SnCl2·2H2O as a precatalyst in MCR: Synthesis of pyridine derivatives via a 4-component reaction in water

Article abstract of DOI:10.1016/j.tetlet.2015.06.008

For the first time SnCl₂·2H₂O has been identified as a convenient precatalyst for the synthesis of pyridine derivatives via an MCR in water. The 4-component reaction of alkyl/(hetero)aryl aldehydes, β-keto esters (or 1,3-diketones),

Full text of DOI:10.1016/j.tetlet.2015.06.008

Accepted Manuscript
SnCl2·2H2O as a precatalyst in MCR: Synthesis of pyridine derivatives via a 4-
component reaction in water
Dinne Naresh Kumar Reddy, Kothapalli Bannoth Chandrasekhar, Yaddanapudi
Sesha Siva Ganesh, Burra Sathish Kumar, Raju Adepu, Manojit Pal
PII:
S0040-4039(15)00989-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.008
TETL 46400
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 April 2015
29 May 2015
3 June 2015
Please cite this article as: Reddy, D.N.K., Chandrasekhar, K.B., Ganesh, Y.S.S., Kumar, B.S., Adepu, R., Pal, M.,
SnCl2·2H2O as a precatalyst in MCR: Synthesis of pyridine derivatives via a 4-component reaction in water,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.06.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
SnCl2·2H2O as a precatalyst in MCR: synthesis
of pyridine derivatives via a 4-component
reaction in water
Leave this area blank for abstract info.
Dinne Naresh Kumar Reddy, Kothapalli Bannoth Chandrasekhar, Yaddanapudi Sesha Siva Ganesh, Burra
Sathish Kumar, Raju Adepu and Manojit Pal*
alkyl /
(het)aryl
O
R1
alkyl /
alkoxy
R3
NH2
CN
NH
R2
O
O
'Sn' catalysis
H2O, air, 60 o
R1 CHO
+
+
R3
N
+
NC
CN
R4
R2
C
17 examples
82-91% yields
R4

1
Tetrahedron Letters
journal homepage: www.elsevier.com
SnCl2·2H2O as a precatalyst in MCR: synthesis of pyridine derivatives via a 4-
component reaction in water
Dinne Naresh Kumar Reddy,a,b Kothapalli Bannoth Chandrasekhar, b Yaddanapudi Sesha Siva Ganesh,a
Burra Sathish Kumar,a Raju Adepu c and Manojit Palc,*
a Custom Pharmaceutical Services, Dr. Reddys Laboratories Limited, Bollaram road, Miyapur, Hyderabad 500 049, India.
b College of Engineering, Jawaharlal Nehru Technological University, Anantapur 533 003, Andhra Pradesh, India.
cDr Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
ARTICLE INFO
ABSTRACT
Article history:
Received
For the first time SnCl2·2H2O has been identified as a convenient precatalyst for the synthesis of
pyridine derivatives via an MCR in water. The 4-component reaction of alkyl / (hetero)aryl
aldehydes, β-keto esters (or 1,3-diketones), anilines and malononitrile afforded a range of new
polysubstituted pyridines including 4-alkyl/heteroaryl derivatives in 78-91% yields. The use of
less expensive catalyst in aqueous media and good yield of products with wider substrate scope
are the key features of this methodology.
Received in revised form
Accepted
Available online
Keywords:
