Unexpected ipso-Substitutions at the β-Carboline Nucleus

Article abstract of DOI:10.1081/SCC-120026305

Minisci-type radical carbamoylation of 1-bromo-β-carboline (1) gives the 3-substituted product in low yield, whereas 1-acetyl-β-carboline (3a) reacts under ipso-substitution of the acetyl group. Cyanations of the N-oxides of 1 and 3a occur under clean ipso-substitution of the groups in 1-position. 1-Methyl derivatives show no tendency to react under ipso-substitution.

Full text of DOI:10.1081/SCC-120026305

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Unexpected ipso-Substitutions at the β-Carboline
Nucleus
Oliver Kast a & Franz Bracher a
a Department Pharmazie, Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität,
Munich, Germany
Version of record first published: 19 Aug 2006.
To cite this article: Oliver Kast & Franz Bracher (2003): Unexpected ipso-Substitutions at the β-Carboline Nucleus, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:22, 3843-3850
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 22, pp. 3843–3850, 2003
Unexpected ipso-Substitutions at the
b-Carboline Nucleus
*
Oliver Kast and Franz Bracher
Department Pharmazie, Zentrum fur Pharmaforschung,
¨
Ludwig-Maximilians-Universitat, Munich, Germany
¨
ABSTRACT
Minisci-type radical carbamoylation of 1-bromo-b-carboline (1)
gives the 3-substituted product in low yield, whereas 1-acetyl-b-
carboline (3a) reacts under ipso-substitution of the acetyl group.
Cyanations of the N-oxides of 1 and 3a occur under clean ipso-
substitution of the groups in 1-position. 1-Methyl derivatives show
no tendency to react under ipso-substitution.
Key Words: b-Carbolines; ipso-Substitution; N-oxides; Minisci
reaction; Cyanation.
*Correspondence: Franz Bracher, Department Pharmazie, Zentrum fur
¨
Pharmaforschung, Ludwig-Maximilians-Universitat, Butenandtstr. 5-13 81377
¨
Munich, Germany; Fax: þ49-89-218077802; E-mail: Franz.Bracher@cup.uni-
muenchen.de.
3843
DOI: 10.1081/SCC-120026305
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3844
Kast and Bracher
b-Carbolines represent a large group of biologically active alkaloids
widespread in nature.[1] The majority of these alkaloids is substituted only
in 1-position, and numerous synthetic approaches to 1-substituted
b-carbolines have been published.[2] In continuation of our work on
biologically active b-carboline alkaloids[3] we focussed our interest on
1,3-disubstituted b-carbolines. Compounds of this type occur in nature
(e.g., the antibiotic pyridindolol[4]) and synthetic b-carbolines with electron
attracting groups in 3-position have been shown to have antifilarial
activity[5] and affinity to brain benzodiazepine receptors.[6]
In order to develop a general access to 1,3-disubstituted b-carbolines,
we planned to start from readily available 1-bromo-b-carboline (1) and
1-acetyl-b-carboline (3a). These building blocks have reactive functional
groups in 1-position, that can be converted to a large number of
substituents using methods developed in our laboratories.[3] For the
introduction of substituents at C-3 without prior activation of this
position we wanted to take advantage from the special reactivites of
the pyridine ring. Protonated pyridines can undergo ring substitution
with nucleophilic radicals on ortho or para position to the ring nitrogen
(Minisci reaction[7]). So we expected that the 1-substituted b-carbolines 1
and 3a should give the desired 3-carbamoyl product on reaction with a
radical generated from formamide. On the other hand pyridine N-oxides
can be converted to 2-cyano derivatives with trimethylsilanecarbonitrile
and diethylcarbamoyl chloride.[8] Thus, b-carbolines 1 and 3a should give
the corresponding 3-cyano derivatives.
Both the carbamoyl and the cyano groups would offer the possibility
for further modification at 3-position.
Scheme 1. Carbamoylations of 1-substituted b-carbolines under Minisci
conditions.

