Synthesis of 6-substituted pyrido[2,3-b]indoles by electrophilic substitution

Article abstract of DOI:10.1055/s-2007-985566

Regioselective electrophilic aromatic substitutions, acylation, bromination, and formylation, of unprotected pyrido[2,3-b]indole (α-carbolines) at the C-6 position are described. Alternative conditions for the nitration were investigated, which led to the unexpected appearance of the minor C-8 isomer. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-985566

LETTER
2237
Synthesis of 6-Substituted Pyrido[2,3-b]indoles by Electrophilic Substitution
a
a
b
b
a
S
C
ynthesis of 6-Su
é
bstituted P
d
yrido[2, 3-
b
]i
r
ndoles ic Schneider, David Gueyrard, Florence Popowycz, Benoît Joseph, Peter G. Goekjian*
a
ICBMS, CNRS, UMR5246, Laboratoire Chimie Organique 2 – Glycochimie, Université de Lyon, Université Lyon 1, Bât. 308, CPE
Lyon, 43, Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax +33(4)72448349; E-mail: peter.goekjian@univ-lyon1.fr
b
ICBMS, CNRS, UMR5246, Laboratoire Chimie Organique 1, Université de Lyon, Université Lyon 1, Bât. 308, CPE Lyon, 43, Bd du 11
Novembre 1918, 69622 Villeurbanne Cedex, France
Received 14 May 2007
Dedicated to Prof. Yoshito Kishi on the occasion of his 70 birthday
th
es, the substitution is incorporated prior to the formation
of the a-carboline ring system, resulting in lengthy syn-
thetic routes or in limitations in the availability of substi-
tuted starting materials. These approaches are thus based
Abstract: Regioselective electrophilic aromatic substitutions, acy-
lation, bromination, and formylation, of unprotected pyrido[2,3-
b]indole (a-carbolines) at the C-6 position are described. Alter-
native conditions for the nitration were investigated, which led to
the unexpected appearance of the minor C-8 isomer.
5–7
8
9
on substituted indole, arylalkyne or arylalkene, oxo-
indole,1 azaindole, or pyridine
0,11
12
13,14
starting materials.
Key words: electrophilic aromatic substitutions, regioselectivity,
heterocycles, acylations, halogenation, azacarbazole
O2N
Me
N
O
Me
Me
N
S
H
Pyrido[2,3-b]indoles (a-carbolines) display a number of
O
O
1
interesting biological properties. For example, natural
products such as grossularine-1 and grossularine-2
HN
N
N
N
H
(
Figure 1), marine alkaloids isolated from Dendrodoa
I
II
grossularia in 1989, have attracted considerable interest
since the report of their antiproliferative activity. Similar-
Figure 2 a-Carboline CDK inhibitors.
2
ly, mescengricin, isolated from Streptomyces griseo-
flavus, was found to protect neuronal cells by suppressing
the excitotoxicity induced by L-glutamate (Figure 1).3
Surprisingly, the direct functionalization of the a-carbo-
line skeleton has been studied only briefly.4 Nitration at
the C-6 position was described in 1966 by Saxena using
concentrated nitric acid.1 Stephenson later prepared the
C-6 halogenated compound via the derived diazonium
b,15
5a
NMe2
N
NMe2
N
15b
HN
HN
salt. More recently, reports on the bromination, nitra-
O
O
15d
tion and carboxylation of a-carbolines by Dininno et al.
and Sennhenn et al.4b have appeared in the patent litera-
ture. A more detailed investigation of the electrophilic
aromatic substitution of the pyrido[2,3-b]indole system
thus seemed warranted as a simple and flexible access to
substituted analogues. This paper describes new routes to
N
N
N
N
H
N
H
H
OH
grossularine-1
grossularine-2
OH
O
6
-acyl-, 6-bromo-, 6-nitro- and 6-carboxaldehyde pyri-
OH
O
N
O
do[2,3-b]indoles.
