reaction conditions but most of them require either the use
of multiple reagents or prior preparation of the actual
reagent.5,8 Moreover, a few of them were found to be
incompatible with several functional groups especially
halogens7 where dehalogenation was observed frequently.
Thus there is a continuing demand for the development of
alternative methods which depropargylate amines/ethers more
efficiently under mild conditions.
In connection with our studies on the development of
various diaryl heterocycles for biological testing in different
therapeutic areas, we have reported the synthesis of 3,4-diaryl
furanones,9 3,4-diarylmaleic anhydrides,10 and pyrrolo[1,2-
b]pyridazines.11 In further pursuance of our research under
the new drug discovery program a wide variety of ap-
propriately functionalized phenols and anilines were needed
for the synthesis of compounds of potential biological
interest. Therefore a general and straightforward method was
required for the cleavage of the C-X (X ) O, N) bond in
propargyl ethers/amines toward the synthesis of such com-
pounds. We have a long-term interest on palladium-catalyzed
reactions12 and now wish to present here our exploratory
work on the development of novel palladium-mediated
depropargylation of aromatic ethers and amines under mild
conditions.
of oxygen or other reagents.14 Since CuI in the presence of
excess amine base seemed to have a significant role in such
oxidative homocoupling of terminal acetylenes, copper-free
palladium-catalyzed reactions have been developed12a,15 for
the coupling of aryl halides with terminal alkyne. However,
we have observed that cleavage of the C-X (where X ) O,
N) bond16 occurs when the reaction was performed employ-
ing propargyl ether or amine as the terminal acetylene in
the absence of aryl halide in dimethylformamide (DMF) in
the presence of water (Method B, Scheme 1). Thus when
propargyl ethers/amines17 (I) were treated with (PPh3)2PdCl2
in aqueous DMF in the presence of triethylamine at 80 °C
for 2 to 3 h corresponding phenols/amines (II) were isolated
in good yields. The results of this study are summarized in
Table 1.
By use of this palladium-catalyzed depropargylation reac-
tion a wide variety of aryl propargyl ethers and amines were
cleaved to the corresponding phenols and amines (Table 1).
Various substituents on the phenyl ring of the starting ether
or amine (I) are well tolerated during the course of the
reaction. Ethers afforded good yields of products irrespective
of the presence of an electron-withdrawing group such as
aldehyde, ketone, nitro (entry 1-4, Table 1), or electron
donating group, e.g. chloro and methoxy (entries 7 and 9,
Table 1), on the phenyl ring. However, yields were satisfac-
tory in the case of amines (entries 14-16, Table 1). Halogens
were found to be well tolerated in this palladium-mediated
reaction, as no dehalogenated products were detected in
theses cases (entries 5, 8, 9, 11, and 16, Table 1). Also,
reducible functional groups present in the substrate remained
unaffected (entries 1-6, 8, and 14-15, Table 1).
The palladium-catalyzed coupling (Sonogashira coupling)
reaction of aryl halides with terminal alkynes provides a
powerful tool for the C-C bond formation reaction.12,13 This
reaction is usually carried out in the presence of catalytic
amounts of a palladium(II) complex as well as copper(I)
iodide in an amine as solvent under inert atmosphere and
the methodology has been extended well for the coupling
of propargyl ether with aryl halides (Method A, Scheme 1).13c
The palladium-catalyzed C-X bond cleavage was found
to be regioselective as alkoxy groups such as methoxy
remained unaffected during the course of the reaction (entries
5-7, Table 1). However, propargylic ester along with the
ether was cleaved under the conditions employed in the
reaction (entry 13, Table 1).
