Indium trichloride catalyzed one-pot synthesis of indolo[2,1-a]pyrrolo[4′,3′:2,3]-7a,8,13,13b-tetrahydroquinolines through intramolecular imino Diels-Alder reactions

Article abstract of DOI:10.1016/j.tetlet.2007.03.170

An efficient synthesis of tetrahydroquinolines has been achieved by the reaction of aldimines derived from various substituted aromatic amines and indole-2-carbaldehyde containing an internal dienophile using 20 mol % InCl₃ in acetonitrile at r

Full text of DOI:10.1016/j.tetlet.2007.03.170

Tetrahedron Letters 48 (2007) 4139–4142
Indium trichloride catalyzed one-pot synthesis of
indolo[2,1-a]pyrrolo[40,30:2,3]-7a,8,13,13b-tetrahydroquinolines
through intramolecular imino Diels–Alder reactions
Rathna Durga R. S. Manian,a Jayadevan Jayashankaranb
and Raghavachary Raghunathana,*
aDepartment of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
bLaboratoire de Chimie Moleculaire et Thioorganique (LCMT) UMR CNRS 6507, Ensicaen et Universite de Caen Basse
Normandie, 6, Boulevard du Marechul Juin, F-14050 Caen, France
Received 12 February 2007; revised 20 March 2007; accepted 29 March 2007
Available online 4 April 2007
Abstract—An efficient synthesis of tetrahydroquinolines has been achieved by the reaction of aldimines derived from various substi-
tuted aromatic amines and indole-2-carbaldehyde containing an internal dienophile using 20 mol % InCl3 in acetonitrile at room
temperature. The reactions are very fast and the products are isolated in good yields and in pure form.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
biological activities such as psychotropic, anti-allergic,
anti-inflammatory, and estrogenic. In addition, the
indole nucleus annealated to carbocyclic or heterocyclic
ring(s) is present in an astonishing variety of natural
products with potent and varied biological activity.8
Hence, new and efficient syntheses of such compounds
is still important.
The Diels–Alder reaction of 2-azadienes is a valuable
methodology for synthesis of nitrogen heterocycles1
bearing endocyclic enamine moieties that are key inter-
mediates in the preparation of complicated heterocycles
and natural products.2 The 4p activity of simple 2-azadi-
enes is rarely observed in normal [4+2] cycloaddition
reactions; however, this problem can be circumvented
by introducing either electron-withdrawing1,3 or elec-
tron-donating4 substituents onto the nitrogen. Fowler2
and Boger5 have shown that substitution of the azadiene
nitrogen by a strongly electron-withdrawing N-acyl or
N-sulfonyl group favors considerably the inverse elec-
tron demand Diels–Alder reactivity of the azadienes.
Nevertheless, significant efforts have been made toward
production of electron-deficient 2-aza-1,3-butadienes
which enable 4p participation of a,b-unsaturated imines
in [4+2] cycloaddition reactions.6
Indium trichloride (InCl3) has emerged as a mild and
water-tolerant Lewis acid imparting high regio and che-
moselectivity in various organic transformations.9 It can
be conveniently used in both aqueous and non-aqueous
medium and, in addition, it can be recovered from the
aqueous layer on work-up and recycled for use in subse-
quent reactions. Furthermore, InCl3 is highly efficient in
activating nitrogen-containing compounds such as imi-
nes and hydrazones10 (Scheme 1).
With this in mind, we herein report a facile Lewis acid
catalyzed imino Diels–Alder reaction for the synthesis
of novel tetrahydroquinolines from N-alkylated indole-
2-carbaldehydes containing substituted terminal alkenes
and various p-substituted anilines.