Pyridine
MCR
2009 Elsevier Ltd. All rights reserved.
water
SnCl2
Development of cost effective and environmentally friendly
MCRs (multicomponent reactions) is of tremendous importance
in both organic and medicinal chemistry as these protocols
provide easy and quick access to the diversity based
combinatorial library of small molecules useful for new drug
discovery effort. One of the important features of MCRs is that
they offer highly convergent and rapid routes to densely
functionalized molecules. Additionally, these methods do not
require the isolation and purification of intermediates thereby
reducing the time, cost and more importantly waste production.1
It is therefore not a surprising fact that MCRs have attracted
considerable attention of researchers especially working in the
area of organic / medicinal / pharmaceutical chemistry. Indeed,
MCRs have been used largely to generate library of small organic
molecules having diverse substituents.2 These libraries of
potentially bioactive molecules were found to be attractive for
high-throughput pharmacological screen leading to the
identification of a pre-hit or lead molecule in a particular
therapeutic area. While various transition metal catalysts
including gold, silver3 and iron salts4 have been employed in a
range of MCRs earlier, the use of tin catalysts in MCRs are rather
uncommon. However, in view of their easy availability and low
cost tin based salts seemed to have potential and are worth
exploring as catalysts in MCRs. While SnCl2·2H2O has been
explored as an effective and eco-friendly catalyst for a number of
organic transformations,5a,b only few examples of using
SnCl2·2H2O as a mild Lewis acid catalyst in MCRs (e.g. Biginelli
reaction,5c 3-component synthesis of homoallylic amines5d and
4(3H)-quinazolinones5e) have been reported and none as a
precursor of Sn(IV) species in a MCR. Moreover, as a Lewis
acid, SnCl4 has been used in several chemical transformations
(e.g. the reduction of glycopyranosyl azides,5f the ring-opening of
4,5-dihydropyrroles,5g conversion of glucose into 5-
hydroxymethylfurfural5h and synthesis of tetracyclic terpenoids5i)
highlighting its potential as an effective catalyst. However,
SnCl4 being a colorless liquid at room temperature (that fumes on
contact with air) is inconvenient to handle as a catalyst. The
aqueous solution of SnCl2 in the presence of air on the other hand
is known to produce SnCl4 in situ. This prompted us to explore
SnCl2·2H2O as a convenient precatalyst for the synthesis of
pyridine derivatives via an MCR.
The pyridine nucleus has been found to be an integral part of
many natural products6 (e.g. coenzyme vitamin B6 family and
numerous alkaloids) and biologically active compounds.7 Several
elegant and effective methods have been reported for the
synthesis of pyridine derivatives8 including MCRs.9 For example,
in 2012 we reported the synthesis of pyridine derivatives via a
montmorillonite K-10 catalyzed 4-component reaction of β-
ketoester, arylaldehyde, malononitrile and an alcohol.10 More
recently, a FeCl3-catalyzed similar 4-component reaction (using
arylamine in place of alcohol as a nucleophile) has been reported
for the synthesis of pyridine derivatives in 38-86% yield via a
----------------
* Corresponding author: Tel.: +91 40 6657; fax: +91 40 6657 1581
E-mail address: manojitpal@rediffmail.com (M. Pal)

2
Tetrahedron Letters
nucleophilic addition
/
intermolecular cyclization.11 We
Table 1: Effect of reaction conditions on the MCR of 1a, 2a,
3a and 4.a
anticipated that this type of 4-component reaction can be
performed under more environmentally friendly conditions with
better yield and wider substrate scope by using a tin salt as a
catalyst and water as a solvent. Being a stable solid, easily
handled and less corrosive, SnCl2·2H2O appeared to be an
attractive precursor for Sn(IV) based Lewis acid catalyst in
aqueous media. Due to our longstanding interest in the synthesis
of pyridine derivatives10,12 we now report the Sn(IV)-catalyzed 4-
component reaction of alkyl/(hetero)aryl aldehydes (1), β-keto
esters (or 1,3-diketones) (2), anilines (3) and malononitrile (4)
leading to a range of pyridine derivatives (Scheme 1).
