Carbon-Silicon Bond Formation in the Synthesis of Benzylic Silanes

Article abstract of DOI:10.1021/acs.orglett.6b01223

Sterically encumbered organosilanes can be difficult to synthesize with conventional, strongly basic reagents; the harsh reaction conditions are often low yielding and not suitable for many functional groups. As an alternative to the typical anionic strat

Full text of DOI:10.1021/acs.orglett.6b01223

Letter
pubs.acs.org/OrgLett
Carbon−Silicon Bond Formation in the Synthesis of Benzylic Silanes
Michael D. Visco, Joshua M. Wieting,† and Anita E. Mattson*
The Ohio State University, Department of Chemistry and Biochemistry, 100 West 18th Avenue, Columbus, Ohio 43210, United
States
S
* Supporting Information
ABSTRACT: Sterically encumbered organosilanes can be difficult to synthesize with conventional, strongly basic reagents; the
harsh reaction conditions are often low yielding and not suitable for many functional groups. As an alternative to the typical
anionic strategies to construct silanes, the coupling of benzylic halides and arylhalosilanes with sonication has been identified as a
high yielding and general strategy to access bulky and functionalized benzylic silanes. This new methodology provides a solution
for the synthesis of families of bulky benzylic silanes for study in catalysis and other areas of chemical synthesis.
rganosilanes1 are valuable products of chemical synthesis
obstacles that hindered progress in several of our silanediol
Othat offer interesting platforms for study in drug
catalyst syntheses: (1) they were plagued with exceedingly low
yields and (2) they were not functional group tolerant enough
discovery,2 catalysis,3,4 and sensing.5 Yet, despite recent
to enable access to families of silanediols for structure−activity
relationship studies. In an attempt to overcome these
challenges associated with the available methods, we explored
more general approaches to synthesize benzylic organosilanes
(1) that could easily be converted into organosilanols. This
letter details our findings of benzylic C(sp3)−Si bond formation
via the Barbier-type coupling of suitable silicon reagents (3)
and benzylic halides (2).
We routinely take advantage of lithiation followed by
silylation in the construction of BINOL-based silanediol
catalysts.4 For example, cyclic BINOL-based silanediol 4 was
isolated in a useful synthetic yield after a three-step one-flask
lithiation and silacyclization sequence (eq 1, Scheme 2). To our
surprise, this approach did not translate to similar acyclic
variants. Several attempts at lithiation under a variety of
conditions followed by reaction with a number of different
electrophilic silyl reagents (e.g., SiCl4, Si(OMe)4, PhSiH2Cl)
failed to form the desired C−Si bond (Scheme 2a). The
formation of the benzylic Grignard reagent followed by
treatment with a silylating agent did not provide the desired
product regardless of our efforts at optimizing various reaction
parameters, such as solvent, reaction temperature, and benzylic
halide (Scheme 2b). Briefly, success was encountered with the
desired C−Si bond formation after swapping the polarity of the
reaction partners (i.e., nucleophilic silicon and electrophilic
carbon): the addition of phenylsilyllithium to benzylic bromide
2 gave rise to the desired silane 1a in 52% yield (Scheme 2c).
progress, difficulties in carbon−silicon bond construction can
hamper the development of organosilanes and their associated
applications. The limitations of the available methods became
strikingly apparent to us when we sought to synthesize
somewhat complex organosilanes to study in the context of
catalysis.
In connection with our ongoing research program focused on
metal-free catalyst3a,b,4 design, we met the challenge of
constructing enantiopure benzylic silanediols (e.g., 1, X =
OH, Scheme 1), organosilanes with two OH groups on silicon
(R2Si(OH)2). Benzylic carbon−silicon bonds are frequently
constructed under strongly basic reaction conditions (i.e.,
organolithiums or Grignards, Scheme 1). The conventional
strongly basic reaction conditions presented at least two
Scheme 1. Barbier-Type Benzylic C−Si Bond Formation
Received: April 26, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01223
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Organic Letters
Letter
Scheme 2. Benzylic C−Si Bond Forming Strategies
Attempted
Table 1. Optimization of Barbier-Type Coupling for
BINOL-Based Silanediol Synthesis
a
entry
X
equiv 3
yield (%)
b
b
c
1
2
3
4
5
Br
Br
Br
Cl
I
5
95
92
94
81
90
3
1.5
1.5
1.5
c
c
a
Reactions conducted in THF (0.2 M) for 30 min at 23 °C. See
b
1
Supporting Information for details. Yield determined by H NMR
spectroscopic analysis. Isolated yields after flash column chromatog-
c
raphy on silica gel.
Table 2. Examples of Silanes Prepared via Barbier-Type
a
Coupling
Unfortunately, the silyl lithium approach was not a general
solution, as the phenyl ring on the silyl species could not be
altered even slightly: electron-donating or -withdrawing groups
on the phenyl ring were not acceptable. Not even naphthyl
rings were tolerated on the silyl lithium species.
