically pure form. 36a: colorless oil (8.7 mg, 31%); 36b: colorless oil (7.2 mg, 27%).

[0129] (3S * ,5R * )-2,2-Dimethyl-3-(prop-1-en-2-yl)-1,6-dioxaspiro[4.4]nonane (37) [ka] The representative procedure was followed from enyne S42 (39.1 mg, 0.20 mmol); a colorless oil (25.6 mg, 65%) was obtained.

[0130] (1S * ,5S * ,7S * )-7-(prop-1-en-2-yl)-5-((trimethylsilyl)oxy)-2-oxabicyclo[3.2.1]octane (40) [ka] Prepared in a similar manner from enyne 39 (23.8 mg, 0.1 mmol); a colorless oil (16.9 mg, 70%).

[0131] 3-(Prop-1-en-2-yl)-1,7-dioxaspiro[4.4]nonane (41) [ka] Colorless oil (19.9 mg, 68%, mixture of diastereoisomers ~1.2:1).

[0132] tert-Butyl 3-(prop-1-en-2-yl)-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (42) [ka] Prepared in a similar manner from enyne S30 (26.0 mg, 0.098 mmol); colorless oil (20.0 mg, 77% (containing 5% unknown impurity), 1:1 mixture of diastereoisomers). 13 The analysis is further complicated by the fact that the signals in the C NMR spectrum are split (approximately 1:1) due to the presence of rotamers of the Boc group. Repeated flash chromatography gave a pure sample of one diastereoisomer, while the second was identified by an unidentified impurity. See the "Spectrum" copy below.

[0133] (1S * ,5S * ,7S * )-7-(prop-1-en-2-yl)-2-tosyl-5-((trimethylsilyl)oxy))-2-azabicyclo[3.2.1]octane (43) [ka] Prepared in a similar manner from enyne S44 (38.8 mg, 0.099 mmol), but with 4 mol% of [Cp*RuCl]4 (30.0 mg, 77%)

[0134] 6-(Prop-1-en-2-yl)-4-((trimethylsilyl)oxy)-2-oxabicyclo[2.2.1]heptane (44) [ka] Prepared in a similar manner from enyne S45 (27.7 mg, 0.12 mmol); colorless oil (14.0 mg, 51%).

[0135] tert-Butyl 4-hydroxy-6-(prop-1-en-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (45) [ka] [Cp *RuCl4 (5.4 mg, 4 mol%) was added to a stirred solution of enyne S46 (40.8 mg, 0.13 mmol) in 1,2-dichloroethane (1.6 mL, 0.1 M) in a flame-dried Schlenk tube under argon. While maintaining a static atmosphere of H2 (ambient pressure, balloon filled with H2), H2 was bubbled through the mixture for 2 min before the flask was immersed in a preheated oil bath at 70 °C. After stirring at 70 °C for 3 h, the mixture was cooled to room temperature and filtered through a plug of Florisil, eluting with Et2O (10 mL). The filtrate was evaporated and the residue was redissolved in THF (2.0 mL).

[0136] TBAF-3H2O (79.5 mg, 0.25 mmol) was added to the solution of this crude material and the mixture was stirred for 2 h before being poured into water. The aqueous phase was extracted with Et2O (3x5 mL), the combined organic layers were dried over MgSO4, evaporated and the residue was purified by flash chromatography (silica, Hex / EtOAc, 6:4) to give the title product as a colorless oil (25.9 mg, 81%).

[0137] 2,2-Dimethyl-4-(prop-1-en-2-yl)-1-tosylpyrrolidine (47) [ka] Prepared in a similar manner from enyne 46 (56.9 mg, 0.195 mmol); white solid (52.1 mg, 90%).

[0138] tert-Butyl 2,2-dimethyl-4-(prop-1-en-2-yl)pyrrolidine-1-carboxylate (48) [ka] The representative procedure was followed from enyne S47 (30.8 mg, 0.13 mmol); a colorless oil (17.2 mg, 55%) was obtained.

[0139] tert-Butyl (2R * ,3R *) 5,5-Dimethyl-3-(prop-1-en-2-yl)-1-tosylpyrrolidine-2-carboxylate (49) [ka] Prepared in a similar manner from enyne S48 (38.5 mg, 0.10 mmol); colorless oil (26.0 mg, 67%).

