Indium chloride/silica gel supported synthesis of pyrano/thiopyranoquinolines through intramolecular imino Diels-Alder reaction using microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2008.02.128

A facile synthesis of pyrano/thiopyranoquinolines is accomplished in excellent yields through imino Diels-Alder reaction using silica gel impregnated with indium trichloride as catalyst.

Full text of DOI:10.1016/j.tetlet.2008.02.128

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2810–2814
Indium chloride/silica gel supported synthesis
of pyrano/thiopyranoquinolines through intramolecular
imino Diels–Alder reaction using microwave irradiation
Ekambaram Ramesh, Tarakkad Krishnaji Sree Vidhya, Raghavachary Raghunathan *
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Received 24 November 2007; revised 16 February 2008; accepted 22 February 2008
Available online 4 March 2008
Abstract
A facile synthesis of pyrano/thiopyranoquinolines is accomplished in excellent yields through imino Diels–Alder reaction using silica
gel impregnated with indium trichloride as catalyst.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Imino Diels–Alder; Silica gel; Indium trichloride; Intramolecular
The importance of pyranoquinoline derivatives is well
recognized by synthetic and biological chemists. Com-
pounds possessing these types of ring systems have wide
application as drugs and pharmaceuticals. Pyranoquino-
lines are an important class of compounds that constitute
the basic framework of a number of alkaloids of biological
significance, such as geibalasine, ribalinine, flindersine,1–3
simulenoline, huajiaosimuline, demethoxyzanthodioline,
khaplofoline, lunacrine and demethoxylunacrine.4,5 In
addition, thiopyranoquinolines are reported as interleu-
kin-1 inhibitors.6
It is therefore not surprising that many synthetic meth-
ods have been developed for these compounds.7–16 Among
them, the aza-Diels–Alder reaction between N-arylimines
with electron rich internal dienophiles is a powerful method
for the construction of polycyclic heterocyclic ring systems.
Since the pioneering work of Povarov,17 BF3ꢀOEt2 has
been the most commonly used catalyst for this reaction.
Transition metal and transition metal complexes such as
Co2(CO)8 and Ni(CO)4 are also effective. However, many
of these catalysts are not fully satisfactory with regard to
operational simplicity and isolated yield. Hence, there is a
quest to find a better and improved methodology for the
synthesis of such molecules.
Recently, microwave irradiation (MWI) has become an
established tool in organic synthesis,18–23 because of the
rate enhancements, higher yields and often, improved selec-
tivity, with respect to conventional reaction conditions. In
addition, solvent-free MW processes are also clean and effi-
cient and moreover, using either organic or inorganic solid
supports, have received increased attention.24 There are
several advantages of performing syntheses in solvent-free
media: (i) short reaction times, (ii) increased safety, (iii)
economic advantages due to the absence of solvent. Silica
gel is effective solid support because the end products can
easily be separated. Moreover, silica gel can function as a
mild acidic catalyst (Table 1).
In continuation of our interest in cycloaddition chemis-
try,25–27 we herein describe the excellent catalytic activity of
28
InCl3 in acetonitrile/silica gel impregnated InCl3 for the
synthesis of tetrahydropyrano/thioquinoline derivatives
through intramolecular imino Diels–Alder reaction.
Thus, 2-chloro-3-formylquinoline29 1 (prepared from
acetanilide, Scheme 1) on treatment with prenyl thiolate,
generated by the decomposition of S-prenyl isothiourea
salt with NaOH, furnished S-alkenyl aldehyde 330 in a
good 84% yield (Scheme 2).
*
Corresponding author. Fax: +91 44 22300488, 22342494.
E-mail address: ragharaghunathan@yahoo.com (R. Raghunathan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.128

E. Ramesh et al. / Tetrahedron Letters 49 (2008) 2810–2814
2811
Table 1
Synthesis of tetrahydroquinoline[4,3:2,3]pyrano/thiopyrano[2,3-b]quinoline derivatives
R
Entry
R
X
Method A
Method B
R
HN
X
HN
X
H
H
H
Ratio of products
cis:trans
Time
(h)
Yield
(%)
Ratio of products
cis:trans
Time
(min)
Yield
(%)
H
N
N
H
H
H
H
1
2
3
4
5
6
7
8
9
H
S
S
S
S
S
S
O
O
O
O
O
O
5a
5b
5c
5d
5e
5f
6a
6b
65:35
70:30
76:24
77:23
81:19
82:28
67:33
70:30
77:23
79:21
80:20
83:27
2
1.5
1
1.5
2.0
3.5
2
1.5
1
73
77
87
79
80
58
71
73
82
75
79
55
69:31
74:26
75:25
78:22
78:22
80:20
68:22
73:27
77:23
81:19
82:18
84:26
1
1.2
1
1.4
1.4
2.5
1
1.2
1
92
95
97
90
80
75
89
93
90
89
87
89
CH3
OCH3
Cl
Br
NO2
H
CH3
OCH3
Cl
Br
NO2
6c
6d
6e
6f
9a
9b
9c
9d
9e
9e
10a
10b
10c
10d
10e
10f
10
11
12
1.5
2.0
3.5
1.4
1.4
3
Method A: InCl3 in CH3CN.
