'On-Water' Multicomponent Reaction for the Diastereoselective Synthesis of Functionalized Tetrahydropyridines and Mechanistic Insight

Article abstract of DOI:10.1055/s-0035-1561296

An ecofriendly approach for the synthesis of highly substituted tetrahydropyridines by an 'on-water' multicomponent reaction has been demonstrated. The use of water as the reaction medium is essential under the catalytic influence of a surfactant. The use of a variety of anionic, cationic, and non-ionic surfactants in water was examined and the reaction was successfully catalyzed by anionic surfactants sodium dioctyl sulfosuccinate (SDOSS) and sodium dodecyl sulfate (SDS), with the former being superior. The use of an organic solvent together with a catalytic amount of sodium dioctyl sulfosuccinate to form homogeneous conditions afforded inferior yields and highlighted the specific role of water through the creation of microreactors at the water surfactant interface. A mechanistic insight for the five-component reaction leading to the formation of tetrahydropyridines is provided invoking a tandem inter- and intramolecular Mannich reaction pathway.

Full text of DOI:10.1055/s-0035-1561296

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
N. Parikh et al.
Paper
Synthesis
‘On-Water’ Multicomponent Reaction for the Diastereoselective
Synthesis of Functionalized Tetrahydropyridines and Mechanistic
Insight
R3
Naisargee Parikh
Sudipta Raha Roy
Kapileswar Seth
Asim Kumar
O
HN
N
H
O
NH2
H2O
R4
O
O
Asit K. Chakraborti*
SDOSS (5 mol%)
+
+
R4
r.t., 4–10 h
R1
Department of Medicinal Chemistry National Institute
of Pharmaceutical Education and Research (NIPER),
Sector 67, S. A. S. Nagar 160 062, Punjab, India
akchakraborti@niper.ac.in
R3
R2
R2
R2
R1
R1
R1, R2, R3 = H, Me, Br, F, OMe, OCH2O
R4 = OMe, OEt, Ot-Bu
R3
akchakraborti@rediffmail.com
(RS)
63–86%, 17 examples
highly diastereoselective
Received: 30.07.2015
Accepted after revision: 23.11.2015
Published online: 29.12.2015
The multicomponent reactions have favorable attri-
butes, especially atom economy, as well as efficient genera-
tion of chemical diversity and rapid exploration of chemical
space.8 In continuation of our efforts towards the develop-
ment of ecofriendly synthetic methodologies based on the
distinct advantages of rate acceleration in water as the reac-
tion medium9 and using a multicomponent reaction strate-
gy,10 we report herein a water-assisted multicomponent re-
action strategy for the diastereoselective formation of func-
tionalized tetrahydropyridines with the double benefit of
green chemistry, i.e., use of a green reaction medium and
one-pot synthesis.
The formation of tetrahydropyridine was explored us-
ing a model reaction involving benzaldehyde (1a), aniline
(2a), and ethyl acetoacetate (3a) in a 2:2:1 molar ratio for
the formation of ethyl (RS)-1,2,6-triphenyl-4-(phenylami-
no)-1,2,5,6-tetrahydropyridine-3-carboxylate [(RS)-4a] at
room temperature (35–40 °C) in various polar and nonpolar
reaction media (Table 1). An initial attempt to perform the
reaction in water without a catalyst gave a poor yield (entry
1). Anticipating that the poor result in water could be due to
the lack of miscibility/solubility of the reactants in aqueous
medium, various surfactants (anionic, cationic, and neu-
tral) were used as catalysts, as surfactants are known to be
solubility enhancers of water-insoluble organics.11
DOI: 10.1055/s-0035-1561296; Art ID: ss-2015-n0585-op
Abstract An ecofriendly approach for the synthesis of highly substitut-
ed tetrahydropyridines by an ‘on-water’ multicomponent reaction has
been demonstrated. The use of water as the reaction medium is essen-
tial under the catalytic influence of a surfactant. The use of a variety of
anionic, cationic, and non-ionic surfactants in water was examined and
the reaction was successfully catalyzed by anionic surfactants sodium
dioctyl sulfosuccinate (SDOSS) and sodium dodecyl sulfate (SDS), with
the former being superior. The use of an organic solvent together with
a catalytic amount of sodium dioctyl sulfosuccinate to form homoge-
neous conditions afforded inferior yields and highlighted the specific
role of water through the creation of microreactors at the water surfac-
tant interface. A mechanistic insight for the five-component reaction
leading to the formation of tetrahydropyridines is provided invoking a
tandem inter- and intramolecular Mannich reaction pathway.
Key words tetrahydropyridines, multicomponent reaction, diastereo-
selective, surfactant, on-water
Tetrahydropyridines are common structural motifs in
biologically active compounds.1 This has generated interest
in the development of methodologies for their synthesis,2
but some of the existing routes have some undesirable at-
tributes.
Modern chemical manufacturing is evaluated using the
‘triple bottom line’ philosophy of green chemistry.3 Eco-
friendly/green approaches for the preparation of drugs and
pharmaceuticals are of current interest to minimize ad-
verse effects on the environment.4 The push for clean, green
manufacturing processes requires atom economy, minimal
waste generation, and environmentally benign reagents
and solvents,5 with water being the preferred solvent
whenever possible.4b,6 Thus, there has been an upsurge in
the use of water as nonclassical reaction medium.7
Poor results were obtained with the non-ionic (entries
2–5) and cationic surfactants (entries 6–10). Amongst the
anionic surfactants sodium dioctyl sulfosuccinate (SDOSS,
entry 11) and sodium dodecyl sulfate (SDS, entry 12) exhib-
ited very good catalytic activity affording (RS)-4a in 72 and
65% yields, respectively, however sodium deoxycholate
(SDC) (entry 13) gave a poor yield.
To identify the advantages of using water as the reaction
medium, the five-component reaction of 1a, 2a, and 3a in
2:2:1 molar ratio was performed in various commonly used
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
N. Parikh et al.
Paper
Synthesis
nonpolar, weakly polar, aprotic polar, and protic polar or-
ganic solvents (entries 16–23) in the presence of SDOSS (5
mol%). The inferior yields obtained in organic solvents
clearly reflect the distinct advantage of using water as the
reaction medium, which could be related to micelle forma-
tion by SDOSS in aqueous media and these micelles could
act as microreactors.12
Further experiments to optimize the various reaction
parameters, such as the effective amount of SDOSS, reaction
time, and temperature, for the multicomponent reaction of
1a, 2a, and 3a in 2:2:1 molar ratio were performed (Table
2). The use of 5 mol% SDOSS at room temperature for four
hours (entry 3) afforded 4a in 72% yield and increasing the
reaction time to 10 hours improved the yield to 84% (entry
8). The use of smaller amounts (2–4 mol%) of SDOSS had a
detrimental effect on product yield (entries 1 and 2), while
the use of larger amounts (6–10 mol%) did not have a bene-
ficial effect such as increasing the yield of the product or re-
ducing the reaction time (entries 4, 8, and 10). Increasing
the reaction temperature (60–100 °C) did not have a bene-
ficial effect in terms of product yield or reduction of the re-
action time (entries 12–20).
