Three-component coupling of arynes, aminosilanes, and aldehydes

Article abstract of DOI:10.1021/ol071347a

A three-component coupling of arynes, aminosilanes, and aldehydes enables diverse amino and hydroxymethyl groups to be incorporated directly into 1,2-positions of aromatic rings.

Full text of DOI:10.1021/ol071347a

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3367-3370
Three-Component Coupling of Arynes,
Aminosilanes, and Aldehydes
Hiroto Yoshida,* Takami Morishita, Hiroyuki Fukushima, Joji Ohshita, and
Atsutaka Kunai
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima
UniVersity, Higashi-Hiroshima 739-8527, Japan
yhiroto@hiroshima-u.ac.jp
Received June 7, 2007
ABSTRACT
A three-component coupling of arynes, aminosilanes, and aldehydes enables diverse amino and hydroxymethyl groups to be incorporated
directly into 1,2-positions of aromatic rings.
The development of a convenient and powerful method for
functionalization of aromatic rings endowed with high
chemo- and regioselectivities has been an essential subject
in synthetic organic chemistry.1 In particular, a synchronous
introduction of two different functional groups into the
aromatic rings would have higher synthetic significance,
because the reaction enables various multisubstituted arenes
to be constructed in a straightforward manner. In this context,
we have recently disclosed ortho-selective double function-
alization via insertion reactions of arynes into nucleophilic-
electrophilic σ-bonds2,3 and three-component couplings using
arynes.4,5 Although a variety of functional groups can be
introduced through the reactions, versatility of this function-
alization would further be enhanced by novel coupling
reactions with use of arynes. We report herein a new method
for simultaneous introduction of two functionalities (amino
and hydroxymethyl moieties) into aromatic rings based on
a three-component assembly of arynes, aminosilanes, and
aldehydes, which gives 2-aminobenzyl alcohol derivatives
of structural diversity in a straightforward manner.6
We first examined the reaction of in situ generated benzyne
(from 1a7 and KF/18-Crown-6), (diethylamino)trimethyl-
silane (2a), and benzaldehyde (3a) in the presence of benzoic
acid (10 mol %), and observed that the three-component
coupling product, 2-(diethylamino)benzhydrol (4a), was
formed in 76% yield (Table 1, entry 1). No trace of 4a was
obtained in the absence of benzoic acid, which confirms its
vital role in the present reaction (vide infra). Dialkyl-
aminosilanes (2b or 2c), alkoxy-substituted aminosilanes (2d
or 2e), or an aminosilane bearing a tetrahydrofuranyl moiety
(1) Reviews: (a) Taylor, R. Electrophilic Aromatic Substitution; John
Wiley & Sons: Chichester, UK, 1990. (b) Kakiuchi, F.; Chatani, N. AdV.
Synth. Catal. 2003, 345, 1077. (c) Bandini, M.; Melloni, A.; Umani-Ronchi,
A. Angew. Chem., Int. Ed. 2004, 43, 550.
(2) Pen˜a, D.; Pe´rez, D.; Guitia´n, E. Angew. Chem., Int. Ed. 2006, 45,
3579.
(3) Our recent results: (a) Yoshida, H.; Mimura, Y.; Ohshita, J.; Kunai,
A. Chem. Commun. 2007, 2405. (b) Yoshida, H.; Watanabe, M.; Morishita,
T.; Ohshita, J.; Kunai, A. Chem. Commun. 2007, 1505. (c) Yoshida, H.;
Tanino, K.; Ohshita, J.; Kunai, A. Chem. Commun. 2005, 5678. (d) Yoshida,
H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem. Commun. 2005, 3292.
(4) Three-component coupling of arynes with nucleophiles and electro-
philes: (a) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. J. Am. Chem.
Soc. 2006, 128, 11040. (b) Jeganmohan, M.; Cheng, C.-H. Chem. Commun.
2006, 2454. (c) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A.
Tetrahedron Lett. 2004, 45, 8659. (d) Yoshida, H.; Fukushima, H.; Ohshita,
J.; Kunai, A. Angew. Chem., Int. Ed. 2004, 43, 3935.
(5) Transition metal-catalyzed three-component coupling of arynes: (a)
Henderson, J. L.; Edwards, A. S.; Greaney, M. F. J. Am. Chem. Soc. 2006,
128, 7426. (b) Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H. Org. Lett.
2005, 7, 2921. (c) Chatani, N.; Kamitani, A.; Oshita, M.; Fukumoto, Y.;
Murai, S. J. Am. Chem. Soc. 2001, 123, 12686. (d) Yoshikawa, E.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2000, 39, 173.
(6) The reaction of benzyne with benzaldehyde was reported to produce
2-(dimethylamino)benzhydrol (12% yield), whose dimethylamino moiety
was derived from a benzyne precursor (1-(2-carboxyphenyl)-3,3-dimeth-
yltriazene). However, this reaction was not developed as a useful synthetic
procedure, because it required harsh conditions (160 °C) and excess aldehyde
(ca. 39 equiv): Nakayama, J.; Yoshida, M.; Simamura, O. Chem. Lett. 1973,
451.
(7) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
10.1021/ol071347a CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/24/2007

