Efficient and simple synthesis of 6-aryl-1,4-dimethyl-9H-carbazoles

Article abstract of DOI:10.3390/molecules13061312

A synthetic method for the preparation of 6-aryl-1,4-dimethyl-9H-carbazoles involving a palladium catalyzed coupling reaction of 1,4-dimethyl-9H-carbazole- 6-boronic acids and (hetero)aryl halides is described.

Full text of DOI:10.3390/molecules13061312

Molecules 2008, 13, 1312-1320; DOI: 10.3390/molecules13061312
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.org/molecules
Article
Efficient and Simple Synthesis of
6-Aryl-1,4-dimethyl-9H-carbazoles
Anna Caruso 1,2, Anne Sophie Voisin-Chiret 1, Jean-Charles Lancelot 1,
Maria Stefania Sinicropi 2, Antonio Garofalo 2 and Sylvain Rault 1,*
1
Université de Caen Basse-Normandie, U.F.R. des Sciences Pharmaceutiques, Centre d’Etudes et de
Recherche sur le Médicament de Normandie, UPRES EA-4258 FR CNRS INC3M, 5, rue
Vaubénard, 14032 Caen Cedex, France
2 Università della Calabria, Dipartimento di Scienze Farmaceutiche, 87036 Arcavacata di Rende (CS),
Italy
* Author to whom correspondence should be addressed; E-mail: sylvain.rault@unicaen.fr;
Tel: +33 (0)2 31 93 64 58; Fax: +33 (0)2 31 93 11 88
Received: 3 June 2008; in revised form: 10 June 2008 / Accepted: 10 June 2008 / Published: 11 June
2008
Abstract: A synthetic method for the preparation of 6-aryl-1,4-dimethyl-9H-carbazoles
involving a palladium catalyzed coupling reaction of 1,4-dimethyl-9H-carbazole-6-boronic
acids and (hetero)aryl halides is described.
Keywords: Carbazole, ellipticine, boronic acid, cross-coupling reaction.
Introduction
Several alkaloids based on a carbazole structure are known to possess interesting biological
activities. Antitumor, antibacterial, anti-inflammatory, psychotropic and anti-histamine properties have
been attributed to many of such compounds [1]. More recently, carbazoles have also been used as
photoconductors, semiconductors and for their light-emitting properties, making them interesting
organic tools for physics experiments [2]. The introduction of functional groups onto the carbazole
scaffold is essential to generate compounds suitable for biological and physical investigations.

Molecules 2008, 13
1313
Standard electrophilic substitution reactions on readily available 1,4-dimethyl-9H-carbazoles are
usually unselective, taking place indifferently at positions 3, 6, or 9 [3,4], while methods for the
selective substitution on a given position are lacking. We herein describe a method for the conversion
of (5,8-dimethyl-9H-carbazol-3-yl)boronic acid, easily prepared starting from the known 6-bromo-1,4-
dimethyl-9H-carbazole, to the corresponding 6-aryl-1,4-dimethyl-9H-carbazoles by a Suzuki-Miyaura
cross-coupling reaction.
Many examples of Suzuki-Miyaura cross-coupling reactions between heterocyclic halides and
phenyl boronic acids have been so far described [5,6], while the use of heteroaryl boronic acids or
esters in the type of reactions is of limited utility [7,8]. Nevertheless, the reactivity of heteroaryl
boronic derivatives continues to be of great interest. We reported in a previous paper the synthesis of
carbazol-3-yl-boronic acid 1 (Figure 1), which was converted, via a hydroxydeboronation reaction,
into the corresponding 3-hydroxy derivative 2 [9], a precursor of new analogs of the anticancer agent
9-hydroxyellipticine (3) [10-12].
Figure 1. Carbazol-3-yl boronic acid 1, its 3-hydroxy derivative 2 and hydroxyellipticine (3).
