Synthesis of new methylated thieno[2,3-a] and [3,2-b]carbazoles by reductive cyclization of 6-(2′-nitrophenyl)benzo[b]thiophenes obtained by palladium-catalyzed cross-coupling

Article abstract of DOI:10.1002/jhet.5570380334

The synthesis of new methylated thieno[2,3-a] and [3,2-b]carbazoles (5) (R=H) was achieved by a palladium-catalyzed cross-coupling, intramolecular reductive cyclization sequence of reactions. The cyclization precursors 6-(2′-nitrophenyl)benzo[b]thiophenes (3) were obtained by Suzuki cross-coupling of 6-boronated methylbenzo[b]thiophenes intermediates (2) with 2-bromo or iodonitrobenzene. The boronated intermediates (2) were prepared via bromine-lithium exchange followed by boron transmetalation and coupled in situ using Pd(OAc)₂ giving thus a one-pot three steps reaction from the 6-bromobenzo[b]thiophenes (1) to the cyclization precursors (3). In the reductive cyclization step, N-ethylthienocarbazoles (5) (R=Et) were also obtained. Several experiments have been made varying the amount of triethylphosphite and the time of reaction, to avoid their formation.

Full text of DOI:10.1002/jhet.5570380334

May-Jun 2001
Synthesis of New Methylated thieno[2,3-a] and [3,2-b]carbazoles by
Reductive Cyclization of 6-(2'-Nitrophenyl)benzo[b]thiophenes
Obtained by Palladium-catalyzed Cross-coupling
749
Isabel C.F.R. Ferreira and Maria-João R.P. Queiroz*
Departamento de Química, Universidade do Minho, 4700-320 Braga, Portugal
Gilbert Kirsch
Groupe de Synthèse Organique et Hétérocyclique, Université de Metz, 57045 Metz, France
Received February 24, 2001
The synthesis of new methylated thieno[2,3-a] and [3,2-b]carbazoles (5) (R=H) was achieved by a
palladium-catalyzed cross-coupling, intramolecular reductive cyclization sequence of reactions. The
cyclization precursors 6-(2'-nitrophenyl)benzo[b]thiophenes (3) were obtained by Suzuki cross-coupling of
6-boronated methylbenzo[b]thiophenes intermediates (2) with 2-bromo or iodonitrobenzene. The boronated
intermediates (2) were prepared via bromine-lithium exchange followed by boron transmetalation and
coupled in situ using Pd(OAc) giving thus a "one-pot" three steps reaction from the 6-bromobenzo[b]thio-
2
phenes (1) to the cyclization precursors (3). In the reductive cyclization step, N-ethylthienocarbazoles (5)
(R=Et) were also obtained. Several experiments have been made varying the amount of triethylphosphite
and the time of reaction, to avoid their formation.
J. Heterocyclic Chem., 38, 749 (2001).
Thienocarbazoles are considered bioisosteres [1a,b] of
In this paper we describe the synthesis of new methylated
thieno[2,3-a] and [3,2-b]carbazoles (5) by reductive
cyclization of 6-(2'-nitrophenyl)benzo[b]thiophenes (3),
which were prepared by Suzuki cross-coupling [7] under
phosphine-free and mild conditions [8] in a "one-pot" three
steps reaction, starting with 6-bromobenzo[b]thiophenes
(1). Reductive cyclization occurred at 160 °C with triethyl
phosphite for 3 or 5 hours depending on the substituents.
The corresponding N-ethylthienocarbazoles (5) (R=Et)
were also isolated, sometimes in significant amounts.
Our work is an example of symbiosis of palladium-
catalyzed cross-coupling and intramolecular cyclization in
order to obtain potentially biological active polycyclic
compounds.
the well known anti-tumour pyridocarbazoles [2], ellip-
ticines and olivacines. The presence of the sulphur atom
could provide the establishment of additional long distance
hydrogen bonds with the DNA chains thus enhancing the
biological activity of these intercalating compounds. The
importance for biological activity of the presence of
methyl groups in key positions of the structure of pyrido-
carbazoles had been evaluated [3] and led us to the
synthesis of different methylated thienocarbazoles.
In earlier work [4] we tried to obtain methylated thieno-
[2,3-b]carbazoles by a ring B convergent method of synthesis.
