Article Cite This: J. Am. Chem. Soc. 2018, 140, 506−514
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Highly Enantioselective Synthesis of Propargyl Amides through Rh‑Catalyzed Asymmetric Hydroalkynylation of Enamides: Scope, Mechanism, and Origin of Selectivity Xiao-Yan Bai, Wen-Wen Zhang, Qian Li,† and Bi-Jie Li* Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing 100084, China S Supporting Information *
ABSTRACT: Chiral propargyl amides are particularly useful structural units in organic synthesis. The enantioselective synthesis of propargyl amide is highly desirable. Conventional approach involves the use of a stoichiometric amount of metal reagent or chiral auxiliary. In comparison, direct alkynylation with terminal alkyne is attractive because it avoids the use of stoichiometric organometallic reagent. The asymmetric coupling of aldehyde, amine, and alkyne (A3-coupling) provides an efficient method for the synthesis of N-alkyl and N-arylsubstituted propargyl amines, but this strategy is not amenable for the direct enantioselective synthesis of propargyl amide. We have developed a new strategy and report here a Rh-catalyzed asymmetric hydroalkynylation of enamides. Alkynylations occur regioselectively at the α position of an enamide to produce chiral propargyl amides. High yield and enantioselectivity were observed. Previous alkynylation methods to prepare chiral propargyl amine involve the nucleophilic addition to an electrondeficient imine. In contrast, our current approach proceeds through regioselective hydroalkynylation of an electron-rich alkene. Kinetic studies indicated that migratory insertion of the enamide to the rhodium hydride is turnover limiting. Computational studies revealed the origin of regio- and enantioselectivities. This novel strategy provides an efficient method to access chiral propargyl amides directly from terminal alkynes.
1. INTRODUCTION Stereochemically defined propargyl amides are valuable synthetic intermediates during the synthesis of a number of natural products and biologically relevant compounds.1 In addition, they are important building blocks in asymmetric synthesis because the alkyne group can be functionalized in many ways.2 Existing alkynylation methods to prepare chiral propargyl amide involve the nucleophilic addition of an alkynyl metallic reagent to N-acyl imine assisted by a stoichiometric amount of chiral auxiliary.3−6 The alkynyl metal compounds require an additional step to be generated and could limit the functional group tolerance. In this respect, catalytic asymmetric alkynylation using a terminal alkyne is advantageous because it could overcome these limitations. Currently, the prevailing strategy to access chiral propargyl amine involves the copper- and silver-catalyzed asymmetric alkynylation of imines, which are generated from amine and aldehyde, with terminal alkyne (A3-coupling).7−9 However, these methods generate chiral propargyl amines with N-alkyl or N-aryl substituents, which are not readily removable in many cases.9a,10 Recently, several examples of asymmetric alkynylation with terminal alkyne for the synthesis of propargyl thiophosphinoic amide,11 sulfonamide,12 and carbamate12,13 have appeared, but the substrates were limited to Nphosphinoyl, sulfonyl, and alkoxycarbonyl imines that bear no enolizable α proton. Asymmetric synthesis of α-alkyl propargyl amide through direct alkynylation with terminal alkyne represents a distinct © 2017 American Chemical Society
synthetic challenge. First, N-acyl imine derived from aliphatic aldehyde is usually unstable.14 It may not be compatible with the conditions of metal-catalyzed asymmetric alkynylations. Second, in some cases, N-acyl imine bearing enolizable α proton could isomerize to an enamide.15 Once this isomerization occurs, the substrate loses its electrophilicity. As a result, a highly enantioselective method to access α-alkyl propargyl amide from terminal alkyne has not been reported. Moreover, all of the current asymmetric alkynylations of imines appear to occur under proton-transfer conditions.7−13 To achieve an asymmetric synthesis of α-alkyl propargyl amide from terminal alkyne, a new synthetic strategy must be adopted to circumvent the challenges associated with the alkynylation of alkylsubstituted N-acyl imine. Recently, our group reported the first example of iridiumcatalyzed enantioselective hydroalkynylation of enamides.16 The alkynylation occurred regioselectively at the β position of the enamides to produce homopropargyl amides (Scheme 1). We reasoned that if the regioselectivity of the hydroalkynylation could be reversed and the stereochemistry could be controlled, this strategy could provide access to chiral propargyl amide. Because enamides can be prepared from a variety of existing methods,17 our enamide hydroalkynylation strategy would provide a straightforward method for the synthesis of enantioenriched propargyl amides. Although Received: November 14, 2017 Published: December 12, 2017 506
