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

Article abstract of DOI:10.1055/s-0028-1083182

The diastereoselective pot, atom, and step economic (PASE) synthesis of highly functionalized piperidines is reported. The procedure simply involves mixing methyl acetoacetate, two equivalents of aldehyde and two equivalents of aniline together in the presence of indium(III) chloride. In most cases the piperidine precipitates out of solution. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083182

3530
PRACTICAL SYNTHETIC PROCEDURES
Pot, Atom, and Step Economic (PASE) Synthesis of Highly Substituted
Piperidines: A Five-Component Condensation
PASE Synthe
s
a
is of Piper
i
u
dines l A. Clarke,* Andrey V. Zaytsev, Adrian C. Whitwood
Department of Chemistry, University of York, Heslington, York, North Yorks YO10 5DD, UK
Fax +44(1904)432516; E-mail: pac507@york.ac.uk
PSP
Received 15 April 2008
No135
Abstract: The diastereoselective pot, atom, and step economic (PASE) synthesis of highly functionalized piperidines is reported. The pro-
cedure simply involves mixing methyl acetoacetate, two equivalents of aldehyde and two equivalents of aniline together in the presence of
indium(III) chloride. In most cases the piperidine precipitates out of solution.
Key words: piperidines, PASE, one pot, multicomponent
X
X
O
O
HN
HN
N
NH2
MeO2C
MeO
1
MeO2C
InCl3
X
CHO
MeCN
N
CHO
Y
X
Y
Y
2
3
Y
Y
X
Scheme 1
the b-keto ester’s a-carbon by the formation of an enam-
ine derivative (Scheme 1). We hoped that it may prove
Introduction
Functionalized piperidines and their derivatives are im- possible to develop a one-pot, multicomponent reaction
portant pharmacophores which are present in many phar- which coupled the in situ formation of the enamine of the
maceuticals and many molecules in clinical and pre- b-keto ester with formation of an imine and sequential
clinical trials.1 Piperidines also occur with great regularity condensation of the enamine with the aldehyde (Knoeve-
in the natural product arena and many of these natural nagel reaction), followed by condensation with the imine
products possess promising pharmaceutical potential. (Mannich reaction) and cyclization (Michael reaction) to
Consequently a huge amount of effort has been directed at form the piperidine. If successful this would generate the
their construction by synthetic chemists the world over.2 desired piperidine in a pot, atom, and step economic man-
We recently reported the Pot, Atom, and Step Economic ner. A survey of the literature indicated that indium(III)
(PASE) synthesis of functionalized tetrahydropyran-4- chloride was efficient at promoting imine formation,5
ones.3 This involved the condensation of diketene with an Mannich reactions,5 Knoevenagel reactions,6 and Michael
equivalent of two different aldehydes under the promotion reactions,7 so this was chosen as the Lewis acid.
of a Lewis acid, all in one pot. With the success in apply-
We initially focused on the reaction of methyl acetoace-
ing a PASE approach to the synthesis of THPs, we wished
tate, aniline, and benzaldehyde. Mixing the pre-formed
to investigate the possibility of extending this methodolo-
enamine 1 (X = H), the pre-formed imine 2 (Y = H) in
acetonitrile with benzaldehyde and indium(III) chloride
gy to the synthesis of highly functionalized piperidines.4
While our work on the synthesis of THPs used diketene as (33 mol%) led to the formation of 3 (X = Y = H) in 46%
a b-keto ester derivative, we reasoned that the synthesis of yield. Piperidine 3 (X = Y = H) could also be formed in
piperidines may grant us the opportunity to use a b-keto 44% yield by mixing the pre-formed Knoevenagel adduct
ester itself. Our idea was to increase the nucleophilicity of of methyl acetoacetate and benzaldehyde with imine 2
(X = H) in acetonitrile with indium(III) chloride (33
mol%). Gratifyingly, a simpler procedure was developed
that involved mixing methyl acetoacetate, aniline (2
equiv), and benzaldehyde (2 equiv) with indium(III) chlo-
SYNTHESIS 2008, No. 21, pp 3530–3532
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083182; Art ID: M10208SS
x
x.
x
x
.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
PASE Synthesis of Piperidines
3531
ride (33 mol%) in acetonitrile. This furnished piperidine 3 substituted in the ortho-position then the yields of piperi-
(X = Y = H) in 60% yield.
dine formed were low (entries 7 and 11), probably due to
increased steric congestion around the carbonyl group.
