Synthesis of 3,4-disubstituted piperidines by carbonyl Ene and Prins cyclizations: A switch in diastereoselectivity between Lewis and Bronsted acid catalysts

Article abstract of DOI:10.1021/ol0266929

(graph presented) A novel diastereoselective approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 6a-e catalyzed by the Lewis acid methyl aluminum dichloride in refluxing chloroform affords trans piperidines 8a-e with diastereomeric ratios of up to 93:7. By contrast, Prins cyclization of 6a-e catalyzed by hydrochloric acid at low temperatures affords cis products 7a-e with diastereomeric ratios of up to 98:2.

Full text of DOI:10.1021/ol0266929

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3727-3730
Synthesis of 3,4-Disubstituted
Piperidines by Carbonyl Ene and Prins
Cyclizations: A Switch in
Diastereoselectivity between Lewis and
Brønsted Acid Catalysts
Jodi T. Williams, Perdip Singh Bahia, and John S. Snaith*
School of Chemical Sciences, The UniVersity of Birmingham,
Edgbaston, Birmingham, B15 2TT, UK
j.s.snaith@bham.ac.uk
Received August 7, 2002
ABSTRACT
A novel diastereoselective approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 6a−e
catalyzed by the Lewis acid methyl aluminum dichloride in refluxing chloroform affords trans piperidines 8a−e with diastereomeric ratios of
up to 93:7. By contrast, Prins cyclization of 6a−e catalyzed by hydrochloric acid at low temperatures affords cis products 7a−e with diastereomeric
ratios of up to 98:2.
The piperidine ring system is ubiquitous in natural products
and synthetic pharmaceuticals.1 Many piperidine-containing
alkaloids have interesting biological and pharmacological
properties, and a variety of stereoselective approaches to
these compounds have been developed.2 Nevertheless, the
variety of functionality and substitution patterns found in
piperidine targets continues to drive the search for new
methodologies.3
Intramolecular carbonyl ene reactions present an attractive
method for ring closure, forming two contiguous stereo-
centers with an often high degree of stereocontrol.4 One of
the best studied carbonyl ene reactions is the cyclization of
citronellal 1 to a mixture of isopulegol 2 and neoisopulegol
3, Scheme 1. Cyclization can be effected under Lewis acidic
conditions with a diastereomeric ratio of up to 95:5 in favor
of the trans diastereoisomer isopulegol.5 Cyclization in
aqueous acid results in formation of the menthane diols 4
and 5.
(3) (a) Souers, A. J.; Ellman, J. A. J. Org. Chem. 2000, 65, 1222-1224.
(b) Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org. Chem. 2000, 65,
4435-4439. (c) Tan, C.-H.; Holmes, A. B. Chem. Eur. J. 2001, 7, 1845-
1854. (d) Ma, D.; Sun, H. J. Org. Chem. 2000, 65, 6009-6016. (e) Amat,
M.; Bosch, J.; Hidalso, J.; Canto, M.; Perez, M.; Llor, N.; Molins, E.;
Miravitlles, C.; Modesto, O.; Lugue, J. J. Org. Chem. 2000, 65, 3074-
3084. (f) Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001,
123, 1004-1005. (g) Amat, M.; Perez, M.; Llor, N.; Bosch, J.; Lago, E.;
Molins, E. Org. Lett. 2001, 3, 611-614. (h) Watson, P. S.; Jiang, B.; Scott,
B. Org. Lett. 2000, 2, 3679-3681. (i) Kuethe, J. T.; Comins, D. L. Org.
Lett. 1999, 1, 1031-1033. (j) Brooks, C. A.; Comins, D. L. Tetrahedron
Lett. 2000, 41, 3551-3553. (k) Shu, C.; Alcudia, A.; Yin, J.; Liebeskind,
L. S. J. Am. Chem. Soc. 2001, 123, 12477-12487. (l) Harris, J. M.; Padwa,
A. Org. Lett. 2002, 4, 2029-2031.
(1) (a) Findlay, J. A. In The Alkaloids; Brossi, A., Ed.; Academic Press:
London, 1985; Vol. 26, pp 89-183. (b) Pinder, A. R. Nat. Prod. Rep. 1986,
3, 171-180. (c) Pinder, A. R. Nat. Prod. Rep. 1987, 4, 527-537. (d) Pinder,
A. R. Nat. Prod. Rep. 1989, 6, 67-78. (e) Pinder, A. R. Nat. Prod. Rep.
1986, 3, 171-180. (f) Pinder, A. R. Nat. Prod. Rep. 1990, 7, 447-455. (g)
Pinder, A. R. Nat. Prod. Rep. 1992, 9, 491-504.