O
CN
NH
CHO
NH2
EtO
O
O
CN
CH3
+
Catalyst
Solvent
H3C
N
+
+
CN
H3C
EtO
3a
2a
4
5a
1a
Entry
Catalyst
Solvent
Temp (°C)/
Time (h)
Yield (%)b
O
R1
R3
CN
NH
SnCl2.2H2O
R2
1
PMA-SiO2
Amberlite
Indion resin
SiO2
H2O
80/10
80/10
80/10
80/10
80/10
80/11
80/10
80/10
80/10
80/10
80/10
65/10
80/10
80/14
90/10
60/8
40
30
32
15
82
65
40
17
50
35
30
60
50
15
65
82
15c
NH2
O
O
CN (10 mol%)
R1
+
R3
N
+
2
H2O
+
CHO
H2O, 60 o
C
CN
3
H2O
R4
R2
air, 7-10h
4
1
2
5
3
4
H2O
R4
5
SnCl2.2H2O
BiCl3
H2O
Scheme 1. Sn-catalyzed synthesis of pyridines via a 4-
component reaction.
6
H2O
7
L-proline
Clay
H2O
The reaction of benzaldehyde (1a), ethyl acetoacetate (2a), o-
toluidine (3a) and malononitrile (4) was examined in the
presence of air under various conditions as shown in Table 1.
Initially, a recyclable phosphomolybdic acid (PMA)-SiO2 (10
mol%) was used as a catalyst and water as a solvent which
afforded the desired compound 5a though in low yield (entry 1,
Table 1). This prompted us to examine this 4-component reaction
in water in the presence of other catalysts to achieve better
product yield. However, the use of catalysts like amberlite,
indion resin and silicon dioxide did not improve the product yield
(entries 2-4, Table 1). We then examined the use of SnCl2·2H2O
that to our satisfaction afforded 5a with improved yield (entry 5,
Table 1). Several other inorganic / organic catalysts e.g. BiCl3,
clay (montmorillonite K-10), CeCl3.7H2O (entries 6, 8 and 9,
Table 1), and L-proline, citric acid, PTSA (entries 7, 10-11, Table
1) also afforded 5a but with decreased yield. While all these
reactions were performed in water the use of other solvents like
MeOH, i-PrOH, MeCN and PEG-400 was examined and found
to be less effective (entry 5 vs entries 12-15, Table 1). Except
entry 12, 16 and 17 the MCR was performed at 80 ºC for 10h in
all the cases. However, we observed that the product yield was
not affected when the reaction was performed at 60 ºC for 8h
(entry 16, Table 1). A further decrease in reaction time and
temperature decreased the yield of 5a. Generally, 10 mol%
catalyst was used in all our study as decrease in catalyst quantity
decreased the product yield significantly. Notably, the reaction
did not proceed in the absence of a catalyst indicating the key
role played by the catalyst in the present MCR (entry 17, Table
1). Overall, the use of 10 mol% SnCl2.2H2O in water at 60 °C for
8 h in the presence of air was found to be optimum for the
present MCR.
8
H2O
9
CeCl3.7H2O
Citric acid
PTSA
H2O
10
11
12
13
14
15
16
17
H2O
H2O
SnCl2.2H2O
SnCl2.2H2O
SnCl2.2H2O
SnCl2.2H2O
SnCl2.2H2O
No catalyst
CH3OH
iPrOH
CH3CN
PEG-400
H2O
H2O
60/8
a Reactions were carried out using 1a (1 mmol), 2a (1 mmol),
3a (1 mmol), 4 (1 mmol) and 10 mol% catalyst in solvent (4 mL)
under open air.
b Isolated yield.
c Reaction was performed without catalyst.
reactants participated well in this MCR. Similarly, arylamines (in
addition to aniline) containing substituents like CH3, F and Br
(3a-d) also participated well in the reaction. Thus, all the
polysubstituted pyridine derivatives were isolated in good yields
(82-91%). Since alkyl / heteroaryl aldehydes (in addition to aryl
aldehydes) and 1,3-diketones (in addition to β-keto esters) were
used in the present MCR hence the methodology offers wider
substrate scope compared to that reported earlier.11
Except compound 3d all other synthesized compounds are
new and are characterized by spectral (NMR, IR, MS and
HRMS) data. The presence of –CN and carbonyl group (ketone
or ester) was confirmed by the IR absorptions near 2210 and
1710 or 1690 cm-1, respectively. Additionally, a signal near 167
or 203 ppm in the 13CNMR spectra indicated the presence of
ester or keto group.
