Novel diastereoselective synthesis of Trans-fused pyrrolo[3,4-b]quinolines through intramolecular imino Diels-Alder reaction

Article abstract of DOI:10.1080/00397911.2011.572218

(Chemical Equation Presented) Synthesis of a series of 1aR,2S,4aS- hexahydropyrrolo[3,4-b]quinolines has been achieved by the intramolecular cyclization reaction of aldimines derived from aromatic amines and (S)-2-(N-(3-methylbut-2-enyl)-N-tosyamino)-3-methylpropanal/(S) -2-(N-(3-methylbut-2-enyl)-N-tosyamino)-3-phenylpropanal in acetonitrile with InCl₃ as a catalyst, in excellent yields and in short duration of time, under mild conditions. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.572218

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Novel Diastereoselective Synthesis of
trans-Fused Pyrrolo[3,4-b]quinolines
Through Intramolecular Imino Diels–Alder
Reaction
Mathesan Jayagobi a & Raghavachary Raghunathan a
a Department of Organic Chemistry, University of Madras, Chennai,
India
Available online: 02 Jan 2012
To cite this article: Mathesan Jayagobi & Raghavachary Raghunathan (2012): Novel Diastereoselective
Synthesis of trans-Fused Pyrrolo[3,4-b]quinolines Through Intramolecular Imino Diels–Alder Reaction,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:19, 2917-2930
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Synthetic Communications1, 42: 2917–2930, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.572218
NOVEL DIASTEREOSELECTIVE SYNTHESIS
OF TRANS-FUSED PYRROLO[3,4-b]QUINOLINES
THROUGH INTRAMOLECULAR IMINO
DIELS–ALDER REACTION
Mathesan Jayagobi and Raghavachary Raghunathan
Department of Organic Chemistry, University of Madras, Chennai, India
GRAPHICAL ABSTRACT
Abstract Synthesis of a series of 1aR,2S,4aS-hexahydropyrrolo[3,4-b]quinolines has been
achieved by the intramolecular cyclization reaction of aldimines derived from aromatic
amines and (S)-2-(N-(3-methylbut-2-enyl)-N-tosyamino)-3-methylpropanal/(S)-2-(N-
(3-methylbut-2-enyl)-N-tosyamino)-3-phenylpropanal in acetonitrile with InCl3 as a
catalyst, in excellent yields and in short duration of time, under mild conditions.
Keywords Arylamines; diastereoselectivity; hexahydropyrrolo[3,4-b]quinolines; imino
Diels–Alder reaction; indium trichloride
INTRODUCTION
The development of methodology for the synthesis of enantiomerically pure
compounds has become a core area of research in organic chemistry because of
increasing demand for these compounds by the pharmaceutical industry. Because
naturally occurring chiral compounds are often too expensive for use as starting
materials, a more economical approach is to employ substoichiometric amounts of
chiral compounds in catalytic enantioselective processes, which produce large quan-
tities of optically pure compounds.[1] The stereoselective synthesis of partially
unsaturated N-heterocycles such as tetrahydroquinolines are important for pharma-
cological research.[2] Quinoline ring systems are widely distributed in nature, and
synthesis of quinoline ring systems could be achieved by various methods. However,
Received December 14, 2010.
Address correspondence to Raghavachary Raghunathan, Department of Organic Chemistry,
University of Madras, Guindy Campus, Chennai 600 023, India. E-mail: ragharaghunathan@yahoo.com
2917

2918
M. JAYAGOBI AND R. RAGHUNATHAN
for asymmetric synthesis of quinoline derivatives, only limited methods are avail-
able.[3] Tetrahydroquinolines exhibit a wide range of biological activities.[4–7] Pyrro-
lidines and hexahydropyrroloquinolines have also been shown to possess various
types of bioactivities.[8,9]
Tetrahydroquinoline derivatives have been synthesized by various methods in
recent years,[10] of which the imino Diels–Alder (IMDA) reaction provides a rapid
means of constructing such molecules with control of regio- and stereo selectivity.
Imines, which serve as dienophiles in this reaction, can be synthesized from a variety
of aldehydes and ketones.[11]
Although IMDA reaction is catalyzed by many reagents,[12] InCl3 is the reagent
of choice for catalyzing this reaction because it is a mild and water-tolerant Lewis
acid imparting high regio- and chemoselectivity.[13] Unlike intermolecular Diels–
Alder reaction of aza dienes generated from the reactions of arylaldehydes with ary-
lamines, there are only a few reports available for the IMDA reaction of dienes gen-
erated from allyl tethered aliphatic aldehyde with arylamines.[14]
In continuation of our research interest in the IMDA reaction, we herein
describe a simple method for the synthesis of hexahydropyrrolo[3,4-b] quinolines
from aromatic amines and N-allyl derivatives of chiral aldehydes via intramolecular
[4 þ 2] cyclization of imines catalyzed by InCl3.[15]
RESULTS AND DISCUSSION
We started with a known simple chiral substrate for the synthesis of hexahydro-
pyrrolo[3,4-b]quinolines. Thus, starting from (S)-phenyl alanine 1, chiral alkenyl
aldehydes 4a and 4b were synthesized and imine dienophiles, generated from the reac-
tions of aldehydes 4 with various arylamines 5a–e, were trapped intramolecularly to
yield a variety of enantiomerically pure hexahydropyrrolo[3,4-b]quinolines 6a–j.
Synthesis of Enantiomerically Pure N-Alkenyl Aldehyde
(S)-Phenyl alanine was converted to its ethylester hydrochloride by treatment
with excess of thionyl chloride in dry ethanol. The hydrochloride salt of the ester
was then reduced by sodium borohydride in aqueous ethanolic solution to obtain
the amino alcohol 1 in good yield f[a] ¼ ꢀ24.1 (c 1, EtOH)g.[16] The amino group
of the alcohol was protected using using p-toluenesulfonyl chloride to afford com-
pound 2 in good yield. Compound 2 was characterized by spectroscopic data.
The N-sulfonyl chiral alcohol 2 was then subjected to N-prenylation using pre-
nyl bromide with anhydrous potassium carbonate in dry acetone to obtain the N-pre-
nylated alcohol 3a in good yield. The alkenyl alcohol was then oxidized quantitatively
to the alkenyl aldehyde, (S)-2-(N-allyl-N-tosylamino)-3-phenylpropanal, by stirring
the suspension of IBX (iodoxybenzoic acid) in dimethylsulfoxide (DMSO) with the
alcohol for 4 h (Scheme 2). The structure of alkenyl aldehyde 4a was confirmed on
the basis of spectroscopic data. The same methodology was followed for the synthesis
of 4b by using cinnamyl bromide. The N-substituted cinnamyl alcohol 3b was
oxidized quantitatively to the alkenyl aldehyde, (S)-2-(N-cinnamyl-N-tosylamino)-3-
phenylpropanal (4b) by using IBX in DMSO as an oxidizing agent (Scheme 1).[17]

