Proline catalyzed, one-pot three component Mannich reaction and sequential cyclization toward the synthesis of 2-substituted piperidine and pyrrolidine alkaloids

Article abstract of DOI:10.1016/j.tetlet.2015.03.001

Abstract A very effective one-pot three component reaction of 4-bromobutanal or 5-bromopentanal, acetone, and p-anisidine catalyzed by proline is reported. A three component Mannich reaction followed by cyclization leading to the synthesis of 2-substituted pyrrolidine and piperidine derivatives through simultaneous formation of two C-N and one C-C bond is reported. The usefulness of the reaction is demonstrated by the synthesis of (±)coniine, (±)pelletrine, (±)sedridine, and (±)allosedridine.

Full text of DOI:10.1016/j.tetlet.2015.03.001

Tetrahedron Letters 56 (2015) 2023–2026
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Tetrahedron Letters
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Proline catalyzed, one-pot three component Mannich reaction
and sequential cyclization toward the synthesis of 2-substituted
piperidine and pyrrolidine alkaloids
⇑
Shibin Chacko, Ramesh Ramapanicker
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A very effective one-pot three component reaction of 4-bromobutanal or 5-bromopentanal, acetone, and
p-anisidine catalyzed by proline is reported. A three component Mannich reaction followed by cyclization
leading to the synthesis of 2-substituted pyrrolidine and piperidine derivatives through simultaneous
formation of two C–N and one C–C bond is reported. The usefulness of the reaction is demonstrated
by the synthesis of ( )coniine, ( )pelletrine, ( )sedridine, and ( )allosedridine.
Received 21 January 2015
Revised 21 February 2015
Accepted 1 March 2015
Available online 5 March 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
Organocatalysis
Pyrrolidine
Piperidine
Mannich reaction
2-Substituted piperidine and pyrrolidine subunits are widely
found in natural products and synthetic compounds of pharmaco-
logical importance.1 Various synthetic routes are available for syn-
thesizing these classes of compounds and the available strategies
are largely based on, but not limited to cycloaddition reactions,
iminium-ion cyclization, ring closing metathesis, and Mannich
type of reactions.2 We report an organocatalytic one-pot three
component reaction to achieve the synthesis of 1-(piperidin-2-
yl)propan-2-one and 1-(pyrrolidin-2-yl)propan-2-one in excellent
yields. The products thus obtained have the potential to be very
useful synthetic precursors for 2-substituted piperidine alkaloids
such as coniine, pelletrine, sedridine, and allosedridine and 2-sub-
stituted pyrrolidine alkaloids such as hygrine, norhygrine, and
hygroline (Fig. 1).3 The reaction is based on the proline catalyzed
three component asymmetric Mannich reaction reported by List
et al.4 One-pot three component Mannich reactions have been used
for the effective generation of amino ketones, which are further
transformed to alkaloids, sugar derivatives, amino acids, and amino
alcohols.5 Multicomponent reactions in general have received
recent attention in synthetic organic chemistry for providing sim-
pler and milder procedures to synthesize complex products along
with the added advantages of atom efficiency and waste reduc-
tion.6 Organocatalytic Mannich reactions leading to asymmetric7
O
OH
OH
N
H
N
H
N
H
N
H
(+)Coniine
(-)Pelletierne
(+)Allosedridine
(+)Sedridine
O
O
OH
OH
N
H
N
N
N
(-)Norhygrine
(-)Hygrine
(-)Hygroline
(-)Pseudohygroline
Figure 1. 2-Substituted piperidine and pyrrolidine alkaloids.
and racemic8 products have thus become an active area of
research.9
We assumed that a proline catalyzed three component reaction
of 5-bromopentanal, a primary amine and acetone could result in
an organocatalytic Mannich reaction followed by a cyclization
through nucleophilic attack of the secondary amine on the bro-
mide to yield 2-substituted piperidine derivatives. Accordingly,
when 5-bromopentanal (1 equiv), p-anisidine (1 equiv), and ace-
tone (1 equiv) were treated with proline (10 mol %) in CH2Cl2
(30 °C), the piperidine derivative, 1 was obtained albeit in low yield
(6%, Scheme 1). However, the yield increased substantially (78%),
on using triethylamine (1 equiv) to neutralize the HBr generated
during the course of the reaction (Scheme 1). This is the first
Letter of an organocatalytic Mannich reaction, followed by
cyclization to give piperidine derivatives.
