Sequential three-component reactions: Synthesis, regioselectivity and application of functionalized dihydropyridines (DHPs) for the creation of fused naphthyridines

Article abstract of DOI:10.1016/j.tetlet.2011.04.098

Facile and efficient synthesis of tetrasubstituted 1,4- and 1,6-dihydropyridines (DHPs) has been achieved by employing three-component domino reaction using dimethyl acetylenedicarboxylate (DMAD), aliphatic amines, and α,β-unsaturated aldehyde in the presence of 30 mol % trifluoroacetic acid. Interestingly, regioselectivity for the synthesis of 1,4-dihydropyridines can be increased by using 30 mol % triflic acid. In addition, the synthesis of fused-naphthyridine derivatives has been accomplished involving imino-Diels-Alder reaction by employing 1,4-dihydropyridines, aromatic aldehydes, and aromatic amines.

Full text of DOI:10.1016/j.tetlet.2011.04.098

Tetrahedron Letters 52 (2011) 3455–3459
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sequential three-component reactions: synthesis, regioselectivity
and application of functionalized dihydropyridines (DHPs) for the creation
of fused naphthyridines
⇑
Abu T. Khan , Md. Musawwer Khan
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Facile and efficient synthesis of tetrasubstituted 1,4- and 1,6-dihydropyridines (DHPs) has been achieved
by employing three-component domino reaction using dimethyl acetylenedicarboxylate (DMAD), ali-
Received 3 February 2011
Revised 25 April 2011
Accepted 26 April 2011
Available online 1 May 2011
phatic amines, and
a,b-unsaturated aldehyde in the presence of 30 mol % trifluoroacetic acid. Interest-
ingly, regioselectivity for the synthesis of 1,4-dihydropyridines can be increased by using 30 mol %
triflic acid. In addition, the synthesis of fused-naphthyridine derivatives has been accomplished involving
imino-Diels–Alder reaction by employing 1,4-dihydropyridines, aromatic aldehydes, and aromatic
amines.
Keywords:
Sequential multicomponent reactions
Dihydropyridines
Ó 2011 Published by Elsevier Ltd.
Imino-Diels–Alder reactions
Substituted naphthyridines
Multi-component reactions (MCRs) have been proven to be an
elegant and sophisticated approach to access complex structures
in a single step from readily available synthetic precursors.1 Supe-
rior atom economy, simpler procedures, lower costs, high variabil-
ity, and high bond forming efficiency (BFE) are some important
features of MCRs.2
With this objective, the reaction of dimethyl acetylenedicarbox-
ylate (DMAD, 1, 1 mmol), benzylamine (2a, 1 mmol), and crotonal-
dehyde (3a, 1 mmol) was carried out with 20 mol % of
trifluoroacetic acid (TFA) in dicholoromethane and afforded two
products 4a and 5a with overall 62% yield with the ratio of 56:44.
The structures of compounds 4a and 5a were determined by IR, 1H
NMR, 13C NMR spectra and from their elemental analysis. After
obtaining the desired products, a suitable reaction condition was
tried to find out both in terms of yield and selectivity of products.
A series of experiments were performed with various catalysts such
as TFA, acetic acid, pTSA, and triflic acid (TfOH) by varying the
amounts of catalysts. Different solvents, such as DCM, DCE, MeOH,
MeCN, THF, and toluene were also screened. The results and obser-
vations are summarized in Table SI-1, (Supplementary data). From
these experiments, two optimized reaction conditions were ob-
tained. Method A in which both the products 4a and 5a were ob-
tained nearly in equal amounts with 82% overall yield from the
reaction of 1, 2a, and 3a using 30 mol % of TFA in THF. In method B
a regioselective 1,2,3,4-tetrasubstituted dihydropyridine (4a) was
obtained in 76% yield using TfOH acid (30 mol %) in THF.
Nitrogen containing heterocycles are widely distributed in nat-
ural products and pharmaceutically important small molecules.
