Ortho-selective nucleophilic addition of primary amines to silylbenzynes: Synthesis of 2-silylanilines

Article abstract of DOI:10.1002/anie.201100360

Cause and effect: The first ortho-selective nucleophilic addition reaction of amines to 3-substituted benzynes has been achieved. Despite a large trimethylsilyl substituent, primary amines attack the C2 position of 3-silylbenzynes to produce 2-silylanilines (see scheme). This outcome is likely to result from the inductive electron-donating effect of the silyl group, which overrides its steric repulsion with the approaching amines. Copyright

Full text of DOI:10.1002/anie.201100360

Communications
DOI: 10.1002/anie.201100360
Synthetic Methods
ortho-Selective Nucleophilic Addition of Primary Amines to
Silylbenzynes: Synthesis of 2-Silylanilines**
Takashi Ikawa, Tsuyoshi Nishiyama, Takashi Shigeta, Shinya Mohri, Shinsuke Morita,
Sho-ichi Takayanagi, Yuki Terauchi, Yuki Morikawa, Akira Takagi, Yoshinobu Ishikawa,
Satoshi Fujii, Yasuyuki Kita, and Shuji Akai*
One of the most notable discoveries in aromatic chemistry
was that of benzyne intermediates.[1,2] This achievement has
opened the way for designing new molecules as a result of the
unique and extraordinary reactivity of benzynes. Among the
various reactions of benzynes, nucleophilic addition has been
one of the most important and widely used in modern organic
synthesis.[3,4] However, the regioselectivity of the nucleophilic
addition to unsymmetrically substituted benzynes has been a
longstanding challenge. High selectivity has been limited to
the reaction of benzynes having chlorine or fluorine,[5a,b]
alkoxy,[5b,c] alkylamino,[5a] phenyl,[5f] and bulky groups[5d,e] at
the C3 position, in which the nucleophiles react at the
C1 position to give the meta-disubstituted arenes. These
results are thought to result from the inductive electron-
withdrawing effect and/or steric effect of the substituents.[6]
On the contrary, the inductive electron-donating effect of the
substituent of the benzyne may prefer the nucleophilic
addition at its ortho position. However, the repulsive steric
interaction between the substituent and the nucleophile
significantly hampers this reaction, and therefore, the prefer-
ential preparation of the ortho-disubstituted arenes has
seldom been achieved.[3] The only example of the ortho-
selective nucleophilic addition was reported by Meyers and
co-workers, which was attained by the coordinative interac-
tion of organolithium compounds and 3-oxazolinylbenzyne,
while similar addition reactions of the dialkylcuprates with
the same benzyne took place at the meta position.[4a]
controlled the regiochemistry of their Diels–Alder reaction
with substituted furans to give adducts possessing the silyl
group and the substituents of the furans in a remote position
on the ring.[7] Because the silyl groups on aromatic com-
pounds are stable under ordinary conditions and can be
replaced with various functional groups including halo,
hydroxy, aryl, and alkyl groups,[8] the silyl-group-control
strategy should be widely applicable in providing a solution
for the problem of controlling the regioselectivity of various
reactions of substituted benzynes. Herein, we report the first
ortho-selective nucleophilic addition reaction of amines to 3-
substituted benzynes. Despite a large trimethylsilyl group,
primary amines 2 attacked the C2 position of 3-silylbenzynes
1, which are generated under mild reaction conditions using a
fluoride ion, to produce 2-silylanilines 3 (Scheme 1).
The 3-(trimethylsilyl)benzynes 1 have been generated
from 2-bromo-6-(trimethylsilyl)phenyl triflates 4 using nBuLi
in THF or toluene at À788C. Besides our Diels–Alder
Scheme 1. ortho-Selective nucleophilic addition of primary amines 2 to
silylbenzynes 1.
Our research group has recently reported that a silyl
group attached at the C3 position of benzynes effectively
reactions,[7] 1 has been applied to [3+2] cycloaddition reac-
tions[9] and nucleophilic addition reactions of carbanions.[10]
These reactions also took place regioselectively probably as a
result of the steric and/or electronic nature of the silyl group.
