Aryne insertion into α-cyanocarbonyl compounds: Direct introduction of carbonyl and cyanomethyl moieties into the aromatic skeletons

Article abstract of DOI:10.1016/j.tetlet.2005.07.119

Two different carbon functional groups can be introduced simultaneously into 1,2-positions of aromatic skeletons based upon a novel insertion reaction of arynes into a carbonyl-cyanomethyl σ-bond of α-cyanocarbonyl compounds.

Full text of DOI:10.1016/j.tetlet.2005.07.119

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6729–6731
Aryne insertion into a-cyanocarbonyl compounds:
direct introduction of carbonyl and cyanomethyl moieties into
the aromatic skeletons
*
*
Hiroto Yoshida, Masahiko Watanabe, Joji Ohshita and Atsutaka Kunai
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University, Higashi-Hiroshima 739-8527, Japan
Received 1 July 2005; revised 25 July 2005; accepted 25 July 2005
Available online 15 August 2005
Abstract—Two different carbon functional groups can be introduced simultaneously into 1,2-positions of aromatic skeletons based
upon a novel insertion reaction of arynes into a carbonyl–cyanomethyl r-bond of a-cyanocarbonyl compounds.
Ó 2005 Elsevier Ltd. All rights reserved.
1
Insertion reactions of arynes into a nucleophilic–elec-
trophilic r-bond have engaged much attention as
unique straightforward methods for synthesis of substi-
tuted arenes, in which two functional groups are intro-
duced into the adjacent positions of the aromatic
skeletons. In this context, we have already reported the
First the reaction of benzyne, prepared in situ from 2-
(trimethylsilyl)phenyl triflate (1a) and a fluoride ion
9
(KF/18-crown-6), with pivaloylacetonitrile (2a) was
conducted in THF at room temperature to afford an
82% yield of tert-butyl 2-(cyanomethyl)phenyl ketone
(3aa) (Scheme 1). The reaction occurred exclusively at
the carbonyl–methylene bond, and a product arising
from insertion into the cyano–methylene bond did not
2
insertion reactions into a nitrogen–carbonyl, sulfur–
3
4
tin or nitrogen–silicon r-bond, and furthermore, even
a carbon–carbon r-bond has been found to be applicable
to the reaction by the use of b-dicarbonyl compounds,
enabling two carbon–carbon bond-forming processes
1
0
form at all. The reaction was also applicable to 2,3-
naphthalyne (from 1b) or 4,5-dimethylbenzyne (from
1c), giving the respective insertion products (3ba or
3ca) in high yields. A cyclopentene- or cyclohexene-con-
densed aryne (from 1d or 1e) underwent the addition to
furnish excellent yields of the products (3da or 3ea), and
furthermore, 3,6-dimethoxybenzyne (from 1f) reacted
smoothly with 2a irrespective of its steric congestion
around the triple bond. Facile insertion of 3-meth-
oxybenzyne (from 1g) was observed as well to provide
3ga as the sole product, bearing the cyanomethyl moiety
at the meta position of the methoxy group. In marked
contrast, the reaction of 4-methylbenzyne (from 1h) pro-
5
–7
to take place simultaneously. Since then we have been
studying the reactions of arynes with other active meth-
ylene compounds, and have found that a-cyanocarbonyl
compounds add across arynes at their carbonyl–methyl-
ene moieties exclusively under very mild conditions.
Herein, we disclose that carbonyl and cyanomethyl moie-
ties can be efficiently introduced into 1,2-positions of
aromatic skeletons depending upon the novel carbon–
8
carbon r-bond-addition reaction (Eq. 1).
duced a mixture of regioisomeric products (3ha and
CN
O
CN
O
R
0
3
ha) in the ratio of 50:50, which implies that the present
R
+
reaction certainly proceeds through an aryne
intermediate.
R'
R'
ð1Þ
We next investigated the reaction of other a-cyanocar-
bonyl compounds (Scheme 2). Thus, when benzoyl-
acetonitrile (2b) or propanoylacetonitrile (2c) was
treated with benzyne, the respective insertion product
(3ab or 3ac) was produced in 63% or 57% yield, being
accompanied by the formation of a 2:1 coupling product
(4ab or 4ac), which holds the phenyl moiety at the
Keywords: Arynes; Carbon–carbon r-bond cleavage; a-Cyanocar-
bonyl compounds; Insertion reactions.
*
Corresponding authors. Tel.: +81 82 424 7724; fax: +81 82 424
494; e-mail addresses: yhiroto@hiroshima-u.ac.jp; akunai@
5
hiroshima-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.119