Other points of note were that in the cases of aniline/
4-tolualdehyde (entry 3) and aniline/benzaldehyde (entry
1), hydrolysis of the final enamine-piperidine occurred to
Scope and Limitations
A variety of piperidines were formed using this procedure some extent yielding the enol-piperidines in 3% and 11%,
(Table 1).
respectively. The stereochemistry of the 2,6-substituents
was determined as trans by single crystal X-ray analysis
(Figure 1) and the lack of a NOE between H2 and H6,
which would have been expected if the relative stereo-
chemistry of these substituents were cis. It was also found
that certain aldehyde–aniline combinations did not form
any piperidine, as the reaction stopped due to the precipi-
tation of an insoluble imine (Table 2).
Table 1 Piperidines Prepared
Ar2
NH
O
O
InCl3
MeO2C
Ar1
+ 2 Ar1CHO + 2 Ar2NH2
MeCN
MeO
N
Ar2
Ar1
We attempted to extend this procedure to the formation of
piperidines with alkyl substituents in the 2,6-positions.
Use of aliphatic aldehydes (benzyloxy)acetaldehyde, bu-
tanal, and isobutyraldehyde with both aniline and anisi-
3
Entry Ar1CHO
Ar2NH2
Ph
Product
3a
Yield (%)
60
1
2
Ph
4-MeOC6H4
4-MeC6H4
3-MeC6H4
4-O2NC6H4
4-MeO2CC6H4
2-MeC6H4
4-MeC6H4
3-MeC6H4
Ph
Ph
3b
3c
52
Table 2 Insoluble Imines
Ar1
3
Ph
50
N
Ar2
InCl3
O
4
Ph
3d
3e
64
+ 2 Ar1CHO + 2 Ar2NH2
2, insoluble
+
MeO2C
MeCN
5
Ph
52
Ar1CHO
6
Ph
3f
24
+
NHAr2
7
Ph
3g
16
MeO2C
1
8
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
3h
3i
45
Entry Ar1CHO
Ar2NH2
Product Yield (%)
9
48
10
11
12
13
3j
74
1
2
3
4
4-MeOC6H6
4-MeOC6H6
4-MeOC6H6
4-MeOC6H6
4-MeOC6H6
2a
2b
2c
2d
59
42
58
83
2-MeC6H4
3-F3CC6H4
4-MeOC6H4
3k
3l
27
4-O2NC6H4
2-naphthyl
57
3m
52
4-MeO2CC6H4
We chose a number of electronically and sterically differ-
ent aldehydes and elected to react these with either
aniline, p-anisidine, p-chloroaniline, or p-nitroaniline,
which covered the range of electronically activated
through to electronically deactivated aromatic amines.
The general trends in the series of anilines was not surpris-
ing, with p-anisidine reacting the fastest. In general when
p-anisidine was used (entries 8–12) the reactions were
over in 24 hours rather than the usual 48 hours as was the
case when aniline was used (entries 1–7). When p-chloro-
aniline was used (entry 13) the reaction was much slower
and took 7 days to produce a 52% yield of the piperidine.
p-Nitroaniline did not react at all. This trend undoubtedly
reflects the relative nucleophilicities of the aniline nitro-
gen’s lone pair, and hence the relative abilities to form the
imine 2 and the enamine 1, as well as the nucleophilicity
of the resulting enamine 1. While the nature of the elec-
tronic substitution on the aldehyde did not seem to have a Figure 1 ORTEP diagram of the X-ray crystal structure of 3a (ADP
shown at 50%)
great effect on the rate of the reaction, if the aldehyde was
Synthesis 2008, No. 21, 3530–3532 © Thieme Stuttgart · New York

3532
P. A. Clarke et al.
PRACTICAL SYNTHETIC PROCEDURES
HRMS (ESI): m/z [M + H]+ calcd for C33H33N2O4: 521.2435; found:
521.2438.
dine led in all cases to multiple and intractable products.