N
H3C
Me
R
HO
CH3
Me
N
N
H
1 R = B(OH)2
2 R = OH
H
3
Herein, we describe an efficient method involving a cross-coupling reaction, which would allow
the preparation of a library of 6-aryl substituted carbazoles, as potential antitumoral agents. The key
step is the reaction of (5,8-dimethyl-9H-carbazole-3-yl)boronic acid with (hetero)aryl halides to give
3-(hetero)arylcarbazole derivatives. Some typically used reaction conditions proved to be ineffective
when applied to 6-bromo-1,4-dimethyl-9H-carbazole and (hetero)arylboronic acids.
Results and Discussion
The starting 6-bromo-1,4-dimethyl-9H-carbazole (4) was prepared by a known procedure [13-14].
Classic cross-coupling conditions (Na2CO3/Pd(PPh3)4/1,4-dioxane/water/80°C) [6] applied to the
reaction of this compound with arylboronic acids I and II proved to be ineffective for the production of
the desired 6-aryl-1,4-dimethyl-9H-carbazoles 5 (Scheme 1).
Scheme 1. Cross-coupling reaction with 6-bromo-1,4-dimethyl-9H-carbazole 4.
H3C
H3C
F
Br
Ar
i
HO
HO
HO
HO
X
B
B
CH3
CH3
N
N
H
H
OMe
II
4
5
I
Reagents: (i) ArB(OH)2 (I and II), 1,4-dioxane/H2O, Na2CO3, Pd(PPh3)4, 80°C, 48h.

Molecules 2008, 13
1314
However a similar experimental procedure was effective when applied to the reaction of
arylboronic acids I and II and 6-bromo-1,4-dimethyl-3-nitro-9H-carbazole (6), giving aryl-1,4-
dimethyl-3-nitro-9H-carbazoles 7a and 7b, in reasonable yields (Scheme 2). As already described in
numerous cases, the presence of a strong electron-withdrawing group favored the success of the
reaction [15].
Scheme 2. Cross-coupling reaction with 6-bromo-1,4-dimethyl-3-nitro-9H-carbazole (6).
NO2
NO2
H3C
H3C
Br
Ar
i
CH3
CH3
N
N
H
H
6
7a-b
Reagents: (i) ArB(OH)2 (I and II), 1,4-dioxane/H2O, Na2CO3, Pd(PPh3)4, 80°C, 48h.
ArB(OH)2
Compounds/Yields
HO
B
7a / 67%
HO
I
F
HO
B
7b / 45%
HO
II
OMe
Faced with these difficulties and also because the nitro group was considered undesirable, we have
studied the reverse strategy, consisting in the preparation of the boronic acid 1. We have already
described the synthesis of this N-unprotected boronic acid 1 [9] starting from 6-bromo-1,4-dimethyl-
9H-carbazole (4).
Scheme 3. Cross-coupling reaction with 5,8-dimethyl-9H-carbazole-3-boronic acid (1).
H3C
H3C
OH
B
i
Ar
HO
CH3
CH3
N
N
H
H
1
5a-c
Reagents: (i) ArX (A to C), 1,4-dioxane/H2O, Na2CO3, Pd(PPh3)4, 80°C, 24-48h.
ArX
Compounds/Yields
Br
5a / <10%
N
A
I
OMe
5b / <10%
5c / 28%
B
O
S
Br
H
C

Molecules 2008, 13
1315
Unfortunately, this boronic acid is a very poor partner in cross-coupling reactions and yields
obtained with (hetero)aryl halides such as 3-bromopyridine (A) and p-iodoanisole (B) remained very
modest (<10%), the exception being a heteroaryl halide bearing an electron withdrawing group such as
5-bromo-2-thiophenecarboxaldehyde (C), which gave the product 5c in 28% yield (Scheme 3).
These failures prompted us to protect the nitrogen atom of 5,8-dimethyl-9H-carbazole-3-boronic
acid (1). Thus, we prepared N-Boc-5,8-dimethyl-9H-carbazol-3-boronic acid (8), which was obtained
after N-Boc-protection and successive lithiation-boronation of compound 4. We previously described
the use of this reaction sequence for the preparation of 5,8-dimethyl-9H-carbazole-3-ol [9].