Among them, dihydropyridines (DHPs) represent an important
class of the nitrogen-heterocycle. They exhibit a diverse range of
biological activities3 such as those for the treatment of cardiovas-
cular disease and hypertension,4 potent calcium channel antago-
nist, and agonist.5 They also have potential application in other
pharmacological activities.6–10 In addition, they have been used
as a hydride source for reductive amination11 and used as synthetic
intermediates.12,13 After the first synthesis of dihydropyridines re-
ported by Hantzsch,14 many synthetic efforts have been made from
all over the world to access these compounds due to their medic-
inal and synthetic usefulness.15,16 In this Letter, we wish to report
a three-component domino reaction for the synthesis of unsym-
metrically substituted 1,4- and 1,6-DHPs, an improved method
for regioselective synthesis of 1,4-DHPs and its application for
the synthesis of naphthyridine derivatives using imino-Diels–Alder
reaction.
After optimizing the reaction conditions, the reaction was per-
formed with DMAD (1, 1 mmol), n-butylamine (2b, 1 mmol), and
crotonaldehyde (3a, 1.2 mmol) by the following method A. Both
the products 4b and 5b were obtained in the ratio of 55:45, respec-
tively with 83% being the total yield. The scope of this protocol was
further examined with various aliphatic amines, such as iso-butyl-
amine, iso-propylamine, n-hexylamine, cyclohexylamine, and fur-
furylamine. The corresponding dihydropyridine derivatives 4c–g
⇑
Corresponding author. Tel.: +91 361 2582305; fax: +91 361 2582349.
E-mail address: atk@iitg.ernet.in (A.T. Khan).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.04.098

3456
A. T. Khan, Md. Musawwer Khan / Tetrahedron Letters 52 (2011) 3455–3459
and 5c–g were obtained in good yields and the ratio of the prod-
ucts is shown in Table 1 (entries 3–7).
ination product A. The intermediate A reacts with
aldehyde in two ways either path a or path b. In path a, the inter-
mediate A on reaction with ,b-unsaturated aldehyde leads to
the formation of intermediate imine B which on electrocyclic cycli-
zation gives the 1,4-dihydropyridine derivative 4. In path b, the
intermediate C is formed from the intermediate A on reaction with
a,b-unsaturated
We turned our attention toward synthesis of regioselective
1,4-DHPs by the following method B. The mixture of DMAD (1,
1 mmol), n-butylamine (2b, 1 mmol) and crotonaldehyde (3a,
1.2 mmol) was stirred using method B and the major product 4b
was obtained in 72% yield.
a
a,b-unsaturated aldehyde via Michael addition reaction. Finally,
Encouraged by this result, the reaction of various other amines,
such as iso-butylamine, iso-propylamine, n-hexylamine, cyclohex-
ylamine, furfurylamine, and ethylamine was also studied with
DMAD and crotonaldehyde under identical reaction conditions.
The reaction time and percentage yield of the products 4c–h are
summarized in Table 1.
1,6-dihydropyridine derivative 5 is obtained through cyclization
from C followed by dehydration as shown in Scheme 1. We believe
that path a is preferred to path b in the case of TfOH (pKa = ꢀ15)
which is highly acidic as compared to TFA (pKa = 0.5), which favors
imine formation by protonation of the carbonyl group as compared
to Michael addition reaction.
Cinnamaldehyde exhibits similar regioselectivity pattern in
both protocols as mentioned in Table 1, however method B fur-
nished good yields of products 4i and j. All these products were
characterized by IR, 1H NMR, and 13C NMR spectra as well as ele-
mental analysis. The structure of compound 4i was confirmed by
X-ray crystallographic analysis (Fig. SI1). The present methods
were unsuccessful for the synthesis of substituted N-aryl dihydro-
pyridines using aniline by following both the methods; this may be
due to less nucleophilicity of aniline as compared to aliphatic
amines.