The modified Graebe–Ullmann synthesis was chosen as a
convenient route to the starting pyrido[2,3-b]indole
nucleus (Scheme 1).16 This reaction can be realized in
polyphosphoric acid (PPA) under photolysis,1
mescengricin
O
HO
Me
N
6b
H
HO
thermal,1 or microwave irradiation
6c
16d
conditions. As
Figure 1 a-Carboline natural products.
previously described, yields depend on the nature of the
substituents on the pyridylbenzotriazole intermediate.1
The desired pyrido[2,3-b]indole 4a was prepared accord-
ing to Alvarez–Builla’s procedure,1 followed by protec-
tion of the nitrogen. The Graebe–Ullmann reaction allows
readily for substitution on the pyridine ring, via substi-
tuted pyridines, but substitution on the benzene ring is
more troublesome, as substituted benzotriazole starting
materials are not widely available and lead to regio-
isomeric mixtures of a-carbolines.1
6b,c
Recently, the syntheses of substituted a-carbolines I and
II with potent cyclin-dependent kinase (CDK) inhibitory
activities have been disclosed (Figure 2). Much effort has
6d
4
been devoted to the synthesis of a-carbolines. In most cas-
SYNLETT 2007, No. 14, pp 2237–2241
0
3
.0
9
.2
0
0
7
Advanced online publication: 13.08.2007
DOI: 10.1055/s-2007-985566; Art ID: G15207ST
6b,d
©
Georg Thieme Verlag Stuttgart · New York

2
238
C. Schneider et al.
LETTER
Cl
lated intermediate 4c. The regiochemistry of 5a could be
assigned unambiguously based on the three-bond correla-
tions from the carbonyl carbon to the H-5 proton, from the
H-5 proton to the C-4a carbon, and from the C-4a carbon
to the H-3 proton in the heteronuclear multiple bond
correlation spectra (HMBC).
N
N
N
i
ii
N
N
N
+
N
H
N
N
R
1
2
N
3
The synthesis of a series of 6-acylated a-carbolines 6–8
4
a: R = H
4b: R = SO2Ph
c: R = Ac
iii
(Scheme 3) was achieved under these conditions in good
iv
yields (71–90%).1
9–21
Reactions were realized at room
4
temperature or at reflux depending on the electrophilic
character of the acyl chloride. Structure assignments were
based on NMR data, and on the chemical correlation of
the acid 7 to the known ethyl ester derivative prepared by
an independent route.4
Scheme 1 Reagents and conditions: (i) 150–160 °C, 2 h, 77%
solvent-free); (ii) PPA, 150–160 °C, 2 h, 36%; (iii) NaH, PhSO Cl,
(
2
THF, r.t., 12 h, 63%; (iv) NaH, Ac O, DMF, r.t., 12 h, 75%.
2
a
We first studied the acetylation reaction of the a-carboline
scaffold (4a–c) by screening various parameters (Scheme
O
O
2
). We decided to work with an excess of Lewis acid (4.5
R
H
equiv), according to a recent procedure for the acylation
i
ii
1
7
4a
of 7-azaindole developed by Wang et al. We investi-
gated the nature of the Lewis acid (SnCl or AlCl ), the
N
N
4
3
N
H
iii
N
solvent (CS , CHCl or CH Cl ), the temperature, and the
H
2
3
2
2
9
presence and the nature of the protective group on the
central nitrogen of the carboline (Table 1).
6, 7, 8
Br
N
O
N
H
4
5
Me
3
10
4a
i
2
7
Scheme 3 Reagents and conditions: (i) AlCl (4.5 equiv), RCOCl
3
N
N
8
N
N
R
(2 equiv; MeO COCl, (COCl) , or PhCOCl), CH Cl , r.t. or reflux,
2
2
2
2
R
2–4 h, see Table 2; (ii) (a) AlCl (7 equiv), MeOCHCl (3 equiv),
3
2
CH Cl , –78 °C to r.t., 12 h; (b) H O, 46%; (iii) Br (1.1 equiv),
4a: R = H, 4b: R = SO2Ph, 4c: R = Ac
5a: R = H
2
2
2
2
CH Cl , r.t., 1 h, 91%.
2
2
Scheme 2 Reagents and conditions: (i) Lewis acid (4.5 equiv),
MeCOCl (2 equiv), solvent, reflux, 4 h, see Table 1.
Table 2 Acylation Reaction on a-Carbolines
Table 1 Optimization of the Acetylation Reaction on a-Carbolines
Compound
COR
COCO Me
T (°C)
r.t.