In particular, the latter addition reactions proceeded prefer-
entially at the meta position of the silyl group. According to
these precedents, we began this project by carrying out the
reaction of 5-methyl-3-(trimethylsilyl)benzyne 1a, generated
from 2-bromo-4-methyl-6-(trimethylsilyl)phenyl triflate 4a
using nBuLi, with n-butylamine 2a in THF at À788C. The
reaction provided the meta-silylaniline derivative 5a exclu-
sively in 45% yield (Table 1, entry 1). On the other hand, we
found that 1a, generated from 2,6-bis(trimethylsilyl)-4-meth-
ylphenyl triflate 6a using Bu4NF (TBAF), reacted with 2a at
À408C to give the ortho-silylaniline derivative 3a preferen-
tially (Table 1, entry 5), although there must have been
significant steric repulsion between the bulky trimethylsilyl
group and the approaching 2a. This result was in stark
contrast to similar addition reactions of 2a with 3-isopropyl-
[*] Dr. T. Ikawa, T. Nishiyama, T. Shigeta, S. Mohri, S. Morita,
Dr. S. Takayanagi, Y. Terauchi, Y. Morikawa, A. Takagi, Dr. Y. Ishikawa,
Prof. Dr. S. Fujii, Prof. Dr. S. Akai
School of Pharmaceutical Sciences, University of Shizuoka
52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526 (Japan)
Fax: (+81)54-264-5672
E-mail: akai@u-shizuoka-ken.ac.jp
Prof. Dr. Y. Kita[+]
Graduate School of Pharmaceutical Sciences, Osaka University
1-6, Yamadaoka, Suita, Osaka 565-0871 (Japan)
[+] Current Address: School of Pharmaceutical Sciences, Ritsumeikan
University, 1-1-1 Noji Higashi, Kusatsu, Shiga, 525-8577 (Japan)
[**] This work was supported by Grants-in-Aid for Scientific Research
(KAKENHI; no. 21790020) and a Grant-in-Aid for the Global COE
Program from the MEXT (Japan). T.I. also thanks the Daicel
Chemical Industry award in Synthetic Organic Chemistry (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100360.
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Angew. Chem. Int. Ed. 2011, 50, 5674 –5677

Table 1: Nucleophilic addition of butylamine 2a to the 3-(trimethylsilyl)-
benzyne 1a, generated from the precursors (4a or 6a).
Table 2: Nucleophilic addition of various nucleophiles 2 to the 3-
(trimethylsilyl)benzyne 1a, generated from 6a.[a]
Entry 2, RX
t [h] Products 3/5[b]
Yield [%][c]
1
2
3
4
5
6
2b, H2N
2c, MeNH
2d, nC10H21NH
2e, CH2 =CHCH2NH
2 f, PhCH2NH
2g, tBuNH
9
3
7
3
3
3
3b, 5b
3c, 5c
3d, 5d
3e, 5e
3 f, 5 f
3g, 5g
12:1.0
6.2:1.0
7.6:1.0
6.6:1.0
7.3:1.0
63 (79)[d]
62
86
83
73
Entry
Precursor
T [8C]
t [h]
3a/5a[a]
Yield [%][b]
1[c]
4a
6a
6a
6a
6a
6a
6a
6a
À78
60
25
0.5
0.5
0.5
1.0
5
48
48
12
1.0:>50
2.0:1.0
2.7:1.0
3.7:1.0
7.7:1.0
6.5:1.0
8.6:1.0
10:1.0
45
91
89
88
2[d]
3[d]
4[d]
5[d]
6[d,e]
7[d,g]
8[d]
1.0:>50 78
7
2h, 4-MeC6H4NH
2i, Et2N
2j, EtO
6.5 3h, 5h
1.0:1.6
1.0:1.2
10:1.0
78
80
41
0
8
12
3i, 5i
9[e]
8.5 3j, 5j
À40
À40
À40
À78
92
17[f]
16[f]
31[f]
[a] Reaction conditions: 6a (1.0 equiv), 2 (3.0 equiv), TBAF (2.0 equiv) in
THF (0.10m) under nitrogen. [b] Determined by 1H NMR analysis
(500 MHz) for a crude reaction mixture and also by the yield of isolated
product. [c] Total yield of isolated 3 and 5. [d] Yield getermined by GC.
[e] 4.0 equiv of TBAF was used.
[a] Determined by 1H NMR analysis (500 MHz) of a crude reaction
mixture and also by the yield of isolated product. [b] Total yield of isolated
3a and 5a. [c] Reaction conditions: 4a (1.0 equiv), 2a (3.0 equiv), nBuLi
(5.0 equiv) at À788C in THF (0.20m) under nitrogen. [d] Reaction
conditions: 6a (1.0 equiv), 2a (3.0 equiv), TBAF (2.0 equiv) in THF
(0.10m) under nitrogen. [e] KF and 18-crown-6 were used instead of
TBAF. [f] Total yield of 3a and 5a determined by 1H NMR analysis.
