chloroform and the resulting counteranion (Cl3C-) would
work as a nucleophile. However, if the reaction proceeds
along this mechanism in the deuteration experiment, 2a
should be produced predominantly over d-2a because 6 has
proton and deuterium on the nitrogen atom in a 2:1 ratio as
shown in Scheme 4. Since the deuteration experiment was
sponding product 2k was obtained in 83% yield. The reaction
of 1c, having a phenyl group, also gave 2l in 89% yield under
similar conditions (70 °C for 0.8 d) (Scheme 5).
Scheme 5
Scheme 4
The obtained products would be useful as precursors of
tetrahydroisoquinoline alkaloids.7 For instance, 2b was
converted to 8 in 76% yield in two steps (Scheme 6).
Scheme 6
carried out with 1 equiv of aniline against 1a, it might be
possible to consider that most of the aniline would react with
1a to form imine 3a and only the remaining small amount
of aniline might work as a catalyst. In that case, due to the
formation of the deuterated aniline (PhND2), which would
be formed by repeating the abstraction of deuterium from
CDCl3, selective formation of d-2a might be possible. To
check whether this mechanism is acceptable or not, we
examined the deuteration experiment using 2 equiv of aniline.
Although D content was slightly decreased to 95%, d-2a was
obtained selectively in 81% yield and these results support
our proposed mechanism as shown in Scheme 3.
To explore the scope of the present reaction, we examined
reactions using other pronucleophiles instead of CHCl3, such
as nitromethane, dimethyl malonate, and phenylacetylene.
All of reactions using these pronucleophiles completed within
2 d at room temperature and the corresponding products,
2h-j, were obtained in 78%, 59%, and 72% yields,
respectively.
An efficient and atom economical synthetic method of 1,2-
dihydroisoquinoline derivatives 2 has been developed through
the three-component process, i.e., o-alkynylbenzaldehydes
1, primary aliphatic or aromatic amines, and pronucleophiles,
which involves an interesting mechanistic aspect. It is
obvious that the present reaction is a simple and environ-
mentally benign preparation method because neither catalysts
nor any highly reactive reagents are needed. In particular,
the noncatalyzed self-construction of 2 was observed in the
reactions using 1a by just mixing three components at room
temperature. The obtained products are known to be versatile
intermediates for various kinds of bioactive compounds, such
as tetrahydroisoquinoline alkaloids. Further studies to elu-
cidate the mechanism of this reaction and to extend the scope
of synthetic utility are in progress in our laboratory.
Supporting Information Available: Spectroscopic and
analytical data for 2a-l and 8, and the procedure for the
synthesis of 2 and 8. This material is available free of charge
OL0618104
(5) Larock and co-workers have reported the palladium-catalyzed
synthetic methods of isoquinolines using o-alkynylarylaldimines, having a
tert-butyl group on the nitrogen atom, see: (a) Huang, Q.; Larock, R. C. J.
Org. Chem. 2003, 68, 980-988. (b) Dai, G.; Larock, R. C. J. Org. Chem.
2003, 68, 920-928. (c) Dai, G.; Larock, R. C. J. Org. Chem. 2002, 67,
7042-7047. (d) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem.
2002, 67, 3437-3444. (e) Roesch, K. R.; Larock, R. C. J. Org. Chem.
2002, 67, 86-94. (f) Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org. Chem.
2001, 66, 8042-8051. (g) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1,
553-556.
We next examined the three-component reaction using
substrates having substituents at the terminus of the alkyne
part. When the reaction of 1b, having a butyl group, was
carried out with allylamine and chloroform in CH2Cl2 at room
temperature, the reaction was very sluggish and only a trace
amount of product was obtained. However, the reaction
proceeded in (CH2Cl)2 at 70 °C for 0.9 d and the corre-
(6) Addition of chloroform to quaternary protoberberine alkaloids was
reported, see: Marek, R.; Secˇka´rˇova´, P.; Hulova´, D.; Marek, J.; Dosta´l, J.;
Sklena´rˇ, V. J. Nat. Prod. 2003, 66, 481-486.
(7) For reviews, see: (a) Chrzanowska, M.; Rozwadowska, M. D. Chem.
ReV. 2004, 104, 3341-3370. (b) Bentley, K. W. Nat. Prod. Rep. 2004, 21,
395-424. (c) Scott, J. D.; Williams, R. M. Chem. ReV. 2002, 102, 1669-
1730.
Org. Lett., Vol. 8, No. 18, 2006
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