Sulfinylnitriles: Sulfinyl–Metal Exchange–Alkylation Strategies

Abstract

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.

Sulfone–Metal Exchange and Alkylation of Sulfonylnitriles

“…Metalation strategies lie at the core of organic synthesis . Formation of metalated nitriles is illustrative of the different metalation strategies used to generate organometallics: traditional base‐promoted deprotonation ( 1 → 2 or 3 ; Scheme ), halogen–metal exchange ( 5 → 2 or 3 ), sulfoxide–metal exchange ( 6 → 2 or 3 ), and sulfide–metal exchange ( 7 → 2 or 3 ) . Each strategy has distinct advantages by providing selective access to either C‐metalated ( 2 ) or N‐metalated nitriles ( 3 ) which intrinsically control the chemo‐, regio‐, and stereoselectivity of alkylations .…”

Sulfone–Metal Exchange and Alkylation of Sulfonylnitriles

“…[1] Formation of metalated nitriles is illustrative of the different metalation strategies used to generate organometallics:traditional base-promoted deprotonation (1!2 or 3;Scheme 1), [2] halogen-metal exchange (5!2 or 3), [3] sulfoxide-metal exchange (6!2 or 3), [4] and sulfide-metal exchange (7!2 or 3). [1] Formation of metalated nitriles is illustrative of the different metalation strategies used to generate organometallics:traditional base-promoted deprotonation (1!2 or 3;Scheme 1), [2] halogen-metal exchange (5!2 or 3), [3] sulfoxide-metal exchange (6!2 or 3), [4] and sulfide-metal exchange (7!2 or 3).…”

“…Metalation strategies lie at the core of organic synthesis. [1] Formation of metalated nitriles is illustrative of the different metalation strategies used to generate organometallics:traditional base-promoted deprotonation (1!2 or 3;Scheme 1), [2] halogen-metal exchange (5!2 or 3), [3] sulfoxide-metal exchange (6!2 or 3), [4] and sulfide-metal exchange (7!2 or 3). [5] Each strategy has distinct advantages by providing selective access to either C-metalated (2)o rN -metalated nitriles (3)w hich intrinsically control the chemo-, [6] regio-, [3] and stereoselectivity of alkylations.…”

Chemoselective Alkylations with N- and C-Metalated Nitriles

“…Despite a high reactivity of both electrophiles, the benzylated nitrile 6a was formed exclusively. An alternative preparation of the N-lithiated nitrile 2a, through a sulfinyl−lithium exchange (1c → 2a, Scheme 2), 8 followed by addition of a 1:1 ratio of methyl cyanoformate and benzyl bromide afforded the benzyl nitrile 6a in essentially the same yield as from the LDA-initiated deprotonation. Collectively, these alkylations imply that the diisopropylamine formed during the deprotonation, which typically coordinates to lithiated nitriles, 11 does not play a role in determining the chemoselectivity.…”

“…In contrast to the alkylations of lithiated nitrile 2a, magnesiated cyclohexanecarbonitrile 7a exhibits a complemen- tary chemoselectivity preference for methyl cyanoformate (Scheme 2). Preparation of the C-magnesiated nitrile 7a by bromine− or sulfinyl−magnesium exchange reactions (1b → 7a and 1c → 7a, respectively), 8 and addition of a 1:1 mixture of benzyl bromide and methyl cyanoformate afforded only the cyanoester 8a in 73% from 1b and in 96% yield from 1c. 12 Alternatively, sequential deprotonation of 1a with LDA, transmetalation with MgBr 2 to form the C-magnesiated nitrile 7a, and addition of a 1:1 mixture of benzyl bromide and methyl cyanoformate exclusively afforded the ester nitrile 8a (96%).…”