Steric effects compete with aryne distortion to control regioselectivities of nucleophilic additions to 3-silylarynes

Article abstract of DOI:10.1021/ja306723r

We report an experimental and computational study of 3-silylarynes. The addition of nucleophiles yield ortho-substituted products as a result of aryne distortion, but meta-substituted products form predominately when the nucleophile is large. Computations correctly predict the preferred site of attack observed in both nucleophilic addition and cycloaddition experiments. Nucleophilic additions to 3-tert-butylbenzyne, which is not significantly distorted, give meta-substituted products.

Full text of DOI:10.1021/ja306723r

Communication
pubs.acs.org/JACS
Steric Effects Compete with Aryne Distortion To Control
Regioselectivities of Nucleophilic Additions to 3‑Silylarynes
Sarah M. Bronner, Joel L. Mackey, K. N. Houk,* and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
ABSTRACT: We report an experimental and computa-
tional study of 3-silylarynes. The addition of nucleophiles
yield ortho-substituted products as a result of aryne
distortion, but meta-substituted products form predom-
inately when the nucleophile is large. Computations
correctly predict the preferred site of attack observed in
both nucleophilic addition and cycloaddition experiments.
Nucleophilic additions to 3-tert-butylbenzyne, which is not
significantly distorted, give meta-substituted products.
espite once being a subject of controversy,1 arynes are
2
Dnow a thriving area of chemical discovery.
Modern
methods of aryne generation have led to greater control of
reactivity, thus enabling the use of arynes in a host of synthetic
applications.3 Nonetheless, the control and understanding of
regioselectivity in reactions of unsymmetrical arynes remains an
important area of research.2
Figure 1. Influence of 3-methoxy and 3-silyl substituents on aryne
regioselectivity.
The aryne distortion model, reported by our laboratories in
2010,4 shows that regioselectivity in nucleophilic additions and
cycloadditions of arynes is governed by the inherent distortion
present in unsymmetrical arynes and transition state distortion
energies.5 The model allows for reliable regioselectivity
predictions to be made using simple computations, and has
been validated for ring-fused arynes and arynes that possess
neighboring inductively withdrawing substituents.4,6 In the case
of 3-methoxybenzyne,7 the aryne is pre-distorted as suggested
in Figure 1. Addition of the nucleophile occurs at the more
electrophilic site, with flattening at the carbon undergoing
attack, to give meta-substituted products.8,9 As a means to
further probe the aryne distortion model, we examined the
influence of inductively donating silyl substituents on aryne
regioselectivities.10 Our experimental and computational study
demonstrates that the sense of regioselectivity in silylaryne
reactions is variable, but aryne distortion can play a significant
role. Computations correctly predict the preferred site of attack
observed in both nucleophilic addition and cycloaddition
experiments.
additions of organolithium reagents to silylarynes occur with
meta-selectivity,10a−c whereas additions of amines are primarily
ortho-selective.10g,13
With the aim of studying regioselectivity patterns of
silylarynes in a variety of nucleophilic addition and cyclo-
addition reactions, we prepared bis(silyl)triflate 5, which was
envisioned to be a suitable precursor to triethylsilylbenzyne 1
(Scheme 1).14 Commercially available dibromophenol 2 was
elaborated to known compound 315 via a two-step procedure
involving O-silylation followed by halogen−metal exchange-
mediated O-to-C migration of the silyl substituent.16 Next, an
analogous sequence was employed to install the triethylsilyl
Scheme 1
Geometry optimization of 3-triethylsilylbenzyne was con-
ducted using DFT methods (B3LYP/6-311+G(d,p)).11 The
silyl group severely distorts the aryne, such that the internal
angles at C2 and C1 are 134° and 122°, respectively.12
Following the aryne distortion model, nucleophilic addition at
C2, the more electropositive terminus of the aryne, is favored
electronically; however, meta substitution should be preferred
based on steric factors. Only few examples of silylaryne
reactions have been reported, but it should be noted that
Received: July 10, 2012
Published: August 9, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
group, thus providing 4.17 Triflation of 4 afforded the desired
Table 2. Cycloaddition Reactions with Triethylsilylbenzyne
1
bis(silyl)triflate 5.18
a
A comparative regioselectivity study was performed, where
triethylsilylbenzyne 1 was generated in situ upon treatment of 5
with CsF in acetonitrile, in the presence of a variety of
nucleophiles (Table 1).19,20 Upon trapping of the aryne with
a
Table 1. Nucleophilic Additions to Triethylsilylbenzyne 1
a
b
See Supporting Information for experimental details. Yields
1
determined by H NMR analysis with external standard.