Diarylamides were obtained by Goldberg coupling [5] of
arylbromides with 6-acetamides of methylated benzo[b]-
thiophenes. After hydrolysis to the corresponding diaryl-
amines, cyclisation using palladium acetate in acidic media
[6] only gave a very low yield of the 2,3,10-trimethyl-9H-
thieno[2,3-b]carbazole along with many by-products (may be
acetoxylation products) which were not identified.
Methylated benzo[b]thiophenes (4) were first prepared
from methylthiophenols and 3-bromobutan-2-one [9] and
were regioselectively brominated at the 6-position accord-
ing to literature proceedure [10] to give bromo compounds
(1). The boron intermediates (2) were prepared from the

750
I. C.F.R. Ferreira, M.-J. R.P. Queiroz and G. Kirsch
Vol. 38
6-bromomethylbenzo[b]thiophenes (1) by bromine-
lithium exchange and boron transmetalation using tributyl
or triisopropylborates, and were not isolated. The coupling
reaction with 2-bromo (or 2-iodo) nitrobenzene was made
in situ using palladium acetate and sodium hydrogen-
carbonate in acetone/water heating for 1 hour at 65 °C
(Scheme 1). Methylbenzo[b]thiophenes (4) were isolated
as by-products at the end of the reactional sequence.
conditions, the yield did not increase for (3a) (32%) but
increased significantly from 30% to 53% for (3b). The
corresponding methylbenzo[b]thiophenes (4) were still
isolated at the end, (4a) in 20% and (4b) in 15%.
The advantages of this palladium-catalyzed cross-
coupling lie in working under phosphine free conditions,
avoiding the isolation of boronic acids and working in situ
from the 6-bromo derivatives (1) with only changing the
solvent of the reaction, replacing ether, after vacuum evap-
oration, by acetone/water. Suzuki couplings are largely
unaffected by the presence of water and tolerate a broad
range of functionality.
The reductive cyclization of compounds (3), using triethyl
phosphite [12], afforded the thienocarbazoles (5) (R=H) in
fair to moderate yields and the corresponding N-ethylated
compounds (5) (R=Et) (Scheme 2 and Table 2).
The presence of methyl groups in ring C together with
the formation of N-ethyl thienocarbazoles (5) (R=Et)
may explain partially the low range of yields obtained.
The same remarks have been made for the synthesis of
methylated carbazoles by Ames et al. [13]. For
1
The H nmr of the crude intermediates (2), before
adding acetone/water, showed already the presence of the
corresponding methylbenzo[b]thiophenes (4) as by-
products, indicating that their isolation at the end of the
sequence was not only due to deboronation that normally
occurs in the coupling reaction. In order to study the effect
of the temperature of the two first steps, halogen-lithium
exchange and transmetalation using tributylborate, in the
formation of compounds (4), several experiments were
carried out and the results were compared in terms of
coupling product and by-products yields (Table 1). The
yields were calculated based in the initial amounts of
6-bromomethylbenzo[b]thiophenes (1).
Table 1
Yields of Coupling Products (3) and by-Products (4) Changing the Temperatures of Halogen-Lithium Exchange and of Transmetalation steps, using
(BuO) B
3
SM
Lithiation
Transmetalation
Temperature
NO -Benzene
compound
Coupling
product
[a]
By-product
(4) (%)
2
Temperature
o
o
( C)
( C)
(3) (%)
(1a)
0
0
0
0
0
0
2-Br
2-Br
2-I
2-Br
2-I
29
34
21
30
17
51
49
38
5
26
10
25
-20
-70
-20
-70
-20
-20
(1b)
(1c)
0
-20
2-Br
2-Br
20
__[b]
[a] 3 Mol% of Pd (OAc) were used in the coupling reaction; [b] Starting material (1c)was recovered in 38%.
2
From the analysis of Table 1, the best temperature condi-
tions are 0 °C for the halogen-lithium exchange and -20 °C
for the transmetalation step. For compound (3c) the yield
was 49% even performing the halogen-lithium exchange at
-20 °C, with the recover of 38% of starting material (1c).