Yield (%)
6
7
8
90
71
78
Entry
Compound Lewis acid Solvent
Yield
SMa
2
CO H
r.t.
1
2
3
4
5
4a
4b
4a
4a
4b
4c
SnCl4
SnCl4
SnCl4
CS2
CS2
2
COPh
Reflux
SM
CH Cl
SM
2
2
The formylation of pyrido[2,3-b]indole 4a was investigat-
ed. While the experimental conditions described by Vils-
meier–Haack22 and Duff did not afford the desired
formylated a-carboline, the use of a,a-dichloromethyl
AlCl3
CH Cl
2
2
5a (78%)
degradation
SM
23
AlCl3
CHCl3
6
AlCl3
CH Cl
2
2
methyl ether (MeOCHCl ) associated with a Lewis acid
2
2
2a
a
according to the Rieche procedure allowed us to obtain
the desired compound. Thus, treatment of 4a with an ex-
cess of AlCl in CH Cl at –78 °C followed by the addition
of three equivalents of MeOCHCl afforded the pyri-
do[2,3-b]indole-6-carboxaldehyde (9) in a moderate 46%
yield (Scheme 3). The halogenation of 4a was investi-
gated in order to extend our methodology to the prepara-
tion of a larger range of 6-substituted a-carbolines. The
treatment of 4a with a slight excess of bromine in CH Cl2
at room temperature gave the compound 10 in 91% yield
in one hour (Scheme 3). Finally, we investigated alter-
native conditions for the nitration of 4a (Scheme 4). While
the use of HNO has been described for the nitration of the
SM: Starting material.
3
2
2
Acetylation at the C-6 position was observed only with
the unprotected a-carboline 4a, using 4.5 equivalents of
2
AlCl and two equivalents of acetyl chloride in refluxing
24
3
CH Cl (Table 1, entry 4). These conditions afforded 5a
2
2
1
8
in a good yield (78%). The remaining conditions were
either too mild, or led to decomposition of the protected a-
carboline. The fact that the unprotected a-carboline gave
better results than the protected forms, in addition to being
of practical significance, suggests that the reactive species
2
25
1
7
may be an aluminum complex, rather than the N-acety-
3
Synlett 2007, No. 14, 2237–2241 © Thieme Stuttgart · New York

LETTER
Synthesis of 6-Substituted Pyrido[2,3-b]indoles
2239
1
5
a-carboline scaffold at the C-6 position, we found that References and Notes
2
6
nitronium tetrafluoroborate (BF NO ) or cerium(IV)
4
2
(
1) (a) Bolton, D.; Forbes, I. T.; Hayward, C. J.; Piper, D. C.;
2
7
ammonium nitrate (CAN) also allowed the nitration of
pyrido[2,3-b]indole. The use of CAN as nitrating agent
afforded, after Boc protection, compounds 11 and 12 in a
higher overall yield of 83% from 4a. Nevertheless, two
regioisomers at the C-6 and C-8 positions were obtained
in ca. 3.5:1 ratio with both reagents. It is interesting to
note that Saxena reported a highly regioselective nitration
Thomas, D. R.; Thompson, M.; Upton, N. Bioorg. Med.
Chem. Lett. 1993, 3, 1941. (b) Love, B. E. Top. Heterocycl.
Chem. 2006, 2, 93.
(2) Moquin-Pattey, C.; Guyot, M. Tetrahedron 1989, 45, 3445.
(
3) Kim, J.-S.; Shinya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1997, 38, 3431.
4) (a) Joseph, B.; Meijer, L.; Liger, F. Fr. Patent, FR 28976377,
(
2006; Chem. Abstr. 2006, 144, 390900. (b) Sennhenn, P.;
1
5a
of 4a using nitric acid at 0 °C. Repeating this reaction
at room temperature led to the appearance of a small
amount of the minor 8-nitro isomer. The lower selectivity
observed with BF NO and CAN may thus reflect a tem-
Mantoulidis, A.; Treu, M.; Tontsch-Grunt, U.; Spevak, W.;
McConnell, D.; Schoop, A.; Brückner, R.; Jacobi, A.;
Guertler, U.; Schnapp, G.; Klein, C.; Himmelsbach, F.;
Pautsch, A.; Betzemeier, B.; Herfurth, L.; Mack, J.;
Wiedenmayer, D.; Bader, G.; Reiser, U. Int. Appl., WO
2006131552, 2006; Chem. Abstr. 2006, 146, 62695.
