Pyrrolidine catalyzed novel domino reaction for the synthesis of polysubstituted 4-oxocyclohexanecarbaldehyde derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.12.125

A novel domino reaction catalyzed by an organic molecule based on α,β-unsaturated aromatic aldehydes and methylethylketones has been developed. The progress allows one-pot and efficient synthesis of polysubstituted 4-oxocyclohexanecarbaldehyde derivatives via pyrrolidine mediated under mild conditions. The reaction consists of three consecutive reactions: an aldol condensation reaction and a tandem inter-Michael-intra- Michael addition reaction. Copyright

Full text of DOI:10.1016/j.tetlet.2012.12.125

Tetrahedron Letters 54 (2013) 1405–1408
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pyrrolidine catalyzed novel domino reaction for the synthesis
of polysubstituted 4-oxocyclohexanecarbaldehyde derivatives
⇑
Feng-Zu Bao, Xiao-Bing Wang, Ling-Yi Kong
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009,
People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel domino reaction catalyzed by an organic molecule based on a,b-unsaturated aromatic aldehydes
Received 16 October 2012
Revised 19 December 2012
Accepted 28 December 2012
Available online 9 January 2013
and methylethylketones has been developed. The progress allows one-pot and efficient synthesis of poly-
substituted 4-oxocyclohexanecarbaldehyde derivatives via pyrrolidine mediated under mild conditions.
The reaction consists of three consecutive reactions: an aldol condensation reaction and a tandem inter-
Michael–intra-Michael addition reaction.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalyst
Domino reaction
One-pot
4
-Oxocyclohexanecarbaldehyde
Aldol–Michael–Michael
Over the past few decades, creation of molecular complexity
and diversity from simple and readily available substrates has in-
spired most interest in organic chemists. One aspect in this area
that draws much attention is the development of novel tandem
or domino reactions catalyzed by organic molecules.1 Those pro-
cesses allow multiple bond-forming events to occur in a single ves-
sel with lower costs, shorter reactions, and higher efficiency.
Recently, methodologies relying on the tandem/domino/cascade
catalytic strategies have received increasing attention in the
synthetic community.2 The ability to promote domino reactions
by organocatalysts further expands the realm of its synthetic
applications.
Michael–Michael reaction for the synthesis of polysubstituted
4-oxocyclohexanecarbaldehydes has not been reported. Our goal
in this work is to develop inexpensive reagents, short reaction time,
and high yield methodology.
As an initial study for the pyrrolidine catalyzed novel domino
reaction, some simple starting materials, such as cinnamaldehyde
and benzylacetone were optimized. At the outset of our work,
benzylacetone reacted with cinnamaldehyde using pyrrolidine as
5
catalyst and acetic acid as additive, diethyl ether as solvent
under the condition of room temperature for 60 h. The procedure
successfully obtained the desired functionalized polysubstituted
4-oxocyclohexanecarbaldehyde 3a in poor yield (Table 1). The struc-
ture of the polysubstituted 4-oxocyclohexanecarbaldehyde 3a (mp
However, to the best of our knowledge, an effective triple-
cascade and multi-component organocatalytic reaction for the
synthesis of polysubstituted 4-oxocyclohexanecarbaldehyde deriv-
atives remains elusive. Moreover, polysubstituted cyclohexanones
are prevalent in natural products that display biological activities,
and their derivatives have long served as important intermediates
1
146–147 °C) was confirmed on the basis of spectra (IR, H NMR,
1
3
6
C NMR, DEPT, COSY, HSQC, HMBC, NOESY, and HRMS). In order
to improve the yield, the reaction condition was optimized under
different solvents and temperatures. The observed results are sum-
marized in Table 1. Since the choice of solvent plays an important
3
7
in organic synthesis. To extend the application of the organocata-
role in domino reactions, the effect of various solvents including
4
lysts in tandem reactions, a reaction that intrigued us most was the
diethyl ether, ethanol, dichloromethane, tetrahydrofuran, DMF,
acetonitrile, and toluene in this reaction was investigated (Table 1,
pyrrolidine mediated novel domino reaction between cinnamalde-
hyde and benzylacetone observed in our laboratory, which pro-
vided polysubstituted 4-oxocyclohexanecarbaldehyde in one pot
8
entries 1–10) under the specified conditions first. Unfortunately,
solvents like dichloromethane and toluene afforded a trace amount
of product. Moreover, the yield is lower when the reaction was
carried out in ethanol, tetrahydrofuran, acetonitrile, and DMF than
that afforded in diethyl ether. So, diethyl ether as solvent is suitable
for the reaction. With the optimized solvent in hand, we further
(Scheme 1). Our literature survey at this stage revealed that use
of small organic molecules as catalysts in the domino aldol–
⇑
Corresponding author. Tel./fax: +86 25 8327 1405.
E-mail address: cpu_lykong@126.com (L.-Y. Kong).
9
observed the effect of temperature on the reaction. Using the same
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.125

