Cross double Mannich reaction catalyzed by I2: Synthesis of highly substituted 4-piperidones

Article abstract of DOI:10.1016/j.cclet.2011.12.008

Cross double Mannich reaction and tandem cyclization were achieved under iodine catalyzed conditions, yielding a series of highly substituted 4-piperidones. Among the possible diastereomers, only one diastereomer was isolated, which could be ascribed to the chair-like transition state in six-membered ring, in which all of the hindered groups are located in the pseudoequatorial orientation.

Full text of DOI:10.1016/j.cclet.2011.12.008

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 309–312
www.elsevier.com/locate/cclet
Cross double Mannich reaction catalyzed by I2: Synthesis
of highly substituted 4-piperidones
*
Xiao Dong Jia , Xiang Ning Chen, Cong De Huo, Fang Fang Peng,
*
Chang Qing, Xi Cun Wang
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, Gansu Key Laboratory of Polymer Materials,
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, China
Received 20 October 2011
Available online 25 January 2012
Abstract
Cross double Mannich reaction and tandem cyclization were achieved under iodine catalyzed conditions, yielding a series of
highly substituted 4-piperidones. Among the possible diastereomers, only one diastereomer was isolated, which could be ascribed
to the chair-like transition state in six-membered ring, in which all of the hindered groups are located in the pseudoequatorial
orientation.
# 2011 Xiao Dong Jia. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Mannich reaction; 4-Piperidone; Tandem cyclization; Iodine
The Mannich reaction has been a fundamental tool of the synthetic chemists for the construction of b-amino
carbonyls for decades. Different from original dialkylamino methylation, the scope of Mannich reaction has been
expanded in recent years to include a wide variety of amines, ammonia equivalents, imines and acylated imines.
Additionally, a variety of tandem variants including the aza-Cope Mannich [1] and Mannich–Michael [2]
methodologies have been well constructed together with the developments in the asymmetric versions of the reaction.
Based on these great developments of Mannich and Mannich-type reaction, numerous catalyst systems have been built
to promote these kind of reactions between carbonyl compounds and imines, including proline and its derivatives [3],
Lewis acids [4], amino sulfonamides [5], cinchona alkaloids [6] and amino thioureas [7].
In the process of seeking new and more efficient catalysts, we found a new version of Mannich reaction, in which
the skeleton of 4-piperidones could be efficiently constructed via so-called double Mannich reaction and the
corresponding tandem cyclization (Scheme 1) [8]. Our method provided a convenient approach towards the synthesis
of 4-piperidones, due to its efficiency and the ready availability of starting materials (simple ketones and imines). In
our previous research, only one kind of imine was involved in the reaction, producing the 4-piperidones with the same
R2 substituted on position 2 and 6 (see Scheme 1). To obtain more diverse products and extend this methodology, we
wondered if different imines could be involved in the reaction with ketones (cross double Mannich reaction).
In recent years, the use of molecular iodine as an inexpensive, nontoxic, readily available, environmentally friendly
catalyst for various organic transformations has received considerable attention [9]. Thereby, as part of our ongoing
* Corresponding authors.
E-mail addresses: jiaxd1975@163.com (X.D. Jia), wangxicun@nwnu.edu.cn (X.C. Wang).
1001-8417/$ – see front matter # 2011 Xiao Dong Jia. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.12.008

310
X.D. Jia et al. / Chinese Chemical Letters 23 (2012) 309–312
1
O
O
NHR
catalyst
1
R
+
2
R
General Mannich reactions
N
R
2
R
R
O
R
R
O
O
catalyst
1
R
1
Double Mannich reaction (ref. )
8
2
+
R
R
N
R
2
2
N
R
R
1
O
R
O
R
2
R
N
R
catalyst
Cross double Mannich reaction (this work)
+
+
2
1
3
3
2
N
R
R
R
R
3
N
R
R
N
R
1
1
R
Scheme 1. Different versions of Mannich reaction.
research program on the exploration of synthetic transformations by using commercially available materials as
catalysts [8], we report herein a synthesis of 4-piperidones by a cross double Mannich reaction and tandem cyclization
catalyzed by iodine.
1. Experimental
General experimental procedure for I2 induced reaction of 1a, 2a and 2b: a solution of 1a, 2a and 2b in CH3CN
(10 mL) was mixed fully and then I2 (20 mol%) was added. After completion monitored by TLC, the reaction was
quenched with 10% aq Na2S2O3 solution (10 mL). After extraction, the organic phase was then dried over anhydrous
magnesium sulfate, filtered, and the solvent was removed under reduced pressure and the products were separated by
silica gel column chromatography eluted with petroleum ether/acetone (v/v, 50:1) to afford the products.
Representative spectral data of the products. Mixtureof 3aand3b: 1H NMR(400 MHz, CDCl3):d 0.84–0.88(m, 3H),
2.75–2.82 (m, 1H), 3.07–3.21 (m, 2H), 4.09–4.13 (m, 1H), 4.54–4.60 (m, 1H), 6.72–6.79 (m, 1H), 6.81–6.91 (m, 4H),
7.31–7.36 (m, 1H), 7.41–7.49(m, 2H), 7.53–7.60 (m, 1H), 7.95–7.99(m, 1H), 8.02–8.05(m, 2H), 8.16–8.24(m, 1H); 13
C
NMR (100.6 MHz, CDCl3): d 10.6 (two 13C), 49.3, 49.5, 50.5, 50.6, 67.5, 67.6, 74.2, 74.3, 122.3, 122.5, 123.1, 123.3,
125.7, 125.8, 127.0, 127.1 (three 13C), 128.4, 128.8 (two 13C), 129.0, 129.1, 133.6 (two 13C), 134.4, 134.5, 142.3, 143.0,
146.8, 147.4 (two 13C), 147.8, 148.1, 206.1, 206.2; ESI-MS m/z (relative intensity, %): 432 (100%).
2. Results and discussion
According to the results of our previous research [8c], the optimized reaction conditions were 20 mol% iodine in
MeCN, so we also conducted the cross double Mannich reaction under these standard conditions. Initially, we chose
the reaction of imine 2a, 2b and ketone 1a as a model reaction to confirm the feasibility of our hypothesis. To our
delight, the reaction occurred smoothly and a mixture of two 4-piperidone was obtained in high yield. According to 1H
NMR, 13C NMR and MS spectroscopy analysis, the nearly 1:1 mixture of 3a and 4a was fully identified (Scheme 2).
The structure of the cross Mannich products was also fully identified by X-ray (compound 4o, Scheme 2).
With these results in hand, we next screened different imines and ketones to extend the substrate scope. The results
were summarized in Table 1. Overall, butan-2-one gave better results than pentan-2-one together with shorter reaction
Scheme 2. Cross double Mannich reaction: (c) I2 (20 mol%), MeCN, r.t., 12 h.

