Copper-catalyzed multicomponent reaction: Facile access to novel phosphorus amidines

Article abstract of DOI:10.1021/ol800160q

The synthesis of a novel class of phosphorus amidines via a copper-catalyzed multicomponent reaction of sulfonyl azides, alkynes and iminophosphoranes is described. The protocol is efficient and general.

Full text of DOI:10.1021/ol800160q

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1267-1269
Copper-Catalyzed Multicomponent
Reaction: Facile Access to Novel
Phosphorus Amidines
Sun-Liang Cui, Jing Wang, and Yan-Guang Wang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, P.R. China
orgwyg@zju.edu.cn
Received January 22, 2008
ABSTRACT
The synthesis of a novel class of phosphorus amidines via a copper-catalyzed multicomponent reaction of sulfonyl azides, alkynes and
iminophosphoranes is described. The protocol is efficient and general.
The amidine functional group is found in many biological
molecules1 and is widely used in heterocyclic synthesis.2 The
benzamidine variant is often employed as an excellent
guanidine surrogate in medicinal chemistry.3 Consequently,
a number of synthetic methods have been developed for the
preparation of amidines. Most of these methods rely on the
nucleophilic addition of amines or ammonia equivalents to
nitriles under forcing conditions or to suitably activated
carboxylate equivalents, such as imidoyl chlorides, imidoyl-
benzotriazoles, imidates, and thioimidates,4 while transition
metal-catalyzed strategies have also been investigated for the
synthesis of amidines.5 We herein report a copper-catalyzed
three-component domino approach to a novel class of
phosphorus amidines.
Iminophosphoranes have attracted much attention due to
their wide application in organic synthesis since they were
first prepared in 1919 by Staudinger and Meyer.6 As
isoelectronic compounds of the Wittig reagent, iminophos-
phoranes were proved to have versatile properties and to
undergo a series of interesting chemical reactions.7 Previ-
ously, we developed three-component reactions of sulfonyl
azides, alkynes and salicaldehydes, 2-acylanilines or aziri-
dines, which furnished iminocoumarins, 2-imino-1,2-dihy-
droquinolines and 5-arylidene-2-imino-3-pyrrolines, respec-
tively.8 The domino process involves a N-sulfonyl keteneimine
intermediate in situ generated from the copper-catalyzed
cycloaddition of sulfonyl azide and terminal alkyne.5a,9 We
anticipated that this kind of keteneimine intermediates would
(1) Patai, S.; Rappoport, Z. The Chemistry of Amidines and Imidates;
Wiley: New York, 1991; Vol. 27.
(2) (a) No¨tzel, M. W.; Rauch, K.; Labahn, T.; de Meijere, A. Org. Lett.
2002, 4, 839-841. (b) Szczepankiewicz, B. G.; Rohde, J. J.; Kurukulasuriya,
R. Org. Lett. 2005, 7, 1833-1835.
(3) (a) Zablocki, J. A.; Miyano, M.; Garland, R.; Pireh, D.; Schretzman,
L.; Rao, S. N.; Lindmark, R. J.; Panzer-Knodle, S. G.; Nicholson, N. S.;
Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. J.
Med. Chem. 1993, 36, 1811-1819. (b) Greenhill, J. V.; Lue, P. In Amidines
and Guanidines in Medicinal Chemistry, Progress in Medicinal Chemistry;
Ellis, G. P., Luscombe, D. K., Eds.; Elsevier: New York, 1993; Vol. 30,
Chapter 5, pp 203-326.
(6) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635-646.
(7) (a) Eric, F. V. S.; Kenneth, T. Chem. ReV. 1988, 88, 297-368. (b)
Johnson, A. W. Ylides and Imines of Phosphorus; John Wiley & Sons:
New York, 1993. (c) Monina, P.; Alajar´ın, M.; Lo´pez-Leondardo, C.;
Claramunt, R. M.; Foces-Foces, M. C.; Cano, F. H.; Catala´n, J.; de la Paz,
J. L. G.; Elguero, J. J. Am. Chem. Soc. 1989, 111, 355-363. (d) Molina,
P.; Alajar´ın, M.; Vidal, A. J. Org. Chem. 1992, 57, 6703-6711. (e) Alajar´ın,
M.; Ort´ın, M. M.; Sanchez-Andrada, P.; Vidal, A.; Bautista, D. Org. Lett.
2005, 7, 5281-5284. (f) Alajar´ın, M.; Ort´ın, M. M.; Sanchez-Andrada, P.;
Vidal, A. J. Org. Chem. 2006, 71, 8126-8139. (g) Alajar´ın, M.; Bonillo,
B.; Sanchez-Andrada, P.; Vidal, A.; Bautista, D. J. Org. Chem. 2007, 72,
5863-5866.
(4) (a) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. Org. Lett.
2006, 8, 1347-1350. (b) Katritzky, A. R.; Cai, C. M.; Singh, S. K. J. Org.
Chem. 2006, 71, 3375-3380 and the cited references.
(5) (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038-
2039. (b) Chang, S.; Lee, M.; Jung, D. Y.; Yoo, E. J.; Cho, S. H.; Han, S.
K. J. Am. Chem. Soc. 2006, 128, 12366-12367. (c) Kissounko, D. A.;
Hoerter, J. M.; Guzei, I. A.; Cui, Q.; Gellman, S. H.; Stahl, S. S. J. Am.
Chem. Soc. 2007, 129, 1776-1783. (d) Kusturin, C. L.; Liebeskind, L. S.;
Neumann, W. L. Org. Lett. 2002, 4, 983-985.
(8) (a) Cui, S. L.; Lin, X. F.; Wang, Y. G. Org. Lett. 2006, 8, 4517-
4520. (b) Cui, S. L.; Wang, J.; Wang, Y. G. Tetrahedron 2008, 64, 487-
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10.1021/ol800160q CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/20/2008