nucleophilic attack, the major regioisomer observed in each
cycloaddition is presumably that which arises from the least
sterically encumbered transition state.
These results demonstrate that nucleophilic additions and
cycloadditions of 3-triethylsilylbenzyne do occur with signifi-
cant regioselectivities, but the orientation of attack varies as a
function of the trapping agent. DFT calculations were carried
out to provide additional insights into the origins of these
observations. All geometry optimizations were performed using
Gaussian 0924 using the B3LYP density functional and the 6-
311+G(d,p) basis set. A frequency calculation was performed
on all reactants and transition states to verify minima and first
order saddle points, respectively, and an ultra fine grid was used
for all numerical integration. Unscaled zero-point energies were
used, and Truhlar’s anharmonic correction was applied to
frequencies that are less than 100 cm−1.25 Trimethylsilylben-
zyne was used as a model for triethylsilylbenzyne.26
Figure 2 shows optimized transition states for the
nucleophilic additions of benzylamine and aniline to 3-
trimethylsilylbenzyne. The barrier for attack of benzylamine
at C2 is predicted to be 0.7 kcal/mol lower than for attack at
C1. Addition at C2 is favored because the aryne’s pre-distorted
bond angles favor nucleophilic attack at the flatter, more
electrophilic carbon, which is C2 in this case. During the attack,
the aryne has to undergo geometric changes, including an
increase of the CCC angle at the site of attack and compression
of the other terminus of the aryne. The terminus with the larger
angle, like C2 in triethylsilylbenzyne, will be attacked
preferentially. In contrast, for aniline, attack is predicted to be
favored at C1 rather than C2 by 3.7 kcal/mol. Because aniline is
a more bulky nucleophile, it suffers from more steric hindrance
with the silyl group of the benzyne. As shown in Figure 2, the
H−H distance of the two closest hydrogens in the C2 attack of
aniline are very close at 2.13 Å. In the case of benzylamine the
closest H−H distance is 2.52 Å. This steric interaction is
overriding the aryne distortion preference for attack at C2.
Although the magnitude of selectivity is exaggerated,
computations correctly predict experimental regioselectivities.27
a
b
See Supporting Information for experimental details. Yields
1
determined by H NMR analysis with external standard.
benzylamine, reaction occurred to give a 1:2 ratio of products
favoring ortho substitution (entry 1). However, when aniline
was employed, the regioselective preference switched to favor
meta addition (entry 2), which is consistent with the
observations reported by Akai.10g Other trapping agents that
have not been used with silylbenzynes previously were also
tested. Thiophenol based reagents also gave products of meta
substitution predominantly (entries 3 and 4); in the later case,
selectivity was 10:1. An enamine reagent, which functions as a
carbon nucleophile, exclusively yielded the meta-substituted
product (entry 5). Use of 4-t-Bu-benzoic acid, however, gave
1:3 selectivity, favoring ortho addition (entry 6).