Having optimized the reaction conditions for the synthesis of a
polysubstituted pyridine derivative in water we then examined
the scope of the MCR and results are presented in Table 2. Thus
a wide range of pyridine derivatives were prepared13 by using this
SnCl2-mediated MCR. The benzaldehyde (entry 1-4, Table 2)
and its derivatives containing groups like OMe, Br and F
participated well in this reaction (entries 5-9, Table 2). Aryl
aldehydes containing electron withdrawing groups like CN and
NO2 also participated in this MCR affording the desired pyridine
derivatives (entries 10-11, Table 2). Other aldehydes e.g.
heteroaryl (entries 12-15, Table 2) and aliphatic aldehydes
(entries 16-19, Table 2) also afforded the corresponding products
(entry 12-19, Table 2). The use of three types of carbonyl group
containing reactants e.g. ethyl acetoacetate (2a), methyl 3-
oxovalerate (2b) and acetyl acetone (2c) was examined. All these
Our earlier synthesis of pyridine derivative via an MCR
involved the use of microwave irradiation.10 We examined if the
same pyridine derivative can be prepared by using the present
MCR without using any microwave irradiation. Accordingly, the
MCR of 1a, 2a, 4 and EtOH was performed under the present
condition and the desired product 6 was obtained in 80% yield
(Scheme 2).

3
5q
Table 2: Synthesis of poly substituted pyridines in aqueous
mediaa
n-Pr, CH3,
CH3, 2-
CH3 5r
R1
18
19
n-Pr, 1j
i-Pr, 1k
2c
2c
3a
3a
8
8
81
78
O
CN
NH
R2
R3
SnCl2.2H2O
(10 mol%)
NH2
i-Pr, CH3,
CH3, 2-
CH3 5s
R1
CN
O
O
R3
N
+
+
+
CHO
H2O, 60 o
air
C
CN
R4
R2
a Reactions were carried out using 1a (1 mmol), 2a (1 mmol),
3a (1 mmol), 4 (1 mmol) and 10 mol% catalyst in H2O (4 mL) at
60 °C under open air.
5
4
2
3
1
R4
Ketone
Product
b Isolated yield.
Entry Aldehyde
Aniline
Time
(h)
Yield
(%)b
R2, R3
(2)
R1, R2, R3,
R4 (5)
R1 (1)
R4 (3)
OMe
OEt,
CH3
Ph, OEt,
CH3, 2-
CH3, 5a
EtOH
2-CH3,
3a
1
2
Ph, 1a
8
8
82
85
CHO
SnCl2.2H2O
(10 mol%)
O
O
O
2a
CN
CN
CN
+
EtO
H3C
+
OMe,
Et
Ph, OMe,
Et, 2-CH3,
H2O, 60 οC
air, 11h
1a
3a
3a
EtO
N
OEt
OMe
2b
5b
1a
2a
4
6 (80%)
Ph, CH3,
CH3, 2-
CH3,
CH3,
CH3
3
1a
1a
9
89
Scheme 2: Synthesis of 2-ethoxy substituted pyridine.
2c
5c
A probable reaction mechanism of the present one-pot 4-
component reaction is shown in Scheme 3. The aqueous solution
of SnCl2 is known to produce SnCl4 in situ in the presence of
air.14 Moreover, comparison of the DSC (Differential Scanning
Calorimetry) thermal analysis and IR spectra obtained for the
commercially available SnCl2.2H2O used in the MCR and the
solid obtained from the reaction mixture after completion of the
reaction (by treating the mixture with EtOAc followed by
filtration) clearly indicated a change in the nature of Sn(II) salt
employed (see Fig.S-1 and S-2 in the supplementary data file).
