A 2:1 coupling reaction of arynes with aldehydes via o-quinone methides: Straightforward synthesis of 9-arylxanthenes

Article abstract of DOI:10.1021/ol048298b

(Chemical Equation Presented) A novel coupling reaction, where an aldehyde and two molar amounts of an aryne are assembled selectively, has been demonstrated to afford diverse 9-arylxanthene derivatives in one step. o-Quinone methide arising from the [2 + 2] cycloaddition of an aldehyde with an aryne was postulated as a transient intermediate.

Full text of DOI:10.1021/ol048298b

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4049-4051
A 2:1 Coupling Reaction of Arynes with
Aldehydes via o-Quinone Methides:
Straightforward Synthesis of
9-Arylxanthenes
Hiroto Yoshida,* Masahiko Watanabe, 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; akunai@hiroshima-u.ac.jp.
Received August 26, 2004
ABSTRACT
A novel coupling reaction, where an aldehyde and two molar amounts of an aryne are assembled selectively, has been demonstrated to afford
diverse 9-arylxanthene derivatives in one step. o-Quinone methide arising from the [2
postulated as a transient intermediate.
+ 2] cycloaddition of an aldehyde with an aryne was
The [2 + 2] cycloadditions of arynes1 with alkenes or
carbon-heteroatom double bonds have attracted considerable
attention as an efficient method for construction of benzo-
cyclobutene skeletons, which are valence isomers of syn-
thetically useful o-quinoid species (Scheme 1).2,3 Although
carbonyl compounds with arynes. We have recently disclosed
electrophilic coupling reactions of arynes, that is, synthesis
of N-alkyl-N′-arylimidazolium salts via addition of imida-
zoles to arynes,7a insertion of arynes into an N-CO σ-bond
of ureas,7b and three-component coupling of arynes with
isocyanides and aldehydes,7c demonstrating that diverse
heterocyclic skeletons were assembled straightforwardly from
neutral neucleophiles and arynes. Based upon these results,
we envisaged that a carbonyl oxygen atom may act as a
nucleophilic site to arynes, leading to a new type of coupling
reactions for the synthesis of heterocycles.8-10 Herein we
Scheme 1
(3) (a) For a review on o-quinone methides, see: Van De Water, R. W.;
Pettus, T. R. R. Tetrahedron 2002, 58, 5367. (b) For a review on
o-quinodimethanes, see: Segura, J. L.; Martin, N. Chem. ReV. 1999, 99,
3199.
(4) Wasserman, H. H.; Solodar, J. J. Am. Chem. Soc. 1965, 87, 4002.
(5) (a) Hosoya, T.; Hamura, T.; Kuriyama, Y.; Suzuki, K. Synlett 2000,
520. (b) Hamura, T.; Ibusuki, Y.; Sato, K.; Matsumoto, T.; Osamura, Y.;
Suzuki, K. Org. Lett. 2003, 5, 3551.
various electron-rich alkenes including vinyl ethers,4 ketene
acetals,5 and enamines6 readily undergo the [2 + 2] cycload-
dition, few reports have been available on the reaction of
(1) For reviews on arynes, see: (a) Kessar, S. V. In ComprehensiVe
Organic Synthesis; Trost, B. M., Flemming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 4, p 483. (b) Pellissier, H.; Santelli, M. Tetrahedron
2003, 59, 701.
(2) For a review on the valence isomerization of cyclobutenes, see: Durst,
T.; Breau, L. In ComprehensiVe Organic Synthesis; Trost, B. M., Flemming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 675.
(6) (a) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Hayasaka, T.; Kusama,
O. J. Chem. Soc. C 1971, 1051. (b) Gingrich, H. L.; Huang, Q.; Morales,
A. L.; Jones, M., Jr. J. Org. Chem. 1992, 57, 3803.
(7) (a) Yoshida, H.; Sugiura, S.; Kunai, A. Org. Lett. 2002, 4, 2767. (b)
Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem., Int.
Ed. 2002, 41, 3247. (c) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A.
Angew. Chem., Int. Ed. 2004, 43, 3935.
10.1021/ol048298b CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/05/2004