The tetrahydroquinoline unit is a feature of many alka-
loids and derivatives thereof are found to exhibit a wide
range of biological activities.7 Examples such as flinder-
sine, oricine, and veprisine and their derivatives exhibit
The precursors for the imino Diels–Alder reaction were
readily obtained by the treatment of ethyl-1H-indole-
2-carboxylate and 1-bromo-3-methylbut-2-ene/cinn-
amyl bromide in benzene with 50% aqueous sodium
*
Corresponding author. Tel.: +91 044 09444333883; e-mail:
ragharaghunathan@yahoo.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.170

4140
Rathna Durga R. S. M. et al. / Tetrahedron Letters 48 (2007) 4139–4142
NH2
H
Ha
H
Ha
20 mol %InCl3
acetonitrile, rt
N
N
CHO
N
N
N
R
Hd
Hc
R
Hd
Hb
3a-e
Hb
R
2a-e
Hc
1a
4a-e
R = a) H, b) Me, c) OMe, d) Cl, e) NO2
Scheme 1.
Table 2. Study of the mole ratio of InCl3 on the reaction of 1a with 2c
hydroxide in the presence of a catalytic amount of
TEBA at room temperature for 1–2 h to furnish the
ethyl-1-N-alkenyl-1H-indole-2-carboxylate in moderate
yield, which was then reduced to the corresponding alco-
hol by LiAlH4 in dry THF at 0 °C. The alcohol was then
subjected to Swern oxidation to yield 1a in 85% and 1b
in 83% yield.11
Entry
InCl3 (mol %)
Yield (%)
1
2
3
4
5
10
15
20
20
53
65
84
Reaction of 1a with 2a–e in the presence of MgSO4 in
acetonitrile afforded the corresponding imine, which
was characterized by spectroscopic analysis. The imine
(without further purification) underwent [4+2] cycload-
dition in the presence of a Lewis acid catalyst to yield
cis-tetrahydroquinolines 3a–e and trans-tetrahydroquin-
olines 4a–e.12–15
Table 3. Effect of solvent on the yield of the reaction of 1a and 2c with
20 mol % of InCl3
Entry
Solvent
Time (min)
Yield (%)
1
2
3
4
Toluene
CH2Cl2
CHCl3
70
55
48
30
65
72
70
84
CH3CN
In order to study the scope and limitations of the cyclo-
addition reaction, various Lewis acid catalysts, namely,
AlCl3, BF3ÆOEt2, ZnCl2 and InCl3 were investigated.
The cis-tetrahydroquinoline derivative was the major
product when 1a and 2c were reacted in the presence
of a Lewis acid. The best overall yield of 3c and 4c
(84%) was obtained when InCl3 was used as the catalyst
(Table 1).
gave 3c and 4c in 84% yield, while other solvents fur-
nished compounds 3c and 4c in 65–72% yields as sum-
marized in Table 3. This outcome probably results
from the high polarity of the solvent and miscibility with
water during imine formation. The structures assigned
to cycloadducts 3c and 4c were confirmed by examina-
1
tion of their respective H NMR spectra.
Similarly, the mole ratio of InCl3 was studied and the re-
sults are listed in Table 2. It was found that the amount
of InCl3 affects the yield of the product, with 20 mol %
of InCl3 being optimum.
The Ha proton of 3c appears as a doublet at d 4.99
(J = 6.3 Hz), which is coupled to the Hb proton. This
small coupling constant is consistent with a cis-diaxial
relationship for these two protons. Furthermore, the ste-
reochemistry of Ha was confirmed by the observation of
a strong (8.1%) NOE enhancement of Ha upon the irra-
diation of Hb. In a similar fashion, the Ha proton of 4c
exhibited a doublet at d 5.08 (J = 10.6 Hz) indicating the
trans stereochemistry of Ha with respect to Hb (Scheme
2).
