Enantioselective Olefin Hydrocyanation Without Cyanide Alexander W. Schuppe,† Gustavo M. Borrajo-Calleja,† Stephen L. Buchwald* Department of Chemistry, Massachusetts Institute of TechnoloGy, 77 Massachusetts Avenue, CambridGe, Massachusetts 02139, United States Supporting Information Placeholder A. Prototypical Asymmetric Olefin Hydrocyanation ▪ ABSTRACT: The enantioselective hydrocyanation of ole- ▪ fins represents a conceptually straightforward approach CN In situ generated or direct use of HCN R2 H-CN R2 Typically non-commercially available ligands (L*) R1 R1 * to prepare enantiomerically enriched nitriles. These, in [Ni], L* Highly regioselective, limited to vinyl arenes turn, comprise or are intermediates in the synthesis of many pharmaceuticals and their synthetic derivatives. B. This Approach Herein, we report a cyanide-free dual Pd/CuH-catalyzed O cyanide-free CN 2 protocol for the asymmetric Markovnikov hydrocya- R R2 R1 formal asymmetric R1 N nation of vinyl arenes and the anti-Markovnikov hydro- 1 X 2 olefin hydrocyanation 3 cyanation of terminal olefins in which oxazoles function as nitrile equivalents. After an initial hydroarylation pro- O Cu Pd retro-[4+2] cess, the oxazole substructure was deconstructed using a [4+2]/retro-[4+2] sequence to afford the enantioenriched 6 O nitrile product under mild reaction conditions. O R N N R R1 [4+2] R R R2 R1 R2 4 5 Nitriles are a ubiquitous class of compounds present in many [not isolated] pharmaceuticals,1 secondary metabolites,2 and polymers.3 OwinG C. Proposed Dual Catalytic Cycle to their unique chemical reactivity, nitriles often serve as precursors L Pd X L*Cu to numerous additional important functional Groups in organic syn- O R2 N thesis, includinG N-heterocycles, carbonyl compounds, and R1 4 O N amines. AlthouGh nitriles can be accessed by many methods, the R2 II X R1 IV 2 conversion of olefins to alkyl nitriles via transition metal-catalyzed 1 olefin hydrocyanation represents one of the most conceptually straiGhtforward processes. While hydrocyanation of feedstock ole- L*CuH Copper Palladium LPd I III fins is conducted on a million-metric ton scale annually to produce nitrile precursors to polymers,3 these protocols employ hydroGen R3SiOR, MX R1 O cyanide and form almost exclusively achiral products. Despite the L Pd N numerous improvements in the racemic hydrocyanation of olefin R2 L*CuX 2 5 6 N R R1 feedstocks and fine chemicals, the reaction conditions and sub- R3SiH, O MOR VI 4 strates employed in the analoGous asymmetric variant of this trans- V formation have advanced minimally since the seminal work by Figure 1. A. Traditional approaches to asymmetric olefin hydro- 7a 7b–7d,7g Jackson and RajanBabu. cyanation. B. Our dual Pd/CuH-catalyzed asymmetric olefin hy- Asymmetric olefin hydrocyanation is typically achieved through drocyanation usinG oxazoles as masked nitriles, followed by a ther- the formal addition of hydroGen cyanide, either generated in situ or mal deconstruction of 4 to the enantioenriched nitrile. C. Proposed employed directly in gaseous form, across an olefin facilitated by a dual Pd/CuH catalytic cycles for the hydrofunctionalization pro- chiral phosphine-ligated metal catalyst (Scheme 1A).7–8 Aside from cess involvinG a 2-halo-oxazole (2). the potential safety concerns of workinG with hydroGen cyanide,9 many of these asymmetric methods are limited to vinyl arenes and Our continued interest in enantioselective alkene hydrofunction- employ non-commercially available ligands.7,10–11 Alternative alization reactions led us to envision the development of a catalytic methods to access enantioenriched nitriles, includinG C–H cya- protocol to access enantioenriched α-alkyl-α-arylnitriles, repre- nation,12 α-arylation of prefunctionalized nitriles13 and enantiose- sented by 3 (FiGure 1B).16–18 We proposed that the critical C–CN lective protonation of silyl ketene imines,14 have also been devel- bond of the nitrile could be forged through an initial dual Pd/CuH- oped employinG various precursors.15 catalyzed asymmetric olefin hydroarylation17 reaction using a N- heterocyclic compound as a nitrile surroGate, thus obviating the need to employ cyanide either directly or transiently formed. A Table 1. Optimization of the enantioselective hydrocyanation of subsequent thermal-[4+2]/retro-[4+2] sequence with the appropri- styrene (1a).a ate dienophile could furnish the enantioenriched nitrile. However, i. P1 (6.0 mol%), Me2PhSiH (2.0 equiv) NaOTMS (2.0 equiv), BrettPhos (6.0 mol%) at the outset, it was unclear to us which N-heterocycle would best R O [Pd(cinnamyl)Cl]2 (6.0 mol% [Pd]), CN serve as a masked nitrile, since pyrimidines, pyrazines, oxazoles Ph THF [0.6], 45 ºC, 16 h Ph N Ph Me X ii. EtO2C CO2Et (7a) (3.5 equiv) and several other heterocycles have all been shown to expel nitriles PhMe [4.0], 110 C, 8 h 19–21 1a 2a-c 3a as byproducts in cycloaddition reactions with alkynes. We rea- (1.0 equiv) (1.3 equiv) soned that an oxazole, despite its limited precedent in forminG ni- entry variation from standard conditions % yield er 19 triles, would be an ideal nitrile precursor for this transformation 1 none, 2a (X=Br, R=Me) 96% 97:3 as it does not introduce any regiochemical complications and is an 2 P2 88% 80:20 3 6.0 mol% CuOAc + 7.0 mol% L1 94% 97:3 21 electron-rich aza-diene. 