Scheme 4. Cross-coupling reaction with N-Boc-5,8-dimethyl-9H-carbazol-3-boronic acid (8).
H3C
H3C
H3C
OH
B
Ar
Ar
ii
i
HO
CH3
CH3
CH3
N
N
N
H
O
O
O
O
8
9a-f
5a-f
Reagents: (i) ArX (A to E), 1,4-dioxane/H2O, Na2CO3, Pd(PPh3)4, 80°C, 24-48h;
(ii) HCl(g)/1,4-dioxane.
ArX
Compounds/Yields Compounds/Yields
Br
9a / 50%
5a / 95%
N
A
I
OMe
9b / 70%
9c / 90%
9d / 45%
5b / 95%
5c / 90%
5d / 92%
B
O
S
Br
H
C
N
Br
D
O
O
Br
H
9e / 60%
9f / 40%
5e / --
E
H3C
Br
CH3
N
O
5f* / 94%
O
F
* The compound 5f corresponds to 1,1’,4,4’-tetramethyl-9H-
dicarbazole; the deprotection is not selective.
Compound 8 was then subjected to the Suzuki cross-coupling reaction with a variety of
(hetero)aryl halides under standard conditions [6]. An aqueous solution of Na2CO3 and Pd(PPh3)4 was
slowly added to a mixture of compound 8 and the appropriate (hetero)aryl halide in 1,4-dioxane at
room temperature. The resulting mixture was then heated to reflux for the given time. After the usual

Molecules 2008, 13
1316
work-up, compounds 9a-f were obtained in good yields. The N-deprotection of 9a-f was carried out
with gaseous HCl in 1,4-dioxane, giving compounds 5a, 5b, 5c, 5d and 5f in quantitative yields
(Scheme 4). We were unable to isolate compound 5e, probably due to the instability of the furfural
moiety in an acidic medium.
Conclusions
We have found a good methodology to produce 6-aryl-1,4-dimethyl-9H-carbazoles using a N-
protected 5,8-dimethyl-9H-carbazol-3-boronic acid. This methodology allows us to prepare new
derivatives with potent interest in cancerology, especially biscarbazoles similar to Clausenamine A
(Figure 2) [16-19].
Figure 2. Clausenamine A.
MeO
Me
OH
H
N
MeO
OMe
OMe
N
H
OH
Me
Experimental
General
Commercial reagents were purchased from Aldrich, Acros Organics or Alfa Aesar and used
without additional purification. Melting points were determined on a Kofler melting point apparatus.
IR spectra were taken with a Perkin Elmer BX FT-IR. Mass spectra were taken on a JEOL JMS
GCMate spectrometer at ionizing potential of 70 eV (EI) or were performed using a LC-MS Waters
1
Alliance 2695 spectrometer (ESI+). H-NMR (400 MHz) was recorded on a JEOL Lambda 400
spectrometer; 13C-NMR were not recorded due to the low solubility of the compounds. Chemical shifts
are expressed in parts per million downfield from tetramethylsilane as an internal standard. Thin layer
chromatography (TLC) was performed on silica gel 60F-264 (Merck).
General procedure for the preparation of compounds 7a-b
The preparation of 1,4-dimethyl-3-nitro-6-phenyl-9H-carbazole (7a) is reported as a representative
example: to a solution of 6-bromo-1,4-dimethyl-3-nitro-9H-carbazole (6, 1.50 g, 4.70 mmol) in 1,4-
dioxane (70 mL), kept under an argon atmosphere, phenylboronic acid (I, 0.63 g, 5.17 mmol), Na2CO3
(1.25 g, 11.79 mmol) in H2O (3.50 mL) and Pd(PPh3)4 (0.30 g, 0.26 mmol) were added sequentially.