We believe that this was due to the propensity for aliphatic
aldehydes to favour enamine formation rather than imine Anal. Calcd for C32H32N2O4: C, 81.12; H, 6.60; N, 5.73. Found: C,
81.04; H, 6.62; N, 5.70.
formation and, that these enamines formed preferentially
to the desired enamine of the b-keto ester and then con-
Methyl 1,2,5,6-Tetrahydro-1-(4-methoxyphenyl)-4-(4-
densed with any remaining aldehyde before the desired pi-
methoxyphenylamino)-2,6-bis(4-tolyl)pyridine-3-carboxylate
(3h); Typical Procedure
peridine forming reaction occurred.
A round-bottom flask was charged with MeCN (4 mL) and to this
was added methyl acetoacetate (0.232 g, 2.0 mmol), p-anisidine
(0.492 g, 4.0 mmol), p-tolualdehyde (0.48 g, 4.0 mmol), and InCl3
(0.148 g, 0.67 mmol). The mixture was stirred at r.t. for 24 h. After
this time the product was isolated by filtration of the precipitate and
washing with a small amount of MeCN. The product was recrystal-
lized (CH2Cl2–MeOH) to yield piperidine 3h as a white solid; yield:
Additionally we attempted to form piperidines using ben-
zylamine rather than an aniline. However, in this instance
benzylamine hydrochloride precipitated from the reaction
mixture. This is probably due to the higher basicity of
benzylamine compared to aniline, and hence salt forma-
tion with any HCl present in the indium(III) chloride.
0.495 g (45%); mp 203 °C.
In conclusion we have developed straightforward and ro-
bust procedure for the one-pot, multicomponent forma-
tion of highly substituted piperidines from commercially
available starting materials. The procedure is applicable to
a wide range of aromatic aldehydes and anilines and in
general the product precipitated from the reaction solvent.
Sadly, this procedure is incompatible with either alkyl-
substituted aldehydes or alkylamines. The attractive fea-
tures of this chemistry are that all the reagents can be
stirred together in one pot and, in the majority of cases, the
products can be collected by filtration after 24 hours or 48
hours.
IR (KBr): 3446, 3247, 2949, 2917, 1655, 1611, 1512, 1264, 1248,
786 cm–1.
1H NMR (400 MHz, CDCl3): d = 10.08 (s, 1 H, NH), 7.16 (d, J =
7.9 Hz, 2 H, Ar), 7.01–7.00 (m, 6 H, Ar), 6.63 (d, J = 9.2 Hz, 2 H,
Ar), 6.59 (d, J = 8.8 Hz, 2 H, Ar), 6.42 (d, J = 9.2 Hz, 2 H, Ar), 6.26
(s, 1 H, H2), 6.19 (d, J = 8.8 Hz, 2 H, Ar), 4.99 (br dd, J = 5.6, 2.8
Hz, 1 H, H6), 3.86 (s, 3 H, COOCH3), 3.73 (s, 3 H, OCH3), 3.64 (s,
3 H, OCH3), 2.76 (dd, J = 15.3, 5.6 Hz, 1 H, H5a), 2.61 (dd, J = 15.3,
2.8 Hz, 1 H, H5b), 2.33 (s, 3 H, CH3), 2.30 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 168.6 (C, COOCH3), 157.7 (C),
157.0 (C), 150.7 (C), 141.6 (C), 141.2 (C), 140.2 (C), 135.6 (C),
130.7 (C), 129.2 (CH), 128.8 (CH), 127.8 (CH), 126.7 (CH), 126.4
(CH), 114.4 (CH), 113.9 (CH), 113.9 (CH), 97.0 (C, C3), 57.9
(CH), 55.6 (CH3), 55.4 (CH), 55.4 (CH3), 50.8 (CH3), 32.6 (CH2,
C5), 21.1 (CH3), 21.0 (CH3).
Reagents and solvents were used as purchased from the suppliers.
The MeCN was used directly from the bottle and was not dried, the
InCl3 was used directly without recrystallization. The reactions
were run without an inert gas shield. Full spectroscopic and physical
data for the other piperidines prepared can be found in the support-
ing information.