(4) For a review, see: Snider, B. B. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 527-
561.
(2) For a review, see: Laschat, S.; Dickner, T. Synthesis 2000, 1781-
1813.
10.1021/ol0266929 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/12/2002

Scheme 1a
Table 1. Cyclization of 6a under Lewis and Brønsted Acid
Conditions
entry
acid
equiva
time (h)
7a :8a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CH3AlCl2
CH3AlCl2
CH3AlCl2
CH3AlCl2
CH3AlCl2
AlCl3
Sc(OTf)3
SnCl4
FeCl3
CF3SO3H
HCl
HCl
HCl
HCli
0.3
0.5
1.0
0.3c
1.0d
0.1
0.5
0.5
0.5
0.5
3.0
1.0
3.0d
n/a
8
8
7
16
16
7
7
7
7
8
70:30
67:33
73:27
33:67
8:92e
83:17
50:50
67:33
tracef
78:22
95:5g
93:7
a Reagents and conditions: (a) Lewis acids; (b) aqueous acid.
Application of the carbonyl ene cyclization to piperidine
synthesis has been little explored,6 and we were interested
to see whether the method could be used to synthesize 3,4-
disubstituted piperidines.
16
64h
16
6
86:14
94:6j
The cyclization precursors were straightforwardly synthe-
sized (Scheme 2) from 3-aminopropanol. N-Tosylation7
a All reactions were performed at -78 °C in dichloromethane unless
otherwise stated. b Ratio was determined by integration of 1H NMR spectra
of a crude mixture of piperidines. Crude reaction yields were typically in
excess of 90%. c Reaction was performed at 25 °C. d Reaction was
performed at 61 °C in chloroform. e Isolated yields: 7a (6%), 8a (74%).
f There was evidence of slight reaction (ca. 5%) after this time. g Isolated
yields: 7a (79%), 8a (4%). h Reaction was only 80% complete after this
time. i Reaction was performed using a solution of dry HCl gas in
dichloromethane; the concentration was not determined. j Around 35% of
chloride 9 was present in the crude product.
Scheme 2a
Conversion to the diastereomeric mixture of piperidines
was essentially quantitative, with isolated yields of the crude
piperidine mixtures typically in excess of 90%. Methyl
aluminum dichloride proved to be a useful catalyst for the
carbonyl ene reaction.8 Surprisingly, even substoichiometric
amounts of the Lewis acid were able to catalyze the
cyclization at -78 °C (entries 1-3). At this temperature,
the major product was cis diastereoisomer 7a, and the
diastereomeric ratio proved to be relatively insensitive to the
amount of Lewis acid. Raising the temperature at which the
reaction was performed to 25 °C resulted in preferential
formation of piperidine 8a (entry 4), suggesting that under
these conditions the carbonyl ene reaction is reversible and
that 7a is the kinetic product, equilibrating to 8a on warming.
This was confirmed by raising the temperature to 61 °C
(entry 5); under these conditions, piperidine 8a predominated,
with a ratio of 8a:7a of 92:8. This product ratio was also
reached by heating piperidine 7a under the same conditions.
The diastereoisomers were readily separated by column
chromatography to afford the piperidines as crystalline solids.