[g] CsF in MeCN was used instead of TBAF in THF. Tf=trifluorometh-
anesulfonyl, THF=tetrahydrofuran.
entry 9). On the other hand, the adducts of an aromatic amine
2h (Table 2, entry 7) and a secondary amine 2i (Table 2,
entry 8) were obtained with low selectivities. The reaction of
tert-butylamine 2g exclusively gave the meta-addition product
5g owing to its bulkiness (Table 2, entry 6).
The versatile applicability of the ortho selectivity was
further demonstrated with the successful addition of various
functionalized amines 2k–r to 3-silylbenzynes 1 (Scheme 2).
The exclusive N arylation of furfurylamine 2k with 1a took
place and gave 3k, with the furan framework intact.[17]
Notably, the amino alcohol 2l and the diamine 2m reacted
with 1a in a one-to-one ratio with high fidelity and provided
3l and 3m, respectively. The ortho selectivity has not been
significantly affected by substituents such as fluoro (1b,
generated from 6b), phenyl (1c, from 6c), methoxy (1e, from
6e) and chloro (1 f, from 6 f) groups at the C5 position of 1.
Interestingly the OTBDMS group of the product 3p was
tolerant under the reaction conditions when using TBAF at
À408C.[18] The nucleophilic addition reaction of the tert-butyl
carbazate 2q and the benzyl carbazate 2r exclusively gave the
amination products (3r–u) instead of the amidation products
which were selectively obtained by the palladium-[19a] and
copper-catalyzed[19b] coupling reactions. Moreover, the
ortho regioselectivities of the reactions using the carbazates
(2q and 2r) were higher than those of the primary amines
(2a–f and 2k–p). Although two kinds of benzynes could have
been generated from the unsymmetrical benzyne precursor
6g, 5,6-dimethyl-3-(trimethylsilyl)benzyne 1g was selectively
generated to give 3u. This result is worth noting because the
fluoride ion preferentially attacked at the congested tri-
methylsilyl group of 6g.
benzyne 7 that exhibited high meta selectivity,[11] although the
steric size of the isopropyl group (A value = 2.2) is slightly
smaller than that of the trimethylsilyl group (A value =
2.5).[12] The ortho regioselectivity was higher at lower temper-
ature, and led us to suggest that this reaction was kinetically
controlled (Table 1, entries 2–5 and 8). The reaction at around
À408C seemed to be the best conditions and gave 3a in 81%
yield along with its regioisomer 5a (11%; Table 1, entry 5).
The conversion of the reaction dropped down to about 30%
at À788C even after 12 hours (Table 1, entry 8). Notably, the
use of TBAF was the key in carrying out the reaction
effectively at such a low reaction temperature like À408C.
This was because the use of common fluoride sources, such as
KF/18-crown-6 and CsF, for the generation of 1a from 6a,
resulted in very slow reactions probably owing to their poor
solubility (Table 1, entries 5–7).
Under the optimal reaction conditions (Table 1, entry 5),
various nucleophiles 2 were subjected to the regioselective
addition reaction with the silylbenzyne 1a (Table 2). The
reactions of various primary amines 2c–f selectively produced
2-silylanilines 3c–f in good yields (Table 2, entries 2–5).[13,14]
Notably, the smallest nucleophile, ammonia 2b, exhibited
even higher regioselectivity and gave the silylated aniline 3b
(Table 2, entry 1).[15] The diarylation product was not
observed in this reaction probably because the bulky tri-
methylsilyl group interfered with the second addition reaction
of 3b with another molecule of 1a. To the best of our
knowledge, this is the first example of the addition of
It was of interest to discover what kind of effects
determined the regioselectivity of the nucleophilic addition
of 2 to 1. In the presence of 2 equivalents of a fluoride source,
tetrabutylammonium triphenyldifluorosilicate (TBAT),[20] the
reaction of 2a and 1a, generated from 4a using nBuLi, gave a
significant amount of 3a along with 5a [Eq. (1)]. This result
À
[16]
ammonia to benzyne without using NH2
.