SYNTHESIS OF TRANS-PYRROLO[3,4-b]QUINOLINES
2919
Scheme 1. Synthesis of N-alkenyl aldehydes. Reagents and conditions: (i) TBAB, 10% NaOH=benzene,
tosyl chloride, 0 ꢁC–rt; 8 h, 90%; (ii) prenyl bromide=cinnamyl bromide, K2CO3=acetone, 12 h, 90%;
and (iii) iodoxybenzoic acid, DMSO, 4 h, 98%.
Scheme 2. Synthesis of enantiopure hexahydropyrrolo[3,4-b]quinolines.
Synthesis of Enantiopure Hexahydropyrrolo[3,4-b]quinolines
The aldehyde 4a, when reacted with aromatic amines (5a–e) in the presence of
20 mol% indium trichloride in acetonitrile at room temperature, generated the imi-
nes, which then cyclized with olefines intramolecularly in a one-pot reaction to yield
a series of pyrroloquinoline derivatives, with the trans isomer as the major product.
The same reaction was extended to the aldehyde 4b with aromatic amines (5a–e) to
yield a series of novel pyrroloquinolines (Scheme 2).
We have tried the same reaction with various other Lewis acids, but the yield of
the products obtained was moderate, and it took a long time for completion of the
reaction (Table 1). We have found InCl3 to be the best catalyst for the reaction in
terms of yield and reaction time, and 20 mol% was found to be the optimum concen-
tration for carrying out the reaction with high efficiency (Table 2).

2920
M. JAYAGOBI AND R. RAGHUNATHAN
Table 1. Influence of Lewis acids on the reaction of 6a with 5a
Entry
Lewis acid
Reaction time
Overall yield (%)
1
2
3
4
BF3 ꢂ OEt2
Yb(OTf)3
Sc(OTf)3
InCl3
3 h
1.5 h
1 h
62
78
72
93
10 min
Table 2. Study of molar ratio of InCl3 on the reaction of 6a with 5a
Entry
InCl3 (mol%)
Overall yield (%)
1
2
3
4
5
10
15
20
30
55
67
93
The structures of the cycloadducts were confirmed by spectroscopic data. All
the cycloadducts were obtained as a single diastereomer, and the specific rotation
values were found to be constant after repeated crystallizations. In all cases, only
the trans-isomer was obtained as the major product and characterized on the basis
of detailed 2D NMR studies (Table 3). The cycloadduct 6a as typical example of
the series with optical rotation þ6.79o (c 1, CHCl3) showed infrared (IR) absorption
stretching bands at 3391 cmꢀ1 due to a NH group and at 1160.0 and 1344.7 cmꢀ1 due
to the presence of a sulfonyl group.
1
The H NMR spectrum of the compound 6a exhibited singlets at d 1.07 and
1.12 due to the geminal methyl protons. The ring junction proton Ha appeared as
a doublet of triplet at d 1.30 (dt, 1Ha, J ¼ 6.00, 12.00 Hz). A sharp singlet was exhib-
ited at d 2.39 due the aromatic methyl protons and a broad singlet at d 2.69 for NH.
The -NCH2 protons exhibited a triplet d 3.28 (J ¼ 12.0 Hz) and a doublet of triplet
appeared at d 3.47 (dt, 1H, J ¼ 3.00, 6.00). A doublet of doublet was observed at
Table 3. InCl3-catalyzed synthesis of hexahydropyrrolo[3,4-b]quinoline derivatives
Entry
R
R1
R2
Compound
Time (min)
Yield (%)
1
2
H
Me
Ome
Br
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
Me
Ph
6a
6b
6c
6d
6e
6f
10
15
17
17
15
10
12
12
12
10
93
87
89
96
97
97
92
90
95
98
3
4
5
Cl
H
6
7
Me
OMe
Br
H
Ph
Ph
6g
6h
6i
8
H
9
10
H
Ph
Ph
Cl
H
6j