The unreacted 2-bromo or iodonitrobenzenes were also
isolated in the chromatographic purification, being easier
separated from products (3) when mixtures of chloro-
form/petroleum ether were used.
decreasing the formation of N-alkylation products,
lower excess of triethyl phosphite and lesser time of
reaction
were used and the yields for (5a) (R=H) and
(5b) (R=H)
were increased. In the case of the synthesis
(R=H) 4 equivalents were needed and 5 hours of
to obtain a 36% yield. Following the reaction by
was observed that after 3 hours of reflux using
of (5c)
reflux
tlc it
only 2
equivalents of triethyl phosphite a significant
amount of
starting material remained. Addition of 2
To compare yields, triisopropylborate [11] was used in
the transmetalation step, which was performed at -10 °C,
in the synthesis of (3a) and (3b) and in these experiments
we followed the suggestion of Wallow and Novak [8] in
order to decrease deboronation that occurs in the coupling
reaction, using a 10% excess of the boronated compound
(2) relative to the other coupling component. With these
more equivalents and 2 additional hours of reflux
increased product (5c) formation, which was isolated in
36% yield. No N-ethyl compound was isolated in this
+
experiment but another by-product (5d) (m/z M 265)
was isolated (2%), resulting from loss of the methyl
group ortho to the C-C bond formed in compound (3c)
and cyclization at that position.

May-Jun 2001
Synthesis of New Methylated thieno[2,3-a] and [3,2-b]carbazoles
751
We have shown that reductive cyclization of nitro
derivatives presents a new way to thienocarbazoles
synthesis. It has been pointed out that a halogen-lithium
exchange reaction followed by boronation and palladium
catalyzed coupling could be made in a "one pot" reaction.
EXPERIMENTAL
Melting points were determined in a Gallenkamp apparatus
and are uncorrected. The ir spectra were recorded as nujol mulls
on a Perkin-Elmer 1600-FTIR spectrophotometer. The uv spectra
were recorded in ethanol on a Hitachi U-2000 spectrophotometer.
1
The H nmr spectra were measured on a Varian Unity Plus at
300MHz, using the signal of the solvents (chloroform of the
deuteriochloroform or dimethylsulfoxide of dimethyl-
sulfoxide-d ) as internal references. Spin-spin decoupling
6
13
technique was used. The C nmr spectra were measured in the
same instrument at 75,4MHz (using DEPT θ 45º). The mass
spectra were obtained on a Unicam GC/MS 120 spectrometer by
an electronic impact (70eV) direct injection method. Elemental
analyses were determined on a LECO CHNS 932 elemental
analyser.
Flash chromatography was made on silica gel 230-400 mesh.
Petroleum ether refers to the boiling range 40-60 °C.
General Procedures for Bromine-Lithium Exchange,
Transmetalation and in situ Coupling Reaction.
Procedure A.
To a 0 °C (unless stated otherwise, Table 1) solution of
6-bromo compound (1) (6 mmol) in dry ether (30 mL) under Ar,
a 1.6 M solution of nBuLi in hexane (4 mL, 7 mmol) was added
dropwise. The solution was stirred for 20 minutes, cooled to -20
°C (unless stated otherwise, Table 1) and tributylborate (2 mL,
7 mmol) was added under Ar. After 10 minutes the mixture was
left stirring at room temperature for 2 hours, and the solvent was
then removed under vacuum. Acetone (15 mL), water (15 mL),
2-bromo or iodonitrobenzene (6 mmol), NaHCO (15 mmol) and
3
Table 2
Pd(OAc) (3 mol%) were added. The mixture was heated at 65
2
Comparative Yields of Compounds (5) Changing the
Amount of Triethyl Phosphite and the Time of Reaction
°C for 1 hour and after cooling was extracted with ether (3x50
mL). The organic phase was washed with water, treated with
activated carbon, dried (MgSO ), and the solvent removed to
4
SM
Equiv. of
Reaction
time (h)
(5)(R=H) (5)(R=Et)
Unreacted
(3) (%)
give a mixture which was submitted to flash chromatography
(ether/petroleum ether) to give coupling products (3) and
by-products (4).
(EtO) P
(%)
(%)
3
(3a)
(3b)
(3c)
4
2
2.5
4.5
4.5
3.5
3
5
3
4
5
5
11
22
53
6
22
23
36
42
6
__
11
8
__
__
6
__
10
17
12
13
__
5
Procedure B.
Same as procedure A with 1.1 equivalents of nBuLi at 0 °C
2
and 1.1 equivalent of (iPrO) B at -10 °C. In the coupling reaction
3
3
4 (2+2)
4
0.9 equivalents of 2-bromonitrobenzene was used. Extractions
with chloroform gave oily green solids which were submitted to
flash chromatography (chloroform/petroleum ether) to give
compounds (3) and by-products (4).
__
4
6-(2'-Nitrophenyl)-2,3,5-trimethylbenzo[b]thiophene (3a).
