The addition of BuLi, Bu3MgLi, Et2ZnBuLi, or Me2CuLi to α-arylthioalkanenitriles triggers an arylthio-metal exchange. NMR spectroscopic analyses implicate organometallic attack on sulfur forming a three-coordinate sulfidate as the key intermediate. Electrophilic trapping affords tertiary and quaternary nitriles in high yield. The method addresses the challenge of improving the functional group tolerance and preventing polyalkylations.

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, ...

Metalated nitriles exhibit complementary chemoselectivities in electrophilic alkylations. N-Lithiated or C-magnesiated nitriles can be prepared from the same nitrile precursor and selectively reacted with a 1:1 mixture of methyl cyanoformate and benzyl bromide or bifunctional electrophiles through chemoselective attack onto either an alkyl halide or a carbonyl electrophile. A mechanistic explanation for the chemoselectivity preferences is provided that rests on the structural and complexation differences between N- and C-metalated nitriles.

Adding organolithiums, Grignard reagents, or zincates to sulfinylnitriles triggers a facile sulfinyl-metal exchange to afford N- or C-metalated nitriles. Sulfinyl-magnesium exchange-alkylations efficiently install quaternary and tertiary centers, even in the case of tertiary sulfinylnitriles that contain a highly acidic methine proton. α-Sulfinylalkenenitriles afford moderately nucleophilic magnesiated nitriles, and the reactivity can be dramatically increased by conversion to the corresponding magnesiates. The sulfinyl-metal exchange is extremely fast, proceeds efficiently with quaternary, tertiary, and vinylic α-sulfinylnitriles, and exhibits an exceptional functional group tolerance in nitrile alkylations.

Small molecule agonism of PPARα represents a promising new avenue for the development of non-invasive treatments for oculovascular diseases like diabetic retinopathy and age-related macular degeneration. Herein we report initial structure-activity relationships for the newly identified quinoline-based PPARα agonist, Y-0452. Preliminary computational studies led to the hypothesis that carboxylic acid transposition and deconstruction of the Y-0452 quinoline system would enhance ligand-protein interactions and better complement the nature of the binding pocket. A focused subset of analogs was designed, synthesized, and assessed for PPARα agonism. Two key observations arose from this work 1) contrary to other PPARα agonists, incorporation of the fibrate "head-group" decreases PPARα selectivity and instead provides pan-PPAR agonists and 2) computational models reveal a relatively unexploited amphiphilic pocket in PPARα that provides new opportunities for the development of novel agonists. As an example, compound 10 exhibits more potent PPARα agonism (EC = ∼6 µM) than Y-0452 (EC = ∼50 µM) and manifests >20-fold selectivity for PPARα over the PPARγ and PPARδ isoforms. More detailed biochemical analysis of 10 confirms typical downstream responses of PPARα agonism including PPARα upregulation, induction of target genes, and inhibition of cell migration.