Method B: Silica gel impregnated InCl3 under microwave irradiation.
Hb, a doublet of doublets at d 4.77 (J = 3.5, 11.2 Hz) for
Hc and a triplet at d 3.88 (J = 11.2 Hz) due to proton
Hd. The Ha proton appeared as a doublet at d 4.45
(J = 3.3 Hz). The coupling of Hd with Hb resulted in a dou-
blet with a large J value (J = 8.3 Hz) and this was further
split into a triplet with a small J value (J = 3.0 Hz) by cou-
pling of the Ha and Hc protons. The aromatic protons
exhibited multiplets in the region d 6.61–7.83.
NHCOCH3
CHO
Cl
POCl3 /DMF
N
°
0 C
1
78%
Scheme 1.
S-Alkenyl aldehyde 3 thus prepared is well poised to
undergo imino Diels–Alder reactions with a variety of ani-
lines. Thus, the reaction of aniline 4a with 2-S-prenyl-3-
formylquinoline 3 in the presence of InCl3 in acetonitrile
resulted in the formation of a mixture of cis and trans
products 5a and 6a in the ratio 65:35 by intramolecular
cycloaddition reaction of the imine generated in situ in
the one pot– reaction (Scheme 3).
The trans isomer 6a, exhibited a triplet of doublets at d
2.06 (J = 11.2, 3.3 Hz) for the Hb proton, a triplet at d 3.98
(J = 11.2 Hz) due to proton Hd, a doublet of doublets at d
4.89 (J = 3.3, 10.89 Hz) due to proton Hc, a doublet at d
4.45 (J = 11.4 Hz) due to proton Ha and multiplets in the
range d 6.68 and 7.89 due to the aromatic protons.
As a further extension of this work, reaction of 1 with
prenyl alcohol 7 at 0 °C in the presence of potassium
tert-butoxide yielded O-prenyl-3-formylquinoline31 (8) in
a good 72% yield (Scheme 4).
The ratio of the products was determined by isolating
the two diastereoisomers in pure form by flash column
chromatography and the stereochemistry of the products
Under similar conditions,32 O-prenyl-3-formylquinoline
(8) reacted with various substituted anilines in the presence
of InCl3 in acetonitrile resulting in the formation of cis and
trans 9a–f and 10a–f in 55–71% yields (Scheme 5).
1
was based on coupling constants in their H NMR spectra
and NOE experiments.
The structural assignments of the products were based
on the analysis of NMR spectra. Compound 5a exhibited
a doublet of triplets at d 2.11 (J = 3.3, 10.2 Hz) due to
1
The stereochemistry of each isomer was assigned by H
NMR and NOE studies.33 In 9a, the coupling constant
S
NH2
S
Na
S
H2N
Ethanol/reflux
CHO
Cl
NH2
Br
Excess NaOH
CHO
NH
2 Br
2
S
Na
2
N
N
S
Ethanol / reflux
84%
1
3
Scheme 2.

2812
E. Ramesh et al. / Tetrahedron Letters 49 (2008) 2810–2814
R
R
CHO
S
N
10 mol% InCl3
CH3CN/rt
NH2
N
N
S
3
4a-f
R = H, Me, OMe, Cl, Br, NO2
R
R
HN
S
HN
S
Ha
Ha
Hb
Hc
Hb
Hc
N
N
Hd
Hd
5a-
f
6a-f
Scheme 3.
Further, we examined the effect of various solvents on
the above reaction and found acetonitrile to be the best sol-
vent for obtaining good yields of the products.