Table 1 The Multicomponent Reaction of 1a, 2a, and 3a To Form (RS)-
4a under Various Conditionsa
H
O
NH
N
O
NH2
O
O
OEt
+
+
OEt
Table 2 Evaluation of Various Reaction Parameters for the Multicom-
ponent Reaction of 1a, 2a, and 3a To Form (RS)-4a in Water in the Pres-
ence of SDOSSa
3a
(2 mmol)
1a
(4 mmol)
2a
(4 mmol)
(RS)-4a
Entry
SDOSSb (mol%) Time (h)
Temp (°C)
Yieldc (%)
Entry
Surfactant
Solvent
H2O
Yieldb (%)
10
1
2
2
4
4
4
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
60
22
58
72
73
47
63
72
84
76
52
85
72
57
81
71
60
82
70
59
80
1
–
3
5
4
non-ionic
PEG-600
4
6
4
2
3
4
5
H2O
H2O
H2O
H2O
29
25
19
17
5
5
2
PEG-10000
Tween 40
Span 80
cationic
TBAB
6
5
3
7
5
5
8
5
10
4
9
10
10
10
5
6
7
H2O
H2O
H2O
H2O
H2O
17
14
12
20
26
10
11
12
13
14
15
16
17
18
19
20
2
TBAC
10
4
8
TBAF
9
CTAB
5
3
60
10
benzalkonium chloride
anionic
SDOSS
5
10
4
60
5
80
11
12
13
14
15
16
17
18
19
20
21
H2O
72
65
32
19
21
33
26
34
45
38
41
5
3
80
SDS
H2O
5
10
4
80
SDC
H2O
5
100
100
100
SDOSS
hexane
5
3
SDOSS
cyclohexane
toluene
THF
5
10
SDOSS
a Reaction conditions: 1a (4 mmol), 2a (4 mmol), 3a (2 mmol), SDOSS, H2O
(2 mL), magnetic stirring.
SDOSS
b The amount of SDOSS used with respect to 3a.
c The yield of (RS)-4a after crystallization (EtOH) of the isolated crude prod-
uct.
SDOSS
EtOAc
SDOSS
MeCN
SDOSS
MeOH
EtOH
SDOSS
To establish the generality of the method, various aryl
and heteroaryl aldehydes 1, amines 2, and 1,3-dicarbonyl
compounds 3 were subjected to the multicomponent reac-
tion in water catalyzed by SDOSS to give the functionalized
tetrahydropyridines 4; the results are summarized in Table
a Reaction conditions: 1a (4 mmol), 2a (4 mmol), 3a (2 mmol), catalyst (5
mol%), solvent (2 mL), magnetic stirring, r.t. (35–40 °C), 4 h.
b Yield of (RS)-4a after crystallization (EtOH) of the crude product.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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N. Parikh et al.
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Synthesis
3. In general, the reactions were performed for four hours
instead of ten hours in view of the overall cost that is in-
volved when performing the reaction for a longer period.
However, in a few selective cases the product yield for a ten
hour reaction period is provided in the parenthesis in the
yield column of Table 3. In all the cases, the reaction pro-
ceeded smoothly to afford the corresponding substituted
tetrahydropyridines 4 in 63–86% yields after crystallization
(EtOH) of the isolated crude product. The reaction with 4-
methoxybenzaldehyde (1d), considered to be a less electro-
philic aldehyde, worked efficiently giving 4g in 74% yield
(entry 7). Substitution at the ortho position in the aniline 2-
methylaniline (2d) (entry 11) resulted in a lower yield of 4k
and the reaction required a longer time due to the steric ef-
fect. No aromatic nucleophilic substitution of the halogen
atom took place for aldehydes 1b,c bearing F/Br at the para
position (entries 4–6, and 17). Attempts were made to syn-
thesize tetrahydropyridines 4 from aliphatic aldehydes, but
in each case it was difficult to isolate the corresponding tet-
rahydropyridines and a complicated reaction mixture was
obtained.2w However, the reaction with an aliphatic amine
butylamine (2h) proceeded smoothly to afford the corre-
sponding tetrahydropyridine 4q (entry 17).
Table 3 SDOSS-Catalyzed ‘On-Water’ Multicomponent Reaction for the Synthesis of Functionalized Tetrahydropyridinesa
R3
H
O
O
HN
N
NH2
H2O
R4O
O
O
SDOSS (5 mol%)
+
+
OR4
r.t.
R1
R3
R2
R2
R2
3
1
2
R1
R1
(RS)-4
R3
Entry
1
2
3
Time (h)
4
Yieldb–d (%)
R1
R2
R3
R4
1
2
H
H
H
Et
4
4a
72 (84)e
75 (86)
76
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
Me
t-Bu
Et
4.5
4.5
5
4b
4c
4d
4e
4f
3
4
70
5
F
Me
Et
5
71 (85)
73 (86)
74
6
Br
4.5
4
7
OMe
Me
H
Et
4g
4h
4i
8
Et
4
73
9
4-OMe
4-OCF3
2-Me
4-Br
Et
4.5
5
75
10
11
12
13
14
15
16
17
H
Et
4j
70 (81)
63 (79)
72
H
Et
6
4k
4l
H
Et
5
H
4-Cl
Et
5
4m
4n
4o
4p
4q
70
OMe
OMe
4-Me
4-OMe
H
Me
Me
Et
4.5
5
75
74
OCH2O
H
5
70 (83)
69 (81)
f
F
–
t-Bu
4
a Reaction conditions: aldehyde 1 (4 mmol), amine 2 (4 mmol), 1,3-dicarbonyl compound 3 (2 mmol), SDOSS (5 mol%), H2O (2 mL), magnetic stirring, r.t. (35–
40 °C).
b Isolated yield.
c The trans diastereomer was formed in each case as determined by 1H NMR.
d The figure in parentheses is the isolated yield of the tetrahydropyridine for a 10 h reaction period.
e The tetrahydropyridine was formed in 84% yield after performing the reaction overnight (~20 h).
f Butylamine (BuNH2) was used as the substrate.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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N. Parikh et al.