⇑
Corresponding author.
E-mail address: rameshr@iitk.ac.in (R. Ramapanicker).
http://dx.doi.org/10.1016/j.tetlet.2015.03.001
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

2024
S. Chacko, R. Ramapanicker / Tetrahedron Letters 56 (2015) 2023–2026
Table 1
H2N
O
Br
CHO
Role of solvents in the one-pot Mannich reaction and cyclization
+
+
OMe
Entry
Solvent
Time
Yield (%)
1
2
3
4
5
6
7
8
DMF
DMSO
CH3CN
THF
CH2Cl2
CHCl3
C6H5CH3
CH3OH
C2H5OH
(CH3)3COH
H2O/brine
Neat
24
24
24
24
8
10
24
3
3
4
24
18
0
6
0
CH2Cl2
L-proline
0
78
81
63
99
91
85
0
O
N
9
10
11
12
75
OMe
1
Yield = 6% without any base and
78% (on using 1 equiv Et3N)
(L-proline, Et3N, 30 °C), in different solvents (Table 1). It was
observed that polar aprotic solvents such as DMSO, DMF, CH3CN,
and THF gave extremely poor results, while relatively nonpolar sol-
vents such as CH2Cl2, CHCl3, and toluene resulted in good yields.
Protic solvents such as CH3OH, C2H5OH, and (CH3)3COH yielded
the best results and the reaction proceeded quantitatively in
CH3OH. However, the reaction did not work, when performed
using H2O/brine as the solvent. Doing the reaction neat, but with
an equivalent of Et3N yielded 1 in 75% yield. However, in no
solvents did the reaction work with stereoselectivity and all of
the reactions yielded 1 as a racemic mixture.
Scheme 1. One-pot three component reaction leading to 2-substituted piperidine
derivatives.
The substantial increase in yields of the reaction in the presence
of equivalent amount of triethylamine was a possible indication of
a base catalyzed reaction without the involvement of proline in the
catalysis. However, when the reaction was carried out with tri-
ethylamine (2 equiv) and in the absence of proline, even trace
amount of 1 was not formed. This has confirmed the role of proline,
suggestive of an organocatalytic pathway for the reaction. It is
assumed that the reaction proceeds through the formation of an
enamine derived from acetone and proline, which undergoes a
Michael reaction with the imine formed from p-anisidine and 5-
bromopentanal to give the iminium ion intermediate A. The inter-
mediate A cyclizes to give a piperidine unit, which on hydrolysis
forms the piperidine derivative 1 (Scheme 2). In the absence of a
base, HBr generated during the reaction maybe interfering with
the reaction, either by protonating the catalyst (proline) or through
acidolysis of the intermediates.
Identifying CH3OH as the best solvent for this reaction, we
carried out the reaction in the presence of various bases (1 equiv,
L-proline, CH3OH, 30 °C) in an effort to achieve stereoselectivity
(Table 2). We observed that there was no reaction in the presence
of inorganic bases such as KOH, K2CO3, NaHCO3, and NaOAc even
after 24 h. The rate and yields of the reaction were substantially
high on using bases such as DBU, DABCO, DMAP, Et3N, and
DIPEA. However, none of the reaction conditions showed any stere-
oselectivity and 1 was isolated as a racemic mixture in all cases.10
We assumed that the use of excess L-proline as a base to neutralize
HBr, we might be able to avoid any base induced loss of stere-
oselectivity. Although the reaction proceeded smoothly in the
Although, the reaction was very high yielding and proceeded
smoothly, no enantioselectivity was observed. Reactions catalyzed
with L-proline and DL-proline proceeded with the same rate and
presence of 1.2 equiv of L-proline and in the absence of any other
gave racemic mixtures of the products as determined by HPLC ana-
lysis and optical rotation measurements. It was interesting to note
that pyrrolidine could not catalyze the reaction and formation of 1
was not observed on using pyrrolidine (10 mol %, Et3N, 30 °C,
CH2Cl2) instead of proline as the catalyst. We assumed that sol-
vents may be playing a substantial role in the catalysis and might
be affecting the rate and stereoselectivity of the reaction. To deter-
mine the role of solvents we performed the reaction as in Scheme 1
base to give 1 in 80% yield, no stereoselectivity was observed.