HO
CHO
O
CHO
Cl
7
KOBut/THF
N
To improve the yield, we carried out the same reaction
using InCl3 impregnated silica gel as catalyst under micro-
wave irradiation and we found that there was a dramatic
increase in the overall yield of the products, but the ratio
of the cis and trans adducts remained almost the same in
all cases. The method avoids the use of a solvent and the
reaction was complete within 1–3 min.
N
°
8
rt
0 C
1
72%
Scheme 4.
between Ha and Hb had a small J value (J = 3.2 Hz). This
indicates cis-fusion at the ring junction, which was further
confirmed by a strong NOE between Ha and Hb. For the
trans isomer, the coupling constant between Ha and Hb
had a large J value (J Ha–Hb = 9.0 Hz), the trans
arrangement was further confirmed by the absence of an
NOE.
Our attempts to accelerate the imino Diels–Alder cyclo-
addition by solid supported microwave irradiation were
successful. For example, the reaction of 3 with p-substi-
tuted nitroanilines took 3.5 h for completion when per-
formed using InCl3 in acetonitrile, whereas the same
cycloaddition using InCl3/silica gel under microwave irra-
diation was complete in 2.5 min (entry 6).
R
R
CHO
N
10 mol % InCl3
CH3CN/rt
N
O
NH2
N
O
8
4a-f
R = H, Me, OMe, Cl, Br, NO2
R
R
HN
O
HN
Ha
Ha
Hb
Hc
Hb
Hc
N
N
O
Hd
Hd
9a-f
Scheme 5.
10a-f

E. Ramesh et al. / Tetrahedron Letters 49 (2008) 2810–2814
2813
28. Prepared by adding silica gel to a stirred solution of InCl3 (20 mol %)
in dry CHCl3 (5 mL) followed by complete evaporation of the solvent
under reduced pressure.
29. Meth-Cohn, O.; Narine, B.; Tarnowski, B. Tetrahedron Lett. 1979, 33,
3111.
In conclusion, the present procedure using indium tri-
chloride on silica gel provides an efficient one-pot synthesis
of novel pyranoquinoline derivatives. The notable advanta-
ges of this procedure are: (a) ecofriendly process (b) oper-
ational simplicity, (c) high reaction rate, (d) good yields
and (f) general applicability, We believe that this process
will provide a more practical alternative to the existing
methods for the synthesis of pyranoquinolines.
30. 2-(3-Methylbut-2-enylthio)quinoline-3-carbaldehyde 3: A solution of
prenyl bromide (25 mmol) and thiourea (25 mmol) in ethanol (30 mL)
was refluxed for 1 h, and then continued for another 1 h after the
addition of ethanolic NaOH. The chloroaldehyde 1 was then added to
the mixture, which was refluxed for 30 min. The mixture was
extracted with dichloromethane, then the solvent was dried and
evaporated to give 3 as a viscous liquid. 1H NMR (500 MHz, CDCl3):
d 1.74 (s, 3H), 1.81 (s, 3H), 4.06 (d, J = 7.0 Hz, 2H, SCH2), 5.46 (t,
J = 7.0 Hz, 1H, vinylic proton), 7.26–8.46 (m, 5H), 10.28 (s, 1H,
CHO). 13C NMR (125 MHz, CDCl3): d 18.08, 25.78, 28.11, 118.87,
124.57, 126.09, 127.28, 128.08, 129.26, 132.92, 136.84, 141.97, 149.61,
159.53, 184.90. Anal. Calcd for C15H15NOS: C, 70.03; H, 5.83; N,
5.44. Found: C, 69.82; H, 5.90; N, 5.53.
Acknowledgement
E.R. thanks CSIR-SRF, New Delhi for financial sup-
port. R.R. thanks UGC, New Delhi for financial supports
and DST-FIST for NMR facilities.