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Synthesis
In each case the reaction was found to be highly diaste-
The earliest report2w endorsing the Knoevenagel con-
densation–aza-Diels–Alder reaction route (path A) seems
inconclusive as it was based on the observation that tetra-
hydropyridine formation took place in 44% yield during the
treatment of the preformed imine II and the Knoevenagel
condensation product (of methyl acetoacetate and 1a) with
1a. However, the formation of tetrahydropyridine 4a in
comparable yield (46%) during the reaction of the pre-
formed I and II with 1a also suggests path B. A subsequent
report1b proposed path A based on the fact that during the
reaction of 3-methoxybenzaldehyde, aniline (2a), and
methyl acetoacetate (3b) the corresponding imine and the
Knoevenagel condensation product (of methyl acetoacetate
and 3-methoxybenzaldehyde) were isolated in 10% yield to-
gether with the desired tetrahydropyridine (20% yield). A
further mechanistic proposal2q invoking path A was based
on the formation of the desired tetrahydropyridine through
the reaction of the preformed enamine [of 4-chloroaniline
(2f) and methyl acetoacetate (3b)] with benzaldehyde (1a)
reoselective affording the trans diastereomer confirmed by
1
analysis of H NMR and comparing these with the litera-
ture.2v In a representative example, the 1H NMR of the
crude product (product isolated through extraction of the
reaction mixture with EtOAc without any purification such
as crystallization with EtOH) obtained from the reaction of
benzaldehyde (1a), 4-chloroaniline (2f) and ethyl acetoace-
tate (3a) was compared with the 1H NMR of the pure trans-
isomer 4m (Table 3, entry 13) which showed only the pres-
ence of H5 as a multiplet at δ = 5.12–5.14 and there were no
other peaks in the range of δ = 4.7–6.0; H6 of ‘cis’ tetrahy-
dropyridines generally appears as a doublet of doublets (dd)
at δ = 4.52–4.54.13 Furthermore, the HPLC profile of the
crude product obtained from the reaction of benzaldehyde
(1a), 4-chloroaniline (2f), and ethyl acetoacetate (3a) was
compared to that of the pure trans-isomer 4m (tR = 30.407
min). The HPLC data (Supporting Information) suggests that
the crude product contains only the trans-isomer 4m (tR =
30.417 min) as there was no other peak in the range of tR =
10–55 min.
Table 4 Comparison of the Lewis/Protic Acid Catalyzed Multicompo-
nent Reactions of 1a, 2a, and 3a To Form (RS)-4aa
The efficacy of the present protocol in water was com-
pared to that of some of reported Lewis/protic acid cata-
lyzed procedures performed in organic solvents. This would
highlight the specific advantages, if any, of SDOSS in water
vs Lewis acid catalyst in water (Table 4). The results in Table
4 clearly demonstrate the superiority of our methodology
over these reported procedures. The results further high-
light that inferior results are obtained for the Lewis/protic
acid catalyzed reaction in water compared to those per-
formed in organic solvents. Similar observation have been
made in some literature reports on tetrahydropyridine syn-
thesis.2l–n These suggest that the use of water as the reac-
tion medium may not be advantageous for the Lewis/protic
acid catalyzed processes, compared to those carried out in
the presence of surfactant, as the Lewis/protic acid in water
does not have the beneficial microenvironment effect.11
The multicomponent reaction involving an aldehyde, an
amine, and a 1,3-dicarbonyl compound in 2:2:1 molar ratio
is proposed to proceed via two different pathways: (i) the
Knoevenagel condensation–aza-Diels–Alder reaction route
(path A)1a,2l,q,v,w and (ii) tandem inter- and intramolecular
Mannich reaction route (path B)2g,h,l,n,r,t,u (Scheme 1) via the
initial formation of the enamine I and the imine II. In path A
the enamine I, formed by the condensation of 2a and 3a,
undergoes Knoevenagel condensation with 1a to form III,
which is subsequently involved in an aza-Diels–Alder reac-
tion with the imine II to form tetrahydropyridine 4a. In
path B, the imine II and the enamine I undergo intermolec-
ular Mannich-type reaction to form IV, which upon further
condensation with 1a forms V and that undergoes intramo-
lecular Mannich-type reaction to give tetrahydropyridine
4a.
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
1
2
L-proline–TFA
MeCN
H2O
4
4
32
L-proline–TFA
15
3
L-proline–TFA
L-proline–TFA
CSA
MeCN
H2O
17
17
4
751a
15
4
5
neat
622d
12
6
CSA
H2O
4
7
CAN
MeCN
H2O
4
15
8
CAN
4
10
9
CAN
MeCN
H2O
23
23
4
822r
17
10
11
12
13
14
15
16
17
18
19
20
21
22
CAN
TBATBc
TBATB
TBATB
TBATB
I2
EtOH
H2O
10
4
17
EtOH
H2O
24
24
4
762t
18
MeOH
H2O
34
I2
4
15
I2
MeOH
H2O
8
822u
21
I2
8
InCl3
MeOH
H2O
4
12
InCl3
4
trace
652w
18
InCl3
MeOH
H2O
24
24
InCl3
a Reaction conditions: 1a (4 mmol), 2a (4 mmol), 3a (2 mmol) catalysts [5
mol%, except for entry 1 (20 mol%)], solvent, magnetic stirring, r.t. (35–
40 °C).
b The yield of 4a after crystallization (EtOH) of the isolated crude product.
c TBATB = tetrabutylammonium tribromide.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

E
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Paper
Synthesis
Ph
Ph
N
NH
O
O
Ph
Ph
N
O
NH
O
1a
path A
path B
OEt
OEt
N
Ph
+
OEt
OEt
Ph
+
N
Ph
N
Ph
Ph
Ph
Ph
N
H
Ph
Ph
II
V
IV
Ph
III
Ph
(RS)-4a
PhCHO
1a
+
II
I
Ph
O
O
NH
O
+
PhNH2
OEt
OEt
2a
+
1a 2a 2a
+
3a
3a
I
Scheme 1 Mechanistic pathways for tetrahydropyridine formation via five-component reaction
followed by treatment of the reaction mixture with the
imine (of 4-chloroaniline and 1a) with the anticipation that
the enamine would react with the aldehyde to form the
Knoevenagel condensation product (not isolated), which in
turn would undergo aza-Diels–Alder reaction with the
imine to form the end product (tetrahydropyridine). On the
other hand, the operational feasibility of path A was ruled
out based on the observation that the diene (generated
from Knoevenagel condensation of the enamine and the al-
dehyde) that could be involved in an aza-Diels–Alder reac-
tion with the imine could not be trapped with other reac-
tive dienophiles (e.g., dimethyl acetylenedicarboxylate, ma-
leic anhydride, and dihydropyran).2o,u The proposal for
Mannich reaction pathway (path B) emanates from the ob-
servation that the preformed imine undergoes Mannich-
type reaction with diethyl malonate2n,t,u or the isolation of
the intermediate imine and the enamine and the formation
of the tetrahydropyridine by the reaction of the aldehyde
with the preformed imine and the enamine.2r Thus, it ap-
pears that there is no concurrence in opinions on the mech-
anistic course of the multicomponent reaction to form tet-
rahydropyridines. In view of these proposals and the lack of
distinct experimental evidence to support either of the two
proposed mechanistic pathways (paths A and B), an explo-
ration was made of the mechanistic rationale behind tetra-
hydropyridine formation. The possible reaction pathways
could be identified by the following strategies: (i) the holis-
tic approach to isolate/identify the intermediates involved
by intercepting the progress of the reaction at an intermit-
tent stage and (ii) the bottom-up approach to treat the pre-
formed intermediates with suitable reacting partners un-
der identical reaction conditions to form the desired prod-
uct.