[0140] (4R * ,5S * ) 5-Methoxy-2,2-dimethyl-4-(prop-1-en-2-yl)-1-tosylpyrrolidine (50) [ka] Prepared similarly from enyne S49 (33.5 mg, 0.10 mmol); a colorless oil (20.1 mg, 60%).

[0141] 5,5,5-Trimethoxy-2-methylpent-1-en-3-yne (58) [ka] nBuLi (1.79 mL, 2.86 mmol, 1.6 M in hexane) was slowly added to a solution of 2-methyl-1-buten-3-yne (0.27 mL, 2.86 mmol) in THF (120 mL) at -78 °C, and the resulting mixture was stirred for 30 min. In parallel, BF3Et2O (0.74 mL, 2.86 mmol) was added dropwise to a solution of tetramethyl orthocarbonate (0.40 mL, 3.01 mmol) in Et2O (20 mL) at -78 °C. After the addition, the temperature was allowed to rise to 0 °C for 1 h, and the mixture was finally cooled again to -78 °C. Then, the solution of the organolithium reagent was added via cannula to the solution of the oxonium salt. After the addition was complete, the mixture was stirred at -78 °C for 1 h and at 25 °C for another 1 h. Finally, the mixture was cooled to −20° C. and then poured into a solution of Na2CO3 (70 mL) at 0° C. The aqueous phase was extracted with CH2Cl2 (3×50 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated to give the desired product as a colorless oil, which was used without further purification (377 mg, 77%).

[0142] 5,5,5-Triethoxy-2-methylpent-1-en-3-yne (61) [ka] Prepared similarly from tetraethyl orthocarbonate as a colorless oil.

[0143] 2,2-Dimethoxy-4-(prop-1-en-2-yl)tetrahydrofuran (59) [ka] (η 5 -Cp *

[0046] RuCl (8.9 mg, 2 mol%) was added to a stirred solution of 5,5,5-trimethoxy-2-methylpent-1-en-3-yne (70.0 mg, 0.41 mmol) in 1,2-dichloroethane (4.1 mL) in a flame-dried Schlenk flask under an argon atmosphere. While maintaining an atmosphere of H (atmospheric pressure, H-filled balloon), H was bubbled through the mixture for 2 min before immersing the flask in a preheated oil bath at 70 °C. After stirring at 70 °C for 3 h, the mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude product was purified by flash chromatography (silica, hexane / EtOAc) to give the desired product as a colorless oil (53.8 mg, 76%).

[0144] Methyl-4-(prop-1-en-2-yl)dihydrofuran-2(3H)-one (60) [ka] p-Toluenesulfonic acid monohydrate (3.1 mg, 0.016 mmol) was added to a stirred solution of 2,2-dimethoxy-4-(prop-1-en-2-yl)tetrahydrofuran (28.0 mg, 0.16 mmol) in acetone (1.0 mL) in a flame-dried Schlenk tube under an argon atmosphere. The mixture was concentrated and the residue was purified by flash chromatography (silica, CHCl) to give the desired product as a colorless oil (16.9 mg, 82%).

[0145] 5-Methyl-4-(prop-1-en-2-yl)dihydrofuran-2(3H)-one (62) [ka] (η 5 -Cp *

[0046] RuCl (22.0 mg, 2 mol%) was added to a stirred solution of 5,5,5-triethoxy-2-methylpent-1-en-3-yne (213 mg, 1.00 mmol) in 1,2-dichloroethane (10 mL) in a flame-dried Schlenk tube under an argon atmosphere. While maintaining an atmosphere of H (atmospheric pressure, H-filled balloon), H was bubbled through the mixture for 2 min before immersing the flask in a preheated oil bath at 70 °C. After stirring at 70 °C for 5 h, the mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica, hexane / EtOAc) to give the desired product as a colorless oil (87.3 mg, 62%).

[0146] conclusion As mentioned above, the hydrogenation CH insertion process of the present invention is a conceptually novel mode of H2-transfer to organic substrates, which the present inventors' group was able to discover after a century of intensive research devoted to catalytic hydrogenation in numerous academic and industrial laboratories. The present invention relates to the use of 1,3-eneynes bearing propargyl substituents, preferably in the form of [Cp * We demonstrate the suitability of this methodology for the use of [RuCl]4 as a catalyst. The resulting reaction has high preparative potential, particularly for the ready use of spiro and bridged ring systems as building blocks in medicinal chemistry and chemical biology. The method scales up well and is also suitable for the preparation of deuterated isotopes. This novel hydrogenative C-H insertion process provides a noteworthy addition to the growing list of reactions that utilize gem-hydrogenation as a means to generate reactive intermediates and is well suited for further exploration of this research area.

