(3b, 3g, or 3m; 1.1 equiv) and Bu3P (1.2 equiv) reacted
nicely with a wide variety of functional alkanes bearing
the ketone, ester, amide, urea, cyano, or nitro functional-
ities (2bÀh) within 0.5À5 h at room temperature, affording
the corresponding phosphorus zwitterions 1 in very high
yields. Interestingly, five-component reactions can be per-
formed when the aldehyde 3p or 3q was employed in the
reaction with a functional alkane such as 2a, 2c, or 2d and
Bu3P, giving rise to the corresponding adduct 1aap, 1ccp,
1ddp, or 1aaq in excellent yields.
Scheme 3. Synthesis of Zwitterions 1 Starting from 2, 3p, and Bu3P
Scheme 2. Synthesis of Zwitterions 1 Starting from 2aÀh, 3, and
Bu3Pa
interesting molecules using the intramolecular Wittig reac-
tion as the key step.9 After the optimization of reaction
conditions,10 phosphorus zwitterions with the coumarin
functionality 1 reacted smoothly with various acid chloride
6, affording the corresponding furo[3,2-c]coumarins 5 in
high yields (Table 3). When the aryl-substituted zwitterion
such as 1aa was used, its reaction with aryl-, heteroaryl-, or
even alkyl-substituted acid chloride 6 (1.3 equiv) in the
presence of Et3N (1.5 equiv) underwent reaction smoothly
within 0.25À5 h at room temperature, providing the
corresponding adduct 5 in 76À99% yields (entries 1À7).
The substitution R of zwitterions 1 as well as R1 of 6
showed a significant influence on the reactivity for the
formation of 5 (entry 2 vs 10 and 14; entry 1 vs 13, 16, 17,
and 18). It is also noteworthy that even with the expected
long reaction time necessary for the reaction of 1ah and 6i,
the reaction proceeded successfully under the modified
reaction conditions, furnishing the desired product 5k in
high yield (90%; 17 h; entry 11). Remarkably, the zwitter-
ions 1ap with an aldehyde functionality can be employed
successfully with benzoyl chloride (6a) in the presence of
Et3N, giving the adduct 5r in 85% yield (entry 18).
a The structure of 1hg was determined by X-ray analysis.6 b0.5 mmol
of 3p and 3q (3q = isophthalaldehyde), 2.1 equiv of 2a, 2c, or 2d, and
2.4 equiv of Bu3P were used.
Surprisingly, under the same proposed reaction condi-
tions, a highly chemoselective three-component reaction
of 3p, Bu3P, and an alkane such as 2c or 2d proceeded
smoothly and efficiently (Scheme 3). The extra aldehyde
functionality can be tolerated, and the corresponding
phosphorus zwitterion 1cp or 1dp was provided effectively
in high yields (90% or 93% yield; 0.5 h). Remarkably,
further installation of an additional phosphorus zwitterion
as the moiety of the unsymmetrical dizwitterion such as
1dap (96%; 7 h), 1cap (97%; 2 h), or 1cdp (95%; 0.5 h) was
very successful, when a different functional alkane such as
2a or 2d was employed.
Furo[3,2-c]coumarins 5 are important heterocycles well-
known as many natural products and exhibit potential
biological activity.8 Among the phosphorus zwitterions 1,
those bearing coumarin as the functional moiety (Table 2)
provide an easy access to the preparation of these
Furthermore, our developed protocol provides an effi-
cient route for the facile synthesis of complex heteroaro-
matic rings, such as 7 and 8, with both furan and
furocoumarin as moieties (Scheme 4). The zwitterion
1gp, which was prepared from 2g, 3p, and Bu3P according
to the typical procedure, could be efficiently converted to
(9) For selected examples of furocoumarin synthesis, see: (a) Chen,
L.; Li, Y.; Xu, M.-H. Org. Biomol. Chem. 2010, 8, 3073. (b) Raffa, G.;
Rusch, M.; Balme, G.; Monteiro, N. Org. Lett. 2009, 11, 5254. (c)
Cheng, G.; Hu, Y. J. Org. Chem. 2008, 73, 4732. (d) Cheng, G.; Hu, Y.
Chem. Commun. 2007, 3285. For the preparation of furo[3,4-
c]coumarins starting from the corresponding Michael acceptors via
intramolecular Wittig reactions, see: (e) Jang, Y.-J.; Syu, S.; Chen,
Y.-J.; Yang, M.-C.; Lin, W. Org. Biomol. Chem. 2012, 10, 843.
(10) For the optimization of reaction conditions, please see Support-
ing Information.
(8) (a) Donnelly, D. M. X.; Boland, G. M. Nat. Prod. Rep. 1998, 241.
(b) Wang, X.; Bastow, K. F.; Sun, C.; Lin, Y.; Yu, H.; Don, M.; Wu, T.;
Nakamura, S.; Lee, K. J. Med. Chem. 2004, 47, 5816. (c) Grese, T.;
Pennington, L. D.; Sluka, J. P.; Adrian, M. D.; Cole, H. W.; Fuson,
T. R.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Shetler, P. K.; Short,
L. L.; Venugopalan, M.; Yang, N. N.; Sato, M.; Glasebrook, A. L.;
Bryant, H. U. J. Med. Chem. 1998, 41, 1272. (d) Zhao, L.; Brinton, R. D.
J. Med. Chem. 2005, 48, 3463.
1908
Org. Lett., Vol. 14, No. 7, 2012