Pot, atom and step economic (PASE) synthesis of highly functionalized piperidines: a five-component condensation

Article abstract of DOI:10.1016/j.tetlet.2007.05.141

The diastereoselective pot, atom and step economic (PASE) synthesis of highly functionalized piperidines has been realized. The procedure simply involves mixing methyl acetoacetate, 2 equiv of aldehyde and 2 equiv of aniline together in the presence of InCl₃. In most cases the piperidine precipitates out of solution.

Full text of DOI:10.1016/j.tetlet.2007.05.141

Tetrahedron Letters 48 (2007) 5209–5212
Pot, atom and step economic (PASE) synthesis of
highly functionalized piperidines: a five-component condensation
Paul A. Clarke,* Andrey V. Zaytzev and Adrian C. Whitwood
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
Received 19 April 2007; revised 15 May 2007; accepted 24 May 2007
Available online 31 May 2007
Abstract—The diastereoselective pot, atom and step economic (PASE) synthesis of highly functionalized piperidines has been real-
ized. The procedure simply involves mixing methyl acetoacetate, 2 equiv of aldehyde and 2 equiv of aniline together in the presence
of InCl3. In most cases the piperidine precipitates out of solution.
Ó 2007 Elsevier Ltd. All rights reserved.
Functionalized piperidines occur with great regularity in
the natural product arena and as important units in
pharmaceuticals. Consequently, a huge amount of effort
has been directed towards developing ever more efficient
methods to synthesize them.1 For example, over the last
ten years thousands of piperidine-containing com-
pounds have been entered into preclinical and clinical
trials.2 We have recently become interested in the devel-
opment of ‘Greener’ methods for the synthesis of organ-
ic molecules of medium complexity, and have reported
the pot, atom and step economic (PASE) synthesis of
highly substituted tetrahydropyran-4-ones.3 Pot, atom4
and step5 economy aims to combine as many transfor-
mations as possible into a single reaction vessel, without
the need for work-up and isolation of intermediate com-
pounds. Ideally, all the reagents should also be incorpo-
rated into the final product. This should lead to a
reduction in the amount of waste generated by a syn-
thetic route due to the minimization of by-products,
reaction and extraction solvents, silica gel for chromato-
graphic purification of intermediate compounds and
alike. Process chemists in industry have long been apply-
ing these criteria to synthetic routes and during our dis-
cussions with them we became aware of a need to extend
our PASE synthesis of THPs to the synthesis of func-
tionalized piperidines. This Letter reports our success
at developing a five-component, pot, atom and step eco-
nomic, diastereoselective synthesis of highly functional-
ized piperidines.
Our initial strategy was similar to the one we had devel-
oped for our synthesis of THPs,3,6 that is, disconnection
of the target piperidine to a b-ketoester derivative and
two aldehyde derived reaction partners (Scheme 1). In
this instance we envisaged using an imine as one of the
reaction partners and an aldehyde as the other, giving
us the potential for diversification at the greatest num-
ber of positions around the piperidine ring.
We initially considered using diketene as the b-ketoester
derivative, however, problems with supply and the haz-
ards associated with its use prompted us to consider
other alternatives. One interesting possibility was to
use a b-ketoester itself and to increase the nucleophilic-
ity of its a-carbon by formation of the enamine deriva-
tive. We rationalized that it may then be possible to
develop a multi-component reaction which coupled the
in situ formation of the enamine of the b-ketoester, with
formation of an imine and the sequential condensation
of the enamine to the aldehyde and then the imine,
O
"
"
O
O
O
O
e.g.
RO
RO2C
R3
Keywords: Piperidines; PASE; One-pot; Multi-component.
O
O
N
R2
R1
*
Corresponding author. Tel.: +44 01904 432614; e-mail: pac507@
R2NH2
R1
R3
york.ac.uk
Corresponding author for information concerning X-ray crys-
tallography.
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.141