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Journal of the American Chemical Society Table 1. Evaluation of Bisphosphine Ligandsa
Scheme 1. Design of an Enamide Hydroalkynylation for the Synthesis of Propargyl Amide
Knochel and co-workers reported the only example of catalytic asymmetric addition of alkynes to enamines,18 it occurred through an iminium intermediate formed by enamine isomerization,8b which is the identical intermediate in A3 coupling. As our continuing interest in asymmetric alkynylation,16,19 we report the identification of a rhodium catalyst system that catalyzes the regioselective and enantioselective hydroalkynylation of enamide and delivers the α-alkyl propargyl amides in excellent enantioselectivities. Mechanistic studies suggest that this hydroalkynylation occurs through hydroalkynylation of the electron-rich double bond, which is in contrast with previous alkynylations of electron-deficient CN bonds that proceed through a proton-transfer mechanism.7−13
a Reaction conditions: 1 (1.0 equiv), 2 (3.0 equiv), Rh(COD)2OTf (5.0 mol %), ligand (6.0 mol %), 75 °C, 12 h. Isolated yields were reported. The ee values were determined by HPLC on a chiral stationary phase.
Table 2. Hydroalkynylation of Enamidesa
II. RESULTS AND DISCUSSION 2.1. Reaction Development. To verify our hypothesis, we began to study the catalyst system of hydroalkynylation of enamides (Table 1). The catalysts formed from Ir(COD)2OTf with a series of bisphosphine ligands did not provide any propargyl amide in the hydroalkynylation (see the Supporting Information). Thus, we turned our attention to rhodium-based catalysts.20,21 The combination of Rh(COD)2OTf and chiral ligands was tested in the hydroalkynylation. A large difference between iridium- and rhodium-based catalysts was observed. The regioselectivity was completely reversed from β-alkynylation to α-alkynylation. When DIOP (L1) was used as a ligand, 62% yield of propargyl amide was obtained, although with low enantioselectivity. The use of a Josiphos ligand (L2) and a ferrocelane ligand (L3) provided slightly improved enantioselectivities. Further improvement of ee was obtained when MeDuphos (L4) was used as a ligand. Thus, we further tested other alkyl-substituted chiral bisphosphine ligands. Both high yield and high enantioselectivity of hydroalkynylation were achieved when the ligand was switched to iPr-MeOBIPhep (L5). The alkyl substituent on the phosphine atom is important for both reactivity and enantioselectivity, as indicated by the lower yield and ee obtained with ligand L6. In all of these cases, hydroalkynylation occurs exclusively at the α-position. No product from β-alkynylation was observed. Hydroalkynylations with various aryl- and alkyl-substituted enamides showed that the substituents on the amide had an influence on the yield and enantioselectivity (Table 2), probably as a result of their delicate difference in coordination with rhodium catalyst. The reaction with a phenyl-substituted
a Reaction conditions: 1 (1.0 equiv), 2 (3.0 equiv), Rh(COD)2OTf (5.0 mol %), L5 (6.0 mol %), 75 °C, 12 h. Isloated yields were reported. b60 °C.
enamide afforded the alkynylation product in 84% yield and 90% ee (3a). Slightly decreased enantioselectivity was obtained in the alkynylation of the methyl group-substituted enamide (3b). However, the enantioselectivities were increased with enamides bearing a larger alkyl group (3c, 3d). The hydroalkynylation of t-butyl-substituted enamide can be conducted at 60 °C to afford higher yield and enantioselectivity (3d). The stereochemistry of the enamide had an impact on the alkynylation (eq 1). The reaction of E-enamide produced the product in significantly lower yield. However, the major enantiomer has the same configuration as that observed in the reaction of Z-enamide. The same enantiofacial selection indicated that the sense of enantioselectivity is not primarily determined by the configuration of the enamide. 507
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Journal of the American Chemical Society
dimerization,20g a process that could lead to catalyst deactivation. The scope of Z-enamides of the Rh-catalyzed enantioselective hydroalkynylation is demonstrated in Table 4. The Table 4. Scope of Enamidesa 2.2. Substrate Scope. After identification of an effective catalyst for the regioselective hydroalkynylation, the scope of the substrates was further probed. First, the reactivities of various alkynes were tested. As shown in Table 3, the reaction Table 3. Scope of Alkynesa
a
Reaction conditions: 1 (1.0 equiv), 2 (3.0 equiv), Rh(COD)2OTf (5.0 mol %), (R)-L5 (6.0 mol %), 60 °C, 12 h. Isolated yields were reported. bTriisopropylsilyl acetylene was used. a
Reaction conditions: 1 (1.0) equiv), 2 (3.0 equiv), Rh(COD)2OTf (5.0, mol %), (R)-L5 (6.0 mol %), 60 °C, 12 h. Isloated yields were reported. b10 mol % Rh catalyst, 70 °C.