5) (a) Levacher, V.; Boussad, N.; Dupas, G.; Bourguignon, J.;
Queguiner, G. Tetrahedron 1992, 48, 831. (b) Molina, P.;
Fresneda, P. M.; Sanz, M. A. Tetrahedron Lett. 1997, 38,
4
2
perature effect, although other factors may also play a
2
8
role. Protection of the nitrogen atom was necessary for
the separation of the two regioisomers due to solubility
(
1
13
problems. NMR data ( H, C NMR, HSQC, COSY,
HMBC) showed that N-Boc-6-nitro-a-carboline 11 was
the major product. Finally, treatment of 11 and 12 with
TFA in refluxing CH Cl led to the deprotected com-
6909. (c) Molina, P.; Fresneda, P. M.; Sanz, M. A.; Foces-
Foces, C.; Ramirez de Arellano, M. C. Tetrahedron 1998,
54, 9623.
2
2
2
9
30
(6) Tanaka, K.; Kitamura, M.; Narasaka, K. Bull. Chem. Soc.
Jpn. 2005, 78, 1659.
(
pounds 13 and 14, respectively, in 79% and 80%
yields.
7) (a) Molina, P.; Fresneda, P. Synthesis 1989, 878.
b) Bonini, C.; Funicello, M.; Spagnolo, P. Synlett 2006,
574.
(
1
NO
2
(8) (a) Tahri, A.; Buysens, K. J.; Van Der Eycken, E. V.;
Vandenberghe, D. M.; Hoornaert, G. J. Tetrahedron 1998,
i or ii
54, 13211. (b) Zhang, Q.; Shi, C.; Zhang, H. R.; Wang, K. K.
4a
+
N
N
N
J. Org. Chem. 2000, 65, 7977. (c) Schmittel, M.;
Rodriguez, D.; Steffen, J.-P. Molecules 2000, 5, 1372.
9) (a) Saito, T.; Ohmori, H.; Furuno, E.; Motoki, S. J. Chem.
Soc., Chem. Commun. 1992, 22. (b) Molina, P.; Alajarin,
M.; Vidal, A.; Sanchez-Andrada, P. J. Org. Chem. 1992, 57,
N
NO
2
Boc
12
Boc
(
1
1
iii
iii
NO
2
929.
(
(
(
10) Barun, O.; Patra, P. K.; Ila, H.; Junjappa, H. Tetrahedron
Lett. 1999, 40, 3797.
11) Beccalli, E. M.; Clerici, F.; Marchesini, A. Tetrahedron
N
N
N
N
H
H
NO
2
2001, 57, 4787.
1
3
14
12) Joseph, B.; Da Costa, H.; Mérour, J.-Y.; Léonce, S.
Scheme 4 Reagents and conditions: (i) BF NO (2 equiv), tetra-
Tetrahedron 2000, 56, 3189.
4
2
methylene sulfone (0.5 M), 150 °C, 12 h, then Boc O (1.1 equiv),
DMAP, MeCN, r.t., 12 h, 11 (55%), 12 (15%); (ii) CAN (2 equiv),
(13) (a) Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.
Tetrahedron 1993, 49, 49. (b) Achab, S.; Guyot, M.; Potier,
P. Tetrahedron Lett. 1993, 34, 2127.
(14) Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin
Trans. 1 1999, 1505.
2
MeCN (0.5 M), reflux, 12 h, then Boc O (1.1 equiv), DMAP, MeCN,
2
r.t., 12 h, 11 (63%), 12 (20%); (iii) TFA, CH Cl , reflux, 2 h, 13
2
2
(
79%), 14 (80%).
(
15) (a) Saxena, J. P. Indian J. Chem. 1966, 4, 148.
b) Stephenson, L.; Warburton, W. K. J. Chem. Soc. C 1970,
355. (c) Wieczorek, J.; Peczynska-Czoch, W.; Mordarski,
(
1
In summary, we have developed efficient regioselective
acylation, formylation, bromination and nitration at the C-
M.; Kaczmarek, L.; Nantka-Namirski, P. Arch. Immunol.