The reaction mixture was heated to reflux for 48h, and then volatiles were evaporated under reduced
pressure. The solid formed was recrystallized from acetonitrile to give 1,4-dimethyl-3-nitro-6-phenyl-
9H-carbazole (7a). Yellow solid (67 % yield), mp = 226 °C; IR (KBr): 3451, 1584, 1521, 1302, 1301,
817, 758 cm-1; 1H-NMR (DMSO-d6) δ 11.94 (s, 1H, NH); 8.35 (s, 1H, H2); 7.86 (s, 1H, H5); 7.83-7.83

Molecules 2008, 13
1317
(m, 7H, H7, H8, C6H5); 2.96 (s, 3H, CH3); 2.55 (s, 3H, CH3); MS (EI) m/z (%): 316 (M+ •, 98), 271
(48) (M+ •-NO2).
1,4-Dimethyl-3-nitro-6-(2’-fluoro-5'-methoxyphenyl)-9H-carbazole (7b)
Prepared following the general procedure but employing 2-fluoro-5-methoxyphenylboronic acid
(II) in place of I. Yellow solid (45 % yield), mp = 240 °C; IR (KBr): 3309, 1578, 1299, 1205, 1034,
810, 756 cm-1; 1H-NMR (DMSO-d6) δ 12.06 (s, 1H, NH); 8.36 (s, 1H, H2); 7.87 (s, 1H, H5); 7.71-7.65
(m, 2H, H8, H6’); 7.28-7.23 (m, 1H, H7); 7.17-7.14 (m, 1H, H4’); 6.95-6.93 (m, 1H, H3’); 3.80 (s, 3H,
OCH3); 2.99 (s, 3H, CH3); 2.58 (s, 3H, CH3); MS (ESI+): 364 (M++1).
General procedure for the preparation of compounds 9a-f
The preparation of 1,4-dimethyl-6-pyridin-3-yl-9-tert-butoxycarbonyl-9H-carbazole (9a) is reported
as a representative example: to a solution of 3-bromopyridine (A, 0.08 mL, 0.80 mmol) in 1,4-dioxane
(50 mL), kept under an argon atmosphere, 9-tert-butoxycarbonyl-5,8-dimethyl-9H-carbazole-3-
boronic acid (8, 0.30 g, 0.88 mmol), Na2CO3 (0.21 g, 2 mmol) in H2O (2 mL) and Pd(PPh3)4 (0.05 g,
0.04 mmol) were added sequentially. The reaction mixture was heated to reflux for 48 h, and then
concentrated under reduced pressure. The solid residue was recrystallized from acetonitrile. Compound
9a was obtained as a light brown solid (50 % yield), mp = 167 °C; IR (KBr): 3435, 2972, 1731, 1458,
1
1288, 1246, 1145, 1084, 809, 721, 619 cm-1; H-NMR (DMSO-d6) δ 9.01 (s, 1H, H2’); 8.60-8.56 (m,
1H, H6’); 8.35 (s, 1H, H5); 8.20 (d, JH4’-5’ = 7.8 Hz, 1H, H4’); 8.11 (d, JH7-8 = 8.8 Hz, 1H, H7); 7.87 (d,
JH8-7 = 8.8 Hz, 1H, H8); 7.53-7.50 (m, 1H, H5’); 7.24 (d, JH2-3 = 7.8 Hz, 1H, H2); 7.15 (d, JH3-2 = 7.8
Hz, 1H, H3); 2.84 (s, 3H, CH3); 2.40 (s, 3H, CH3); 1.67 (s, 9H, 3CH3); MS (EI) m/z (%): 372 (M+ •, 1),
316 (100) (M+ •- tBu), 272 (100) (M+ •- CO2tBu). MS (ESI+): 373 (M++1).