Table 1. Three-Component Coupling of Benzyne,
Aminosilanes, and Aldehydesa
Table 2. Three-Component Coupling of Arynes, 2d and 3fa
a The reaction was carried out at 0 °C in THF (1 mL) with 1a (0.18
mmol), 2 (0.15 mmol), 3 (0.23 mmol), KF (0.51 mmol), and 18-crown-6
(0.36 mmol) in the presence of benzoic acid (0.015 mmol). b Isolated yield
based on 2. c Mixture of two diastereomers (ratio ) 1:1).
(2f) also reacted smoothly to give high yields of respective
products 4b-f (entries 2-6), whereas the reaction of 2g-i
resulted in moderate yield (entries 7-9). In addition,
electron-deficient (3b), electron-rich (3c), or sterically con-
gested aromatic aldehydes (3d or 3e) were applicable to the
reaction, affording the products (4j-m) in 76-82% yield
(entries 10-13). It is worth noting the excellent chemo-
selectivity of the reaction: treatment of cyano- (3f), meth-
oxycarbonyl- (3g), or bromo-substituted benzaldehyde (3h)
with benzyne and 2d provided 4n-p exclusively, leaving
these functional groups intact (entries 14-16). A hetero-
aromatic aldehyde (3i) or an aliphatic aldehyde (3j)8 could
also participate in the reaction (entries 17 and 18), and
furthermore, (E)-cinnamaldehyde (3k) underwent 1,2-addi-
tion to give an 80% yield of 4s, whose stereochemistry was
retained unchanged (entry 19).
a The reaction was carried out at 0 °C in THF (1 mL) with 1 (0.18 mmol),
2d (0.15 mmol), 3f (0.23 mmol), KF (0.51 mmol), and 18-crown-6 (0.36
mmol) in the presence of benzoic acid (0.015 mmol). b Isolated yield based
on 2d. c 4z:4′z ) 50:50. d 4R:4′R ) 67:33. e 4â:4′â ) 60:40.
of such unsymmetrical arynes as 4-methoxy- (from 1h),
4-fluoro- (from 1i), or 3-methylbenzyne (from 1j) resulted
in the formation of a mixture of regioisomers (entries 7-9),
whereas 3-methoxybenzyne (from 1k) yielded exclusively
4γ having the amino moiety at the meta position of the
methoxy moiety (entry 10).9
Similarly to the cases with simple benzyne, 4,5-disubsti-
tuted arynes (from 1b-d) or 2,3-naphthalyne (from 1e)
efficiently reacted with 2d and 3f to furnish 4t-w in high
yield, and even 3,6-disubstitued arynes (from 1f or 1g) could
be applied to the reaction, despite the steric congestion
around the triple bond (Table 2, entries 1-6). The reaction
We next investigated the reaction pathway as depicted in
Scheme 1. In the absence of benzoic acid, the reaction of
(8) Unfortunately, the reaction of such an enolizable aldehyde as propanal
resulted in the formation of a complex mixture.
(9) Similar regioselectivities were observed in other electrophilic cou-
plings of these unsymmetrical arynes. See refs 3 and 4.
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Org. Lett., Vol. 9, No. 17, 2007

