The stereoselectivity and reactivity were scarcely affected
by the incorporation of electron-donating substituents on
the aromatic ring, such as methoxy (Table 1, entries 1–3),
methyl (entries 4–6), or tert-butyl (entry 7) groups, and ex-
cellent enantioselectivities were obtained. The presence of a
chlorine on the aromatic ring (entry 8) led to similar results,
but slightly lower enantioselectivity (90% ee). However, the
diastereoselectivity decreased when the furyl or an aromatic
ring bearing an electron-withdrawing group, such as
bonyl group compared to the ester moiety in the model re-
action, which renders the formation of adduct 5p more fa-
vored than 5’p. The reaction was not affected by changes in
the substituents of the imine 1. 3,4-Dihydroisoquinoline
(1b), 7-methyl-3,4-dihydroisoquinoline (1c), and 6-bromo-7-
methoxy-3,4-dihydroisoquinoline (1d, Table 2, entries 6–8)
all gave the product in good yield and enantioselectivity.
The versatility of the products obtained by the three-com-
ponent [3+2]-cycloaddition is further enhanced by the trans-
formations shown in Scheme 2. The importance of alkynes[18]
encouraged us to perform the homologation of 6 in an at-
tempt to obtain a terminal alkyne. Treatment of 6 with the
Ohira–Bestmann reagent,[19] afforded the alkyne 7 in excel-
lent yield without affecting the stereochemistry. The abso-
lute configuration of the product was determined for the hy-
drochloride salt of 7 (see the Supporting Information, for
structures of the major and minor diastereomers). To prove
the versatility of alkyne 7, we performed a Sonogashira cou-
pling under mild conditions, obtaining the aryl derivative 8
in good yield. Alternatively, the reaction of 6 with the
Levine reagent[20] and subsequent hydrolysis with p-TsOH
in acetone yielded a new aldehyde 9 with an additional
carbon atom after two steps.
A computational study was undertaken to provide insight
into the mechanism and selectivity of the [3+2]-cycloaddi-
tion (Scheme 3).[21] A conformational analysis of the ylide
intermediate shows intermediate A to be favored over B by
2.2 kcalmolÀ1.[22] This conformational preference results
from an unfavorable steric interaction between the methyl
group and the hydrogens on the sp3-carbon atom of the het-
erocycle.[23] Interestingly, the lower energy conformation of
the ylide does not lead to the major diastereomer of the
product. To obtain the major diastereomer of the reaction,
the [3+2]-cyclization must proceed through the higher
energy conformer of the intermediate B. To understand why
the reaction proceeds more readily with the higher energy
trifluoroACHTUNGTRENNUNGmethyl was present (entries 9 and 10). In the case of
the furyl-substituted a,b-unsaturated aldehyde (entry 9) the
reactivity was low, resulting in longer reaction time and
lower yield. Moreover, the naphthyl moiety (entry 11) was
tolerated in the cycloaddition. It is noteworthy that all the
a,b-unsaturated aldehydes used provided high enantioselec-
tivity (more than 89% ee), in particular for electron-donat-
ing substituents (96–98% ee). The possibility to employ ali-
phatic enal as the dipolarophile was also evaluated
(entry 12). However, the reaction gave no conversion under
the standard conditions. The reaction can be scaled up to
1 mmol for aldehyde 3b and the product was obtained with
similar results in terms of yield and selectivity.[16]
The behavior of different imines 1 and a-bromo deriva-
tives 2 was studied to evaluate the electronic influence of 1
and the size of the substituents in 2 on the reaction out-
come. The reaction between imine 1a, a-bromoester 2a,
and aldehyde 3b was chosen as a model for this purpose
(Table 2, entry 1). Employing the methyl 2-bromobutanoate
2b (entry 2) resulted in a slight decrease in yield and stereo-
selectivity. The introduction of an ethoxy or phenoxy group
(entries 3 and 4) resulted in comparable yield and excellent
enantioselectivity, and gave increased diastereoselectivity.
Interestingly, replacing the propanoate 2a by 2-bromo-1-
phenylpropan-1-one (2e) led to an increase in diastereose-
lectivity (compare Table 2, entries 1 and 5). The enhanced
selectivity could be due to more steric hindrance of the car-
Table 2. Results indicating the scope of the organocatalytic three-component reaction of imines 1a–d, a-bromoalkanes 2a–e, and a,b-unsaturated alde-
hyde 3b.[a]
Entry
Product
R1
R2
Imine
R3
R4
Bromoalkane
Time
Yield
[%][b]
d.r.
(5/5’)[c]
ee
[%]
N
1
2
3
4
5
6
7
8
5b
5m
5n
5o
5p
5q
5r
OMe
OMe
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
H
1a·HCl
1a·HCl
1a·HCl
1a·HCl
1a·HCl
1b
Me
Et
OMe
OMe
OEt
OPh
Ph
OMe
OMe
OMe
2a
2b
2c
2d
2e
2a
2a
2a
23 h
52 h
26 h
26 h
12 h
42 h
38 h
50 h
85 (70)
69 (52)
84 (69)
84 (68)
84 (77)
83 (61)
62 (50)
69 (65)
82:18
76:24
84:16
84:16
90:10
86:14
81:19
>95
98
96
98
98
99
99
99
99
Me
Me
Me
Me
Me
Me
H
Br
Me
OMe
1c
1d
5s
[a] For reaction conditions and separation details see Supporting Information. [b] Yield after FC. Yield of major diastereoisomer in parentheses. [c] Ste-
reoisomer 5ꢀ is inverted at C3.
2774
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2773 – 2776