1
406
F.-Z. Bao et al. / Tetrahedron Letters 54 (2013) 1405–1408
Scheme 1. Pyrrolidine-mediated novel domino reaction.
Table 1
Table 3
Screening of the reaction conditions for the domino reaction
Scope and limitations of the domino reaction
Entrya
Solvent
Et
EtOH
CH Cl
THF
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
2
O
25
25
25
25
0 ? rt
15
5
37
13
Trace
18
45
42
48
54
35
2
2
Et
Et
Et
Et
Et
2
2
2
2
2
O
O
O
O
O
Entrya
Yieldb (%)
R
1
6
R
2
Time (h)
Product
0
1
2
3
4
5
6
7
8
9
C
H
5
CH
2
Ph
Ph
4-MeOC
Ph
Ph
Ph
4-MeOC
Ph
Ph
4-BrC
4-BrC
4-MeOC
4-MeOC
4-MeC
4-MeC
4-MeC
Ph
60
60
60
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
3a
3b
3c
3d
54
58
47
39
78
60
55
55
43
49
42
51
43
58
53
36
41
43
37
À20
4-MeOC
CH
6
H
5
CH
2
10
11
12
DMF
CH CN
Toluene
0
17
32
Trace
C
6
H
5
2
6
H
4
4
0
0
Me
H
4-MeOC
4-MeOC
4-MeC
4-BrC
4-MeOC
4-MeC
4-MeC
4-BrC
4-MeOC
4-MeC
4-BrC
Et
3
c
3e
6
H
H
4
4
3f
a
Reactions were carried out on a 1.0 mmol scale in 25.0 mL of solvent with
6
6
H
3g
3h
3i
3j
3k
3l
3m
3n
3o
3o
3q
3r
3s
cinnamaldehyde (2.0 equiv), benzylacetone (1.0 equiv) for 60 h.
6
H
4
b
Yield of isolated product.
6
H
4
10
11
12
13
14
15
16
17
18
19
6
H
4
4
6
H
H
4
4
6
6
6
H
H
4
6
6
4
H
H
4
Table 2
6
H
4
4
Screening of the catalyst and additive for the domino reaction
6
H
6
6
6
H
4
H
4
H
4
6
H
4
6 4
H
Et
4-MeOC
4-NO
6
H
4
C
6
H
5
CH
2
2
C
6
H
4
a
Entrya
Yieldb (%)
Unless otherwise specified, all reactions were carried out with 1 (1.0 mmol), 2
Catalysts
Amide (equiv) Additive (equiv)
Solvent
(
2.0 mmol), catalyst (1.0 equiv), and additive (1.0 equiv) in 25 mL solvent.
b
Isolated yield of the products after flash chromatography.
Only the corresponding aldol condensation product was obtained.
c
1
2
3
4
5
6
7
8
9
I (0.2)
I (1.0)
—
—
—
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
O
O
O
O
O
O
O
O
O
O
O
Trace
12
c
AcOH (1.0)
AcOH (1.0)
AcOH (1.5)
PNB (1.0)
N
I (1.0)
I (1.5)
I (1.0)
I (1.0)
I (1.0)
I (1.0)
II (1.0)
III (1.0)
IV (0.2)
IV (1.0)
V (0.2)
54
54
Trace
34
7
dine, the reaction afforded the desired product with lower yield.
Next, we examined the effect of additive on the organic catalyzed
novel domino reaction, various additives were employed (Table 2,
entries 4–8) and found that all additives promoted the reaction to
afford the desired product in lower yield compared to acetic acid.
Thus we preferred to perform this domino reaction with acetic acid
as the additive.
Having established optimal reaction conditions, the scope and
generality of the reaction were next explored, and the results are
summarized in Table 3. First of all, a series of ketones (1.0 mmol)
were reacted with cinnamaldehyde 2a (2.0 mmol) under the opti-
BF
TFA (1.0)
HCl (1.0)
3
ÁOEt
2
(1.0)
N
1
1
1
1
1
0
1
2
3
4
AcOH (1.0)
AcOH (1.0)
—
Trace
23
N
N
N
DMF
Toluene
Toluene
—
PNS (0.2)
a
Reactions were performed under 0 °C and 1.0 mmol scale in 25 mL of solvent
with benzylacetone (1.0 equiv), cinnamaldehyde (2.0 equiv).
b
Yield of isolated product.
Not detected.
c
2
mized conditions (Et O, 0 °C, pyrrolidine catalysis and acetic acid
as additive). The reaction with methylethylketones proceeded
smoothly to afford the corresponding products in moderate to good
yields. However, for acetone the corresponding tandem reaction
product could not have been obtained. Similar to the results re-
ported, only the aldol condensation product 3e was separated in
substrate and solvent, good yield was achieved by decreasing the
temperature to 0 °C. But as the temperature decreased, the yield re-
fused to increase. Therefore, diethyl ether at 0 °C is suitable for the
novel organic catalyzed domino reaction.
1
2
78% yield. Then we set out to examine the scope of the domino
reaction with a series of ,b-unsaturated aromatic aldehydes and
After optimization of the reaction conditions, we performed a
a
1
0
catalyst screening with various common imine catalysts, and
found that pyrrolidine could catalyze the reaction efficiently to fur-
nish the desired product in good yield, but the other catalysts, such
as II, IV as well as catalyst V,11 could not effectively catalyze the
reaction (Table 2, entries 9, 11–13). When catalyzed with piperi-
methylethylketones with different substituted groups. Conse-
quently, all reactions with cinnamaldehyde (entries 1, 2, 4–6, 8, 9,
and 17),
groups (entries 3, 7, 12–16, and 18), and
aldehydes with electron-deficient groups (entries 10, 11, and 19)
a,b-unsaturated aromatic aldehydes with electron-rich
a
,b-unsaturated aromatic

