Iodine catalyzed one-pot five-component reactions for direct synthesis of densely functionalized piperidines

Article abstract of DOI:10.1016/j.tet.2010.07.075

A simple and convenient one-pot multicomponent reaction (MCR) has been developed for the synthesis of highly functionalized piperidines catalyzed by molecular iodine. This strategy demonstrated five-component reactions of 1,3-dicarbonyl compounds, amines and aromatic aldehydes in methanol using 10 mol % of iodine at room temperature. This methodology provides an alternative approach for easy access of highly and fully substituted piperidines in moderate to good yields using three readily available starting materials. Notably, this method is mild, cheap, straight forward, applicable to broad range of substrates and environmentally friendly as compared to the existing methods. Synthetic and mechanistic studies are presented here.

Full text of DOI:10.1016/j.tet.2010.07.075

Tetrahedron 66 (2010) 7762e7772
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iodine catalyzed one-pot five-component reactions for direct synthesis
of densely functionalized piperidines
*
Abu T. Khan , Md. Musawwer Khan, Kranthi K.R. Bannuru
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam 781 039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 April 2010
Received in revised form 22 July 2010
Accepted 24 July 2010
Available online 3 August 2010
A simple and convenient one-pot multicomponent reaction (MCR) has been developed for the synthesis
of highly functionalized piperidines catalyzed by molecular iodine. This strategy demonstrated five-
component reactions of 1,3-dicarbonyl compounds, amines and aromatic aldehydes in methanol using
10 mol % of iodine at room temperature. This methodology provides an alternative approach for easy
access of highly and fully substituted piperidines in moderate to good yields using three readily available
starting materials. Notably, this method is mild, cheap, straight forward, applicable to broad range of
substrates and environmentally friendly as compared to the existing methods. Synthetic and mechanistic
studies are presented here.
Keywords:
Heterocycles
Piperidines
Iodine
Ó 2010 Elsevier Ltd. All rights reserved.
1,3-Dicarbonyl compounds
Amines
Aldehydes
1. Introduction
via MCRs using catalysts, such as a combination of L
-proline/TFA,6
bromodimethylsulfonium bromide (BDMS),15a tetrabutylammo-
nium tribromide (TBATB)15b and InCl3.16 The aforesaid methods
have some of the disadvantages such as use of expensive and excess
amount of catalysts and failure in some of the cases to obtain the
desired product. Therefore, there is a need for simple and greener
methods, which are applicable to a broad range of substrates to
access these compounds.
The piperidine and its analogues are widely distributed in many
natural products, biologically active molecules and organic fine
chemicals.1 Some of them also act as therapeutic agents.2 Com-
pounds containing piperidine structural motif exhibit anti-hyper-
tensive,3 anti-bacterial,4 anti-convulsant and anti-inflammatory
activities.5 Recently, Tripathi et al. reported that some of the
substituted piperidines also display antimalarial activity.6 As a re-
sult, a considerable efforts have been made from all over the world
towards the synthesis of this important class of compounds due to
their medicinal properties.7 Some of the synthetic strategies for
their preparation are imino-Diels-Alder reactions,8 aza-Prins-cy-
clizations,9 intramolecular Michael reactions10 and intramolecular
Mannich reaction onto iminium ions.11 An alternative strategy for
the synthesis of functionalized piperidines is using multicompo-
nent reactions (MCRs). Recently, MCRs have emerged as a powerful
synthetic tool in organic synthesis due to their advantages over the
conventional multi-step synthesis.12,13 In addition, MCRs are
eco-friendly, superior atom economic as well as they avoid costly
purification processes and protection-deprotection steps with
minimum synthetic effort and time.14 Therefore, MCRs satisfy some
of the tenets of ‘Green Chemistry’. Literature reveals only a few
methods to synthesis highly functionalized piperidine derivatives
Molecular iodine has emerged as an inexpensive, non-toxic,
non-metallic, readily available and environmentally benign cat-
alyst for various organic transformations, which has been
reviewed recently.17 The current literature reveals that molecular
iodine can be used as an efficient catalyst for a diverse range of
multicomponent reactions18aed as well as synthesis of various
heterocycles.18eeh We conceived that molecular iodine is to be an
ideal Lewis acid for one-pot synthesis of highly substituted pi-
peridine derivatives from aromatic aldehydes, amines and b-keto
esters. Herein, we disclose the synthesis and mechanistic aspects
of densely functionalized piperidine derivatives (1) using MCRs
(Scheme 1).
2. Results and discussion
Initially, the mixture of 4-methylbenzaldehyde (1 mmol), ani-
line (1 mmol) and methyl acetoacetate (1 mmol) in acetonitrile
(5 mL) was treated with 10 mol % of iodine at room temperature.
We obtained a highly functionalized piperidine 1a in 36% yield
* Corresponding author. E-mail address: atk@iitg.ernet.in (A.T. Khan).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.075

A.T. Khan et al. / Tetrahedron 66 (2010) 7762e7772
7763
R2
NH2
CH2CO2R1
NH
N
O
NH2
OR1
R3
O
O
CHO
+
R2
R
OR1
N
I2/THF/reflux
I2/MeOH/rt
R = Me
R3
R3
R3
R = Me
Ref.18a
NH2
I2/MeOH/rt
R = OEt
3
R2
R2
1
R2
NH
O
OR1
O
OEt
R3
2
Scheme 1. Direction of product formation in iodine catalyzed MCRs.
along with unreacted methyl acetoacetate and the product was
characterized from 1H NMR, 13C NMR spectra, HRMS and by ele-
mental analysis. It is quite clear that the product 1a was obtained
via five-component reactions.
other b-keto esters like tert-butyl acetoacetate and allyl aceto-
acetate also provided the corresponding piperidine derivatives 1c
and 1d in good yields (Table 2, entries 3 and 4). From these
observations, we may conclude that the alkoxy (eOR) moiety
For optimization of the amount of catalyst and choosing the
suitable solvent, various trial reactions were investigated with
a combination of 4-methylbenzaldehyde, aniline and methyl
acetoacetate to obtain the best yield of 1a, which is summarized in
Table 1. We have noted that 10 mol % of the catalyst gives the best
result for the formation of product. It has also been observed that
methanol is the best solvents for the present reaction among
various other solvents, such as acetonitrile, dichloromethane,
ethanol and ethyl acetate. For this transformation, ethanol can be
a second choice of solvent. Under solvent-free conditions, the
product was obtained in a moderate yield (48%) that may be due to
lack of effective interaction of reactants with the catalyst in the
absence of solvent.
present in the b-keto ester does not have any significant role in
determining the course of the reaction. However, in case of
diethylmalonate (Table 2, entry 5), yielded the corresponding
b
-amino carbonyl compound (2) under identical reaction condi-
tions. This can be attributed to the lack of enolizable alkyl group
in the -position.
In addition, the effect of an alkyl group was also studied by
varying the substitutents at the -position of the -keto esters. The
b
b
b
reaction of ethyl propionylacetate with 4-chlorobenzaldehyde and
aniline afforded fully substituted piperidine 1e in 42% yield in the
presence of 10 mol % molecular iodine (Table 2, entry 6). Similarly,
the reaction of ethyl butyrylacetate with 4-chlorobenzaldehyde
and aniline also provided the desired piperidine 1f in 36% yield
under similar reaction conditions (Table 2, entry 7). The fully
substituted piperidine derivatives were derivatives not reported
earlier.6,15a,16 From these observations, it is clear that methyl and
ethyl group can be introduced easily at the 5-position of the pi-
Having established the optimal reaction conditions, the mix-
ture of 4-methylbenzaldehyde, aniline and ethyl acetoacetate in
methanol was treated with 10 mol % iodine to obtain the desired
piperidine derivative 1b as shown in Table 2. Similarly, various
peridine ring by choosing a suitable
to incorporate a phenyl group at the 5-position in the piperidine
ring. For this purpose, the required -keto ester (ethyl 3-oxo-4-
phenylbutanoate) was prepared by following the literature pro-
cedure.19 Then it was subjected with 4-chlorobenzaldehyde and
aniline in presence of 10 mol % catalyst under identical reaction
conditions (Table 2, entry 8). Unfortunately, we did not get the
desired piperidine derivative after 48 h of stirring. These in-
vestigations suggest that not only methyl group but any enolizable
b-keto ester. Next, we wanted
Table 1
b
Optimization of reaction conditions for the synthesis of functionalized piperidine 1aa
O
O
NH
O
CHO
+
3
I2
OMe
5
OMe
4
1
Me
2
NH2
6 N
Me
Me
alkyl group present in the b position of b-keto esters, is a necessary
and sufficient condition for the formation of highly substituted
piperidines using MCRs (Table 2).
1a
We proceeded further to investigate the reaction of various ar-
omatic aldehydes having substituents, such as OMe, Cl, Br, F and
NO2 with aniline and methyl acetoacetate under the same reaction
conditions (Table 3, entries 1e8). The reaction time and yield of the
products 1gen are shown in Table 3. The low yields obtained in
case of entries 7 and 8 is caused by: (i) formation of more stable
imine due to extra conjugation in the presence of nitro group,
which is less reactive and (ii) partial or less solubility in methanol.
Unfortunately, some of the aldehydes, such as b-naphthaldehyde
and n-butanal, did not give the corresponding functionalized
piperidines.
We have noted, in some cases, such as benzaldehyde, 4-chloro-
benzaldehyde and 4-nitrobenzaldehyde, a small quantity of
Entry
Solvent
Catalyst (mol %)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
C2H5OH
CH3OH
EtOAc
Neat
No catalyst
5
12
12
12
12
12
10
8
0
52
72
69
60
78
84
62
48
10
20
10
10
10
10
10
12
12
a
Reaction conditions: 4-Methylbenzaldehyde, aniline and methyl acetoacetate
were taken in 2:2:1 ratio at rt.
b
Isolated yields.