SYNTHESIS OF TRANS-PYRROLO[3,4-b]QUINOLINES
2921
d 3.68 (dd, 1H, J ¼ 9.00, 12.00 Hz), and the benzyl methylene protons resonated as a
doublet of doublet at d 2.86 (dd, 1H, J ¼ 12.00, 12.00 Hz) and d 3.68 (dd, 1H,
J ¼ 3.00, 6.00, 12.00 Hz). The ring junction proton Hb exhibited a doublet of doublet
at d 3.21 (dd, 1Hb, J ¼ 3.00, 6.00, 12.00 Hz). The ring junction proton showed a
doublet of triplet at d 1.30 (dt, 1Ha, J ¼ 6.00, 12.00 Hz) for the Ha proton and doub-
let of doublet at d 3.21 (dd, 1Hb, J ¼ 3.00, 6.00, 12.00 Hz) for the Hb proton. The
trans-fusion of the two rings is ascertained by the large coupling constant exhibited
by Ha and Hb protons (J ¼ 12.00 Hz) The aromatic protons resonated as multiplets
in the range d 5.92–7.81.
Further 13C NMR spectrum of the compound 6a showed signals at 21.54,
27.02, 28.60, 34.04, 42.27, 47.92, 49.25, 57.72, 66.85, 115.65, 118.78, 126.86,
127.14, 127.42, 128.97, 129.56, 129.90, 130.63, 134.53, 137.01, 143.05, and
143.77 ppm.
The molecular ion peak for the compound 6a appeared at m=z 446.32 (Mþ) in
mass spectrum. Further, the products were confirmed through elemental analysis.
Moreover, the structure and stereochemistry of the cycloadducts 6f and 6g
were established by single-crystal x-ray diffraction analysis.[18] The trans-stereo-
chemistry of the products was assigned based on the values of the coupling
1
constants of the protons in the H NMR spectra and also by direct comparison
with literature data wherever available.[19] The trans-fusion at the ring junction
was further confirmed by the absence of a nuclear Overhauser effect (NOE)
between Ha and Hb.
CONCLUSION
The chiral N-alkenyl aldehydes were successfully subjected to intramolecular
cycloaddition reaction with various aromatic amines to obtain a series of
enantiopure hexahydropyrrolo[3,4-b]quinolines. The cycloaddition reactions were
found to be stereoselective and gave trans-fused cycloadducts. The reaction was
effectively catalyzed by InCl3, which resulted in good yield of the products with high
stereoselectivity.
EXPERIMENTAL
All melting points are uncorrected. Infrared (IR) spectra were recorded on a
Shimadzu IR-8300 series Fourier transform (FT)–IR spectrophotometer. 1H
NMR and 13C NMR spectra were recorded on Bruker 300-MHz instruments in
CDCl3 solvent with tetramethylsilane (TMS) as standard. Mass spectra were
recorded on a JEOL-DX303 HF mass spectrophotometer. Elemental analysis was
carried out by Perkin-Elmer CHNS 2400 instrument. Single-crystal x-ray diffraction
analysis was performed by Bruker SMART APEX CCD area-detecter diffract-
ometer and Bruker SMART APEXII CCD area-detector diffracrometer.
Column chromatography was performed on silica gel (ACME, 100–200 mesh).
Routine monitoring of the reaction was done using thin-layer chromatography
(TLC) developed on glass plates coated with silica gel-G (ACME) of 25 mm thick
and visualized with iodine.

2922
M. JAYAGOBI AND R. RAGHUNATHAN
Preparation of (S)-2-Amino-3-phenylpropan-1-ol
(S)-2-amino-3-phenylpropan-1-ol was prepared in two stages from (S)-phenyl
alanine.
Stage 1: Preparation of (S)-phenylalanine ethyl ester hydrochloride. To
a stirred, ice-cold suspension of (S)-phenyl alanine (30 g, 0.182 mol) in absolute etha-
nol (800 mL), thionyl chloride (32.5 g, 0.273 mol) was added dropwise, and the reac-
tion mixture was heated at reflux for 3.5 h. The pale yellow solution was allowed to
stand overnight at room temperature, and the ethanol was evaporated in vacuo to
obtain a colorless solid. The vacuum-dried (S)-phenylalanine ethyl ester hydrochlor-
ide was washed with dry diethyl ether, filtered, and dried in vacuo. The solid thus
obtained was used as such in the next step.
Stage 2: Preparation of (S)-phenylalaninol from (S)-phenylalanine ethyl
ester hydrochloride. A solution of (S)-phenylalanine ethyl ester hydrochloride
(40 g, 0.176 mol) in 50% aqueous ethanol (400 mL) was added dropwise to solution
of sodium borohydride (28 g, 0.736 mol) in 50% aqueous ethanol (400 mL), and the
resulting mixture was refluxed for 4.5 h. Ethanol was evaporated in vacuum. The
aqueous solution thus obtained was the extracted with ethyl acetate. The extract
was washed with saturated brine solution and dried over anhydrous sodium hydrox-
ide. Evaporation of the ethyl acetate under reduced pressure afforded (S)-phenyl ala-
26
ninol 3 as a pale yellow solid. Pale yellow solid, 72% (19.16 g); ½aꢃD ¼ ꢀ24:2 (c 1,
EtOH); mp: 85–87 ꢁC; IR (KBr): 2990 and 3452 cmꢀ1
.
Synthesis of (S)-3-Phenyl-2-(tosylamino)propan-1-ol, 2
Half a portion of 19.06 g (0.1 mol) p-toluenesulfonyl chloride was added to a
solution of 15.10 g (0.1 mol) of (S)-2-amino-3-phynylpropan-1-ol in 100 mL benzene
at 0 ꢁC. The reaction mixture was stirred vigorously, and after 10 min, 30 mL of ben-
zene was added, followed by the remaining portion of p-toluenesulfonyl chloride and
a catalytic amount (500 mg) of the phase-transfer catalyst, tetrabutylammonium bro-
mide (TBAB). To this stirred mixture, a 25% solution of sodium hydroxide (0.1 mol)
was added dropwise using an additional funnel, resulting in a thick flocculation. The
temperature of the reaction mixture was raised to room temperature once the
addition of sodium hydroxide was complete. After 8–10 h, the reaction mixture
was diluted with 100 mL of water. It was then extracted with 100 mL of benzene
and washed with brine solution. The organic layer was then dried over anhydrous
sodium sulfate and concentrated in vacuum to yield crude N-sulfonylated-(S)-phenyl
alaninol. The pure 4 was obtained by column chromatography using a 9:1 mixture of
34
hexane–ethyl acetate. Colorless solid, 89% (27.18 g); ½aꢃD ¼ ꢀ24:36ꢁ (c 1, CHCl3);
mp: 76–78 ꢁC; IR (KBr): 1339, 1163, 3100 and 3452 cmꢀ1 1H NMR (CDCl3,
;
300 MHz): d 2.40 (s, 1H, OH), 2.40 (s, 3H, Ar-CH3), 2.66 (dd, 1H, J ¼ 6.0,
15.0 Hz), 2.77 (dd, 1H, J ¼ 6.0, 15.0 Hz), 3.39–6.65 (m, 3H), 5.06 (d, 1H, J ¼ 6.0 Hz,
including NH), 6.95–7.59 (m, 9H, Ar-H); 13C NMR (CDCl3, 75 MHz): d 20.09,
36.32, 55.22, 62.58, 125.24, 125.57, 127.21, 127.72, 128.25, 135.32, 135.43 and
141.95 ppm; MS m=z, 305.31 (Mþ). Anal. calcd. for C16H19NO3S: C, 62.93, H,
6.27, N, 4.59%. Found: C, 62.83, H, 6.21, N, 4.63%.

