Chemoselective Benzylation of Aldehydes Using Lewis Base Activated Boronate Nucleophiles

Article abstract of DOI:10.1021/acs.organomet.8b00085

A benzylation of aldehydes using primary and secondary benzylboronic acid pinacol esters is reported. Activation of the boronic ester with s-butyllithium rendered it nucleophilic toward aldehydes. The activated nucleophile chemoselectively transfers the benzyl group over the sec-butyl group, providing excellent yields of the benzylated products. ¹¹B NMR experiments were performed to study the mechanism of this transformation.

Full text of DOI:10.1021/acs.organomet.8b00085

Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
Chemoselective Benzylation of Aldehydes Using Lewis Base
Activated Boronate Nucleophiles
Michael R. Hollerbach and Timothy J. Barker*
Department of Chemistry and Biochemistry, College of Charleston, 66 George Street, Charleston, South Carolina 29424, United
States
S
* Supporting Information
ABSTRACT: A benzylation of aldehydes using primary and
secondary benzylboronic acid pinacol esters is reported. Activation
of the boronic ester with s-butyllithium rendered it nucleophilic
toward aldehydes. The activated nucleophile chemoselectively
transfers the benzyl group over the sec-butyl group, providing
excellent yields of the benzylated products. 11B NMR experiments
were performed to study the mechanism of this transformation.
Scheme 1. Reactions with BnBpin
Organoboron reagents are useful intermediates in organic
synthesis.1 The boronic acid pinacol ester functional group has
been exploited in natural product synthesis through the
Suzuki−Miyaura cross-coupling reaction.1a Benzylboronic
esters are a subclass of organoboron reagents that are less
developed in their synthetic applications than the widely used
arylboronic acids.2 Traditionally, benzylboronic esters are
synthesized from the corresponding alkyl halide through either
Grignard formation3 or the use of a transition-metal catalyst.4−6
More recently, these compounds have been prepared through
C−H activation using transition-metal catalysts7−10 or other
methods.11−14
While our interests were in developing a reaction between
the primary benzylboronic acid pinacol ester and aldehydes, the
use of secondary and tertiary benzylic boronic esters has
received much attention in the development of stereospecific
transformations employing enantioenriched benzylic boronic
esters.15 Stereospecific synthesis and subsequent oxidations of
tertiary boronic esters have provided tertiary alcohols16 and
amines.17,18 Numerous other stereospecific reactions have
provided arylation,19 protodeboronation,20 halogenation,21
and various carbon homologations of secondary and tertiary
benzylic boronic esters.15a There are examples of Rh-catalyzed
addition of secondary benzylboronic esters to aldehydes22 and
imines;23 however, electrophiles required electron-withdrawing
groups to obtain good yields.
In contrast, there are only a few reported examples of
primary benzylboronic esters as reactants (Scheme 1). Previous
reports have demonstrated the oxidation of benzylboronic acid
pinacol ester (BnBpin) to the corresponding alcohol, iodide,
and amine compounds.8,17 Additionally, BnBpin has been
employed in Pd-catalyzed cross-coupling reactions as well as
Cu-catalyzed Chan−Lam type couplings with anilines and
phenols.8,24 BnBpin is commercially available and not moisture
sensitive, making it an attractive reagent for further develop-
ment. We sought to develop a reaction using BnBpin as a
nucleophile with aldehydes.
Primary benzylboronic esters are more challenging substrates
in comparison to substituted benzylboronic esters. Mayr and
Aggarwal have combined BnBpin and phenyllithium to form a
boronate nucleophile and measured its nucleophilicity in
reactions with dibenzylic carbocations.25 These studies found
the boronate species generated from BnBpin to be less
nucleophilic than boronates from secondary benzylboronic
esters. We anticipated that using an alkyllithium to generate the
boronate nucleophile would increase the nucleophilicity of the
benzyl moiety, opening a new class of reactivity.
We began our investigations with examining the nucleophilic
addition of BnBpin to benzaldehyde (Table 1). Activating
Received: February 8, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.organomet.8b00085
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Table 1. Optimization of Reaction Conditions
Table 2. Aldehyde Substrate Scope
a
entry
change from standard conditions
yield, %
1
2
3
4
5
6
7
8
9
n-BuLi
38
82
71
74
n-BuLi with NMP
n-BuLi with DMPU
n-BuLi with TMEDA
s-BuLi with NMP
s-BuLi with no additives
MeLi
82
b
100 (98)
54
6
PhLi
MeMgBr
20
a
b
Yields determined by NMR using an internal standard. Isolated yield
in parentheses.
BnBpin with n-BuLi and no additives provided a 38% yield of
the desired product along with benzyl alcohol and trace
amounts of benzoic acid (entry 1). Formation of benzyl alcohol
can be formed by β-hydride transfer from the butyl group when
it is attached to the boronate,26 a Cannizzaro side reaction