The synthetic utility of 1,4-DHPs as a dienophile in imino-Diels–
Alder reaction (Povarov reaction),17 has been demonstrated for the
synthesis of substituted naphthyridine derivatives for the creation
of molecular diversity. The applications of 1,4-dihydropyridine as a
dienophile have been described for Povarov reaction by others.13
However, the newly designed 1,2,3,4-tetrasubstituted dihydropyri-
dines having
a and b amino acid functionality have remained
unexplored, which may offer a new platform for the synthesis of
different substituted naphthyridine derivatives.
With this idea in mind, a three component one-pot reaction was
conducted with 1,4-DHP (4a), benzaldehyde, and aniline catalyzed
by 20 mol % of BF3ꢁOEt2 in acetonitrile. The cycloaddition reaction
We propose a plausible mechanism for the formation of 1,4 and
1,6-DHPs. Initially, the amine reacts with DMAD to form hydroam-
Table 1
Synthesis of various 1,2,3,4- and/or 1,2,3,6-tetrasubstituted dihydropyridines 4 and 519
R2
O
CO2Me
MeO2C
MeO2C
MeO2C
MeO2C
R2
H
TFA or TfOH
and/or
3
N
R1
5
R2
N
R1
4
MCR1
R1NH2
CO2Me
2
1
Entry
1
R1NH2
R2
Method A
Method B
Ratioa (4:5)
Yieldb(%)
82
Ratioa (4:5)
Yieldc (%)
NH2
NH2
Me
51:49
88:12
4a, 76
2
3
Me
Me
55:45
58:42
83
83
86:14
87:13
4b, 72
4c, 75
NH2
4
5
6
Me
Me
Me
60:40
55:45
54:46
82
82
81
83:17
86:14
88:12
4d, 69
4e, 72
4f, 73
NH2
( )3
NH2
NH2
NH2
7
8
Me
Me
48:52
83
—
86:14
78:22
4g, 72
4h, 57
O
NH2
NH2
9
Me
No reaction
—
No reaction
NH2
NH2
10
11
Ph
Ph
80:20
75:25
59
56
82:18
80:20
4i, 62
4j, 58
Method A: DMAD (1 mmol), Amines (1 mmol), enals (1.2 mmol) and TFAA (0.3 mmol) in THF at rt.
Method B: DMAD (1 mmol), Amines (1 mmol), enals (1.2 mmol) and TfOH (0.3 mmol) in THF at rt.
a
Product ratio determined by crude 1H NMR.
Combined yields of 4 and 5.
Isolated yields.
b
c

A. T. Khan, Md. Musawwer Khan / Tetrahedron Letters 52 (2011) 3455–3459
3457
R2
MeO2C
MeO2C
MeO2C
MeO2C
cyclization
O
N
R2
R1
R2
H
N
B
R1
path a
4
CO2Me
MeO2C
MeO2C
R1 NH2
hydroamination
CO2Me
NH
R1
A
path b
MeO2C
MeO2C
MeO2C
MeO2C
H
O
cyclization
R2
H
N
O
R2
R1
N
R2
R1
C
5
Scheme 1. Proposed mechanism for amination reaction of DMAD promoting for cascade reaction.
Table 2
Synthesis of substituted naphthyridine derivatives 820
R3
R3
OHC
R2
R2
R2
H
H
MeO2C
H
H
R3 BF3.OEt2
MCR2
MeO2C
MeO2C
MeO2C
MeO2C
NH
R4
NH
R4
H
H
6
MeO2C
N
H2N
N
N
R1
R1
R1
R4
4
major, 8
minor, 8'
7
Entry
R1
R3
R4
Time (h)
Ratioa
Yieldb (%)
1
2
3
4
5
6
7
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
H
H
H
H
H
H
6
6
6
8
8
10
6
4:1
3:1
4:1
4:1
4:1
3:1
2:1
8a, 65
8b, 61
8c, 63
8d, 54
8e, 62
8f, 51
8g, 52
8g0, 21
8h–h0, 76
8i, 59
Me
MeO
Cl
Br
NO2
Cl
MeO
8
9
Bn
n-C4H9
Cl
H
Me
H
6
10
2:1
3:1
a
Ratio determined by crude 1H NMR.
