Microwave-enhanced cadogan cyclization: An easy access to the 2-substituted carbazoles and other fused heterocyclic systems

Article abstract of DOI:10.1055/s-2004-836030

A microwave-enhanced Suzuki-Miyaura cross-coupling reaction in combination with a microwave-assisted Cadogan reductive cyclization is presented as an easy access to a variety of 2-substituted carbazoles and other fused heterocyclic systems. Microwave irradiation was found very useful in minimizing the proto-deboronation issues in the cross-coupling reaction, and enhances the rate of reductive cyclization in a dramatic manner.

Full text of DOI:10.1055/s-2004-836030

LETTER
127
Microwave-Enhanced Cadogan Cyclization: An Easy Access to the
2-Substituted Carbazoles and other Fused Heterocyclic Systems
M
icrowave-En
r
hanced
a
C
adogan
C
s
Departement of Chemistry, K. U. Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax +32(16)327990; E-mail: wim.dehaen@chem.kuleuven.ac.be
Received 14 September 2004
proposed in the literature for the synthesis of these highly
interesting targets.
Abstract: A microwave-enhanced Suzuki–Miyaura cross-coupling
reaction in combination with a microwave-assisted Cadogan reduc-
tive cyclization is presented as an easy access to a variety of 2-sub-
stituted carbazoles and other fused heterocyclic systems.
Microwave irradiation was found very useful in minimizing the pro-
to-deboronation issues in the cross-coupling reaction, and enhances
the rate of reductive cyclization in a dramatic manner.
The majority of the work that has been performed
concerning the synthesis of 2-substituted carbazoles is
based on the phosphite-mediated Cadogan reductive
cyclization7 of the corresponding 2-nitro-biaryls. Howev-
er, this nitrene-mediated reductive cyclization procedure
often demands drastic conditions and long reaction times,
making it a less-favored synthetic method. Even though
there has been a large amount of literature on palladium-
catalyzed cyclization strategies8 as well as CO induced C-
H activations9 to serve the purpose, these methods often
demand sensitive reaction conditions including high-pres-
sure media, cause catalytic contamination of the products
and often requires the use of expensive catalysts. Micro-
wave irradiation has recently emerged as a valuable tool
in organic synthesis, as is evident from the richness of the
available literature.10 Dramatic rate enhancements and su-
perior yields are often observed when the reactions are
carried out under focused microwave irradiation. As part
of our research towards the microwave-assisted palladi-
um-catalyzed Suzuki–Miyaura reactions of electron-poor
boronic acids, we chose to develop a convenient, econom-
ic and general pathway for the synthesis of 2-substituted
carbazoles. Our strategy was based on the generation of
ortho-nitro-phenylboronic acid (1), in view to generate
the required biaryl intermediates by Suzuki–Miyaura re-
action with a suitable para-substituted aryl bromide. We
envisaged that these biaryl intermediates, after the micro-
wave-assisted Cadogan cyclization, would furnish the 2-
substituted carbazoles, which are otherwise difficult to
obtain.
Key words: microwave-enhanced, Suzuki–Miyaura cross-cou-
pling reaction, Cadogan reductive cyclization
Novel strategies for the synthesis of functionalized carba-
zole analogues recently have gained considerable interest,
due to their widespread applications as light-emitting de-
vices,1 conjugate polymers,2 dendrimers,3 etc. There has
also been much research done on the biological activities
of the carbazole analogues in recent years and a great
number of carbazole alkaloids has been isolated and syn-
thesized.4 Furthermore, the synthesis of aromatic fused
systems like benzo- and indolocarbazoles, as well as het-
erocyclic fused systems such as a- and b-carbolines,
thieno-indoles, etc. have found a rapidly increasing inter-
est of the pharmaceutical industry due to their versatile
and potent, though still scarcely explored, biological ac-
tivities.5 However, research carried out to improve the
properties of these interesting carbazole analogues have
mainly been restricted to the functionalizations of the 3,6-
and 1,8-positions of the carbazole skeleton, owing to the
relative inertness of the 2,7-positions towards electro-
philic substitution. A large number of naturally occurring
and biologically active carbazoles including mukonal, in-
dizoline, glycozolidine and glycosinine6 (Figure 1) as
well as light-emitting devices features the 2- or 2,7-substi-
tution pattern in their skeleton. However, a reliable, effi-
cient and non-expensive strategy has scarcely been
Furthermore, this strategy enables us to carry out the
cross-coupling reaction with a variety of cheap and com-
mercially available heterocyclic halides, and these inter-
CHO
MeO
Me
OMe
CHO
OMe
CHO
OH
N
H
N
H
N
H
N
H
OMe
Glycozolidine
Glycosinine
Indizoline
Mukonal
Figure 1 Some naturally occurring 2-substituted carbazole alkaloids.