SYNTHESIS OF TRANS-PYRROLO[3,4-b]QUINOLINES
2923
Synthesis of (S)-2-(N-(3-Methyl but-2-enyl)-N-tosylamino)-3-
phenylparopan-1-ol, 3a / (S)-2-(N-Cinnamyl-n-tosylamino)-
3-phenylparopan-1-ol, 3b
To a solution of 20 mmol of (S)-3-phenyl-2-(tosylamino)propan-1-ol in 100 mL
of dry acetone under a nitrogen atmosphere was added 60 mmol of potassium car-
bonate. To this stirred solution, 20 mmol of prenyl=cinnamyl bromide in 50 mL of
dry acetone was added. The stirring was continued for 8–10 h. After completion of
the reaction, the solid was filtered off. The residue was washed several times with
acetone, and the filtrate was concentrated in vacuum and extracted with dichlorome-
hane (100 mL) and water (100 mL). The organic extract was washed with brine sol-
ution and concentrated under reduced pressure. The crude product was subjected to
column chromatography with hexane–ethylacetate mixture (9:1) to obtain pure N-
allylated (S)-3-phenyl-2-(tosylamino) propan-1-ol, 3a.
34
Compound 3b. Colorless oil, 80% (5.52 g); ½aꢃD ¼ ꢀ29:96ꢁ (c 1, CHCl3); IR
1
(KBr): 1330, 1169, 1600 and 3546 cmꢀ1; H NMR (CDCl3, 300 MHz): d 1.68 (s,
6H), 2.39 (s, 3H), 2.17 (bs, 1H, OH), 2.65–2.78 (m, 2H), 3.54–3.67 (m, 2H), 3.86
(d, 2H, J ¼ 6.0 Hz), 4.03–4.13 (m, 1H), 5.16 (dd, 1H, J ¼ 3.0, 9.0 Hz), 7.03–7.61
(m, 9ArH); 13C NMR (CDCl3, 75 MHz): 15.83, 19.44, 23.10, 34.32, 40.52, 59.65,
60.62, 119.54, 124.49, 125.16, 126.51, 126.97, 127.49, 133.37, 135.80, 135.91 and
141.09 ppm; MS m=z: 373.90 (Mþ). Anal. calcd. for C21H27NO3S; C, 67.53; H,
7.29; N,3.75%; Found: C, 67.44; H, 7.71; N, 3.69%.
(S)-2-(N-Cinnamyl-N-tosylamino)-3-phenylparopan-1-ol, 3b. Colorless
34
solid, 80% (5.52 g); ½aꢃD ¼ 29:96ꢁ (c 1, CHCl3); mp: 89–91; IR (KBr): 1330, 1169,
1
1600 and 3546 cmꢀ1; H NMR (CDCl3, 300 MHz): d 2.21 (bs, 1H, OH), 2.35 (s,
3H), 2.76 (dq, 2H, J ¼ 6.0, 12.0 Hz), 3.58–3.74 (m, 2H), 3.97–4.21 (m, 3H),
6.05–6.15 (m, 1H), 6.52 (d, 1H, J ¼ 15.0 Hz), 7.01–7.60 (m, 14ArH); 13C NMR
(CDCl3, 75 MHz): d 21.49, 36.51, 46.98, 61.90, 62.69, 126.53, 126.61, 127.36,
127.94, 128.30, 128.62, 129.10, 129.64, 132.94, 136.29, 137.78, 137.85 and
143.34 ppm; MS m=z: 421.72 (Mþ). Anal. calcd. for C25H27NO3S: C, 71.23; H,
6.46; N, 3.32%. Found: C, 71.12; H, 6.35; N, 3.34%.
Synthesis of (S)-2-(N-(3-Methyl but-2-enyl)-N-tosylamino)-3-phenyl
Propanal, 4a
To a stirred solution of IBX (2.94 g, 0.010 mmol), dissolved in DMSO (10 mL)
was added 2.07 g (0.006 mmol) of (S)-2-(N-allyl-N-tosylamino)-3-phenylpropan-1-
ol, 5. After 2 h of vigorous stirring, the reaction mixture was diluted with water,
and the precipitate that formed was filtered and washed with ethyl acetate
(2 ꢄ 20 mL). The organic layer was dried over anhydrous sodium sulfate, and the sol-
vent was distilled off at reduced pressure to obtain a brown crude aldehyde in quan-
titative yield. It was subjected to column chromatography (silica gel, 100–200 mesh)
using a hexane–ethyl acetate mixture (9:1) to obtain pure (S)-2-(N-(3-methyl but-2-
34
enyl)-N-tosylamino)-3-phenylpropanal 4a. Yellow oil, 90% (1.86 g); ½aꢃD ¼ ꢀ14:78ꢁ
1
(c 1, CHCl3); IR (KBr): 1335, 1161 and 1735 cmꢀ1; H NMR (CDCl3, 300 MHz):
d 1.44 (s, 3H), 1.55 (s, 3H), 2.30 (s, 3H), 2.60 (dd, 1H, J ¼ 6.0, 15.0 Hz), 3.68