Isolated yield.
b
afforded two diastereomers 8a and 8a0 with a ratio of 4:1. The ma-
jor isomer 8a was isolated in 65% yield. Likewise, the reaction of 4a
with aniline and other aromatic aldehydes substituted with Me,
MeO, Cl, Br, and NO2 at position 4 was also investigated. The reac-
tions proceeded smoothly and various substituted naphthyridine
derivatives 8b–f were obtained in good yields. The reaction of ani-
line derivatives such as 4-methylaniline and 4-methoxyaniline was
also studied under similar conditions and the results are summa-
rized in Table 2. Similar diastereoselectivity was observed by oth-
ers18 for imino-Diels–Alder reaction with an electron rich
dienophile. However, we have obtained relatively lower diastere-
oselectivity in the case of 4-methyl aniline and 4-methoxyaniline
due to steric repulsion between the benzyl group and a methyl
or methoxy group present at the 4th-position. Finally, the reaction
of 1,4-DHP 4b with benzaldehyde and aniline was performed and
gave major isomer 8i in 59% yield.
The functionalized naphthyridine derivatives have four contig-
uous stereocenters, and gave only two diastereoisomers. A fairly
good diastereoselectivity was observed in the above study. The
structures of all the compounds were ascertained by usual spectro-
scopic studies as well as the literature precedent.13 For example,
the structure of compound 8i was established by NMR (1H, 13C,
COSY, NOESY). This isomer shows 1H NMR peaks with d values
4.42, 1.93, and 4.16 for H1, H2, and H4, all having doublets with cou-
pling constants J1,2 = 2.0 Hz and J2,4 = 10.8 Hz, representing cis
arrangement of hydrogen between two ring fusions. The proton
H4 is trans with ring junction proton H2. In addition, H1, H2, and
Me are all in same plane, however, H3 and H4 are in other planes
depicted by NOE as shown in Figure 1. Finally, the observed struc-
ture and stereochemistry were fully supported by single crystal X-
ray structure determination of compound 8b (major isomer) and
8g0 (minor isomer) as shown in Figure 2.21

3458
A. T. Khan, Md. Musawwer Khan / Tetrahedron Letters 52 (2011) 3455–3459
3. (a) Janis, R. A.; Silver, P. J.; Triggle, D. J. Adv. Drug Res. 1987, 16, 309; (b) Hesse,
M. Alkaloids: Nature’s Curse or Blessing; Wiley-VCH: Weinheim, 2003.
4. (a) Gordeev, M. F.; Patel, D.; Gordon, E. M. J. Org. Chem. 1996, 26, 924; (b) Shan,
R.; Velaskez, C.; Knaus, E. E. J. Med. Chem. 2004, 47, 254.
5. Triggle, D. J.; Rampe, D. Trends Pharmacol. Sci. 1989, 12, 507.
6. Klusa, V. Drugs Future 1995, 20, 135.
7. Donkor, I. O.; Zhou, X.; Schmidt, J.; Agrawal, K. C.; Kishore, V. Bioorg. Med. Chem.
1998, 6, 563.
8. Straub, T.; Boesenberg, C.; Gekeler, V.; Boege, F. Biochemistry 1997, 36, 10777.
9. (a) Abbas, H. A. S.; El Sayed, W. A.; Fathy, N. M. Eur. J. Med. Chem. 2010, 45, 973;
(b) Robert, J.; Jarry, C. J. Med. Chem. 2003, 46, 4805.
10. (a) Hilgeroth, A. Mini-Rev. Med. Chem. 2002, 2, 235; (b) Hilgeroth, A.; Lilie, H.
Eur. J. Med. Chem. 2003, 38, 495.
11. (a) Hoffmann, S.; Nicoletti, M.; List, B. J. Am. Chem. Soc. 2006, 128, 13074; (b) Li,
G.; Antilla, J. C. Org. Lett. 2009, 11, 1075; (c) He, R.; Toy, P. H.; Lama, Y. Adv.
Synth. Catal. 2008, 350, 54.
Figure 1. Diagnostic 1H NMR and NOE of 8i.