SYNLETT 2005, No. 1, pp 0127–0133
0
5.
0
1.
2
0
0
5
Advanced online publication: 29.11.2004
DOI: 10.1055/s-2004-836030; Art ID: G33904ST
© Georg Thieme Verlag Stuttgart · New York

128
P. Appukkuttan et al.
LETTER
Br
B(OH)2
NO2
X
[ ]
X
[ ]
n
n
ii
X
i
R2
R2
[ ]
n
N
H
NO2
3a–r
R2
4a–r
1a
2a–r
R
2 = H, Alk, OAlk, CN, Cl, NMe2, COMe, etc. ; n = 0, 1; X = CH, N, S, etc.
Scheme 1 Synthesis of 2-substituted carbazoles and other indolo-fused systems. (i) Suzuki–Miyaura cross-coupling; (ii) Cadogan reductive
cyclization.
mediates could easily be cyclized to a variety of fused benzene being the proto-deboronated product. Further
heterocyclic systems with presumably interesting biolog- optimization studies to increase the yield of the biaryl
ical potentials. Even though the combination of Suzuki- compound as well as to minimize the proto-deboronation
type reactions with Cadogan reductive cyclization, albeit were performed, altering the base, catalyst, solvent and
rarely, has been demonstrated in the literature11 to gener- temperature. Best results were obtained when NaHCO3 or
ate the carbazoles and/or fused heterocyclic systems, Cs2CO3 were used as bases, in a 1:1 mixture of DMF and
these methods generally uses cross-coupling of an ortho- water at a pre-selected temperature of 150 °C for 15 min-
halogenated nitro compound with (hetero)arylboronic ac- utes. After chromatographic purification, the product was
ids or stannanes that are expensive and rather difficult to isolated in excellent yields of 86% and 84%, respectively,
generate.
while the proto-deboronated product was considerably
minimized.
Our initial task was the optimization of the Suzuki reac-
tions between the ortho-nitro-phenylboronic acid (1a) and Thus, after optimizing the reaction parameters, our next
the halide, as this specific cross-coupling reaction impos- goal was to extend our strategy by incorporating a wide
es a challenge to the classical reaction conditions. It is a variety of electron-rich, electron-poor and hetero(aryl) ha-
well-established fact from the recent literature that the lides in view of generating a small library of biaryl nitro
presence of the electron-withdrawing nitro group in the compounds so as to try the Cadogan cyclization at a later
ortho-position of the C-B bond makes it susceptible to- stage. The details of the cross-couplings carried out under
wards proto-deboronation,12 thereby causing the yields to microwave irradiation are presented in Table 1.
diminish. Most of the available literature advocates the
As can be viewed from Table 1, the reactions were found
use of non-aqueous, and thereby non-homogenous and
to proceed very smoothly, with very low extent of homo-
slower reaction conditions as well as the use of bulky
coupling or proto-deboronation. Electron-rich halides 2b–
d were found to undergo the cross-coupling reaction in 15
minutes under microwave irradiation (Table 1, entries 2–
4), and the corresponding biaryl compounds 3b–d were
isolated in yields of 84%, 89% and 79%, respectively.