Single crystals of the major diastereoisomer 8a were grown
from petroleum ether and ethyl acetate, and X-ray analysis
confirmed the trans relationship between the two substituents.
a Reagents and conditions: (a) pTsCl, Et3N, CH2Cl2, 0 °C, 68%;
(b) BrCH2CHdC(CH2R)2, Cs2CO3, DMF, 25 °C, 59-86%; (c)
PCC, celite, CH2Cl2, 25 °C, 57-70% or TPAP, NMO, 4 Å sieves,
25 °C, 83% 6c.
followed by N-alkylation with the corresponding allylic
bromide and subsequent oxidation with PCC or TPAP
afforded aldehydes 6a-e. We initially focused on cyclization
of the unsubstituted system 6a to diastereomeric piperidines
7a and 8a using a variety of Lewis acids in dry dichloro-
methane solution (Table 1).
(5) (a) Nakatani, Y.; Kawashima, K. Synthesis 1978, 147-148. (b)
Aggarwal, V. K.; Vennall, G. P.; Davey, P. N.; Newman, C. Tetrahedron
Lett. 1998, 39, 1997-2000.
(6) For examples, see: (a) Laschat, S.; Fox, T. Synthesis 1997, 475-
479. (b) Monsees, A.; Laschat, S.; Kotila, S.; Fox, T.; Wurthwein, E.-U.
Liebigs Ann. 1997, 533-540 and 1041. For a highly diastereoselective
approach to indolizidines and quinolizidines via carbonyl ene reaction,
see: (c) Laschat, S.; Grehl, M. Chem. Ber. 1994, 127, 2023-2034. Overman
has reported piperidine synthesis via type II ene reactions: Overman, L.
E.; Lesuisse, D. Tetrahedron Lett. 1985, 26, 4167-4170.
(7) Bailey, T. R.; Garigipati, R. S.; Morton, J. A.; Weinreb, S. M. J.
Am. Chem. Soc. 1984, 106, 3240-3245.
(8) Snider, B. B.; Karras, M.; Price, R. T.; Rodini, D. J. J. Org. Chem.
1982, 47, 4535-4545.
3728
Org. Lett., Vol. 4, No. 21, 2002

Other Lewis acids were examined in an effort to favor
formation of the kinetic product 7a. Aluminum chloride was
found to be an effective catalyst, and favored formation of
7a (entry 6). Scandium triflate and tin tetrachloride were both
effective catalysts for the reaction (entries 7 and 8), but
diastereoselectivities were poor. Ferric chloride afforded only
trace amounts of products (entry 9), while zinc bromide,
ytterbium triflate, and copper(II) triflate were completely
ineffective.
Table 2. Cyclization Reactions of 6b-e
Closely related to the carbonyl ene reaction is the Prins
reaction, the addition of an aldehyde to an alkene catalyzed
by a Brønsted acid. Reports of Prins cyclizations to form
six-membered rings are less common than their carbonyl ene
counterparts, but we were intrigued by a report from Holker
and co-workers of a highly diastereoselective example
catalyzed by HCl.9 Thus, we undertook an investigation into
the diastereocontrol exerted by a small number of Brønsted
acids on the cyclization of 6a.
entry
aldehyde
acida
time (h)
7:8
yield %b
1
2
3
4
5
6
7
8
6b
6b
6c
6c
6d
6d
6e
6e
CH3AlCl2
HCl
CH3AlCl2
HCl
CH3AlCl2
HCl
CH3AlCl2
HCl
35
16
27
16
27
16
27
16
22:78
>98:2
30:70
90:10
7:93
89:11
25:75
80:20
55 (15)
86
53 (22)
71 (7)
74 (4)
72 (9)
61 (20)
60 (14)
p-Toluenesulfonic acid did not catalyze the reaction at low
temperature, while the stronger trifluoromethane sulfonic acid
was effective but the diastereoselectivity was modest (entry
10). However, to our surprise we found that addition of 3.0
equiv of concentrated hydrochloric acid to the dichloro-
methane solution of 6a at -78 °C effected quantitative
cyclization to 7a and 8a with a diastereomeric ratio of better
than 95:5 in favor of the kinetic isomer 7a (entry 11).
Frequently, a trace (<5%) of a side product, identified as
the cis chloride 9, was also produced under these conditions.
Chloride 9 was difficult to separate from 7a chromatographi-
cally, but simply stirring a solution of a mixture of 7a and
9 with silica gel10 or aqueous ammonia induced an elimina-
tion to afford pure 7a.