Next, we examined the effect of solvent on the cyclo-
addition reaction. Reaction of 1a and 2c in acetonitrile
Table 1. Influence of Lewis acid on the reaction of 1a with 2c
Entry
Lewis acid
Reaction time
Overall yield (%)
1
2
3
4
AlCl3
24 h
16 h
18 h
30 min
20
18
40
84
BF3ÆOEt2
ZnCl2
InCl3
The preparation of tetrahydroquinolines with other p-
substituted aromatic anilines 2a,b and 2d,e under the
NH2
H
Ha
H
Ha
20 mol %InCl3
acetonitrile, rt
N
N
CHO
H
N
N
N
R
Hd
Hc
R
Hd
Hb
Hb
R
2a-e
H
Hc
H
1b
6a-e
5a-e
R = a) H, b) Me, c) OMe, d) Cl, e) NO2
Scheme 2.

Rathna Durga R. S. M. et al. / Tetrahedron Letters 48 (2007) 4139–4142
4141
Table 4. The reaction of 1a/1b and 2a–e in the presence of 20 mol % indium trichloride in acetonitrile
Entry
R
R1
R2
Products
Time (min)
Ratio of products
cis:trans
Yield (%)
1 R2
1 R2
R
R
H
H
R
R
N
N
N
N
H
H
H
H
1
2
3
4
5
6
7
8
9
H
CH3
CH3
CH3
CH3
CH3
Ph
Ph
Ph
Ph
Ph
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
3a
3b
3c
3d
3e
5a
5b
5c
5d
5e
4a
4b
4c
4d
4e
6a
6b
6c
6d
6e
45
30
35
30
42
35
25
30
40
35
84:16
80:20
88:12
92:8
78
84
80
76
81
86
90
92
90
87
CH3
OCH3
Cl
NO2
H
CH3
OCH3
Cl
95:5
87:13
82:18
90:10
95:5
10
NO2
96:4
optimized conditions was carried out and the results are
shown in Table 4.
hyde or 1-cinnamyl-indole-2-carbaldehyde (1 mmol) in
acetonitrile (5 mL). The reaction mixture was stirred at
room temperature until completion of the reaction as
indicated by TLC. The mixture was then quenched with
water and extracted with ethyl acetate. The organic layer
was washed with water and dried over MgSO4. The sol-
vent was evaporated in vacuo and the crude product was
purified by chromatography on silica gel (ethyl acetate–
hexane) to afford cis- and trans-isomers in good yields.
Further, to examine the effect of introducing substitution
at the terminus of the dienophile on the cycloaddition
process, we prepared 1-cinnamyl-1H-indole-2-carbalde-
hyde 1b as previously described. Thus, 1b and 2d
underwent [4+2] cycloaddition to afford the correspond-
ing cis-and trans-cycloadducts 5d and 6d in 90% overall
yield.16,17
The structures of cycloadducts 5d and 6d were estab-
lished by examination of their H NMR spectra and
Acknowledgment
1
NOE experiments. The enhanced yields and short
reaction time for the formation of products 5d and 6d
relative to the cycloaddition of 1a with 2c in acetonitrile
is clearly a testament to the greater reactivity of the
phenyl-substituted dienophile in 1b.
R.D. and J.J. thank the CSIR-SRF, New Delhi, for
financial support.
References and notes
Likewise, other p-substituted aromatic anilines 2a–c,e
reacted smoothly with 1b at room temperature in the
presence of 20 mol % of InCl3 to give the corresponding
cis- and trans-tetrahydroquinoline derivatives in fairly
good yields. The yields and ratios of the isomers are pre-
sented in Table 4.
1. (a) Boger, D. L. Tetrahedron 1983, 39, 2869; (b) Weinreb,
S. M.; Scola, P. M. Chem. Rev. 1989, 89, 1525.
2. (a) Hwang, Y. O.; Fowler, F. W. J. Org. Chem. 1985, 50,
2719; (b) Cheng, Y. S.; Lupo, A. T., Jr.; Fowler, F. W. J.
Am. Chem. Soc. 1983, 105, 7696.