7764
A.T. Khan et al. / Tetrahedron 66 (2010) 7762e7772
Table 2
Scope of
b
-keto esters in the formation of product with aromatic aldehydes and amines using iodine as catalysta
R2
R2
NH
N
O
O
O
O
O
R4
NH
O
O
NH2
R4
OR1
CHO
OR1
EtO
OEt
OEt
OEt
R3
R3
R3
R3
I2/MeOH/rt
I2/MeOH/rt
R2
2
R2
1
Entry
1
b
-Keto esters
Time (h)
8
Product
Yieldb (%)
84
O
O
OMe
NH
N
O
OMe
H3C
CH3
1a
2
8
O
O
78
OEt
NH
N
O
OEt
H3C
CH3
1b
3
10
68
O
O
OC(CH3)3
NH
N
O
OC(CH3)3
CH3
H3C
1c
66
4
10
O
O
O
NH
N
O
O
H3C
CH3
1d
5
O
O
8
88c
OEt
O
OEt
O
EtO
OEt
HN
Cl
2
6
48
42
O
O
OEt
NH
N
O
OEt
Cl
Cl
1e

A.T. Khan et al. / Tetrahedron 66 (2010) 7762e7772
7765
Table 2 (continued )
Entry
7
b
-Keto esters
Time (h)
48
Product
Yieldb (%)
36
O
O
OEt
NH
N
O
OEt
Cl
Cl
1f
8
O
O
48
00d
Ph
OEt
NH
O
Ph
OEt
N
Cl
Cl
a
Reactions were performed in the ratio of 2:2:1 (aldehydes: amines:
Isolated yields.
b-keto esters) in presence of 10 mol % iodine in 5 mL methanol at rt.
b
c
Unreacted imine (0.150 g) was recovered from the reaction.
d
Determined by crude 1H NMR.
Table 3
Scope for one-pot five-component reactions of methyl acetoacetate with aromatic
aldehydes and aminesa
enol-piperidines were formed along with the desired piperidines as
shown in Scheme 2. For example, the reaction of benzaldehyde with
aniline and methyl acetoacetate in presence of iodine at room
temperature provided, a mixture of desired piperidine 1g and enol-
piperidine 4g in 53% and 27%, respectively.
It is speculated that the formation of 4 may be due to either
hydrolysis of the enamine-piperidines 1 or through a four-com-
ponent reaction. If the product 4 is forming from hydrolysis of 1,
then we expected the enol-piperidine derivative 4 should have
obtained in more quantities at elevated temperature. To investigate
this, the reaction was carried out at 55 ꢀC and surprisingly, we
isolated the piperidine 1g exclusively in 81% yield not enol-piper-
idine after 5 h. Further, we did not obtain the hydrolysed product 4g
from 1g even upon hydrolysis under both acidic and basic reaction
conditions. From these observations, we may conclude that the
enol-piperidine 4g is obtained exclusively through a four-compo-
nent reaction rather from hydrolysis of 1.
To find the generality and scope of this MCR, various amines were
also examined. A wide variety of anilines tethered with substituents,
such as Me, Et, OMe, Br, NO2 were treated with 4-methyl-
benzaldehyde and methyl acetoacetate under similar reaction con-
ditions. All the reactions underwent smoothly to provide the
corresponding piperidine derivative 1oes, in moderate to good yields
(Table 3, entries 9e13). Likewise, aliphatic amines viz. n-butylamine
and benzylamine also afforded the corresponding piperidines 1t and
1u, respectively, in moderate yields. It is worthwhile to mention that
R1
O
O
NH
O
NH2
R1
10% I2
OMe
+
OMe
CHO
Ar
N
Ar
MeOH, rt
Ar
R1
1g-1u
Entry
Ar
Ph
R1
Time (h)
Product
Yieldb (%)
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
8
8
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
81c
74
68
85c
81
74
36
38c
68
65
74
68
57
48
55
2
4-CH3OC6H4
3
4
3,4,5-(CH3O)3C6H2
4-ClC6H4
18
6
5
4-BrC6H4
6
8
6
6
6
4-FC6H4
7
8
9
10
11
12
13
14
15
3-NO2C6H4
4-NO2C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
8
4-C2H5C6H4
4-CH3OC6H4
4-BrC6H4
4-NO2C6H4
n-C4H9
10
8
8
38
48
48
C6H5CH2
1u
a
Aldehyde, amine and methyl acetoacetate were taken in 2:2:1 ratio in presence
of 10 mol % iodine at rt.
b
Isolated yields.
Reaction was carried out at 55 ꢀC.
c
NH2
OH
N
O
CHO
NH
N
O
NH
N
O
OMe
OMe
OMe
R
I2
I2
O
O
MeOH, rt
MeOH, 55 o
C
R
R
R
R
R
R
OMe
1
1
4
81%
85%
38%
R = H
R = Cl
R = NO2
53%
66%
26%
4g 27%
1g
1j
1g
1j
4j
13%
4n
1n
1n
12%
Scheme 2. Formation of product at different reaction conditions.

7766
A.T. Khan et al. / Tetrahedron 66 (2010) 7762e7772
4-nitroaniline and aliphatic amines did not give the corresponding
piperidine derivatives by using InCl3.15
undergoes Diels-Alder reaction with imine 6 to give the desired
product. To prove this mechanism, we had tried to trap the in-
termediate diene with other reactive dienophiles such as maleic
anhydride, dihydropyran and dimethyl acetylenedicarboxylate.
Unfortunately, we did not get any desired cycloaddition products.
However, in the case of diethylmalonate on reaction with imine 6
furnished the Mannich-type product 2 (Table 2, entry 5). There-
fore, we would like to propose an alternate plausible mechanism
in which the product formed via double Mannich-type reactions.
The enamine 4 and imine 5 were formed initially in the presence
of iodine (Scheme 4). It is well known that enamine 5 would be
a better nucleophile as compared to diethylmalonate. So, it is quite
obvious that the nucleophilic attack by enamine 5 will take place
preferentially on the iodine-activated imine 6 to give Mannich-
It is interesting to point out here, in our experimental conditions
when 2-naphthylamine was treated with methyl acetoacetate and
aldehydes, such as benzaldehyde and 4-methylbenzaldehyde to
give the desired piperidine derivatives 1v and 1w in 53% and 51%,
respectively. However, Wang et al. recently reported18a that same
combination of 2-naphthylamine and benzaldehyde with methyl
acetoacetate catalyzed by molecular iodine in THF at reflux
temperature provided 3-aryl-1-substituted benzo[f]quinoline
derivative 3 in good yield (Scheme 3). Unfortunately, 1-naphthyl-
amine did not give the expected piperidine derivative under similar
reaction conditions. This may be due to the steric hindrance of the
bulky naphthyl group.
NH
N
O
NH2
NH2
CH2CO2Me
OMe
CHO
O
O
I2/THF/reflux
Ref.18a
I2/MeOH/rt
OMe
N
3
1v
Scheme 3. Role of reaction condition towards different product formation.
The products were characterized by IR, 1H NMR and 13C NMR
spectra, HRMS and by elemental analysis. The assignment of the
piperidine ring protons and carbons were made by using 1He1H-
COSY and 1He13C-COSY spectra. And finally, the structures as well
as the relative stereochemistry of piperidine 1f (Fig. 1) and 1k (Fig.
S1) were confirmed by X-ray crystallographic analysis. From the
structures, it was found that the piperidine ring adopted a boat
conformation in case of compound 1f in which flag pole positions 2
and 5 of the piperidine ring, as well as the CO group of the ester and
the eNH are on the same side of the plane and having intra-
molecular hydrogen bonding, as shown in Figure 1.
type intermediate 7 like diethylmalonate. Then the intermediate 7
reacts with aldehyde to give 8 by elimination of water molecule.
Further, there will be a spontaneous tendency in the presence of
iodine for tautomerization to give the intramolecular hydrogen
bonded species either 9 or 10. However, the tautomer 9 immedi-
ately undergoes intramolecular Mannich-type reaction to
form intermediate 11. The tautomer 10 would have given a four-
membered ring product 12, which is unfavourable. Finally, the
intermediate 11 tautomerizes to give the final piperidine
derivative 1 due to conjugation with the ester group. However, the
exact explanation is not yet clear and under investigation.
Figure 1. Crystal structures of 1f (CCDC no. 756203).
Finally, we turned our attention towards mechanistic studies
for this transformation. Earlier, reported papers6,15a,16 proposed
that the formation of piperidine is going through [4þ2] aza-Diels-
The formation of four-component product in a few cases
discussed earlier (Scheme 3) may be explained as follows: the
enol form of methyl acetoacetate reacts with imine 6 instead of
enamine 5 to form a Mannich-type intermediate, which is ana-
logue to 7. The remaining steps may be similar as depicted in
Scheme 4.
Alder reaction. It was expected that b-keto ester reacts with amine
to give enamine 5 and it reacts with aldehyde to provide Knoe-
venagel type product, which acts as the reactive diene. Finally, it

A.T. Khan et al. / Tetrahedron 66 (2010) 7762e7772
7767
CHO
R3
O
O
R3
R2
OR1
R2
NH2
NH O
R2
N
OR1
6
5
R2
O
O
R2
R2
N
O
Isolated
EtO
HN
OEt
NH O
OR1
5
OR1
R3
Inter-molecular
HN
R3
Mannich reaction
N
Cl
I2
R2
2
7
6
CHO
-H2O
R2
R3
R2
H
R2
H
N
O
N
O
N
O
OR1
R3
OR1
R3
OR1
R3
I2
I2
N
N
N
R3
R3
R3
R2
R2
R2
10
9
8
Intra-molecular
X
Mannich reaction
R2
R2
R2
NH O
N
N
O
NH
CO2R1
OR1
OR1
R3
I2
N
R3
N
R3
R3
R3
R3
R2
R2
R2
1
11
12
Scheme 4. A plausible mechanism for the formation of highly substituted piperidine in the presence of iodine.
3. Conclusions
Q-TOF premier and data analyzed using Mass Lynx 4.1. Elemental
analyses were carried out using PerkineElmer 2400 Series II CHNS/
O analyzer at the Department of Chemistry, Indian Institute of
Technology, Guwahati. Crystal data were collected with Bruker
Smart Apex-II CCD diffractometer using graphite monochromated
In summary, a general methodology is reported for the forma-
tion of highly as well as fully functionalized piperidines in presence
of iodine as catalyst via one-pot five-component reaction from
common available starting materials. The salient features of this
protocol are good yields, mild reaction conditions, environmentally
benign, superior atom economy, the readily accessibility of the
catalyst and its cost effectiveness. In addition, we propose the
possibility for the formation of piperidines via double Mannich-
type intermediates and mechanism is under investigation.
Mo K
a
radiation (l¼0.71073 Å) at 298 K.