2924
M. JAYAGOBI AND R. RAGHUNATHAN
(d, 2H, J ¼ 6.0 Hz), 4.35 (dd, 1H, J ¼ 6.0, 6.0 Hz), 3.95 (dd, 1H, J ¼ 6.0, 9.0 Hz),
6.95–7.41 (m, 9ArH), 9.56 (s, 1H, CHO); 13C NMR (CDCl3, 75 MHz): d 16.89,
20.45, 24.68, 31.84, 42.77, 66.12, 118.29, 125.55, 126.23, 127.57, 127.99, 128.63,
136.21, 136.44, 137.75, 142.44 and 197.86 ppm; MS m=z: 371.47 (Mþ). Anal. calcd.
for C21H25NO3S: C, 67.89; H, 6.78; N, 3.77%. Found: C, 67.93; H, 6.83; N, 3.65%.
Synthesis of (S)-2-(N-Cinnamyl-N-tosylamino)-3-phenylpropanal, 4b
To a stirred solution of IBX (2.94 g, 0.010 mmol) dissolved in DMSO (10 mL)
was added 2.07 g (0.006 mmol) of (S)-2-(N-cinnamyl-N-tosylamino)-3-
phenylpropan-1-ol. After 2 h of vigorous stirring, the reaction mixture was diluted
with water, and the precipitate that formed was filtered and washed with ethyl acet-
ate (20 mL). The filtrate was then extracted with ethyl acetate (2 ꢄ 20 mL). The
organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled
off at reduced pressure to get a brown crude aldehyde in quantitative yield. It was
subjected to column chromatography (silica gel, 100–200 mesh) using a hexane–ethyl
acetate mixture (9:1) to obtain pure (S)-2-(N-cinnamyl-N-tosylamino)-3-phenylpro-
34
panal 4b. Yellow semisolid, 90% (1.86 g); ½aꢃD ¼ ꢀ4:99ꢁ (c 1, CHCl3); mp: 94–
1
96 ꢁC; IR (KBr): 1335, 1161 and 1735 cmꢀ1; H NMR (CDCl3, 300 MHz): d 2.40
(s, 3H), 2.82 (dd, 1H, J ¼ 9.0, 12.0 Hz), 3.41 (dd, 1H, J ¼ 6.0, 12.0 Hz), 3.84 (dd,
1H, J ¼ 9.0 15.0 Hz), 3.97 (dd, 1H, J ¼ 9.0, 15.0 Hz), 4.52 (dd, 1H, 6.0, 6.0 Hz), 5.94–
5.98 (m, 1H), 6.34 (d, 1H, J ¼ 15.0 Hz), 7.06–77.56 (m, 14ArH, 9.70 (s, CHO); 13C
NMR (CDCl3, 100 MHz): d 21.50, 0.90, 33.47, 48.6, 67.45, 124.05, 126.58, 126.73,
127.44, 128.26, 128.64, 128.67, 129.11, 129.75, 135.21, 135.77, 137.20, 143.73 and
198.73 ppm; MS m=z: 419.19 (Mþ). Anal. calcd. for C25H25NO3S: C, 71.57; H,
6.01; N, 3.34%. Found: C, 71.45; H, 5.89; N, 3.42%.
Synthesis of Enantiopure trans-2-Benzyl-5,5-dimethyl-3-tosyl-
pyrrolo[3,4-b]quinolines, 6a–j
InCl3 (20mol%) was added to a mixture of (N-(3-methylbut-2-enyl)-N-
tosylamino)-3-phenyl propanal 4a (1mmol), arylamine 5a (1 mmol), and acetonitrile
(20 mL). The reaction mixture was stirred at room temperature for 10 min. On com-
pletion of the reaction as indicated by TLC, the mixture was quenched with water
and extracted with ethyl acetate; the organic layer was washed with brine and dried over
Na2SO4. The solvent was evaporated in vacuo, and the crude product was chromato-
graphed with silica gel (100–200 mesh) hexane–ethylacetate (9:1) to afford the cycload-
ducts 6a–e, (1aR,2S,4aR)-2-benzyl-5,5-dimethyl-3-tosyl-pyrrolo[3,4-b] quinolines.
(1aR,2S,4aS)-trans-2-Benzyl-5,5-dimthyl-3-tosyl
pyrrolo[3,4-b]quino-
34
line, 6a. Brown viscous oil, 93% (0.415 g); ½aꢃD ¼ þ7:19ꢁ (c 1, CHCl3); IR (KBr):
1
3338, 1339 and 1169 cmꢀ1; H NMR (CDCl3, 300 MHz): d 1.09 (s, 3H, CH3), 1.12
(s, 3H, CH3), 1.30 (dt, Ha, J ¼ 3.0, 12.0 Hz, CHa), 2.39 (s, 3H, Ar-CH3), 2.69 (bs,
NH), 2.86 (dd, 1H, J ¼ 12.0, 12.0 Hz, CH), 3.18–3.32 (m, 2H, CH, including
CHb), 3.46 (dt, 1H, J ¼ 3.0, 6.0 Hz, CH), 3.68 (dd, 1H, J ¼ 9.0, 12.0 Hz, CH), 3.80
(dd, 1H, J ¼ 3.0, 6.0, 12.0 Hz, CH), 5.92–7.82 (m, 13ArH); 13C NMR (CDCl3,
75 MHz): d 21.54, 27.02, 28.60, 34.04, 42.27, 47.92, 49.25, 57.72, 66.85, 115.65,