HRMS (ESI): m/z [M + H]+ calcd for C35H37N2O4: 549.2748; found:
549.2744.
Anal. Calcd for C35H36N2O4: C, 76.72; H, 6.61; N, 5.11. Found: C,
76.34; H, 6.59; N, 5.07.
Methyl 1,2,5,6-Tetrahydro-2,6-bis(4-methoxyphenyl)-1-phe-
nyl-4-(phenylamino)pyridine-3-carboxylate (3b); Typical
Procedure
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
A round-bottom flask was charged with MeCN (4 mL) and to this
was added methyl acetoacetate (0.232 g, 2.0 mmol), aniline (0.37 g,
4.0 mmol), p-anisaldehyde (0.54 g, 4.0 mmol), and InCl3 (0.148 g,
0.67 mmol). The mixture was stirred at r.t. for 48 h. After this time
the solvent was removed and the residue was submitted to flash col-
umn chromatography (petroleum ether–EtOAc, 85:15). The prod-
uct was recrystallized (CH2Cl2–MeOH) to yield piperidine 3b as a
white solid; yield: 0.543 g (52%); mp 146 °C.
Acknowledgment
We thank the EPSRC for funding under the ‘Greener’ chemistry in-
itiative (EP/C523970/1), AstraZeneca for an unrestricted research
award (PAC) and Mr. Andrew Reeder for the collection of physical
data of 3b and 3h.
IR (KBr): 3446, 2949, 2837, 1653, 1610, 1593, 1505, 1498, 1247,
1189, 1071, 1033 cm–1.
References
1H NMR (400 MHz, CDCl3): d = 10.20 (s, 1 H, NH), 7.14 (d, J =
8.5 Hz, 2 H, Ar), 7.05–6.98 (m, 7 H, Ar), 6.73 (d, J = 8.6 Hz, 4 H,
Ar), 6.61 (t, J = 7.2 Hz, 1 H, Ar), 6.45 (d, J = 8.3 Hz, 2 H, Ar), 6.29–
6.27 (m, 3 H, Ar and H2), 5.01 (br dd, J = 5.5, 2.5 Hz, 1 H, H6), 3.84
(s, 3 H, COOCH3), 3.71 (s, 3 H, OCH3), 3.70 (s, 3 H, OCH3), 2.77
(dd, J = 14.9, 5.5 Hz, 1 H, H5a), 2.67 (dd, J = 14.9, 2.5 Hz, 1 H,
H5b).
(1) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679.
(2) For recent reviews on the synthesis of piperidines see:
(a) Laschat, S.; Dickner, T. Synthesis 2000, 1781.
(b) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding,
D. R. Tetrahedron 2003, 59, 2953. (c) Buffat, M. G. P.
Tetrahedron 2004, 60, 1701.
(3) Clarke, P. A.; Santos, S.; Martin, W. H. C. Green Chem.
13C NMR (100 MHz, CDCl3): d = 168.6 (C, COOCH3), 158.6 (C),
158.0 (C), 156.3 (C), 147.0 (C), 137.9 (C), 135.8 (C), 134.6 (C),
128.8 (CH), 128.8 (CH), 127.7 (CH), 127.4 (CH), 125.7 (CH),
115.6 (CH), 116.0 (CH), 113.9 (CH), 113.5 (CH), 112.9 (CH), 98.1
(C, C3), 57.5 (CH), 55.3 (CH3), 55.2 (CH3), 54.5 (CH), 51.0 (CH3),
33.7 (CH2, C5).
2007, 9, 438.
(4) Clarke, P. A.; Zaytsev, A. V.; Whitwood, A. C. Tetrahedron
Lett. 2007, 48, 5209.
(5) Loh, T.-P.; Wei, L.-L. Tetrahedron Lett. 1998, 39, 323.
(6) Prajapati, D.; Gohain, M. Beilstein J. Org. Chem. 2006, 2,
11; http://bjoc.beilstein-journals.org/.
(7) Loh, T.-P.; Wei, L.-L. Synlett 1998, 975.
Synthesis 2008, No. 21, 3530–3532 © Thieme Stuttgart · New York