31. 2-(3-Methylbut-2-enyloxy)quinoline-3-carbaldehyde 8: To a stirred
ice-cooled solution of aldehyde 1 (5.52 g, 25 mmol) and prenyl alcohol
7 (2.9 g, 50 mmol) in tetrahydrofuran (50 mL) was added potassium
tert-butoxide (3.08 g, 27 mmol). The reaction mixture was brought to
room temperature and stirred for 1 h. After the addition of diethyl
ether (200 mL), the mixture was filtered, and the filtrate was
evaporated to give a low melting solid 8. 1H NMR (500 MHz,
CDCl3): d 1.79 (s, 3H), 1.81 (s, 3H), 5.04 (d, J = 7.0 Hz, 2H, OCH2),
5.55 (t, J = 7.0 Hz, 1H, vinylic proton), 7.26–7.94 (m, 5H), 10.32 (s,
1H, CHO). 13C NMR (125 MHz, CDCl3): d 18.28, 25.86, 62.97, 19.68,
124.12, 125.03, 125.22, 126.91, 127.39, 129.15, 135.48, 138.37, 145.91,
159.86, 189.99. Anal. Calcd for C15H15NO2: C, 74.59; H, 6.21; N,
5.80. Found: C, 74.37; H, 6.32; N, 5.94.
32. Method A: InCl3 (20 mol %) was added to a mixture of aniline and O/
S-prenyl-3-formylquinoline 3/8 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
evaporated in vacuo and the crude product was purified by column
chromatography on silica gel (ethyl acetate–hexane) to afford cis- and
trans-isomers 5a–f, 6a–f, 9a–f and 10a–f in good yields.
References and notes
1. Corral, R. A.; Orazi, O. Tetrahedron Lett. 1967, 7, 583.
2. Puricelli, L.; Innocenti, G.; Delle Monache, G.; Caniato, R.; Filippini,
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6. Skotnicki, J. S.; Steinbaugh, B. A.; Fitzgerald, J. J., Jr.; Kearney, R.
M.; Musser, J. H.; Adams, L. M.; Caccere, R. G.; Chang, J. Y.;
Gilman, S. C. Med. Chem. Res. 1991, 1, 245.
7. Weinreb, S. M. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 401.
8. Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder Methodology in
Organic Synthesis; Academic Press: San Diego, 1987. Chapters 2 and
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9. Nomura, Y.; Kimura, M.; Takeuchi, Y.; Tomoda, S. Chem. Lett.
1978, 267.
10. Boger, D. L. Tetrahedron 1983, 39, 2869.
11. Kametani, T.; Takeda, H.; Suzuki, Y.; Honda, T. Heterocycles 1984,
22, 275.
Method B: A mixture of O/S-prenyl-3-formylquinoline 3/8 (1 mmol)
and substituted anilines (1 mmol) was added to silica gel impregnated
with indium(III) chloride (20 mol %). The whole mixture was stirred
for 5 min for uniform mixing and was then irradiated with
microwaves for 1–3 min as required to complete the reaction (TLC).
The reaction mixture was extracted with ethyl acetate (20 mL) and the
extract was washed with brine, dried over CHCl3 and evaporated to
leave the crude product which was purified by column chromatog-
raphy over silica gel (EtOAc–hexane 98:2) to afford cis- and trans-
products 5a–f, 6a–f, 9a–f and 10a–f in good yields.
12. Kametani, T.; Takeda, H.; Suzuki, Y.; Kasai, H.; Honda, T.
Heterocycles 1986, 24, 3385.
13. Koichi, N.; Takanori, S. Heterocycles 1993, 35, 1039.
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53, 2251.
15. Lucchini, V.; Prato, M.; Scorrano, G.; Stivanello, M.; Valle, G. J.
Chem. Soc., Perkin Trans. 2 1992, 259.
16. Makioka, Y.; Shindo, T.; Taniguchi, Y.; Takaki, K.; Fujiwara, Y.
Synthesis 1995, 801.
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18. Caddick, S. Tetrahedron 1995, 51, 10403–10432.
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1999, 55, 10851–10870.
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57, 9225–9283.
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Ed. 2001, 40, 650–679.
22. Varma, R. S. Pure Appl. Chem. 2001, 73, 193–198.
23. Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH: Weinheim,
2002.
33. 8a,14b-cis-9,9-Dimethylquinolino[2,3-b]thiopyrano[40,30:2,3]8a,9,14,
14b-tetrahydroquinoline 5a: mp 152–154 °C; 1H NMR (400 MHz,
CDCl3): 1.73 (s, 3H, CH3), 1.76 (s, 3H, CH3), 2.11 (dt, 1H, Hb,
J = 3.5, 10.2 Hz), 3.88 (t, 1H, Hd, J= 10.2 Hz), 4.45 (d, 1H, Ha,
3.3 Hz), 4.77 (dd, 1H, Hc, J = 3.3, 10.2 Hz), 6.61–7.83 (m, 9H); 13C
NMR (100 MHz, CDCl3): 27.02, 27.51, 43.36, 47.25, 60.15, 65.40,
112.12, 116.23, 121.42, 121.53, 123.9, 123.39, 124.34, 124.75, 127.14,
128.71, 129.50, 132.02, 143.61, 146.82, 161.55; MS (EI) m/z = 332.13.