Thus, Sn(IV) species appeared to be the actual catalysts in the
present reaction.15 Consequently, coordination of the nitrogen
lone pair of intermediate E-1 (formed via the Knoevenagel
condensation between 1 and 4) with the Sn(IV) species could
facilitate the Michael type of reaction with the enol form of 2
affording the intermediate E-2. A further coordination of nitrogen
lone pair of E-2 with the SnCl4 could facilitate a nucleophilic
attack by the arylamine 3 followed by isomerization of the
resulting species to give the intermediate E-3. An intramolecular
cycloaddition of E-3 (via the loss of a water molecule) followed
by oxidative aromatization afforded the desired product 5.
Overall, four new bonds were formed in a single pot operation to
afford the polysubstituted pyridines 5 under environmentally
friendly conditions.
Ph, OEt,
CH3, H,
4
5
2a
H, 3b
8
8
84
86
5d
4-OMe-
Ph, OEt,
CH3, 2-
CH3, 5e
4-MeO-
Ph, 1b
2a
2a
3a
4-OMe-
2,3-di
CH3, 3c
Ph, OEt,
CH3, 2,3-
di CH3, 5f
6
1b
10
88
4-Br-Ph,
CH3, CH3, 86
2-CH3, 5g
4-Br-Ph,
1c
7
2c
2c
2c
2a
2a
2a
2c
2c
2c
3a
8
2-F-Ph,
CH3, CH3, 90
4-F, 5h
2-F-Ph,
1d
8
4-F, 3d
8
2-F-Ph,
CH3, CH3, 87
4-Br, 5i
4-Br,
3e
9
1d
9
4-CN-Ph,
OEt, CH3,
2-CH3, 5j
4-CN-Ph,
1e
10
11
12
13
14
15
3a
3a
3b
3b
3b
3d
7
90
89
86
4-NO2-Ph,
OEt, CH3,
2-CH3, 5k
4-NO2-
Ph, 1f
7
6SnCl2 (aq) + O2 (g) + 2H2O (l)
2SnCl4 (aq) + 4Sn(OH)Cl (s)
N
Sn
2-
Thienyl,
1g
2-Thienyl,
OEt, CH3,
H, 5l
R1
CN
CN
(Cl)n
SnCl4
R1
C
9
1 + 4
2
E-1
CN
2-Thienyl,
CH3, CH3, 91
H, 5m
SnCl4
HO
Sn
R2
1g
8
R2
R2
O
O
R1
(Cl)n
2-Furyl,
CH3, CH3, 85
H, 5n
O
R1
2-Furyl,
1h
O
10
9
SnCl4
R3
CN
O
CN
R3
C
2-Furyl,
CH3, CH3, 88
4-F, 5o
R3
NC
E-2
R1
(Cl)n Sn N
1h
R2
O
R1
R2OC
R3
CN
NH
[O]
iBu, CH3,
CH3, 2-
CH3,
3
5
O
CN
NH
iBu, 1i
2c
2c
3a
3b
9
8
85
90
N
H
R3
H2N
C
16
17
E-3
5p
iBu,CH3,
CH3, H,
1i
Scheme 3. The probable reaction mechanism

4
Tetrahedron Letters
(b) Cosford, N. D. P.; Tehrani, L.; Roppe, J.; Schweiger, E.;
Smith, N. D.; Anderson, J.; Bristow, L.; Brodkin, J.; Jiang, X.;
McDonald, I.; Rao, S.; Washburn, M.; Varney, M. A. J. Med.
Chem. 2003, 46, 204; (c) Enyedy, I. J.; Sakamury, S.; Zaman, W.
A.; Johnson, K. M.; Wang, S. Biorg. Med. Chem. Lett. 2003, 13,
513; (d) Faul, M. M.; Ratz, A. M.; Sullivan, K. A.; Trankle, W.