3. (a) Boger, D. L.; Weinreb, S. M. In Hetero Diels–Alder
Methodology in Organic Synthesis; Academic Press: San
Diego, 1987; p 239; (b) Uyehara, T.; Suzuki, I.; Yama-
moto, Y. Tetrahedron Lett. 1990, 31, 3753; (c) Uyehara,
T.; Chiba, W.; Suzuki, I.; Yamamoto, Y. Tetrahedron
Lett. 1991, 32, 4371.
In summary, the work represents our first attempt to use
1a and 1b as useful precursors in the synthesis of
tetrahydroquinolines.
4. (a) Serckx-Poncin, B.; Hesbain-Frisque, A.-M.; Ghosez,
L. Tetrahedron Lett. 1982, 23, 3261; (b) Ghosez, L.;
Serckx-Poncin, B.; Rivera, M.; Bayard, P.; Sainte, F.;
Demoulin, A.; Hesbain-Frisque, A.-M.; Mokel, A.;
Munoz, L.; Bernard-Henriat, C. J. Heterocycl. Chem.
1985, 22.
From our study it is evident that InCl3 catalyzes the
intramolecular Diels–Alder reactions of 1 and 2 effi-
ciently, also the phenyl substituent at the terminal of
dienophile proves to be reactive.
5. (a) Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A.
M. J. Am. Chem. Soc. 1991, 113, 1713; (b) Boger, D. L.;
Kasper, A. M. J. Am. Chem. Soc. 1989, 111, 1517; (c)
Boger, D. L.; Corbett, W. L.; Wiggins, J. M. J. Org. Chem.
1990, 55, 2999.
6. (a) Yadav, J. S.; Reddy, B. V. S.; Sadasiv, K.; Reddy, P. S.
R. Tetrahedron Lett. 2002, 43, 3853–3856; (b) Yadav, J. S.;
Subba Reddy, B. V.; Sunitha, V.; Srinivasa Reddy, K.;
Ramakrishna, K. V. S. Tetrahedron Lett. 2004, 45,
2. Experimental
General procedure for the synthesis of tetrahydroquinoline
derivatives:
InCl3 (20 mol %) was added to a mixture of aniline 2a–e
(1 mmol) and 1-(3-methylbut-2-enyl)-indole-2-carbalde-

4142
Rathna Durga R. S. M. et al. / Tetrahedron Letters 48 (2007) 4139–4142
7947–7950; (c) Buonora, P.; Olsen, J. C.; Oh, T. Tetra-
hedron 2001, 57, 6099–6138.
14. 7a,13b-cis-8,8-Dimethyl-10-methoxyindolo[2,1-a]pyrrolo[40,
30:2,3]-7a,8,13,13b-tetrahydroquinoline 3c: Pale yellow
7. (a) Katritzky, A. R.; Rachwal, B. Tetrahedron 1996, 52,
15031–15070, and references cited therein; (b) Yamada,
N.; Kadowaki, S.; Takahashi, K.; Umezu, K. Biochem.
Pharmacol. 1992, 44, 1211; (c) Faber, K.; Stueckler, H.;
Kappe, T. J. Heterocycl. Chem. 1984, 21, 1177; (d)
Johnson, J. V.; Rauckman, B. S.; Baccanari, D. P.; Roth,
B. J. Med. Chem. 1989, 32, 1942.
8. (a) Szantay, C. In The Alkaloids; Cordell, G. A., Ed.;
Academic: London, 1998; Vol. 50, (b) Lounasmaa, M.;
Hankinen, P.; Westersund, M. In The Alkaloids; Cordell,
G. A., Ed.; Academic: London, 1999; Vol. 52, Chapter 2.
9. (a) Mukaiyama, T.; Ohno, T.; Han, J. S.; Kobayashi, S.
Chem. Lett. 1991, 949; (b) Mukaiyama, T. Org. React.
1982, 28, 203; (c) Loh, T. P.; Pei, J.; Lin, M. Chem.