Triethysilylaryne 1 was next evaluated in a series of
cycloaddition reactions. As shown in Table 2, the selectivity
patterns varied as a function of the trapping agent employed. A
nitrone cycloaddition gave a 73% yield of a single regioisomer
of product (entry 1), suggestive of ortho attack, as seen in
previous nitrone cycloadditions of silylarynes.10d Trapping of
the silylaryne with pyridine N-oxide21 also proceeded with a
significant preference for ortho addition (entry 2). Conversely,
cycloaddition with a diazo ester22 exclusively afforded the
product resulting from initial meta attack (entry 3). Reaction
with benzyl azide23 gave a 6:1 ratio of products, favoring initial
meta addition (entry 4). Despite variations in the initial site of
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Journal of the American Chemical Society
Communication
a
Table 3. Nucleophilic Additions to 3-tert-Butylbenzyne (6)
a
b
See Supporting Information for experimental details. Ortho-
c
1
substituted products were not observed. Yields determined by H
NMR analysis with external standard.
Benzylamine and 4-t-Bu-benzoic acid were also tested with
aryne 6. In contrast to the outcome seen in reactions of 1, only
meta substitution was observed (entries 2 and 3). These results
support the notion that aryne distortion plays a significant role
in reactions of 3-silylaryne 1. Quantum chemical calculations
were performed for the reaction of 6 with aniline and
benzylamine, and in both cases the attack at C1 was strongly
favored.29
Figure 2. Transition states for nucleophilic additions of benzylamine
and aniline to 3-trimethylsilylbenzyne.
The cycloaddition of methyl azide with 3-trimethylsilylben-
zyne was also examined computationally, with methyl azide
serving as a model for benzyl azide. Transition states are shown
in Figure 3. C1 attack is favored, which is consistent with
The effects of the inductively donating silyl group on arynes
have been studied both experimentally and computationally. It
has been shown that if the incoming nucleophile is not bulky,
the aryne distortion model holds true and the flatter terminus
of the aryne is the site of attack. If however, there is sufficient
steric bulk on the nucleophile, then attack on the more
accessible carbon of the aryne is favored. When the substituent
adjacent to the aryne is an alkyl group, steric effects dominate,
since there is no significant differential distortion of the aryne
bond angles.
Figure 3. Cycloaddition of methyl azide with 3-trimethylsilylbenzyne.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and compound character-
ization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
experimental results, by 0.7 kcal/mol. Aryne distortion would
favor attack of the nucleophilic substituted terminus at C2, but
steric hindrance overrides this electronic preference leading to
preferential attack at C1.
S
For comparison, we studied 3-tert-butylbenzyne (6),28 which
is sterically similar to 3-triethylsilylbenzyne (1), but varies
electronically (Figure 4). The geometry-optimized structure of
AUTHOR INFORMATION
Corresponding Author
houk@chem.ucla.edu; neilgarg@chem.ucla.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the NIH-NIGMS (R01
GM090007), Boehringer Ingelheim, DuPont, Eli Lilly,
Amgen, AstraZeneca, the Foote Fellowship (S.M.B.), the
Stauffer Charitable Trust (S.M.B.), and the University of
California, Los Angeles, for financial support. We thank Joshua
Melamed (UCLA) for experimental assistance, and Dr. John
Greaves (UC Irvine) for mass spectra. We are grateful to the
National Science Foundation (CHE-0548209 to K.N.H.) for
financial support. Computer time was provided in part by the
UCLA Institute for Digital Research and Education (IDRE)
and the XSEDE supercomputers Trestles and Gordon at San
Diego Supercomputer Center. These studies were supported by
shared instrumentation grants from the NSF (CHE-1048804)
Figure 4. Geometry-optimized structure of 3-tert-butylbenzyne (6)
and predicted regioselectivity.
6 (B3LYP/6-311+G(d,p)) revealed internal angles of 129° and
127° at C2 and C1, respectively. Given the minimal distortion
present, 6 was predicted to undergo sterically guided attack at
C1 to give meta-substituted products.
A silyl triflate precursor to aryne 6 was prepared from o-t-Bu-
phenol and examined in nucleophilic addition reactions (Table
3).29 When aniline was used as the trapping agent, formation of
the meta-substituted product was preferred (entry 1), similar to
the trend observed in the reaction of 3-triethylsilylbenzyne.
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Communication
termini generally give synthetically useful regioselectivities, regardless
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(13) The ortho selectivity for the addition of amines has previously
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and the National Center for Research Resources
(S10RR025631).
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