Rhodium‐Catalyzed Asymmetric Intramolecular Hydroamination of Unactivated Alkenes

Metal-catalyzed enantioselective intramolecular hydroamination of olefins1 is one of the most conceptually simple and atom-economical approaches to the construction of enantioenriched nitrogen heterocycles,2 which are valuable synthons in the preparation of natural products and biologically active molecules.3 Despite significant advances,4,5,6 no general solution for this challenging transformation has yet been realized. Some of the most reactive catalysts are based on lanthanides5 and group 4 transition metals,6 but only a small number of highly enantioselective (>90% ee) reactions have been described.5a, 6b, 6c Noteworthy is Schafer’s6c elegant report of chiral zirconium amidate complexes which provide good enantioselectivity for a range of terminal alkenes, but require a geminal dialkyl group7 to bias the substrates toward cyclization. Furthermore, the sensitivity of rare earth and group 4 metal catalysts toward air and moisture and their low functional group tolerance have limited their synthetic utility and motivated efforts to develop alternative systems. Some late transition metal complexes have been investigated for enantioselective hydroamination, with good results for alkynes,8 allenes,9 dienes,10 and vinylarenes.11 Very recently one example of an intermolecular hydroamination of unactivated 1-alkenes with an ee up to 78% was reported.12,13 To the best of our knowledge, however, there are no examples of late transition metal-catalyzed enantioselective intramolecular hydroamination of unactivated olefins. Herein we disclose the first example of a rhodium-catalyzed14 asymmetric intramolecular addition of amines to olefins for the synthesis of a variety of enantioenriched 2-methylpyrrolidines with good enantioselectivity (up to 91% ee). Recent reports of the successful application of the dialkylbiaryl phosphines DavePhos15a, t-BuDavePhos15b and JohnPhos15c in rhodium-, platinum- and gold-catalyzed intramolecular hydroamination by Hartwig14a and Widenhoefer16,17 respectively, stimulated us to develop a late transition metal-catalyzed enantioselective version of this process using chiral ligands of the type developed in our laboratory.15 We began by examining the cyclization of N-benzyl-2,2-diphenyl-4-pentenamine 1a to 1-benzyl-2-methyl-4,4-diphenylpyrrolidine 1b as a test reaction (eq. 1). Following the seminal work of Hartwig,14a we exposed 1a to 5 mol% [Rh(COD)2]BF4 and 6 mol% KenPhos L1,18 providing pyrrolidine 1b in 95% yield (GC) and 38% ee (entry 1). Varying the size of the substituent on nitrogen or phosphorus provided ligands19,20 that gave the product in good yield but poor ee (entries 2 and 4). Control experiments in which the metal was omitted or replaced by a protic acid resulted in no product formation. No improvement in yield or enantioselectivity was seen if alternative Rh sources were employed (see supporting information). We next turned our attention to MOP21 derivatives, the use of Cy-MOP L6,22 afforded 1b in 96% yield with 53% ee (entry 6). Given this promising result, several Cy-MOP-type ligands were prepared using a slight modification of the literature procedure.22 The selectivity of the hydroamination reaction improved with increasing size of the oxygen substituent (entries 6-8). We found that the dialkylphosphino group was essential for high activity; attempts to employ the diphenylphosphine L10 furnished <10% yield of product (entry 10). Among the ligands evaluated, L9 with a (diphenyl)methyl-substituted alkoxy group provided the best combination of reactivity and enantioselectivity, affording 1b in 95% yield and 80% ee (entry 9). The scope of the reaction is summarized in Table 2. Cyclization of substrates with geminal substitution in the homoallylic position proved to be the most facile, the reactions proceeding in the highest yields and with good enantioselectivities. Typically these reactions could be carried out at 70 °C with 5 mol% Rh. However, for the easiest substrates the reaction still proceeded at an acceptable rate at 50 °C, affording a slight increase in enantioselectivity (entry 2 and 5). In the case of substrates lacking substitution that facilitate cyclization, the use of the less sterically demanding ligand L8 was more efficient. Using a catalyst system based on L8, these substrates could be cyclized with comparable enantioselectivity, although in somewhat lower yield (entries 10-13). These results are some of the best reported for the enantioselective cyclization of unbiased substrates using a transition metal-based catalyst.5a,5d In the case of racemic N-2-methylbenzyl-2-phenyl-4-pentenamine 5a no kinetic resolution was observed, the diastereomeric products were obtained in a 1.1:1 ratio with high enantiomeric excess (87% and 91% ee respectively, entry 8). Table 2 Rhodium-Catalyzed Enantioselective Intramolecular Hydroamination of Aminoalkenes[a] The nature of the protecting group on nitrogen had a pronounced influence on the outcome of the reaction. We found that N-(2-methyl)benzyl aminoolefins gave higher enantioselectivity than N-benzyl aminoolefins in some cases, without adversely effecting the yield (entries 3-8). Presumably the substituent at the 2-position results in a more ordered transition state. Increasing the size of this substituent or using a 2,6-dimethylbenzyl protecting group, however, elicited a profound decrease in reactivity, perhaps as a result of inhibition of metal binding. Varying the para-substituent on the aryl ring of the nitrogen protecting group had little effect on the enantioselectivity, but electron-donating substituents retarded the reaction and resulted in a lower yield. 23 Typically, unprotected aminoolefins exhibited poor reactivity, however, 2-allylaniline did undergo hydroamination to yield 2-methylindoline with moderate enantioselectivity (entry 14). Functional groups including esters and aryl chlorides were tolerated under the reaction conditions rendering the products amenable to further synthetic manipulation (entry 11 and 13). The absolute configuration of the products was determined to be (S) by conversion of 1b to the known (S)-MPTA amide,6c 6b-10b to the known N-naphthyl amides5e and 11b to the previously reported N-acetyl-2-methylindoline. 24 The N-protecting groups on the products in Table 2 were easily removed to reveal the free amines via catalytic transfer hydrogenation25 with ammonium formate as hydrogen source. For example, treatment of the cyclized product 2b (Table 2, entry 5) with palladium on activated carbon and ammonium formate at 68 °C in methanol afforded the 2-methylpyrrolidine 2c in 92% yield. In summary, we have developed the first enantioselective rhodium-catalyzed intramolecular hydroamination of unactivated terminal alkenes. A variety of enantioenriched pyrrolidines have been synthesized in up to 91% ee using a binaphthyl-based electron-rich phosphine ligand. Further investigations to increase the generality of the process and to expand the scope to include intermolecular reactions are currently underway in our laboratories.