Thus, an aliquot of the reaction mixture during the
treatment of 1a, 2a, and 3a in 2:2:1 molar ratio in water (2
mL) in the presence of SDOSS (5 mol%) at room temperature
(35–40 °C) was withdrawn after two hours (the reaction
takes 4 h for completion) and subjected to GC-MS. The GC-
MS analysis revealed the presence of the desired tetrahy-
dropyridine 4a, enamine I, and imine II in 15, 20, and 45%
yield, respectively (Scheme 2) and confirmed the involve-
ment of enamine I and the imine II. However, it was diffi-
cult to conclude the possible reaction paths (A or B) as the
involvement of I and II is common to both pathways
(Scheme 1).
Therefore, the bottom-up approach was adopted to gain
further insight into the reaction pathway. Initially, 1a was
treated with the preformed enamine I under the standard
reaction condition (Scheme 3). However, the Knoevenagel
condensation product III was not isolated/detected and no
desired tetrahydropyridine was formed; instead the imine
II was isolated as the sole product in high yield. This sug-
gests that the reaction does not proceed through path A.
The formation of II arises due to the hydrolytic conversion
of I into parent compounds 3a and 2a followed by conden-
sation of the amine 2a with the aldehyde 1a to form the
imine II.
Ph
NH
O
Ph
SDOSS
(5 mol%)
O
O
NH
O
OEt
N
Ph
PhCHO
PhNH2
+
+
+
+
Ph
OEt
OEt
H2O, r.t., 2 h
Ph
N
Ph
1a
2a
3a
II
I
Ph
20%
45%
(RS)-4a
15%
Scheme 2 Identification of the reactive intermediates through GC-MS during the progress of the SDOSS-catalyzed reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
N. Parikh et al.
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Synthesis
(path B) rather than through the Knoevenagel–aza-Diels–
Alder reaction pathway (path A).
Ph
SDOSS
(5 mol%)
NH
O
N
Ph
PhCHO
+
Ph
A green synthetic protocol for the synthesis of function-
alized tetrahydropyridines has been demonstrated through
a surfactant promoted ‘on-water’ five-component reaction
involving a benzaldehyde, an amine, and a β-keto ester in
2:2:1 molar ratio. Amongst various non-ionic, cationic, and
anionic surfactants tested, the most effective catalysts were
the anionic surfactants SDOSS and SDS, with the former be-
ing superior. The use of water as the reaction medium was
superior to organic solvents, which afforded relatively poor
yields, suggesting that water facilitates the reaction through
the formation of microreactors at the water–SDOSS (surfac-
tant) interface. The desired tetrahydropyridines are formed
with high diastereoselectivity affording the trans-2,6-di-
phenyl diastereomers exclusively, as confirmed by NMR
analyses (particularly the coupling constants of H6) and in
accord with earlier reports.2v An insight into the mechanis-
tic pathway has been provided through identification of the
intermediates by GC-MS and a bottom-up approach in syn-
thesizing the tetrahydropyridine through reaction of the
preformed intermediates with suitable reactants. The re-
sults supported the tandem inter- and intramolecular
Mannich reaction pathway. High yields, room temperature
reaction, shorter reaction period, purification through crys-
tallization using ethanol (a preferred solvent in the context
of the solvent selection guide of pharmaceutical industry),
use of water (green reaction medium) and one-pot multi-
component reaction are the advantages of this ecofriendly
synthetic protocol.
OEt
H2O, r.t.
4 h
I
II
1a
84%
1a
PhNH
+
3a
2
Ph
N
Ph
O
NH
O
2a
OEt
OEt
Ph
Ph
IIIa
III
(not formed)
Scheme 3 SDOSS-catalyzed reaction of I with benzaldehyde (1a) in
water
To gain experimental evidence in support of path B, the
preformed enamine I was treated with one molar equiva-
lent of the imine II in the presence of SDOSS (5 mol%) in
water at room temperature (35–40 °C) (Scheme 4). Howev-
er the Mannich-type product IV was not isolated and in-
stead the tetrahydropyridine (RS)-4a was the sole product
isolated in 18% yield. The yield of (RS)-4a increased to 56%
when molar equivalents of I, II, and benzaldehyde (1a) were
treated under similar condition. The formation of (RS)-4a
from I and II can be rationalized by the fact that the imine
undergoes hydrolytic cleavage to generate the starting alde-
hyde 1a which is involved in the reaction with the enamine
I and the unhydrolyzed imine II to form the tetrahydropyri-
dine (RS)-4a. However, it is interesting to note that (RS)-4a
is obtained in much higher yield (72%, Table 3, entry 1)
when all of the reactants are added together at the same
time rather than in the case when the preformed interme-
diates I and II are treated with benzaldehyde (1a) and this
reflect the multicomponent nature of the reaction rather
than the stepwise formation of the possible intermediates.
This further exemplifies the advantage of the multicompo-
nent reaction over the stepwise process.
1H and 13C NMR spectra were recorded on a Bruker Avance 400 MHz
NMR spectrometer in CDCl3 with residual undeuterated solvent (CD-
Cl3: δ = 7.26/77.0) using TMS as internal standard. The IR spectra
were recorded either on KBr pellets (for solids) or neat or CCl4 (for liq-
uids) on a Nicolet Impact 410 FTIR spectrophotometer. HPLC were re-
corded on a analytical grade HPLC (Shimadzu). Mass spectra were re-
corded on a GCMS-QP 5000 (Shimadzu). Mass spectra for mechanistic
study were recorded in advance Bruker Daltonics® APCI-TOF instru-
ment and ESI-MS in advance Thermo Scientific LTQ-XL mass spec-
trometer. The HRMS spectra were recorded on Bruker Maxis instru-
ment. Melting points were measured with Gupta scientific, India
Thus, under the present protocol, it is most likely that
the formation of the tetrahydropyridines proceeds via tan-
dem inter- and intramolecular Mannich-type reactions
Ph
Ph
NH
O
N
O
Ph
SDOSS
(5 mo%)
NH
O
OEt
OEt
N
O
Ph
+
Ph
OEt
H2O, r.t.
4 h
Ph
N
Ph
HN
Ph
I
II
Ph
Ph
Ph
IV
(not isolated/identified)
(RS)-4a
18%
SDOSS (5 mol%)
H2O, r.t., 4 h
H
1a
(RS)-4a
56%
Scheme 4 SDOSS-catalyzed reaction of I with II and the reaction of I, II, and 1a in water
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
N. Parikh et al.
Paper
Synthesis
melting point apparatus. Open column chromatography, TLC was per-
formed on silica gel (CDH silica gel 60–120 mesh, F254 and Merck sil-
ica gel, respectively). Evaporation of solvents was performed at re-
duced pressure, using a Büchi rotary evaporator. All chemicals were
purchased from Aldrich, Lancaster and Fluka Chemicals and used as
received.