Ther. Exp. 1986, 34, 315. (d) Dininno, F. P.; Guthikonda, R.
N.; Meurer, L. C. US Patent, US 5532261, 1996; Chem.
Abstr. 1996, 125, 167688.
6
position of pyrido[2,3-b]indoles. These methods permit
the preparation of various 6-substituted a-carbolines in
only three steps from 2-chloropyridines.
(
16) (a) Semenov, A. A.; Tolstikhina, V. V. Chem. Heterocycl.
Compd. (Engl. Transl.) 1984, 20, 345. (b) Mehta, L. K.;
Parrick, J.; Payne, F. J. Chem. Soc., Perkin Trans. 1 1993,
Acknowledgment
1261. (c) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O.
The authors thank the ‘Ministère de la Recherche et de l’Enseigne-
ment Supérieur’ for a fellowship (C.S.). Financial support from the
European Union (Contract No LSHB-CT-2004-503467) is grate-
fully acknowledged.
V. Chem. Rev. 1998, 98, 409. (d) Vera-Luque, P.; Alajarin,
R.; Alvarez-Builla, J.; Vaquero, J. J. Org. Lett. 2006, 8, 415.
17) Zhang, Z.; Yang, Z.; Wong, H.; Zhu, J.; Meanwell, N. A.;
Kadow, J. F.; Wang, T. J. Org. Chem. 2002, 67, 6226.
(
(
18) Typical Procedure for Acylation: At r.t. and under an inert
atmosphere, AlCl (714 mg, 5.36 mmol, 4.5 equiv) and
3
acetyl chloride (178 mL, 2.38 mmol, 2 equiv) were added to
a suspension of 4a (0.2 M, 200 mg, 1.19 mmol) in anhyd
CH Cl . The mixture was stirred at reflux until completion
2
2
Synlett 2007, No. 14, 2237–2241 © Thieme Stuttgart · New York

2
240
C. Schneider et al.
LETTER
of the reaction (monitored by TLC). In the case of methyl
oxalyl chloride and oxalyl chloride, the chloride was added
as a 50% solution in CH Cl and the reaction was stirred at
(C), 115.9 (CH), 115.5 (C), 111.1 (CH). MS (ESI): m/z = 273
+
[M + H ]. Anal. Calcd for C H N O: C, 79.40; H, 4.44; N,
1
8
12
2
10.29. Found: C, 79.48; H, 4.44; N, 10.29.
2
2
r.t. The resulting mixture was then cautiously quenched at
°C with H O. The mixture was extracted with a mixture of
EtOAc–DMF (99:1). The resulting organic layer was
(22) (a) Mayer, S.; Joseph, B.; Guillaumet, G.; Mérour, J.-Y.
Synthesis 2002, 1871. (b) Lee, T. H.; Tong, K. L.; So, S. K.;
Leung, L. M. Synth. Met. 2005, 155, 116.
0
2
washed with a sat. aq NaHCO solution and brine, dried over
(23) Plug, J. M.; Koomen, G.-J.; Pandit, U. Synthesis 1992, 1221.