6-(4’-Methoxy-phenyl)-1,4-dimethyl-9-tert-butoxycarbonyl-9H-carbazole (9b)
Following a procedure identical to that described for 9a, but using 4-iodoanisole (B, 0.30 g, 1.34
mmol), 9b was obtained as a white solid (70 % yield), mp = 122 °C; IR (KBr): 2977, 1728, 1451,
1285, 1246, 1150, 1081, 804, 757, 697 cm-1; 1H-NMR (DMSO-d6) δ 8.36 (s, 1H, H5); 8.15 (d, JH7-8
=
8.8 Hz, 1H, H7); 7.89-7.83 (m, 2H, H8, H3’); 7.58-7.55 (m, 2H, H2’, H6’); 7.46-7.44 (m, 1H, H5’);
7.29 (d, JH2-3 = 7.8 Hz, 1H, H2); 7.20 (d, JH3-2 = 7.8 Hz, 1H, H3); 3.47 (s, 3H, OCH3); 2.89 (s, 3H,
CH3); 2.45 (s, 3H, CH3); 1.71 (s, 9H, 3CH3); MS (EI) m/z (%): 401 (M+ •, 1), 271 (100) (M+ •- OCH3 -
CO2tBu).
5-(5’,8’-Dimethyl-9’-tert-butoxycarbonyl-9’H-carbazol-3’-yl)-thiophene-2-carbaldehyde (9c)
Following a procedure identical to that described for 9a, but using 5-bromo-2-thiophene-
carboxaldehyde (C, 0.27 g, 1.54 mmol) and a reflux time of 24 h, compound 9c was obtained as a
yellow solid (90 % yield), mp = 168 °C; IR (KBr): 3428, 2971, 1739, 1657, 1428, 1225, 1149, 1061,
1
797, 665 cm-1; H-NMR (DMSO-d6) δ 9.90 (s, 1H, CHO); 8.38 (s, 1H, H4’) 8.07-8.05 (m, 2H, H1’,

Molecules 2008, 13
1318
H3); 7.94 (d, J2-1 = 8.8 Hz, 1H, H2); 7.82 (d, JH4-3 = 3.9 Hz, 1H, H4); 7.24 (d, JH7-6 = 7.8 Hz, 1H, H7);
7.15 (d, JH6-7 = 7.8 Hz, 1H, H6); 2.81 (s, 3H, CH3); 2.40 (s, 3H, CH3); 1.66 (s, 9H, 3CH3); MS (ESI+):
405 (M++1).
1,4-Dimethyl-6-pyridin-2-yl-9-tert-butoxycarbonyl-9H-carbazole (9d)
Following a procedure identical to that described for 9a, but using 2-bromopyridine (D, 0.09 mL,
0.98 mmol), 9d was obtained as a light brown solid (45 % yield), mp = 212 °C; IR (KBr): 3370, 2977,
1
1701, 1457, 1290, 1252, 1149, 1088, 803, 780, 670 cm-1; H-NMR (DMSO-d6) δ 8.66 (s, 1H, H5);
8.08 (d, JH7-8 = 8.8 Hz, 1H, H7); 8.07-7.95 (m, 1H, H6’); 7.75 (d, JH8-7 = 8.8 Hz, 1H, H8); 7.71-7.68
(m, 2H, H4’, H3’); 7.20-715 (m, 1H, H5’); 7.10 (d, JH2-3 = 7.8 Hz, 1H, H2); 7.02 (d, JH3-2 = 7.8 Hz,
1H, H3); 2.72 (s, 3H, CH3); 2.41 (s, 3H, CH3); 1.62 (s, 9H, 3CH3); MS (ESI+): 373 (M++1).