Anal. Calcd for C21H20N2S: C, 75.87; H, 6.02; N, 8.43. Found: C,
75.63; H, 6.17; N, 8.54.
8a,14b-trans-Dimethylquinolino[2,3-b]thiopyrano[40,30:2,3]-8a,9,14,14b-
tetrahydroquinoline 6a: mp 147–149 °C; 1H NMR (400 MHz, CDCl3):
1.71 (s, 3H, CH3), 1.74 (s, 3H, CH3), 2.06 (td, 1H, Hb, J = 11.2,
3.3 Hz), 3.98 (t, 1H, Hd, J = 10.8 Hz), 4.45 (d, 1H, Ha, J = 11.4 Hz),
4.89 (dd, 1H, Hc, J = 3.3, 10.8 Hz), 6.68–7.89 (m, 9H). 13C NMR
(100 MHz, CDCl3): 29.35, 29.57, 40.02, 46.02, 61.13, 65.92, 114.10,
116.21, 120.45,122.50,123.19, 123.3, 124.12, 124.45, 127.17, 128.32,
129.39, 32.16, 143.53, 146.42, 161.73; MS (EI) m/z = 332.13. Anal.
Calcd for C21H20N2S: C, 75.87; H, 6.02; N, 8.43. Found: C, 75.66; H,
24. Diddams, P.; Butters, M. In Solid Supports and Catalysts in Organic
Synthesis; Smith, K., Ed.; Ellis Harwood and PTR Prentice Hall: New
York and London, 1992. Chapters 1 and 3.
25. Ramesh, E.; Elamparathi, E.; Raghunathan, R. Synth. Commun.
2006, 36, 1431–1434.
26. Rathna Durga, R.; Jayashankaran, J.; Raghunathan, R. Tetrahedron
Lett. 2006, 47, 7571.
27. Rathna Durga, R.; Jayashankaran, J.; Raghunathan, R. Tetrahedron
Lett. 2007, 48, 4139–4142.

2814
E. Ramesh et al. / Tetrahedron Letters 49 (2008) 2810–2814
6.20; N, 8.58. 8a,14b-cis-9,9-Dimethylquinolino[2,3-b]pyrano[40,30:
8a,14b-trans-9,9-Dimethylquinolino[2,3-b]pyrano[40,30:2,3]-8a,9,14,14b-
tetrahydroquinoline 11a: mp 119–121 °C; 1H NMR (400 MHz,
CDCl3): d 1.73 (s, 3H), 1.79 (s, 3H), 2.08 (td, J = 3.0, 8.1 Hz, 1Hb),
3.93 (t, J = 11.1 Hz,1Hd), 4.48 (dd, J = 3.0, 7.8 Hz, 1Hc), 4.42
(d, J = 9.0 Hz, 1Ha), 6.66–7.32 (m, 9H). 13C NMR (100 MHz,
CDCl3): d 27.26, 27.85, 34.32, 43.51, 47.70, 65.73, 116.23, 117.16,
118.65, 120.74, 123.72, 125.68, 126.89, 127.11, 127.33, 128.43, 129.13,
131.52, 131.53, 143.25, 158.23; MS (EI) m/z = 316.16. Anal. Calcd for
C21H20N2O: C, 79.64; H, 6.32; N, 8.84. Found: C, 79.45; H, 6.47; N,
8.95.
2,3]-8a,9,14,14b-tetrahydroquinoline 10a: mp 126–128 °C; 1H NMR
(400 MHz, CDCl3): d 1.73 (s, 3H), 1.44 (s, 3H), 1.81 (dt, J = 3.0,
8.3 Hz, 1Hb), 3.85 (t, J = 11.2 Hz, 1Hd), 4.26 (dd, J = 3.5, 11.2 Hz,
1Hc), 4.56 (d, J = 3.2 Hz, 1Ha), 6.36–7.24 (m, 9H); 13C NMR
(100 MHz, CDCl3): d 27.29, 27.95, 34.51, 43.95, 47.68, 65.61, 116.18,
117.11, 118.84, 120.86, 123.77, 125.62, 126.92, 127.03, 127.52, 128.53,
129.03, 131.50, 131.56, 143.05, 158.18; MS (EI) m/z = 316.16. Anal.
Calcd for C21H20N2O: C, 79.64; H, 6.32; N, 8.84. Found: C, 79.40; H,
6.47; N, 8.98.