G.; Winnerroski, L. L. J. Org. Chem. 2001, 66, 5772.
In conclusion, SnCl2·2H2O has been found to be an effective
precatalyst for the synthesis of pyridine derivatives via an MCR
in pure water. The methodology involved 4-component reaction
of alkyl / (hetero)aryl aldehydes, β-keto esters (or 1,3-diketones),
anilines and malononitrile in the presence of air. The reaction
seemed to proceed via in situ generation of Sn(IV) species that
actually catalyzed the MCR in water. This operationally simple
methodology afforded a range of polysubstituted pyridines
including 4-alkyl/heteroaryl derivatives in good (78-91%) yields.
Many of these pyridines are amenable for further
functionalization to generate diversity based library of molecules
of potential pharmacological interest. The use of less expensive
catalyst in aqueous media and good yield of products with wider
substrate scope are the key features of this methodology. The
methodology therefore may find applications both in organic and
medicinal chemistry.
8. (a) Chenand, M. Z.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134,
1352, and references therein; (b) Henry, G. D. Tetrahedron, 2004,
60, 6043; (c) Murugan, R.; Scriven, E. F. J. Heterocycl. Chem.
2000, 37, 451.
9. (a) Siddiqui, Z. N.; Ahmed, N.; Farooq, F.; Khan, K. Tetrahedron
Lett. 2013, 54, 3599; (b) Evdokimov, N. M.; Magedov, I. V.;
Kireev, A. S.; Kornienko, A. Org. Lett. 2006, 8, 899; (c)
Evdokimov, N. M.; Kireev, A. S.; Yakovenko, A. A.; Antipin, M.
Y.; Magedov, I. V.; Kornienko, A. J. Org. Chem. 2007, 72, 3443;
(d) Ranu, B. C.; Jana, R.; Sowmiah, S. J. Org. Chem. 2007, 72,
3152; (e) Sridhar, M.; Ramanaiah, B. C.; Narsaiha, C.; Mahesh,
B.; Kumarswamy, M.; Mallu, K. K. R.; Ankathi, V. M.; Rao, P. S.
Tetrahedron Lett. 2009, 50, 3897; (f) Thirmurugan, P.; Perumal,
P. T. Tetrahedron 2009, 65, 7620; (g) Xin, X.; Wang, Y.; Kumar,
S.; Liu, X.; Lin, Y.; Dong, D. Org. Biomol. Chem. 2010, 8, 3078;
(h) Shaabani, A.; Seyyedhamzeh, M.; Maleki, A.; Behnam, M.;
Rezazadeh, F. Tetrahedron Lett 2009, 50, 2911.
Acknowledgements
D. N. K. Reddy thanks Dr. Krishanji Thadipatri, Dr. H
Ramamohan, Dr. Vilas Dhanukar and the management of CPS,
DRL, Hyderabad, India for support and encouragements.
10. Reddy, T. R.; Reddy, G. R.; Reddy, L. S.; Jammula, S.; Lingappa,
Y.; Kapavarapu, R.; Meda, C. L. T.; Parsa, K. V. L.; Pal, M. Eur.
J. Med. Chem. 2012, 48, 265.
11. He, X.; Shang, Y.; Yu, Z.; Fang, M.; Zhou, Y.; Han, G.; Wu, F. J.
Org. Chem. 2014, 79, 8882.
Supplementary data
12. (a) Pal, M.; Batchu, V. R.; Dager, I.; Swamy, N. K.; Padakanti, S.
J. Org. Chem. 2005, 70, 2376; (b) Gade, N. R.; Devendram, V.;
Pal, M.; Iqbal, J. Chem. Commun. 2013, 49, 7926.