X.D. Jia et al. / Chinese Chemical Letters 23 (2012) 309–312
311
Table 1
Cross double Mannich reaction of ketone and imine.
O
N
O
N
R
R
I2 (20 mol %)
O
1
Ar1
Ar1
Ar3
N
Ar2
+
+
N
R
MeCN, r.t.
+
Ar2
Ar3
Ar3
Ar2
Ar1
Ar1
2
3
4
Entry
R
Ar1
Ph
Ar2
Ar3
Products
Time (h)a
Yield (%)b
1
2
Me
Et
p-NO2Ph
m-NO2Ph
m-NO2Ph
m-NO2Ph
3a, 4a
3b, 4b
3c, 4c
3d, 4d
3e, 4e
3f, 4f
12
24
12
24
12
24
24
24
36
24
36
24
24
24
24
24
24
24
24
24
48
73
63
92
88
93
91
62
54
42
24c
Tracec
35
24
64
61
78
74
70
70
56
47
3
Me
Et
p-CH3OPh
p-CH3Ph
p-NO2Ph
p-NO2Ph
4
5
Me
Et
6
7
Me
Me
Et
p-ClPh
p-NO2Ph
p-NO2Ph
m-NO2Ph
m-NO2Ph
3g, 4g
3h, 4h
3i, 4i
8
o-CH3Ph
9
10
11
12
13
14
15
16
17
18
19
20
21
Me
Et
2, 4-CH3Ph
p-NO2Ph
m-NO2Ph
3j, 4j
3k, 4k
3l, 4l
Me
Me
Bz
p-CH3Ph
p-ClPh
Ph
p-CNPh
p-CNPh
p-NO2Ph
m-NO2Ph
m-NO2Ph
m-NO2Ph
3m, 4m
3n, 4n
3o, 4o
3p, 4p
3q, 4q
3r, 4r
3s, 4s
3t, 4t
sec-Bu
Bz
p-CH3OPh
p-CH3Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
m-NO2Ph
m-NO2Ph
m-NO2Ph
sec-Bu
Bz
sec-Bu
Bz
m-CH3Ph
o-CH3Ph
Bz
3u, 4u
a
Detected by TLC.
b
c
Overall isolated yields of 3 and 4.
The corresponding b-aminoketones were isolated as major products.
time (entries 1–11). We also investigated the influence of the substituents on Ar1. Electron-donating groups on Ar1
promoted the reaction and electron-withdrawing groups decreased the yield of the desired products (entries 1–7).
Imines with o-substituted groups on Ar1 lead to extremely drop of the yield due to steric effect (entries 8 and 9). In
some cases, b-aminoketones of the corresponding imines were isolated as major products which implied the great
influence of steric hindrance in this reaction (entries 10 and 11).
Bad result was also obtained when an imine substituted by a cyano group was used as one of the imine acceptor,
which showed high difference of reactivity towards ketones between cyano and nitro substituted imines (entries 12 and
13). We also screened some more bulk ketones to test the scope of the Mannich donor, but the efficiency of the reaction
Scheme 3. Proposed mechanism.

312
X.D. Jia et al. / Chinese Chemical Letters 23 (2012) 309–312
was not affected obviously, which also implied that the substituents on Ar1 exert higher steric effect than the
corresponding ketones (entries 14–21).
An I2 catalyzed mechanism was proposed to rationalize the formation of the products (Scheme 3). Firstly, imines
and ketones were coordinated with I2, which accelerated the addition of ketones to imines, giving the b-aminoketones
A. Then the Mannich base A was further coordinated with I2 and the second addition occurred, producing the double
Mannich adducts C, which gave the 4-piperidone derivatives via intramolecular substitution. Similar to our previous
results, only one stereoisomer was isolated [10]. This stereoselectivity was ascribed to the chair-like transition state D
in six-membered ring, in which all of the hindered groups are located in the pseudoequatorial orientation.
3. Conclusion
In conclusion, we have designed and executed an efficient cross double Mannich reaction towards the synthesis of
4-piperidone derivatives under iodine induced conditions. Further applications in synthesis of more variable
heterocyclic compounds are underway in our laboratory.
Acknowledgments
We thank NSFC (No. 21002079) and Project (No. 20096203120002) supported by the Ministry of Education of the
People’s Republic of China. We also thank the third Knowledge and Technological Innovation Project (Nos. NWNU-
KJCXGC-03-75 and NWNU-KJCXGC-03-64) of Northwest Normal University for supporting our research.
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