Organocatalyst-mediated aldolrobinson cascade reactions: A convenient synthesis of substituted cyclohex-2-enones

Article abstract of DOI:10.1246/cl.2011.138

A convenient organocatalytic process for the chemoselective synthesis of substituted cyclohex-2-enones was developed. The cascade reaction involves a remarkable Michael addition of an acyclic ketone-based enamine onto unmodified enones. The enamine-mediated aldolRobinson cascade reactions of aromatic and aliphatic aldehydes with acetone produced substituted cyclohex-2-enones in moderate to high yields under mild reaction conditions.

Full text of DOI:10.1246/cl.2011.138

doi:10.1246/cl.2011.138
138
Published on the web December 28, 2010
Organocatalyst-mediated Aldol-Robinson Cascade Reactions:
A Convenient Synthesis of Substituted Cyclohex-2-enones
Li Wang, Qing-Ping Gong, Xiao-Jun Liu, Yong-Hong Li, Ping Huang, Bi-Qin Wang, and Ke-Qing Zhao*
Department of Chemistry and Materials Science, Sichuan Normal University, No. 5 Jing’An Rd., Chengdu 610068, P. R. China
(Received October 12, 2010; CL-100870; E-mail: kqzhao@sicnu.edu.cn)
R3 R4
R3
R4
R2
O
A convenient organocatalytic process for the chemoselective
N
H
O
N
O
3
R1
5
R2
synthesis of substituted cyclohex-2-enones was developed. The
cascade reaction involves a remarkable Michael addition of
an acyclic ketone-based enamine onto unmodified enones. The
enamine-mediated aldol-Robinson cascade reactions of aromatic
and aliphatic aldehydes with acetone produced substituted
cyclohex-2-enones in moderate to high yields under mild
reaction conditions.
+
R1
H
R1
4
R2
enamine-mediated
aldol condensation
unactivated
Michael acceptor
1
2
activated
Michael acceptor
enamine-mediated
Michael addition
R3
R4
N
R3
R4
R2
R2
N
R1
6
In recent years, secondary amine catalyzed reactions have
drawn much attention. Most research in this area has been
focused on the development of novel methodologies for
asymmetric aldol reactions or conjugated additions.1
Figure 1. Our proposed cascade process.
Table 1. Reaction optimizationsa
O
O
O
OH
pyrrolidine (x mol%)
propionic acid (x mol%)
Enamine-mediated Michael reactions, however, have been
very restricted, particularly for the intermolecular version. To the
best of our knowledge, the enamine-mediated conjugate addition
of unactivated ketones and unmodified enones is very rare
and has only been presented very recently by Wang and Li
independently.2 Additionally, two other reports have only
mentioned such transformations as minor side-reactions.3
During the course of our research, we have been attracted by
the enone side-products 5 produced by enamine-mediated aldol
reactions (Figure 1). We were intrigued by the possibility that
the in situ generated iminium form of the enone side-products 4
could be utilized as excellent Michael acceptors for inter-
molecular Michael reactions or Robinson annulations to provide
substituted cyclohex-2-enones, a family of biologically active
molecules and important synthetic building blocks (Figure 1).4
In our preliminary investigations, we employed 4-hydroxy-
benzaldehyde (7) as the model substrate and pyrrolidine/
propionic acid as the cocatalysts.5 Under 20 °C, the reaction
provided approximately 1:3.76 molar ratio of enone 9 and the
aldol-Robinson product cyclohex-2-enone 10 (Entry 1, Table 1).
As depicted in our proposed cascade process (Figure 1), the
thermodynamically favored enone intermediate 5 is crucial for
the cascade reaction, we then decided to carry out our reaction
optimizations at elevated temperature to facilitate the formation
of enones and complete the conversion of starting materials
to the cyclohex-2-enone 10. Under 45 °C and 50 mol % of
catalysts, the reaction was dramatically improved, and only
aldol-Robinson cascade product 10 was produced (Entry 2,
Table 1). Furthermore, we found that reactions with lower
catalytic loadings had longer reaction times and provided a
lower ratio of the desired cyclohex-2-enone 10 versus the enone
9, and consequently lower yield of 10 was obtained (Entries 3-5,
Table 1). Our proposed intermediate, enone 9, increasing in
prevalence at low catalytic loading highly suggests that the
cyclohex-2-enone 10 was derived from a Robinson reaction of 9,
providing further support for our proposed reaction pathway
(Figure 2).
+
+
HO
CHO
acetone (0.2 molL−1
)
OH
OH
45°C
8
10
9
OH
7
Catalytic loading Time
8:9:10 molar
ratiob
Yield
Entry
x/mol %
/h
/%c
1d
2
3
4
5
50
50
30
20
10
24
24
24
30
48
®:21:79
®:®:100
®:6:94
®:8:92
®:25:75
47
73
68
66
58
aAll reactions were performed on a 1.0 mmol scale. bThe molar
1
c
ratios were calculated based on H NMR integrations. Yield
d
of pure and isolated product 10. The reaction was carried out
under 20 °C.
O
OH
O
R
N
17
O
12
H
and
dehydration
O
propionic acid
11
R
R
N
H
18
22
Catalytic
Cycle
I
and
propionic acid
11
N
R=aryl, alkyl
N
OH
13
Aldol
R
16
dehydration
R
O
Catalytic
Cycle
II
Aldol
N
N
R
or its mono-/
diiminium 21
19
RCHO
14
O
R=aryl, alkyl
15
N
N
Michael
R
14
N
20
Figure 2. Proposed reaction mechanism for the cascade
process.
In the proposed reaction mechanism (Figure 2), iminium ion
intermediate 13 deprotonates into enamine 14, which undergoes
an aldol condensation with aldehyde 15 to give iminium 19.
Chem. Lett. 2011, 40, 138-139
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

