SCHEME 1
Selective Generation of Lithiated Benzonitriles:
the Importance of Reaction Conditions
Sergiusz Lulin´ski* and Katarzyna Zajac
Warsaw UniVersity of Technology, Faculty of Chemistry,
Noakowskiego 3, 00-664 Warsaw, Poland
the generation of related magnesiated benzonitriles using
Knochel’s approach based on halogen-magnesium exchange.9
The lack of full information has prompted us to investigate the
generation of simple and related silylated lithiobenzonitriles via
Br/Li interconversion.
ReceiVed June 27, 2008
We have found that the choice of the proper addition mode
is essential for the high-yield preparation of lithiated benzoni-
triles unless harsh cryogenic conditions (ca. -100 °C) are used.
When we treated a solution of 4-bromobenzonitrile 1 in THF
with n-BuLi at ca. -70 °C (internal temperature) followed by
the quench with B(OMe)3, we obtained an impure 4-cyanoben-
zoic acid 1a in ca. 30% crude yield. However, when a solution
of 1 in THF was added to a precooled solution of n-BuLi in
THF (reverse addition) the resulting lithiate 1-Li was formed
much more cleanly as evidenced by the subsequent high yield
conversion into pure 1a (Scheme 1). Similar behavior was
observed for Br/Li exchange with 3-bromobenzonitrile 2 as the
substrate as the acid 2a was isolated in a comparable yield. The
conversion of 2-bromobenzonitrile 3 into the corresponding
boronic acid 3a was also successful using reverse addition of
n-BuLi but failed completely with normal addition. It should
be noted that the reported preferred routes to related cyanophe-
nylboronic acids involve the addition of n-BuLi to a solution
of the bromobenzonitrile (1 or 2, respectively) in THF containing
in situ B(O-i-Pr)3.10 Thus, the preformed aryllithium intermedi-
ates 1-Li and 2-Li are rapidly trapped with the electrophile,
which efficaciously prevents undesired competitive reactions.
Our results suggest that under optimal conditions (reverse
addition of n-BuLi, THF as a solvent) Br/Li interconversion
proceeds with good chemoselectivity. Hence, the nitrile group
is not susceptible to nucleophilic attack of n-BuLi. Moreover,
the resulting aryllithiums 1-Li and 2-Li are quite stable. It seems
that the carbanionic character of the aromatic ring in these
intermediates significantly decreases the electrophilic properties
of the CN group due to the negative charge cumulation at this
group effected via polarization.11 As a result, the nitrile function
becomes quite resistant against attack with carbanionic nucleo-
philes present in a reaction system; that is, with unreacted
n-BuLi and/or another molecule of a cyanophenyllithium the
latter reaction would result in oligomerization. It should be
stressed that the proper choice of solvent is crucial for the
Lithiated benzonitriles can be generated in high yields from
reactions of bromobenzonitriles with n-BuLi in THF under
standard cryogenic conditions (ca. -70 °C) provided the
reverse addition mode is employed. The resultant aryllithiums
are fairly stable at temperatures up to -60 °C. The formation
of lithiated benzonitriles via Br/Li exchange under normal
addition mode conditions is plagued by deprotonation and
extensive CN-addition reactions. The generation of related
aryllithiums from disilylated bromobenzonitriles is compara-
tively less sensitive to reaction conditions.
Lithiation of benzonitriles is a useful method for a function-
alization of these versatile reagents. Directed ortho-metalation
has been successfully applied for the generation of selected
o-lithiobenzonitriles.1,2 In general, these intermediates were
preferentially trapped in situ with suitable electrophiles such
as B(O-i-Pr)3 and TMSCl to give various ortho-boronated3 and
ortho-silylated4,5 derivatives, respectively. It has been reported
that the clean generation of 3- as well as 4-lithiobenzonitrile
by halogen-lithium exchange from the corresponding haloben-
zonitriles and n-BuLi6 requires very low temperatures (-100
°C)7 as under standard cryogenic conditions employing dry ice/
acetone cooling (effective internal temperature of ca. -70 °C)
extensive degradation occurs, thus decreasing yields of desired
aryllithium intermediates.8 However, no details concerning the
nature of these undesired side reactions were reported. It should
be noted that significant progress has been made recently in
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10.1021/jo8013808 CCC: $40.75
Published on Web 08/22/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7785–7788 7785