Electron-poor aryl halides 2e–h were found to undergo
the cross-coupling in only 10 minutes, owing to the fast
phosphine ligands that, besides having the apparent draw-
back of being expensive, demands sensitive reaction con-
ditions.13 We have recently demonstrated, using a number
of 2-formyl boronic acids, that the undesired proto-debo-
ronation can be considerably diminished if the cross-cou-
pling reactions are carried out under microwave-enhanced
conditions.14 We therefore decided to extend our success-
oxidative addition of the catalyst to the C-X bond, and the
ful strategy towards the cross-coupling reactions of 1a
products 3e–h were isolated in good yields (Table 1, en-
tries 5–8). The sterically hindered halide 1,4-dibromo-
with a variety of (hetero)aryl bromides 2a–r (Scheme 1).
The commercially available phenylboronic acid (1) was 2,5-dihexyl-benzene (2i) underwent the cross-coupling
converted to the 2-nitro analogue according to the litera- reaction in 15 minutes, resulting in the formation of 2¢,5¢-
ture procedure,15 using fuming HNO3 as the nitrating dihexyl-2,2¢¢-dinitro-[1,1¢,4¢,1¢¢]-terphenyl (3i) in good
agent in the presence of a catalytic amount of urea, and the yield of 87% (Table 1, entry 9). Bromonaphthalenes 2j
product 1a was isolated in good yield of 63% with an and 2k were cross-coupled successfully according to the
excellent ortho/para selectivity of (96:4). In order to optimized conditions and the products, 3j and 3k were
optimize the cross-coupling parameters, we chose bro- isolated in good yields (Table 1, entries 10, 11).
mobenzene (2a), being the simplest case, as the initial
At this point, we decided to introduce heteroaryl moieties
coupling partner. In a typical procedure, the halide was
into our investigation. Our initial attempts were focusing
sealed in a 10 mL sealed glass vial together with the bo-
on the indole skeleton, as a variety of indole containing
ronic acid (1.3 equiv), Na2CO3 (3.0 equiv) and Pd(Ph3P)4
compounds is well known for their biological activities.
[5 mol%] in a 1:1 mixture of toluene and water (3 mL) and
We decided to direct our explorations to the 4-, 5-, 6- and
7-analogues 2l–o, as the cross-coupling reactions and sub-
sequent manipulations at these centers are scarcely inves-
irradiated with a CEM-Discover16 mono-mode micro-
wave apparatus at 125 °C for 15 minutes, using a maxi-
mum power of 150 W. The reaction proceeded smoothly
tigated compared to the well-explored 2- and 3-positions.
and the required biaryl compound 3a was isolated in good
We could successfully perform the cross-coupling
yield of 70%, together with a minor amount of nitro-
reactions under microwave irradiation conditions in 20
Synlett 2005, No. 1, 127–133 © Thieme Stuttgart · New York

LETTER
Microwave-Enhanced Cadogan Cyclization
129
minutes and the products, 4-(2-nitrophenyl)-1H-indole 2- and 3-bromothiophenes as well as the 4-bromopyridine
(3l), 5-(2-nitrophenyl)-1H-indole (3m), 6-(2-nitrophe- 2p–r were successfully cross-coupled in the same manner
nyl)-1H-indole (3n) and 7-(2-nitrophenyl)-1H-indole in 15 minutes under microwave irradiation and the prod-
(3o), were isolated in excellent yields (Table 1, entries ucts 3p–r were isolated in good yields (Table 1, entries
12–15). As expected, the unprotected nitrogen atom of the 16–18).