Supplementary data associated with this article can be found,
in the on line version, at xxxxxxxxx
13. Typical procedure for the synthesis of 5a: To a mixture of
benzaldehyde (1a, 1 mmol), ethyl aceto acetate (2a, 1 mmol), o-
toluedine (3a, 1 mmol), and malononitrile (4, 1 mmol) in water (4
mL) was added SnCl2.2H2O (10 mol%) at room temp. The mixture
was then stirred at 60 °C for 8h in the presence of air. After
completion of the reaction (indicated by TLC) the mixture was
diluted with EtOAc (4 mL), and filtered. The residue was washed
with EtOAc (3 x 2 mL). The filtrates were combined. The
separated organic layer was collected, washed with cold water (4
mL), dried over anhydrous Na2SO4, filtered and concentrated
under low vacuum. The residue was purified by column
chromatography over silica gel using EtOAc-hexane to give the
desired productas an off white solid; mp: 178.2-180.6 °C; Rf =
0.62, mobile phase: 20% Ethyl acetate: Hexane; IR (KBr): 3344,
2214, 1717, 1559, 1479, 1446, 1366, 1275, 1137, 1077, 770, 669
cm−1; 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.0 Hz, 1H),
7.48-7.45 (m, 3H), 7.40-7.37 (m, 2H), 7.28-7.27 (m, 1H), 7.26-
7.25 (m, 1H), 7.14-7.11 (m, 1H), 7.07 (s, 1H), 3.98 (q, J = 7.2 Hz,
2H), 2.53 (s, 3H), 2.34 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 167.3, 160.4, 155.8, 153.8, 136.4, 135.9,
130.6, 130.2, 129.4, 128.5 (2C), 127.8 (2C), 126.5, 125.0, 123.0,
120.2, 115.9, 90.5, 61.2, 23.8, 18.07, 13.4; HRMS (ESI) ([M] +1)
calcd for C23H22N3O2: 372.1712, found: 372.1704. Spectral data of
5b: off white solid; mp: 193.6-195.6 °C; Rf = 0.65, mobile phase:
20% Ethyl acetate: Hexane; IR (KBr): 3407, 2215, 1719, 1680,
1557, 1520, 1479, 1430, 1215, 1046, 771, 669 cm−1; 1H NMR
(400 MHz, CDCl3): δ 8.03 (d, J = 8.0 Hz, 1H), 7.49-7.46 (m, 3H),
7.39-7.37 (m, 2H), 7.26-7.21 (m, 2H), 7.20-7.17 (m, 1H), 7.13-
7.05 (m, 1H), 3.48 (s, 3H), 2.82 (q, J = 7.6 Hz, 2H), 2.54 (s, 3H),
1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 167.9,
161.5, 156.1, 153.6, 136.5, 135.7, 130.5, 129.5, 128.6 (2C), 127.8
(2C), 127.2, 127.1, 126.4, 124.7, 122.9, 116.0, 90.4, 52.0, 25.0,
18.0, 12.7; HRMS (ESI) ([M] +1) calcd for C23H22N3O2: 372.1712,
found 372.1730.
References and notes
1. (a) Maiti, S.; Biswas, S.; Jana, U. J. Org. Chem. 2010, 75, 1674;
(b) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439; (c) Gu,
Y. L. Green Chem. 2012, 14, 2091; (d) Domling, A.; Ugi, I.
Angew. Chem., Int. Ed. 2000, 112, 3168; (e) Gers, C. F.;
Nordmann, J.; Kumru, C.; Frank,W.; Muller, T. J. J. J. Org. Chem.
2014, 79, 3296.
2. (a) Maiti, B.; Chanda, K.; Selvaraju, M.; Tseng, C. -C.; Sun, C. -
M. ACS Comb. Sci. 2013, 15, 291; (b) Ganem, B. Acc. Chem. Res.
2009, 42, 463; (c) Isambert, N.; Duque, M. M. S.; Plaquevent, J.
C.; Genisson, Y.; Rodriguez, J.; Constantieux, T. Chem. Soc. Rev.
2011, 40, 1347; (d) Bhattacharya, A. K.; Rana, K. C.; Raut, D. S.;
Mhaindarkar, V. P.; Khan, M. I. Org. Biomol. Chem. 2011, 9,
5407.