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ipso-Substitutions at the b-Carboline Nucleus
3845
In the present communication we describe unexpected results of our
experiments aimed at the introduction of new substituents at C-3.
RESULTS AND DISCUSSION
Treatment of 1-bromo-b-carboline (1)[3e] with formamide, FeSO4, and
tert-butylhydroperoxide under standard conditions[9] gave the expected
3-carbamoyl derivative 2 in very poor yield. Large amounts of starting
material were recovered. In contrast, 1-acetyl-b-carboline (3a)[3b,3f] did
not give any 3-carbamoyl derivative. To our surprise we isolated the
carboxamide 4 in 60% yield. 4 is a natural product isolated from several
plants like Nauclea diderrichii, Odyendea gabonensis, Neisosperma kilneri,
Ailanthus altissima, and Ailanthus malabarica.[10a–e] So this reaction gave a
clean ipso-substitution of the acetyl group in 1-position. Few examples of
ipso-substitutions of strongly electron-withdrawing substituents (mainly
nitro and acyl groups) at aromatic and heteroaromatic ring systems by
nuclephilic alkyl radicals have been described in literature.[11]
Scheme 2. Cyanations of 1-substituted b-carboline-N-oxides.

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Kast and Bracher
In order to explore the scope of this reaction, we also reacted harman
(1-methyl-b-carboline) with formamide under the conditions used before,
but there was absolutely no conversion. On the other hand, norharman
(3b) gave the expected 1-substituted product 4 in 80% yield. This is in
accordance with our former finding, that C-1 is the preferred position for
substitution of b-carbolines with nucleophilic radicals.[3f]
For the ring cyanation experiments, 1 and 3a were first converted to
the corresponding N-oxides 7 and 5a under standard conditions.
Reactions of these N-oxides with trimethylsilanecarbonitrile and diethyl-
carbamoyl chloride[8] gave the same product, 1-cyano-b-carboline (6). So
here again clean ipso-substitutions of substituents had occurred. In con-
trast to the experiments described above, not only the acetyl group, but
also the bromo substituent was eliminated. In order to control, whether the
N-oxide group was really involved in the replacement of bromine, we also
reacted 1-bromo-b-carboline (1) with trimethylsilanecarbonitrile, but no
conversion was observed at all.
As could be expected from these results, cyanation of norharman-
N-oxide (5b)[12] gave 6 again. The yield was 90% and so our methodology
represents a very short and effective approach to this important building
block for alkaloid synthesis.[3d,13]
Finally, we also reacted harman-N-oxide (8)[14] with trimethylsilane-
carbonitrile and diethylcarbamoyl chloride. We obtained a mixture of the
3-cyano product 9 and the carbamate 10. Product 10 obviously results
from reaction of the N-oxide with the carbamoyl chloride according to
the Boekelheide reaction[15] without involvement of trimethylsilane-
carbonitrile. In the original article[8] no substitutions at 2-methyl groups
of pyridines have been described. In analogy to the radical reactions,
1-alkyl-b-carbolines show no tendency to undergo ipso-substitution at
1-position.
In conclusion, we have found surprising ipso-substitutions of
1-substitited b-carbolines and their N-oxides under different reaction
conditions. Appropriate leaving groups (acetyl, bromine) can be
substituted by carbamoyl or cyano groups. 1-Alkyl groups do not show
this reactivity. In addition, the interesting building blocks 4 and 6 were
obtained from norharman in unprecedented efficiency.
EXPERIMENTAL
General
Melting points were determined with Buchi B-50 apparatus. Infrared
¨
spectra were run on a Perkin Elmer IR-881 infrared spectrometer

