A facile aminocyclization for the synthesis of pyrrolidine and piperidine derivatives

Article abstract of DOI:10.1039/b304157c

Bromination of an isolated double bond followed by aminocyclization furnishes a highly stereoselective protocol for the intramolecular formation of pyrrolidine and piperidine ring containing subunits that are presented in numerous biologically active natu

Full text of DOI:10.1039/b304157c

A facile aminocyclization for the synthesis of pyrrolidine and piperidine
derivatives†
Zhihui Shao,ab Jingbo Chen,a Yongqiang Tu,b Liang Lia and Hongbin Zhang*a
a School of Pharmacy, Yunnan University, Kunming, Yunnan 650091, P. R. China.
E-mail: zhang_hongbin@hotmail.com; Fax: 86-871-5035538; Tel: 86-871-5031119
b National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R.
China
Received (in Cambridge, UK) 15th April 2003, Accepted 12th June 2003
First published as an Advance Article on the web 26th June 2003
Bromination of an isolated double bond followed by
aminocyclization furnishes a highly stereoselective protocol
for the intramolecular formation of pyrrolidine and piper-
idine ring containing subunits that are presented in numer-
ous biologically active natural products.
as required by Lycorine. However, on careful analysis of the
literature there are few examples for intramolecular haloamida-
tion of isolated double bonds forming hexahydroindole and
octahydroquinoline ring systems.16 Development of a general
method for the synthesis of the core heterocyclic ring system,
intermediate 1, was thus initiated.
Nitrogen heterocycles, especially pyrrolidine and piperidine
containing sub-structures, are presented in a large class of
biologically active natural products.1 Selected examples are
Dysinosin A,2 Lycorine,3 Stenine4 and Lepadin B5 as shown in
Fig. 1. Those ring systems are also found in numerous
therapeutic agents.6 Synthesis of the core heterocyclic center
has been an evergreen topic of the synthetic community since
the early 1980s. Efforts towards this field have generated
numerous synthetic methodologies.7 Recent progresses can be
found in the intramolecular hydrovinylation carried out by
Johannsen,8 synthesis of 2,5,6-trisubstituted piperidines by
Padwa,9 radical cyclization by Zard,10 amidation of g-iodoole-
fin by Komatsu,11 a Mitsunobu-promoted intramolecular dis-
placement of allylic alcohol by Banwell12 and transition metal
catalyzed amidation of double bonds by Livinghouse,13 Stahl14
and McDonald.15 Here we report a new method for the synthesis
of the core hexahydroindole and octahydroquinoline ring
system presented in numerous natural products.
Treatment of commercially available cyclohexenylethyl-
amine with benzaldehyde followed by reduction with NaBH4
afforded intermediate 4. Following the iodoamidation proce-
dure reported in the literature,16a we did not get the desired
iodocyclization product, but a complex mixture instead.
Variation of solvent (DCM, THF, acetone, DMF), temperature
as well as reagents (NBS, NIS) for haloamidation were fruitless,
complex mixtures were obtained in all cases. To our delight, the
target reaction was finally realized when bromine was em-
ployed. Treatment of intermediate 4 with bromine at 220 °C in
dichloromethane followed by reflux in the presence of K2CO3
provided the desired hexahydroindole 7 in good yield. The
process combined two reactions in one pot. In the initial stage,
dibromide 5, which could be isolated by flash chromatography,
was formed by addition of bromine. By treatment with base, the
hexahydroindole 7 was obtained; likely through an allylic
bromide intermediate (6) as depicted in Scheme 2. A number of
secondary amines were thus prepared and aminocyclizations
were carried out. The results are summarized in Table 1 (entries
1 to 6). We also tested different protecting groups in the amino
side. It was found that amides as well as sulfonamides could not
undergo this process to afford the desired cyclization product.
Free amines such as 3 are less effective, possibly due to
relatively poor nucleophilicity of the primary amino group.
The protocol described herein is flexible; it could be extended
to prepare the octahydroquinoline as well as hexahydro-1H-
pyridine ring systems (entries 7, 8 and 9). Although the
aminocyclization could be carried out in dichloromethane,
better yields are generally obtained by using higher boiling
point solvents such as THF, acetone or DMF. In principle, for
entries 5 to 9, four stereoisomers (2n, RS, RR, SR and SS) were
expected. In our cases, however, only one unassigned diaster-
eoisomer (RS and SR or RR and SS) were isolated.17
In the course of developing an efficient but flexible strategy
towards the total synthesis of Lycorine and its analogues, a
general method for the synthesis of the N-heterocyclic core
center was needed by our group (see Scheme 1).
It was envisaged that intramolecular haloamidation of the
double bond might be an ideal method to serve our purpose,
since the halogen can be further manipulated to a double bond
In order to further confirm the diastereoselectivity observed
for entries 5 to 9 in Table 1, chiral secondary amines such as 8,
Fig. 1 Examples of pyrrolidine and piperidine containing natural prod-
ucts.
Scheme 1 Retrosynthetic analysis of Lycorine.
† Electronic supplementary information (ESI) available: experimental
details and characterization data. See http://www.rsc.org/suppdata/cc/b3/
b304157c/
Scheme 2 Formation of the pyrrolidine and piperidine ring system.
1918
CHEM. COMMUN., 2003, 1918–1919
This journal is © The Royal Society of Chemistry 2003