(24) Typical Procedure and Analytical Data for Compound 9:
3
MgSO , filtered, and solvents were removed under reduced
4
pressure. Trituration of the crude residue from MeOH
At –78 °C and under an inert atmosphere, AlCl (714 mg,
3
followed by filtration afforded 6-acetylpyrido[2,3-b]indole
5.36 mmol, 4.5 equiv) was added portionwise to a
5
a (168 mg) as a white solid. The filtrate was evaporated and
purified by flash chromatography [gradient: EtOAc–PE
1:1) → EtOAc] to give additional 5a (26 mg); yield: 78%;
mp 242 °C (MeOH). IR (KBr): 3045, 1668, 1602, 1571,
suspension of 4a (0.02 M, 200 mg, 1.19 mmol) in anhyd
CH Cl . After stirring for 5 min, a,a-dichloromethyl methyl
ether (318 mL, 3.57 mmol, 3 equiv) was added dropwise to
the mixture. The reaction mixture was stirred at –78 °C and
then allowed to warm to r.t. for 12 h. The resulting mixture
2
2
(
–
1 1
1496, 1468, 1246, 763, 710 cm . H NMR (300 MHz,
DMSO-d ): d = 12.21 (br s, 1 H, NH), 8.90 (d, J = 1.5 Hz, 1
was then cautiously quenched at 0 °C with H O and
6
2
H, H-5), 8.67 (dd, J = 1.7, 7.7 Hz, 1 H, H-4), 8.47 (dd, J =
extracted with a mixture of EtOAc–DMF (99:1). The
combined organic layers were washed with a sat. aq
NaHCO solution, dried with MgSO , filtered and
1
7
.7, 4.9 Hz, 1 H, H-2), 8.08 (dd, J = 1.5, 8.5 Hz, 1 H, H-7),
.56 (d, J = 8.5 Hz, 1 H, H-8), 7.29 (dd, J = 4.9, 7.7 Hz, 1 H,
3
4
1
3
H-3), 2.67 (s, 3 H, Me). C NMR (75 MHz, DMSO-d ): d =
evaporated under reduced pressure. The crude residue was
purified by flash chromatography (EtOAc–PE, 1:1) to afford
9 (100 mg, 46%) as a white solid; mp 262 °C (MeOH). IR
(KBr): 3043, 3014, 2824, 1690, 1604, 1569, 1470, 1410, 761
6
1
1
1
97.0 (CO), 151.6 (C), 145.7 (CH), 141.8 (C), 129.9 (CH),
29.2 (C), 127.0 (CH), 123.0 (CH), 120.1 (C), 116.2 (C),
15.9 (CH), 111.3 (CH), 26.7 (Me). MS (EI): m/z = 210
+
–1 1
[
M ·]. Anal. Calcd for C H N O: C, 74.27; H, 4.79; N,
cm . H NMR (300 MHz, DMSO-d ): d = 12.35 (br s, 1 H,
1
3
10
2
6
1
3.32. Found: C, 74.35; H, 4.81; N, 13.26.
NH), 10.06 (s, 1 H, CHO), 8.79 (d, J = 1.1 Hz, 1 H, H-5),
8.66 (dd, J = 1.1, 7.7 Hz, 1 H, H-4), 8.50 (dd, J = 1.5, 4.9 Hz,
1 H, H-2), 7.99 (dd, J = 1.5, 8.5 Hz, 1 H, H-7), 7.64 (d, J =
(
19) Analytical Data of Compound 6: The compound 6 was
obtained by flash chromatography [gradient: EtOAc–PE
1
3
(
1:1) → EtOAc]; yield: 90%; white solid; mp 207 °C
8.5 Hz, 1 H, H-8), 7.30 (dd, J = 4.7, 7.7 Hz, 1 H, H-3).
NMR (75 MHz, DMSO-d ): d = 191.9 (CO), 152.6 (C),
C
(MeOH). IR (KBr): 3049, 2850, 1734, 1622, 1599, 1496,
6
–
1 1
1473, 1408, 1234, 1201, 752 cm . H NMR (300 MHz,
147.1 (CH), 142.8 (C), 129.3 (CH), 128.9 (C), 127.5 (CH),
124.9 (CH), 120.6 (C), 116.1 (CH), 115.4 (C), 111.7 (CH).
DMSO-d ): d = 12.5 (br s, 1 H, NH), 8.86 (d, J = 1.5 Hz, 1
H, H-5), 8.74 (dd, J = 1.6, 7.8 Hz, 1 H, H-4), 8.52 (dd, J =
6
+
+
+
MS (EI): m/z = 196 [M ·], 195 [M ·– H], 167 [M ·– H – CO].
1
7
.6, 4.9 Hz, 1 H, H-2), 8.05 (dd, J = 1.5, 8.6 Hz, 1 H, H-7),
.66 (d, J = 8.6 Hz, 1 H, H-8), 7.33 (dd, J = 4.9, 7.8 Hz, 1 H,
Anal. Calcd for C H N O: C, 73.46; H, 4.11; N, 14.28.
Found: C, 73.15; H, 4.39; N, 14.28.