indole did not cause any complexation problem with the
catalyst, and no substantial homo-coupling or proto-de-
boronation was observed during the reaction course. The
Table 1 Suzuki–Miyaura Cross-Coupling Reactions of 1a with Bromides 2a–ra,b
NO2
NO2
Pd(Ph3P)4, NaHCO3, MW
DMF-H2O (1:1), 10–20 min
R
B(OH)2
R-Br
3a–r
1a
R = aryl, heteroaryl
2a–r
Entry
R
Time (min) Yield (%)
Entry
R
Time (min)
15
Yield (%)
83
Br
Br
1
2
15
15
86
84
10
11
2a
2j
Br
Br
15
20
81
76
Me
2k
2b
Br
Br
3
4
MeO
15
15
89
79
12
13
2c
N
H
2l
Br
Br
Me
20
74
N
N
Me
H
2d
2m
Br
Br
5
6
10
10
88
74
14
15
20
20
77
73
Cl
N
H
2e
2n
Br
NC
N
H
Br
2f
2o
Br
Br
S
7
10
81
16
15
86
2p
O
2g
Synlett 2005, No. 1, 127–133 © Thieme Stuttgart · New York

130
P. Appukkuttan et al.
LETTER
Table 1 Suzuki–Miyaura Cross-Coupling Reactions of 1a with Bromides 2a–ra,b (continued)
NO2
NO2
B(OH)2
Pd(Ph3P)4, NaHCO3, MW
DMF-H2O (1:1), 10–20 min
R
R-Br
3a–r
1a
R = aryl, heteroaryl
2a–r
Entry
R
Time (min) Yield (%)
Entry
R
Time (min)
15
Yield (%)
Br
Br
8
10
84
17
89
MeOOC
S
2h
2q
2r
C6H13
Br
Br
9
15
87
18
15
85
Br
N
C6H13
2i
a All reactions were carried out on a 0.25 mmol scale with 1.3 equiv of boronic acid and 3.0 equiv of NaHCO3 in 3 mL of DMF–H2O (1:1) as
solvent at a ceiling temperature of 150 °C and a maximum power of 150 W for the times indicated in Table 1. All yields are isolated yields.
b 2.5 Equiv of boronic acid and 5.0 equiv base were used.
Thus, after having synthesized all the needed biaryl nitro tions, we found that the best parameters for microwave
compounds, we decided to direct our attention towards the irradiation were a maximum irradiation power of 300 W
Cadogan reductive cyclization. Microwave irradiation and a ceiling temperature of 210 °C. Even though the
was found to be extremely useful in this regard and the re- reaction proceeds also at a lower temperature of 180 °C, it
actions were remarkably faster compared to conventional was found to be slower, requiring a time of 25 minutes for
heating conditions. In a typical reaction, 0.25 mmol of the the completion.
2-nitro-biphenyl (3a) was suspended in 3 mL of triethyl
Our next aim was to explore the scope and limitations of
phosphite in a 10 mL sealed glass vial and the reaction
the strategy and we decided to extend our investigation to-
mixture was irradiated at 300 W maximum power with a
wards the entire range of 2-nitro-biaryls 3a–r generated
via the previously mentioned Suzuki–Miyaura cross-cou-
pre-selected temperature of 210 °C. The reaction was
found to be over in 15 minutes and after the usual acidic
pling reactions. The details of our experiments are sum-
work-up to remove the phosphate by-products, the
marized in Table 2.
product 4a was isolated in good yield (Table 2, entry 1).
The fact that reaction times could be brought down from
the order of hours to mere minutes clearly outlines the
benefit of microwave irradiation. After further optimiza-
Table 2 Microwave-Assisted Cadogan Cyclization of Nitro Compounds 3a–ra
X
X
Cadogan reaction
(EtO)3P, MW
n
n
R
R
N
H
NO2
4a-r
3a-r
No.
1
R
Time (min)
Yield (%) No.
R
Time (min)
Yield (%)
N
15
74
10
15
72
NH
H
4a
4j
Synlett 2005, No. 1, 127–133 © Thieme Stuttgart · New York

LETTER
Microwave-Enhanced Cadogan Cyclization
131
Table 2 Microwave-Assisted Cadogan Cyclization of Nitro Compounds 3a–ra (continued)
X
X
Cadogan reaction
(EtO)3P, MW
n
n
R
R
N
H
NO2
4a-r
3a-r
No.