Scheme 1
The depropargylation reaction of ether/amine was usually
carried out in DMF-H2O (2:1) with use of triethylamine as
a base. The advantage in the use of DMF as solvent is its
ability to solubilize a wide variety of substrates and palladium
catalyst as well as its miscibility with water, which therefore
facilitates the cleavage of the C-X bond. Nevertheless, the
On the other hand, this palladium-copper-catalyzed reaction
led to the dimerization of the terminal alkynes in the presence
(8) (a) Zhang, H. X.; Guibe, F.; Balavoine, G. Tetrahedron Lett. 1988,
29, 619. (b) Inanaga, J.; Sugimoto, Y.; Hanamoto, T. Tetrahedron Lett.
1992, 33, 7035. (c) Aurrecoechea, J. M.; Anton, R. F. J. Org. Chem. 1994,
59, 702. (d) Swamy, V. M.; Ilankumaran, P.; Chandrasekaran, S. Synlett
1997, 513. (e) Sinha, S.; Ilankumaran, P.; Chandrasekaran, S. Tetrahedron
Lett. 1999, 40, 771.
(9) (a) Pal, M.; Rao, Y. K.; Rajagopalan, R.; Misra, P.; Kumar, P. M.;
Rao, C. S. World Patent WO 01/90097, 29 Nov 2001; Chem. Abstr. 2002,
136, 5893. (b) Padakanti, S.; Veeramaneni, V. R.; Pattabiraman, V. R.;
Pal, M.; Yeleswarapu, K. R. Tetrahedron Lett. 2002, 43, 8715. (c) Pal, M.;
Rao, V. V.; Srinivas, P.; Murali, N.; Akhila, V.; Premkumar, M.; Rao, C.
S.; Misra, P.; Ramesh, M.; Rao Y. K. Indian J. Chem. 2003, in press.
(10) Pattabiraman, V. R.; Padakanti, P. S.; Veeramaneni, V. R.; Pal, M.;
Yeleswarapu, K. R. Synlett 2002, 947.
(13) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467. (b) Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3, p 521.
(c) Nguyen, B. V.; Yang, Z. Y.; Burton, D. J. J. Org. Chem. 1993, 58 (26),
7368-76.
(14) (a) Rossi, R.; Carpita, A.; Bigelli, C. Tetrahedron Lett. 1985, 26,
523. (b) Kundu, N. G.; Pal, M.; Chowdhury, C. J. Chem. Res. Synop. 1993,
432. (c) Lei, A.; Srivastava, M.; Zhang, X. J. Org. Chem. 2002, 67, 1969
and references therein.
(15) (a) Fu, X.; Zhang, S.; Yin, J.; Schumacher, D. P. Tetrahedron Lett.
2002, 43, 6673. (b) Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.;
Ryu, I. Org. Lett. 2002, 4, 1691. (c) Wu, M.-J.; Wei, L.-M.; Lin, C.-F.;
Leou, S.-P.; Wei, L.-L. Tetrahedron 2001, 57, 7839.
(11) Pal, M.; Batchu, V. R.; Khanna, S.; Yeleswarapu, K. R. Tetrahedron
2002, 9933.
(12) (a) Pal, M.; Parasuraman, K.; Gupta, S.; Yeleswarapu, K. R. Synlett
2002, 1976. (b) Pal, M.; Kundu, N. G. J. Chem. Soc., Perkin Trans. 1 1996,
449. (c) Kundu, N. G.; Pal, M. J. Chem. Soc., Chem. Commun. 1993, 86.
(d) Kundu, N. G.; Pal, M.; Mahanty, J. S.; Dasgupta, S. K. J. Chem. Soc.,
Chem. Commun. 1992, 41.
(16) For the cleavage of the C-S bond with concurrent S-arylation under
palladium-copper catalysis see: Kundu, N. G.; Nandi, B. Tetrahedron 2001,
57, 5885 and references therein.
(17) Aryl propargyl ethers were prepared according to the procedure
described in the literature, see for example: Ishikawa, T.; Mizutani, A.;
Miwa, C.; Oku, Y.; Komano, N.; Takami, A.; Watanabe, T. Heterocycles
1997, 45, 2261.
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