reactions occurred with a range of alkyl-substituted enamides in good yields and high enantioselectivities (4a−4i). Functional groups including alkyl halide, alcohol, silyl ether, benzyl ether, acetal, carbamate, and ester were all compatible with the reaction conditions (4b−4h). Vinyl and propenyl enamide also underwent regioselective alkynylation, although slightly lower enantioselectivities were observed (4i−4i′′). Currently, alkynylation of trisubstituted enamides has not been successful. Further effort is ongoing in this direction. The asymmetric alkynylations of styryl enamides were also investigated (Table 5). The reaction of tert-butyl-substituted styryl enamide gave a significantly lower yield despite increased catalyst loading (4j), probably as a result of increased steric hindrance of a phenyl as compared to an alkyl group. A change of amide structure revealed that the iso-butyl group is the substituent of choice, which promoted the alkynylation to occur in 77% yield and 95% ee (4k). Reactions of acetamide and benzamide occurred in lower yields (4l, 4m). The current catalytic system is applicable to a variety of styryl enamides (Table 6). Both electron-donating (4n−4p) and electron-withdrawing (4q−4u) groups on the phenyl ring were tolerated. Aryl chloride and even aryl bromide were compatible with the reaction conditions, which provided opportunities for
occurred with a range of silyl-, alkyl-, and aryl-substituted alkynes in good yields and high enantioselectivities (3d−3o), although higher catalyst loading was necessary for alkyl and aryl acetylenes. In our previous Ir-catalyzed as well as a number of other catalytic hydroalkynylation reactions, the alkynes were limited to silylacetylenes.16,19a,20a−e,g Thus, the current catalyst system has an expanded alkyne scope. A number of silyl acetylenes substituted with different groups underwent alkynylation in high yields and excellent enantioselectivities (3d−3g). In addition, sterically hindered alkyl alkynes also participated in the hydroalkynylation, as demonstrated by the alkynylation products 3h−3j. Similarly, high yields and enantioselectivities were obtained in the reactions of 2,6disubstituted aryl acetylenes (3l, 3m). The alkynylation with 2methylphenyl acetylene provided the product in lower yield but high enantioselectivity (3n). The low reactivity observed for npentyl (3k)- and phenyl (3o)-substituted acetylenes further demonstrated the importance of steric hindrance of the alkyne. It is likely that the bulky substituent suppresses alkyne 508
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Journal of the American Chemical Society Table 5. Reactivity of Styrylamidea
molecules. For example, an enamide substituted by a cholesterol framework underwent alkynylation smoothly, generating the corresponding product in 75% yield and excellent diastereocontrol (4v) (Scheme 2). Chemoselective Scheme 2. Functionalization of Cholesterol-Substituted Enamide
a Reaction conditions: 1 (1.0 equiv), 2 (3.0 equiv), Rh(COD)2OTf (10.0 mol %), (R)-L5 (12.0 mol %), 60 °C, 12 h. Isolated yields were reported.
Table 6. Scope of Aromatic Enamidea alkynylation of enamide was observed in the presence of a double bond. Moreover, many naturally occurring molecules contain enamide structure (Scheme 3).17f,23 When the current Scheme 3. Functionalization of Z-Alatamide and Lansiumamide A
asymmetric alkynylation is applied to Z-alatamide,24 the product was afforded in good yield and enantioselectivity, although a higher reaction temperature was necessary. Lansiumamide A23 contains two electronically distinct alkenes, an electron-rich alkene and an electron-deficient alkene. This molecule provided a platform to probe the chemoselectivity for the alkynylation reaction. Hydroalkynylation occurred exclusively at the enamide, affording the propargyl amide in good yield and enantioselectivity. This mode of reactivity has not been observed with any other alkynylation catalyst. 2.4. Transformation of Products. The alkyne group provides a useful handle for further functionalization of the hydroalkynylation product (Scheme 4).25 Treatment of 3d with TBAF resulted in quantitative formation of terminal alkyne, which could undergo a variety of further transformations. For example, hydrozirconation of 5 followed by treatment with elemental iodine delivered the vinyl iodide trans-6 in good
a
Reaction conditions: 1 (1.0 equiv), 2 (3.0 equiv), Rh(COD)2OTf (10.0 mol %), (R)-L5 (12.0 mol %), 60 °C, 12 h. Isolated yields were reported. The ee values were determined by HPLC on a chiral stationary phase.