5-(5’,8’-Dimethyl-9’-tert-butoxycarbonyl-9’H-carbazol-3’-yl)-furan-2-carbaldehyde (9e)
Following a procedure identical to that described for 9a, but using 5-bromo-2-furaldehyde (E, 0.27
g, 1.54 mmol) and a reflux time of 24 h, compound 9e was obtained as a yellow solid (60 % yield), mp
= 110 °C; IR (KBr): 3430, 2975, 1744, 1672, 1450, 1285, 1149, 1084, 795 cm-1; 1H-NMR (DMSO-d6)
δ 9.62 (s, 1H, CHO); 8.48 (s, 1H, H4’) 8.10 (d, JH1’-2’ = 8.8 Hz, 1H, H1’); 8.03 (d, JH2’-1’ = 8.79 Hz, 1H,
H2’); 7.67 (d, JH3-4 = 3.9 Hz, 1H, H3); 7.34 (d, JH4-3 = 3.9 Hz, 1H, H4); 7.25 (d, JH7-6 = 7.8 Hz, 1H,
H7); 7.16 (d, JH6-7 = 7.8 Hz, 1H, H6); 2.82 (s, 3H, CH3); 2.42 (s, 3H, CH3); 1.67 (s, 9H, t-Bu); MS
(ESI+): 390 (M++1).
1,1’,4,4’-Tetramethyl-9-tert-butoxycarbonyl-9H-dicarbazole (9f)
Following the identical procedure to that described for 9f, but using 6-bromo-1,4-dimethyl-9-tert-
butoxycarbonyl-9H-carbazole (F, 0.30 g, 0.80 mmol), 9f was obtained as a white solid (40 % yield),
mp = 214 °C; IR (KBr): 3439, 2979, 1726, 1453, 1295, 1248, 1154, 1083, 804, 541 cm-1; 1H-NMR
(DMSO-d6) δ 8.40 (s, 2H, H5, H5’); 8.20-8.10 (m, 2H, H7, H7’); 8.00-7.90 (m, 2H, H8, H8’); 7.10-
7.30 (m, 4H, H2, H3, H2’, H3’); 2.85 (s, 6H, 2CH3); 2.42 (s, 6H, 2CH3); 1.68 (s, 18H, 6CH3); MS (EI)
m/z (%): 588 (M+ •, 1), 388 (100) (M+ • - 2 CO2tBu).
General procedure for the deprotection of compounds 9a-f
The preparation of 1,4-dimethyl-6-pyridin-3-yl-9H-carbazole (5a) is reported as a representative
example: to a mixture of 1,4-dioxane (70 mL) and gaseous HCl (saturated solution) cooled to 0 °C
compound 9a (2.36 mmol) was added. The reaction mixture was heated to reflux for 48 h, then
concentrated under reduced pressure. The oil formed residue was crystallized from acetonitrile.
Compound 5a was obtained as a yellow solid (95 % yield), mp > 260 °C; IR (KBr): 3426, 2518, 1470,
1
1258, 790, 671 cm-1; H-NMR (DMSO-d6) δ 11.51 (s, 1H, NH); 9.30 (d, JH2’4’ = 2.4 Hz, 1H, H2’);
8.84 (dd, JH6’-5’ = 4.4 Hz, JH6’-4’ = 1.2 Hz, 1H, H6’); 8.77 (part A of AB system, JAB = 8.3 Hz, JHA-2’
2.4 Hz, JHA-6’ = 1.2 Hz, 1H, H4’); 8.49 (s, 1H, H5); 8.03 (part B of AB system, JAB = 8.3 Hz, JHB-6’
=
=

Molecules 2008, 13
1319
4.4 Hz, 1H, H5’); 7.85 (d, JH7-8 = 8.8 Hz, 1H, H7); 7.68 (d, JH8-7 = 8.8 Hz, 1H, H8); 7.13 (d, JH2-3 = 6.8
Hz, 1H, H2); 6.91 (d, JH3-2 = 6.8 Hz, 1H, H3); 3.42 (1H, NH+Cl-); 2.85 (s, 3H, CH3); 2.52 (s, 3H, CH3);
MS (ESI+): 273 (M++1).