Reducing the amount of acid led to an unacceptably slow
reaction without improvement in diastereomeric ratio (entry
12). Although raising the temperature of the reaction lowered
the diastereoselectivity, the cyclization still favored cis
product 7a. Thus, heating 6a with 3.0 equiv of concentrated
hydrochloric acid at reflux in chloroform (entry 13) afforded
a 86:14 ratio of 7a:8a. Diastereoselectivity using a solution
of dry HCl gas in dichloromethane was essentially identical
(entry 14), although the procedure was less convenient, and
the presence of excess HCl led to an increase in the amount
of chloride side product 9.
a CH3AlCl2 refers to 1 equiv at 61 °C in chloroform. HCl refers to 3
equiv of concentrated hydrochloric acid at -78 °C in dichloromethane.
b Isolated yields of major (minor) isomers following chromatography.
detectable by NMR either before or after hydrogenation
(entry 2). Paralleling our findings for 6a, around 5% of the
chloride resulting from addition of HCl to the double bond
of 7b was also obtained.
Further extending our study, we examined the cyclization
of aldehydes 6c-e, in which the alkene is exocyclic to a
five-, six-, and seven-membered ring, respectively. Under
acidic conditions, the preference for formation of cis dia-
stereoisomers 7c-e was again marked (entries 4, 6, and 8),
although not as high as the acyclic examples. Under
equilibrating Lewis acidic conditions, all three favored the
trans diastereoisomer (entries 3, 5, and 7), a preference that
was particularly marked in the case of the cyclohexyl system
(entry 5).
As a reference point, we performed the cyclization of
citronellal under our optimal hydrochloric acid conditions.
The reaction was clearly a little more sluggish, since 25%
of the citronellal remained unchanged after the usual period
of 16 h at -78 °C. The principal products were isopulegol
and neoisopulegol, although there was evidence from the
NMR and GC-mass spectra that a number of side products
were also present resulting from dimerization (and possibly
higher oligomerization) of citronellal, presumably by aldol
chemistry. Interestingly, the cyclization process favored cis
product neoisopulegol 3, but in marked contrast with our
own system, the ratio of cis:trans products was only 75:25.
Both the acid- and the Lewis acid-catalyzed cyclizations
of 6 appear to proceed initially through the formation of the
kinetic product 7, with conversion to the thermodynamic
product 8 only proceeding at a significant rate under Lewis
acidic conditions. In contrast, the cyclization of citronellal
affords the thermodynamically more stable trans isomer
isopulegol with a variety of Lewis acids. There is no evidence
that cyclization proceeds through a kinetic intermediate that
isomerizes. Indeed Nakatani demonstrated that under the
Cyclization of the remaining aldehydes 6b-e was studied
under the optimized Lewis and Brønsted acid conditions;
the results are shown in Table 2.
Analysis of products 7b and 8b from cyclization of 6b
was complicated by the presence of E and Z double-bond
isomers, so the diastereomeric ratio was verified after
hydrogenation to the saturated products. Lewis acid-catalyzed
cyclization of 6b afforded predominantly trans product 8b
as a mixture of double-bond stereoisomers (entry 1). Under
Brønsted acid conditions, 6b exhibited a remarkable dia-
stereoselectivity of at least 98:2, with no trans product
(9) Chexal, K. K.; Holker, J. S. E.; Simpson, T. J.; Young, K. J. Chem.
Soc., Perkin Trans. 1 1975, 543-548.
(10) Iwamatsu, S. I.; Kondo, H.; Matsubara, K.; Nagashima, H.
Tetrahedron 1999, 55, 1687-1706.