When this reaction was repeated beginning with 4
equivalents of triethyl phosphite and heating for 5 hours, by-
product (5c) (R=Et) was isolated (5%) but the yield for
thienocarbazole (5c) (R=H) increased to 42%. In this exper-
iment no formation of the by-product (5d) was observed.
Compound 3a was prepared by Procedure A at 0 °C in the two
first steps, 2-bromonitrobenzene in the coupling reaction and
solvent gradient from petroleum ether to 5% ether/petroleum
ether in the flash chromatography. Two products were obtained,
the less polar was isolated as a white solid and showed to be

752
I. C.F.R. Ferreira, M.-J. R.P. Queiroz and G. Kirsch
Vol. 38
2,3,5-trimethylbenzo[b]thiophene (4a) (38%), mp 56-58 °C
128.16, 128.94 (Cq), 131.88 (Cq), 132.21, 132.74, 134.27 (Cq),
1
(lit.[9] 56-57 °C), H nmr (CDCl ): δ 2.26 (s, 3 H, Me), 2.47 (s, 6
136.36 (Cq), 138.96 (Cq), 140.67 (Cq), 149.59 (Cq); ms: m/z (%)
3
+
H, 2xMe), 7.10 (dd, 1 H, J = 8 and 1.5 Hz, 6-H), 7.49 (broad s,
1 H, 4-H), 7.61 (d, 1 H, J = 8 Hz, 7-H), and the second isolated as
a yellow solid showed to be compound (3a) (29%), mp
140-142 °C; ir: 1608, 1571, 1521, 1459, 1377, 1350, 1299, 1270,
1249, 1148, 1093, 956, 868, 851, 787, 771, 748, 730, 711, 674,
297 (M , 80).
Anal. Calcd. for C
H NO S: C, 68.7; H, 5.1; N, 4.7; S, 10.8.
17 15 2
Found: C, 68.7; H, 5.0; N, 4.7; S, 10.9.
Performing the transmetalation step at -70 °C and using
2-iodonitrobenzene in the coupling reaction, the yield for
compound (4b) was 25% and (3b) was obtained in 17%.
Following procedure B and using in the flash chromatography
mixtures from 20% to 45% chloroform/ petroleum ether,
by-product (4b) was obtained in 15% and the yield for compound
(3b) increased to 53%.
-1
3
-1
-1
666, 630 cm ; uv: λ
(EtOH) (ε,dm mol cm ) 275
max
1
(sh, 17857), 262 (inf., 20833), 241 (42560) nm; H nmr (CDCl ):
3
δ 2.21 (s, 3 H, Me), 2.32 (s, 3 H, Me), 2.50 (s, 3 H, Me), 7.38
(dd, 1 H, J = 7.63 and 1.5 Hz, 6'-H), 7.47 (s, 2 H, 4 and 7-H), 7.53
(oct, 1 H, J = 7.93, 7.63 and 1.5 Hz, 4'-H), 7.65 (td, 1H, J = 7.63
and 1.5 Hz, 5'-H), 8.02 (dd, 1 H, J = 7.93 and 1.5 Hz, 3'-H).
Irradiation at δ 7.38 changed the octet centred at δ 7.53 into an
apparent triplet and the td centred at δ 7.63 into a dd. Irradiation
at δ 7.53 changed the dd at δ 8.02 into a meta doublet, the td
centred at δ 7.63 into a dd and the dd at δ 7.37 into a doublet.
Irradiation at δ 7.65 changed the dd at δ 7.38 into a meta doublet,
the octet centred at δ 7.53 into a broad d and the dd at δ 8.02 into
6-(2'-Nitrophenyl)-2,4,3,7-trimethylbenzo[b]thiophene (3c).
Compound 3c was prepared by Procedure A. Purification by
flash chromatography using solvent gradient from petroleum
ether to 5% ether/petroleum ether, gave a less polar product as a
white solid that showed to be 2,3,4,7-tetramethylbenzo[b]−
1
thiophene (4c) (20%), mp 63-65 °C (lit.[14] 67.5 °C), H nmr
an ortho doublet. Irradiation at δ 8.02 turned the octet centred at
(CDCl ): δ 2.45 (s, 3 H, Me), 2.48 (s, 3 H, Me), 2.52 (s, 3 H,
3
13
δ 7.53 into a dd and the td centered at δ 7.63 into an triplet.