2
R
Time (min)
Yield (%) No.
R
Time (min)
15
Yield (%)
Me
15
15
71
68
11
12
74
69
N
H
N
H
4b
4k
NH
OMe
3
20
N
H
N
H
4c
4l
Me
N
NH
4
5
15
10
63
74
13
14
20
20
73
64
Me
N
H
N
H
4d
4e
4m
H
N
Cl
N
H
N
H
4n
4o
HN
CN
6
10
68
15
20
67
N
H
N
H
4f
S
7
8
10
10
74
71
16
17
15
15
78
76
O
N
H
N
H
4g
4h
4p
4q
4r
S
COOMe
N
H
N
H
C6H13
H2N
N
9
15
59
18
15
79
N
H
N
H
C6H13
4i
a All reactions were carried out on a 0.25 mmol scale, in 3 mL of triethyl phosphite at a ceiling temperature of 210 °C and a maximum irradiation
power of 300 W for the times indicated in Table 2. All yields are isolated yields.
Synlett 2005, No. 1, 127–133 © Thieme Stuttgart · New York

132
P. Appukkuttan et al.
LETTER
As can be viewed from Table 2, the reactions proceeded In conclusion, we have demonstrated a versatile, efficient
smoothly in 10–20 minutes, and the products were isolat- and economical microwave-assisted pathway for the syn-
ed in good yields. The reaction times were slightly longer thesis of 2-substituted carbazoles and other difficultly ob-
(20 min) when electron-donating groups were present in tainable indolo-fused heterocyclic systems. Suzuki–
the biaryl compounds, presumably due to the more diffi- Miyaura cross-coupling reactions of 2-nitro-phenylboron-
cult insertion of the in situ generated nitrene to the elec- ic acid provides an easy access to the biaryl compounds
tron-rich ring system, and the products 4b–d were isolated required for the Cadogan cyclization, avoiding the use of
in acceptable yields (Table 2, entries 2–4). The synthesis expensive and difficult to synthesize heterocyclic boronic
of 2-methoxy-9H-carbazole (4c) was particularly interest- acids or stannanes. Microwave irradiation was found to be
ing, as a variety of naturally occurring carbazole alkaloids highly effective in minimizing the proto-deboronation, a
contain one or more methoxy groups on their skeleton. notoriously common problem associated with the cross-
When the biaryls were bearing electron-withdrawing coupling of boronic acids bearing electron-poor groups in
groups, the reactions were found to proceed smoothly in the ortho-position. The biaryl intermediates were then
10 minutes and the products 4e–h were isolated in good successfully ring-closed to the corresponding fused ring
yields (Table 2, entries 5–8). These examples clearly heterocycles under microwave-enhanced Cadogan cy-
show the usefulness of the methodology, as the usual way clization conditions and dramatic increases of the reaction
of synthesizing these molecules is often not straightfor- rates were observed. Further studies to extend this strate-
ward and rather long reaction times are needed for the gy towards a variety of novel heterocyclic skeletons are
conversion.17 In the case where the sterically hindered under current investigation.
biaryl nitro compound 3i was irradiated, only one of the
nitro groups underwent Cadogan cyclization generating
2-(1,4-dihexyl-9H-carbazol-2-yl)aniline (4i) as the sole
Acknowledgment
We thank the F.W.O. [Fund for Scientific Research – Flanders
(Belgium)] and Katholieke Universiteit Leuven for financial
support. P. A. thanks K. U. Leuven for the doctoral-fellowship
received. We also wish to thank Mr. K. Duerinckx and Prof. Dr.
S. Toppet for their valuable help with the NMR experiments.
product (Table 2, entry 9). This can be due to the com-
petitive overreduction of the nitrene, generating the amine
phosphate as the by-product, which on acidic work-up
sets free 4i.