F.-Z. Bao et al. / Tetrahedron Letters 54 (2013) 1405–1408
1407
Scheme 2. Selected HMBC (?) and ROESY (M) correlations of 3a.
Scheme 3. Proposed mechanism for the pyrrolidine-catalyzed domino reaction.
Scheme 4. The reaction between 1,7-diphenylhepta-4,6-dien-3-one and cinnamaldehyde.
afforded desired products. But the reactions with electron-deficient
groups gave lower yields than those ,b-unsaturated aromatic alde-
reaction is proposed as shown in Scheme 3, taking the synthesis
of 3a as an example. The novel organic catalyzed domino reaction
process initiates with benzylacetone 1a and pyrrolidine 1 reacting
to form enamine 2, which undergoes aldol condensation reaction
with a molecule of cinnamaldehyde 2a to generate 3. The aldol
product 3 would then release the catalyst to provide 1,7-diphenyl-
a
hydes with electron-rich groups. Thus, we have developed a dom-
ino reaction which provides a highly efficient method to construct
the 4-oxocyclohexanecarbaldehyde backbone with multifunctional
1
3
groups in one step.
All the products were characterized by IR, 1H NMR, 13C NMR,
hepta-4,6-dien-3-one
4 or undergoes tandem inter-Michael–
1
4
and HRMS studies. Purities of the compounds were determined
by HPLC analysis (>95%), which were performed on an Agilent
intra-Michael addition reaction to give 6 with another molecule
of cinnamaldehyde 1a. Moreover, the aldol condensation product
4 would further react with pyrrolidine 1 to form enamine 3 to
continue the domino reaction. And the tandem reaction product
6 would then release the catalyst to afford the final polysubstitut-
ed 4-oxocyclohexanecarbaldehyde 3a. This novel domino reaction
consists of three consecutive reactions: an aldol condensation
1
200 equipment with a reversed-phase C18 column. The relative
configuration of the product was confirmed by HMBC correlations
and ROESY correlations as illustrated for 3a as a representative
1
5
example (Scheme 2).
Based on previous experiences with imine catalyzed aldol
condensation as well as Michael addition reactions,16 a mechanis-
tic rationalization for the pyrrolidine-mediated novel domino
reaction and
reaction.
a tandem inter-Michael–intra-Michael addition

1
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F.-Z. Bao et al. / Tetrahedron Letters 54 (2013) 1405–1408
In order to gain insights into the novel domino reaction and
confirm the proposed mechanism, the reaction between 1,7-diphe-
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