3. (a) For a review, see: Abbiati, G. and Rossi, E. Beilstein J. Org.
Chem. 2014, 10, 481.
4. (a) Hatakeyama,T.; Imayoshi, R.;Yoshimoto,Y.; Ghorai, S. K.;
Jin, M.; Takaya, H.; Norisuye, K.; Sohrin,Y.; Nakamura, M. J.
Am. Chem. Soc. 2012, 134, 20262; (b) Nguyen, T. B.; Ermolenko,
L.; Al-Mourabit, A. J. Am. Chem. Soc. 2013, 135, 118; (c) Li, W.-
J.; Zheng, X.-J.; Li, Z.-P. Adv. Synth. Catal. 2013, 355, 181; (d)
Sengoden, M.; Punniyamurthy, T. Angew. Chem., Int. Ed. 2013,
52, 572; (e) Sengupta, T.; Gayen, K. S.; Pandit, P.; Maiti, D. K.
Chem. Eur. J. 2012, 18, 1905; (f) Zhu,S.-F.; Xiao, Y.-L.; Guo, Z.-
J.; Jiang, H.-F. Org. Lett. 2013, 15, 898; (g) Becerra-Figueroa, L.;
Ojeda-Porras, A.; Gamba-Sanchez, D. J. Org. Chem. 2014, 79,
4544.
5. (a) Taylor, R. J. K.; Reid, M. Tetrahedron Lett. 2004, 45, 4181;
(b) Taylor, R. J. K.; Schmidt, P. J.; Moyon, C. M.; Cox, R. J.;
Cayley, A. N. Tetrahedron Lett. 2007, 48, 6556; (c) Russowsky,
D.; Lopes, F. A.; da Silva, V. S. S.; Canto, K. F. S.; D’Oca, M. G.
M.; Godoi, M. N. J. Braz. Chem. Soc. 2004, 15, 165; (d)
14. Nechamkin, H. The Chemistry of the Elements. New York:
McGraw-Hill, 1968.
Akiyama, T.; Onuma, Y. J. Chem. Soc., Perkin Trans. 1, 2002,
15. For further confirmation we have performed the reaction of 1a (1
mmol), 2a (1 mmol), 3a (1 mmol) and 4 (1 mmol) in the presence
of SnCl4 (10 mol%) in water (4 mL) at 60° C for 8h when the
desired product 5a was isolated in 84% yield. It is therefore
evident that SnCl4 generated in situ from SnCl2 is the actual
catalytic species in the present MCR.
1157; (e) Wang, M.; Song, Z.; Zhang, T. J. Heterocyclic Chem.
2010, 47, 468. (f) Sahoo, L.; Singhamahapatra, A.; Paul, K. J. V.;
Loganathan, D. Tetrahedron Lett. 2013, 54, 5361. (g) Zhang, Z.
G.; Wang, D.; Wang, B.; Liu, Q. F.; Liu, T. X.; Zhang, W.; Yuan,
B. B.; Zhao, Z. J.; Han, D. D.; Zhang, G. S. Tetrahedron 2013,
69, 9063. (h) Hu, S.Q.; Zhang, Z. F.; Song, J. L.; Zhou, Y. X.;
Han, B.X. Green Chem. 2009, 11, 1746. (i) Zhao, Y. J.; Loh, T. P.
Chem. Commun. 2008, 1434.
6. For reviews, see: (a) Plunkett, A. O. Nat. Prod. Rep. 1994, 11,
581; (b) Daly, J. W.; Pinder, A. R. Nat. Proc. Rep. 1992, 9, 491;
(c) Spande, T. F. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1987; Vol.31.
7. For selected example, see: (a) Sutherland, A.; Gallagher, T.;
Sharples, C. G. V.; Wonnacott, S. J. Org. Chem. 2003, 68, 2475;