139
Table 2. Reaction scope of the organocatalytic cascade proc-
this is the first example of an organocatalytic one-step synthesis
of («)-celery ketone from inexpensive, readily available starting
materials.
ess8
pyrrolidine/
O
propionic acid
(30 mol%)
RCHO
In summary, we have successfully developed an efficient
organocatalytic aldol-Robinson cascade reaction from commer-
cially available and inexpensive starting materials. This reaction
proceeded chemoselectively to produce substituted cyclohex-2-
enones in moderate to high yields. A variety of cyclohex-2-
enones with different substituted groups were readily accessed.
This cascade process has disclosed a novel intermolecular
Michael addition that will be employed in future studies. An
enantioselective version of this cascade reaction, as well as the
synthetic applications of its products are currently under
investigation.
acetone (0.2 molL−1
)
R
45°C, 24 h
15
10 and 23~35
Entry
R
Products
Yields/%a
1
2b
3
4
5
6
7
8
9d
10
11
12
13
14
4-HOC6H4
4-CH3OC6H4
4-(CH3)2NC6H4
2-CH3OC6H4
4-ClC6H4
2,6-Cl2C6H4
4-CH3C6H4
3-HOC6H4
4-NO2C6H4
2-Furanyl
10
23
24
25
26
27
28
29
30
31
32
33
34
35
b
68c
50
81
52
90
66c
76
62
53
52
91
64
56
53
We would like to thank the National Natural Science
Foundation of China (No. 20872104 and No. 50973076) for
generous financial support. The authors would like to acknowl-
edge Dr. Michel Gravel (University of Saskatchewan) for useful
discussions and Ms. Janice M. Holmes for proofreading the
manuscript.
2-Thienyl
2-Pyrryl
2-Naphthyl
Propyl
References and Notes
aYield of pure and isolated product. 50 mol % catalysts, 96 h.
c3% and 26% of aldol condensation products were isolated in
Entries 1 and 6, respectively. Prolonged reaction time only
1
For recent reviews of enamine-mediated reactions: a) S.
Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev. 2007,
107, 5471. b) P. M. Pihko, I. Majander, A. Erkkilä, Enamine
Catalysis in Asymmetric Organocatalysis in Topics in Current
Chemistry, 2010, Vol. 291, pp. 29-75. doi:10.1007/128_2008_21.
The references of enamine-mediated Michael addition of unac-
tivated ketones and unmodified enones: a) J. Wang, H. Li, L. Zu,
W. Wang, Adv. Synth. Catal. 2006, 348, 425. b) J.-F. Wang, X.
Wang, Z.-M. Ge, T.-M. Cheng, R.-T. Li, Chem. Commun. 2010,
46, 1751. c) J.-F. Wang, C. Qi, Z.-M. Ge, T.-M. Cheng, R.-T. Li,
Chem. Commun. 2010, 46, 2124.
d
resulted in complex mixtures. 50 mol % catalysts, 10 h.
Alternatively, 19 could also be formed via the dehydration of
¢-hydroxyketone 17 followed by formation of iminium ion. The
Michael addition between the acyclic ketone-derived enamine
14 and the enone iminium intermediate 19 delivers intermediate
20, which is then hydrolyzed to form 4-substituted-2,6-hep-
tanediones 21 (or its mono-/diiminium forms). Intramolecular
aldolization (The Amagi cyclization)6 of 21 produces the desired
product 22.
We then examined the scope of our methodology by
screening structurally diverse aldehydes, as shown in Table 2.