The following compounds were similarly obtained:
6-(4’-Methoxyphenyl)-1,4-dimethyl-9H-carbazole (5b). White solid (95 % yield), mp = 200 °C; IR
(KBr): 3020, 1454, 1320, 1250, 1170, 1076, 799, 770, 676 cm-1; 1H-NMR (DMSO-d6) δ 10.00 (s, 1H,
NH); 7.85 (s, 1H, H5); 7.58-7.56 (m, 2H, H2’, H6’); 7.40 (d, JH8-7 = 8.8 Hz, 1H, H8); 7.30 (d, JH7-8
=
8.8 Hz, 1H, H7); 7.05-7.00 (m, 2H, H3’, H5’); 6.98 (d, JH2-3 = 7.8 Hz, 1H, H2); 6.89 (d, JH3-2 = 7.8 Hz,
1H, H3); 3.85 (s, 3H, OCH3); 2.84 (s, 3H, CH3); 2.54 (s, 3H, CH3); MS (EI) m/z (%): 301 (M+ •, 100).
5-(5’,8’-Dimethyl-9’H-carbazol-3’-yl)-thiophene-2-carbaldehyde (5c). Yellow solid (90 % yield), mp
= 262 °C; IR (KBr): 3435, 3267, 1634, 1430, 1241, 1058, 800, 669 cm-1; 1H-NMR (DMSO-d6) δ 11.58
(s, 1H, NH); 9.94 (s, 1H, CHO); 8,50 (s, 1H, H4); 8.11-8.10 (d, J3’-4’= 3.9 Hz 1H, H3’); 7.89 (d, J2-1=
8.8 Hz 1H, H2); 7.83 (d, JH4’-3’ = 3.9 Hz 1H, H4’); 7.67 (d, J1-2 = 8.8 Hz 1H, H1); 7.19 (d, JH7-6 = 7.8
Hz, 1H, H7); 6.97 (d, JH6-7= 7.8 Hz, 1H, H6); 2.89 (s, 3H, CH3); 2.58 (s, 3H, CH3); MS (ESI+): 306
(M++1).
1,4-Dimethyl-6-pyridin-2yl-9H-carbazole (5d). White solid (92 % yield), mp > 260 °C; IR (KBr):
1
3424, 2516, 1468, 1270, 800, 673 cm-1; H-NMR (DMSO-d6) δ 11.48 (s, 1H, NH); 8.64 (s, 1H, H5);
8.10 (d, JH7-8 = 8.8 Hz, 1H, H7); 8.09-7.92 (m, 1H, H6’); 7.79 (d, JH8-7 = 8.8 Hz, 1H, H8); 7.70-7.69
(m, 2H, H4’, H3’); 7.22-718 (m, 1H, H5’); 7.13 (d, JH2-3 = 7.8 Hz, 1H, H2); 7.07 (d, JH3-2 = 7.8 Hz,
1H, H3); 3.43 (1H, NH+Cl-); 2.73 (s, 3H, CH3); 2.45 (s, 3H, CH3); MS (ESI+): 273 (M++1).
1,1’,4,4’-Tetramethyl-9H-dicarbazole (5f). White solid (94 % yield), mp = 254 °C; IR (KBr): 3454,
2987, 1457, 1300, 1254, 1187, 1067, 812, 570 cm-1; 1H-NMR (DMSO-d6) δ 10.20 (s, 2H, NH); 7.99-
7.94 (m, 2H, H5, H5’); 7.59-7.38 (m, 4H, H7, H8, H7’, H8’); 7.15-6.98 (m, 4H, H2, H3, H2’, H3’);
2.85 (s, 6H, 2CH3); 2.55 (s, 6H, 2CH3); MS (EI) m/z: 388 (M+ •, 100).
Acknowledgements
The authors thank ‘Les Laboratories Servier’ and the ‘Conseil Regional de Basse-Normandie’ for
their financial support and Dr. R. Legay for helpful in mass spectroscopy.
References
1. Liu, Z.; Larock, R.C. Synthesis of carbazoles and dibenzofurans via cross-coupling of o-
iodoanilines and o-iodophenols with silylaryl triflates and subsequent Pd-catalyzed cyclization.
Tetrahedron 2007, 63, 347-355.
2. Zhang, Y.; Wada, T.; Sasabe, H. Carbazole photorefractive materials. J. Mater. Chem. 1998, 8,
809-828.