C
Me), 2.57 (s, 3 H, Me), 6.93 (dd, 1 H, J = 8, 5-H), 7.00 (d, 1 H,
J = 8 Hz, 6-H), followed by compound (3c) as a yellow solid
(51%), m.p. 169-171 °C; ir: 1610, 1571, 1523, 1456, 1378, 1352,
1302, 1271, 1183, 1145, 1112, 1091, 1029, 1015, 959, 919, 867,
nmr (CDCl ): δ 11.38 (CH ), 13.84 (CH ), 20.23 (CH ), 121.38,
122.04, 124.07, 126.63 (Cq), 128.33, 131.52 (Cq), 132.46,
132.53, 133.48 (Cq), 134.58(Cq), 135.42 (Cq), 136.70 (Cq),
141.12 (Cq), 149.23 (Cq); ms: m/z (%) 297 (M , 100), 282
(M -Me, 25), 266 (40), 250 (70), 235 (60), 221 (30), 215 (20),
3
3
3
3
+
-1
857, 843, 800, 786, 759, 722, 710, 684, 665, 642, 627 cm . uv:
+
λ
(EtOH) 307 (ε, 6526), 296 (sh, 7792), 274 (sh, 12987), 260
max
1
202 (21), 189 (23), 165 (20).
(inf. 14610), 238 (35584) nm; H nmr (CDCl ): δ 2.33 (s, 3 H,
3
Anal. Calcd. for C
H NO S: C, 68.7; H, 5.1; N, 4.7; S, 10.8.
Me), 2.49 (s, 3 H, Me), 2.53 (s, 3 H, Me), 2.73 (s, 3 H, Me), 6.85
17 15 2
Found C, 68.5; H, 5.2; N, 4.8; S 10.7.
(s, 1 H, 5-H), 7.37 (dd, 1 H, J = 7.63 and 1.5 Hz, 6'-H), 7.53
Performing the transmetalation step at -20 °C the yield for (3a)
increased to 34% and the yield of by-product (4a) decreased to
5%, with recovery of some 2-bromonitrobenzene.
Performing the transmetalation step at -70 °C and using 2-
iodonitrobenzene in the coupling reaction (3a) was obtained in
21% and (4a) in 26%.
(oct, 1 H, J =7.93, 7.63 and 1.5Hz, 4'-H), 7.63 (td, 1 H, J = 7.63
13
and 1.5 Hz, 5'-H), 7.98 (dd, 1 H, J = 7.93 and 1.5 Hz, 3'-H);
C
nmr (CDCl ): δ 14.16 (CH ), 15.19 (CH ), 17.60 (CH ), 21.31
3
3
3
3
(CH ), 123.93, 126.61 (Cq), 127.58, 128.05, 129.31 (Cq), 130.30
3
(Cq), 131.39 (Cq), 132.17, 132.76, 133.52 (Cq), 136.31 (Cq),
+
138.81 (Cq), 139.44 (Cq), 149.57 (Cq); ms: m/z (%) 311 (M ,
Following procedure B and using in the flash chromatography
100).
mixtures from 20% to 45% CHCl /petroleum ether, by-product
Anal. Calcd. for C H NO S: C, 69.4; H, 5.5; N, 4.5; S 10.3.
3
18 17 2
(4a) was obtained in 20%, followed by 2-bromonitrobenzene,
and (3a) was obtained in 32% yield.
Found C, 69.3; H, 5.7; N, 4.5; S, 10.1.
Performing the halogen-lithium exchange at -20 °C, starting
material (1c) was recovered in 38% and (3c) was obtained in
49%.
6-(2'-Nitrophenyl)-2,3,7-trimethylbenzo[b]thiophene (3b).
Compound 3b was prepared by Procedure A. Purification by
flash chromatography using solvent gradient from petroleum
ether to 15% ether/petroleum ether, gave 2,3,7-trimethylbenzo-
[b]thiophene (4b) (10%) as a white solid, mp 46-48 °C (lit.[9] 51-
General Procedure for the Reductive Cyclisation.
To compounds (3) (0.3 to 1 mmol) triethyl phosphite
(2-4 equivalents) was added under Ar. The mixture was heated at
160 °C for 3 to 5 hours (Table 2). The excess triethyl phosphite
was removed directly under vacuum or after a work-up with
water and extractions with chloroform. The orange oils obtained
were submitted to flash chromatography using mixtures of
1
52 °C), H nmr (CDCl ): δ 2.32 (s, 3 H, Me), 2.51 (s, 3 H, Me),
3
2.52 (s, 3 H, Me), 7.08 (dd, 1 H, J = 8 and 1.5 Hz, 6-H), 7.30 (t,
1 H , J = 8 Hz, 5-H) 7.45 (d, 1 H, J = 8 Hz, 4-H), followed by
compound (3b) isolated as a yellow solid mp 116-118 °C,
contamined with 2-bromonitrobenzene. Crystallization from
ether/petroleum ether or CHCl /petroleum ether to give
3
CHCl /petroleum ether gave (3b) as yellow crystals (30%) mp
compounds (5).