4.2. General procedure for the synthesis of highly
functionalized piperidines 1
To a solution of amine (2 mmol) and methyl acetoacetate
(1 mmol) in 5 mL of methanol was added iodine (0.1 mmol) and
stirred at room temperature. After 20 min, aromatic aldehyde
(2 mmol) was added to the reaction mixture and stirring was
continued for completion. The reaction time of individual cases is
indicated in Tables 2 and 3. The thick precipitate was filtered off and
washed with ethanol to give pure products.
4. Experimental section
4.1. General
Melting points were determined on a Büchi melting point ap-
paratus and are uncorrected. IR spectra were recorded on Per-
kineElmer 281 IR spectrophotometer. 1H and 13C NMR spectra were
recorded on Varian 400 spectrometer TMS as an internal reference;
4.2.1. Methyl 2,6-bis(4-methylphenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (1a). White solid (0.410 g,
84%); [found: C, 80.96; H, 6.55; N, 5.80. C33H32N2O2 requires C,
81.12; H, 6.60; N, 5.73%]; mp 215e217 ꢀC; Rf (5% ethyl acetate/
chemical shifts (d
scale) are reported in parts per million (ppm). 1H
NMR Spectra are reported in the order: no of protons, multiplicity
and coupling constant (J value) in hertz (Hz); signals were char-
acterized as s (singlet), d (doublet), t (triplet), m (multiplet), br s
(broad singlet), dq (doublet of quartet) and ddt (doublet of doublet
of triplet). HRMS spectra were recorded using WATERS MS system,
hexane) 0.46; nmax (KBr) 1657 (C]O), 1591 (C]C) cmꢁ1
; dH
(400 MHz, CDCl3) 10.25 (1H, s, NH), 7.19 (2H, d, J 8.0 Hz, ArH),
7.10e7.02 (11H, m, ArH), 6.59 (1H, t, J 7.2 Hz, ArH), 6.52 (2H, d, J
8.0 Hz, ArH), 6.39 (1H, s, H-2), 6.30 (2H, d, J 8.0 Hz, ArH), 5.11 (1H, d,

7768
A.T. Khan et al. / Tetrahedron 66 (2010) 7762e7772
J 3.2 Hz, H-6), 3.92 (3H, s, OMe), 2.86 (1H, dd, J 15.2, 5.6 Hz, H-50),
2.75 (1H, dd, J 15.2, 2.4 Hz, H-500), 2.33 (3H, s, Me), 2.32 (3H, s, Me);
dC (100 MHz, CDCl3) 168.8 (C]O), 156.5 (C-4), 147.2, 141.1, 139.8,
138.1, 136.8, 136.0, 129.4, 129.1, 129.0, 128.9, 126.7, 126.5, 126.0,
125.8, 116.1, 113.0, 98.2 (C-3), 58.1 (C-6), 55.0 (C-2), 51.2, 33.8 (C-5),
21.3, 21.2; HRMS (ESI): MHþ, found 489.2556. C33H32N2O2 requires
489.2542.
(100 MHz, CDCl3) 169.0 (C]O), 159.8 (C-4), 147.4, 142.8, 141.8, 138.2,
132.8, 132.2, 129.4, 129.3, 129.0, 128.7, 128.8, 128.1, 127.1, 126.7, 117.9,
115.5, 96.1 (C-3), 64.0 (C-6), 60.1 (C-2), 55.7, 38.7 (C-5), 19.2, 14.8.
4.2.6. Ethyl
2,6-bis(4-chlorophenyl)-5-ethyl-1-phenyl-4-(phenyl-
amino)-1,2,5,6-tetrahydropyridine-3-carboxylate (1f). White solid
(0.206 g, 36%); [found: C, 71.34; H, 5.53; N, 5.02. C34H32N2O2Cl2 re-
quiresC,71.45;H, 5.64;N, 4.90%];mp239e241 ꢀC;Rf (5%ethyl acetate/
4.2.2. Ethyl
2,6-bis(4-methylphenyl)-1-phenyl-4-(phenylamino)-
hexane) 0.47; nmax (KBr) 1655 (C]O),1594 (C]C) cmꢁ1
; dH (400 MHz,
1,2,5,6-tetrahydropyridine-3-carboxylate (1b). White solid (0.392 g,
78%); [found C, 81.13; H, 6.76; N, 5.69. C34H34N2O2 requires C, 81.24;
H, 6.82; N, 5.57%]; mp 228e231 ꢀC; Rf (5% ethyl acetate/hexane)
CDCl3) 10.78 (1H, s, NH), 7.43e7.38 (4H, m, ArH), 7.34 (2H, d, J 8.4 Hz,
ArH), 7.25e7.12 (10H, m, ArH), 6.78(2H, d, J 8.0 Hz, ArH), 5.99 (1H, s, H-
2), 4.86(1H, d, J 4.0 Hz, H-6), 4.33e4.25(1H, m, CHaHb), 4.15e4.07 (1H,
m, CHaHb), 3.05e3.04 (1H, m, H-5),1.22 (3H, t, J 7.2 Hz, Me), 0.85e0.77
(1H, m, CHaHb), 0.76e0.67 (1H, m, CHaHb), 0.18 (3H, t, J 7.2 Hz, Me); dC
(100 MHz, CDCl3) 169.2 (C]O), 161.8 (C-4), 151.2, 145.8, 139.9, 139.1,
132.7, 132.4, 129.6, 129.0, 128.9, 128.5, 128.4, 126.6, 126.3, 119.2, 116.8,
95.6 (C-3), 63.8 (C-6), 61.7 (C-2), 60.0, 43.1 (C-5), 22.2, 14.6, 12.1.
0.48; nmax (KBr) 1649 (C]O), 1592 (C]C) cmꢁ1
; dH (400 MHz,
CDCl3) 10.29 (1H, s, NH), 7.22 (2H, d, J 8.0 Hz, ArH), 7.10e7.02 (11H,
m, ArH), 6.59 (1H, t, J 7.2 Hz, ArH), 6.53 (2H, d, J 8.8 Hz, ArH), 6.40
(1H, s, H-2), 6.30 (2H, d, J 7.6 Hz, ArH), 5.11 (1H, d, J 2.4 Hz, H-6),
4.51e4.40 (1H, m, OCHaHb), 4.36e4.26 (1H, m, OCHaHb), 2.86 (1H,
dd, J 15.2, 5.6 Hz, H-50), 2.76 (1H, dd, J 15.2, 2.4 Hz, H-500), 2.33 (3H, s,
Me), 2.32 (3H, s, Me), 1.46 (3H, t, J 7.2 Hz, OCH2CH3); dC (100 MHz,
CDCl3) 168.4 (C]O), 156.2 (C-4), 147.2, 141.2, 139.9, 138.2, 136.8,
135.9, 129.4, 129.1, 129.0, 128.9, 126.7, 126.5, 125.9, 125.7, 116.1, 113.1,
98.5 (C-3), 59.8, 58.1 (C-6), 55.0 (C-2), 33.8 (C-5), 21.3, 21.2, 15.0;
HRMS (ESI): MHþ, found: 503.2683. C34H34N2O2 requires 503.2699.
4.2.7. Methyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydropyr-
idine-3-carboxylate(1g). To a solution of amine (2 mmol) and methyl
acetoacetate (1 mmol) in 5 mL of methanol was added iodine
(0.1 mmol) and stirred at 55 ꢀC. After 10 min, benzaldehyde (2 mmol)
was added to the reaction mixture and stirring was continued for
completion at the same temperature. The reaction mixture was
cooled to room temperature. The thick precipitate was filtered off
and washed with ethanol to give pure products as white solid
(0.373 g, 81%); [found: C, 80.72; H, 6.07; N, 6.09. C31H28N2O2 requires
C, 80.84; H, 6.13; N, 6.08%]; mp 185e186 ꢀC; Rf (5% ethyl acetate/
hexane) 0.38; nmax (KBr) 3444 (NeH), 1661 (C]O), 1591 (C]
4.2.3. tert-Butyl 2,6-bis(4-methylphenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (1c). Light yellow solid
(0.361 g, 68%); [found C, 81.32; H, 7.31; N, 5.37. C36H38N2O2 requires C,
81.47; H, 7.22; N, 5.28%]; mp 171e173 ꢀC; Rf (5% ethyl acetate/hexane)
0.64; nmax (KBr) 3447 (NeH), 1648 (C]O), 1592 (C]C) cmꢁ1
; dH
(400 MHz, CDCl3) 10.25 (1H, s, NH), 7.23 (2H, d, J 8.0 Hz, ArH),
7.09e7.03 (11H, m, ArH), 6.58 (1H, t, J 7.2 Hz, ArH), 6.51 (2H, d, J 8.4 Hz,
ArH), 6.35 (1H, s, H-2), 6.29 (2H, d, J 7.2 Hz, ArH), 5.08 (1H, d, J 3.2 Hz,
H-6), 2.82 (1H, dd, J 15.2, 5.6 Hz, H-50), 2.74 (1H, dd, J 15.2, 2.8 Hz, H-
500),1.64 (9H, s, CMe3), 2.31 (3H, s, Me), 2.33 (3H, s, Me); dC (100 MHz,
CDCl3) 168.4 (C]O), 155.3 (C-4), 147.4, 141.5, 140.0, 138.5, 136.7, 135.8,
129.4, 129.1, 128.9, 126.7, 126.6, 125.7, 125.4, 116.1, 113.1, 100.2 (C-3),
80.1, 58.2 (C-6), 55.4 (C-2), 33.8 (C-5), 29.0, 21.3, 21.2; HRMS (ESI):
MHþ, found: 531.3013. C36H38N2O2 requires 531.3012.
C) cmꢁ1
; dH (400 MHz, CDCl3) 10.24 (1H, s, NH), 7.32e7.24 (8H, m,
ArH), 7.16 (2H, d, J 8.0 Hz, ArH), 7.10e7.03 (5H, m, ArH), 6.59 (1H, t, J
7.2 Hz, ArH), 6.51 (2H, d, J 8.8 Hz, ArH), 6.44 (1H, s, H-2), 6.27 (2H, d, J
8.0 Hz, ArH), 5.14 (1H, d, J 4.4 Hz, H-6), 3.93 (3H, s, Me), 2.86 (1H, dd, J
15.2, 5.6 Hz, H-50), 2.75 (1H, dd, J 15.2, 2.4 Hz, H-500), dC (100 MHz,
CDCl3) 168.7 (C]O), 156.4 (C-4), 147.1, 144.0, 142.9, 137.9, 129.0,
128.9, 128.8, 128.4, 127.3, 126.8, 126.5, 126.0, 125.9, 116.3, 113.0, 98.0
(C-3), 58.3 (C-6), 55.2 (C-2), 51.2, 33.8 (C-5); HRMS (ESI): MHþ,
found: 461.2256. C31H28N2O2 requires 461.2229.