report that a 2:1 coupling reaction of arynes with aryl
aldehydes via the [2 + 2] cycloaddition as a key step offers
straightforwardly diverse xanthene derivatives,11 which con-
stitute such functionalized molecules as dyes and pharma-
ceuticals.12
We first examined the reaction of in situ-generated
benzyne (from 1a and KF/18-crown-6) with 2-benzyloxy-
1-naphthaldehyde (2a) in THF at 0 °C and observed that
two molar amounts of benzyne were coupled with 2a to give
9-(2-bezyloxy-1-naphthyl)xanthene (3aa) in 70% yield (Table
1, entry 1). Treatment of 2-methoxy-1-naphthaldehyde (2b)
rich aldehyde is indispensable for the reaction to proceed
smoothly. Similarly to the naphthaldehydes, the coupling
reaction was applicable to a variety of benzaldehydes. Thus,
when 2,6-dimethoxy- (2d) or 2,6-dibenzyloxybenzaldehyde
(2e) was allowed to react with benzyne, the corresponding
xanthene (3ad or 3ae) was formed in 61% or 60% yield
(entries 4 and 5). Furthermore, the reaction of a variously
substituted methoxybenzaldehyde (2f-i) took place ef-
fectively, leading to the formation of the product (3af-ai)
in a modest yield (entries 6-9). A methyl-substituted
benzaldehyde (2j-l) could participate in the reaction as well
to afford a reasonable to good yield of the respective
xanthene (3aj-al), in contrast to the reaction of benzalde-
hyde (2m, 22% yield) or 4-trifluoromethylbenzaldehyde (2n,
xanthene was not formed at all) (entries 10-14).
Table 1. 2:1 Coupling of Benzyne with an Aryl Aldehydea
We next investigated the 2:1 coupling reaction of a
substituted aryne. As depicted in Scheme 2, a symmetrical
Scheme 2
entry
R
time (h)
yieldb (%)
product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
BnO
MeO
H
2,6-(MeO)2
2,6-(BnO)2
2-MeO
2,4-(MeO)2
2,4,6-(MeO)3
4-MeO
2,4,6-Me3
2,4-Me2
2,6-Me2
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
23
24
26
20
27
7
70
66
17
61
60
54
53
44
42
58
41
38
22
0
3a a
3a b
3a c
3a d
3a e
3a f
3a g
3a h
3a i
5
21
18
4
8
5
3a j
3a k
3a l
20
19
3a m
4-CF3
a The reaction was carried out in THF at 0 °C using 1a (0.45 mmol), 2
(0.15 mmol), KF (0.90 mmol) and 18-crown-6 (0.90 mmol). b Isolated yield
based on 2.
with benzyne also produced 66% yield of 3ab (entry 2),
whereas the reaction of 1-naphthaldehyde (2c) resulted in a
low yield (entry 3), indicating that the use of an electron-
(8) Heaney and Nakayama reported independently on the synthesis of
1,3-benzodioxanes (ca. 20% yield) via a 1:2 coupling reaction of arynes
with aryl aldehydes, where a large excess of aldehydes (ca. 40 equiv to
aryne precursors) was used: (a) Heaney, H.; McCarty, C. T. Chem.
Commun. 1970, 123. (b) Nakayama, J.; Yoshida, M.; Simamura, O. Chem.
Lett. 1973, 451.
(9) Heaney also reported reactions of arynes with R,â-unsaturated
aldehydes: Heaney, H.; Jablonski, J. M.; McCarty, C. T. J. Chem. Soc.,
Perkin Trans. 1 1972, 2903.
aryne (from 1b-d) efficiently underwent the coupling
reaction, giving the polysubstituted xanthene (3ba, 3ca, or
3di) in 51%, 50%, or 45% yield, respectively. In addition,
the reaction of 3-methoxybenzyne (from 1e), an unsym-
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Org. Lett., Vol. 6, No. 22, 2004

metrical aryne, with 2j provided 64% yield of two regio-
isomers (3ej and 3′ej) in a 3:1 ratio.
Scheme 3 describes a plausible reaction pathway of the
2] cycloaddition between the resulting o-quinone methide
and 3-methoxybenzyne may take place at each orientation,
resulting in the formation of two regioisomers (3ej and 3′ej).
Finally, utility of the coupling reaction has been demon-
strated by application to diformyldiphenyl ether 2o. As shown
in Scheme 4, each formyl group was coupled with two molar
Scheme 3
Scheme 4
2:1 coupling. First, a nucleophilic attack of a carbonyl oxygen
atom to an aryne gives a zwitterion (4), which then undergoes
intramolecular cyclization to afford a benzoxete (5). Sub-
sequent isomerization to an o-quinone methide (6), followed
by [4 + 2] cycloaddition with a second aryne provides a
xanthene. As was the case of the other electrophilic couplings
of 3-methoxybenzyne, the carbonyl oxygen of 2j would
attack exclusively the aryne carbon at the meta position of
the methoxy moiety.1a,7 On the contrary, the following [4 +
amounts of benzyne to provide bis(xanthylphenyl) ether 3ao
straightforwardly in 25% yield.
In conclusion, a general and straightforward method for
the synthesis of diverse xanthene derivatives has been
accomplished based upon the novel 2:1 coupling reaction
of arynes with aldehydes. Further studies on synthetic
applications to other carbon-heteroatom double bonds are
in progress.
(10) For [2 + 2] cycloadditions of arynes with other carbon-heteroatom
double bonds, see the following references. (a) Imines: Aly, A. A.;
Mohamed, N. K.; Hassan, A. A.; Mourad, A.-F. E. Tetrahedron 1999, 55,
1111. (b) Thiones: Okuma, K.; Shiki, K.; Sonoda, S.; Koga, Y.; Shioji,
K.; Kitamura, T.; Fujiwara, Y.; Yokomori, Y. Bull. Chem. Soc. Jpn. 2000,
73, 155. (c) Selones: Okuma, K.; Okada, A.; Koga, Y.; Yokomori, Y. J.
Am. Chem. Soc. 2001, 123, 7166.
Acknowledgment. We thank Central Glass Co. Ltd. for
a generous gift of trifluoromethanesulfonic anhydride. We
also thank Mr. Yoshiaki Nakao and Prof. Tamejiro Hiyama
(Kyoto University) for HRMS measurements.
(11) For synthesis of xanthenes by a nucleophilic coupling with arynes,
see: (a) Va´zquez, R.; de la Fuente, M. C.; Castedo, L.; Dom´ınguez, D.
Synlett 1994, 433. (b) Knight, D. W.; Little, P. B. J. Chem. Soc., Perkin
Trans. 1 2001, 1771.
(12) Hepworth, J. D. In ComprehensiVe Heterocyclic Chemistry; Katrit-
zky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 3, p
874.
Supporting Information Available: Experimental pro-
cedures and characterization of the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL048298B
Org. Lett., Vol. 6, No. 22, 2004
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