It was very disappointing that although an ideal catalyst system
for the reaction in terms of conversion could be attained, no selec-
tivity was observed with any of the attempted reaction conditions.
As an effort to achieve enantioselectivity, we carried out the reac-
tion with various proline derivatives (Fig. 2). Although the catalysts
II, III, and IV catalyzed the reaction, no stereoselectivity was
observed. Catalysts I, V, and VI did not result in the formation of
1. While
L-proline (II) provided the best conversion (99%), catalysts
III and IV yielded 1 in 82% and 78% yields, respectively and the
reaction times were longer (7 h). a-Amino acids other than proline
COOH
N
NAr
O
H
O
H2O
Table 2
+
HBr
Role of bases in the one-pot Mannich reaction and cyclization
Entry
Base
Time
Yield (%)
Br
1
2
3
4
5
6
7
8
9
10
KOH
24
24
24
24
6
6
6
3
4
0
0
0
COOH
COOH
N
N
ArNH
K2CO3
NaHCO3
NaOAc
DBU
DABCO
DMAP
Et3N
0
A
45
60
69
99
87
80
Br
CHO
Br
ArNH2
DIPEA
NAr
8
L-Proline
11
—
24
3
Scheme 2. Proposed mechanism for the one-pot Mannich reaction and cyclization.

S. Chacko, R. Ramapanicker / Tetrahedron Letters 56 (2015) 2023–2026
2025
HO
1. CAN,
CH3CN
O
O
O
Pd/C, H2
EtOAc
N
N
N
H
COOH
II
COOH
2. CbzCl,
N
H
I
N
H
N
H
PMP
Cbz
1
3 (84%)
( )pelletrine
(97%)
III
O
OH
OH
TBSO
NaBH4
CH3OH
Pd/C, H2
EtOAc
Ph
Ph
OH
Ph
Ph
OTBS
N
N
N
H
Cbz
Cbz
COOH
N
N
H
N
3
4 (99%)
( )sedridine (49%)
and
( )allosedridine (48%)
H
H
IV
V
VI
Figure 2. Various catalysts used for the one-pot Mannich reaction and cyclization.
1. (CH2SH)2
BF3.Et2O
CH2Cl2
1. CAN,
CH3CN
O
2. Boc2O,
N
N
N
2. NiCl2
NaBH4
H2N
Br
PMP
PMP
Boc
O
1
5 (78%)
N-Boc-( )coniine
+
+
(80%)
CHO
OMe
Scheme 4. Synthesis of ( )pelletrine, ( )sedridine, ( )allosedridine and N-
Boc( )coniine.
CH2Cl2
L-proline
O
group in 3 yielded a 1:1 diastereomeric mixture of the alcohol 4
in quantitative yields. The diastereomers were isolated and the
Cbz group was removed to get ( )sedridine and ( )allosedridine.
Conversion of the keto group in 1 as a dithiolane and its reductive
removal yielded PMP protected coniine derivative 5, which was
deprotected using CAN and treated with Boc anhydride to get ( )-
coniine as the N-Boc derivative in very good yields. It would be
possible to extend the method to synthesize hygroline, pseudohy-
groline, norhygrine, and hygrine from compound 2, using the same
synthetic transformations.