Claims

1. Hydrogenating the compound of formula (I) in an organic solvent in the presence of a Ru catalyst to obtain a compound of formula (II).

1. A method for C—H insertion by gem-hydrogenation of internal alkynes comprising: 【Chemistry 1】 wherein in formulas (I) and (II) -R １ and R ２ are each independently: hydrogen, but optionally R １ , R ２ at least one of which is not hydrogen; ○ Si(C １ ~C １２ alkyl) ３ , C(=O)-O-(C １ ~C １２ alkyl), or ○ (C １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) alkyl, Here, R １ and R ２ may form a ring system together via an alkyl or heteroalkyl; -R ３ and R ４ are each independently: ○ OSi(C １ ~C １２ alkyl) ３ , C(=O)-O-(C １ ~C １２ alkyl); or ○ (C １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) alkyl, Here, R ３ and R ４ may form a ring system together via an alkyl or heteroalkyl; -R ５ and R ６ are each independently: Hydrogen, deuterium, ○ (C １ ~C １２ ) alkyl, C(═O)—(C １ ~C １２ alkyl), C(═O)—O—(C １ ~C １２ alkyl), ○NR Ｎ１ R Ｎ２ , where R Ｎ１ is an arylsulfonyl group, (C １ ~C １２ ) alkylsulfonyl group, (C １ ~C １２ ) alkoxycarbonyl group, or —C(═O)—(C １ ~C １２ alkyl), and R Ｎ２ is C １ ~C １２ represents an alkyl group, or R Ｎ１ and R Ｎ２ are C １ ~C １２ represents an alkyl group, or ○ (C １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) alkyl, Here, R ５ and R ６ may form a ring system together via an alkyl or heteroalkyl; Here, R １ and R ２ do not form a ring with each other, R ２ and R ３ can form a ring system together, and / or R ３ and R ４ do not form a ring with each other, R ４ and R ５ can form a ring system with each other; - where Q is CH ２ , CH(C １ ~C １２ alkyl), C(C １ ~C １２ alkyl) ２ , O or NR Ｎ where R Ｎ is an arylsulfonyl group, (C １ ~C １２ ) alkylsulfonyl group, (C １ ~C １２ ) alkoxycarbonyl group or —C(═O)—(C １ ~C １２ alkyl), However, Q is CH ２ , CH(C １ ~C １２ alkyl), or C(C １ ~C １２ alkyl) ２ When expressing R ４ and R ５ are each independently １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) alkyl, and O or NR Ｎ and R Ｎ is an arylsulfonyl group, (C １ ~C １２ ) alkylsulfonyl group, (C １ ~C １２ ) alkoxycarbonyl group or —C(═O)—(C １ ~C １２ alkyl), R ３ is C １ ~C １２ Alkyl, hetero(C １ ~C １２ ) alkyl or OSi(C １ ~C １２ alkyl) ３ represents R ６ is hydrogen, deuterium, C １ ~C １２ Alkyl, or hetero(C １ ~C １２ ) represents alkyl, and R １ , R ２ , each independently represent: hydrogen, but optionally R １ , R ２ at least one of which is not hydrogen; ○ Si(C １ ~C １２ alkyl) ３ , C(=O)-O-(C １ ~C １２ alkyl), or ○ (C １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) alkyl, wherein the Ru catalyst is represented by formula (III): 【Chemistry 2】 Here, R ｃｐ１ ~R ｃｐ５ each independently represents a C which may be branched or linear; １ ~C ５ Alkyl, C ３ ~C ５ Cycloalkyl, OR Ｈ or NR Ｈ ２ , C(=O)-O-(C １ ~C １２ alkyl), C(=O)N(C １ ~C １２ alkyl) ２ and X represents Cl, Br, I, OTf, or BF ４ , P.F. ６， O (C １ ~C １２ alkyl), and L represents a ligand or a di-, tri- or tetramer thereof, such as [Cp ＊ RuCl] ４ That is, A method for C—H insertion via gem-hydrogenation of internal alkynes.