Commun. 1996, 2315; (d) Kobayashi, S.; Busujima, T.;
Nagayama, S. Tetrahedron Lett. 1998, 39, 1579; (e) Babu,
G.; Nagarajan, R.; Perumal, P. T. Synthesis 2000, 661; (f)
Babu, G.; Perumal, P. T. Aldrichim. Acta 2000, 33, 16.
10. (a) Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149; (b)
Ghosh, R. Ind. J. Chem. 2001, 40B, 550.
solid; mp 176–178 °C; IR (KBr): 3398 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): d 1.66 (s, 3H), 2.01 (s, 3H), 3.71 (s,
3H), 4.99 (d, J = 6.3 Hz, 1Ha), 5.08 (dd, J = 15.0, 8.0 Hz,
1Hc), 5.23 (dt, J = 15.0, 6.8 Hz, 1Hb), 5.36 (t, J = 6.8 Hz,
1Hd), 6.59–7.47 (m, 8H); 13C NMR (125 MHz, CDCl3): d
18.42, 18.62, 25.67, 25.75, 41.43, 42.96, 55.75, 97.00,
108.15, 108.97, 114.89, 115.15, 118.41, 118.50, 120.07,
120.27, 122.69, 123.04, 125.38, 125.99, 152.76; MS:
m/z = 318 (M+). Anal. Calcd for C21H22N2O: C, 79.24;
H, 6.92; N, 8.80. Found: C, 79.40; H, 6.77; N, 8.92.
15. 7a,13b-trans-8,8-Dimethyl-10-methoxyindolo[2,1-a]pyrrolo-
[40,30:2,3]-7a,8,13,13b-tetrahydroquinoline 4c: Red liquid;
IR (KBr): 3397 cmꢀ1; 1H NMR (400 MHz, CDCl3): d 1.75
(s, 3H), 1.93 (s, 3H), 3.52 (s, 3H), 5.08 (d, J = 10.6 Hz,
1Ha), 5.17 (dd, J = 14.6, 7.8 Hz, 1Hc), 5.30 (t, J = 7.0 Hz,
1Hd), 5.35 (td, J = 14.6, 7.0 Hz, 1H), 6.54–7.51 (m, 8H);
13C NMR (100 MHz, CDCl3): d 19.49, 20.07, 27.81, 29.44,
44.65, 47.84, 50.51, 107.14, 112.48, 117.84, 121.14, 121.36,
123.26, 125.89, 126.72, 127.61, 129.54, 131.33, 133.28,
138.11, 140.49; MS: m/z = 318 (M+). Anal. Calcd for
C21H22N2O: C, 79.24; H, 6.92; N, 8.80. Found: C, 79.45;
H, 7.10; N, 8.72.
11. Rathna Durga, R. S. M.; Jayashankaran, J.; Raghuna-
than, R. Tetrahedron Lett. 2007, 48, 1385.
12. 7a,13b-cis-8,8-Dimethyl-10-methylindolo[2,1-a]pyrrolo[40,
30:2,3]-7a,8,13,13b-tetrahydroquinoline 3b: Yellow solid;
16. 7a,13b-cis-8-Phenyl-10-chloroindolo[2,1-a]pyrrolo[40,30:2,
3]-7a,8,13,13b-tetrahydroquinoline 5d: Yellow solid; mp
mp 180–181 °C; IR (KBr): 3387 cmꢀ1
;
1H NMR
168–170 °C; IR (KBr): 3396 cmꢀ1 1H NMR (400 MHz,
;
(400 MHz, CDCl3): d 1.65 (s, 3H), 2.01 (s, 3H), 2.22 (s,
3H), 5.01 (d, J = 5.7 Hz, 1Ha), 5.09 (dd, J = 14.5, 7.8 Hz,
1Hc), 5.21 (t, J = 6.6 Hz, 1Hd), 5.36 (dt, J = 14.5, 6.6 Hz,
1Hb), 6.55–8.19 (m, 8H); 13C NMR (100 MHz, CDCl3): d
18.25, 18.44, 20.43, 25.47, 25.57, 41.38, 42.88, 97.07,
108.05, 108.92, 113.81, 118.36, 119.95, 120.27, 122.61,
123.01, 125.29, 125.87, 130.04; MS: m/z = 302 (M+). Anal.