12. (a) Charette, A. B.; Mathieu, S.; Martel, J. Org. Lett. 2005, 7, 5401; (b) Chai, L. Z.;
Zhao, Y. K.; Sheng, Q. J.; Liu, Z.-Q. Tetrahedron Lett. 2006, 47, 9283; (c) Chen, J.;
McNeil, A. J. J. Am. Chem. Soc. 2008, 130, 16496.
13. (a) Lavilla, R.; Bernabeu, M. C.; Carranco, I.; Diaz, J. L. Org. Lett. 2003, 5, 717; (b)
Carranco, I.; Diaz, J. L.; Jimenez, O.; Vendrell, M.; Albericio, F.; Royo, M.; Lavilla,
R. J. Comb. Chem. 2005, 7, 33; (c) Vicente-Garcia, E.; Catti, F.; Ramon, R.; Lavilla,
R. Org. Lett. 2010, 12, 860; (d) Maiti, S.; Sridharan, V.; Menéndez, J. C. J. Comb.
Chem. 2010, 12, 713.
14. Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1.
15. (a) Wang, L. M.; Sheng, J.; Zhang, L.; Han, J. W.; Fan, Z. Y.; Tian, H.; Qian, C. T.
Tetrahedron 2005, 61, 1539; (b) Sharma, G. V. M.; Reddy, K. L.; Lakshmi, P. S.;
Krishna, P. R. Synthesis 2006, 55; (c) Kumar, A.; Maurya, R. A. Tetrahedron 2007,
63, 1946; (d) Kumar, A.; Maurya, R. A. Synlett 2008, 883; (e) Debache, A.;
Ghalem, W.; Boulcina, R.; Belfaitah, A.; Rhouati, S.; Carboni, B. Tetrahedron Lett.
2009, 50, 5248.
16. (a) Weller, D. D.; Rapoport, H. J. Am. Chem. Soc. 1976, 98, 6650; (b) Evdokimov,
N. M.; Magedov, I. V.; Kireev, A. S.; Kornienko, A. Org. Lett. 2006, 8, 899; (c)
Sridharan, V.; Perumal, P. T.; Avendaño, C.; Menéndez, J. C. Tetrahedron 2007,
63, 4407; (d) Bartoli, G.; Babiuch, K.; Bosco, M.; Carlone, A.; Galzerano, P.;
Melchiorre, P.; Sambri, L. Synlett 2007, 2897; (e) Singh, L.; Ishar, M. P. S.;
Elango, M.; Subramanian, V.; Gupta, V.; Kanwal, V. P. J. Org. Chem. 2008, 73,
2224; (f) Li, M.; Zuo, Z.; Wen, L.; Wang, S. J. Comb. Chem. 2008, 10, 436; (g)
Kumar, A.; Maurya, R. A. Tetrahedron 2008, 64, 3477; (h) Mojarrad, J. S.; Miria,
R.; Knaus, E. E. Bioorg. Med. Chem. 2004, 12, 3215; (i) Sun, J.; Xia, E. Y.; Wu, Q.;
Yan, C. G. Org. Lett. 2010, 12, 3678; (j) Ogawa, A. K.; Willoughby, C. A.; Bergeron,
R.; Ellsworth, K. P.; Geissler, W. M.; Myers, R. W.; Yao, J.; Harris, G.; Chapman,
K. T. Bioorg. Med. Chem. Lett. 2003, 13, 3405.
17. (a) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656; (b) Glushkov, V. A.; Tolstikov, A.
G. Russ. Chem. Rev. 2008, 77, 137; (c) Liu, H.; Dagousset, G.; Masson, G.;
Retailleau, P.; Zhu, J. J. Am. Chem. Soc. 2009, 131, 4598; (d) Bello, D.; Ramón, R.;
Lavilla, R. Curr. Org. Chem. 2010, 14, 332; (e) Bergonzini, G.; Gramigna, L.;
Mazzanti, A.; Fochi, M.; Bernardi, L.; Ricci, A. Chem. Commun. 2010, 46, 327.