4 6.0 mol% Cu(OAc)2 + 7.0 mol% L1 82% 72:28 5 6.0 mol% CuOAc + 7.0 mol% L2 81% 99:1 FiGure 1C details our proposed dual Pd/CuH catalytic cycle for 6 XPhos (L4) 61% 87:13 7 t-BuBrettPhos (L5) 14% nd the aforementioned approach. Enantioselective hydrocupration of 8 no Pd and BrettPhos 0% nd 9 2b (X=Br, R=Ph) 35% 90:10 an olefinic substrate (1) by a CuH catalyst (I), Generated in situ 10 2c (X=Cl, R=Me) 5% nd throuGh the use of a Cu(I) salt, chiral phosphine ligand, and silane, 1 O R would form an enantioenriched Cu(I) alkyl intermediate (II). Ar2 O 1 2 P MeO P(Ar)2 R P(R )2 Meanwhile, the Pd catalytic cycle would begin with oxidative ad- CuX P MeO P(Ar) i-Pr dition of a ligated Pd(0) species (III) into a 2-halo-oxazole (2) O 2 i-Pr L3: BrettPhos Ar2 (R1: OMe, R2: Cy) forminG complex IV. Stereospecific transmetallation of II with Pd O P1: X = OAc L4: XPhos 1 2 species IV would result in an alkyl Pd(II) complex (V), which fol- P2: X = Cl L2: i-Pr (R : H, R : Cy) Ar= 3,5-(t-Bu)2-4-MeOC6H2 Ar= 3,5-(t-Bu)2-4-MeOC6H2 L5: t-BuBrettPhos lowinG reductive elimination furnishes an intermediate enantioen- (S)-DTBM-SEGPHOS (L1) (R)-DTBM-OMe-BIPHEP (R1: OMe, R2: t-Bu) riched oxazole (4). The formed copper(I) halide (VI) could reGen- erate the active CuH catalyst after a s-bond metathesis reaction in aReaction conditions: 0.2 mmol styrene (1.0 equiv), yields were the presence of an appropriate base and silane.17–18 For this ap- determined by 1H NMR spectroscopy of the crude reaction mix- proach to be successful, the rates of both catalytic cycles would ture, usinG 1,1,2,2-tetrachloroethane as internal standard. Enantio- need to be well aliGned to prevent any deleterious side pathways or meric ratio (er) was determined by chiral SFC. nd: not determined 17 the racemization of the alkyl copper species II. After this hy- droarylation process, as depicted in Figure 1B, a subsequent ther- mal [4+2] cycloaddition between oxazole 4 and an alkyne would performed well as dienophiles. Notably, the judicious choice of form a hiGhly strained 7-oxa-2-azabicyclo[2.2.1]heptadiene deriv- dienophile coupling partner aided in the purification of the nitrile ative (5), and upon a retro-[4+2] cycloaddition the nitrile product products (see below and the Supporting Information for details). is liberated alonG with an electron deficient furan (6). Thus, we rea- HavinG established appropriate reaction conditions for the asym- soned that the judicious choice of a 2,5-disubstituted-4-halo-oxa- metric olefin hydrocyanation reaction, we investigated the scope of zole (2) couplinG partner would be paramount to achievinG both a vinyl arene substrates (Scheme 1) . Vinyl arenes bearinG a substitu- highly enantioselective hydroarylation step and an efficient ent at the para-position, such as phenyl (3b), isobutyl (3d), or thi- [4+2]/retro-[4+2] sequence. omethyl (3e), were well tolerated under the reaction conditions, re- AccordinGly, we focused on findinG a suitable halo-oxazole cou- sultinG in Good yields and enantioselectivity of the nitrile product. pling partner (2) and a set of experimental reaction conditions for Facile enantiospecific hydrolysis could convert nitrile 3d and 3g to ibuprofen10 and cicloprofen,14 respectively, both of which are non- the asymmetric olefin hydrocyanation using styrene (1a) as a model 23 substrate (Table 1). Our investigation of the optimal reaction con- steroidal anti-inflammatory druGs (NSAIDs). A vinyl arene con- ditions identified oxazole 2a as an excellent nitrile surrogate and taininG ortho-substitution was effectively converted to the nitrile the commercially available alkyne 7a as a suitable dienophile. (3c) in high yield and enantiopurity. Moreover, substrates contain- When 2a and 7a were utilized in conjunction with [Pd(cin- inG heterocycles, includinG benzofuran (3f), indoline (3h), N-tosyl- indole (3i), carbazole (3j), pyrazole (3k), morpholine (3m), and N- namyl)Cl]2, BrettPhos (L3), P1, NaOTMS, and Me2(Ph)SiH, the desired nitrile 3a was formed in high yield and enantioselectivity Boc-piperzine (3o), were smoothly transformed to the nitrile prod- (entry 1, 96% 1H NMR yield and 97:3 er), without isolation of the uct with excellent selectivity.