SYNTHESIS OF TRANS-PYRROLO[3,4-b]QUINOLINES
2925
118.78, 126.86, 127.14, 127.42, 128.42, 128.97, 129.56, 129.90, 130.63, 134.53, 137.01,
142.95, 143.05 and 143.77 ppm; MS m=z: 446.32 (Mþ). Anal. calcd. for
C27H30N2O2S: C, 72.61; H, 6.77; N, 6.27%. Found: C, 72.70; H, 6.68; N, 6.18%.
(1aR,2 s,4aS)-trans-2-Benzyl-5,5-dimethyl-7-methyl-3-tosyl-pyrrolo[3,4-
34
b]quinoline, 6b. Colorless semisolid, 90% (0.414 g); ½aꢃD ¼ þ3:79ꢁ (c 1, CHCl3);
mp: 142–145 ꢁC; IR (KBr): 3338, 1339 and 1169 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 1.10 (s, 3H, CH3), 1.11 (s, 3H, CH3), 1.30 (dt, Ha, J ¼ 3.0, 12.0 Hz,
CH), 2.14 (s, 3H, Ar-CH3), 2.39 (s, 3H, Ar-CH3), 2.60 (bs, NH), 2.86 (dd, 1H,
J ¼ 12.0, 12.0 Hz,CH), 3.15–3.31 (m, 2H, CH, including CHb), 3.44–3.52 (m, 1H,
CH), 3.67 (dd, 1H, J ¼ 6.0, 12.0 Hz, CH), 3.78 (dd, 1H, J ¼ 6.0, 12.0 Hz, CH),
5.92–7.82 (m, 12ArH); 13C NMR (CDCl3, 75 MHz): 20.54, 21.25, 27.06, 28.71,
34.04, 42.33, 47.95, 49.41, 57.95, 66.89, 115.73, 127.05, 127.11, 127.44, 127.58,
128.01, 128.96, 129.57, 129.89, 130.65, 134.57, 137.05, 140.66 and 143.74 ppm; MS
m=z: 460.10 (Mþ). Anal. calcd. for C28H32N2O2S: C, 73.01; H, 7.00; N, 6.08%.
Found: C, 73.12; H, 6.89; N, 6.20%.
(1aR,2 s,4aS)-trans-2-Benzyl-7-methoxy-5,5-dimethyl-3-tosyl-pyrrolo[3,4-
34
b]quinoline, 6c. Yellow fluffy solid, 88% (0.418 g); ½aꢃD ¼ þ3:39ꢁ (c 1, CHCl3); mp:
1
107–109 ꢁC; IR (KBr): 3334, 1339 and 1166 cmꢀ1; H NMR (CDCl3, 300 MHz): d
1.10 (s, 3H, CH3), 1.11 (s, 3H, CH3), 1.30 (dt, Ha, J ¼ 6.0, 12.0 Hz, CHa), 2.40 (s,
3H, Ar-CH3), 2.69 (bs, NH), 2.86 (dd, 1H, J ¼ 12.0, 12.0 Hz, CH), 3.15–3.31 (m,
2H, CH, including CHb), 3.50 (dt, 1H, J ¼ 3.0, 6.0 Hz, CH), 3.65–3.71 (m, 1H,
CH), 3.66 (s, 3H, OCH3), 3.78 (dd, 1H, J ¼ 3.0, 6.0, 12.0 Hz, CH), 5.92–7.82 (m,
12ArH); 13C NMR (CDCl3, 75 MHz): 21.55, 27.00, 28.80, 34.36, 42.26, 47.96,
49.25, 55.74, 58.14, 66.85, 112.58, 112.64, 116.48, 127.10, 127.44, 128.71, 128.95,
129.58, 129.91, 132.07, 134.59, 136.96, 13.06, 143.75 and 152.89 ppm; MS m=z:
476.91 (Mþ). Anal. calcd. for C28H32N2O3S: C, 70.56; H, 6.77; N, 5.88%. Found:
C, 70.76; H, 6.68; N, 5.96%.
(1aR,2 s,4aS)-trans-2-Benzyl-7-bromo-5,5-dimethyl-3-tosyl-pyrrolo[3,4-
34
b]quinoline, 6d. Yellow viscous liquid, 98% (0.512 g); ½aꢃD ¼ ꢀ24:56ꢁ (c 1, CHCl3);
1
IR (KBr): 3336, 1347 and 1167 cmꢀ1; H NMR (CDCl3, 300 MHz): d 1.07 (s, 3H,
CH3), 1.10 (s, 3H, CH3), 1.26 (dt, Ha, J ¼ 6.0, 12.0 Hz, CHa), 2.39 (s, 3H, Ar-CH3),
2.70 (bs, NH), 2.85 (dd, 1H, J ¼ 12.0, 12.0 Hz, CH), 3.15–3.28 (m, 2H,CH, including
CHb), 3.44–3.51 (m, 1H, CH) 3.67 (dd, 1H, J ¼ 6.0, 12.0 Hz, CH), 3.79 (dd, 1H,
J ¼ 3.0, 12.0 Hz, CH), 5.79–7.81(m, 12ArH); 13C NMR (CDCl3, 75 MHz): 21.59,
26.94, 28.48, 34.28, 42.20, 47.80, 48.89, 57.66, 66.71,110.45, 116.75, 117.22, 127.25,
127.42, 129.05, 129.40, 129.55, 129.63, 129.97, 131.97, 132.76, 134.50, 136.93,
142.13 and 143.90 ppm; MS m=z: 526.01 (Mþ). Anal. calcd. for C27H29BrN2O2S:
C, 61.71; H, 5.56; N, 5.33%. Found: C, 61.79; H, 5.47; N, 5.47%.
(1aR,2 s,4aS)-trans-2-Benzyl-7-chloro-5,5-dimethyl-3-tosyl-pyrrolo[3,4-
34
b]quinoline, 6e. Yellow viscous liquid, 96% (0.450 g); ½aꢃD ¼ ꢀ60:12ꢁ (c 1, CHCl3);
1
IR (KBr): 3336, 1342 and 1163 cmꢀ1; H NMR (CDCl3, 300 MHz): d 1.08 (s, 3H,
CH3), 1.11 (s, 3H, CH3), 1.28 (dt, Ha, J ¼ 6.0, 12.0 Hz, CHa), 2.40 (s, 3H, Ar-CH3),
2.67 (bs, NH), 2.85 (dd, 1H, J ¼ 12.0, 12.0 Hz, CH), 3.16–3.30 (m, 2H, CH, including
CHb), 3.44–3.52 (m, 1H, CH) 3.67 (dd, 1H, J ¼ 9.0, 12.0 Hz, CH), 3.80 (dd, 1H,
J ¼ 3.0, 12.0 Hz, CH), 5.83–7.81 (m, 12ArH); 13C NMR (CDCl3, 75 MHz): 21.58,