1
2
8
2
1
3
H-3), 4.00 (s, 3 H, Me). C NMR (75 MHz, DMSO-d ): d =
(25) Typical Procedure and Analytical Data for Compound
10: At r.t. and under an inert atmosphere, a solution of
bromine (1.2 equiv, 0.7 M) in anhyd CH Cl was added to a
6
1
1
1
86.2 (CO), 165.3 (CO), 152.7 (C), 147.9 (CH), 143.2 (C),
29.7 (CH), 127.9 (CH), 125.1 (CH), 123.4 (C), 120.7 (C),
2
2
16.4 (CH), 115.3 (C), 112.0 (C), 52.9 (Me). MS (ESI):
suspension of 4a (0.45 M, 200 mg, 1.19 mmol) in anhyd
+
m/z = 255 [M + H ]. Anal. Calcd for C H N O : C, 66.14;
CH Cl . The mixture was stirred for 1 h at r.t. Excess
1
4
10
2
3
2
2
H, 3.96; N, 11.02. Found: C, 66.22; H, 4.03; N, 10.92.
20) Analytical Data of Compound 7: The compound 7 was
obtained by trituration from MeOH; yield: 71%; white solid;
mp >295 °C (MeOH). IR (KBr): 3219, 1682, 1597, 1493,
bromine was destroyed by addition of a sat. aq Na S O
solution. The resulting mixture was extracted with EtOAc–
DMF (99:1). The combined organic phases were washed
2 2 3
(
with brine, dried over MgSO , filtered and evaporated under
4
–
1 1
1
476, 1405, 909, 746 cm . H NMR (300 MHz, DMSO-d ):
reduced pressure. Trituration of the crude residue from
MeOH followed by filtration afforded 10 (241 mg). The
filtrate was evaporated and purified by flash chromatog-
raphy [gradient: EtOAc–PE (1:1) → EtOAc] to give
6
d = 12.73 (br s, 1 H, OH), 12.18 (br s, 1 H, NH), 8.83 (br s,
1
1
7
H, H-5), 8.66 (dd, J = 1.6, 7.6 Hz, 1 H, H-4), 8.47 (dd, J =
.6, 4.9 Hz, 1 H, H-2), 8.06 (dd, J = 1.7, 8.6 Hz, 1 H, H-7),
.55 (d, J = 8.6 Hz, 1 H, H-8), 7.27 (dd, J = 4.9, 7.6 Hz, 1 H,
1
5a
additional 10 (27 mg); yield: 91%; mp 250 °C (MeOH, lit.
mp 266–270 °C). IR (KBr): 3052, 1604, 1586, 1493, 1448,
13
H-3). C NMR (75 MHz, DMSO-d ): d = 167.9 (CO), 152.5
6
–
1 1
(
(
(
C), 146.8 (CH), 141.7 (C), 129.2 (CH), 127.9 (CH), 123.5
768, 610 cm . H NMR (300 MHz, DMSO-d ): d = 11.95
6
CH), 121.9 (C), 120.2 (C), 115.8 (CH), 115.4 (C), 111.0
(br s, 1 H, NH), 8.56 (dd, J = 1.5, 7.7 Hz, 1 H, H-4), 8.45 (dd,
J = 1.5, 4.7 Hz, 1 H, H-2), 8.43 (d, J = 1.9 Hz, 1 H, H-5), 7.58
(dd, J = 1.9, 8.5 Hz, 1 H, H-7), 7.46 (d, J = 8.5 Hz, 1 H, H-
+
CH). MS (EI): m/z = 212 [M ·]. HRMS (EI): m/z calcd for
C H N O : 212.0586; found: 212.0584.
12
8
2
2
1
3
(
21) Analytical Data for Compound 8: The compound 8 was
8), 7.23 (dd, J = 4.7, 7.7 Hz, 1 H, H-3). C NMR (75 MHz,
obtained by flash chromatography [gradient: EtOAc–PE
DMSO-d ): d = 152.0 (C), 146.9 (CH), 137.5 (C), 129.2
6
(
1:1) → EtOAc]; yield: 78%; white solid; mp 212 °C
(CH), 128.9 (C), 123.8 (CH), 122.3 (C), 115.4 (CH), 114.3
(C), 113.2 (CH), 111.4 (C). MS (EI): m/z = 246 [M ·].