4.2.4. Allyl 2,6-bis(4-methylphenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate (1d). Light yellow solid (0.339 g,
66%); [found C, 81.56; H, 6.57; N, 5.51. C35H34N2O2 requires C, 81.68; H,
6.66; N, 5.44%]; mp 186e188 ꢀC; Rf (5% ethyl acetate/hexane) 0.49;
4.2.8. Methyl 2,6-bis(4-methoxyphenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (1h). White solid (0.385 g,
74%); [found C, 76.01; H, 6.11; N, 5.49. C33H32N2O4 requires C, 76.13;
H, 6.20; N, 5.38%]; mp 186e188 ꢀC; Rf (5% ethyl acetate/hexane)
nmax (KBr) 3242 (NeH), 1658 (C]O), 1591 (C]C) cmꢁ1
;
dH (400 MHz,
0.16; nmax (KBr) 1654 (C]O), 1593 (C]C) cmꢁ1
; dH (400 MHz,
CDCl3) 10.26 (1H, s, NH), 7.21 (2H, d, J 8.0 Hz, ArH), 7.15e7.02 (11H, m,
ArH), 6.58(1H, t, J 7.2 Hz, ArH), 6.52 (2H, d, J 8.4 Hz, ArH), 6.43 (1H, s, H-
2), 6.30 (2H, dd, J 8.0, 2.4 Hz, ArH), 6.15e6.06 (1H, m, ]CH), 5.45 (1H,
dq, J 17.2, 1.2 Hz, ]CHaHb), 5.31 (1H, dq, J 10.4, 1.2 Hz, ]CHaHb), 5.10
(1H, d, J 3.6 Hz, H-6), 4.87 (1H, ddt, J 13.6, 5.6,1.6 Hz, CHaHb), 4.80 (1H,
ddt, J13.6, 5.5,1.6 Hz, CHaHb), 2.86 (1H, dd, J15.2, 5.6 Hz, H-50), 2.76 (1H,
dd, J 15.2, 2.4 Hz, H-500), 2.32 (3H, s, Me), 2.31 (3H, s, Me); dC (100 MHz,
CDCl3) 168.0 (C]O), 156.8 (C-4), 147.2,141.2, 139.8,138.1, 136.8, 136.0,
133.3,129.4,129.1,129.04,128.98,126.8,126.5,126.0,125.8,117.8,116.2,
113.1, 98.2(C-3), 64.5, 58.1(C-6), 55.1(C-2), 33.9(C-5), 21.3,21.2;HRMS
(ESI): MHþ, found: 515.2697. C35H34N2O2 requires 515.2699.
CDCl3) 10.27 (1H, s, NH), 7.21 (2H, d, J 8.8 Hz, ArH), 7.11 (2H, d, J
7.2 Hz, ArH), 7.07 (1H, t, J 7.2 Hz, ArH), 7.06 (2H, d, J 8.8 Hz, ArH),
7.05 (2H, d, J 8.4 Hz, ArH), 6.81 (4H, d, J 8.8 Hz, ArH), 6.60 (1H, t, J
7.2 Hz, ArH), 6.52 (2H, d, J 8.0 Hz, ArH), 6.38e6.34 (3H, m, ArH and
H-2), 5.07 (1H, d, J 3.2 Hz, H-6), 3.92 (3H, s, OMe), 3.79 (3H, s, OMe),
3.78 (3H, s, OMe), 2.85 (1H, dd, J 15.2, 5.6 Hz, H-50), 2.75 (1H, dd, J
15.2, 2.4 Hz, H-500); dC (100 MHz, CDCl3) 168.8 (C]O), 158.8, 158.2,
156.5 (C-4), 147.1, 138.1, 136.0, 134.8, 129.0, 127.8, 127.6, 125.9, 125.8,
116.2, 114.1, 113.7, 113.1, 98.2 (C-3), 57.7 (C-6), 55.4, 54.7 (C-2), 51.2,
33.9 (C-5); HRMS (ESI): MHþ, found: 521.2449. C33H32N2O4 re-
quires 521.2440.
4.2.5. Ethyl 2,6-bis(4-chlorophenyl)-5-methyl-1-phenyl-4-(phenyl-
amino)-1,2,5,6-tetrahydropyridine-3-carboxylate (1e). White solid
(0.234 g, 42%); [found: C, 71.01; H, 5.33; N, 5.12. C33H30N2O2Cl2 re-
quiresC,71.09;H, 5.42;N, 5.02%];mp198e199 ꢀC;Rf (5%ethylacetate/
4.2.9. Methyl 2,6-bis(3,4,5-trimethoxyphenyl)-1-phenyl-4-(phenyl-
amino)-1,2,5,6-tetrahydropyridine-3-carboxylate (1i). Light yellow
solid (0.435 g, 68%); [found: C, 69.28; H, 6.24; N, 4.46. C37H40N2O8
requires C, 69.36; H, 6.29; N, 4.37%]; mp 197e199 ꢀC; Rf (30% ethyl
hexane) 0.45; nmax (KBr) 1651 (C]O),1594 (C]C) cmꢁ1
;
dH (400 MHz,
acetate/hexane) 0.22; nmax (KBr) 1655 (C]O), 1594 (C]C) cmꢁ1
; dH
CDCl3) 10.38 (1H, s, NH), 7.27e7.18 (9H, m, ArH), 7.09 (2H, t, J 7.6 Hz,
ArH), 7.00 (2H, d, J 8.4 Hz, ArH), 6.68 (1H, t, J 7.2 Hz, ArH), 6.57 (2H, d, J
8.4Hz, ArH),6.52e6.50(2H, m, ArH), 6.20(1H, s, H-2), 4.87(1H, s,H-6),
4.43e4.35 (1H, m, CHaHb), 4.32e4.24 (1H, m, CHaHb), 3.01 (1H, dq, J
7.2 Hz,1.6 Hz, H-5),1.37 (3H, t, J 7.2 Hz, Me),1.04 (3H, d, J 7.2 Hz, Me); dC
(400 MHz, CDCl3) 10.26 (1H, s, NH), 7.15 (2H, d, J 7.6 Hz, ArH), 7.12
(1H, t, J 7.2 Hz, ArH), 7.09 (2H, d, J 8.0 Hz, ArH), 6.65 (1H, t, J 7.6 Hz,
ArH), 6.57 (2H, d, J 8.0 Hz, ArH), 6.53 (2H, s, ArH), 6.39 (2H, d, J
7.7 Hz, ArH), 6.35 (2H, s, ArH), 6.34(1H, s, H-2), 5.03 (1H, d, J 3.2 Hz,
H-6), 3.90 (3H, s, OMe), 3.85 (3H, s, OMe), 3.84 (3H, s, OMe), 3.74

A.T. Khan et al. / Tetrahedron 66 (2010) 7762e7772
7769
(6H, s, 2ꢂOMe), 3.70 (6H, s, 2ꢂOMe), 2.95 (1H, dd, J 15.2, 5.6 Hz, H-
0.21; nmax (KBr) 3436 (NeH), 1655 (C]O), 1595 (C]C) cmꢁ1
; dH
50), 2.77 (1H, dd, J 15.2, 2.4 Hz, H-500); dC (100 MHz, CDCl3) 168.5
(C]O), 157.0 (C-4), 153.4, 153.1, 147.0, 139.7, 138.5, 137.8, 137.0,
136.5, 128.9, 126.3, 126.2, 116.6, 113.1, 103.9, 103.2, 97.3 (C-3), 61.0,
58.3 (C-6), 56.0, 55.6 (C-2), 51.1, 33.8 (C-5); HRMS (ESI): MHþ,
found: 641.2800. C37H40N2O8 requires 641.2863.
(400 MHz, CDCl3) 10.30 (1H, s, NH), 8.22 (1H, s, ArH), 8.15e8.10 (2H,
m, ArH), 7.94 (s,1H, ArH), 7.66 (1H, d, J 7.6 Hz, ArH), 7.50e7.45 (3H, m,
ArH), 7.16e7.14 (3H, m, ArH), 7.10 (2H, t, J 7.2 Hz, ArH), 6.70 (1H, t, J
7.2 Hz, ArH), 6.48 (1H, s, H-2), 6.44 (2H, d, J 8.8 Hz, ArH), 6.41e6.38
(2H, m, ArH), 5.33 (1H, t, J 4.0 Hz, H-6), 3.99 (3H, s, OMe), 2.88 (2H, d,
J 4.0 Hz, CH2); dC (100 MHz, CDCl3) 168.2 (C]O), 155.7 (C-4), 148.8,
148.7, 146.5, 145.9, 144.6, 137.3, 132.7, 129.8, 129.5, 129.3, 126.7, 125.8,
122.6, 122.0, 121.7, 121.5, 117.9, 113.2, 96.9 (C-3), 57.2 (C-6), 55.3 (C-2),
51.6, 33.9 (C-5).