Following the same protocol, the naphthalene derivatives
3j and 3k were successfully ring-closed in 25 minutes at
210 °C into the corresponding 7H-benzo[c]carbazole (4j)
and 5H-benzo[b]carbazole (4k) in good yields of 72% and
74%, respectively (Table 2, entries 10, 11). No side prod-
ucts of nitrene insertion at the alternative positions were
isolated during the course of the reaction. Our next goal
was the ring-closure of the indole analogues 3l–o, and we
started our explorations with 3l, as this intermediate gives
the possibility of two different Cadogan cyclization path-
ways, arising from the possible nitrene insertion at the C-
3 or C-5 position of the indole ring. The reaction was fin-
ished in 20 minutes at 210 °C and the only product isolat-
ed was 3,6-dihydropyrrolo[2,3-c]carbazole (4l, Table 2,
entry 12, 69%); no traces of C-3 insertion product were
detected throughout the course of the reaction. The 5-(2-
nitrophenyl)-1H-indole (3m) underwent Cadogan cy-
clization at the C-6 position of indole ring and the 1,9-di-
hydropyrrolo[2,3-b]carbazole (4m) was isolated in good
yield of 73% (Table 2, entry 13). No trace of the isomer
arising from the nitrene insertion at the C-4 position of the
indole was observed. Similarly the 6- and 7-analogues
3n,o underwent the reductive cyclization in 20 minutes
generating the products 1,5-dihydropyrrolo[3,2-b]carba-
zole (4n) and 1,6-dihydropyrrolo[3,2-c]carbazole (4o) in
moderate to good yields of 64% and 67%, respectively
(Table 2, entries 14, 15). The thiophene derivatives 3p,q
and the pyridine analogues 3r were similarly ring-closed
in 15 minutes under microwave irradiation18 at 210 °C
and the products 4p,r were isolated in good yields
(Table 2, entries 16–18).
References
(1) (a) Lee, J. H.; Park, J. W.; Chot, S. K. Synth. Met. 1997, 88,
31. (b) Cho, C. S.; Wang, W. T. Macromol. Chem. Phys.
2001, 202, 2864. (c) Thomas, J. K. R.; Jian, L. T. J. Am.
Chem. Soc. 2001, 123, 9404.
(2) (a) Romeo, D. B.; Schaer, M.; Leclerc, M.; Ades, D.; Siove,
A.; Zuppiroli, L. Synth. Met. 1996, 80, 271. (b) Morin, J.-
F.; Leclerc, M. Macromolecules 2002, 35, 8413; and
references cited therein.
(3) McClenaghan, N. D.; Passalacqua, R.; Loiseau, F.;
Campagna, S.; Verheyde, B.; Hameurlaine, A.; Dehaen, W.
J. Am. Chem. Soc. 2003, 125, 5356.
(4) For a recent review about the synthesis of biologically active
carbazole alkaloids, see: Knölker, H.-J.; Reddy, K. R. Chem.
Rev. 2002, 102, 4303.
(5) (a) Cao, R.; Chen, Q.; Hou, X.; Chen, H.; Guan, H.; Ma, Y.;
Peng, W.; Xu, A. Bioorg. Med. Chem. 2004, 12, 4613.
(b) Kanekiyo, N.; Kuwada, T.; Choshi, T.; Nobuhiro, J.;
Hibino, S. J. Org. Chem. 2001, 66, 8793. (c) Hino, T.;
Nakagawa, M. J. Heterocycl. Chem. 2000, 37, 567.
(d) Beria, I.; Cozzi, P.; Baraldi, P. G.; Spalluto, G.; Geroni,
M. C. Brit. UK Pat. Appl. GB 2344818 CAN 133:321873,
2000. (e) Jakobsen, P.; Kanstrup, A.; Faarup, P.; Olesen, P.
H.; Lundbech, J. M. U.S. 5,536,721, 1998. (f)Olesen,P. H.;
Hansen, J. B.; Engelstoft, M. J. Heterocycl. Chem. 1995, 32,
1641.