further functionalization (4q−4s, 4u).22 The absolute configuration of compound 4s was determined by X-ray crystallography of its desilylated product (4s-H). 2.3. Functionalization of Complex Molecules. To demonstrate the synthetic utility of the alkynylation reaction, we sought to apply our catalytic system to functionalized 509
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Journal of the American Chemical Society Scheme 4. Transformation of Propargyl Amidea
N-acyl imine, the hydroalkynylation of E-enamide 1y was analyzed. If the isomerization of enamide to N-acyl imine occurred, the hydroalkynylations of Z- and E-enamides would give the propargyl amide in identical ee because the same Nacyl imine intermediate would be involved in both reactions.26b However, hydroalkynylations of Z- and E-enamides afforded the product in 89% and 82% ee, respectively. The difference in ee values provided further evidence against a mechanism involving enamide-to-imine isomerization. Rather, the low yield of product observed from N-benzoyl imine 9 is likely a result of its isomerization to the more stable E-enamide. The similar ee values obtained from the reactions of E-enamide E-1y and Nbenzoyl imine 9 also support the imine-to-enamide isomerization process. To gain further insight into the mechanism, we sought to analyze the stereochemistry of the hydroalkynylation product. If the reaction occurred through hydroalkynylation of the alkene, a stereospecific syn-addition product would be observed. In contrast, if the reaction occurred through alkynylation of an imine intermediate, a syn-addition would not be expected, because the proton and the alkynyl group would be added to the alkene in separated steps. To investigate the stereochemistry, deuterium labeling experiments were conducted (Scheme 6). To minimize deuterium scrambling through
a Reaction conditions: (a) TBAF, THF, r.t. (b) Cp2ZrHCl, I2, THF, 0 °C, r.t., −78 °C. (c) H2, Pd/C, MeOH, r.t. (d) Boc2O, DMAP, CH3CN, r.t. (e) LiOH, H2O2, THF/H2O/MeOH, r.t.
Scheme 6. Investigation of Stereochemistry
yield. In addition, alkyne 5 underwent complete hydrogenation to afford an alkyl amide 7 in high yield. High enantioselectivities were maintained in the products during these transformations. The amide group of the products can be removed under mild reaction conditions. Activation of 3c with Boc2O and subsequent treatment with LiOH/H2O2 gave the product 8. The Boc group in 8 could be easily removed under acidic conditions to afford a free propargyl amine. 2.5. Identification of the Reaction Pathway. In a possible scenario, the enamide could isomerize to N-acyl imine.26 This imine intermediate could undergo a subsequent alkynylation to generate propargyl amide. To test this hypothesis, control experiments were conducted (Scheme 5). Scheme 5. Reactivity of Enamides and N-Acyl Imine exchange with acidic proton, the protons in enamide 1c were deuterated before rhodium-catalyzed hydroalkynylation with Dlabeled alkyne. The hydroalkynylation product was further converted to pyrrolidine amide 11 through an intramolecular cyclization. NOE experiment established a cis-configuration of the deuterium and the alkyne group in 11 (see the Supporting Information for the synthesis of the other diastereoisomer). These results suggest that the alkynylation occurs exclusively through a syn-addition process, which further supports a mechanism involving the hydroalkynylation of the alkene rather than an imine. Moreover, although some deuterium was lost during the hydroalkynylation, 2D NMR experiment indicated that no deuterium was incorporated trans to the alkyne in product 11 (see the Supporting Information for details). This suggests that the alkene insertion is an irreversible step, because reversible alkene insertion would result in deuterium exchange at the β vinylic position of the enamide 1c and consequently deuterium incorporation trans to the alkyne. 2.6. Characterization of the Resting State Rh Complex. The Rh-catalyzed hydroalkynylation reaction of
N-Benzoyl imine 9 was independently synthesized and used immediately after its preparation due to its instability.27 Alkynylation of 9 under the standard conditions afforded the product in 12% yield and 88% ee. The low yield observed in the alkynylation of 9 indicated that 9 is less likely to be an active intermediate. To further probe the isomerization of enamide to 510
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Journal of the American Chemical Society vinyl enamide 1i was monitored by 31P NMR. One major rhodium complex was observed throughout the major course of the reaction. Two doublet of doublets at 58.2 and 24.7 ppm indicated that the two phosphorus atoms are inequivalent. Control experiments revealed that the major species can be formed from a combination of rhodium precursor, phosphine ligand, and enamide (eq 2). The 31P NMR of the independently synthesized complex 13 matches that of the major species observed in a catalytic reaction. Thus, the resting state of the catalytic reaction is the enamide bound rhodium complex 13.