5210
P. A. Clarke et al. / Tetrahedron Letters 48 (2007) 5209–5212
PhNH2
PhNH2
O
A
B
F
O
COOMe
COOMe
PhCHO
1
Ph
InCl3 (33 mol%),
MeCN, RT
InCl3 (33 mol%),
MeCN, RT
Ph
PhCHO
2
N
PhNH2
Ph
60%
44%
NHPh
PhNH2
O
E
O
COOMe
NHPh
HCl
3
InCl3 (33 mol%),
K2CO3
COOMe
COOMe
O
Ph
PhCHO
o
1
Ph
MeCN
RT
(10 mol%), 3A MS,
Ph
Ph
N
2
N
Ph
dry MeCN, RT
Ph
4i
2
N
Ph
0%
19%
Ph
PhNH2
O
C
D
O
O
NHPh
0%
46%
HCl
InCl3 (33 mol%),
MeCN, RT
COOMe
COOMe
3
Ph
o
1
PhCHO
Ph
(10 mol%), 3A MS,
dry MeCN, RT
2
Ph
N
2
N
Ph
Ph
Scheme 2.
forming the desired piperidine in a pot, atom and step
economic fashion. To assess the feasibility of this
approach, we conducted a few investigative studies on
the reactivity of the potential reacting partners (Scheme
2).
of the 2,6-phenyl groups in 4i was confirmed as trans-
by single crystal X-ray analysis (Fig. 1). These studies
provided proof of concept that a five-component conden-
sation reaction was indeed a viable approach to the
PASE synthesis of highly functionalized piperidine
rings.
We elected to use InCl3 as a Lewis acid promoter as it
had been used previously to catalyze Knoevenagel reac-
tions,7 Mannich-like reactions and imine formation8 and
Michael reactions.9 Initially we pre-formed Knoevena-
gel adduct 1 and imine 2 and mixed them with aniline
in the presence of InCl3 and we were pleased that the de-
sired piperidine was formed in a reasonable yield (A).
However, when this reaction was repeated in the pres-
ence of anhydrous potassium carbonate no reaction
took place (B). This led us to speculate that the reaction
was actually promoted by trace amounts of HCl present
in the InCl3, although when we ran the reaction using a
solution of HCl in 1,4-dioxane no product was formed
(C). We next examined the reaction of pre-formed
enamine 3 with benzaldehyde and imine 2 in the presence
of InCl3. In this case the desired piperidine 4 was again
formed in a moderate yield (D). The Brønsted acid
promoted reaction was also investigated, and in this
instance a 19% yield of piperidine 4i was recovered from
the reaction (E). Given the success of routes A and D, we
investigated the in situ formation of both the enamine
and the imine and their condensation/cyclization reac-
tions, which is in effect a five-component condensation
reaction. We were delighted to find that not only did
this reaction yield piperidine 4i, but it did so in an in-
creased yield of 60% (F). The relative stereochemistry
We suggest that a plausible mechanism for the forma-
tion of piperidine 4i involves the Lewis acid promoted
Figure 1. ORTEP diagram of the X-ray crystal structure of 4i (ADP
shown at 50%).

P. A. Clarke et al. / Tetrahedron Letters 48 (2007) 5209–5212
5211
Table 2.
NHPh
NHPh
NHPh
CO2Me
Ph
O
O
O
CO2Me
Ph
CO2Me
Ph
Ar2
NPh
InCl3 (33 mol%)
MeCN, RT
MeO
N
Ph
N
5
6
4i
Ph
Ph
Ar1
Ar2NH2
2 x
2 x
Ar1
Scheme 3.
Ar1CHO
Ar2NH2
Yield (%)
formation of imine 2 and enamine 3, enamine 3 can then
undergo a ‘Knoevenagel-like’ condensation with benzal-
dehyde to form the iminium ion–Knoevenagel product
5. Loss of a proton and tautomerisation of the imine
to the enamine generates a diene 6, which can undergo
either an aza-Diels–Alder cyclization or a tandem Man-
nich–Michael reaction to furnish piperidine 4 (Scheme
3).
4-CH3OC6H4
4-NO2C6H4
2-Naphth
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
59
42
58
83
4-MeO2CC6H4
We next investigated the use of the aliphatic aldehydes,
benzyloxyacetaldehyde, butanal and iso-butyl aldehyde
with both aniline and p-anisidine, but in all cases multi-
ple products arose. This can be attributed to a number
of reasons: (i) the propensity for aliphatic aldehydes to
favour enamine formation rather than imine formation
and, (ii) the enamines of the aliphatic aldehydes forming
preferentially to the enamine of the b-ketoester and then
condensing with any remaining aldehyde before the
desired reaction occurs. Additionally, we investigated
the use of benzylamine instead of aniline; however, only
the HCl salt of the amine was isolated, presumably due
to the more basic nature of aliphatic amines compared
to anilines.
Given the success of these preliminary studies, we
decided to investigate the scope of the reaction and the
results are displayed in Table 1.10 Some interesting
observations were made during these studies. p-Anisi-
dine reacted faster than aniline, and in general reactions
were complete within 24 h rather than 48 h. While 4-
chloroaniline reacted very slowly and took 7 days to
generate a 52% yield of the piperidine product, p-nitro-
aniline did not react at all. This is undoubtedly due to
the reduced nucleophilicity of these anilines compared
to p-anisidine and aniline. A wide range of aromatic
aldehydes could be used in the reaction. Yields were
found to be lower when 2-substituted aldehydes were
employed and this is probably due to steric effects. In
the cases of aniline/4-methylbenzaldehyde 4g and ani-
line/benzaldehyde 4i, hydrolysis of the final enamine-
piperidine occurred to some extent yielding the enol-pip-
eridines in 3% and 11%, respectively. It was also found
that certain aldehyde–aniline combinations did not form
any piperidine, as the reaction stopped due to the
precipitation of an insoluble imine (Table 2).
In summary, we have developed a five-component con-
densation reaction for the formation of highly substi-
tuted piperidines, which is pot, atom and step
economic. In general the yields are good and the piper-
idine product precipitates from the reaction allowing for
easy isolation. Work is underway to extend the proce-
dure to the synthesis of piperidines using different alde-
hyde and imine components in order to form piperidines
with different 2,6-substituents and also to the asymmet-
ric synthesis of such compounds. These studies will be
reported in due course.
Table 1.
Acknowledgements
O
O
O
NHAr2
We thank the EPSRC for funding under the ‘Greener’
chemistry initiative (EP/C523970/1) and AstraZeneca
for an unrestricted research award (P.A.C.).
MeO2C
Ar1
InCl3 (33 mol%)
MeCN, RT
MeO
Ar2NH2
2 x
N
Ar2
Ar1
2 x
Ar1
4
Ar1CHO
Ar2NH2
Yield (%)
References and notes
a
b
c
d
e
f
4-CH3C6H4
3-CH3C6H4
Ph
2-CH3C6H4
3-CF3C6H4
4-MeOC6H4
4-CH3C6H4
3-CH3C6H4
Ph
4-NO2C6H4
2-CH3C6H4
4-MeO2CC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
45
48
74
27
57
52
50
64
60
52
16
24
52
1. For recent reviews on the synthesis of piperidines see:
Laschat, S.; Dickner, T. Synthesis 2000, 1781; Weintraub,
P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953; Buffat, M. G. P. Tetrahedron
2004, 60, 1701.
2. Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679.
3. Clarke, P. A.; Santos, S.; Martin, W. H. C. Green Chem.
2007, 9, 438.
4. (a) Trost, B. M. Science 1991, 254, 1471; (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
5. (a) Wender, P. A.; Bi, F. C.; Gamber, G. G.; Gosselin, F.;
Hubbard, R. D.; Scanio, M. J. C.; Sun, R.; Williams, T. J.;
Zhang, L. Pure Appl. Chem. 2002, 74, 25; (b) Wender, P.
g
h
i
j
k
l
m
4-ClC6H4