18. (a) Sridharan, V.; Avendano, C.; Menendez, J. C. Tetrahedron 2007, 63, 673; (b)
Yadav, J. S.; Reddy, B. V. S.; Sadasiv, K.; Reddy, P. S. R. Tetrahedron Lett. 2002, 43,
3853; (c) Kouznetsov, V. V. Tetrahedron 2009, 65, 2721.
8b (CCDC no. 810814)
8g' (CCDC no. 810813)
Figure 2. X-ray crystal structures of 8b and 8g0.
In conclusion, the Brønsted acid catalyzed synthesis of
unsymmetrical tetrasubstituted 1,4- and 1,6-DHPs using one-pot
three-component reactions of DMAD, aliphatic amines, and
a,b-
unsaturated aldehydes have been accomplished. The regioselective
synthesis of tetrasubstituted 1,4-DHPs were also achieved in good
yields. These 1,4-DHPs can be used for a new class of dienophiles
for imino-Diels–Alder reaction for the construction of highly
substituted naphthyridine derivatives. The significant advantages
of present protocol are simple experimental procedure, nontoxic
byproduct, high atom economy, good regioselectivity, and diaste-
reoselectivity. The new heterocyclic entities containing b-amino
acid skeleton might exhibit interesting pharmacological activities.
Further studies on regioselectivity and applications of these DHPs
are going on in our laboratory which will be reported in due course
of time.
19. General procedure for 1,4- and 1,6-dihydropyridines 4 and 5: Method A: To a
stirred solution of dimethyl acetylenedicarboxylate 1 (DMAD, 1.0 mmol) in
THF (2 mL) was added amine 2 (1.0 mmol) at room temperature. After 10 min
of stirring,
a,b-unsaturated aldehyde 3 (1.2 mmol) and trifluoroacetic acid
(0.3 mmol) were added successively and kept for further stirring. After
completion of reaction (monitored by TLC), the reaction mixture was
neutralized with NaHCO3 solution and it was extracted with DCM
(20 mL ꢂ 2). The organic phase was washed with water, brine solution, and
dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude
mixture was purified through silica gel chromatography using hexane/ethyl
acetate/NEt3 (92:7:1) and it afforded the products 4a–j and 5a–j, respectively
in good yields. For Method B, the same procedure was followed except that the
catalyst triflic acid (30 mol %) is used in place of TFA. Compound 4a: yellow
liquid (126 mg, 42%); 1H NMR (400 MHz, CDCl3): d 7.36–7.24 (m, 5 H), 5.75 (d,
1H, J = 7.2 Hz), 4.87 (dd, 1H, J = 7.2 Hz, J = 5.6 Hz), 4.36 (d, 1H, J = 16.4 Hz), 4.28
(d, 1H, J = 16.4 Hz), 3.78 (s, 3H), 3.68 (s, 3H), 3.39–3.32 (m, 1H), 1.08 (d, 3H,
J = 6.4 Hz); 13C NMR (100 MHz, CDCl3): d 167.9, 166.1, 144.3, 137.0, 128.9,
128.0, 127.6, 127.3, 110.6, 101.2, 54.6, 52.9, 51.6, 27.1, 25.3; IR mmax (KBr):
cmꢀ1 2951, 1739, 1695, 1575, 1434, 1269, 1216, 1187, 734. Anal Calcd for
Acknowledgment
M.M.K. is grateful to the UGC, New Delhi, India for research fel-
lowship. We are also thankful to Dr. S. Ranganathan, Assistant Pro-
fessor, IIT Patna for necessary correction of the manuscript. The
authors are greatful to the referees for their valuable comments
and suggestions.
Supplementary data
C
17H19NO4 (301.34): C, 67.76; H, 6.36; N, 4.65; found: C, 67.71; H, 6.32; N, 4.58.