3
127-129 °C; ir: 1607, 1573, 1522, 1460, 1377, 1359, 1298, 1282,
2,3,5-Trimethyl-10H-thieno[2,3-a]carbazole (5a).
1192, 1160, 1145, 1096, 1001, 853, 819, 810, 784, 758, 749, 731,
-1
716, 666, 638 cm ; uv: λ
(EtOH) 273(sh, ε 17973), 257 (inf,
Compound (3a) (0.3 mmol), triethyl phosphite (0.6 mmol),
were heated under reflux for 3.5 hours. Flash chromatography
using solvent gradient from petroleum ether to 5% ether/-
petroleum ether gave starting material (11%) as less polar
product and compound (5a) as a white solid (22%) mp
214-216 °C. ir: 3392, 1612, 1553, 1457, 1377, 1353, 1323,
1286, 1245, 1226, 1172, 1152, 1122, 1086, 1036, 878, 839,
max
1
19865), 238 (51250), 205 (84628) nm; H nmr (CDCl ): δ 2.28
3
(s, 3H, Me), 2.32 (s, 3H, Me), 2.52 ( s, 3H, Me), 7.15 (d, 1H, J =
8.24 Hz, 5-H), 7.39 (dd, 1H, J = 7.63 and 1.5 Hz, 6'-H), 7.48
(d, 1 H, J = 8.24 Hz, 4-H), 7.54 (oct, 1 H, J = 7.93, 7.63 and
1.5 Hz, 4'-H), 7.65 (td, 1 H, J = 7.63 and 1.2 Hz, 5'-H), 8.00
13
(dd, 1 H, J = 7.93 and 1.2 Hz, 3'-H); C nmr: δ 11.49 (CH ),
3
-1
1
13.87 (CH ), 18.05 (CH ), 118.66, 123.97, 125.00, 127.84 (Cq),
772, 745, 733, 666 cm ; H nmr: (CDCl ): δ 2.39 (s, 3 H,
3
3
3

May-Jun 2001
Synthesis of New Methylated thieno[2,3-a] and [3,2-b]carbazoles
753
Me), 2.57 (s, 3 H, Me), 2.99 (s, 3 H, Me), 7.25 (s, 1 H, 4-H),
7.30 (spet, 1 H, J = 7.93, 7.63 and 1.22 Hz, 7-H), 7.42 (td,1 H,
J = 7.63 and 1.22 Hz, 8-H), 7.52 (dt, 1 H, J = 7.63, 1.22 and
0.92 Hz, 9-H), 8.21 (broad d, 1 H, J = 7.93 Hz, 6-H), 8.23
(s, 1H, H/D exchangeable, NH). Irradiation at δ 8.21 changed
the sept centred at δ 7.30 into an o,m dd, the td centred at
δ 7.42 into an ortho triplet and the dt centred at 7.52 into an
From other preparation using compound (3b) (0.46 mmol)
triethyl phosphite (1.4 mmol) and heating for 4 hours, N-ethyl
derivative (5b) (R=Et) was isolated in 13% yield , and compound
(5b) (R=H) in 23% yield after flash chromatography (from 20 to
40% CHCl /petroleum ether).
3
2,3,4,10-Tetramethyl-5H-thieno[3,2-b]carbazole (5c).
13
o,m dd. C nmr (CDCl ): δ 11.87 (CH ), 13.9 (CH ), 21.17
Compound (3c) (0.5 mmol) triethyl phosphite (1 mmol
+1 mmol after 3 hours of reflux) were heated for 5 hours. Flash
chromatography using petroleum ether to 10% ether/petroleum
ether gave 2,3,4-trimethyl-10H-thieno[2,3-a]carbazole (5d) (2%)
3
3
3
(CH ), 110.63, 114.59, 117.59 (Cq), 118.15 (Cq), 119.77,
3
122.05, 124.36, 124.78 (Cq), 128.36 (Cq), 129.85 (Cq),
131.83 (Cq), 133.80 (Cq), 138.96 (Cq), 140.24 (Cq).
