Nitrile Alkylations through Sulfinyl–Metal Exchange

Abstract

Nitriles play pivotal roles in a diverse range of pharmaceuticals.[1] The nitrile pharmacophore often engages in key hydrogen bonding, as in the blockbuster drug anastrazole (1), [2] in other cases a covalent attachment occurs, as in the anti-diabetic vildagliptin (2, Scheme 1).[3] Syntheses of many nitrile-containing pharmaceuticals, particularly of those bearing quaternary centers, such as anastrazole [1] and the cyclohexylnitriles levocabastine (3) [4] and cilomilast (4), [5] typically involve multiple alkylations.Most alkylations of nitriles employ alkyllithium or metal amide bases, [6] in these cases, monoalkylation is often complicated by overalkylation. [7] A conceptually appealing solution for multiple controlled alkylations of acetonitrile includes two sequential alkylations of an activated acetonitrile (5!6) with a mild base followed by a functional group/ metal exchange alkylation (6!7!8, Scheme 2). The execution of this strategy would allow three consecutive alkylations, require only one equivalent of strong base, and install quaternary centers, as can be found in numerous nitrilecontaining pharmaceuticals.Metal-exchange reactions [8] usually employ halides, [9] trialkylstannanes, [10] or sulfoxides [11] as transferrable precursors. Recently reported halogen-metal exchange reactions of bromo-, iodo-, [12] and even chloronitriles [13] with organolithium and Grignard reagents allow the selective generation of N-lithiated and C-magnesiated nitriles, respectively. Conceptually, an analogous sulfinyl-metal exchange [14] represents a significant advance by avoiding the aggressive reagents typically required for the synthesis of halonitriles, allowing the performance of two alkylations with mild base, and introducing a greater functional-group tolerance.Access to the symmetrical sulfinylnitrile 6 a was achieved by two complementary alkylations [15] of phenylsulfinylacetonitrile [16] (5 a; Scheme 3, conditions 1 and 2). In each case, 1,5-dibromopentane was used as a prototypical bis-electrophile because the resulting nitrile 6 a contains the core cyclohexylnitrile motif embedded within several nitrile-containing pharmaceuticals (see 3 and 4 in Scheme 1). Heating 5 a and 1,5-dibromopentane with Cs 2 CO 3 to reflux in THF smoothly provides 6 a, whereas the use of NaH in DMF allows the analogous alkylation at ambient temperature. Alternatively, the sulfinylnitrile 6 a can be prepared by sulfinylating nitrile 9 with methyl phenylsulfinate.[17] Sequential alkylation and oxidation of phenylthioacetonitrile provides another versatile route to sulfinyl nitriles that is ideal for nonsymmetrical substrates (see the Supporting Information for details).[18]The sulfinyl-metal exchange of 6 a is remarkably facile. iPrMgCl triggers a rapid exchange that is complete within 5 minutes at À78 8C.[19] In sequential sulfinyl-magnesium exchange alkylations, quaternary centers are efficiently installed by the reaction of the magnesiated nitriles with a diverse range of electrophiles (Table 1). Carbonyl-containing ketone, ester, ...

Sulfinylnitriles: Sulfinyl–Metal Exchange–Alkylation Strategies

“…Subsequently deploying the sulfinyl group as a latent nucleophile by adding an organometallic reagent (12!13) permits a third alkylation to form quaternary nitriles 10. This full account significantly expands the range of substrates and electrophiles that was reported previously in the preliminary sulfoxide-metal exchange-alkylation reaction, [17] addresses the challenge of preparing tertiary nitriles through exchange-alkylation sequences with tertiary sulfinylnitriles, and demonstrates exchange-alkylations at the sp 2 centers of sulfinylalkenenitriles.…”

“…Nucleophilic addition to benzylidene malononitrile, a carbonyl surrogate, [23] proceeds well, as does the addition of the electrophiles propylene oxide and diphenyl disulphide (Table 1, entries [15][16][17]. Cyclohexenone is attacked selectively at the carbonyl carbon (Table 1, entry 11), which is likely a consequence of strong chelation between the alkoxymagnesium intermediate and the p-electrons of the nitrile, [24] which prevents equilibration to the more stable conjugate adduct.…”

“…[17] In addition, the use of phenylsulfinyl acetonitrile (11 a) as a precursor allows two sequential alkylations with mild base (11 a!12). Subsequently deploying the sulfinyl group as a latent nucleophile by adding an organometallic reagent (12!13) permits a third alkylation to form quaternary nitriles 10.…”

Synthesis of Nitrile‐Bearing Quaternary Centers by an Equilibrium‐Driven Transnitrilation and Anion‐Relay Strategy

“…[11] Ac ommercially available solution of s-BuLi (1.4 m in cyclohexane) was used as the model substrate (Scheme 3). [11] Ac ommercially available solution of s-BuLi (1.4 m in cyclohexane) was used as the model substrate (Scheme 3).…”

Metalated nitriles: SNi′ cyclizations with a propargylic electrophile

“…Metalated nitriles, although not used previously for S N i′ displacements, are ideal because of their facile formation through deprotonation, 11 halogen-metal, 12 sulfoxide-metal, 13 and sulfide-metal 14 exchange and because their formation is highly tolerant of delicate functionality. In addition, the tunable nucleophile geometry, through metal counter-ion selection, 2 allows control over developing bond angles for stereoselective cyclization.…”