Scheme 1
.
Two Proposed Reaction Pathways for Tandem
Table 1. Screening for the Lewis acid Co-catalyst for the
Three-Component Reaction of 1a, 2a, and 3aa
Reactions of Various Nucleophiles with
2-(1-Alkynyl)arylaldimine
entry
Lewis acid
yield (%)b
drc
1
2
3
4
5
9
0
3
27
0
2
50:50
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2
Cu(OTf)2
CuI
45:55
reaction afforded highly substituted amino acid frameworks
with quaternary stereogenic centers in one step. We envi-
sioned that the oxonium ylide, generated in situ from a diazo
compound with an alcohol or water, would serve as a
nucleophile to attack a Lews acid activated 2-alkynylaryla-
ldimine affording new functionalized 1,2-dihydroisoquino-
lines bearing an adjacent R-hydroxy-ꢀ-amino carboxylate
skeleton in one step (Scheme 2). In this multicomponent
6
7
8
Cu(CN)4PF6
AgOTf
AgOTf
AgOTf
In(OTf)3
28
83
29
0
46:54
60:40
60:40
9d
10e
11
0
a Reaction conditions: Unless otherwise noted, the reaction was carry
out in refluxing CH2Cl2 with 1a:2a:3a ) 1:1.2:1.2, catalyzed by 1 mol %
of Rh2(OAc)4 and 5 mol % of Lewis acid.. b Isolated yield based on 2-(1-
alkynyl)phenylaldimine 1a. c Determined by 1H NMR analysis. d 1 mol %
of catalyst was used. e In the absence of Rh2(OAc)4 catalyst, methyl 2-oxo-
2-phenylacetate was isolated.
Scheme 2
.
1,2-Dihydroisoquinoline Synthesis via Dual-Metal
Co-catalyzed Three-Component Reaction
To verify the practicability of the strategy shown in
Scheme 2, our studies commenced with screening of an
effective cocatalyst in a reaction of methyl phenyldiazoac-
etate (1a), H2O (2a), and 2-(1-alkynyl)phenylaldimine 3a and
the results are shown in Table 1. In the absence of a Lewis
acid cocatalyst, the reaction afforded only 9% yield of desired
product 4a with a significant amount of starting material 3a
recovered (Table 1, entry 1). Soft metal salts such as
palladium, copper, or silver with mild Lewis acidity were
examined to activate the triple bond functionality of 3a.5f
PdCl2 was found to be an effective cocatalyst among the Pd
catalysts screened, affording the desired product 4a in 27%
yield (entries 2-4). Similar results were observed with
reaction, two metal catalysts, Rh2(OAc)4 and a Lewis acid
catalyst, must be compatible and activate the desired
component selectively.
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Figure 1
4t
.
ORTEP representation of the crystal structure of threo-
Org. Lett., Vol. 12, No. 4, 2010
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