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ipso-Substitutions at the b-Carboline Nucleus
3847
as KBr plates. 1H NMR and 13C NMR spectra were recorded on a
Joel GSX 400 and Joel GSX 500 in DMSO-d6 or CDCl3 solution.
Chemical shifts are expressed in ppm with reference to TMS as an inter-
nal standard. Mass spectra were measured on a Hewlett Packard 5989 A
Mass Spectrometer. Flash chromatography was carried out using silica
gel (Merck, Kieselgel 60).
General Procedure for Carbamoylation
One mmol of the b-carboline derivative is suspended at room tem-
perature in a mixture of 5 mL formamide and 0.5 mL conc. sulfuric acid
by means of ultrasound irradiation. Then a solution of FeSO4 ꢀ 7 H2O
(420 mg, 1.5 mmol) in 1 mL water and tert-BuOOH (70% solution in
water; 0.205 mL, 1.5 mmol) are added simultaneously over a period of
10 min and stirring is continued for 15 min. The addition of t-BuOOH
and FeSO4 ꢀ 7 H2O can be repeated until there is no starting material left
(TLC control). The reaction mixture is poured into water (100 mL) fol-
lowed by neutralization with K2CO3 and extraction with ethyl acetate
(3 ꢀ 50 mL). The combined organic layers are washed twice with brine
(100 mL), dried with Na2SO4 and evaporated. The residue is purified by
flash column chromatography (ethyl acetate/ hexanes 1:1).
1-Carbamoyl-b-carboline (4) from norharman (3b). Yield: 169 mg
(80%); m.p. 228ꢁC (Lit.[10d] 230ꢁC); analytical data in accordance
with Lit.[10e]
1-Carbamoyl-b-carboline (4) from 1-acetyl-b-carboline (3a). Yield:
127 mg (60%).
1-Bromo-3-carbamoyl-b-carþboline (2). Yield: 20 mg (7%). M.p.
303ꢁC. MS (m/z, %): 291 (M , 80), 289 (Mþ,74), 248 (61), 246 (67),
182 (46), 166 (66). IR, ꢀ (cmꢂ1): 3443, 3303, 2924, 1692, 1629, 1580,
1
1535, 1375, 1248, 1202, 745. H NMR (DMSO-d6): 12.14 (s, 1 H, N-H),
8.86 (s, 1 H, 4-H), 8.38 (d, J ¼ 7.9 Hz, 1 H, 5-H), 7.91 (s, 1 H, N-H), 7.68
(d, J ¼ 8.0 Hz, 1 H, 8-H), 7.62 (m, 1 H, 7-H), 7.57 (s, 1 H, N-H), 7.33 (m, 1
H, 6-H). 13C NMR (DMSO-d6): 166.1 (C¼O), 141.6 (C-8a), 141.0 (C-3),
136.5 (C-9a), 130.1 (C-4a), 129.7 (C-7), 123.1 (C-5), 122.6 (C-1),122.0
(C-4b), 121.3 (C-6), 114.9 (C-4), 113.2 (C-8).
General Procedure for N-Oxidation
One mmol of the b-carboline derivative is dissolved in a mixture of
5 mL chloroform and 5 mL ethanol and 3 mmol (670 mg) of 3-chloroper-

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3848
Kast and Bracher
oxybenzoic acid is added. The reaction mixture is refluxed for 2 h, then
allowed to cool to room temperature. Three milliliters of 0.1 M NaOH
are added and stirring is continued for 30 min. The organic layer is dried
with Na2SO4 and the solvents are evaporated. The residue is purified by
flash column chromatography (ethyl acetate/MeOH 95:5).
Norharman-2-oxide (5b). Yield: 156 mg (85%). M.p. 256ꢁC (Lit.[12]
268–271ꢁC).
Harman-2-oxide (8). Yield: 184 mg (93%). M.p. 237ꢁC (Lit.[14]
182–184ꢁC, Lit.[12] 246–248ꢁC).
1-Acetyl-b-carboline-2-oxide (5a). Yield: 57 mg (25%). M.p. 180ꢁC.
MS (m/z, %): 226 (Mþ, 15), 210 (57), 168 (100), 140 (28); IR, ꢀ (cmꢂ1):
3315, 1653, 1427, 1319, 1185, 1040, 735. 1H NMR (DMSO-d6): 11.80 (s, 1
H, N-H), 8.31 (d, J ¼ 6.5 Hz, 1 H, 3-H), 8.17 (m, 2 H, 4-H and 5-H), 7.71
(d, J ¼ 8.0 Hz, 1 H, 8-H), 7.48 (m, 1 H, 7-H), 7.27 (m, 1 H, 6-H), 2.84 (s, 3
H, CH3). 13C NMR (DMSO-d6): 196.5 (C¼O), 142.5 (C-8a), 136.4 (C-1),
132.5 (C-4), 131.5 (C-9a), 127.9 (C-7), 121.3–121.2 (C-4a, C-5, C-6), 120.8
(C-4b), 119.9 (C-3), 113.2 (C-8), 32.7 (CH3).
1-Bromo-b-carboline-2-oxide (7). Yield: 150 mg (57%). M.p. 254ꢁC.
MS (m/z, %): 264 (Mþ, 28), 262 (Mþ, 25), 248 (100), 246 (100), 167 (96),
155 (38), 140 (73). IR, ꢀ (cmꢂ1): 3060, 1606, 1480, 1455, 1426, 1318, 1194.
1H NMR (DMSO-d6): 11.90 (s, 1 H, N-H), 8.28 (d, J ¼ 6.4 Hz, 1 H, 3-H),
8.17 ( d, J ¼ 8.0 Hz, 1 H, 5-H), 8.15 (d, J ¼ 6.4 Hz, 1 H, 4-H), 7.60 (d,
J ¼ 8.0 Hz, 1 H, 8-H), 7.51 (m, 1 H, 7-H), 7.28 (m, 1 H, 6-H). 13C NMR
(DMSO-d6): 141.5 (C-8a), 137.2 (C-9a), 131.9 (C-3), 127.5 (C-7), 121.5
(C-4b), 121.4 (C-5), 120.6 (C-6), 119.1 (C-4a), 116.1 (C-1), 115.5 (C-4),
112.2 (C-8).
General Procedure for Cyanation
To a stirred solution of 1 mmol of the b-carboline-2-oxide derivative in
10 mL dry dioxane are added 3 mmol (298 mg) of trimethylsilane-
carbonitrile and 3 mmol (407 mg) of diethylcarbamoylchloride. The
mixture is heated to 80ꢁC and stirred under nitrogen for 16 h. After cooling
to room temperature 3 mmol (834 mg) of FeSO4 ꢀ 7 H2O in 1 mL H2O and
1 mL of 0.1 M NaOH is added and stirring is continued for 15 min. The
mixture is filtered through a celite pad and washed with ethyl acetate. The
filtrate is dried with Na2SO4 and evaporated. The residue is purified by
flash column chromatography (ethyl acetate/hexanes 1:4).
1-Cyano-b-carboline (6) from norharman-2-oxide (5b). Yield: 174 mg
(90%). M.p. 222ꢁC (Lit.[3d] 226ꢁC); analytical data in accordance
with Lit.[3d]