catalyzed by Li ions,27 or air oxidation of BnBpin.28 The
inclusion of polar aprotic additives was then pursued to favor
nucleophilic benzyl addition over formation of benzyl alcohol.29
The addition of NMP was effective, providing the desired
product in 82% yield (entry 2). Use of DMPU and TMEDA as
additives also showed an improvement in the yield (entries 3
and 4). s-BuLi was found to be equally effective as n-BuLi with
NMP as an additive (entry 5). A control experiment revealed
NMP was not necessary when s-BuLi was used (entry 6).
s-BuLi has previously been used to activate alkylboronic esters
for Pd-catalyzed cross-coupling.30 Examination of other
organometal activating agents, including PhLi, found s-BuLi
to be the most effective (entries 7−9).
expected.31 Reactions with heterocyclic aldehydes also gave
respectable yields under these reaction conditions (10 and 11).
A reaction with cyclohexylcarboxaldehyde resulted in a 68%
yield of 12, providing an example of an aliphatic aldehyde
substrate.
11B NMR was used to support the proposed intermediates in
the mechanism (Scheme 2). BnBpin has a 11B NMR resonance
Scheme 2. 11B NMR of Reaction
It is significant that no butyl addition to the aldehyde was
observed, indicating that a chemoselective transfer of the benzyl
group is possible with alkyllithium activation of BnBpin. This
result was consistent across all organometallic Lewis base
reagents examined, with the benzyl group always being
selectively transferred with no evidence of the other group
being transferred during the optimization. Control experiments
confirmed that there was no reaction observed between BnBpin
and benzaldehyde in a variety of solvents with heating.
Activation of BnBpin with metal alkoxides also provided
none of the desired reactivity, suggesting that irreversible
coordination of a Lewis base was necessary to obtain the
desired reactivity.
With optimal conditions in hand, the substrate scope with
respect to the aldehyde was examined. Excellent yields were
obtained with aromatic aldehydes (Table 2). Both electron-
donating and electron-withdrawing substituents performed well
under these reaction conditions, with all of these reactions
going to completion in 3 h. This benzylation proved to be very
tolerant of electronic changes on the aldehyde.22a Given the
lack of difference in reaction efficiency with electronically
differentiated para substituents, a competition experiment was
performed that found p-trifluoromethylbenzaldehyde reacted
more quickly than p-methoxybenzaldehyde as would be
at 33 ppm. Addition of 1 equiv of s-BuLi resulted in the
appearance of a resonance at 8 ppm, consistent with the
chemical shift of LiArBnBpin intermediates previously observed
by Aggarwal.32 At the conclusion of the reaction, a new
resonance was observed at 34.5 ppm, which matches the
reported data for s-BuBpin.33
A secondary benzylic boronic acid pinacol ester was also
examined as a nucleophile (Scheme 3). With benzaldehyde as
the electrophile, the secondary alcohol was isolated in a 79%
yield. The efficiency of this reaction compares favorably to a
previously reported Rh-catalyzed addition of secondary benzylic
trifluoroborate salts to aldehydes that required an electron-
withdrawing substituent on the aldehyde to obtain yields above
50%.22a A 1:1 mixture of diastereomers was isolated. This result
B
DOI: 10.1021/acs.organomet.8b00085
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Organometallics
Article
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Scheme 3. Secondary Benzyl Boronate Nucleophile
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In summary, a method for the benzylation of aldehydes using
Lewis base activated boronate nucleophiles has been described.
Activation of BnBPin by an alkyllithium reagent was necessary
to render the benzyl group nucleophilic. An important
discovery was the chemoselective transfer of the benzyl group
over butyl substituents of the activated boronate nucleophile
under the reaction conditions, allowing for formation of the
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00085.
■
2017, 19, 1204−1207.
S
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Experimental procedures and 1H, 13C, 19F, and 11B NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail for T.J.B.: barkertj@cofc.edu.
ORCID
Timothy J. Barker: 0000-0002-8769-3502
Notes
The authors declare no competing financial interest.
■
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The College of Charleston is acknowledged for financial
support. M.R.H. acknowledges support for a summer stipend
funded by the Howard Hughes Medical Institute to the College
of Charleston as part of their 2012 Undergraduate Science
Education Competition and the National Center for Research
Resources (5 P20 RR016461) and the National Institute of
General Medical Sciences (8 P20 GM103499) from the NIH.
The NMR spectrometer at the College of Charleston was
supported by the National Science Foundation under Grant
No. 1429308.
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DOI: 10.1021/acs.organomet.8b00085
Organometallics XXXX, XXX, XXX−XXX