Unusual formation of β-carboline dimers under Bischler-Napieralski reaction conditions: An old reaction with a new direction

Article abstract of DOI:10.1016/j.tetlet.2004.06.118

L-N-Formyl tryptophan methyl ester (3) underwent a Bischler-Napieralski reaction with POCl₃ at room temperature or under microwave irradiation, resulting in the unusual formation of -carboline dimers 5 and 6. Most importantly, acetylation using Ac₂O of each of the dimers 5 and 6 separately afforded 1-[3′-carbomethoxy-β-carbolinyl]-3- carbomethoxy-9-acetyl-β-carboline (7) as the only product, the structure of which was confirmed by X-ray crystallography studies.

Full text of DOI:10.1016/j.tetlet.2004.06.118

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6489–6492
Unusual formation of b-carboline dimers under
Bischler–Napieralski reaction conditions: an old reaction with
a new direction
Bikash Pal,a Parasuraman Jaisankar,a Venkatachalam Sesha Giri,a,
*
Swastik Mondalb and Monika Mukherjeeb
aDepartment of Medicinal Chemistry, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur,
Calcutta 700 032, India
bDepartment of Solid State Physics, Indian Association for the Cultivation of Science, Jadavpur, Calcutta 700 032, India
Received 16 February 2004; revised 15 June 2004; accepted 25 June 2004
Available online 20 July 2004
Abstract—L-N-Formyl tryptophan methyl ester (3) underwent a Bischler–Napieralski reaction with POCl3 at room temperature or
under microwave irradiation, resulting in the unusual formation of b-carboline dimers 5 and 6. Most importantly, acetylation using
Ac2O of each of the dimers 5 and 6 separately afforded 1-[30-carbomethoxy-b-carbolinyl]-3-carbomethoxy-9-acetyl-b-carboline (7) as
the only product, the structure of which was confirmed by X-ray crystallography studies.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The use of chemotherapeutic agents in cancer has ad-
vanced from the treatment of late diseases to the early
use of effective agents in patients with relatively small
tumors. Among the various chemotherapeutic agents,
1-substituted-b-carboline derivatives,1 including the re-
cently synthesized dimeric b-carboline alkaloid benga-
carboline,2 have attracted the attention of organic
chemists because of their potential anti-tumor activity.
In our endeavor to obtain 1-substituted b-carbolines of
physiological importance, the b-carbolines 2 were syn-
thesized from the corresponding tryptamine derivatives
1 using the microwave assisted Bischler–Napieralski
reaction. The Bischler–Napieralski reaction3 is one of
the most widely used reactions in the synthesis of b-
carboline derivatives. Many indole alkaloids have been
synthesized with the help of this reaction.
oline 2 (R=Me) in very good yields. Surprisingly, reac-
tion of L-N-formyl tryptophan methyl ester 3 with
POCl3 under microwave irradiation resulted in the di-
meric b-carbolines 5 (30%) and 6 (10%) together with
the expected b-carboline derivative 4 (50%) as the major
product (Scheme 1). The same reaction when per-
formed4 with POCl3 at room temperature for 30min
CO2Me
+
2
CO2Me
a or b
N
NH
N
H
N
H
OHC
3 (-)-(2S)
4
5'
Treatment of N-formyl tryptamine 1 (R=H) and N-acetyl
tryptamine 1 (R=Me) with POCl3 under microwave
irradiation or at room temperature gave 3,4-dihydro-
b-carboline 2 (R=H) and 1-methyl-3,4-dihydro-b-carb-
3'
4a'
CO2Me
4b'
9'
CO2Me
+
1'
N
N
7'
N
N
H
HN
8a' 9a'
H
H
N
H
1
8a
N
9a
7
HN
MeO2C
9
4a
3
4b
5
MeO2C
3
Keywords: Bischler–Napieralski; Chiral b-carboline dimers; Trypto-
phan methyl esters; POCl3; Microwave.
5 (-)-(1S, 3S)
6 (-)-(1R, 3S)
*
Scheme 1. Reaction conditions: (a) POCl3, microwave irradiation,
600W, 10min; (b) POCl3, 28ꢁC, 30 min.
Corresponding author. Fax: +91-33-24735197; e-mail: vsgiri@iicb.
res.in
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.118