1
as less polar product, not in a very pure form; H nmr (CDCl )
Anal. Calcd. for C
H NS: C, 76.9; H, 5.7; N, 5.3; S, 12.1.
3
17 15
excluding signals of impurities: δ 2.54 (s, 3 H, Me), 2.61 (s, 3 H,
Found: C, 76.7; H, 5.5; N, 5.2; S, 12.0.
From another preparation using compound (3a) (0.7 mmol),
triethyl phosphite (1.75 mmol), 3 hours of reflux, and using
Me), 2.91 (s, 3 H, Me), 7.24 (broad t, 1 H, partially obscured by
the signal of CHCl , 7-H), 7.38 (broad t, 1 H, J = 8 Hz, 8-H), 7.48
3
(d, 1 H, J =8 Hz, 9-H), 7.72 (s, 1 H, 5-H), 8.03 (d,1 H, J = 8 Hz,
6-H), 8.07 (s, 1 H, H/D exchangeable, NH); ms: m/z (%) 265
mixtures from 20 to 50% CHCl /petroleum ether in the
3
chromatographic purification, by-product (5a) (R=Et) was
+
(M , 40). Compound (5c) (R=H) was isolated in 36% yield as a
isolated (10%) as the less polar product, not in a very pure form,
white solid, m.p. 219-221 °C; ir: 3467, 1602, 1577, 1488, 1456,
1377, 1344, 1324, 1314, 1277, 1252, 1158, 1126, 1111, 1096,
1
as a pink oily solid, H nmr: (CDCl ) excluding signals of
3
impurities: δ 1.52 (t, 3 H, J = 7 Hz, NCH CH ), 2.41 (s, 3 H,
Me), 2.59 (s, 3 H, Me), 3.00 (s, 3 H, Me), 4.70 (q, 2 H, J = 7 Hz,
2
3
-1 1
1019, 1005, 918, 863, 846, 773, 748, 738, 688, 666, 601 cm . H
nmr (DMSO-d ): δ 2.45 (s, 3 H, Me), 2.55 (s, 3 H, Me), 2.88
6
NCH CH ), 7.25-7.34 (m partially obscured by the signal of
2
3
(s, 3 H, Me), 2.90 (s, 3 H, Me), 7.14 (broad t, 1 H, J = 8 Hz, 8-H),
7.37 (broad t, 1 H, J = 8 Hz, 7-H), 7.48 (d, 1 H, J = 8.2 Hz, 6-H),
8.14 (d, 1 H, J = 7.93 Hz, 9-H), 10.97 (s, 1 H, H/D exchangeable,
NH). Irradiation at δ 8.14 changed the broad t centred at 7.14 into
a broad doublet and the broad t centred at 7.37 into a sharpened
triplet. Irradiation at δ 7.48 changed the broad t centred at 7.37
into a dd and the broad t centred at 7.14 into a sharpened triplet.
CHCl , 2 H , 4 and 7-H), 7.45-7.52 (m, 2 H, 8 and 9-H), 8.26
3
+
+
(d, 1 H, J = 8 Hz, 6-H); ms: m/z (%) 293 (M , 100), 278 (M -Me,
30), 265 (20), followed by starting material (3c) (8%) and as the
most polar product compound (5a) (R=H) was isolated in 53%
yield.
2,3,10-Trimethyl-5H-thieno[3,2-b]carbazole (5b).
13
C nmr (DMSO-d ): δ 14.13 (CH ), 14.27 (CH ), 15.57 (CH ),
6
3
3
3
Compound (3b) (0.7 mmol), triethyl phosphite (3.15 mmol)
were heated for 5 hours. Purification by plc, 30% ether/-
petroleum ether, gave the N-ethylated product as a green solid,
18.21 (CH ), 110.43, 110.86 (Cq), 118.28, 118.63 (Cq), 121.71
3
(Cq) 122.08, 122.68 (Cq), 125.08, 128.62 (Cq), 130.10 (Cq),
132.10 (Cq), 136.49 (Cq), 138.84 (Cq), 141.07 (Cq); ms: m/z (%)
1
+
+
not in a very pure form, 5b (R=Et) (17%), mp 132-135 °C; H
279 (M , 100) 264 (M -Me, 20).
Anal. Calcd. for C NS: C, 77.5; H, 6.4; N; 5.3; S, 11.6.
H
nmr (CDCl ) excluding signals of impurities: δ 1.47 (t, 3 H,
18 17
3
Found C, 77.7; H, 6.5; N, 5.2; S, 11.6.