1 H), 6.53 (d, J = 8.5 Hz, 2 H), 6.60 (t, J = 7.2 Hz, 1 H), 7.01–7.11 (m, 5
H), 7.13–7.26 (m, 5 H), 7.28–7.29 (m, 3 H), 7.30–7.33 (m, 2 H), 10.29
(s, 1 H).
MS (APCI): m/z = 475.37 (M + H)+.
(RS)-Methyl 1,2,6-Triphenyl-4-(phenylamino)-1,2,5,6-tetrahydro-
pyridine-3-carboxylate (4b)2w
(RS)-Ethyl 1,2,6-Triphenyl-4-(phenylamino)-1,2,5,6-tetrahydropy-
ridine-3-carboxylate (4a); Typical Procedure
Colorless needles; yield: 0.691 g (75%); mp 174–176 °C.
IR (KBr): 3259, 3037, 2914, 1647, 1588, 1469, 1260, 1089 cm–1
.
A mixture of 1a (0.42 g, 4 mmol), 2a (0.36 g, 4 mmol), and 3a (0.26 g,
2 mmol) was stirred magnetically at r.t. in the presence of SDOSS
(0.022 g, 0.1 mmol, 5 mol%) in water (2 mL). After completion of the
reaction (4 h, TLC), the aqueous layer was decanted and the residue
was washed with water to remove the catalyst. The crude mixture
was crystallized (EtOH) to afford the product (0.682 g, 72%).
1H NMR (400 MHz, CDCl3): δ = 2.79 (dd, J = 2.4, 15.1 Hz, 1 H), 2.90 (dd,
J = 5.8, 15.1 Hz, 1 H), 3.96 (s, 3 H), 5.17–5.19 (m, 1 H), 6.32–6.30 (m, 2
H), 6.48 (s, 1 H), 6.55 (d, J = 8.2 Hz, 2 H), 6.63 (t, J = 7.2 Hz, 1 H), 7.14–
7.07 (m, 5 H), 7.22–7.18 (m, 2 H), 7.36–7.24 (m, 8 H), 10.28 (s, 1 H).
MS (APCI): m/z = 461.17 (M + H)+.
The SDOSS was recovered by concentrating the aqueous layer/portion
under vacuum at 80 °C for 20 min and reused for the fresh batches of
the reaction for five times without any significant loss of catalytic ac-
tivity.
(RS)-tert-Butyl 1,2,6-Triphenyl-4-(phenylamino)-1,2,5,6-tetrahy-
dropyridine-3-carboxylate (4c)2v
Colorless needles; yield: 0.764 g (76%); mp 205–208 °C.
IR (KBr): 3120, 2625, 1637, 1540, 1432, 1260, 1140, 1036, 920, 740
N-Benzylideneaniline (II)
cm–1
.
This compound was synthesized by following the reported proce-
dure.14 A mixture of 1a (0.42 g, 4 mmol), and 2a (0.36 g, 4 mmol) was
stirred magnetically at r.t. in the presence of Mg(ClO4)2 (40 mg, 0.2
mmol, 5 mol%). After completion of the reaction (10 min, TLC), the
crude mixture was crystallized (EtOH) to afford the product (0.655 g,
90%) as a yellow solid; mp 120–123 °C.
1H NMR (400 MHz, CDCl3): δ = 1.65 (s, 9 H), 2.73–2.86 (m, 2 H), 5.12–
5.13 (m, 1 H), 6.28 (d, J = 7.6 Hz, 2 H), 6.41 (s, 1 H), 6.51 (d, J = 7.2 Hz,
2 H), 6.60 (t, J = 7.2 Hz, 1 H), 7.05–7.08 (m, 5 H), 7.16–7.22 (m, 2 H),
7.24–7.30 (m, 6 H), 7.35–7.37 (m, 2 H), 10.27 (s, 1 H).
MS (APCI): m/z = 475.3 (M + H)+.
IR (KBr): 2600, 2360, 1621, 1219, 931, 826 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.22–7.25 (m, 3 H), 7.37–7.41 (m, 2 H),
7.46–7.49 (m, 3 H), 7.89–7.92 (m, 2 H), 8.45 (s, 1 H).
MS (APCI): m/z = 182.2 (M + H)+.
.
(RS)-Ethyl 2,6-Bis(4-fluorophenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (4d)
Colorless needles; yield: 0.715 g (70%); mp 188–190 °C.
IR (KBr): 3058, 2834, 1651, 1594, 1504, 1372, 1247 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.47 (t, J = 7.1 Hz, 3 H), 2.76–2.89 (m, 2
H), 4.34–4.51 (m, 2 H), 5.13–5.14 (m, 1 H), 6.42–6.44 (m, 5 H), 6.53 (d,
J = 8.2 Hz, 1 H), 6.62 (t, J = 7.2 Hz, 4 H), 6.96–7.01 (m, 7 H), 7.11–7.33
(m, 2 H), 10.34 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.8, 33.8, 54.6, 57.3, 60.9, 98.1, 114.9,
115.6, 118.0, 119.3, 125.9, 128.0, 128.2, 128.7, 129.0, 137.8, 138.1,
139.5, 146.6, 155.9, 160.8, 163.2, 168.1.
Ethyl 3-(Phenylamino)but-2-ene (I)
This compound was synthesized by following the reported proce-
dure.15 A mixture of 3a (0.26 g, 2 mmol) and 2a (0.36 g, 4 mmol) was
stirred magnetically at r.t. in the presence of Sc(OTf)3 (98 mg, 0.2
mmol, 5 mol%). After completion of the reaction (2 h, TLC), the mix-
ture was diluted with EtOAc (5 mL) followed by addition of a few
drops of water (to dissolved the catalyst). The supernatant EtOAc
solution was decanted and the aqueous layer/portion was extracted
with EtOAc (2 × 5 mL). The combined EtOAc extracts were dried
(Na2SO4) and concentrated under vacuum. The crude mixture was pu-
rified by column chromatography (60–120 mesh silica gel, hexane–
EtOAc, 1:0 to 9:1) to afford the product (0.733 g, 89%) as a white solid;
mp 164–167 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C32H28F2N2O2Na: 533.2011;
found: 533.2007.
(RS)-Methyl 2,6-Bis(4-fluorophenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (4e)1b
Colorless needles; yield: 0.705 g (71%); mp 182–184 °C.
IR (KBr): 2862, 2642, 2538, 1686, 1429, 1288, 1063, 931 cm–1
.
IR (KBr): 3033, 2817, 1660, 1525, 1500, 1319, 1235 cm–1
.
1 H NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 7.1 Hz, 3 H,), 1.99 (s, 3 H),
4.12 (q, J = 7.1 Hz, 2 H,), 4.69 (s, 1 H), 7.08 (d, J = 7.8 Hz, 2 H,), 7.16 (t,
J = 7.4 Hz, 1 H), 7.31 (t, J = 7.9 Hz, 2 H), 10.38 (s, 1 H).