Scheme 1
Scheme 2
benzyne, 2d, and 3a gave only aminosilylated product 5 in
place of three-component coupling product 4d (eq a),10 and
moreover, 4d was not formed at all in the reaction of 3a
with 5 (eq b), showing that an aminosilylated product is not
an intermediate species in the three-component coupling. In
marked contrast to the case of an aminosilane, treatment of
an amine (6a) with benzyne and 3a was found to produce
4a without added benzoic acid (eq c).11
formed through the above-mentioned coupling followed by
intramolecular cyclization between the resulting alkoxide and
the ester moieties.15
Scheme 3
These results prompt us to propose a plausible reaction
pathway, where in situ generated amine 6 (from aminosilane
2 and benzoic acid)12 serves as an actual nucleophile to afford
zwitterion 7 through action with an aryne (Scheme 2).
Subsequent nucleophilic coupling of 7 with an aldehyde (3)
furnishes 4, which then reacts with 2 to give silyl ether 8
with regeneration of 6.13 The resulting silyl ether would be
transformed into 4 via a workup process.14
Finally, utility of the three-component coupling has also
been demonstrated by construction of heterocycles (Scheme
3). Thus, treatment of methyl 2-formylbenzoate (3l-n) with
benzyne and 2d afforded phthalide 9a-c, which would be
(10) Yoshida, H.; Minabe, T.; Ohshita, J.; Kunai, A. Chem. Commun.
2005, 3454.
(11) A significant amount of N,N-diethylaniline was formed as a by-
product in this reaction, which demonstrates an advantage of use of
aminosilanes in the three-component coupling. The existence of only a
catalytic amount of amines, generated from aminosilanes and benzoic acid,
in the reaction mixture would decrease aniline derivatives. For N-arylation
of amines by the use of arynes, see: (a) Liu, Z.; Larock, R. C. Org. Lett.
2003, 5, 4673. (b) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198.
(12) An amine and a silyl carboxylate are readily formed in the reaction
of an aminosilane and a carboxylic acid: (a) Wissner, A. Tetrahedron Lett.
1978, 2749. (b) Ruhlmann, K. Chem. Ber. 1961, 94, 1876.
In conclusion, we have demonstrated that diverse amino
and hydroxymethyl moieties can be simultaneously intro-
duced into adjacent positions of aromatic rings depending
(13) Various alcohols are readily converted into the respective silyl ethers
via action with aminosilanes: (a) Shirini, F.; Mollarazi, E. Synth. Commun.
2006, 36, 1109. (b) Gautret, P.; El-Ghammarti, S.; Legrand, A.; Couturier,
D.; Rigo, B. Synth. Commun. 1996, 26, 707.
(14) Because there was an excess of fluoride in the reaction mixture,
three-component coupling products would exist as silicates or alkoxides
before a workup process. Therefore, we could only detect trace amounts of
silyl ethers 8 in crude products. For protodesilylation of silyl ethers with a
fluoride ion, see: Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999; Chapter
2, pp 113-148.
(15) We also examined other protic acids and Lewis acids as additives;
however, none of them improved the yield of 9a. See the Supporting
Information for details.
(16) Ejima, A.; Barford, S. C.; Kawakoshi, K.; Mitsuwa, T. Daiichi
Seiyaku Co., Ltd., Japan, JP 11080141, 1999.
(17) Sugita, K.; Yokomizo, A.; Suzuki, M.; Ito, M.; Haginoya, N.; Usui,
H. Daiichi Seiyaku Co., Ltd., Japan, JP 2007022943, 2007.
(18) A three-component coupling of arynes, aminosilanes, and sul-
fonylimines also proceeds to give 2-aminobenzylamine derivatives, which
will be reported in due course.
Org. Lett., Vol. 9, No. 17, 2007
3369

upon the three-component coupling using arynes. The
resulting 2-aminobenzhydrol derivatives comprise an im-
portant group of pharmacologically active compounds such
as antitumors16 and squalene synthase inhibitors.17 Moreover,
the coupling, in combination with intramolecular cyclization,
is applicable to assembly of phthalide skeletons. Studies on
multicomponent coupling of arynes directed toward ortho-
selective double functionalization of aromatic rings are in
progress.18
Acknowledgment. We thank Dr. Yoshiaki Nakao and
Prof. Tamejiro Hiyama (Kyoto University) for HRMS
measurement, and also the Central Glass Co Ltd. for a
generous gift of trifluoromethanesulfonic anhydride.
Supporting Information Available: Experimental pro-
cedure and characterization of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL071347A
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Org. Lett., Vol. 9, No. 17, 2007