J = 7.2 Hz, NCH CH ), 2.41 (s, 3 H, Me), 2.57 (s, 3 H, Me),
2
3
From other preparation using compound (3c) (0.7 mmol)
triethyl phosphite (2.8 mmol) and 5 hours of reflux, by-product
3.06 (s, 3 H, Me), 4.42 (q, 2 H, J = 7.2 Hz, NCH CH ), 7.26
2
3
(m partially obscured by the signal of CHCl , 2H, Ar-H),
3
1
1
(5c) (R=Et) was isolated in 5% yield, H nmr (CDCl ): δ 1.41
7.36-7.52 (m, 2H, Ar-H), 8.27 (d, 1 H, J = 8 Hz , 9-H),
H
3
(t, 3 H, J = 7.02 Hz, NCH CH ), 2.52 (s, 3 H, Me), 2.63 (s, 3 H,
2
3
nmr: δ (DMSO-d ) 1.31 (t, 3 H, J = 7.02 Hz, NCH CH ), 2.37
6
2
3
Me), 2.99 (s, 3 H, Me), 3.12 (s, 3 H, Me), 4.48 (q, 2 H, J = 7.02
Hz, NCH CH ), 7.22 (broad t partially obscured by the CHCl
(s, 3 H, Me), 2.51 (s, 3 H, Me), 2.94 (s, 3 H, Me), 4.50 (q, 2 H,
J = 7.02 Hz, NCH CH ), 7.20 (td, 1 H, J = 8.24 and 0.91 Hz,
2
3
3
2
3
signal, 1 H, 8-H), 7.44 (m, 2 H, 6 and 7-H), 8.22 (d,1H, J = 8 Hz,
9-H), starting material (3c) (4%) and thienocarbazole (5c) (R=H)
in 42% yield.
8H), 7.46 (td, 1 H, , J = 7.94 and 0.91 Hz, 7-H), 7.59 (d, 1 H,
J = 8.24 Hz, 6-H), 7.64 (s, 1 H, 4-H) 8.20 (broad d, 1 H, J =
7.94 Hz, 9-H) and the thienocarbazole (5b) (R=H) as a white
solid (6%) m.p. 212-214 °C; ir: 3392, 3371, 1619, 1606, 1579,
1495, 1456, 1403, 1378, 1354, 1324, 1268, 1223, 1162, 1117,
1095, 1051, 1019, 919, 861, 847, 830, 824, 742, 727, 691,
Acknowledgments.
Thanks are due to the IBQF-UM (Portugal) for financial
support.
-1
1
666, 607 cm ; H nmr (DMSO- d ): δ 2.32 (s, 3 H, Me), 2.50
6
(s, 3 H, Me), 2.93 ( s, 3 H, Me), 7.16 (td, 1 H, J = 7.63 and
1.22 Hz, 8-H), 7.38 (td,1 H, J = 7.94 and 1.22 Hz, 7-H), 7.47
(d, 2 H, J =7.94 Hz, 4-H and 6-H), 8.17 (broad d, 1H, J =7.63
REFERENCES AND NOTES
13
[1a] C. W. Thornber, Chem. Soc. Rev., 8, 563 (1979); [b] G.
A.Patani and E. J. Lavoie, Chem. Rev., 96, 3147 (1996).
[2] L. K.Dalton, S. Demerac, B. C. Elmes, J. W. Loder, J. M.
Swan and T. Teitei, Aust. J. Chem., 20, 2715 (1967).
Hz, 9-H), 11.2 ( s, 1 H, NH); C nmr (CDCl ): δ 11.80
3
(CH ), 14.24 (CH ), 18.79 (CH ), 99.26, 110.01, 119.16,
3
3
3
120.04 (Cq), 122.44, 123.65 (Cq), 125.19, 125.84 (Cq),
127.14 (Cq), 130.99 (Cq), 133.87 (Cq), 138.83 (Cq), 139.70
[3] C. Rosseau-Richard, C. Auclair, C. Richard and R. Martin;
Free Radical Biology & Medicine, 8, 223 (1990).
+
+
(Cq), 140.60 (Cq); ms: m/z (%) 265 (M , 90) 250 (M -Me, 20)
217 (30) 204 (25).
th
[4] M-J. R. P. Queiroz and G. Kirsch, 16 International Congress
Anal. Calcd. for C
Found C, 76.6; H, 6.0; N, 5.4; S 11.8.
H NS: C, 76.9; H, 5.7; N, 5.3; S, 12.1.
17 15
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