1 H NMR (400 MHz, CDCl3): δ = 2.42 (dd, J = 12.5, 15.3 Hz, 1 H), 2.77
(dd, J = 3.5, 15.3 Hz, 1 H), 3.73 (s, 3 H), 4.53 (dd, J = 3.4, 12.4 Hz, 1 H),
6.09 (s, 1 H), 6.75 (t, J = 7.2 Hz, 1 H), 6.82 (d, J = 8.2 Hz, 2 H), 6.88 (t, J =
8.6 Hz, 2 H), 6.98 (d, J = 7.7 Hz, 2 H), 7.16–7.07 (m, 5 H), 7.24–7.20 (m,
2 H), 7.31 (t, J = 7.8 Hz, 2 H), 7.58–7.54 (m, 2 H), 10.62 (s, 1 H).
MS (APCI): m/z = 206.1 (M + H)+.
(RS)-Ethyl 1,2,6-Triphenyl-4-(phenylamino)-1,2,5,6-tetrahydropy-
MS (APCI): m/z = 497.30 (M + H)+.
ridine-3-carboxylate (4a)2v
Light yellow needles; yield: 0.683 g (72%); mp 182–184 °C.
IR (KBr): 3272, 3014, 2850, 1659, 1583, 1484, 1234, 1068 cm–1
(RS)-Ethyl 2,6-Bis(4-bromophenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (4f)
.
1H NMR (400 MHz, CDCl3): δ = 1.44 (t, J = 7.1 Hz, 3 H), 2.74 (dd, J = 2.4,
15.2 Hz, 1 H), 2.78 (dd, J = 5.6, 15.0 Hz, 1 H), 4.30–4.35 (m, 1 H), 4.43–
4.48 (m, 1 H), 5.13–5.15 (m, 1 H), 6.26 (dd, J = 2.2, 7.8 Hz, 2 H), 6.63 (s,
Colorless needles; yield: 0.923 g (73%); mp 160–162 °C.
IR (KBr): 3161, 2980, 1653, 1606, 1588, 1491, 1374, 1321, 1252 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
N. Parikh et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 1.44 (t, J = 7.1 Hz, 3 H), 2.76 (dd, J = 2.6,
15.2 Hz, 1 H), 2.87 (dd, J = 5.5, 15.2 Hz, 1 H), 4.29–4.50 (m, 2 H), 5.14
(br s, 1 H), 6.27–6.29 (m, 2 H), 6.46 (s, 1 H), 6.51–6.54 (m, 2 H), 6.57–
6.62 (m, 1 H), 7.04–7.07 (m, 5 H), 7.16–7.18 (m, 2 H), 7.20–7.35 (m, 6
H), 10.29 (s, 1 H).
1H NMR (400 MHz, CDCl3): δ = 1.47 (t, J = 7.1 Hz, 3 H), 2.69 (dd, J = 2.3,
15.2 Hz, 1 H), 2.88 (dd, J = 5.8, 15.2 Hz, 1 H), 4.29–4.37 (m, 1 H), 4.44–
4.52 (m, 1 H), 5.12–5.13 (m, 1 H), 6.23–6.26 (m, 2 H), 6.40 (s, 1 H),
6.43–6.47 (m, 2 H), 6.59 (t, J = 8.6 Hz, 4 H), 7.15–7.18 (m, 2 H), 7.27–
7.32 (m, 8 H), 10.26 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.8, 33.6, 55.1, 58.7, 59.7, 98.3, 112.8,
116.9, 125.1, 126.7, 127.0, 128.1, 128.4, 128.6, 137.9, 142.1, 144.1,
146.7, 156.2, 168.1.
13C NMR (100 MHz, CDCl3): δ = 14.8, 33.6, 55.4, 55.6, 58.3, 59.7, 97.2,
113.7, 114.2, 114.7, 126.2, 126.5, 126.8, 127.3, 127.7, 128.7, 129.2,
130.7, 141.6, 143.3, 144.4, 150.8, 156.0, 157.2, 168.3.
HRMS (ESI): m/z [M + Na]+ calcd for C32H28Br2N2O2Na: 653.0410;
HRMS (ESI): m/z [M + Na]+ calcd for C34H28F6N2O4Na: 665.1845;
found: 653.0419.
found: 665.1851.
(RS)-Ethyl 2,6-Bis(4-methoxyphenyl)-1-phenyl-4-(phenylamino)-
(RS)-Ethyl 2,6-Diphenyl-1-o-tolyl-4-(o-tolylamino)-1,2,5,6-tetra-
1,2,5,6-tetrahydropyridine-3-carboxylate (4g)
hydropyridine-3-carboxylate (4k)
Colorless needles; yield: 0.791 g (74%); mp 191–193 °C.
Light yellow needles; yield: 0.633 g (63%); mp 212–215 °C.
IR (KBr): 2979, 2328, 1652, 1594, 1501, 1370, 1323, 1248 cm–1
.
IR (KBr): 3435, 1651, 1618, 1515, 1372, 1251, 1067 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.47 (t, J = 7.1 Hz, 3 H), 2.78 (dd, J = 2.5,
15.0 Hz, 1 H), 2.87 (dd, J = 5.5, 15.0 Hz, 1 H), 3.80 (s, 6 H), 4.30–4.38
(m, 1 H), 4.43–4.49 (m, 1 H), 5.10–5.11 (m, 1 H,), 6.38–6.40 (m, 3 H),
6.54–6.64 (m, 3 H), 6.82–6.85 (m, 4 H), 7.07–7.19 (m, 6 H), 7.25–7.27
(m, 3 H), 10.33 (s, 1 H).
1H NMR (400 MHz, CDCl3): δ = 1.45 (t, J = 7.1 Hz, 3 H), 2.15 (s, 3 H),
2.25 (s, 3 H), 2.71 (dd, J = 2.5, 15.2 Hz, 1 H), 2.83 (dd, J = 5.6, 15.2 Hz, 1
H), 4.27–4.35 (m, 1 H), 4.38–4.47 (m, 1 H), 5.10–5.11 (m, 1 H), 6.16 (d,
J = 8.2 Hz, 2 H), 6.40–6.43 (m, 3 H), 6.88 (dd, J = 4.0, 8.4 Hz, 4 H), 7.15–
7.20 (m, 3 H), 7.21–7.51 (m, 7 H), 10.20 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.8, 33.7, 54.6, 55.2, 55.3, 57.5, 59.6,
98.4, 113.0, 113.6, 114.0, 116.0, 125.5, 125.7, 127.4, 127.7, 128.1,
128.6, 128.8, 134.6, 136.0, 138.0, 147.0, 156.1, 158.1, 158.7, 168.3.
HRMS (ESI): m/z [M + Na]+ calcd for C34H34N2O4Na: 557.2411; found:
557.2421.
