A novel heterotricyclic assembly through intramolecular imino Diels-Alder reaction: synthesis of pyrrolo[3,4-b]quinolines

Article abstract of DOI:10.1016/j.tetlet.2008.11.092

The synthesis of a series of hexahydropyrrolo[3,4-b]quinolines has been achieved in excellent yields by the reaction of aldimines derived from aromatic amines and N-prenylated aliphatic aldehydes in acetonitrile with InCl₃ as a catalyst in a sh

Full text of DOI:10.1016/j.tetlet.2008.11.092

Tetrahedron Letters 50 (2009) 648–650
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A novel heterotricyclic assembly through intramolecular imino Diels–Alder
reaction: synthesis of pyrrolo[3,4-b]quinolines
*
Mathesan Jayagobi, Mahalingam Poornachandran, Raghavachary Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a series of hexahydropyrrolo[3,4-b]quinolines has been achieved in excellent yields by
the reaction of aldimines derived from aromatic amines and N-prenylated aliphatic aldehydes in aceto-
nitrile with InCl3 as a catalyst in a short duration of time.
Received 15 October 2008
Revised 12 November 2008
Accepted 22 November 2008
Available online 28 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Indium trichloride
Imino Diel’s–Alder reaction
Pyrroloquinolines
Azomethine ylide
Quinoline- and pyrrole-based structural scaffolds have been
established as the essential part of many natural products. Syn-
thetic compounds having these moieties exhibited a wide range
of biological activities. Tetrahydroquinolines have shown biologi-
cal activities,1–4 such as psychotropic,5 antiallergenic,6 antiinflam-
matory,7 and estrogenic activities.8 Pyrrolidines and their fused
derivatives have shown a wide spectrum of biological activities.9,10
Hexahydro pyrrolo quinolines are considered to be the prime can-
didates in the construction of bacterial topoimerase inhibitors.11 In
particular, the substitution of these bicycloamines attached at the
C-7 position of quinolines has led to the synthesis of various anti-
bacterial agents like moxifloxacin.12,13
It is therefore not surprising that many synthetic methods have
been developed and much interest has been paid to the synthesis
of tetrahydroquinoline derivatives in recent years.14,15 Among the
methods available for the construction of nitrogen containing
six-membered heterocycles, the imino Diels–Alder reaction pro-
vides a rapid means of constructing such molecules with control
of regio-and stereo- selectivities. Imines which are readily pre-
pared from the corresponding aldehydes and ketones allow a vari-
ety of imine dienophiles accessible for this reaction.16–18
Unlike the intermolecular aza Diels–Alder reaction of aza dienes
generated from the reactions of arylaldehydes with arylamines,
there are only a few reports available for the IMDA of dienes gen-
erated from allyl tethered aliphatic aldehyde with arylamines.24
In continuation of our research interest in the area of the imino
Diels–Alder reaction,25,26 we herein describe the synthesis of hexa-
hydropyrrolo[3,4-b]quinolines from aromatic amines and N-allyl
derivatives of aliphatic aldehydes via intramolecular [4+2] cycliza-
tion of imines catalyzed by InCl3.
The electron-rich alkenyl aldehyde precursors required for the
intramolecular cyclization reaction were synthesized by a series
of chemical transformations from an amino alcohol 1. Accordingly,
ethanolamine 1a was N-tosylated by tosyl chloride 2 under stan-
dard PTC reaction conditions to give the corresponding sulphona-
mide derivative 3a which on N-prenylation under mild basic
conditions afforded 2-(N-(3-methylbut-2-enyl)-N-tosylamino)eth-
anol 4a. The N-prenyl tethered amino alcohol 4a was then oxidized
to the N-prenyl aldehyde 5a in IBX in DMSO solvent in excellent
yield. The structures of the synthesized aldehyde and alcohol were
established on the basis of their spectroscopic data. A similar reac-
tion sequence was adopted for the synthesis of alkenyl aldehyde
5b starting from 2-amino butanol 1b (Scheme 1).
Both inter- and intramolecular versions of imino Diels–Alder
reactions are well known in the literature and they have been cat-
alyzed by various catalysts19–21 InCl3 has been found to be one of
the best catalysts, since it is a mild and water-tolerant Lewis acid
imparting high regio- and chemoselectivities.22,23
The aldehydes so prepared (5a and 5b) were then subjected to
the intramolecular imino Diel’s–Alder reaction. A 20 mol % of in-
dium trichloride was added to the reaction mixture containing
alkenyl aldehyde 5a and aniline 6a in acetonitrile solvent to gener-
ate the imine which was trapped by an N-tethered prenyl moiety
and intramolecularly cyclized to give the cycloadducts. It was
noticed that the reaction was complete in 20 min after effective
stirring at room temperature and afforded a 36:64 mixture of
* Corresponding author. Tel.: +91 44 22202811; fax: +91 44 22300488.
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.2008.11.092