Calcd for C21H22N2: C, 83.44; H, 7.28; N, 9.27. Found: C,
83.61; H, 7.14; N, 9.40.
CDCl3): d 4.85 (d, J = 5.8 Hz, 1Ha), 5.10 (dd, J = 15.0,
7.8 Hz, 1Hc), 5.16 (d, J = 9.2 Hz, 1H), 5.22 (t, J = 6.5 Hz,
1Hd), 5.27–5.29 (m, 1Hb), 6.48–7.52 (m, 13H); 13C NMR
(100 MHz, CDCl3): d 24.32, 25.64, 46.23, 48.19, 110.76,
114.95, 119.12, 120.33, 122.36, 123.00, 123.86, 125.51,
125.80, 126.13, 128.42, 130.30, 130.67, 133.11, 135.04,
137.24, 139.34, 142.39, 143.16; MS: m/z = 370.8 (M+).
Anal. Calcd for C24H19N2Cl: C, 77.74; H, 5.13; N, 7.56.
Found: C, 77.91; H, 4.99; N, 7.40.
13. 7a,13b-trans-8,8-Dimethyl-10-methylindolo[2,1-a]pyrrolo[40,
30:2,3]-7a,8,13,13b-tetrahydroquinoline 4b: Red liquid; IR
(KBr): 3394 cmꢀ1; 1H NMR (400 MHz, CDCl3): d 1.70 (s,
3H), 1.85 (s, 3H), 2.17 (s, 3H), 4.97 (d, J = 10.5 Hz, 1Ha),
5.12 (dd, J = 14.6, 7.8 Hz, 1Hc), 5.19 (t, J = 6.8 Hz, 1Hd),
5.25 (td, J = 14.6, 6.8 Hz, 1Hb), 6.32–7.84 (m, 8H); 13C
NMR (100 MHz, CDCl3): d 17.81, 18.13, 18.57, 24.52,
25.32, 39.55, 43.71, 100.85, 110.25, 115.52, 115.91, 120.33,
122.73, 124.08, 126.10, 126.38, 128.26, 130.37, 137.34,
138.05; MS: m/z = 302 (M+). Anal. Calcd for C21H22N2:
C, 83.44; H, 7.28; N, 9.27. Found: C, 83.58; H, 7.38; N,
9.10.
17. 7a,13b-trans-8-Phenyl-10-chloroindolo[2,1-a]pyrrolo[30,40:2,
3]-7a,8,13,13b-tetrahydroquinoline 6d: Red liquid; IR
(KBr): 3398 cmꢀ1 1H NMR (400 MHz, CDCl3): d 5.03
;
(d, J = 11.0 Hz, 1Ha), 5.15 (dd, J = 14.8, 8.0 Hz, 1Hc),
5.23 (d, J = 9.0 Hz, 1H), 5.27 (t, J = 7.0 Hz, 1Hd), 5.33–
5.36 (m, 1Hb), 6.38-7.44 (m, 13H); 13C NMR (100 MHz,
CDCl3): d 23.72, 25.52, 40.85, 46.72, 113.29, 115.76,
120.16, 122.37, 123.53, 124.03, 126.37, 127.11, 127.94,
128.42, 130.25, 131.88, 133.36, 133.53, 136.66, 139.30,
140.21, 143.81, 146.24; MS: m/z = 370.8 (M+). Anal.
Calcd for C24H19N2Cl: C, 77.74; H, 5.13; N, 7.56. Found:
C, 77.56; H, 5.01; N, 7.66.