9, 10 and 11 were thus prepared by the procedure shown in
Scheme 3 and similar aminocyclizations were conducted.
To our delight, only one diastereoisomer was obtained in
those reactions carried out with chiral secondary amines (see
Table 2). For entries 1 and 2 in Table 2, the products obtained
have identical retention time in HPLC (Agilent Extend C8-
column, CH3CN : H2O = 60 : 40) as well as identical spectra of
NMR but with opposite optical rotation.18 The results observed
further supported our speculation that an allylic bromide
intermediate such as 6 in Scheme 2 might exist. Direct
displacement of the secondary bromo-group in dibromides such
as compound 5 would be less likely to afford high diaster-
eoselectivity.
In summary, we have developed an easy to use, efficient yet
flexible procedure for the formation of pyrrolidine and
piperidine ring containing compounds. The bromination fol-
lowed by aminocyclization furnishes a general protocol for the
intramolecular haloamidation of an isolated double bond. It is
noteworthy that a double bond was concomitantly formed upon
the cyclization which is very useful for further manipulation.
Application of this process towards the total syntheses of
Lepadin B and Lycorine is currently underway in our labo-
ratory.
Table 1 Aminocyclization to form pyrrolidine and piperidine ringsa
Entry Secondary amine
1
Product
Yield (%)
78
2
75b
This work was partially supported by a grant from the
Foundation of the Chinese Ministry of Education for the
Promotion of Excellent Young Scholars and a grant (20272049)
from the National Natural Science Foundation of China. We
would like to thank the International Cooperation Division of
Yunnan Provincial Science & Technology Department for
partial financial support (2002GH04).
3
4
5
75
65
70
Notes and references
6
71
1 (a) J. R. Lewis, Nat. Prod. Rep., 2001, 18, 95; (b) D. O’Hagen, Nat.
Prod. Rep., 2000, 17, 435.
2 A. R. Carroll, G. K. Pierens, G. Fechner, P. de Almeida Leone, A. Ngo,
M. Simpson, E. Hyde, J. N. A. Hooper, S-L. Boström, D. Musil and R.
J. Quinn, J. Am. Chem. Soc., 2002, 124, 13340.
3 S. Yui, M. Mikami, M. Kitahara, Y. Mikio and M. Yamazaki, Immuno-
pharmacology, 1998, 40, 151 and references cited therein.
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(b) R. A. Pilli and M. d. C. Ferreira De Oliveira, Nat. Prod. Rep., 2000,
17, 117.
7
8
76
85b
9
73
5 (a) C. Kalaï, E. Tate and S. Z. Zard, Chem. Commun., 2002, 1430; (b)
J. Kubanek, D. E. Williams, E. D. de Silva, T. Allen and R. J. Anderson,
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J. Fletcher and G. B. S. Potts, J. Chem. Soc., Perkin Trans. 1, 2002, 2747
and references cited therein.
a For reaction conditions see ESI. Yields represent isolated yield based on
secondary amines. All products were confirmed by GC-MS, 1H-NMR and
13C-NMR. b The structure was further confirmed by H–H COSY and C–H
COSY.
8 U. Bothe, H. C. Rudbeck, D. Tanner and M. Johannsen, J. Chem. Soc.,
Perkin Trans. 1, 2001, 3305.
9 J. M. Harris and A. Padwa, Org. Lett., 2002, 4, 2029.
10 L. D. Miranda and S. Z. Zard, Org. Lett., 2002, 4, 1135.
11 S. Minakata, D. Kano, Y. Oderaotoshi and M. Komatsu, Org. Lett.,
2002, 4, 2097.
12 M. G. Banwell, A. J. Edwards, K. A. Jolliffe and M. Kemmler, J. Chem.
Soc., Perkin Trans. 1, 2001, 1345.
Scheme 3 Procedure for the formation of chiral secondary amines.
13 Y. K. Kim and T. Livinghouse, Angew. Chem., Int. Ed., 2002, 41,
3645.
14 S. R. Fix, J. L. Brice and S. S. Stahl, Angew. Chem., Int. Ed., 2002, 41,
164.
Table 2 Aminocyclization to form chiral pyrrolidine and piperidine ring
systemsa
Entry
Secondary amine
Productb
Yield (%)
15 J.-S. Ryu, T. J. Marks and F. E. McDonald, Org. Lett., 2001, 3, 3091.
16 To the best of our knowledge, only one paper has dealt with
iodocyclization of homoallylic sulfonamides to form a pyrrolidine ring
system: (a) A. D. Jones, D. W. Knight and D. E. Hibbs, J. Chem. Soc.,
Perkin Trans. 1, 2001, 1182. Other examples were mainly focused on
intramolecular haloamidation of 3-acetyloxybut-1-enylamines or N-
protected 3-hydroxy-4-pentenalamine and 4-hydroxy-5-hexenylamines
as described in: (b) W. S. Lee, K. C. Jang, J. H. Kim and K. H. Park,
Chem. Commun., 1999, 251; (c) Y. Tamaru, S. Kawamura, T. Bando, K.
Tanaka, M. Hojo and Z. Yoshida, J. Org. Chem., 1988, 53, 5491.
17 Although a trace spot in TLC well above the spot of the main product
was suspected to be the other diastereoisomer, however, no product
corresponding to this trace spot was isolated by flash chromatog-
raphy.
1
2
74
83
3
4
71
74
18 Optical rotations were recorded on HORIBA SEPA-300 at 24 ° C. For
entry 1 in Table 2: 1-[1-(R)phenylethyl]-1,2,3,4,6,7,8,8a-octahydroqui-
noline: [a]D = 223.67° (c = 0.0017 g mL21, CHCl3); For entry 2 in
Table 2: 1-[1-(S)phenylethyl]-1,2,3,4,6,7,8,8a-octahydroquinoline:
[a]D = + 26.79° (c = 0.0028 g mL21, CHCl3).
a For reaction conditions see ESI. Yields represent isolated yield. b Absolute
configuration is not determined.
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