5212
P. A. Clarke et al. / Tetrahedron Letters 48 (2007) 5209–5212
A.; Handy, S. T.; Wright, D. L. Chem. Ind. (London)
precipitation occurred, the solvent was evaporated and the
residue was purified by flash column chromatography on
silica gel (Et2O–petrol). Compound 4i mmax (cmÀ1) (KBr)
3446, 2918, 2850, 1662, 1588, 1503, 1254, 1078; dH
(500 MHz, CDCl3) 10.26 (1H, s, NH), 7.33–7.25 (7H, m,
Ar), 7.21 (1H, m, Ar), 7.17 (2H, d, J 7.5, Ar), 7.10–7.05
(5H, m, Ar), 6.61 (1H, t, J 7.0, Ar), 6.53 (2H, d, J 8.5, Ar),
6.46 (1H, s, 2-H), 6.30–6.28 (2H, m, Ar), 5.15 (1H, m, 6-
H), 3.86 (3H, s, Me), 2.88 (1H, dd, J 15.3 and 5.8, 5-Ha),
2.77 (1H, dd, J 15.3 and 2.3, 5-Hb); dH (125 MHz, CDCl3)
168.6 (C, COOCH3), 156.3 (C), 146.9 (C), 143.9 (C), 142.7
(C), 137.8 (C), 128.9 (CH), 128.8 (CH), 128.6 (CH), 128.2
(CH), 127.1 (CH), 126.6 (CH), 126.4 (CH), 126.3 (CH),
125.9 (CH), 125.8 (CH), 116.1 (CH), 112.9 (CH), 97.9 (C,
C-3), 58.2 (CH, C-6), 55.1 (CH, C-2), 51.0 (CH3,
COOCH3), 33.6 (CH2, C-5); MS (ES) 461 (M+H+, 12),
386 (8), 280 (34), 182 (100), 150 (10), 121 (23), 106 (36), 94
(31); HRMS (ES) 461.2224 (M+H+) C31H29N2O2 requires
461.2224.
1997, 765; (c) Wender, P. A.; Miller, B. L. In Organic
Synthesis: Theory and Applications; Hudlicky, T., Ed.;
JAI: Greenwich, 1993; Vol. 2, pp 27–66.
6. Clarke, P. A.; Martin, W. H. C.; Hargreaves, J. M.;
Wilson, C.; Blake, A. J. Chem. Commun. 2005, 1061;
Clarke, P. A.; Martin, W. H. C.; Hargreaves, J. M.;
Wilson, C.; Blake, A. J. Org. Biomol. Chem. 2005, 3, 3551.
7. Prajapati, D.; Gohain, M. Beilstein J. Org. Chem. 2006, 2,
11.
8. Loh, T.-P.; Wei, L.-L. Tetrahedron Lett. 1998, 39, 323.
9. Loh, T.-P.; Wei, L.-L. Synlett 1998, 975.
10. General procedure for the PASE synthesis of piperidines:
Methyl acetoacetate (2 mmol), aldehyde (4 mmol) and
aniline (4 mmol) were dissolved in acetonitrile (4 ml) and
InCl3 (0.147 g, 0.67 mmol) was introduced. The reaction
mixture was stirred at room temperature for 24 or 48 h.
The product was isolated by filtration of the precipitate
and washing with a small amount of acetonitrile or, if no