+
(MeOH). IR (KBr): 3040, 1647, 1603, 1565, 1494, 1466,
–
1 1
1
254, 769, 702 cm . H NMR (300 MHz, DMSO-d ): d =
HRMS (EI): m/z calcd for C H BrN : 245.9793; found:
6
11
7
2
12.29 (br s, 1 H, NH), 8.65–8.67 (m, 2 H, H-4, H-5), 8.48
245.9797
(
dd, J = 1.5, 4.9 Hz, 1 H, H-2), 7.90 (dd, J = 1.5, 8.0 Hz, 1
(26) Schneller, S. W.; Luo, J.-K. J. Org. Chem. 1980, 45, 4045.
(27) Yang, X.; Xi, C.; Jiang, Y. Tetrahedron Lett. 2005, 46, 8781.
(28) The higher temperature required using the more reactive
BF NO salt suggests a possible involvement of an N-nitro
H, H-7), 7.76–7.79 (m, 2 H, H ), 7.56–7.68 (m, 4 H, H-8,
H ), 7.26 (dd, J = 4.9, 8.0 Hz, 1 H, H-3), C NMR (75 MHz,
DMSO-d ): d = 195.5 (CO), 152.6 (C), 147.0 (CH), 141.7
ar
1
3
ar
6
4
2
(
1
C), 138.3 (C), 132.0 (CH), 129.5 (2 ꢀ CH), 129.4 (CH),
28.7 (CH), 128.6 (C), 128.5 (2 ꢀ CH), 124.3 (CH), 120.4
intermediate. Further studies are underway to clarify the
origin of the selectivity.
Synlett 2007, No. 14, 2237–2241 © Thieme Stuttgart · New York

LETTER
29) Analytical Data for Compound 13: mp >295 °C (MeOH)
Synthesis of 6-Substituted Pyrido[2,3-b]indoles
2241
(
(30) Analytical Data for Compound 14: mp 253 °C (MeOH).
15a
–1 1
(
lit. mp >320 °C). IR (KBr): 3066, 1612, 1587, 1573,
IR (KBr): 3046, 1600, 1573, 1525, 1474, 1362, 732 cm . H
–
1 1
1498, 1456, 1327, 749 cm . H NMR (300 MHz, DMSO-
NMR (300 MHz, DMSO-d ): d = 12.15 (br s, 1 H, NH), 8.63
6
d6): d = 12.58 (br s, 1 H, NH), 9.25 (d, J = 2.2 Hz, 1 H, H-5),
(dd, J = 1.5, 7.7 Hz, 1 H, H-4), 8.62 (d, J = 7.7 Hz, 1 H, H-
7), 8.58 (dd, J = 1.5, 4.8 Hz, 1 H, H-2), 8.35 (d, J = 8.2 Hz,
1 H, H-5), 7.43 (dd, J = 7.7, 8.2 Hz, 1 H, H-6), 7.36 (dd, J =
8
1
9
.80 (dd, J = 1.7, 7.8 Hz, 1 H, H-4), 8.54 (dd, J = 1.7, 4.8 Hz,
H, H-2), 8.35 (dd, J = 2.2, 9.0 Hz, 1 H, H-7), 7.65 (d, J =
.0 Hz, 1 H, H-8), 7.35 (dd, J = 4.8, 7.8 Hz, 1 H, H-3).
1
3
4.8, 7.7 Hz, 1 H, H-3). C NMR (75 MHz, DMSO-d ): d =
6
1
3
C NMR (75 MHz, DMSO-d ): d = 153.0 (C), 147.9 (CH),
152.4 (C), 147.6 (CH), 132.1 (C), 131.9 (C), 128.9 (CH),
128.1 (CH), 124.5 (C), 122.1 (CH), 118.9 (CH), 116.5 (CH),
6
1
1
42.6 (C), 140.5 (C), 130.2 (CH), 122.2 (CH), 120.3 (C),
18.4 (CH), 116.6 (CH), 115.5 (C), 111.6 (CH). MS (ESI):
+
114.0 (CH). MS (EI): m/z = 213 [M ·]. HRMS (EI): m/z
+
+
m/z = 214 [M + H ]. HRMS (ESI): m/z [M + H ] calcd for
calcd for C H N O : 213.0538; found: 213.0535.
1
1
7
3
2
C H N O : 214.0617; found: 214.1017.
11
7
3
2
Synlett 2007, No. 14, 2237–2241 © Thieme Stuttgart · New York

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