The limits of our early attempts toward benzylic silanediol
synthesis prompted us to explore more uncommon benzylic
C(sp3)−Si bond forming reaction conditions that may afford us
higher yields and/or be more tolerant of the functional groups
on both of the reaction partners. The results of our own
experimentation, working in combination with Lee and co-
workers’ demonstration of the power of sonication in aryl−
silicon bond formation,6 encouraged us to pursue Barbier-type
reaction conditions to establish the desired C−Si bond. We
were delighted to find that Barbier-type coupling of benzylic
bromide 2 (X = Br) and phenylchlorosilane 3 gave rise to
desired silane 1a in 94% yield (Table 1).
We determined that equivalents of silyl chloride from 5 to
1.5 equiv did not affect the yield, all giving >90% yield of 1a
(entries 1−3). The nature of the benzylic halide had a slight
influence on the yield. The benzylic bromide was the highest
yielding under optimized conditions (entry 3), while both the
chloride and iodide gave rise to lower, but still excellent yields
of product (entries 4 and 5). With straightforward and high
yielding reaction conditions identified for the formation of
benzylic C−Si bonds, we set out to test the limits of the
benzylic halide and chlorosilane reaction partners (Table 2).
Phenylchlorosilane afforded 94% of the desired benzylic silane
product (1a). Both electron-rich and electron-poor aryl silanes
were well tolerated in the process. For example, the more
electron-rich 4-methoxy phenylchlorosilane yielded 88% of
benzyl silane 1b while electron-poor 4-fluoro phenylchlor-
osilane resulted in a 90% yield of 1c. We were pleased to see
a
Isolated yields after flash column chromatography on silica gel.
that our Barbier-type coupling was also tolerant of a variety of
sterically hindered arylchlorosilane reaction partners. For
instance, 1-naphthylchlorosilane gave rise to the highest yield
in this Barbier-type coupling at 95% (1d). We were delighted to
find that the very sterically hindered mesitylchlorosilane yielded
93% of the benzylic silane product 1e.
Curiosity then prompted us to explore our methodology in
coupling reactions of arylchlorosilanes with less complex benzyl
bromides. Subjecting benzyl bromide and phenylchlorosilane to
the standard reaction conditions yielded 67% of the desired
product 1f. The tolerance of the reaction to benzylic bromides
with electron-poor and electron-rich substituents was put to the
test. Pleasingly, 4-fluorobenzyl bromide resulted in the desired
silane 1g in 58% yield, while the 4-methoxybenzyl bromide
gave rise to 67% of 1h. We were also happy to observe the
coupling of a secondary benzyl bromide afforded the silane
product 1i in 78% yield.
The silane products of our Barbier-type coupling were briefly
explored in further reactions of interest to the synthetic
community (Scheme 3). Inspired by our own intent to explore
benzylic silanediols in catalysis, we found that 1a was easily
oxidized to the silanediol 5 in 60% yield upon treatment with
B
DOI: 10.1021/acs.orglett.6b01223
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Organic Letters
Letter
(4) For examples of proposed silanediol anion-binding catalysis, see:
(a) Schafer, A. G.; Wieting, J. M.; Fisher, T. J.; Mattson, A. E. Angew.
Chem., Int. Ed. 2013, 52, 11321−11324. (b) Wieting, J. M.; Fisher, T.
J.; Schafer, A. G.; Visco, M. D.; Gallucci, J. C.; Mattson, A. E. Eur. J.
Org. Chem. 2015, 2015, 525−533.
(5) Kondo, S.; Bie, Y.; Yamamura, M. Org. Lett. 2013, 15, 520−523.
(6) Lee, A. S.-Y.; Chang, Y.-T.; Chu, S.-F.; Tsao, K.-W. Tetrahedron
Lett. 2006, 47, 7085−7087.
Scheme 3. Uses of Benzylic Silanes
(7) Nakamura, M.; Matsumoto, Y.; Toyama, M.; Baba, M.;
Hashimoto, Y. Chem. Pharm. Bull. 2013, 61, 237−241.
(8) Sodner, M.; Sandor, M.; Schier, A.; Schmidbauer, H. Chem. Ber.
1997, 130, 1671−1676.
Pd/C and H2O (eq 1).7 The conversion of 1i to the
chlorosilane, a species now ready for further functionalization,
was achieved with BCl3 and then treated with H2O to yield
silanol 6 in 60% yield (eq 2).8
To conclude, Barbier-type coupling conditions have been
identified as a general strategy for the synthesis of benzylic
silanes. The reaction conditions benefit from being (1)
operationally simple, (2) high yielding, and (3) tolerant of a
broad range of functional groups and sterically encumbered
reaction partners. This new methodology may present a useful
synthetic tactic to enable the construction of more complex
silanes for study as catalysts and reagents, among other things.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01223.
General methods, synthetic details, and NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mattson@chemistry.ohio-state.edu.
Present Address
†Vanderbilt Center for Neuroscience Drug Discovery, 393
Nichol Mill Lane, Suite 1000, Franklin, TN 37067.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Science Foundation for
supporting these investigations (Award Number 1362030).
■
REFERENCES
■
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DOI: 10.1021/acs.orglett.6b01223
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