M. Jayagobi et al. / Tetrahedron Letters 50 (2009) 648–650
649
R
O
Ts
R
N
HO
H
N
Ts
(i)
(iii)
(ii)
H2N
Ts
N
R
R
HO
OH
3a-b
1a-b
4a-b
5a-b
R = H , C2H5;
Scheme 1. Reagents and conditions: (i) TBAB, 10% NaOH/benzene, tosyl chloride 2, 0 °C-RT; 8 h, 90%; (ii) prenyl bromide K2CO3/acetone, 12 h, 90%; (iii) iodoxybenzoic acid,
DMSO, 2 h, 98%.
R
Ha
Ha
O
Ts
N
R1
R1
20 mol% InCl3
CH3CN, rt
H2N
Ts N
R
R1
Ts N
R
N
N
Hb
Hb
H
H
6a-e
trans
8a-j
5a-b
cis
7a-j
R = H , C2H5
R1 = H, CH3, OCH3, Cl, Br
Scheme 2.
Table 1
InCl3-catalyzed synthesis of hexahydropyrrolo[3,4-b]quinoline derivatives
pyrrolidine ring were observed as doublets of doublets in the range
2.99–3.34. Particularly diagnostic were the protons Ha and Hb ring
d
situated at the ring junctions, showing doublets of triplets at d 1.92
(J = 8.0, 12 Hz) and d 3.28 (J = 12.0, 12.0 Hz), respectively. The trans
fusion at the ring junction was discerned by the high value of the
coupling constant (12 Hz). On the other hand, the 1H NMR spec-
trum of 7d exhibited two doublets of triplets at d 2.16 (J = 8.0,
10.8 Hz) and d 3.48 (J = 4.0, 10.8) for the Ha and Hb protons. The
small value for the coupling constant of (4 Hz) between Ha and
Hb in 7 d indicated the cis fusion at the ring junctions.
The cis- and trans stereochemistries of the products were as-
signed on the basis of the coupling constants of the protons at
the ring junctions in analogy to similar systems.28–31cis-Fusion at
the ring junction was further confirmed by a strong NOE between
Ha and Hb. The intramolecular imino Diel’s–Alder reaction was fur-
ther extended with the alkenyl aldehydes 5a–b and aromatic
amines 6a–e to obtain a series of hexahydropyrrolo[3,4-b]quino-
line derivatives 7a–j and 8a–j. Further, the structure and the ste-
reochemistry of the cycloadduct 8i was confirmed by single
crystal X-ray diffraction analysis (Fig. 1).32
Entry
R
R1
Products
Ratio cis:trans
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
7a
8a
8b
8c
8d
8e
8f
36:64
35:65
38:62
39:61
40:60
30:70
35:65
31:69
25:75
23:77
20
25
30
20
20
25
30
25
20
20
92
93
86
94
96
94
91
89
96
97
OCH3
CH3
Cl
Br
H
OCH3
CH3
Cl
7b
7c
7d
7e
7f
H
Et
Et
Et
Et
Et
7g
7h
7i
8g
8h
8i
10
Br
7j
8j
cis–trans isomers of hexahydropyrrolo[3,4-b]quinolines 7a and 8a
in 92% yield (Scheme 2, Table 1). The formation of the cycloadducts
was confirmed by their spectral data.27 Thus, the 1H NMR spectrum