Scheme 7. Kinetic Isotopic Effect
Scheme 8. Proposed Mechanism The relevance of complex 13 to the catalytic cycle was determined by measuring the rate of the alkynylation reaction catalyzed by 13. The initial rate of the reaction catalyzed by 13 is the same as that of a reaction catalyzed by Rh(COD)2OTf and L5. Thus, complex 13 is kinetically competent to be part of the catalytic cycle. 2.7. Kinetic Studies of a Representative Catalytic Reaction. The reaction kinetics of the Rh-catalyzed hydroalkynylation of enamide 1i with 2a was monitored by in situ IR (Figure 1). The lack of induction period enabled us to obtain
by enamide forms the catalyst resting state 13. Coordination and subsequent oxidative addition of silylacetylene generates an alkynyl rhodium hydride intermediate 15. Turnover-limiting migratory insertion of the enamide provides an alkyl rhodium intermediate 16, which is coordinated to the amide. Finally, C− C bond-forming reductive elimination of the rhodium intermediate 16 gives the hydroalkynylation product and regenerates the rhodium catalyst. Further insight into the composition of the highest energy transition state was obtained by analysis of the activation parameters (Figure 2). Eyring analysis of the rate constants for the catalytic hydroalkynylation at temperatures from 313 to 333 K revealed the following activation parameters: ΔH⧧ = 11.2 ± 0.9 kcal/mol and ΔS⧧ = −35 ± 3 eu. The large, negative activation entropy is consistent with the highest energy transition state being formed from the combination of the resting state 13 with alkyne followed by internal structural changes. 2.8. Computational Studies. In parallel with our kinetic studies, we conducted computational studies by density functional theory. The calculations were conducted with the Gaussian 09 package. Geometry optimizations were conducted with B3LYP functionals with the LANL2DZ basis set for Rh and 6-31g(d,p) basis set for all other atoms at 298 K. Singlepoint energy calculations were conducted with the M06 functional with the SDD basis set for Rh and the 6-311+
Figure 1. Kinetic profile for a catalytic reaction under the standard conditions.
kinetic data through initial-rates methods. The reaction was found to be first order in catalyst, first order in alkyne, and zeroth order in enamide. These measurements, together with the identity of the resting state, suggest that the turnoverlimiting step (TLS) is the combination of an alkyne with the resting-state complex containing a bound enamide. The identity of the TLS was further probed by kinetic isotopic effect (KIE). A comparison of the initial rates for the catalytic hydroalkynylations with 2a and 2a−d in separate vessels revealed a KIE of 1.5 ± 0.2 (Scheme 7). This relatively small KIE suggests that the cleavage of the alkynyl C−H bond is less likely to be turnover limiting. We have showed that the alkene insertion is irreversible (via supra). Therefore, the insertion of an electron-rich alkene into Rh−H bond is the turnover-limiting step. A catalytic cycle shown in Scheme 8 is consistent with our mechanistic data. Ligand displacement of the catalyst precursor 511
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is lower than the activation barrier of subsequent migratory insertion (TS-2a). Thus, the C−H cleavage is reversible, which is consistent with our kinetic data. The migratory insertion has the highest activation barrier. This irreversible step is both turnover-limiting and enantioselectivity-determining. During the search for the transition state of reductive elimination from 16a, intermediate 16a′ was located. Facile reductive elimination from intermediate 16a′ through TS-3a occurs with an activation barrier of 19.1 kcal/mol. To gain insight into the origin of enantioselectivity, we computed the reaction pathways for all four possible diastereoisomers of intermediate 14 (Figure 4). Intermediates 14a and 14c contain enamide bound with Si-face, while intermediates 14b and 14d contain enamide bound with Reface. They differ in the spatial arrangement of the enamide and the alkyne. Full energy surfaces of these four pathways are provided in the Supporting Information. A comparison of the activation barriers for the migratory insertion revealed that TS2a has the lowest energy, leading to the major enantiomer observed. TS 2d, connected with intermediate 