(6) (a) Joshi, B. S.; Gawad, D. H. Indian J. Chem. 1974, 12,
437. (b) Bhattacharyya, P.; Chakraborty, A. Phytochemistry
1984, 23, 471. (c) Chakraborty, D. P.; Das, A. P. Sci. Cult.
(India) 1966, 32, 181. (d) Ruangrungsi, N.; Ariyaprayoon,
J.; Lange, G. L.; Organ, M. G. J. Nat. Prod. 1990, 53, 946.
(e) Jash, S. S.; Biswas, G. K.; Bhattacharyya, S. K.;
Bhattacharyya, P.; Chakraborty, A.; Choudhury, B. K.
Phytochemistry 1992, 31, 2503.
Synlett 2005, No. 1, 127–133 © Thieme Stuttgart · New York

LETTER
Microwave-Enhanced Cadogan Cyclization
133
(7) (a) Cadogan, G. I. J.; Carmen-Wood, M. Proc. Chem. Soc.
1962, 361. (b) Cadogan, G. I. J.; Carmen-Wood, M.; Makie,
R. K.; Searle, R. J. G. J. Chem. Soc. 1965, 4831.
(c) Cadogan, G. I. J. Organophosphorus Reagents in
Organic Synthesis; Academic Press Inc.: London, 1979,
279.
(8) (a) Akermark, B.; Eberson, L.; Jonsson, E.; Patterson, E. J.
Org. Chem. 1975, 40, 1365. (b) Ames, D. E.; Bull, D.
Tetrahedron 1982, 38, 383. (c) Ames, D. E.; Opalko, A.
Tetrahedron 1984, 40, 1919. (d) Hegedus, L. S. Angew.
Chem., Int. Ed. Engl. 1988, 27, 1113; Angew. Chem. 1988,
100, 1147.
(18) General Procedure for the Microwave-Enhanced Suzuki
Reaction and Cadogan Cyclization – Synthesis of 8H-
Thieno[2,3-b]indole (4q): 3-Bromothiophene (2q, 0.041 g,
0.25 mmol), 2-nitrophenylboronic acid (0.054 g, 0.325
mmol), NaHCO3 (0.063 g, 0.75 mmol) and
tetrakis(triphenylphosphine)palladium(0) (0.015 g, 5 mol%)
were suspended in DMF (1.5 mL) and H2O (1.5 mL) in a 10
mL glass vial equipped with a small stirring magnet. The vial
was sealed tightly with an aluminium-Teflon® crimp top and
the mixture was irradiated in the cavity of a mono-mode
CEM®-Discover machine for 15 min at a pre-selected
temperature of 150 °C, using a maximum irradiation power
of 100 W. After the reaction, the vial was cooled to 50 °C by
gas jet cooling. The crude mixture was partitioned between
Et2O and H2O (25 mL each) and the aqueous layer was
extracted with Et2O (3 × 20 mL). The combined organic
layers were dried on MgSO4 and solvents were removed
under vacuum to yield the crude product as yellow oil.
Column chromatography [silica gel, heptane–EtOAc (9:1)]
afforded the biaryl compound 3q (0.046 g, 890%) as
yellowish oily material.
(9) (a) Pizzotti, M.; Cenini, S.; Quici, S.; Tollari, S. J. Chem.
Soc., Perkin Trans. 2 1994, 913. (b) Smitrovich, J. H.;
Davies, I. W. Org. Lett. 2004, 6, 533.
(10) (a) Adam, D. Nature 2003, 421, 571. (b) Kaval, N.; Van der
Eycken, J.; Caroen, J.; Dehaen, W.; Strohmeier, G. A.;
Kappe, C. O.; Van der Eycken, E. J. Comb. Chem. 2003, 5,
560. (c) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A.