6730
H. Yoshida et al. / Tetrahedron Letters 46 (2005) 6729–6731
3
6
KF
1
4
2
TMS
CN
O
CN
O
8-crown-6
R
R
+
t-Bu
THF, r.t.
5
1 OTf
t-Bu
KF
TMS
CN
O
CN
O +
CN
O
18-crown-6
1
2a
3
+
1
1
1
1
1
1
1
1
a: R = H
THF, r.t.
OTf R'
R'
R'
b: R = 4,5- -(CH) -
4
c: R = 4,5-Me
2
1a
2
3
4
d: R = 4,5- -(CH ) -
2
3
2
b: R' = Ph
e: R = 4,5- -(CH ) -
2
4
2
2
2
2
c: R' = Et
f: R = 3,6-(MeO)
2
d: R' = MeO(CH ) O
g: R = 3-MeO
h: R = 4-Me
2 2
e: R' = EtO
f: R' = t-BuO
Ph
Me
Me
CN
O
CN
O
CN
O
CN
+
CN
O
3ab: 63%
O
4ab: 11%, 2.5 h
t-Bu
aa: 82% (3 h)
t-Bu
t-Bu
Ph
Ph
4ab
3
3ba: 82% (27.5 h)
3ca: 82% (21 h)
3
ab
Ph
OMe
CN
O
CN
O
CN
O
CN
O
CN
O
3ac: 57%
+
4ac: 10%, 1.5 h
t-Bu
t-Bu
Et
3
Et
4ac
OMe t-Bu
3fa: 79% (8.5 h)
ac
3
da: 91% (19 h)
3ea: 92% (15 h)
Ph
Me
CN
CN
O
CN
O
CN
O
CN
O
3
ad: 68%
+
4
ad: 5%, 3 h
O
+
Me
OMe t-Bu
t-Bu
t-Bu
O(CH2)2OMe
ad
O(CH2)2OMe
4ad
3
3
ga: 82% (5.5 h)
3ha
3'ha
87% (16 h, 3ha:3'ha = 50:50)
Ph
CN
O
CN
O
Scheme 1.
3ae: 61%
+
4ae: 15%, 3 h
OEt
ae
OEt
4ae
benzylic position. A methoxyethyl (2d), ethyl (2e) or
tert-butyl (2f) ester of cyanoacetic acid also took part
in the reaction, providing a mixture of the 1:1 product
3
Ph
(
3ad–3af) and the 2:1 product (4ad–4af).11
CN
O
CN
O
3
af: 32%
+
4af: 36%, 4.5 h
A plausible pathway of the insertion reaction is de-
scribed in Scheme 3. First, an in situ-generated enolate
attacks an aryne to afford aryl anion 5, which then
undergoes intramolecular nucleophilic substitution at a
carbonyl moiety, giving benzyl anion 7 via benzocyclo-
Ot-Bu
af
Ot-Bu
4af
3
Scheme 2.
1
2
butene 6. Proton abstraction of 7 furnishes 3, while
:1 product 4 arises from the reaction of 7 with a second
2
aryne. The perfect regioselectivity observed in the reac-
tion of 3-methoxybenzyne can be rationally explained
by a steric and/or electron-withdrawing effect of the
methoxy group, both of which favor the nucleophilic
attack at m-position of the substituent. In the case of
tions of aromatic skeletons based upon the novel car-
bon–carbon r-bond-addition reaction to arynes.
Further studies on synthetic applications to other active
methylene compounds are in progress.
4
-methylbenzyne, steric and electronic differences
General procedure: To a THF solution (4.0 mL) of 18-
crown-6 (0.127 g, 0.48 mmol), 1 (0.24 mmol) and 2
(0.20 mmol) was added KF (0.028 g, 0.48 mmol), and
the resulting mixture was stirred at room temperature.
After the time specified in Schemes 1 and 2, the solvent
was removed in vacuo. Silicagel column chromatogra-
phy (dichloromethane as an eluent) gave the corre-
sponding product.
around the triple bond would be so slight that an equal
addition to the both ends takes place, leading to the for-
mation of a mixture of regioisomers.
In conclusion, we have demonstrated that two different
carbon functional groups, carbonyl and cyanomethyl
groups, can directly be introduced into adjacent posi-