14d, is slightly higher in activation free energy and leads to the minor enantiomer. Comparison of the diastereomeric transition states (TS-2a, TS-2d) leading to the formation of two enantiomers revealed the origin of enantioselectivity (Figure 5). Three isopropyl groups on the ligand point toward the coordination sites of the ligated substrates, rendering quadrants II, III, and IV less accessible. In TS-2a, the bound enamide experiences steric interaction with isopropyl group in quadrant IV due to the proximity of the vinylic hydrogen with the methine hydrogen on the ligand. However, TS-2d experiences stronger steric repulsion than TS-2a. The bound enamide is positioned in a way that two vinylic hydrogen atoms are pointing toward the isopropyl group in quadrant IV. Moreover, a C−H···O attractive interaction of the carbonyl oxygen and the hydrogen atom on the ligand was observed in TS-2a.28 The analogous
Figure 2. Top: Consumption of enamide 1i versus time at variable temperatures. Bottom: Eyring analysis of the measured rate constants.
+g(d,p) basis set for all other atoms, along with the SMD THF solvent correction. First, the energy surface of the catalytic cycle shown in Figure 3 was calculated. The oxidative addition of the alkynyl C−H bond has an activation barrier of 22.0 kcal/mol (TS-1a), which
Figure 3. Computed pathway for catalytic hydroalkynylation. 512
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Figure 4. Computed transition states for migratory insertions.
interaction in the two diastereomeric transition states for migratory insertion contribute to the observed enantioselectivity. Further investigation to improve the catalyst activity and application of this methodology is currently in progress.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b12054. Experimental procedures, characterization of new compounds, and spectroscopic data (PDF) X-ray crystallographic data for C14H16BrNO (CIF)
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AUTHOR INFORMATION
Corresponding Author
*
[email protected] Figure 5. Computed structures for transition states TS-2a and TS-2d.
ORCID
Bi-Jie Li: 0000-0001-8528-8514
attractive interaction in TS-2d was weaker due to the longer C−H···O distance (2.66 vs 2.62 Å) and smaller C−H−O angle (157.5° vs 174.6°). Therefore, the less steric repulsion and stronger attractive interaction contribute to the lower energy of TS-2a than that of TS-2d. These calculations imply that the difference in orientation of the enamide in the diastereomeric transition states for migratory insertion governs the enantioselectivity of the alkynylation reaction.
Present Address †
The Affiliated High School of Peking University, Beijing 100080, China. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is dedicated to Prof. Qi-Lin Zhou on the occasion of his 60th birthday. This work was supported by the National Natural Science Foundation of China (Grant no. 21672122), 111 Project (B16028), and the National Program for Thousand Young Talents of China. B.-J.L. thanks Prof. Lei Jiao at CBMS for helpful discussions. We thank the analytical center at CBMS for access to the instruments.
3. CONCLUSION In summary, we have developed a rhodium-catalyzed enantioselective hydroalkynylation of enamides with terminal alkyne. The reaction occurs with complete α-selectivity and high enantioselectivity. A wide variety of functional groups were tolerated. This method provides a novel strategy for the enantioselective synthesis of α-alkyl propargyl amides, which could be further elaborated to other useful chiral building blocks. Mechanistic studies indicated that the reaction occurs through stereospecific hydroalkynylation of the electron-rich alkene. This is a completely different mechanism with conventional alkynylations that occur under proton-transfer conditions. Experimental data and computational studies revealed that the migratory insertion is both turnover-limiting and enantioselectivity-determining. Computational studies suggest that the differences of steric repulsion and attractive
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REFERENCES
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DOI: 10.1021/jacs.7b12054 J. Am. Chem. Soc. 2018, 140, 506−514
Article
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DOI: 10.1021/jacs.7b12054 J. Am. Chem. Soc. 2018, 140, 506−514
