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Asmic Isocyanide‐Nitrile Isomerization‐Alkylations
Author(s) -
Alwedi Embarek,
LujanMontelongo J. Armando,
CortésMejía Rodrigo,
del Campo Jorge M.,
Altundas Bilal,
Fleming Fraser F.
Publication year - 2019
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201900903
Subject(s) - isocyanide , chemistry , nitrile , carbene , deprotonation , isomerization , cyanide , alkylation , medicinal chemistry , combinatorial chemistry , stereochemistry , organic chemistry , catalysis , ion
Anisylsulfanylmethylisocyanide, Asmic, is a versatile building block whose alkylations provide a range of substituted isocyanides. The anisylsulfanyl group plays a critical role in the sequenced deprotonation‐alkylation and the subsequent sulfanyl‐lithium exchange. Complexation of the anisylsulfanyl group to BuLi in the presence of TMEDA affords a lithiated isocyanide whose alkylations generate trisubstituted isocyanides. In the absence of TMEDA, BuLi triggers cyanide expulsion to afford a transient carbene; reorientation of cyanide with attack at the carbene affords a lithiated nitrile whose alkylations afford quaternary nitriles . The complexation‐induced isocyanide‐nitrile rearrangement is exceptionally facile, occurring within 5 min at –78 °C. Detailed mechanistic and computational analyses identify the importance of chelation in the bifurcating mechanism: internal chelation favors cyanide extrusion to form a carbene whereas chelating agents favor arylsulfanyl‐lithium exchange to generate a lithiated isocyanide. The combined experimental and computational analyses reveal a new mechanism for isocyanide‐nitrile isomerization which provides valuable insight for rapidly assembling substituted isocyanides.