13C NMR (100 MHz, CDCl3): δ = 14.8, 21.8, 33.6, 54.1, 57.7, 59.8, 98.3,
112.9, 115.9, 125.5, 125.7, 126.3, 126.4, 126.6, 128.6, 128.6, 128.9,
128.9, 129.0, 129.3, 135.3, 136.4, 137.4, 139.4, 141.0, 147.7, 156.1,
168.3.
HRMS (ESI): m/z [M + Na]+ calcd for C34H34N2O2Na: 525.2518; found:
525.2512.
(RS)-Ethyl 1-Phenyl-4-(phenylamino)-2,6-di-p-tolyl-1,2,5,6-tetra-
hydropyridine-3-carboxylate (4h)2u
(RS)-Ethyl 1-(4-Bromophenyl)-4-(4-bromophenylamino)-2,6-di-
phenyl-1,2,5,6-tetrahydropyridine-3-carboxylate (4l)1b
Light yellow needles; yield: 0.734 g (73%); mp 177–179 °C.
Colorless needles; yield: 0.911 g (72%); mp 187–190 °C.
IR (KBr): 2856, 2676, 1542, 1423, 1322, 1140, 892, 756 cm–1
.
IR (KBr): 3578, 2980, 1653, 1606, 1588, 1491, 1374, 1321, 1252, 1068
1H NMR (400 MHz, CDCl3): δ = 1.43 (t, J = 7.1 Hz, 3 H), 2.32 (s, 3 H),
2.32 (s, 3 H), 2.76 (dd, J = 2.4, 15.0 Hz, 1 H), 2.84 (dd, J = 5.6, 15.0 Hz, 1
H), 4.28–4.32 (m, 1 H), 4.42–4.47 (m, 1 H), 5.13–5.14 (m, 1 H), 6.28
(dd, J = 1.5, 7.3 Hz, 2 H), 6.41 (s, 1 H), 6.50 (d, J = 8.2 Hz, 2 H), 6.59 (t,
J = 7.2 Hz, 1 H), 7.02–7.10 (m, 11 H), 7.21–7.26 (m, 2 H), 10.31 (s, 1 H).
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.46 (t, J = 7.1 Hz, 3 H), 2.70 (dd, J = 2.4,
15.2 Hz, 1 H), 2.84 (dd, J = 5.8, 15.1 Hz, 1 H), 4.31–4.37 (m, 1 H), 4.47–
4.49 (m, 1 H), 5.09–5.11 (m, 1 H), 6.09–6.11 (m, 2 H), 6.37–6.43 (m, 3
H), 7.11–7.16 (m, 5 H), 7.19–7.26 (m, 2 H), 7.28–7.47 (m, 7 H), 10.23
(s, 1 H).
MS (APCI): m/z = 504.6 (M + H)+.
MS (APCI): m/z = 631.23 (M + H)+.
(RS)-Ethyl 1-(4-Methoxyphenyl)-4-(4-methoxyphenylamino)-2,6-
diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate (4i)1b
(RS)-Ethyl 1-(4-Chlorophenyl)-4-(4-chlorophenylamino)-2,6-di-
Colorless needles; yield: 0.802 g (75%); mp 172–174 °C.
phenyl-1,2,5,6-tetrahydropyridine-3-carboxylate (4m)2p
IR (KBr): 3239, 2905, 1615, 1610, 1598, 1510, 1451, 1243, 1178, 1068
Colorless needles; yield: 0.761 g (70%); mp 139–142 °C.
cm–1
.
IR (KBr): 3246, 2950, 2837, 1699, 1610, 1513, 1462, 1240 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.46 (t, J = 7.1 Hz, 3 H), 2.66 (dd, J = 2.7,
15.2 Hz, 1 H), 2.82 (dd, J = 5.8, 15.2 Hz, 1 H), 3.68 (s, 3 H), 3.77 (s, 3 H),
4.31–4.37 (m, 1 H), 4.42–4.48 (m, 1 H), 5.07–5.08 (m, 1 H), 6.19–6.24
(m, 2 H), 6.37 (s, 1 H), 6.45–6.49 (m, 2 H), 6.61–6.64 (m, 2 H), 6.65–
6.69 (m, 2 H), 7.19–7.25 (m, 3 H), 7.28–7.35 (m, 7 H), 10.16 (s, 1 H).
1H NMR (400 MHz, CDCl3): δ = 1.50 (t, J = 7.1 Hz, 3 H), 2.73 (dd, J = 2.3,
15.2 Hz, 1 H), 2.89 (dd, J = 5.8, 15.1 Hz, 1 H), 4.33–4.41 (m, 1 H), 4.43–
4.54 (m, 1 H), 5.13–5.14 (m, 1 H), 6.19–6.21 (m, 2 H), 6.42 (s, 1 H),
6.45–6.50 (m, 2 H), 6.99–7.04 (m, 2 H), 7.06–7.09 (m, 2 H), 7.17–7.19
(m, 2 H), 7.23–7.37 (m, 8 H), 10.27 (br s, 1 H).
MS (APCI): m/z = 535.3 (M + H)+.
MS (APCI): m/z = 544.33 (M + H)+.
(RS)-Ethyl 2,6-Diphenyl-1-[4-(trifluoromethoxy)phenyl]-4-[4-(tri-
fluoromethoxy)phenylamino]-1,2,5,6-tetrahydropyridine-3-car-
boxylate (4j)
(RS)-Methyl 2,6-Bis(4-methoxyphenyl)-1-(p-tolyl)-4-(p-tolylami-
no)-1,2,5,6-tetrahydropyridine-3-carboxylate (4n)2v
Colorless needles; yield: 0.900 g (70%); mp 166–169 °C.
Colorless needles; yield: 0.823 g (75%); mp 206–209 °C.
IR (KBr): 3574, 2984, 1653, 1605, 1509, 1253, 1173 cm–1
.
IR (KBr): 3245, 2948, 2835, 1656, 1611, 1510, 1458, 1242, 1037 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
N. Parikh et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 1.45 (s, 3 H), 1.48 (s, 3 H), 2.76 (dd, J =
2.8, 15.2 Hz, 1 H), 2.85 (dd, J = 5.6, 15.0 Hz, 1 H), 4.30 (s, 3 H), 4.44 (s,
6 H), 5.14–5.15 (m, 1 H), 6.26–6.28 (m, 2 H), 6.46 (s, 1 H), 6.55 (d, J =
9.2 Hz, 2 H), 6.61 (d, J = 8.8 Hz, 1 H), 7.05 (d, J = 9.0 Hz, 2 H), 7.09–7.28
(m, 7 H), 7.30 (d, J = 8.0 Hz, 2 H), 10.28 (br s, 1 H).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561296.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
MS (APCI): m/z = 549.30 (M + H)+.
References
(RS)-Methyl 1,2,6-Tris(4-methoxyphenyl)-4-(4-methoxyphenyl-
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(2) (a) Nanomagnetic Fe@Si-Gu-Prs (0.025 g/2 mmol, neat, r.t., 15–
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Rezaeian, S.; Bakavoli, M.; Teymouri, M.; Rostami, A.; Haghbeen,
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Dharbale, N. B.; Sarkate, A. P.; Shinde, D. B. J. Chil. Chem. Soc.