4.2.10. Methyl 2,6-bis(4-chlorophenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (1j). To a solution of amine
(2 mmol) and methyl acetoacetate (1 mmol) in 5 mL of methanol
was added iodine (0.1 mmol) and stirred at 55 ꢀC. After 10 min, 4-
chlorobenzaldehyde (2 mmol) was added to the reaction mixture
and stirring was continued for completion at the same tempera-
ture. The reaction mixture was cooled to room temperature. The
thick precipitate was filtered off and washed with ethanol to give
pure products as white solid 1i (0.450 g, 85%) as white solid;
[found: C, 70.29; H, 4.83; N, 5.34. C31H26Cl2N2O2 requires C, 70.32;
H, 4.95; N, 5.29%]; mp 225e227 ꢀC; Rf (5% ethyl acetate/hexane)
4.2.14. Methyl
2,6-bis(4-nitrophenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (1n). The reaction was
carried out at 55 ꢀC, after completion, the reaction was cool to room
temperature. The thick precipitate was filtered off and washed with
ethanol to give pure products 1n (0.209 g, 38%) as light yellow solid;
[found C, 67.51; H, 4.69; N, 10.31. C31H26N4O6 requires C, 67.63; H,
4.76; N, 10.18%]; mp 239e241 ꢀC; Rf (15% ethyl acetate/hexane) 0.21;
0.27; nmax (KBr) 1660 (C]O), 1591 (C]C) cmꢁ1
;
dH (400 MHz,
nmax (KBr) 3356 (NeH),1660 (C]O),1593 (C]C) cmꢁ1
; dH (400 MHz,
CDCl3) 10.25 (1H, s, NH), 7.36e7.24 (5H, m, ArH), 7.15 (2H, d, J 7.2 Hz,
ArH), 7.10 (2H, t, J 7.6 Hz, ArH), 7.07 (2H, d, J 8.4 Hz, ArH), 7.05 (2H, d,
J 8.0 Hz, ArH), 6.64 (1H, t, J 7.2 Hz, ArH), 6.45 (2H, d, J 8.0 Hz, ArH),
6.40 (2H, d, J 8.0 Hz, ArH), 6.35 (1H, s, H-2), 5.09 (1H, d, J 2.4 Hz, H-
6), 3.92 (3H, s, OMe), 2.82 (1H, dd, J 15.2, 5.6 Hz, H-50), 2.74 (1H, dd, J
15.2, 2.4 Hz, H-500); dC (100 MHz, CDCl3) 168.4 (C]O), 156.2 (C-4),
146.6, 142.5, 141.0, 137.7, 133.0, 132.3, 129.2, 128.9, 128.6, 128.2,
127.9, 126.2, 125.9, 116.9, 113.1, 97.6 (C-3), 57.5 (C-6), 54.8 (C-2), 51.3,
33.8 (C-5); HRMS (ESI): MHþ, found: 529.1445. C31H26N2O2Cl2 re-
quires 529.1450.
CDCl3) 10.26 (1H, br s, NH), 8.14 (2H, d, J 8.8 Hz, ArH), 8.12 (2H, d, J
8.8 Hz, ArH), 7.48 (2H, d, J 8.4 Hz, ArH), 7.27 (2H, d, J 8.8 Hz, ArH),
7.17e7.13 (3H, m, ArH), 7.09 (1H, d, J 7.2 Hz, ArH), 7.07 (1H, d, J 7.2 Hz,
ArH), 6.68 (1H, t, J 7.2 Hz, ArH), 6.46 (1H, s, H-2), 6.42e6.37 (4H, m,
ArH), 5.25e5.24 (1H, m, H-6), 3.95 (3H, s, OMe), 2.85 (2H, d, J 4.0 Hz,
CH2); dC (100 MHz, CDCl3) 168.1 (C]O), 155.7 (C-4), 151.8, 149.9,
147.5, 146.9, 145.9, 137.3, 129.5, 129.4, 127.6, 127.5, 126.6, 125.7, 124.1,
123.9, 117.8, 113.1, 96.8 (C-3), 57.5 (C-6), 55.4 (C-2), 51.6, 33.7 (C-5).
4.2.15. Methyl
2,6-bis(4-methylphenyl)-1-(4-methylphenyl)-4-(4-
methylphenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate
(1o). Light yellow solid (0.351 g, 68%); [found: C, 81.24; H, 7.01; N,
5.53. C35H36N2O2 requires C, 81.36; H, 7.02; N, 5.42%]; mp
206e208 ꢀC; Rf (5% ethyl acetate/hexane) 0.48; nmax (KBr) 3249
4.2.11. Methyl 2,6-bis(4-bromophenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (1k). Light yellow solid
(0.500 g, 77%); [found: C, 60.45; H, 4.15; N, 4.97. C31H26Br2N2O2
requires C, 60.21; H, 4.24; N, 4.53%]; mp 245e247 ꢀC; Rf (5% ethyl
(NeH), 1655 (C]O), 1594 (C]C) cmꢁ1
; dH (400 MHz, CDCl3) 10.17
acetate/hexane) 0.27; nmax (KBr) 1661 (C]O), 1590 (C]C) cmꢁ1
;
dH
(1H, s, NH), 7.20 (2H, d, J 8.0 Hz, ArH), 7.09e7.03 (6H, m, ArH), 6.89
(2H, d, J 8.0 Hz, ArH), 6.87 (2H, d, J 8.8 Hz, ArH), 6.43 (2H, d, J 8.0 Hz,
ArH), 6.35 (1H, s, H-2), 6.18 (2H, d, J 8.0 Hz, ArH), 5.07 (1H, d, J
4.0 Hz, H-6), 3.91 (3H, s, OMe), 2.82 (1H, dd, J 15.2, 5.6 Hz, H-50),
2.72 (1H, dd, J 15.2, 2.4 Hz, H-500), 2.34 (3H, s, Me), 2.32 (3H, s, Me),
2.27 (3H, s, Me), 2.15 (3H, s, Me); dC (100 MHz, CDCl3) 168.8 (C]O),
156.8 (C-4), 145.1, 141.4, 140.1, 136.6, 135.8, 135.6, 135.4, 129.5, 129.4,
129.0, 126.7, 126.5, 126.1, 125.0, 113.0, 97.7 (C-3), 58.0 (C-6), 55.1 (C-
2), 51.0, 33.7 (C-5), 21.3, 21.2, 21.0, 20.3; HRMS (ESI): MHþ, found:
517.2847. C35H36N2O2 requires 517.2855.
(400 MHz, CDCl3) 10.24 (1H, s, NH), 7.40 (2H, d, J 8.4 Hz, ArH), 7.39
(2H, d, J 8.4 Hz, ArH), 7.18 (2H, d, J 8.4 Hz, ArH), 7.16 (2H, d, J 8.0 Hz,
ArH), 7.15 (1H, t, J 7.2 Hz, ArH), 7.08 (2H, t, J 7.2 Hz, ArH), 7.00 (2H, d,
J 8.4 Hz, ArH), 6.65 (1H, t, J 7.2 Hz, ArH), 6.45 (2H, d, J 8.8 Hz, ArH),
6.40 (2H, d, J 7.6 Hz, ArH), 6.34 (1H, s, H-2), 5.08 (1H, d, J 3.6 Hz, H-
6), 3.93 (3H, s, OMe), 2.82 (1H, dd, J 15.2, 5.6 Hz, H-50), 2.74 (1H, dd, J
15.2, 2.4 Hz, H-500); dC (100 MHz, CDCl3) 168.4 (C]O), 156.1 (C-4),
146.5, 143.0, 141.6, 137.7, 131.9, 131.5, 129.2, 129.18, 128.6, 128.3,
126.2, 125.9, 121.1, 120.4, 116.9, 113.0, 97.6 (C-3), 57.5 (C-6), 54.9 (C-
2), 51.3, 33.8 (C-5); HRMS (ESI): MHþ, found: 617.0433.
C31H26N2O2Br2 requires 617.0439.
4.2.16. Methyl 2,6-bis(4-methylphenyl)-1-(4-ethylphenyl)-4-(4-eth-
ylphenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (1p). Light
yellow solid (0.354 g, 65%); [found: C, 81.49; H, 7.07; N, 5.24.
C37H40N2O2 requires C, 81.58; H, 7.40; N, 5.14%]; mp 177e178 ꢀC; Rf
(5% ethyl acetate/hexane) 0.48; nmax (KBr) 3264 (NeH), 1653 (C]
4.2.12. Methyl
2,6-bis(4-fluorophenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (1l). White solid (0.367 g,
74%); [found: C, 74.91; H, 5.11; N, 5.84. C31H26F2N2O2 requires C,
74.98; H, 5.28; N, 5.64%]; mp 193e195 ꢀC; Rf (5% ethyl acetate/hex-
O), 1593 (C]C) cmꢁ1
; dH (400 MHz, CDCl3) 10.17 (1H, s, NH), 7.19
ane) 0.38; nmax (KBr) 1657 (C]O), 1592 (C]C) cmꢁ1
;
dH (400 MHz,
(2H, d, J 8.4 Hz, ArH), 7.09e7.03 (6H, m, ArH), 6.91 (2H, d, J 8.4 Hz,
ArH), 6.88 (2H, d, J 8.8 Hz, ArH), 6.44 (2H, d, J 8.8 Hz, ArH), 6.35 (1H,
s, H-2), 6.19 (2H, d, J 8.4 Hz, ArH), 5.07 (1H, d, J 3.6 Hz, H-6), 3.90
(3H, s, OMe), 2.82 (1H, dd, J 15.2, 5.6 Hz, H-50), 2.73 (1H, dd, J 15.2,
2.4 Hz, H-500), 2.56 (2H, q, J 7.6 Hz, CH2CH3), 2.45 (2H, q, J 7.6 Hz,
CH2CH3), 2.31(3H, s, Me), 2.34 (3H, s, Me), 1.18 (3H, t, J 7.6 Hz, Me),
1.11 (3H, t, J 7.6 Hz, Me); dC (100 MHz, CDCl3) 168.8 (C]O), 156.8 (C-
4), 145.3, 142.0, 141.5, 140.2, 136.7, 135.8, 135.6, 131.5, 129.4, 129.1,
128.3, 126.8, 126.6, 126.2, 113.0, 97.8 (C-3), 58.2 (C-6), 55.2 (C-2),
51.1, 33.8 (C-5), 28.4, 27.8, 21.3, 21.2, 15.9, 15.7; HRMS (ESI): MHþ,
found: 545.3151. C37H40N2O2 requires 545.3168.