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B. Pal et al. / Tetrahedron Letters 45 (2004) 6489–6492
imine tautomerism facilitating addition to another mole-
cule of an imine followed by ring closure. No dimeric
product was formed with N-formyl tryptamine under
the same reaction conditions (Fig. 1).
N
NHCOR
R=H, Me
N
H
N
H
R
2
1
Cook et al.7 have previously shown that the stereochem-
istry at the C-1 and C-3 positions in 1,3-disubstituted
1,2,3,4-tetrahydro-b-carbolines can be assigned from
the chemical shifts of the carbons at C-1 and C-3 in their
13C NMR spectra. The signals for the C-1 and C-3 car-
bons of the cis diastereoisomers are clearly distinct from
those of the analogous signals for the trans diastereoiso-
mers. The reason for the higher yield of the trans isomer
5 compared to the cis isomer 6 is due to the absence of
the 1,4-gauche effect in the trans isomer. It should be
mentioned that Bailey et al.8 have shown that by
employing the kinetically controlled Pictet–Spengler
reaction, the cis 1,3-disubstitued tetrahydro-b-carbo-
lines are the favored products. As expected, the
Bischler–Napieralski reaction when performed using
D-N-formyl tryptophan methyl ester with POCl3
afforded the trans isomer (+)-(1R,3R)-1-(3-carbometh-
Figure 1.
afforded the dimeric b-carbolines 55 and 66 in 70% and
12% yields, respectively, together with 3-carbomethoxy-
b-carboline 4 in 8% yield. This is the first report on
the formation of such chiral dimeric b-carbolines under
the well-known Bischler–Napieralski reaction condi-
tions. The above reaction when performed under an
oxygen-free nitrogen atmosphere gave the same dimeric
b-carbolines 5 and 6 in 50% and 15% yields, respec-
tively. Also, the reaction when performed using an equi-
molar mixture of 3 (246mg; 1mmol) and 4 (226mg;
1mmol) afforded 4 (235mg), 5 (165mg), and 6 (26mg)
in the molar ratio 1.04:0.36:0.05, respectively. Therefore,
it appears that the dimeric b-carbolines 5 and 6 are
probably formed due to the presence of the acidic a-pro-
ton of the COOMe group, which is involved in amine–
oxy-1,2,3,4-tetrahydro-b-carbolinyl)-3-carbo-methoxy-
9
b-carboline,
and the cis isomer (+)-(1S,3R)-1-(3-
carbomethoxy-1,2,3,4-tetra-hydro-b-carbolinyl)-3-carbo-
methoxy-b-carboline10 along with 4 in the same propor-
tion as was obtained from 3.
5
3
4a
CO2Me
H
4b
9
1
N
7
Surprisingly and most importantly, acetylation11 of both
the isomers 5 and 6 separately using Ac2O in pyridine at
80ꢁC for 4h afforded a single compound 712 in near
quantitative yield, wherein acetylation had occurred at
the indole NH (H-90) of the dimer rather than the sec-
ondary amino group (H-2) of the tetrahydro-b-carbol-
inyl moiety (Scheme 2). As anticipated, acetylation of
the corresponding trans and cis isomers obtained from
N
8a
Ac
8a'
N
a
9a'
7'
N
3'
5 or 6
1'
9'
MeO2C
4a'
4b'
5'
7
Scheme 2. Acetylation of chiral b-carbolines
conditions: (a) Ac2O–Py, 80ꢁC, 4h.
5 or 6. Reaction
Figure 2. X-ray crystal structure 1-[30-carbomethoxy-b-carbolinyl]-3-carbomethoxy-9-acetyl-b-carboline (7) with an entrapped CHCl3 in the single
crystal.