H. Yoshida et al. / Tetrahedron Letters 46 (2005) 6729–6731
6731
CN
O
CN
O
+
R'
R'
3
4
CN
-
+
R'
O K
H+
H+
CN
O
-
R'
+
K
5
-
+
K
K+
-
CN
O-
CN
CN
O
O
R'
K+
R'
R'
6
7
Scheme 3.
Acknowledgements
Kunai, A. J. Am. Chem. Soc. 2003, 125, 6638; (c) Yoshida,
H.; Ikadai, J.; Shudo, M.; Ohshita, J.; Kunai, A. Organo-
metallics 2005, 24, 156; (d) Ikadai, J.; Yoshida, H.;
Ohshita, J.; Kunai, A. Chem. Lett. 2005, 34, 56; (e)
Yoshida, H.; Tanino, K.; Ohshita, J.; Kunai, A. Angew.
Chem., Int. Ed. 2004, 43, 5052.
We thank Central Glass Co. Ltd. for a generous gift of
trifluoromethanesulfonic anhydride.
8
. The reaction of arynes with lithiated ethyl cyanoacetate
has been reported to give anthraquinones: Bhawal, B. M.;
Khanapure, S. P.; Zhang, H.; Biehl, E. R. J. Org. Chem.
1991, 56, 2846.
References and notes
1
. For reviews, see: (a) Kessar, S. V. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 4, pp 483–515; (b) Pellissier,
H.; Santelli, M. Tetrahedron 2003, 59, 701.
9. Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett.
1983, 1211.
10. Insertion into
a cyano–methylene r-bond by the
2
3
4
5
6
. Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T.
Angew. Chem., Int. Ed. 2002, 41, 3247.
. Yoshida, H.; Terayama, T.; Ohshita, J.; Kunai, A. Chem.
Commun. 2004, 1980.
. Yoshida, H.; Minabe, T.; Ohshita, J.; Kunai, A. Chem.
Commun. 2005, 3454.
. Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem.
Commun. 2005, 3292.
reaction of arynes with lithiated acetonitrile deriva-
tives has been reported: (a) Meyers, A. I.; Panesgrau,
P. D. Tetrahedron Lett. 1984, 25, 2941; (b) Khanapure,
S. P.; Crenshaw, L.; Reddy, R. T.; Biehl, E. R. J. Org.
Chem. 1988, 53, 4915; (c) Waggenspack, J. H.; Tran, L.;
Taylor, S.; Yeung, L. K.; Morgan, M.; Deshmukh,
A. R.; Khanapure, S. P.; Biehl, E. R. Synthesis 1992,
765.
. Quite recently, a similar insertion reaction of arynes into a
carbon–carbon r-bond of b-ketoesters has been disclosed:
Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127,
11. The reaction with 2a also gave 2:1 products, although the
yields were rather low (trace—3%).
12. Alternatively, benzocyclobutene 6 may be generated
through the [2+2] cycloaddition between arynes and
enolates. For examples, see: (a) Hosoya, T.; Hasegawa,
T.; Kuriyama, Y.; Suzuki, K. Tetrahedron Lett. 1995, 36,
3377; (b) Hosoya, T.; Hasegawa, T.; Kuriyama, Y.;
Matsumoto, T.; Suzuki, K. Synlett 1995, 177.
5
340.
7
. We also reported palladium-catalyzed insertion reactions
of arynes into metallic reagents: (a) Yoshida, H.; Honda,
Y.; Shirakawa, E.; Hiyama, T. Chem. Commun. 2001,
1
880; (b) Yoshida, H.; Ikadai, J.; Shudo, M.; Ohshita, J.;