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ipso-Substitutions at the b-Carboline Nucleus
3849
1-Cyano-b-carboline (6) from 1-acetyl-b-carboline-2-oxide (5a). Yield:
100 mg (50%).
1-Cyano-b-carboline (6) from 1-bromo-b-carboline-2-oxide (7). Yield:
115 mg (60%).
3-Cyanoharman (9) from harman-2-oxide (8). Yield: 52 mg (25%).
M.p. 188ꢁC. MS (m/z, %): 207 (Mþ, 100), 179 (27), 105 (12). IR,
ꢀ (cmꢂ1): 3317, 2221, 1625, 1504, 1407, 1307, 1238, 735. 1H NMR
(DMSO-d6): 12.21 (s, 1 H, N-H), 8.64 (s, 1 H, 4-H), 8.34 (d, J ¼ 8.0 Hz,
1 H, 5-H), 7.70 (m, 2 H, 7-H, and 8-H), 7.38 (m, 1 H, 6-H). 13C NMR
(DMSO-d6): 147.9 (C-9a), 142.2 (C-4), 141.4 (C-8a), 134.1 (C-1), 130.1
(C-7), 126.0 (C-4a), 121.8 (C-5), 120.9 (C-6), 119.3 (C-4b), 118.0 ðC ꢃ NÞ,
113.2 (C-8), 97.7 (C-3), 21.4 (CH3).
N,N-Diethyl-9H-pyrido[3,4-b]indol-1-ylmethylcarbamate (10) from
harman-2-oxide (8). Yield: 193 mg (65%). M.p. 118ꢁC. MS (m/z, %):
297 (Mþ, 35), 197 (100), 181 (57), 154 (26), 127 (13), 100 (17). IR,
ꢀ (cmꢂ1): 3299, 2976, 1671, 1627, 1428, 1274, 1173, 1072, 997, 751.
1H NMR (CDCl3): 10.32 (s, 1 H, N-H), 8.39 (d, J ¼ 5.0 Hz, 1 H, 3-H),
8.07 (d, J ¼ 7.5 Hz, 1 H, 5-H), 7.92 (d, J ¼ 5.0 Hz, 1 H, 4-H), 7.52 (m, 2 H,
8-H, and 7-H), 7.24 (m, 1 H, 6-H), 5.68 (s, 2 H, CH2-O), 3.32
(q, J ¼ 7.0 Hz, 2 H, N-CH2), 3.21 (q, J ¼ 7.0 Hz, 2 H, N-CH2), 1.11
(t, J ¼ 7.0 Hz, 3 H, CH3), 1.01 (t, J ¼ 7.0 Hz, 3 H, CH3). 13C NMR
(CDCl3): 157.2 (C¼O), 140.6 (C-8a), 139.6 (C-1), 138.2 (C-3), 135.3
(C-9a), 129.7 (C-4a), 128.5 (C-7), 121.6 (C-5), 121.5 (C-4b), 119.8
(C-6), 115.3 (C-4), 112.0 (C-8), 66.6 (CH2-O), 42.3 (CH2-N), 41.6
(CH2-N), 13.9 (CH3), 13.4 (CH3).
ACKNOWLEDGMENT
We thank the Fonds der Chemischen Industrie for financial support.
REFERENCES
1. (a) Allen, J.R.; Holmstedt, B.R. Phytochemistry 1980, 19, 1573; (b)
Abramovitch, R.A.; Spenser, I.D. Adv. Het. Chem. 1964, 3, 79.
2. Love, B.E. Org. Prep. Proced. Int. 1996, 28, 1.
3. (a) Bracher, F.; Hildebrand, D. Liebigs Ann. Chem. 1992, 1315;
(b) Bracher, F.; Hildebrand, D. Liebigs Ann. Chem. 1993, 837;
(c) Bracher, F.; Hildebrand, D. Liebigs Ann. Chem. 1993, 1335;
(d) Bracher, F.; Hildebrand, D.; Ernst, L. Arch. Pharm. (Weinheim)
1994, 327, 121; (e) Bracher, F.; Hildebrand, D. Tetrahedron 1994,