Molecules 2008, 13
1320
3. Sundberg, R.J. Comprehensive Heterocyclic Chemistry II; Pergamon: Oxford, 1996.
4. Kuwahara, A.; Nakano, K., Nozaki, K. Double N-arylation of primary amines: carbazole synthesis
from 2,2’-biphenyldiols. J. Org. Chem. 2005, 70, 413-419.
5. Stanforth, S.P. Catalytic cross-coupling reactions in biaryl synthesis. Tetrahedron 1998, 54, 263-
303.
6. Suzuki, A. Recent advances in the cross-coupling reactions of organoboron derivatives with
organic electrophiles, 1995-1998. J. Organomet. Chem. 1999, 576, 147-168.
7. Tyrrell, E.; Brookes, P. The synthesis and applications of heterocyclic boronic acids. Synthesis
2003, 4, 469-483.
8. Abarca, B.; Ballesteros, R.; Blanco, F.; Bouillon, A.; Collot, V.; Domìnguez, J.R.; Lancelot, J.C.;
Rault, S. Synthesis of novel triazolopyridylboronic acids and esters. Study of potential application
to Suzuki-type reactions. Tetrahedron 2004, 60, 4887-4893.
9. Caruso, A.; Voisin-Chiret, A.S.; Lancelot, J.C.; Sinicropi, M.S.; Garofalo, A.; Rault, S. Novel and
efficient synthesis of 5,8-dimethyl-9H-carbazol-3-ol via a hydroxydeboronation reaction.
Heterocycles 2007, 71, 2203-2210.
10. Dugue, B.; Auclair, C.; Meunier, B. Covalent binding of elliptinium acetate (NSC 264137) to
nucleic acids of L1210 cells in culture. Cancer Res. 1986, 46, 3878-3833.
11. Moody, D.L.; Dyba, M.; Kosakowska-Cholody, T.; Tarasova, N.I.; Michejda, C.J. Synthesis and
biological activity of 5-aza-ellipticine derivatives. Bioorg. Med. Chem. Lett. 2007, 17, 2380-2384.
12. Poljakovà, J.; Frei, E.; Gomez, J.E.; Aimovà, D.; Eckschlager, T.; Hrabèta, J.; Stiborovà, M. DNA
adduct formation by the anticancer drug ellipticine in human leukemia HL-60 and CCRF-CEM
cells. Cancer Lett. 2007, 252, 270-279.
13. Cranwell, A.; Saxton, J.E. A synthesis of ellipticine. J. Chem. Soc. 1962, 3482-3487.
14. Lancelot, J.C.; Rault, S.; Robba, M.; Nguyen, H.D. Efficient synthesis of 6H-pyrido[3,2-
b]carbazole derivatives from 3-amino-1,4-dimethylcarbazole. Chem. Pharm. Bull. 1987, 35, 425-
428.
15. Suzuki, A.; Brown, H.C. Organic Syntheses Via Boranes Volume 3: Suzuki coupling; Aldrich
Chemical Company: Milwaukee, 2003.
16. Wu, T.-S.; Huang, S.-C.; Wu, P.-L. Carbazole-pyranocoumarin dimer and binary carbazole
alkaloid from Clausena excavata. Tetrahedron Lett. 1996, 37, 7819-7822.
17. Lin, G.; Zhang, A. Synthesis of Optically Pure Clausenamine A and its Demethoxylated Analogs.
Tetrahedron 2000, 56, 7163- 7171.
18. Zhang, A.; Lin, G. The first synthesis of clausenamine A and cytotoxic activities of three
biscarbazole analogues against cancer cells. Bioorg. Med. Chem. Lett. 2000, 10, 1021-1023.
19. Tasler, S.; Bringmann, G. Biarylic biscarbazole alkaloids: occurrence, stereochemistry, synthesis,
and bioactivity. Chem. Rec. 2002, 2, 114-126.
Sample Availability: Samples of the compounds are available from the authors.
© 2008 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).