2926
M. JAYAGOBI AND R. RAGHUNATHAN
26.92, 28.49, 34.29, 42.23, 47.80, 48.93, 57.77, 66.72, 116.77, 123.32, 126.52, 126.79,
127.24, 127.43, 129.05, 129.5, 129.96, 132.26, 134.54, 136.96, 141.65 and 143.88 ppm;
MS m=z: 481.72 (Mþ). Anal. calcd. for C27H29ClN2O2S: C, 67.41; H, 6.08; N, 5.82%.
Found: C, 67.32; H, 5.96; N, 5.74%.
Synthesis of Enantiopure trans-2-Benzyl-5-phenyl-3-tosyl-
pyrrolo[3,4-b]quinolines, 6f–j
InCl3 (20 mol%) was added to a mixture of (N-cinnamyl-N-tosylamino)-3-
phenyl propanal 4b (1 mmol), arylamine 5a (1 mmol), and acetonitrile (20 mL).
The reaction mixture was stirred at room temperature for 10 min. On completion
of the reaction as indicated by TLC, the mixture was quenched with water and
extracted with ethyl acetate; the organic layer was washed with brine and dried over
Na2SO4. The solvent was evaporated in vacuo, and the crude product was chroma-
tographed with silica gel (100–200 mesh) hexane–ethylacetate (9:1) to afford the
cycloadducts 6f–j, (1aR,2S,4aR)-2-benzyl-5-phenyl-3-tosyl-pyrrolo[3,4-b]quinolines.
(1aR,2 s,4aS)-trans-2-Benzyl-5-phenyl-3-tosyl-pyrrolo[3,4-b]quinoline,
32
6f. White solid, 97% (0.480 g); ½aꢃD ¼ ꢀ1:19ꢁ (c 1, CHCl3); mp: 202–204 ꢁC; IR
1
(KBr): 3328, 1340 and 1163 cmꢀ1; H NMR (CDCl3, 300 MHz): d 1.56 (dq, Ha,
J ¼ 6.0, 12.0 Hz, CHa), 2.40 (s, 3H, Ar-CH3), 2.75 (bs, NH), 2.88 (dd, 1H,
J ¼ 12.0, 12.0 Hz, CH), 3.07 (t, Hb, J ¼ 12.0 Hz, CHb), 3.28 (dd, 1H, J ¼ 9.0,
12.0 Hz, CH), 3.48–3.57 (m, 1H, CH), 3.74–3.79 (m, 1H, Ch), 6.01 (d, 1H, J ¼ 9.0 Hz,
CH), 6.45–7.63 (m, 18ArH); 13C NMR (CDCl3, 75 MHz): d 21.54, 42.23, 47.10,
47.47, 51.64, 62.38, 66.61, 115.62, 118.95, 124.75, 127.06, 127.21, 127.30, 127.38,
128.21, 128.64, 129.01, 129.58, 129.85, 129.99, 134.32, 136.91, 142.76, 143.64 and
144.52 ppm; MS m=z: 494.28 (Mþ). Anal. calcd. for C31H30N2O2S: C, 75.27; H,
6.11; N, 5.66%. Found: C, 75.36; H, 6.02; N, 5.72%.
(1aR,2 s,4aS)-trans-2-Benzyl-5-phenyl-7-methyl-3-tosyl-pyrrolo[3,4-b]
32
quinoline, 6g. White solid, 92% (0.466 g); ½aꢃD ¼ ꢀ1:19ꢁ (c 1, CHCl3); mp:
1
216–218 ꢁC; IR (KBr): 3334, 1342 and 1163 cmꢀ1; H NMR (CDCl3, 300 MHz): d
1.51 (dq, Ha, J ¼ 6.0, 12.0 Hz, CH), 1.97 (s, 3H, Ar-CH3), 2.40 (s, 3H, Ar-CH3),
2.64 (bs, NH), 2.87 (dd, 1H, J ¼ 12.0, 12.0 Hz, CH), 3.06 (t, Hb, J ¼ 12.0 Hz,
CHb), 3.24 (dd, 1H, J ¼ 9.0, 9.0 Hz, CH), 3.43 (t, 1H, J ¼ 9.0 Hz, CH), 3.47–3.56
(m, 1H, CH), 3.70–3.77 (m, 2H,CH2), 5.95 (d, 1H, J ¼ 9.0 Hz, CH), 6.26–7.62 (m,
17ArH); 13C NMR (CDCl3, 75 MHz): d 20.23, 21.55, 42.27, 47.39, 47.53, 51.70,
62.61, 66.66, 115.73, 142.72, 127.01, 127.19, 127.39, 128.00, 128.24, 128.36, 128.63,
129.01, 129.60, 129.86, 130.27, 134.35, 136.96, 142.20, 142.94 and 143.61 ppm; MS
m=z: 508.03 (Mþ). Anal. calcd. for C32H32N2O2S: C, 75.56; H, 6.34; N, 5.51%.
Found: C, 75.42; H, 6.26; N, 5.43%.
(1aR,2 s,4aS)-trans-2-Benzyl-5-phenyl-7-methoxy-3-tosyl-pyrrolo[3,4-b]
32
quinoline, 6h. White solid, 95% (0.506 g); ½aꢃD ¼ ꢀ0:99ꢁ (c 1, CHCl3); mp:
1
192–194 ꢁC; IR (KBr): 3334, 1340 and 1159 cmꢀ1; H NMR (CDCl3, 300 MHz): d
1.54 (dq, Ha, J ¼ 6.0, 12.0 Hz, CHa), 2.40 (s, 3H, Ar-CH3), 2.61 (bs, NH), 2.87
(dd, 1H, J ¼ 12.0, 12.0 Hz, CH), 3.07 (t, Hb, J ¼ 12.0 Hz, CHb), 3.23 (dd, 1H,
J ¼ 9.0, 12.0 Hz), 3.42–3.56 (m, 1H, CH), 3.48 (s, 3H, OCH3), 3.71–3.78 (m, 2H,