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3850
Kast and Bracher
50, 12329; (f ) Bracher, F.; Daab, J. Synth. Commun. 1995, 25, 1557,
and references cited therein.
4. Wu, G.; Yamanaka, E.; Cook, J. Heterocycles 1978, 9, 175.
5. Srivastava, S.K.; Agarwal, A.; Chauhan, P.M.S.; Agarwal, S.K.;
Bhaduri, A.P.; Singh, S.N.; Fatima, N.; Chatterjee, R.K. J. Med.
Chem. 1999, 42, 1667.
6. Cain, M.; Weber, R.W.; Guzman, F.; Cook, J.R.; Barker, S.A.;
Rice, K.C.; Crawley, J.N.; Paul, S.M.; Skolnick, P.J. Med. Chem.
1982, 25, 1081.
7. a) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489;
(b) Minisci, F. Synthesis 1973, 1.
8. Fife, W.K. J. Org. Chem. 1983, 48, 1375.
9. Minisci, F.; Gardini, G.P. Tetrahedron Lett. 1970, 15.
10. (a) McLean, S.; Murray, D.G. Can. J. Chem. 1972, 50, 1478;
(b) Forgacs, P.; Provost, J.; Touche, A. Planta Medica 1982, 46,
187; (c) Batchily, F.; Mehri, H.; Plat, M.; Sevenet, T. Ann.
Pharm. Franc. 1985, 43, 513; (d) Ohmoto, T.; Koike, K. Chem.
Pharm. Bull. 1984, 32, 170; (e) Joshi, B.S.; Kamat, V.N.; Gawat,
D.H. Heterocycles 1977, 7, 193.
11. (a) Traynham, J.G. Chem. Rev. 1979, 79, 323; (b) Tiecco, M. Acc.
Chem. Res. 1980, 13, 51.
12. Ohmoto, T.; Nikaido, T.; Koike, K.; Kohda, K.; Sankawa, U.
Chem. Pharm. Bull. 1988, 36, 4588.
13. (a) Rinehart, K.L.; Kobyashi, J.; Harbour, G.C.; Gilmore, J.;
Mascal, M.; Holt, T.G.; Shield, L.S.; Lafargue, F. J. Am. Chem.
Soc. 1987, 109, 3387; (b) Veeraraghawan, S.; Popp, F.D. J.
Heterocyclic Chem. 1981, 18, 909; (c) Burm, B.E.A.; Blokker, P.;
Jongmans, E.; Van Kampen, E.; Wanner, M.J.; Koomen, G.-J.
Heterocycles 2001, 55, 495.
14. Dachriyanus; Arbain, D.; Putra, D.P.; Sargent, M.V.; Susila, R.;
Wahyuni, F.S. Aust. J. Chem. 2000, 53, 221.
15. Boekelheide, V.; Linn, W.J. J. Am. Chem. Soc. 1954, 76, 1286.
Received in Poland May 10, 2003