2
W. Shi et al. / Tetrahedron Letters xxx (2014) xxx–xxx
showed that the reaction gave the highest yield in protic solvents,
O
R1
R2
H
N
such as CH3OH, C2H5OH, and H2O (entries 2–4). Aprotic solvents,
such as CH2Cl2, CHCl3, DMF, CH3CN, and THF have no positive effect
and the target product 3aa was obtained in lower yields (entries 1,
5–8). The lowest yield (<25%) of the desired product was obtained
(entry 9) with the use of apolar aprotic solvents, for instance tolu-
ene. This may be due to the protic solvents being more favorable
to generate iminium A, thus being easier to react. However, in the
apolar aprotic solvent, the imine ion A was difficult to generate
and the product yield was very low, which is consistent with our
proposed mechanism. After identifying the suitable solvent EtOH,
we attempted to optimize the reaction by varying other elements
systemically. As expected, higher temperature greatly shortened
the reaction time (entries 3 and 10). However, when the reaction
temperature was increased to 80 °C, there was no meaningful
improvement on the reaction rate (entry 11). Changing the ratio of
1a/2a from 1:1.5 to 1:1 or 1:2, we found 1.5 equiv of dipropylamine
(2a) established the optimal reaction conditions (entries 12–13).
With the optimized conditions in hand, we then investigated a
variety of amines using phenylpropiolaldehyde (1a) at 60 °C with
EtOH as the solvent. The results are summarized in Table 2. The
reactions between the various secondary amines 2 and phenyl-
propiolaldehyde (1a) proceed smoothly to furnish the desired
products 3 in overall good yields and high stereoselectivities. Inter-
estingly, it was found that increasing steric hindrance of the amine
slows down the reaction rate and leads to the formation of trans-
b-enaminones. Probably, when steric hindrance increased, the
branched chain connected to nitrogen cannot rotate freely and this
leads to the generation of some trans isomer. For example, acyclic
amines (e.g. long aliphatic chain based dialkyl amine) had good
performance on the cis selectivity (entries 1–7), while several
cyclic or larger sterically hindered amines, such as piperidyl,
pyrrolidine, diisopropylamine, diisobutylamine, and dicyclohexyl-
amine created significant steric effect, and they not only prolonged
the reaction time, but also dramatically lowered the cis selectivity,
further supporting the proposed mechanism (entries 8–12).
However, no reaction occurred under identical conditions using
propylamine and phenylamine as substrates.
R1
R2
- H2O
N
H
H
+
R
H
R
2
1
O
H
A
H
H
Michael
addition
R
N R1
O R2
-H
H
H
H
- H+
R
H
H
R
C
R1
R2
C
C
C
C C
R1
R2
R
N
R1
R2
N
N
O
O
O
H
H
H
H
B
C
D
Scheme 1. Plausible mechanism.
undergo a range of reactions at different sites. In order to success-
fully develop an amine-promoted 1,4-addition of propiolaldehydes
with nucleophiles, we surmise that the key problem is to suppress
the 1,2-addition reaction.
To test the possibility of this hypothesis, initially, the direct reac-
tion of 1 equiv of phenylpropiolaldehyde 1a with equal amount of
dipropylamine 2a in CH2Cl2 was carried out at room temperature
for 3 h. to afford the b-enaminone 3aa, which was isolated in 72%
yield. The structure of the b-enaminone synthesized was well char-
acterized by NMR spectral analysis, which was in conformity with
2,3-dihydrogen-cis-b-enaminone. We found that the cis-b-enami-
none 3aa was generated exclusively, and the regioselectivity and
stereoselectivity of the reaction were excellent. This could serve
as a new method to prepare synthetically interesting, functional-
ized cis-b-enaminone. According to the reported enamine catalysis
of nucleophilic substitution reactions18 and the known Meyer–
Schuster rearrangement mechanism,19 our postulated reaction
mechanism is summarized in Scheme 1. It is proposed that the
reaction is triggered by the generation of iminium A via the reaction
of propiolaldehydes 1 and secondary amine 2. Then one molecule of
water acts as a nucleophile for the 1,4-addition with iminium A to
form the intermediate B. The subsequent stereoselective enol–keto
tautomerization leads to the formation of a six-membered ring
transition state D which is stabilized by intramolecular hydrogen
bonding. The selective formation of cis-b-enaminone can be
illustrated by electrophilic attack from the less sterically hindered
direction and the effect of intramolecular hydrogen bonding to
form a six-membered ring transition state.
To further investigate the generality and substrate scope of our
approach, a wide range of propiolaldehydes (1) were then used in
these optimized reaction conditions. As shown in Table 3, it seems
that the electronic properties and steric hindrance of the substitu-
ents in the phenyl ring had significant influence on stereoselectiv-
ity and chemical yield. For example, phenylpropiolaldehyde
bearing electron-donating groups (2a) not only dramatically
decreased the cis selectivity, but also lowered the chemical yield
(entries 6 and 7); electron-withdrawing groups mainly lowered
the cis selectivity (entries 1–5). Perhaps the increased steric
hindrance of the substituents in the phenyl ring and the push-pull
electronic effect brought about a barrier of rotation around the
C@C bond and decreased the cis selectivity.20
Several elements were then investigated to optimize the reaction
conditions (Table 1). Screening of different solvents in Table 1
Table 1
Optimization of reaction conditionsa
Entry
Solvent
T (°C)
t (h)
Yieldd (%)
Entry
Solvent
T (°C)
t (h)
Yieldd (%)
1
2
3
4
5
6
7
CH2Cl2
MeOH
EtOH
H2O
CHCl3
DMF
60
60
60
60
60
60
60
8
0.25
0.25
0.25
12
72
90
97
82
79
68
77
8
9
10
11
12b
13c
THF
60
60
rt
80
60
60
12
12
3
0.25
0.25
0.25
40
25
92
96
87
95
Toluene
EtOH
EtOH
EtOH
EtOH
6
3
MeCN
a
b
c
Unless otherwise stated, reaction conditions are: 1a (0.4 mmol, 1.0 equiv), 2a (0.6 mmol, 1.5 equiv), 2.0 mL of solvent.
Compound 1a/2a (1:1).
Compound 1a/2a (1:2).
Isolated yield after column chromatography.
d
Shi, Wenjuan