CDCl3) 10.23 (1H, s, NH), 7.25 (2H, t, J 8.4 Hz, ArH), 7.17e7.06 (7H, m,
ArH), 6.96 (4H, t, J 8.4 Hz, ArH), 6.64 (1H, t, J 7.2 Hz, ArH), 6.47 (2H, d, J
8.4 Hz, ArH), 6.39 (2H, d, J 8.0 Hz, ArH), 6.37 (1H, s, H-2), 5.11 (1H, d, J
2.8 Hz, H-6), 3.93 (3H, s, OMe), 2.83 (1H, dd, J 15.2, 5.6 Hz, H-50), 2.75
(1H, dd, J 15.2, 2.4 Hz, H-500); dC (100 MHz, CDCl3) 168.6 (C]O),163.4,
160.5, 156.3 (C-4), 146.7, 139.5, 138.2, 137.8, 129.2, 128.4, 128.3, 128.1,
128.0, 126.2, 125.9, 116.7, 115.8, 115.6, 115.3, 115.1, 113.1, 97.9 (C-3),
57.5 (C-6), 54.7 (C-2), 51.4, 33.9 (C-5); HRMS (ESI): MHþ, found:
497.2245. C31H26N2O2F2 requires 497.2241.
4.2.13. Methyl
2,6-bis(3-nitrophenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (1m). Yellow solid (0.198 g,
36%); [found C, 67.51; H, 4.68; N,10.29. C31H26N4O6 requires C, 67.63;
H, 4.76; N, 10.18%]; mp 182e183 ꢀC; Rf (15% ethyl acetate/hexane)
4.2.17. Methyl 2,6-bis(4-methylphenyl)-1-(4-methoxyphenyl)-4-(4-
methoxyphenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate
(1q). White solid (0.406 g, 74%); [found: C, 76.56; H, 6.55; N, 5.26.

7770
A.T. Khan et al. / Tetrahedron 66 (2010) 7762e7772
C35H36N2O4 requires C, 76.62; H, 6.61; N, 5.11%]; mp 230e231 ꢀC; Rf
(5% ethyl acetate/hexane) 0.20; nmax (KBr) 3442 (NeH), 1657 (C]
C, 81.36; H, 7.02; N, 5.42%]; mp 172e173 ꢀC; Rf (5% ethyl acetate/
hexane) 0.32; nmax (KBr) 3272 (NeH), 1650 (C]O), 1594 (C]
O), 1611 (C]C) cmꢁ1
;
dH (400 MHz, CDCl3) 10.08 (1H, s, NH), 7.16
C) cmꢁ1
; dH (400 MHz, CDCl3) 9.67 (1H, t, J 6.0 Hz, NH), 7.40e7.37
(2H, d, J 8.0 Hz, ArH), 7.09e7.02 (6H, m, ArH), 6.64 (2H, d, J 9.2 Hz,
ArH), 6.60 (2H, d, J 9.2 Hz, ArH), 6.43 (2H, d, J 9.2 Hz, ArH), 6.26 (1H,
s, H-2), 6.21 (2H, d, J 9.2 Hz, ArH), 5.00 (1H, d, J 2.8 Hz, H-6), 3.89
(3H, s, OMe), 3.74 (3H, s, OMe), 3.65 (3H, s, OMe), 2.77 (1H, dd, J
15.2, 5.6 Hz, H-50), 2.62 (1H, dd, J 15.2, 2.8 Hz, H-500), 2.33 (3H, s,
Me), 2.31 (3H, s, Me); dC (100 MHz, CDCl3) 168.9 (C]O), 157.9, 157.2,
151.0 (C-4), 141.9, 141.5, 140.4, 136.7, 135.9, 131.0, 129.4, 129.0, 128.0,
126.9, 126.6, 114.7, 114.3, 114.2, 114.1, 97.3 (C-3), 58.1 (C-6), 55.8 (C-
2), 55.7, 55.6, 51.0, 33.8 (C-5), 21.3, 21.2; HRMS (ESI): MHþ, found:
549.2753. C35H36N2O4 requires 549.2753.
(6H, m, ArH), 7.32 (4H, t, J 8.0 Hz, ArH), 7.24 (2H, d, J 8.4 Hz, ArH),
7.20 (2H, d, J 8.4 Hz, ArH), 7.08 (4H, t, J 8.0 Hz, ArH), 4.73 (1H, s, H-2),
4.63 (1H, dd, J 15.6, 6.4 Hz, H-6), 4.57 (1H, dd, J 15.6, 6.0 Hz, CHaHb),
4.02 (1H, dd, J 11.2, 5.2 Hz, CHaHb), 3.37 (1H, d, J 13.6 Hz, CHaHb),
3.46 (3H, s, OMe), 3.32 (1H, d, J 13.6 Hz, CHaHb), 2.73 (1H, dd, J 17.2,
11.6 Hz, H-50), 2.62 (1H, dd, J 17.2, 5.2 Hz, H-500), 2.28 (3H, s, Me),
2.30 (3H, s, Me); dC (100 MHz, CDCl3) 171.3, 159.0 (C-4), 141.9, 140.5,
139.1,138.7,136.7,135.8,129.1,129.0,128.8,128.4, 128.3,127.6,127.4,
127.0, 126.9, 89.3, 58.1, 52.2, 50.6, 49.7, 46.3, 25.5, 21.3; HRMS (ESI):
MHþ, found: 517.2872. C35H36N2O2 requires 517.2855.
4.2.18. Methyl
2,6-bis(4-methylphenyl)-1-(4-bromophenyl)-4-(4-
4.2.22. Diethyl 2-(phenyl(3-chlorophenylamino)methyl)malonate (2).
White solid (0.295 g, 88%); [found: C, 63.73; H, 5.79; N, 3.63.
C20H22ClNO4 requires C, 63.91; H, 5.90; N, 3.73%]; mp 112e114 ꢀC; Rf
(5% ethyl acetate/hexane) 0.2; nmax (KBr) 3369 (NeH), 1752 (C]
bromophenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate
(1r). Light yellow solid (0.440 g, 68%); [found C, 61.23; H, 4.57; N,
4.46. C33H30Br2N2O2 requires C, 61.32; H, 4.68; N, 4.33%]; mp
230e232 ꢀC; Rf (5% ethyl acetate/hexane) 0.42; nmax (KBr) 3446
O) cmꢁ1
; dH (400 MHz, CDCl3) 7.35e7.32 (5H, m, ArH), 6.99 (1H, t, J
(NeH), 1650 (C]O), 1605 (C]C) cmꢁ1
;
dH (400 MHz, CDCl3) 10.17
8.0 Hz, ArH), 6.61 (1H, d, J 8.0 Hz, ArH), 6.58 (1H, s), 6.46 (1H, d, J
8.4 Hz, ArH), 5.49 (1H, d, J 6.0 Hz), 5.18 (1H, br s), 4.17e4.07 (4H, m),
3.88 (1H, d, J 5.2 Hz), 1.17 (3H, t, J 7.2 Hz), 1.13 (3H, t, J 7.2 Hz); dC
(100 MHz, CDCl3) 168.2, 167.3, 148.0, 139.3, 135.0, 130.3, 128.9, 128.0,
126.8, 117.9, 113.6, 112.1, 62.1, 61.8, 58.1, 57.0, 14.1, 14.0.
(1H, s, NH), 7.20 (2H, d, J 8.4 Hz, ArH), 7.15e7.07 (8H, m, ArH), 7.02
(2H, d, J 8.0 Hz, ArH), 6.38 (2H, d, J 9.2 Hz, ArH), 6.31 (1H, s, H-2),
6.13 (2H, d, J 8.4 Hz, ArH), 5.06 (1H, d, J 3.6 Hz, H-6), 3.93 (3H, s,
OMe), 2.84 (1H, dd, J 15.2, 5.6 Hz, H-50), 2.70 (1H, dd, J 15.2, 2.4 Hz,
H-500), 2.34 (3H, s, Me), 2.32 (3H, s, Me); dC (100 MHz, CDCl3) 168.6
(C]O), 155.6 (C-4), 146.1, 140.2, 139.2, 137.2, 137.1, 136.3, 132.1, 131.7,
129.6, 129.2, 127.4, 126.6, 126.4, 119.2, 114.7, 108.4, 98.9 (C-3), 58.1
(C-6), 55.2 (C-2), 51.3, 33.6 (C-5), 21.3, 21.2; HRMS (ESI): MHþ,
found: 645.0753. C33H30N2O2Br2 requires 645.0752.
4.2.23. Methyl 4-hydroxy-1,2,6-triphenyl-1,2,5,6-tetrahydropyridine-
3-carboxylate (4g). To a solution of amine (2 mmol) and methyl
acetoacetate (1 mmol) in 5 mL of methanol was added iodine
(0.1 mmol) and stirred at room temperature. After 20 min, benz-
aldehyde (2 mmol) was added to the reaction mixture and stirring
was continued for completion. The thick precipitate was filtered off
and washed with ethanol to give mixture of two products of Rf (5%
ethyl acetate/hexane) 0.38 and 0.49, respectively. Products were
purified by column chromatography using ethyl acetate/hexane
(98:2) furnished 4g (0.124 g, 29%) as white solid; [found: C, 77.78;
H, 5.91; N, 3.45. C25H23NO3 requires C, 77.90; H, 6.01; N, 3.63%]; mp
166e168 ꢀC; Rf (5% ethyl acetate/hexane) 0.49; nmax (KBr) 1658 (C]
4.2.19. Methyl 2,6-bis(4-methylphenyl)-1-(4-nitrophenyl)-4-(4-nitro-
phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (1s). Yellow
solid (0.330 g, 57%); [found: C, 68.39; H, 5.14; N, 9.88. C33H30N4O6
requires C, 68.50; H, 5.23; N, 9.68%]; mp 253e255 ꢀC; Rf (15% ethyl
acetate/hexane) 0.20; nmax (KBr) 1658 (C]O), 1587 (C]C) cmꢁ1
; dH
(400 MHz, CDCl3) 10.55 (1H, s, NH), 8.00 (2H, d, J 9.2 Hz, ArH), 7.97
(2H, d, J 9.6 Hz, ArH), 7.13 (6H, s, ArH), 7.02 (2H, d, J 8.0 Hz, ArH), 6.54
(2H, d, J 9.6 Hz, ArH), 6.48 (1H, s, H-2), 6.43 (2H, d, J 9.2 Hz, ArH), 5.27
(1H, d, J 3.2 Hz, H-6), 3.99 (3H, s, OMe), 3.06 (1H, dd, J 15.2, 5.6 Hz, H-
50), 2.94 (1H, dd, J 15.2, 2.4 Hz, H-500), 2.34 (6H, s, 2ꢂMe); dC
(100 MHz, CDCl3) 168.3 (C]O), 153.3 (C-4), 151.9, 144.1, 138.3, 138.1,
137.9, 137.5, 137.2, 130.0, 129.7, 126.2, 126.1, 125.9, 125.1, 123.1, 112.3,
102.0 (C-3), 58.5 (C-6), 55.8 (C-2), 52.0, 33.8 (C-5), 21.3, 21.2; HRMS
(ESI): MHþ, found: 579.2244. C33H30N4O6 requires 579.2244.