Benzaldehyde derivatives with various substituents in the ortho-,
meta-, and para-positions of the phenyl ring all provided the
corresponding cyclohex-2-enones with moderate to high yields
(Entries 1-9). Remarkably, benzaldehyde derivatives with para
and ortho electron-donating groups proceeded efficiently in the
reaction despite the relatively low reactivity of the carbonyl
group, which has been extremely rarely reported in enamine-
mediated aldol reactions. Moreover, p-nitrobenzaldehyde7 of-
fered us a 53% yield of the corresponding cyclohex-2-enone
derivative 30 very efficiently in only 10 h (Entry 9). This is in
sharp contrast to Nhien and co-workers’ recent report,3 in which
they used 100 mol % of catalyst, but only obtained a 4% yield of
the cyclohex-2-enone 30 as a side product.
The substrates of this new cascade reaction were not
limited to functionalized benzaldehydes. Heterocyclic aldehydes
(Entries 10-12) and 1-naphthaldehyde (Entry 13) were all
transformed into the corresponding cyclohex-2-enones. These
results were of particular interest as cyclohex-2-enones bearing
heterocycles (e.g., 32) have shown biological activity (e.g.,
sedative properties).4g
An aliphatic aldehyde, n-butanal was also successfully
employed in the synthesis (Entry 14), to produce («)-celery
ketone, an artificial flavoring ingredient. It should be noted that
2
3
4
a) M. Moura, S. Delacroix, D. Postel, A. N. V. Nhien, Tetrahedron
2009, 65, 2766. b) L. Tuchman-Shukron, T. Kehat, M. Portnoy,
Eur. J. Org. Chem. 2009, 992.
For examples of recent uses of functionalized cyclohex-2-enones
as building blocks: a) B. E. Rossiter, N. M. Swingle, Chem. Rev.
1992, 92, 771. b) D. Basavaiah, A. J. Rao, T. Satyanarayana,
Chem. Rev. 2003, 103, 811. c) H. B. Kagan, O. Riant, Chem. Rev.
1992, 92, 1007. For example of cyclohex-2-enone as potential
pharmaceuticals: d) T. Nakayachi, E. Yasumoto, K. Nakano,
S. R. M. Morshed, K. Hashimoto, H. Kikuchi, H. Nishikawa, M.
Kawase, H. Sakagami, Anticancer Res. 2004, 24, 737. e) B. H.
Bae, K. S. Im, W. C. Choi, J. Hong, C.-O. Lee, J. S. Choi, B. W.
Son, J.-I. Song, J. H. Jung, J. Nat. Prod. 2000, 63, 1511. f) M. A.
González, S. Ghosh, F. Rivas, D. Fischer, E. A. Theodorakis,
Tetrahedron Lett. 2004, 45, 5039, and references cited therein. g)
N. D. P. Cosford, I. A. McDonald, L. S. Bleicher, R. V. Cube, E. J.
Schweiger, J. Vernier, S. D. Hess, M. A. Varney, B. Munoz,
International Patent WO 01/16121 A1, 2001. h) H. A. Luts, W. L.
Nobles, J. Pharm. Sci. 1962, 51, 1173.
5
6
A. Erkkilä, P. M. Pihko, J. Org. Chem. 2006, 71, 2538.
a) C. Agami, H. Sevestre, J. Chem. Soc., Chem. Commun. 1984,
1385. b) C. Agami, N. Platzer, H. Sevestre, Bull. Soc. Chim. Fr.
1987, 2, 358.
7
8
We thank a reviewer for the suggestion that benzaldehyde with a
strong electron-withdrawing group should also be tried for the
cascade process.
Supporting Information is also available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2011, 40, 138-139
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/