react with iminophosphoranes through a [2+2] cycloaddition
to yield 1,2,4-phosphadiazetidines7c,7d or 1,2-phosphazetidines
as intermediates,10 which undergo subsequent domino reac-
tions to give some interesting products. In this regard, we
investigated the three-component reaction of sulfonyl azide
(1a, 0.6 mmol), phenylacetylene (2a, 0.6 mmol) and imi-
nophosphorane (3a, 0.5 mmol) in the presence of CuI (0.1
mmol) and Et3N (1 mmol) (Scheme 1). We found that the
Scheme 1
Figure 1. X-ray analysis of 4a.
With the results in hand, we next explored the protocol
with a variety of sulfonyl azides 1, alkynes 2 and imino-
phosphoranes 3.6,11 As shown in Table 1, the one-pot three-
component reaction afforded the amidine-stabilized phos-
phorus ylides in moderate to excellent yields (65%-95%).
The aromatic iminophosphoranes (Table 1, entries 1-11 and
13) gave higher yields than the olefinic substances (Table
reaction afforded a phosphorus-containing amidine 4a in 93%
yield.
The structure of 4a was unambiguously confirmed by
1
X-ray analysis (Figure 1), which is in accordance with H
NMR, 13C NMR, 31P NMR, and HRMS spectra.
Table 1. Three-Component Reaction of Sulfonyl Azides (1), Alkynes (2), and Iminophosphoranes (3)a
a Reaction conditions: sulfonyl azide (0.6 mmol), alkyne (0.6 mmol), iminophosphorane (0.5 mmol), CuI (0.1 mmol), CH2Cl2 (4 mL), Et3N (1 mmol),
N2, 8 h. b Yields refer to iminophosphoranes.
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Org. Lett., Vol. 10, No. 6, 2008

1, 12). The reaction of sulfonyl azide 1e (1.2 equiv), alkyne
2a (1.2 equiv), and iminophosphorane 3g (1 equiv) afforded
amidine 4n as a minor product and bisamidine 4o as a
major product (Scheme 2). Probably, the keteneimine inter-
the hydrolysis and the tautomerization of product 4p are due
to its unstability.
On the basis of these results, we depicted our working
hypothesis in Scheme 4. The formation of phosphorus
Scheme 4
Scheme 2
mediate generated from methylsulfonyl azide (1e) is more
reactive than the keteneimine from aryl sulfonyl azides,
which leads to the nucleophilic addition of the resulting
product 4n to the keteneimine intermediate and the formation
of bisamidine 4o.
The structure of 4o was firmly established by X-ray
analysis (see Supporting Information).
We also examined aliphatic alkynes such as 1-hexyne (2f)
and found that the resulting phosphorus ylide was completely
hydrolyzed to aliphatic amidine 5a and its tautomer 5b (3:
1) under the reaction conditions (Scheme 3). We then used
amidines can be rationalized as being initiated by the Cu-
catalyzed cycloaddition reaction of azides and alkynes. The
resulting triazolyl Cu-species A releases N2 to result in a
key intermediate keteneimine B.5a,9 Iminophosphorane 3 then
nucleophilically attacks the central carbon atom of ketene-
imine B to form 1,2-phosphazetidine intermediate C. Finally,
the ring-opening of C affords amidine 4.
In conclusion, we have explored a copper-catalyzed three-
component reaction, which furnished a novel class of
functionalized amidines from readily available sulfonyl
azides, alkynes and iminophosphoranes. The procedure is
efficient and general. Moreover, it is possible that the ylide
group of the products can be further transformed through
Wittig reaction. Our method will find its applications in the
synthesis of heterocyclic compounds.
Scheme 3
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (No. 20672093) and the Natural
Science Foundation of Zhejiang Province (R404109).
Supporting Information Available: Detailed experi-
1
mental procedures, characterizaton data, copies of H, 13C,
and 31P NMR spectra for all products, and crystallographic
information files for compounds 4a and 4o. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL800160Q
(9) (a) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc.
2005, 127, 16046-116047. (b) Cassidy, M. P.; Raushel, J.; Fokin, V. V.
Angew. Chem., Int. Ed. 2006, 45, 3154-3157. (c) Whiting, M.; Fokin, V.
V. Angew. Chem., Int. Ed. 2006, 45, 3157-3161.
(10) The cycloaddition reactions of N-sulfonyl substituted keteneimines
with the CdN bond-containing compounds such as carbodiimides have been
reported; see: La´bbe´, G.; Sorgeloos, D.; Toppet, S. Tetrahedron Lett. 1982,
23, 2909-2912.
(11) Iminophosphoranes 3 were easily prepared via Staudinger reaction
of azides with triphenylphosphine; see: Alajar´ın, M.; Vidal, A.; Ort´ın, M.
M.; Bautista, D. New J. Chem. 2004, 28, 570-577.
anhydrous THF as the solvent to perform the reaction and
isolated the desired phosphorus amidine 4p and its tautomer
4q (1:1) in 72% yield (Scheme 3). For prodcuts 4a-m as
presented in Table 1, their R2 groups are aryl, which could
conjugate with the CdP bond in ylides. In this case, however,
4p bears an alkyl group at the carbon atom of its CdP bond,
so it is unstable as compared with 4a-m. We believe that
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