C), 1595 (C]C) cmꢁ1
; dH (400 MHz, CDCl3) 11.94 (1H, br s, OH),
7.28e7.16 (10H, m, ArH), 7.03 (2H, t, J 7.2 Hz, ArH), 6.67 (1H, t, J
7.6 Hz, ArH), 6.55 (2H, d, J 8.4 Hz, ArH), 5.99 (1H, s, H-2), 5.12 (1H, t, J
5.2 Hz, H-6), 3.87 (3H, s, OMe), 3.08 (1H, dd, J 16.2, 5.6 Hz, H-50),
2.73 (1H, dd, J 16.4, 4.8 Hz, H-500); dC (100 MHz, CDCl3) 170.8, 170.5,
142.7, 142.3, 128.9, 128.8, 128.5, 127.3, 127.1,127.0, 126.6, 118.3, 116.5,
102.2, 57.6, 56.9, 52.2, 36.8.
4.2.20. Methyl
2,6-bis(4-methylphenyl)-1-butyl-4-(butylamino)-
4.2.24. Methyl 4-hydroxy-2,6-bis(4-nitrophenyl)-1-phenyl-1,2,5,6-
tetrahydropyridine-3-carboxylate (4n). Purification was performed
by column chromatography using ethyl acetate/hexane (95:5) to
furnished 4n (0.057 g,12%) as light yellow solid; [found: C, 63.02; H,
4.31; N, 8.71. C25H21N3O7 requires C, 63.15; H, 4.45; N, 8.84%]; mp
173e175 ꢀC; Rf (15% ethyl acetate/hexane) 0.26; nmax (KBr) 1638
1,2,5,6-tetrahydropyridine-3-carboxylate (1t). Light yellow solid
(0.215 g, 48%); [found C, 77.51; H, 8.91; N, 6.37. C29H40N2O2 requires
C, 77.64; H, 8.99; N, 6.24%]; mp 158e160 ꢀC; Rf (5% ethyl acetate/
hexane) 0.46; nmax (KBr) 3428 (NeH), 1649 (C]O), 1597 (C]
C) cmꢁ1
; dH (400 MHz, CDCl3) 9.22 (1H, t, J 4.8 Hz, NH), 7.31 (2H, d, J
8.0 Hz, ArH), 7.17 (2H, J 8.0 Hz, ArH), 7.08 (4H, t, J 7.6 Hz, ArH), 4.92
(1H, s, H-2), 3.85 (1H, dd, J 11.6, 5.2 Hz, H-6), 3.55 (3H, s, OMe),
3.38e3.24 (2H, m, CH2), 2.60 (1H, dd, J 17.2, 11.2 Hz, H-50), 2.51 (1H,
dd, J 17.2, 5.2 Hz, H-500), 2.32 (3H, s, Me), 2.30 (3H, s, Me), 2.15e2.08
(2H, m, CH2), 1.68e1.60 (2H, m, CH2), 1.52e1.43 (2H, m, CH2),
1.36e1.26 (2H, m, CH2), 1.23e1.10 (2H, m, CH2), 0.98 (3H, t, J 7.2 Hz,
CH3), 0.79 (3H, t, J 7.2 Hz, CH3); dC (100 MHz, CDCl3) 171.4 (C]O),
159.7 (C-4), 142.4, 139.3, 136.4, 135.6, 128.9, 128.8, 128.4, 127.3, 87.9
(C-3), 58.6 (C-6), 52.5 (C-2), 50.6, 44.7, 42.1, 32.5 (C-5), 31.1, 25.6,
21.3, 20.6, 20.5, 14.3, 14.1; HRMS (ESI): MHþ, found: 449.3160.
C29H40N2O2 requires 449.3168.
(C]O), 1595 (C]C) cmꢁ1
; dH (400 MHz, CDCl3) 11.99 (1H, br s, OH),
8.11 (4H, t, J 7.2 Hz, ArH), 7.36 (2H, d, J 8.4 Hz, ArH), 7.33 (2H, d, J
8.4 Hz, ArH), 7.04 (2H, t, J 7.6 Hz, ArH), 6.76 (1H, t, J 7.2 Hz, ArH), 6.46
(2H, d, J 8.0 Hz, ArH), 5.95 (1H, s, H-2), 5.13 (1H, t, J 5.2 Hz, H-6), 3.85
(3H, s, OMe), 3.07 (1H, dd, J 17.2, 4.8 Hz, H-50), 2.76 (1H, dd, J 17.2,
5.2 Hz, H-500); dC (100 MHz, CDCl3) 170.7, 149.4, 147.5, 129.3, 128.1,
127.8, 124.3, 123.9, 120.7, 118.2, 101.0, 58.4, 56.5, 52.4, 36.9.
4.2.25. Methyl 1-(2-naphthyl)-4-(2-naphthylamino)-2,6-diphenyl-
1,2,5,6-tetrahydropyridine-3-carboxylate (1v). Reaction was carried
out with 2-naphthylamine (1 mmol), methyl acetoacetate
(0.5 mmol) and benzaldehyde (1 mmol) in methanol (3 mL) in the
presence of 10 mol % iodine at room temperature or at 55 ꢀC. After
completion of reaction, solid precipitate was filtered and washed
with ethanol to give 1v (0.297 g, 53%) as white solid; [found: C,
4.2.21. Methyl 2,6-bis(4-methylphenyl)-1-benzyl-4-(benzylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (1u). Light yellow solid
(0.284 g, 55%); [found C, 81.22; H, 7.07; N, 5.57. C35H36N2O2 requires

A.T. Khan et al. / Tetrahedron 66 (2010) 7762e7772
7771
83.38; H, 5.63; N, 5.10. C39H32N2O2 requires C, 83.54; H, 5.75; N,
program and refined by full-matrix least-squares methods on F2.
All non-hydrogen atomic positions were located in difference
Fourier maps and refined anisotropically. The hydrogen atoms were
placed in their geometrically generated positions. Compound 1f
empirical formula C34H32Cl2N2O2, colourless prismatic crystal, for-
mula wt 571.52, monoclinic, P2(1)/n, a¼11.2764(3), b¼12.9186(4),
c¼20.6225(6) Å, V¼2976.78(15) Å3, Z¼4, F (0 0 0)¼1200, GOF(S)¼
0.958. Final indices Robs¼0.0545, wRobs¼0.1747 with I>2r(I);
Rall¼0.1118, wRall¼0.1924 for all data. Compound 1k empirical for-
mula C31H26Br2N2O2, colourless prismatic crystal, formula wt
618.36, triclinic, P-1 a¼10.1710(5), b¼10.7901(5), c¼13.9201(6) Å,
V¼1385.53(11) Å3, Z¼2, F (0 0 0)¼624, GOF(S)¼0.994. Final indices
Robs¼0.0434, wRobs¼0.1026 with I>2r(I); Rall¼0.1047, wRall¼0.1289
for all data.
5.00%]; mp 196e198 ꢀC; Rf (5% ethyl acetate/hexane) 0.30; nmax
(KBr) 3421 (NeH), 1657 (C]O), 1594 (C]C) cmꢁ1
; dH (400 MHz,
CDCl3) 10.45 (1H, s, NH), 7.75 (1H, dd, J 8.0, 2.0 Hz, ArH), 7.59 (2H, t, J
8.4 Hz, ArH), 7.56e7.52 (2H, m, ArH), 7.47e7.41 (3H, m, ArH),
7.34e7.33 (4H, m, ArH), 7.31e7.20 (7H, m, ArH), 7.11 (1H, t, J 8.0 Hz,
ArH), 6.97 (1H, dd, J 9.2, J 2.4 Hz, ArH), 6.77 (1H, d, J 2.4 Hz, ArH),
6.66 (1H, s, ArH), 6.59 (1H, s, H-2), 6.55 (1H, dd, J 8.8, 2.4 Hz, ArH),
5.30 (1H, br s, H-6), 3.99 (3H, s, OMe), 2.93 (2H, d, J 4.0 Hz, CH2); dC
(100 MHz, CDCl3) 168.8 (C]O),156.4 (C-4), 145.1,144.0, 143.1, 135.5,
135.0, 133.5, 131.8, 129.1, 128.8, 128.5, 127.8, 127.7, 127.5, 127.4, 126.9,
126.7, 126.6, 126.5, 126.2, 125.9, 125.0, 123.3, 122.0, 116.2, 107.2, 98.4
(C-3), 58.6 (C-6), 55.4 (C-2), 51.4, 33.7 (C-5).
4.2.26. Methyl 2,6-bis(4-methylphenyl)-1-(2-naphthyl)-4-(2-naph-
thylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (1w). Reaction
carried out with 2-naphthylamine (1 mmol), methyl acetoacetate
(0.5 mmol) and methylbenzaldehyde (1 mmol) in methanol (3 mL)
in the presence of 10 mol % iodine at room temperature. After
completion, solid precipitate formed was filtered and washed with
ethanol to give 1w (0.300 g, 51%) as white solid; [found: C, 83.49; H,
5.91; N, 4.71. C41H36N2O2 requires C, 83.64; H, 6.16; N, 4.76%]; mp
220e222 ꢀC; Rf (5% ethyl acetate/hexane) 0.33; nmax (KBr) 3445
Complete crystallographic data of 1f and 1k for the structural
analysis have been deposited with the Cambridge Crystallographic
Data Centre, as supplementary publication CCDC no. are 756203
and 756204. Copies of this information may be obtained free of
charge from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44 1223 336033,
e-mail: deposit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk).