Interestingly,
the less nucleophilic ethanol 2j was also available to produce
the ethyl 2-silylphenyl ether 3j with high selectivity (Table 2,
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Communications
ion that coordinates to the silicon center to generate a
silicate-like complex 8, the magnitude of the charge
could have been increased. For nucleophilic attack at
the benzyne compounds, steric factors favor meta se-
lectivity, which have been observed in the reactions of
3-silylbenzynes 1, generated from the precursors with
either nBuLi (this experiment) or secBuLi (Schlosser
and co-workers).[10] This enhancement of the polar-
ization was also demonstrated by the DFT calcula-
tions [B3LYP/6-31G(d)][21] of the natural atomic
charge of 1h and 8 (Figure 1). The amines 2 would
preferentially approach the more positive C2 carbon
atom to give the ortho-adducts 3, although the steric
demand of the pentavalent silicate complex 8 might be
larger than that of the tetravalent silicon complex 1h.
In either case, the electronic effect should override the
steric disadvantage.
Figure 1. Natural atomic charge of the tetravalent silylbenzyne
1h and the pentavalent silylbenzyne 8 calculated with the
B3LYP/6-31G(d) method.
In summary, the rare ortho selectivity of the
nucleophilic addition of primary amines 2 to 3-
silylbenzynes 1 has been accomplished as a result of
the strong inductive effect of the silicate, coordinated
by a fluoride ion, to give 2-silylaniline derivatives 3.
Therefore, the use of the 3-silylbenzynes could offer a
solution to the problematic regioselectivity issue in
benzyne chemistry. Exploring the detailed reaction
mechanism and studying the application of this
method are in progress.
Scheme 2. Nucleophilic addition of amines 2 to 3-(trimethylsilyl)benzynes 1,
generated from the precursors 6.[a] [a] Reaction Conditions: 6 (1.0 equiv), 2
(3.0 equiv), TBAF (2.0 equiv) in THF (0.10m) under nitrogen. [b] Yield of
isolated 3. [c] Ratio of 3 to 5 determined by 1H NMR analysis (500 MHz) for a
crude reaction mixture and also by the yield of isolated product. [d] Total yield of
isolated 3 and 5. Boc=tert-butoxycarbonyl, Cbz=benzyloxycarbonyl,
TBDMS=tert-butyldimethylsilyl.
Experimental Section
General procedure for the ortho-selective nucleophilic addition
reactions of primary amines to 3-(trimethylsilyl)benzynes
2
1
(Table 1, Table 2, Scheme 2): An oven-dried flask was charged with
6 (1.0 equiv) and capped with a rubber septum and then evacuated
and back-filled with nitrogen. Anhydrous THF (0.10m) was added
using a syringe and the mixture cooled to À408C. After 5 min, 2
(3.0 equiv) and TBAF (1.0m THF solution, 2.0 equiv) were added in
this order, and the reaction mixture was stirred at À408C for a given
reaction time. The mixture was filtered through a short pad of silica
gel. The filtrate was concentrated under reduced pressure and further
purified by flash column chromatography on silica gel (hexanes/ethyl
acetate or dichloromethane/methanol) to give the 2-(trimethylsilyl)-
aniline derivative 3.
suggested that the fluoride ion played an important role in the
ortho-selective nucleophilic addition reaction.
Plausible mechanisms of these ortho-selective nucleo-
philic reactions are as follows: The inductively electron-
donating effect of the silicon causes the benzyneꢀs triple bond
to become polarized, in which the C2 position has a positive
electric charge.[9] Moreover, in the presence of the fluoride
Received: January 15, 2011
Revised: March 28, 2011
Published online: May 9, 2011
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Angew. Chem. Int. Ed. 2011, 50, 5674 –5677

Please note: Minor changes have been made to this manuscript since
its publication in Angewandte Chemie Early View. The Editor.
[9] Suzuki reported the regioselective [3+2] cycloaddition reactions
between 3-silylbenzynes, generated from the 2-bromo-6-silyl-
phenyl triflates 4 using nBuLi, and nitrones, see: T. Matsumoto,
T. Sohma, S. Hatazaki, K. Suzuki, Synlett 1993, 843 – 846.
[10] Schlosser and co-workers reported the meta-selective nucleo-
philic addition reaction to the 3-silylbenzyne, see: a) C. Heiss, F.
Cottet, M. Schlosser, Eur. J. Org. Chem. 2005, 5236 – 5241; b) C.
Heiss, F. Leroux, M. Schlosser, Eur. J. Org. Chem. 2005, 5242 –
5247; c) V. Diemer, M. Begaud, F. R. Leroux, F. Colobert, Eur. J.
Org. Chem. 2011, 341 – 354.
Keywords: amines · benzynes · nucleophilic addition ·
.
regioselective reactions · silicon
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Supporting Information for full citation.
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