2. The Ru-catalyst is capable of reducing COD, NBD, (C １ ~C １２ alkyl)CN, or (C １ ~C １２ alkyl) ２ O, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, substituted pyridine, η-arene, H ２ and further common readily dissociating donor ligands known in the art, preferably [Cp ＊ RuCl] ４ where R １ ~R ６ and Q is as defined in claim 1. A method for C—H insertion by gem-hydrogenation of internal alkynes according to claim 1.

3. The compound of formula (I) is hydrogenated in the presence of a Ru catalyst in an organic solvent, In formula (I), R ３ and R ４ are each independently １ ~C １２ ) alkyl or (hetero)(C １ ~C １２ ) represents alkyl, R ３ and R ４ preferably form a ring system with each other via an alkyl or heteroalkyl, R １ and R ２ are each independently: hydrogen, but optionally R １ , R ２ at least one of which is not hydrogen; ○ Si(C １ ~C １２ alkyl) ３ , C(=O)-O-(C １ ~C １２ alkyl), or ○ (C １ ~C １２ ) alkyl, or hetero(C １ ~C １２ ) alkyl, and Here, R １ and R ２ can form a ring system with each other via an alkyl or heteroalkyl; R ５ and R ６ are each independently: Hydrogen, deuterium, ○ O (C １ ~C １２ alkyl), C(═O)—(C １ ~C １２ alkyl), C(═O)—O—(C １ ~C １２ alkyl), ○NR Ｎ１ R Ｎ２ , where R Ｎ１ is an arylsulfonyl group, (C １ ~C １２ ) alkylsulfonyl group, (C １ ~C １２ ) alkoxycarbonyl group, or —C(═O)—(C １ ~C １２ alkyl), and R Ｎ２ is C １ ~C １２ represents an alkyl group, or R Ｎ１ and R Ｎ２ are C １ ~C １２ represents an alkyl group, or ○ (C １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) alkyl, Here, R ５ and R ６ can form a ring system with each other via an alkyl or heteroalkyl, and where Q is O or NR Ｎ where R Ｎ is an arylsulfonyl group, (C １ ~C １２ ) alkylsulfonyl group, (C １ ~C １２ ) alkoxycarbonyl group or —C(═O)—(C １ ~C １２ represents a protecting group selected from A method for C-H insertion by gem-hydrogenation of internal alkynes according to claim 1 or 2.

4. The compound of formula (I) is hydrogenated in the presence of a Ru catalyst in an organic solvent, In formula (I), R ３ and R ４ are each independently １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) represents alkyl, R ３ and R ４ preferably form a ring system with each other via an alkyl or heteroalkyl, R ５ and R ６ are each independently hydrogen, deuterium, (C １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) represents alkyl, R １ and R ２ are each independently: hydrogen, but optionally R １ , R ２ at least one of which is not hydrogen; ○ Si(C １ ~C １２ alkyl) ３ , C(=O)-O-(C １ ~C １２ alkyl), or ○ (C １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) alkyl, Here, R １ and R ２ can form a ring system with each other via an alkyl or heteroalkyl, and Here, Q represents O. A method for C-H insertion by gem-hydrogenation of internal alkynes according to claim 1 or 2.

5. The compound of formula (I) is hydrogenated in the presence of a Ru catalyst in an organic solvent, In formula (I), R ３ and R ４ are each independently １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) represents alkyl, R ３ and R ４ preferably form a ring system with each other via an alkyl or heteroalkyl, R １ and R ２ are each independently: hydrogen, but optionally R １ , R ２ at least one of which is not hydrogen; Si(C １ ~C １２ alkyl) ３ , C(=O)-O-(C １ ~C １２ alkyl), or ○ (C １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) alkyl, where R １ and R ２ may form a ring system together via an alkyl or heteroalkyl; R ５ and R ６ are each independently: Hydrogen, deuterium, ○ O (C １ ~C １２ alkyl), C(═O)—(C １ ~C １２ alkyl), C(═O)—O—(C １ ~C １２ alkyl), ○NR Ｎ１ R Ｎ２ , where R Ｎ１ is an arylsulfonyl group, (C １ ~C １２ ) alkylsulfonyl group, alkoxycarbonyl group or —C(═O)—(C １ ~C １２ alkyl), and R Ｎ２ is C １ ~C １２ represents an alkyl group, or R Ｎ１ and R Ｎ２ are C １ ~C １２ represents an alkyl group, or ○ (C １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) alkyl, Here, R ５ and R ６ can form a ring system with each other via an alkyl or heteroalkyl, and where Q is NR Ｎ represents R Ｎ is an arylsulfonyl group, (C １ ~C １２ ) alkylsulfonyl group, alkoxycarbonyl group or —C(═O)(C １ ~C １２ represents a protecting group selected from A method for C-H insertion by gem-hydrogenation of internal alkynes according to claim 1 or 2.