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(0.1 g/2 mmol, EtOH, 60 °C, 7–14 h): Zhang, X.; Wan, Y.; Pang,
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Wu, H. J. Heterocycl. Chem. 2014, 51, 442. (f) Nanocat Fe-Ce (100
mg/5.22 mol% Ce, EtOH, r.t., 18 h): Gawande, M. B.; Bonifácio, V.
D. B.; Varma, R. S.; Nogueira, I. D.; Bundaleski, N.; Ghumman, C.
A. A.; Teodorod, O. M. N. D.; Branco, P. S. Green Chem. 2013, 15,
1226. (g) AcOH (as solvent, r.t., 1–10 h): Lashkari, M.;
Maghsoodlou, M. T.; Hazeri, N.; Habibi-Khorassani, S. M.;
Sajadikhah, S. S.; Doostmohamadi, R. Synth. Commun. 2013, 43,
635. (h) Mixed Acidic Ionic Liquids (10–20 mol%, neat, 100 °C,
~1 h): Shaterian, H. R.; Azizi, K. J. Mol. Liq. 2013, 180, 187.
(i) Fe(NO3)3·9H2O (20 mol%, EtOH, r.t., 5–12 h): Hazeri, N.;
Maghsoodlou, M. T.; Habibi-Khorassani, S. M.; Aboonajimi, J.;
Sajadikhah, S. S. J. Chin. Chem. Soc. 2013, 60, 355. (j) Chiral phos-
phoric acid (10 mol%, toluene, 35 °C, 3-Å molecular sieves, 48
h): Shi, F.; Tan, W.; Zhu, R.-Y.; Xing, G.-J.; Tu, S.-J. Adv. Synth.
Catal. 2013, 355, 1605. (k) Chiral phosphoric acid (10 mol%, tol-
uene, –30 °C, 4-Å molecular sieves, 72 h): Li, X.; Zhao, Y.; Qu, H.;
Mao, Z.; Lin, X. Chem. Commun. 2013, 49, 1401. (l) LaCl3·7H2O
(10 mol%, MeOH, r.t., 3–9 h): Umamahesh, B.; Sathesh, V.;
Ramachandran, G.; Sathishkumar, M.; Sathiyanarayanam, K.
Catal. Lett. 2012, 142, 895. (m) Bi(NO3)3·5H2O (10 mol%, EtOH,
r.t., 12–55 h): Brahmachari, G.; Das, S. Tetrahedron Lett. 2012,
53, 1479. (n) BF3·SiO2 (15 mol%, MeOH, 65 °C, 7–9 h):
Ramachandran, R.; Jayanthi, S.; Jeong, Y. T. Tetrahedron 2012,
68, 363. (o) VCl3 (10 mol%, EtOH, r.t., 5–12 h): Pal, S.;
amino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4o)1b
Colorless needles; yield: 0.859 g (74%); mp 158–160 °C.
IR (KBr): 3678, 3437, 3020, 2360, 1649, 1512, 1461, 1217 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.78 (dd, J = 2.4, 15.0 Hz, 1 H), 2.86 (dd,
J = 5.4, 15.0 Hz, 1 H), 3.77 (s, 6 H), 4.32 (s, 3 H), 4.46 (s, 6 H), 5.10 (br s,
1 H), 6.38 (d, J = 7.6 Hz, 3 H), 6.55 (d, J = 9.0 Hz, 3 H), 6.62 (d, J = 7.8 Hz,
4 H), 6.81–6.84 (m, 4 H), 7.07–7.27 (m, 3 H), 10.33 (br s, 1 H).
MS (APCI): m/z = 581.26 (M + H)+.
(RS)-Ethyl 2,6-Bis(1,3-benzodioxol-5-yl)-1-phenyl-4-(phenylami-
no)-1,2,5,6-tetrahydropyridine-3-carboxylate (4p)
Colorless needles; yield: 0.588 g (70%); mp 162–165 °C.
IR (KBr): 3239, 2983, 2887, 1652, 1593, 1500, 1485, 1250, 1038 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.44 (t, J = 7.1 Hz, 3 H), 2.76 (dd, J = 2.4,
15.1 Hz, 1 H), 2.88 (dd, J = 5.6, 15.2 Hz, 1 H), 4.29–4.34 (m, 1 H), 4.41–
4.46 (m, 1 H), 5.02–5.04 (m, 1 H), 5.93–5.96 (m, 4 H), 6.32 (s, 1 H),
6.42–6.46 (m, 2 H), 6.52 (d, J = 8.2 Hz, 1 H), 6.60–6.65 (m, 6 H), 6.84
(d, J = 1.6 Hz, 1 H), 7.06–7.15 (m, 6 H), 10.36 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.8, 33.7, 54.8, 57.8, 59.8, 98.0, 100.9,
101.0, 107.1, 107.3, 107.7, 108.4, 113.0, 116.3, 119.4, 119.4, 125.6,
125.7, 128.9, 136.8, 137.9, 138.0, 146.0, 146.6, 146.7, 147.6, 147.8,
155.9, 168.1.
HRMS (ESI): m/z [M + Na]+ calcd for C34H30N2O6Na: 585.1996; found:
585.2006.
(RS)-tert-Butyl 1-Butyl-4-(butylamino)-2,6-bis(4-fluorophenyl)-
1,2,5,6-tetrahydropyridine-3-carboxylate (4q)
Colorless needles; yield: 0.688 g (69%); mp 159–162 °C.
IR (KBr): 2850, 2411, 2330, 1715, 1516, 1130, 863 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.08–1.19 (m, 12 H), 1.26–1.37 (m, 11
H), 2.23 (t, J = 16 Hz, 1 H), 2.36–2.40 (s, 1 H), 2.69 (d, J = 16 Hz, 1 H),
3.44 (s, 1 H), 4.01–4.04 (m, 1 H), 4.37 (t, J = 4.4 Hz, 2 H), 6.22 (d, J = 3.2
Hz, 2 H), 6.33 (d, J = 3.2 Hz, 2 H), 7.06 (d, J = 8.2 Hz, 2 H), 7.18 (d, J = 8.2
Hz, 2 H), 7.37 (s, 1 H), 9.16 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 27.9, 28.0, 28.3, 38.8, 39.7, 43.0, 58.4,
68.4, 79.1, 82.1, 94.3, 106.8, 127.8, 129.1, 131.1, 142.1, 145.8, 152.4,
154.8, 169.5, 174.5.
HRMS (ESI): m/z [M + Na]+ calcd for C30H40F2N2O2Na: 521.2950;
found: 521.2947.
Acknowledgment
Financial support received from CSIR (SRF to S.R.R. and K.S.) and DST
(SR/S1/OC-33/2008), New Delhi, India are thankfully acknowledged.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

J
N. Parikh et al.
Paper
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