of compound 8d exhibited a broad singlet at d 4.12 for the NH pro-
ton of the quinoline ring. The two geminal dimethyl protons were
observed at d 1.07 and 1.25 as singlets and the aromatic methyl
group exhibited a singlet at d 2.41. The two NCH2 protons of the
In conclusion, an intramolecular imino Diel’s–Alder reaction be-
tween various substituted N-alkenyl aliphatic aldehydes and aryl
amines were carried out in the presence of an Indium chloride cat-
alyst for the synthesis of hitherto unreported hexahydro pyrrol-
o[3,4-b]quinolines.
Acknowledgments
M.J. thanks the UGC, New Delhi, and M.P. thanks CSIR-SRF, New
Delhi, for financial support. R.R. thanks DST-FIST for the NMR
facility.
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6
reaction mixture was stirred at room temperature for 30 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 chromatographed on silica gel (EtOAc–
hexane mixture) to afford pure diastereoisomers in good yield.
Representative spectral data of the products: Compound 7d: yellow colored
liquid; IR (KBr) 3398.3 (NH), 1339.5, 1156.2 cmÀ1 1H NMR (400 MHz,
;
CDCl3) d 1.15 (s, 3H), 1.24 (s, 3H), 2.16 (dt, Ha, J = 8.0, 10.8 Hz), 2.43 (s, 3H),
2.73 (dd, 1H, J = 8.0,10.8 Hz), 3.31 (dd, 1H J = 10.8, 4.0 Hz), 3.46–3.48 (m,
1H, Hb, J = 4.0, 10.8 Hz), 3.85(t, 1H, J = 4.0 Hz), 4.12 (br s, NH), 6.79–7.63
(Ar-7H); 13C NMR (400 MHz, CDCl3)
d 21.50, 26.97, 32.54, 33.27, 48.71,
49.02, 50.91, 56.49, 114.34, 121.47, 125.54, 126.60, 127.33, 129.09, 129.67,
134.00, 138.99, 143.36; MS (m/z) 390.19 (M+); Anal. Calcd for
C20H23N2O2SCl; C, 61.45, H, 5.93, N, 7.17. Found: C, 61.33, H, 6.07, N,
7.05.Compound 8d: yellow colored liquid; IR (KBr) 3379.1 (NH), 1339.5,
1160.1 cmÀ1 1H NMR (400 MHz, CDCl3) d 1.07 (s, 3H), 1.25 (s, 3H), 1.92 (dt,
;
Ha, J = 8.0,12.0 Hz), 2.41 (s, 3H), 3.00 (t, 1H, J = 12.0 Hz), 3.21 (dd, 1H,
J = 12.0, 12.0 Hz), 3.28 (distorted dt, Hb, J = 12.0, 12.0 Hz), 3.55 (dd, 1H,
J = 8.0, 8.0 Hz), 3.81(dd, 1H, J = 12, 8.0 Hz), 4.12 (br s, NH), 6.40–7.74 (Ar-
7H); 13C NMR (400 MHz, CDCl3) d 21.52, 26.74, 28.55, 34.62, 46.87, 50.09,
50.62, 53.18, 116.97, 123.54, 126.62, 126.97, 127.29, 132.80, 134.07, 141.68,
143.71; MS (m/z) 390.52 (M+); Anal. Calcd For C20H23N2O2SCl; C, 61.45, H,
5.93, N, 7.17. Found: C, 61.36, H, 5.83, N, 7.26.
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