R. J. Comb. Chem. 2002, 2, 95. (d) Kappe, C. O. Curr.
Opin. Chem. Biol. 2002, 6, 314. (e) Lidström, P.; Westman,
J.; Lewis, A. Comb. Chem. High Throughput Screening
2002, 5, 441. (f) Van der Eycken, E.; Appukkuttan, P.; De
Borggraeve, W.; Dehaen, W.; Dallinger, D.; Kappe, C. O. J.
Org. Chem. 2002, 67, 7904.
The nitro compound 3q was suspended in triethyl phosphate
(3 mL) in a tightly sealed 10 mL glass vial and was irradiated
at a maximum irradiation power of 300 W for 15 min at a
pre-selected temperature of 210 °C. After the reaction, the
vial was cooled to 50 °C by gas jet cooling and the contents
were transferred to a 50 mL flask with the help of EtOAc (10
mL). This mixture was then heated to 80 °C with an excess
of HCl (6 N, 10 mL) and maintained at the temperature for 3
h. After cooling to r.t., the mixture was partitioned between
H2O and EtOAc (20 mL each) and the aqueous layer was
further extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried over MgSO4 and solvents were
removed under reduced pressure, and further purification by
column chromatography (silica gel, heptane–EtOAc, 9:1)
afforded the thieno-indole 4q (0.0296 g, 76%). 1H NMR
(300 MHz, CDCl3): d = 6.92 (d, 1 H, J = 5.2 Hz), 7.19–7.27
(m, 2 H), 7.36 (d, 1 H, J = 5.2 Hz), 7.41 (d, 1 H, J = 8.0 Hz),
(11) (a) Bouchard, J.; Wakim, S.; Leclerc, M. J. Org. Chem.
2004, 69, 5705. (b) Morin, J.-F.; Leclerc, M.
Macromolecules 2001, 34, 4680. (c) Holzapfel, C. W.;
Dwyer, C. Heterocycles 1998, 48, 1513.
(12) Monovich, L. G.; Le Huérou, Y.; Rönn, M.; Molander, G. A.
J. Am. Chem. Soc. 2000, 122, 52; and references cited
therein.
(13) (a) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org.
Chem. 1994, 59, 6095. (b) Gronowitz, S.; Hörnfledt, A.-B.;
Yang, Y.-H. Chem. Scr. 1986, 26, 383. (c) Watanabe, T.;
Miyaura, N.; Suzuki, A. Synlett 1992, 207.
(14) Appukkuttan, P.; Orts, A. B.; Chandran, R. P.; Goeman, J.
L.; Van der Eycken, J.; Dehaen, W.; Van der Eycken, E. Eur.
J. Org. Chem. 2004, 3277.
7.81 (dd, 1 H, J = 7.6, 0.8 Hz), 8.22 (br s, 1 H) ppm. 13
C
(15) Seaman, W. J. Am. Chem. Soc. 1931, 53, 711.
(16) CEM-Discover, CEM Corporation P.O. Box 200 Matthews,
NC 28106.
(17) (a) Kikugawa, Y.; Aoki, Y.; Sakamoto, T. J. Org. Chem.
2001, 66, 8612. (b) Hewlins, M. J. E.; Jackson, A. H.; Long,
A.; Campos, A.-O.; Shannon, P. V. R. J. Chem. Res., Synop.
1986, 8, 292. (c) Patel, B. P. J. J. Ind. Chem. Soc. 1985, 62,
534. (d) Clancy, M. G.; Hesabi, M. M.; Otto, M.-C. J. Chem.
Soc., Perkin Trans. 1 1984, 3, 429.
NMR (75 MHz, CDCl3): d = 111.2, 117.1, 117.6, 119.3,
119.9, 122.2, 122.5, 125.6, 141.2, 142.2 ppm. DEPT-NMR
(75 MHz, CDCl3): d = 111.2, 117.1, 117.6, 119.3, 122.5,
125.6 ppm. MS (EI): 173 [M+]. HRMS (EI): m/z calcd for
C10H07NS [M+]: 173.02992; found: 173.02986.
Synlett 2005, No. 1, 127–133 © Thieme Stuttgart · New York