Acknowledgements
(NeH), 1656 (C]O), 1593 (C]C) cmꢁ1
; dH (400 MHz, CDCl3) 10.45
(1H, s, NH), 7.75 (2H, d, J 7.2 Hz, ArH), 7.60 (2H, t, J 8.8 Hz, ArH),
7.54e7.50 (2H, m, ArH), 7.47e7.42 (3H, m, ArH), 7.25e7.23 (3H, m,
ArH), 7.14 (4H, s, ArH), 7.09 (2H, t, J 8.0 Hz, ArH), 6.98 (1H, dd, J 9.2,
2.4 Hz, ArH), 6.77 (1H, d, J 2.0 Hz, ArH), 6.60 (1H, s, H-2), 6.59e6.57
(2H, m, ArH), 5.26 (1H, br s, H-6), 3.98 (3H, s, OMe), 2.91 (2H, d, J
4.0 Hz, CH2), 2.39 (3H, s, Me), 2.32 (3H, s, Me); dC (100 MHz, CDCl3)
168.9 (C]O), 156.4 (C-4), 145.2, 141.0, 140.1, 137.0, 136.1, 135.6,
135.0, 133.6, 131.5, 129.7, 129.2, 129.0, 128.7, 127.8, 127.6, 127.5,
126.8, 126.6, 126.5, 126.4, 126.1, 125.8, 125.0, 123.2, 121.9, 116.2,
107.1, 98.5 (C-3), 58.4 (C-6), 55.2 (C-2), 51.3, 33.7 (C-5), 21.4, 21.2.
M.M.K. is thankful to UGC, New Delhi, India for his research
fellowship. We acknowledge DST, New Delhi for providing single
crystal XRD facility to the Department of Chemistry under FIST
programme (S.No.: SR/FST/CSII-007/2003).
Supplementary data
The general experimental procedures, X-ray crystallographic
data (CIF file) of 1f and 1k as well as copies of 1H and 13C NMR and
HRMS spectra of products. This information can be found in the
online version, at doi:10.1016/j.tet.2010.07.075. These data include
MOL files and InChIKeys of most important compounds described
in this article.
4.2.27. Ethyl 3-oxo-4-phenylbutanoate. It was prepared according
to the literature procedure19 from phenylacetyl chloride. To a so-
lution of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.44 g, 10 mmol) in
CH2Cl2 (6 mL) at 0 ꢀC in 100 mL round-bottomed flask equipped
with a dropping funnel was added pyridine (2 mL) over 5 min. To
this solution was then added a solution of phenylacetyl chloride
(1.33 mL, 10 mmol) in CH2Cl2 (14 mL) over 10 min. This resulted in
the formation of an orange solution. The reaction was stirred at 0 ꢀC
for 30 min and at rt for 1 h. CH2Cl2 (20 mL) was added and the
solution was washed with water (30 mLꢂ4). The organic phase was
dried over MgSO4 and the solvent was removed to give as an orange
oil (2.2 g). This was dissolved in EtOH (30 mL) and heated at reflux
for 3 h. Evaporation of the solvent afforded crude as an orange oil,
which was purified by column chromatography using ethyl ace-
tate/hexane (98:2) furnished (1.65 g, 80%) as a colourless oil; Rf (2%
ethyl acetate/hexane) 0.4; nmax (KBr) 1744 (C]O), 1716 (C]
References and notes
1. (a) Elbein, A. D.; Molyneux, R. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; John Wiley & Son: New York, NY, 1987; Vol. 57; (b) O’Hagan,
D. Nat. Prod. Rep. 2000, 17, 435e446; (c) Daly, J. W.; Spande, T. F.; Garraffo, H. M.
J. Nat. Prod. 2005, 68, 1556e1575.
2. (a) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679e3681; (b) Lebold, T.
P.; Leduc, A. B.; Kerr, M. A. Org. Lett. 2009, 11, 3770e3772.
3. Petit, S.; Nallet, J. P.; Guillard, M.; Dreux, J.; Chermat, R.; Poncelet, M.; Bulach, C.;
Simon, P.;Fontaine, C.; Barthelmebs, M.; Imbs, J. L. Eur. J. Med.Chem.1991, 26,19e32.
4. Zhou, Y.; Gregor, V. E.; Ayida, B. K.; Winters, G. C.; Sun, Z.; Murphy, D.; Haley, G.;
Bailey, D.; Froelich, J. M.; Fish, S.; Webber, S. E.; Hermann, T.; Wall, D. Bioorg.
Med. Chem. Lett. 2007, 17, 1206e1210.
5. Bin, H.; Crider, A. M.; Stables, J. P. Eur. J. Med. Chem. 2001, 36, 265e286.
6. Misra, M.; Pandey, S. K.; Pandey, V. P.; Pandey, J.; Tripathi, R.; Tripathi, R. P.
Bioorg. Med. Chem. 2009, 17, 625e633.
7. (a) Esquivias, J.; Arrayas, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129,
1480e1481; (b) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125,
4716e4717; (c) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
6042e6043; (d) Amat, M.; Bassas, O.; Pericàs, M. A.; Pasto, M.; Bosch, J. Chem.
Commun. 2005, 1327e1329; (e) Martín, R.; Murruzzu, C.; Pericàs, M. A.; Riera, A.
J. Org. Chem. 2005, 70, 2325e2328.
O) cmꢁ1
; dH (400 MHz, CDCl3) 7.36e7.28 (3H, m, ArH), 7.21 (2H, d, J
7.2 Hz, ArH), 4.17 (2H, q, J 7.2 Hz, OCH2), 3.83 (3H, s, PhCH2), 3.45
(2H, s, COCH2CO), 1.26 (3H, t, J 7.2 Hz, CH3); dC (100 MHz, CDCl3)
200.6, 167.2, 133.4, 129.7, 129.0, 127.5, 61.5, 50.1, 48.4, 14.2.
8. (a) Takasu, K.; Shindoh, N.; Tokuyama, H.; Ihara, M. Tetrahedron 2006, 62,
11900e11906; (b) Sales, M.; Charette, A. B. Org. Lett. 2005, 7, 5773e5776.
9. (a) Murty, M. S. R.; Ram, R.; Yadav, J. S. Tetrahedron Lett. 2008, 49, 1141e1145; (b)
Carballo, R. M.; Ramirez, M. A.; Rodriguez, M. L.; Martin, V. S.; Padron, J. I. Org.
Lett. 2006, 8, 3837e3840; (c) Dobbs, A. P.; Guesne, S. J. J. Synlett 2005, 2101e2103.
10. Fustero, S.; Jimenez, D.; Moscardo, J.; Catalan, S.; Pozo, C. D. Org. Lett. 2007, 9,
5283e5386.
4.3. Crystallographic description
Crystal data were collected with Bruker Smart Apex-II CCD dif-
fractometer using graphite monochromated Mo K
a radiation
(
l
¼0.71073 Å) at 298 K. Cell parameters were retrieved using
SMART20a software and refined with SAINT20a on all observed re-
flections. Data reduction was performed with the SAINT software
and corrected for Lorentz and polarization effects. Absorption cor-
rections were applied with the program SADABS20b. The structure
was solved by direct methods implemented in SHELX-9720c
11. Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169e3171.
12. (a) Zhu, J.; Bienayme, H. Multicomponent Reactions, 1st ed.; Wiley-VCH: Wein-
heim, Germany, 2005; (b) Tempest, P. A. Curr. Opin. Drug Discov. 2005, 8,
776e788; (c) Fujioka, H.; Murai, K.; Kubo, O.; Ohba, Y.; Kita, Y. Org. Lett. 2007, 9,
1687e1690; (d) Evdokimov, N. M.; Kireev, A. S.; Yakovenko, A. A.; Antipin, M. Y.;
Magedov, I. V.; Kornienko, A. J. Org. Chem. 2007, 72, 3443e3453.

7772
A.T. Khan et al. / Tetrahedron 66 (2010) 7762e7772
€
13. (a) Domling, A. Chem. Rev. 2006, 106, 17e89; (b) Ramón, D. J.; Yus, M. Angew.
Chem. 2005, 117, 1628e1661; Angew. Chem., Int. Ed. 2005, 44, 1602e1634; (c)
M.; Mothsra, P.; Bansal, V.; Somvanshi, R. K.; Ethayathullah, A. S.; Dey, S.; Singh,
T. P. J. Mol. Cat. A: Chem. 2007, 265, 177e182; (e) Lin, C.; Lai, P.-T.; Liao, S. K.-S.;
Hung, W.-T.; Yang, W.-B.; Fang, J.-M. J. Org. Chem. 2008, 73, 3848e3853; (f)
Kumar, N.; Khan, S. I.; Sharma, M.; Atheaya, H.; Rawat, D. S. Bioorg. Med. Chem.
Lett. 2009, 19, 1675e1677; (g) Wang, X.-S.; Li, Q.; Wu, J.-R.; Tu, S.-J. J. Comb.
Chem. 2009, 11, 433e437; (h) Nath, J.; Patel, B. K.; Jamir, L.; Sinha, U. B.;
Satyanarayana, K. V. V. V. Green Chem. 2009, 11, 1503e1506.
€
Zhu, J. Eur. J. Org. Chem. 2003, 1133e1144; (d) Domling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168e3210.
14. (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259e281; (b) Wender, P. A.;
Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 765e769.
15. (a) Khan, A. T.; Parvin, T.; Choudhury, L. H. J. Org. Chem. 2008, 73, 8393e8402;
(b) Khan, A. T.; Lal, M.; Khan, M. M. Tetrahedron Lett. 2010, 51, 4419e4424.
16. (a)Clarke,P.A.;Zaytzev,A.V.;Whitwood,A.C.Tetrahedron Lett. 2007,48,5209e5212;
(b) Clarke, P. A.; Zaytzev, A. V.; Whitwood, A. C. Synthesis 2008, 3530e3532.
17. Togo, H.; Iida, H. Synlett 2006, 2159e2175.
18. (a) Wang, X.-S.; Li, Q.; Wu, J.-R.; Li, Y.-L.; Yao, C.-S.; Tu, S.-J. Synthesis 2008,
1902e1910; (b) Phukan, P. J. Org. Chem. 2004, 69, 4005e4006; (c) Phukan, P.;
Kataki, D.; Chakraborty, P. Tetrahedron Lett. 2006, 47, 5523e5525; (d) Kidwai,
19. Svenstrup, N.; Simonsen, K. B.; Thorup, N.; Brodersen, J.; Dehaen, W.; Becher, J.
J. Org. Chem. 1999, 64, 2814e2820.
20. (a) Smart V 4.043 Software for the CCD Detector System; Siemens Analytical
Instruments Division: Madison, WI, 1995; (b) Saint V 4.035 Software for the CCD
Detector System; Siemens Analytical Instruments Division: Madison, WI, 1995;
(c) Sheldrick, G. M. SHELXL-97, Program for the Refinement of Crystal Structures;
€
€
University of Gottingen: Gottingen (Germany), 1997.