B. Pal et al. / Tetrahedron Letters 45 (2004) 6489–6492
6491
(t, J=7.5Hz, 1H, H-60), 7.48 (d, J=6.9Hz, 1H, H-5), 7.57
(t, J=7.5Hz, 1H, H-70), 7.74 (d, J=8.1Hz, 1H, H-80), 8.38
(d, J=7.5Hz, 1H, H-50), 8.89 (s, 1H, H-40), 10.27 (s, 1H,
NH), 11.39 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz):
d 24.79 (C-4), 52.57 (–CO2CH3), 52.84 (–CO2CH3), 53.95
(C-3), 55.42 (C-1), 107.24 (C-4a), 112.09 (C-8), 113.75 (C-
80), 117.91 (C-5), 118.55 (C-50), 119.22 (C-60), 121.06
(C-6), 121.67 (C-7), 121.82 (C-4b0), 122.65 (C-40), 127.46
(C-4b), 129.39 (C-70), 129.44 (C-4a0), 133.47 (C-9a), 135.97
(C-9a0), 136.57 (C-8a), 137.15 (C-8a0), 141.57 (C-30),
146.21 (C-10), 166.92 (–CO2CH3), 175.11 (–CO2CH3);
EIMS: m/z: 454 (M+, 100%), 450 (40), 390 (24), 366 (40),
307 (30), 229 (25), 169 (70).
D-N-formyl tryptophan methyl ester gave 7 in similar
yield. The acetylation reaction, when performed under
an oxygen-free nitrogen atmosphere with or without a
base (pyridine), afforded the same product 7. This could
plausibly have arisen by initial acetylation of the second-
ary NH (H-2) followed by transacetylation due to the
close proximity of the indole NH (H-90) and subsequent
aromatization. The structure of compound 7 has been
13
confirmed by X-ray crystallographic studies (Fig. 2).
All new compounds have been characterized from their
spectral data, particularly NMR (including COSY and
HMBC).
6. (À)-(1R,3S)-1-(3-Carbomethoxy-1,2,3,4-tetrahydro-b-carbol-
28
D
inyl)-3-carbomethoxy-b-carboline (6): mp 320-322ꢁC; ½aŠ
In summary, the present observation is the first report of
the formation of dimeric b-carbolines using the well-
known Bischler–Napieralski reaction from N-formyl
tryptophan methyl esters. Moreover the formation of
the fully aromatized system 7 from the chiral dimers 5
or 6 is interesting due to the unusual acetylation as well
as the consequent aromatization.
À13.2 (c 0.155, CHCl3); IR (KBr): 3379, 3319, 1740, 1724,
1
1346, 1262cmÀ1; H NMR (DMSO-d6, 300MHz): d 3.12
(br dd, J=14.8Hz, 3.0Hz, 2H, H-4), 3.67 (s, 3H,
–CO2CH3), 3.84 (br s, 1H, NH), 3.91 (s, 3H, –CO2CH3),
4.39 (br d, J=4.9Hz, 1H, H-3), 6.01 (br s, 1H, H-1), 6.92–
6.99 (m, 2H, H-6, H-7), 7.01–7.19 (m, 1H, H-8 ), 7.26–7.34
(m, 1H, H-60), 7.44–7.52 (m, 1H, H-5), 7.53–7.62 (m, 1H,
H-70), 7.75 (d, J=8.2Hz, 1H, H-80), 8.37 (d, J=7.8Hz,
1H, H-50), 8.89 (s, 1H, H-40), 10.27 (s, 1H, NH), 11.38 (s,
1H, NH); 13C NMR (DMSO-d6, 75 MHz): d 26.15 (C-4),
52.74 (–CO2CH3), 52.82 (–CO2CH3), 55.41 (C-3), 57.74
(C-1), 107.90 (C-4a), 112.10 (C-8), 113.76 (C-80), 117.91
(C-5), 118.17 (C-50), 119.19 (C-60), 121.04 (C-6), 121.64
(C-7), 121.84 (C-4b0), 122.83 (C-40), 127.47 (C-4b), 129.45
(C-70), 129.65 (C-4a0), 133.51 (C-9a), 135.98 (C-9a0),
136.59 (C-8a), 137.16 (C-8a0), 141.82 (C-30), 146.22
(C-10), 166.91 (–CO2CH3), 173.91 (–CO2CH3); LCMS
(ESþ) m/z: 477 (M+Na).
Acknowledgements
One of the authors B.P. thankfully acknowledges CSIR,
New Delhi, India for the financial support in the form of
a Senior Research Fellowship.
References and notes
7. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797–1842.
8. (a) Bailey, P. D.; Hollinshead, S. P.; McLay, N. R.;
Morgan, K.; Palmer, S. J.; Prince, S. N.; Reynolds, C. D.;
Wood, S. D. J. Chem. Soc., Perkin Trans. 1 1993, 431–439;
(b) Bailey, P. D.; McLay, N. R. J. Chem. Soc., Perkin
Trans. 1 1993, 441–449.
1. Farn, Y. S.; Ya-ching, S. U.S. Patent 0040527, 2003.
2. (a) Foderato, T. A.; Barrows, L. R.; Lassota, P.; Ireland,
C. M. J. Org. Chem. 1997, 62, 6064–6065; (b) Pouilhes, A.;
Langlois, Y.; Chiaroni, A. Synlett 2003, 1488–1490.
3. (a) Bischler, A.; Napieralski, B. Chem. Ber. 1893, 26,
1891–1903; (b) Whaley, W. M.; Govindachari, T. R. The
Preparation of 3,4-Dihydroisoquinolines and Related
Compounds by the Bischler–Napieralski ReactionAdams,
