N. Olivi et al. / Tetrahedron Letters 45 (2004) 2607–2610
2609
(entry 9) allows the selective obtention of the mono-
coupling product even when using an excess of propar-
gyl bromide (3 equiv). Under similar conditions,
heteroaromatic bromides such as 2-bromopyridine
underwent the three-component reaction and afforded
the coupling product in 74% yield (entry 12). On the
other hand, this process is also effective even when using
the less reactive vinyl chlorides including 1,2-dichloro-
ethylene12 (entry 15) or chloroenynes (entry 16). In the
process to the preparation of other heteroatom-con-
taining cyclic compounds is already underway.
Acknowledgements
The CNRS is gratefully thanked for support of this
research and for a doctoral fellowship to N.O.
13
latter case, PdCl2(PhCN)2 was used as catalyst instead
of PdCl2(PPh3)2. It should be noted that this three-
component procedure with substituted propargyl chlor-
ides such as 3-chloro-oct-1-yne is also effective to give
the expected products. Its coupling with methyl 4-
iodobenzoate (entry 13) or 4-iodobenzonitrile (entry 14)
provided the desired three-component coupling com-
pound in 74% and 89%, respectively.
References and notes
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Finally, under these reaction conditions, it was also
possible to extend the scope of this three-component
assembling process to perform a tandem amine prop-
argylation-Sonogashira-cyclization sequence to obtain
2-(dialkylaminomethyl)benzo[b]furan or indole deriva-
tives, an important class of heterocycles that exhibit a
wide range of activity14 (Scheme 2). Thus, when ortho
iodophenol was used as substrate, the cyclized benzo-
furan was obtained in a 75% yield. Similarly, 2-iodo
substituted aniline yielded 2-substituted indole deriva-
tive quantitatively. It should be noted, that the effect of
the functional group on the nitrogen atom toward the
cyclization step is crucial since no cyclization reaction
occurred from the compound having an acetyl function
on the nitrogen atom (Table 1, entry 4).
In conclusion, we have successfully developed a new
three-component assembling of amines, organic halides
and propargyl halides for the preparation of function-
alized propargylic amine, indole, and benzofuran
derivatives in high yields. Variation is allowed in each of
the three components, thus making a wide range of
accessible products. This process is not only of interest
for combinatorial synthesis of propargylic amines and
heterocycles, but in many cases also offers considerable
synthetic advantages in terms of yield, selectivity, and
simplicity of the reaction procedure. Extension of this
Br
5% PdCl2(PPh3)2
10% CuI
I
9. Kwatra, M. M.; Simon, D. Z.; Salvador, R. L.; Cooper,
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10. Youngman, M. A.; Dax, S. L. J. Comb. Chem. 2001, 3,
469–472.
N
+
0°C then 50°C
O
OH
75%
HN
11. Unroe, M. R.; Reinhardt, B. A. Synthesis 1987, 981–985.
12. Alami, M.; Peyrat, J. F.; Brion, J. D. Tetrahedron Lett.
2002, 43, 3007–3009, and references cited therein.
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Synthesis 2000, 1499–1518; (b) Alami, M.; Linstrumelle,
G. Tetrahedron Lett. 1991, 32, 6109–6112; (c) Alami, M.;
Crousse, B.; Ferri, F. J. Organomet. Chem. 2001, 624, 114–
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Br
5% PdCl2(PPh3)2
10% CuI
I
N
+
0°C then 50°C
N
97%
NHTs
HN
Ts
14. For a review, see: (a) Cacchi, S.; Fabrizi, G.; Goggiomani,
A. Heterocycles 2001, 56, 613–632; (b) Seefeld, M. A.;
Miller, W. H.; Newlander, K. A.; Burgess, W. J.; Payne,
Scheme 2.