4706
M. Gohain et al. / Tetrahedron Letters 53 (2012) 4704–4707
Table 3
References and notes
Reusability of the Al(OTf)3 catalyst
1. (a) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996; (b) Casapullo, A.;
Entry
Product
1st cycle
2nd cycle
3rd cycle
Bilulco, G.; Bruno, I.; Riccio, R. J. Nat. Prod. 2000, 63, 447; (c) Garbe, T. R.;
Kobayashi, M.; Shimizu, N.; Takesure, N.; Ozawa, M.; Yukawa, H. J. Nat. Prod.
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6469.
1
2
3aa
3ag
94
88
94
87
93
87
2e were subjected to reactions with indoles 1d and 1a, respectively
(Table 2, entries 8 and 9). No indication of elimination was present
and the obtained products could be ascribed exclusively to the di-
rect nucleophilic substitution reaction of the alkynol 2d or 2e OH
functionality with the indole.
Encouraged by these results with 3° benzylic propargylic alco-
hols, we extended the strategy to the reaction of a 2o benzylic alky-
nol 2h with indole 1a, and were pleased to find that the reaction
proceeded smoothly within an acceptable amount of time in excel-
lent yield (100 min, 88%, Table 2, entry 13). Similarly, we per-
formed reactions between the 2o benzylic alkynol 2h and various
substituted indoles, including an indole with electron-withdraw-
ing Cl substituent 1d (Table 2, entry 15), and other substituted in-
doles such as N-methylindole (1b) (Table 2, entry 14) and 2-
methylindole 1c (Table 2, entry 16), and found that all these reac-
tions gave C3-propargylated indoles in a very good to excellent
yield (85–90%).
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Alkynols with different substitution patterns, both at the termi-
nal (R5) and propargylic (R3 and R4) positions were also evaluated.
When the phenyl substituent at the propargylic position (R4) was
changed into an electron-donating or electron-withdrawing aro-
matic entity, for both tertiary (Table 2, entries 6 and 7) and second-
ary propargylic alcohols (Table 2, entries 17 and 18), the desired
C3-propargylated indoles were still obtained in high yield (83–
92%). Replacement of the aromatic group of the alkynol at the ter-
minal (R5) (Table 2, entries 10 and 19) or propargylic position (R3)
by an aliphatic group (Table 2, entry 20), however, only gave good
to moderate yields of the desired products (85, 88 and 54%, respec-
tively). Substituting the aromatic group at the propargylic position
(R4) with a cyclic aliphatic group (Table 2, entries 11 and 12) again
led to excellent yields (94 and 92%, respectively). The higher yields
obtained with the phenyl substituent at both the terminal and
propargylic positions compared to the corresponding alkyl substi-
tuted analogues can be ascribed to the stabilization of the (incipi-
ent) benzylic carbocation, whereas the anomalous behavior of the
linear alkyl and cyclopropyl substituted alkynols is believed to be
due to the known ability of the cyclopropyl group to stabilize (par-
tially) positively charged intermediates.11
5. (a) Sanz, R.; Miguel, D.; Gohain, M.; García-García, P.; Fernandez-Rodríguez, M.
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Tetrahedron 2009, 65, 1758; (b) Kanao, K.; Matsuzawa, H.; Miyake, Y.;
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C. W.; Yong-Jun, C. Synthesis 2007, 1961.
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Electron-donating substituents at the para position of the R4
aromatic ring of the alkynols were found to enhance reactivity,
thus increasing the rate of the reaction (Table 2, entries 7 and 18
vs entries 1 and 13, respectively), while electron-withdrawing sub-
stituents at the same position slowed the substitution (Table 2, en-
tries 6 and 17 vs entries 1 and 13, respectively).
The catalyst was recovered according to a previously reported
13b
procedure
and re-used three times under our optimized reac-
tion conditions without any significant loss of activity (Table 3).
In conclusion, Al(OTf)3 was found to be a highly effective and
reusable Lewis acid catalyst for the direct nucleophilic substitution
of the OH of propargylic alcohols by indoles, thus providing impor-
tant 3-substituted propargylated products in excellent yields and
high selectivities. Moreover, this is the first example of an efficient
process which could be successfully applied to both 3° and 2° prop-
argylic alcohols for the preparation of C3-propargylated indoles in
very high yields.16
Acknowledgments
15. The crystallographic data for product 3da have been deposited at the
Cambridge Crystallographic Data Centre as supplementary publication
Financial support from Sasol Ltd is gratefully acknowledged.