6. The compound of formula (I) is hydrogenated in the presence of a Ru catalyst in an organic solvent, In formula (I), R １ and R ２ are each independently: hydrogen, but optionally R １ , R ２ at least one of which is not hydrogen; Si(C １ ~C １２ alkyl) ３ , C(=O)-O-(C １ ~C １２ alkyl), or ○ (C １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) alkyl, Here, R １ and R ２ may form a ring system together via an alkyl or heteroalkyl; R ３ and R ４ are each independently O(C １ ~C １２ ) represents alkyl, R ５ represents hydrogen, R ６ is hydrogen or (C １ ~C １２ ) represents alkyl, and Here, Q represents O. A method for C-H insertion by gem-hydrogenation of internal alkynes according to claim 1 or 2.

7. The compound of formula (I) is hydrogenated in the presence of a Ru catalyst in an organic solvent, In formula (I), R ４ and R ５ are each independently １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) alkyl, preferably containing O or NR Ｎ and R Ｎ is an arylsulfonyl group, (C １ ~C １２ ) alkylsulfonyl group, (C １ ~C １２ ) alkoxycarbonyl group or —C(═O)—(C １ ~C １２ alkyl), R ３ is (C １ ~C １２ ) alkyl, hetero(C １ ~C １２ ) alkyl or OSi(C １ ~C １２ alkyl) ３ represents R ６ is hydrogen, deuterium, (C １ ~C １２ ) alkyl, or hetero(C １ ~C １２ ) represents alkyl, and R １ , R ２ each independently represents: hydrogen, but optionally R １ , R ２ at least one of which is not hydrogen; Si(C １ ~C １２ alkyl) ３ , C(=O)-O-(C １ ~C １２ alkyl), or (C １ ~C １２ ) alkyl or hetero(C １ ~C １２ ) alkyl, and where Q is CH ２ , CH(C １ ~C １２ alkyl), or C(C １ ~C １２ alkyl) ２ Represents, A method for C-H insertion by gem-hydrogenation of internal alkynes according to claim 1 or 2.

8. 3. A process for C—H insertion by gem-hydrogenation of internal alkynes according to claim 1 or 2, wherein the compound of formula (I) is hydrogenated in the presence of a Ru catalyst in an organic solvent, preferably an organic solvent selected from aprotic non-polar organic solvents.

9. The compound of formula (I) is reacted with an organic solvent in the presence of a Ru catalyst under H 2 at a pressure of 0.1 to 100 bar, preferably 0.5 to 5 bar, more preferably 0.8 to 1.5 bar. ２ 3. A method for C-H insertion by gem-hydrogenation of internal alkynes according to claim 1 or 2, wherein hydrogenation is carried out under partial pressure.

10. 3. A process for C—H insertion by gem-hydrogenation of internal alkynes according to claim 1 or 2, wherein the compound of formula (I) is hydrogenated in an organic solvent in the presence of a Ru catalyst at a temperature ranging from 0° C. to 150° C., preferably from 60° C. to 80° C.

11. 3. The method for C—H insertion by gem-hydrogenation of internal alkynes according to claim 1 or 2, wherein the compound of formula (I) is hydrogenated in an organic solvent in the presence of a Ru catalyst in a molar amount of 1 to 10 mol % based on the molar amount of the compound of formula (I).

12. 3. A process for C—H insertion by gem-hydrogenation of internal alkynes according to claim 1 or 2, wherein the compound of formula (I) is hydrogenated in the presence of a Ru catalyst in an organic solvent for a reaction time of 30 minutes to 600 minutes, preferably 120 minutes to 240 minutes.

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