Org. Lett., Vol. 4, No. 21, 2002
3729

conditions of zinc bromide in benzene, the cyclization of
citronellal to afford chiefly isopulegol is irreversible.5a More
recently, however, Kocovsky has shown that several Lewis
acids, including zinc chloride in dichloromethane, rapidly
isomerize neoisopulegol to isopulegol.11
The effect of Brønsted acid catalysis is remarkable. Here,
citronellal parallels our findings in favoring the thermody-
namically less stable diastereoisomer 3, although the prefer-
ence is much less marked and the reaction is not clean. When
citronellal is cyclized using aqueous acid, the principal
products are the menthane diols 4 and 5 (Scheme 1), which
could be considered as coming from hydration of isopulegol
and neoisopulegol, respectively.15 Interestingly, there is again
a preference for the cis diastereoisomer, with diol 5
predominating over the trans diol 4 in a ratio of 67:33. It is
difficult to explain these results for citronellal on steric
grounds, and the switch in diastereoselectivity observed when
Lewis or Brønsted acids are used may indicate a change in
cyclization mechanism.
In summary, we have discovered a highly diastereoselec-
tive synthesis of cis and trans 3,4-disubstituted piperidines
from simple acyclic precursors, which should have applica-
tion to the synthesis of more complex molecules. Experi-
mental and theoretical studies are currently underway in an
effort to elucidate the origins of the observed stereo-
selectivity.
At present, it is not clear why our system should
preferentially cyclize to the cis diastereoisomer. In the earlier
work of Laschat,6a-c preference for the cis isomer was
explained by the formation of a five-membered chelate
between the Lewis acid, the aldehyde oxygen and the basic
nitrogen. This explanation is less attractive in the case of
our system and, in any event, cannot account for the Brønsted
acid results. Coordination of a Lewis acid by the sulfonamide
nitrogen would be expected to be weak, and results were
poor with the strongly chelating SnCl4, a Lewis acid that
was very effective in Laschat’s system. Attempts to prepare
a cyclization substrate lacking the tosyl group were unsuc-
cessful.
A reversal in the sense of diastereoselectivity of citronellal
cyclization to favor the cis diastereoisomer neoisopulegol 3
(dr ) 75:25) has been achieved with Wilkinson’s catalyst,
although this observation has not been satisfactorily ex-
plained.12 Kocovsky has explored the cyclization with bulky
molybdenum-based Lewis acids, observing a cis:trans ratio
of up to 80:20. In this case, it is suggested that the bulky
Lewis acid forces cyclization through a boatlike transition
state, leading to the switch in diastereoselectivity.11 This
steric argument applied to our system is not compelling.
Methyl aluminum dichloride is not a sterically demanding
Lewis acid and with citronellal it affords predominantly the
trans product.13 A perhaps more plausible explanation is that
citronellal and 6 cyclize via different mechanisms; both
concerted and stepwise mechanisms have been proposed for
ene reactions.14
Acknowledgment. We thank the Engineering and Physi-
cal Sciences Research Council (studentship to J.T.W.), the
University of Birmingham, and Dr. R. N. F. Simpson for
financial support. We also thank Dr. D. Philp for helpful
discussions.
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds up to and
including 6a and all piperidines 7a-e and 8a-e, as well as
a general elimination procedure to remove 9. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0266929
(14) See: (a) Loncharich, R. J.; Houk, K. N. J. Am. Chem. Soc. 1987,
109, 6947-6952. (b) Snider, B. B.; Ron, E. J. Am. Chem. Soc. 1985, 107,
8160-8164. (c) Song, Z.; Beak, P. J. Am. Chem. Soc. 1990, 112, 8126-
8134.
(15) (a) Zimmerman, H. E.; English, J. J. Am. Chem. Soc. 1953, 75,
2367-2370. (b) Naves, Y.-R.; Ochsner, P. HelV. Chim. Acta 1964, 47, 51-
66. (c) Yuasa, Y.; Tsuruta, H.; Yuasa, Y. Org. Process Res. DeV. 2000, 4,
159-161.
(11) Kocovsky, P.; Ahmed, G.; Srogl, J.; Malkov, A. V.; Steele, J. J.
Org. Chem. 1999, 64, 2765-2775.
(12) Funakoshi, K.; Togo, N.; Koga, I.; Sakai, K. Chem. Pharm. Bull.
1989, 37, 1990-1994.
(13) Karras, M.; Snider, B. B. J. Am. Chem. Soc. 1980, 102, 7951-
7953.
3730
Org. Lett., Vol. 4, No. 21, 2002