Compound 5a: yellow liquid (121 mg, 40%); 1H NMR (400 MHz, CDCl3): d 7.37–
7.29 (m, 5H), 6.41 (d, 1H, J = 9.6 Hz), 5.02 (dd, 1H, J = 9.6 Hz, J = 5.2 Hz), 4.37 (d,
1H, J = 15.6 Hz), 4.30 (d, 1H, J = 15.6 Hz), 3.98–3.93 (m, 1H), 3.87 (s, 3H), 3.71 (s,
3H), 1.14 (d, 3H, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3): d 166.3, 166.0, 147.9,
136.4, 128.9, 128.2, 127.7, 121.3, 114.9, 97.8, 54.4, 53.1, 52.7, 51.3, 19.2; IR mmax
(KBr): cmꢀ1 2950, 1739, 1693, 1542, 1434, 1297, 1230, 1125, 728. Anal Calcd
for C17H19NO4 (301.34): C, 67.76; H, 6.36; N, 4.65; found: C, 67.70; H, 6.31; N,
4.60.
Supplementary data (optimization table, X-ray crystallographic
data (CIF file) of 4i, 8b and 8g0, spectral data of all compounds and
copies of 1H and 13C NMR spectra of products) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.04.098.
20. General procedure for synthesis of substituted tetrahydroquinoline derivatives 8:
1,4-DHP 4a (0.3 mmol) was added to a stirring solution of aromatic aldehyde
(0.3 mmol) and aromatic amine (0.3 mmol) in acetonitrile (2 mL). Finally,
catalyst BF3ꢁOEt2 (20 mol %) was added to the reaction mixture and stirring
was continued. After completion of the reaction (monitored by TLC), the
mixture was extracted with DCM (20 mL ꢂ 2). The organic phase was washed
with saturated solution of NaHCO3, brine solution, and dried over Na2SO4. The
References and notes
1. (a) Zhu, J.; Bienaymé, H. Multicomponent Reactions, first ed.; Wiley-VCH:
Weinheim, Germany, 2005; (b) Dömling, A. Chem. Rev. 2006, 106, 17.
2. (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 2006; (b) Trost, B. M. Acc. Chem.
Res. 2002, 35, 695.

A. T. Khan, Md. Musawwer Khan / Tetrahedron Letters 52 (2011) 3455–3459
3459
crude products were purified by silica gel chromatography (hexane/ethyl
acetate, 85:15) to afford the products 8a–i in good yields. Compound 8a: White
solid (94 mg, 65%); mp 242–245 °C; 1H NMR (400 MHz, CDCl3): d 7.38–7.28 (m,
5H), 7.28–7.23 (m, 2H), 7.18–7.12 (m, 2H), 7.10 (t, 2H, J = 7.2 Hz), 6.63 (d, 1H,
J = 7.6 Hz), 6.51–6.47 (m, 2H), 4.42 (d, 1H, J = 2.8 Hz), 4.29 (d, 1H, J = 16.8 Hz),
4.25 (d, 1H, J = 10.8 Hz), 4.17 (s, 1H), 4.14 (d, 1H, J = 16.8 Hz), 3.78 (s, 3H), 3.65
(s, 3H), 2.43–2.36 (m, 1H), 1.92 (d, 1H, J = 10.8 Hz), 1.09 (d, 3H, J = 6.8 Hz); 13C
NMR (100 MHz, CDCl3): d 168.0, 166.9, 147.9, 144.3, 143.0, 137.6, 131.9, 130.2,
128.7, 128.6, 128.2, 128.0, 127.2, 127.1, 115.7, 115.6, 113.8, 98.3, 56.0, 52.8,
52.1, 51.2, 41.8, 26.9, 23.1; IR mmax (KBr): cmꢀ1 3413, 2955, 1744, 1683, 1573,
1498, 1224, 1142, 1088, 735. Anal Calcd for C30H30N2O4 (482.57): C, 74.67; H,
6.27; N, 5.81; found: C, 74.61; H, 6.14; N, 5.71.
21. Complete crystallographic data of 4i, 8b, and 8g0 for the structural analysis
have been deposited with the Cambridge Crystallographic Data Centre, CCDC
No. 810812, 810814 and 810813, respectively. 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: +44 1223 336033, e-mail:
deposit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk).