Arynes in a three-component coupling reaction: Straightforward synthesis of benzoannulated iminofurans

Article abstract of DOI:10.1002/anie.200460009

Mix the components, stir, and ... voila! A variety of benzoannulated iminofurans can be obtained in this straightforward manner from an aryne, an isocyanide, and an aldehyde in modest to high yields (see scheme). Perfect regioselectivity was observed with a 3-substituted aryne and 4-fluorobenzyne, whereas 4-methylbenzyne gave a mixture of regioisomers.

Full text of DOI:10.1002/anie.200460009

Angewandte
Chemie
organic synthesis.[1] Owing to their low-lying LUMO, arynes
exhibit salient electrophilicity, and even neutral nucleophiles,
which are inert towards alkynes, readily add to arynes. Hence,
considerable attention has been paid to nucleophilic coupling
reactions with arynes, and these reactions have been exploited
in the construction of complex organic molecules.[2] The
coupling reactions proceed through an initially formed
zwitterion and can be divided into three categories
(Scheme 1): a) formation of a monosubstituted arene by
Scheme 1. The reaction of arynes with neutral nucleophiles.
proton abstraction, b) insertion into a nucleophilic–electro-
philic s bond (Nu–E) by intramolecular nucleophilic substi-
tution,[3] and c) three-component coupling by trapping the
zwitterion with an electrophile. Although the three-compo-
nent coupling would be the most attractive approach from a
synthetic standpoint for generating molecular complexity and
diversity, examples are limited, probably because of the
difficulty associated with regulating the reactivity of arynes.[4]
We recently reported novel coupling reactions of arynes
with neutral nucleophiles: the synthesis of N-alkyl N’-aryl
imidazolium salts through the addition of imidazoles to
arynes (reaction type a, Scheme 1)[5a] and the insertion of
[5b,6]
À
Multicomponent Reactions
arynes into N CO s bonds of ureas (reaction type b).
Herein we disclose that arynes undergo an unprecedented
three-component coupling with isocyanides and aldehydes,
thus offering a straightforward method for the synthesis of
diverse benzoannulated iminofurans.[7–9]
Arynes in a Three-Component Coupling
Reaction: Straightforward Synthesis of
Benzoannulated Iminofurans**
First, we investigated the reaction of benzyne, generated
in situ from 2-(trimethylsilyl)phenyl triflate (1a)[10] in the
presence of KF and [18]crown-6, with 1,1,3,3-tetramethylbu-
tyl isocyanide (2a) and benzaldehyde (3a) in THF at 08C for
7 h, and observed that the three-component coupling product
N-(3-phenyl-1(3H)-isobenzofuranylidene)-1,1,3,3-tetrame-
thylbutylamine (4a) was formed in 65% yield (Table 1,
entry 1).[11] The aromatic aldehydes 3b, which contains an
electron-donating substituent, and 3c, with an electron-with-
drawing substituent, also underwent the reaction efficiently to
give the expected products in good yields (Table 1, entries 2
and 3). Furthermore, reactions of the meta-substituted
aromatic aldehyde 3d and the sterically congested aldehydes
3e and 3 f proceeded smoothly to provide the corresponding
iminofurans 4d–4 f in good yields (Table 1, entries 4–6). The
thienyl group in 3g was compatible with the reaction
conditions (Table 1, entry 7),[12] and the aliphatic aldehydes
3h and 3i could also be used (Table 1, entries 8 and 9).
Besides 2a, tert-butyl (2b) and 1-adamantyl isocyanide (2c)
Hiroto Yoshida,* Hiroyuki Fukushima, Joji Ohshita,
and Atsutaka Kunai*
Arynes are highly strained and kinetically unstable molecules
that have been recognized as useful reactive intermediates in
[*] Dr. H. Yoshida, H. Fukushima, Prof. J. Ohshita, Prof. A. Kunai
Department of Applied Chemistry
Graduate School of Engineering, Hiroshima University
Higashi-Hiroshima 739-8527 (Japan)
Fax: (+81)82-424-5494
E-mail: yhiroto@hiroshima-u.ac.jp
akunai@hiroshima-u.ac.jp
[**] We thank Central Glass Co. Ltd. for a generous gift of trifluorome-
thanesulfonic anhydride.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 3935 –3938
DOI: 10.1002/anie.200460009
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Table 1: Three-component coupling of benzyne, an isocyanide, and an aldehyde.
Entry Isocyanide
R’’
t
Yield[a] Product
[h] [%]
1
2
3
4
5
6
7
8
9
2a (R’=CMe2CH2CMe3) Ph
2a
2a
2a
3a
4-(MeO)C6H4 3b
4-(CF3)C6H4 3c
3-(MeO)C6H4 3d
7
7
7
5
5
5
7
5
7
5
65
73
69
65
61
73
50
50
40
49
4a
4b
4c
4d
4e
4 f
4g
4h
4i
2a
2a
2a
2a
2,4-Me2C6H3
1-naphthyl
2-thienyl
Et
3e
3 f
3g
3h
3i
2a
tBu
10
11
2b (R’=tBu)
2c (R’=1-Ad)
1-naphthyl
4-(MeO)C6H4 3b 24 77
3 f
4j
4k
[a] Yield of isolated product based on the isocyanide. Tf=trifluoromethanesulfonyl,
TMS=trimethylsilyl.
participated in the reaction to afford the desired product in
49% and 77% yield, respectively (Table 1, entries 10 and 11).
In contrast, the reaction of sterically less congested cyclohexyl
or n-octyl isocyanide resulted in the formation of a complex
mixture of products.
As well as unsubstituted benzyne, variously substituted
arynes could be used in the reaction. When 1-(trimethylsilyl)-
2-naphthyl triflate (1b), a 1,2-naphthalyne precursor, was
treated with 2a and 3b, 4l was formed as the sole product
(Scheme 2). Exclusive formation of 4l was also observed in
Scheme 3. Three-component coupling with variously substituted
arynes.
well as sterically congested 3,6-dimethoxybenzyne (from 1j),
also participated in the reaction to give the corresponding
iminofurans 4q, 4r, and 4s.[13]
The reaction was also found to be applicable to an
aldehyde with two reactive sites. As depicted in Scheme 4,
terephthalaldehyde (3j) reacted with benzyne and 2a to
afford 4t in 38% yield and with a diastereomeric ratio (d.r.) of
50:50. The equivalent reaction of isophthalaldehyde (3k)
gave the product 4u with d.r. 65:35.
Scheme 2. Three-component coupling of 1,2-naphthalyne, 1,1,3,3-tetra-
methylbutyl isocyanide, and p-anisaldehyde.
the reaction of 2-(trimethylsilyl)-1-naphthyl triflate (1c),
which confirms the intermediacy of an aryne in the three-
component coupling. The reactions of 3-substituted arynes
(from 1d or 1e) also took place with perfect regioselectivity,
whereby the imino moiety was introduced at the sterically less
hindered position of the aryne (Scheme 3). The reaction of
the aryne derived from 1 f, with a fluoro substituent at
position 4, occurred regioselectively to afford 4o exclusively,
whereas the reaction of 4-methylbenzyne (from 1g) furnished
almost equal amounts of the regioisomeric products 4p and
4p’. The 4,5-disubstituted arynes derived from 1h and 1i, as
We propose the nucleophilic attack of the carbon atom of
the isocyanide group to the aryne as the initiation step of the
three-component coupling (Scheme 5).[14] The resulting zwit-
terion is then trapped by the aldehyde, and a subsequent
intramolecular cyclization affords the product.[15] The
observed perfect regioselectivities in the reactions of 1,2-
naphthalyne and 3-substituted arynes can be explained
rationally as being due to a steric effect, which favors
nucleophilic attack at the meta position of the substi-
tuent.[2a,16] Owing to the strong electron-withdrawing effect
of a fluoro substituent, developing negative charge at the meta
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Experimental Section
4a: Compound 1a (0.090 g, 0.30 mmol) was added to a solution in
THF (1.0 mL) of KF (0.035 g, 0.60 mmol), [18]crown-6 (0.16 g,
0.60 mmol), 2a (0.021 g, 0.15 mmol), and 3a (0.032 g, 0.30 mmol),
and the resulting mixture was stirred at 08C for 7 h. The reaction
mixture was then diluted with ethyl acetate, filtered through a plug of
celite, and concentrated. Column chromatography on alumina
(eluent: 25% ethyl acetate/hexane) followed by gel-permeation
chromatography (eluent: benzene) gave 4a as a white powder
(0.031 g, 65%). 1H NMR (400 MHz, CDCl3): d = 1.03 (s, 9H), 1.47
(s, 6H), 1.77 (s, 2H), 6.37 (s, 1H), 7.13–7.17 (m, 1H), 7.27–7.41 (m,
7H), 7.78–7.82 ppm (m, 1H); 13C NMR (100 MHz, [D8]THF): d =
30.9, 32.4, 32.7, 56.2, 57.9, 85.6, 122.9, 124.2, 127.4, 129.2, 129.5, 129.7,
131.8, 133.0, 140.7, 147.1, 152.5 ppm; HRMS calcd for C22H27NO
(M+): 321.2093; found: m/z 321.2100.
Received: March 16, 2004 [Z460009]
Keywords: arynes · isocyanides · multicomponent reactions ·
.
oxygen heterocycles · regioselectivity
Scheme 4. Three-component coupling of benzyne, 1,1,3,3-tetramethyl-
butyl isocyanide, and a phthalaldehyde: a) 1a (5 equiv), 2a (2.5 equiv),
KF (10 equiv), [18]crown-6 (10 equiv), THF, 08C, 7 h.
[1] For reviews, see: a) R. W. Hoffmann, Dehydrobenzene and
Cycloalkynes, Academic Press, New York, 1967; b) H. Hart in
The Chemistry of Triple-Bonded Functional Groups, Supplement
C2 (Ed.: S. Patai), Wiley, Chichester, 1994, chap. 18; c) H.
Pellissier, M. Santelli, Tetrahedron 2003, 59, 701.
[2] a) S. V. Kessar in Comprehensive OrganicSynthesis, Vol. 4 (Eds.:
B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, pp. 483 – 515;
b) E. R. Biehl, S. P. Khanapure, Acc. Chem. Res. 1989, 22, 275.
[3] For Te–Te, see: a) N. Petragnani, V. G. Toscano, Chem. Ber. 1970,
103, 1652; for S – S, see: b) J. Nakayama, T. Tajiri, M. Hoshino,
Bull. Chem. Soc. Jpn. 1986, 59, 2907; for C – Si, see: c) Y. Sato, Y.
Kobayashi, M. Sugiura, H. Shirai, J. Org. Chem. 1978, 43, 199.
[4] Three-component coupling reactions of arynes have been
carried out previously with anionic nucleophiles: a) A. I.
Meyers, P. D. Pansegrau, Tetrahedron Lett. 1983, 24, 4935;
b) A. I. Meyers, P. D. Pansegrau, J. Chem. Soc. Chem.
Commun. 1985, 690; c) S. Tripathy, R. LeBlanc, T. Durst, Org.
Lett. 1999, 1, 1973.
[5] a) H. Yoshida, S. Sugiura, A. Kunai, Org. Lett. 2002, 4, 2767;
b) H. Yoshida, E. Shirakawa, Y. Honda, T. Hiyama, Angew.
Chem. 2002, 114, 3381; Angew. Chem. Int. Ed. 2002, 41, 3247.
[6] We also reported palladium-catalyzed insertion reactions of
arynes into element–element s bonds; for carbostannylation (C–
Sn), see: a) H. Yoshida, Y. Honda, E. Shirakawa, T. Hiyama,
Chem. Commun. 2001, 1880; for bissilylation (Si – Si), see: b) H.
Yoshida, J. Ikadai, M. Shudo, J. Ohshita, A. Kunai, J. Am. Chem.
Soc. 2003, 125, 6638.
[7] For previous reports on the synthesis of benzoannulated
iminofurans, see: a) A. I. Meyers, M. A. Hanagan, L. M. Trefo-
nas, R. J. Baker, Tetrahedron 1983, 39, 1991; b) W. Meise, B.
Suedkamp, Arch. Pharm. 1987, 320, 1210.
[8] For the Lewis acid mediated synthesis of iminofurans with
isocyanides, see: a) Y. Ito, H. Kato, T. Saegusa, J. Org. Chem.
1982, 47, 741; b) N. Chatani, M. Oshita, M. Tobisu, Y. Ishii, S.
Murai, J. Am. Chem. Soc. 2003, 125, 7812.
[9] For the three-component coupling of alkynes, isocyanides, and
aldehydes to give 2-aminofuran derivatives, see: a) V. Nair, A. U.
Vinod, Chem. Commun. 2000, 1019; b) A. Fayol, J. Zhu, Angew.
Chem. 2002, 114, 3785; Angew. Chem. Int. Ed. 2002, 41, 3633;
c) A. Fayol, J. Zhu, Org. Lett. 2004, 6, 115.
Scheme 5. Proposed reaction mechanism for the three-component
coupling.
position would be stabilized to a greater extent than at the
para position in the transition state for the addition of an
isocyanide to 4-fluorobenzyne, thus resulting in the regiose-
lective formation of 4o.[17] In contrast, steric and electronic
effects around the triple bond would be negligible in the
reaction of 4-methylbenzyne, and the isocyanide therefore
adds to both ends of the triple bond equally.
In conclusion, we have demonstrated that a variety of
arynes, despite their transient nature, can be utilized in a
selective three-component coupling reaction with a suitable
combination of nucleophile and electrophile. Based upon the
present three-component coupling with isocyanides and
aldehydes, diverse benzoannulated iminofurans, which are
difficult to obtain by conventional methods, can be prepared
readily. Further studies on the multicomponent coupling of
arynes in the presence of a different combination of reagents
are in progress.
[10] Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett. 1983, 1211.
[11] Although structural elucidation of the product of the three-
component coupling by NMR spectroscopy showed it to be a
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single isomer, we could not determine the exact stereochemistry
(E or Z) of the imine unit.
[12] For the Diels–Alder reaction of thiophene with an aryne, see:
D. D. Callander, P. L. Coe, J. C. Tatlow, J. Chem. Soc. Chem.
Commun. 1966, 143.
[13] Owing to the complexity of the reaction mixtures, we did not
pursue the identification of by-products of low-yielding reac-
tions. At present, the reasons for which the desired products
formed in low yields in the reactions of 1e, 1i, and 1j are unclear.
[14] R. Knorr, Chem. Ber. 1965, 98, 4038.
[15] A referee suggested another mechanism, in which the isocyanide
acts as an electrophile: Nucleophilic attack of the oxygen atom
of the carbonyl group of the aldehyde at the carbon atom of the
isocyanide group produces a 1,3-dipole, which then undergoes
1,3-dipolar cycloaddition with an aryne to afford the product.
Although this alternative mechanism can not be ruled out
entirely, the mechanism proposed by us appears more likely, as
the electrophilic coupling of an isocyanide with a neutral
nucleophile is generally known to be sluggish, except in special
cases. Furthermore, if the oxygen atom of the carbonyl group
acted as a nucleophile, it would first interact with the highly
electrophilic aryne, rather than the isocyanide, to provide a
different product to those described herein. For the electrophilic
coupling of an isocyanide with a neutral nucleophile, see: a) M.
Suginome, T. Fukuda, Y. Ito, Org. Lett. 1999, 1, 1977; for the
nucleophilic coupling of a carbonyl compound with an aryne,
see: b) H. Heaney, C. T. McCarty, J. Chem. Soc. Chem.
Commun. 1970, 123.
[16] Because of the electron-donating nature of the methyl substitu-
ent, the regioselectivity of the reaction of 3-methylbenzyne
seems to be unfavorable electronically. However, such regiose-
lectivity is often observed in nucleophilic coupling reactions with
3-methylbenzyne; see: T. K. Vinod, H. Hart, Tetrahedron Lett.
1988, 29, 885.
[17] Similar regioselectivity was observed in nucleophilic coupling
reactions with 4-chlorobenzyne: a) J. F. Bunnett, C. Pyun, J. Org.
Chem. 1969, 34, 2035; b) J. F. Bunnett, J. K. Kim, J. Am. Chem.
Soc. 1973, 95, 2254.
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