SYNTHESIS OF TRANS-PYRROLO[3,4-b]QUINOLINES
2927
Figure 1. Mechanism of indium trichloride–catalyzed reaction. (Figure is provided in color online.)
CH2), 5.99 (d, 1H, J ¼ 9.0 Hz, CH), 6.03–7.63 (m, 17ArH); 13C NMR (CDCl3,
75MHz): d 21.34, 42.20, 47.26, 47.85, 51.79, 55.38, 62.82, 66.65, 113.37, 115.46,
116.54, 125.99, 127.12, 127.17, 127.38, 128.20, 128.66, 128.99, 129.58, 129.86, 134.43,
137.10, 138.47, 142.65, 143.59 and 152.89 ppm; MS m=z: 524.26 (Mþ). Anal. calcd.
for C32H32N2O3S: C, 73.25; H, 6.15; N, 5.34%. Found: C, 73.33; H, 6.07; N, 5.43%.
Figure 2. ORTEP diagram of 6f. (Figure is provided in color online.)

2928
M. JAYAGOBI AND R. RAGHUNATHAN
Figure 3. ORTEP diagram of 6g. (Figure is provided in color online.)
(1aR,2 s,4aS)-trans-2-Benzyl-7-bromo-5-phenyl-3-tosyl-pyrrolo[3,4-b]
33
quinoline, 6i. White solid, 95% (0.543 g); ½aꢃD ¼ ꢀ2:39ꢁ (c 1, CHCl3); mp:
1
221–223 ꢁC; IR (KBr): 3330, 1344 and 1159 cmꢀ1; H NMR (CDCl3, 300 MHz): d
1.51 (dq, Ha, J ¼ 6.0, 12.0 Hz, CHa), 2.41 (s, 3H, Ar-CH3), 2.71 (bs, NH), 2.85
(dd, 1H, J ¼ 12.0, 12.0 Hz, CH), 3.05 (t, Hb, J ¼ 12.0 Hz, CHb), 3.25 (dd, 1H,
J ¼ 9.0, 12.0 Hz, CH), 3.44 (d, 1H, J ¼ 6.0, 12.0 Hz,CH), 3.47–3.54 (m, 1H, CH),
3.69–3.74 (m, 1H, CH), 5.87 (d, 1H, J ¼ 9.0 Hz, CH), 6.53–7.63 (m, 17ArH); 13C
NMR (CDCl3, 75 MHz): d 21.55, 42.18, 46.79, 47.26, 51.43, 62.31, 66.45, 110.69,
117.13, 126.80, 127.27, 127.35, 127.38, 128.08, 128.85, 129.05, 129.52, 129.87,
130.10, 132.34, 134.26, 136.81, 141.83, 143.61 and 143.71 ppm; MS m=z: 572.79
(Mþ). Anal. calcd. for C31H29BrN2O2S: C, 64.92; H, 5.10; N, 4.88%. Found: C,
64.80; H, 5.21; N, 5.01%.
(1aR,2 s,4aS)-trans-2-Benzyl-7-chloro-5-phenyl-3-tosyl-pyrrolo[3,4-b]
34
quinoline, 6j. White solid, 98% (0.517 g); ½aꢃD ¼ ꢀ29:76ꢁ (c 1, CHCl3); mp:
1
245–247 ꢁC; IR (KBr): 3336, 1343 and 1163 cmꢀ1; H NMR (CDCl3, 300 MHz): d
1.52 (dq, Ha, J ¼ 6.0, 12.0 Hz, CHa), 2.41 (s, 3H, CH3), 2.71 (bs, NH), 2.86 (dd,
1H, J ¼ 12.0, 12.0 Hz, CH), 3.05 (t, Hb, J ¼ 12.0 Hz, CHb), 3.26 (t, 1H, J ¼ 9.0 Hz,
CH), 3.42 (t, 1H, J ¼ 6.0 Hz, CH), 3.46–3.55 (m, 1H, CH), 3.68–3.79 (m, 2H, CH),
5.92 (d, 1H, J ¼ 9.0 Hz, CH), 6.40–7.63 (m, 17ArH); 13C NMR (CDCl3, 75 MHz):
d 21.55, 42.21, 46.84, 47.35, 51.48, 62.45, 66.49, 116.71, 123.58, 126.34, 127.29,

SYNTHESIS OF TRANS-PYRROLO[3,4-b]QUINOLINES
2929
127.39, 128.12, 128.87, 129.07, 129.51, 129.55, 129.89, 134.35, 136.87, 141.90, 143.16
and 143.73 ppm; MS m=z: 529.01 (Mþ). Anal. calcd. for C31H29ClN2O2S: C, 70.37;
H, 5.52; N, 5.29%. Found: C, 70.49; H, 5.60; N, 5.21%.
ACKNOWLEDGMENT
M. J. and R. R. thank the University Grants Commission, New Delhi, for
financial support.
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