In conclusion, we have developed an efficient and simple pro-
line catalyzed one-pot three component Mannich reaction, which
proceeds through a cyclization reaction to give piperidine and
pyrrolidine derivatives under solvent and solvent free conditions
at room temperature. The methodology provides one of the short-
est syntheses of pelletrine, sedridine, allosedridine, and coniine
classes of alkaloids. The strategy can be extended to the synthesis
of hygroline, pseudohygroline, norhygrine, and hygrine. The forma-
tion of racemic products may be due to interference by HBr or the
protonated tertiary amine with hydrogen bonding between the
catalyst and the substrate, which is required for stereoinduction.
We believe that the methodology requires further analysis with
various other organocatalysts and that it could be improved to
develop asymmetric versions of the same.
N
OMe
2 (97%)
Scheme 3. One-pot synthesis of 2-substituted pyrrolidine derivative 2.
have also been shown to induce stereoselectivity in organocatalyt-
ic reactions.11 Our efforts to carry out the reaction with
L-serine,
L-
threonine, L-isoleucine, L-leucine, L-glutamic acid, and L-aspartic
acid were unsuccessful. We also attempted to induce selectivity
on the reaction by performing the reaction at lower temperatures.
Carrying out the reaction at lower temperatures with L-proline
reduced the reaction rate considerably and no selectivity was
observed. At À50 °C, the reaction proceeded to give only 41% of 1
as a racemic mixture after 24 h. We tried using other ketones such
as acetophenone and dihydroxyacetone instead of acetone as the
ketone equivalent. While no reaction was observed with acetophe-
none, dihydroxyacetone yielded a complex reaction mixture.
When 4-bromobutanal was used as the bromo aldehyde
equivalent, the reaction proceeded smoothly to give the pyrro-
lidine derivative 2 in excellent yields (Scheme 3), but with no
stereoselectivity. However, we did not observe any formation of
the 4- or 7-membered analogues when the reaction was carried
out with 3-bromopropanal and 6-bromohexanal, respectively.
Although these reactions failed to provide any stereoselectivity
under the conditions studied, they remain to be a very useful
method for the preparation of 2-substituted pyrrolidines and
piperidines. This is more so as the anisole ring attached to 1 and
2 can easily be cleaved using ceric ammonium nitrate (CAN). We
strongly believe that it will be possible to perform these reactions
asymmetrically through a more thorough screening of various
organocatalysts or an asymmetric induction could be achieved
using substituted aldehyde derivatives with adjacent chiral centers
to the carbon bearing bromine. The utility of these reactions is
demonstrated by performing the synthesis of piperidine based
Acknowledgments
The authors thank Department of Science and Technology,
Ministry of Science and Technology for financial support (grant
number: SR/FT/CS-12/2011). S.C. thanks the Council of Scientific
and Industrial Research, New Delhi for Senior Research Fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.03.
001.
References and notes
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1-(1-(4-Methoxyphenyl)piperidin-2-yl)propan-2-one (1): Column chromato-
graphy (95:5 petroleumether/EtOAc); yellow oil (0.245 g, 99%); IR (thin film):
2932, 1711, 1509, 1243 cmÀ1 1H NMR (CDCl3, 500 MHz): d = 6.91 (d, 2H,
;
J = 9.15 Hz), 6.80 (d, 2H, J = 9.2 Hz), 3.95–3.94 (m, 1H), 3.74 (s, 3H), 2.99–2.98 (m,
1H), 2.89–2.88 (m, 1H), 2.53–2.52 (m, 1H), 2.43–2.41 (m, 1H), 1.97 (s, 3H), 1.86–
1.84 (m, 1H), 1.71–1.70 (m, 1H), 1.66–1.49 (m, 4H) ppm; 13C NMR (CDCl3,
125 MHz): d = 208.2, 154.4, 144.9, 121.5, 114.4, 55.5, 54.4, 48.6, 43.0, 30.8, 30.1,
26.0, 20.6 ppm; HRMS (ES): m/z calcd for C15H21NO2 [MH+]: 248.1651, found:
248.1652.
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