R., Ed.; Organic Reactions; John Wiley and Sons: New
York, 1951; Vol. VI, pp 74–150; (c) Tseng, C. K.; Simone,
R. A.; Walke, F. H. J. Org. Chem. 1973, 38, 1746–1747;
(d) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36,
1279–1300, and references cited therein.
4. A solution of 3.0mmol of L-N-formyl tryptophan methyl
ester 3 and 2.0mL of POCl3 was stirred at room
temperature for 30min. After completion, excess POCl3
was decomposed by the addition of ice at 0–5ꢁC and the
reaction mixture neutralized with satd NaHCO3 solution
and extracted with CHCl3 (3·15mL). The organic layer
was washed with H2O (2·15mL), dried (Na2SO4), and the
solvent removed under vacuum to afford a mixture of b-
carbolines 4–6. Fractional crystallization of the mixture
obtained using MeOH yielded the trans isomer 5 (60%).
The filtrate obtained from the above mixture was chro-
matographed over silica-gel using initially CHCl3 and then
a mixture of CHCl3–MeOH, to afford 4 (8%), 5 (10%) and
6 (12%), respectively.
9. (+)-(1R,3R)-1-(3-Carbomethoxy-1,2,3,4-tetrahydro-b-carbo-
28
D
linyl)-3-carbomethoxy-b-carboline: mp 312–314ꢁC; ½aŠ
+13.4 (c 0.156, CHCl3).
10. (+)-(1S,3R)-1-(3-Carbomethoxy-1,2,3,4-tetrahydro-b-carbo-
28
D
linyl)-3-carbomethoxy-b-carboline: mp 318–320ꢁC; ½aŠ
+11.48 (c 0.155, CHCl3).
11. To a solution of 2mmol (908mg) of chiral b-carboline dimer
5 in pyridine (2mL) was added dry acetic anhydride (2mL)
and this reaction mixture was warmed on a water bath at
80ꢁC for 4h. After completion of the reaction [monitored
by TLC; EtOAc–benzene (1:9)], the excess acetic anhydride
was decomposed by the addition of ice-cold water and the
reaction neutralized with satd NaHCO3 solution and then
extracted with CHCl3 (3·20mL). The organic layer was
washed with water (2·20mL), dried (Na2SO4) and then the
solvent was removed. The residue was purified by column
chromatography over silica gel using CHCl3 to yield 7
(865mg; 88%). The same procedure was followed to obtain
compound 7 from each of the other stereoisomers.
12. 1-(30-Carbomethoxy-b-carbolinyl)-3-carbomethoxy-9-acetyl-
b-carboline (7): mp 210–212ꢁC; IR (KBr): 3312, 3029,
1740, 1724, 1619, 1265cmÀ1; 1H NMR (CDCl3, 300MHz):
d 2.32 (s, 3H, –COCH3), 4.14 (s, 3H, –CO2CH3), 4.22 (s,
3H, –CO2CH3), 7.40 (t, J=7.4Hz, 1H, H-6), 7.51 (t,
J=7.3Hz, 1H, H-70), 7.60–7.80 (m, 3H, H-60, H-7, H-8),
8.19 (d, J=7.7Hz, 1H, H-80), 8.26 (d, J=7.8Hz, 1H, H-5),
8.33 (d, J=8.4Hz, 1H, H-50), 8.83 (s, 1H, H-4), 8.98 (s,
1H, H-40), 12.38 (s, 1H, NH); 13C NMR (CDCl3, 75
MHz): 28.17 (–COCH3), 52.79 (–CO2CH3), 58.38
(–CO2CH3), 112.88 (C-8), 115.64 (C-50), 116.50 (C-4),
5. (À)-(1S,3S)-1-(3-Carbomethoxy-1,2,3,4-tetrahydro-b-car-
28
bolinyl)-3-carbomethoxy-b-carboline (5): mp 310–312ꢁC;
½aŠ À13.7 (c 0.165, CHCl3); IR (KBr): 3378, 3320,
D
1738, 1723, 1346, 1262cmÀ1
;
1H NMR (DMSO-d6,
300MHz): d 3.12 (br dd, J=15.2Hz, 3.0Hz, 2H, H-4),
3.67 (s, 3H, –CO2CH3), 3.84 (br s, 1H, NH), 3.90 (s, 3H,
–CO2CH3), 4.39 (br s, 1H, H-3), 6.01 (br s, 1H, H-1), 6.92–
7.01 (m, 2H, H-6, H-7), 7.15 (d, J=6.5Hz, 1H, H-8), 7.29

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B. Pal et al. / Tetrahedron Letters 45 (2004) 6489–6492
119.16 (C-40), 121.46 (2·C, C-6, C-80), 121.93 (C-4b),
13. CCDC-241575 contains the supplementary crystallo-
graphic data for this paper. This data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif,
by emailing data_request@ccdc.cam.ac.uk, or by contact-
ing The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-
336033.
122.30 (C-5), 122.84 (C-4b0), 124.12 (C-70), 129.64 (C-60),
131.08 (C-7), 131.54 (C-4a0), 134.28 (C-4a), 136.32 (C-9a),
136.48 (C-9a0), 137.15 (C-1), 137.84 (C-10), 139.21 (C-8a),
141.74 (C-8a0), 142.13 (C-3), 144.23 (C-30), 165.86
(–CO2CH3), 166.83 (–CO2CH3), 171.41 (–COCH3); EIMS
m/z 492 (M+, 20%), 450 (100), 390 (60), 330 (50).