A route to regioselectively functionalized carbazoles, dibenzofurans, and dibenzothiophenes through anionic cyclization of benzyne-tethered aryllithiums

Article abstract of DOI:10.1021/jo060911c

The treatment of 2-fluorophenyl 2-iodophenylamines, ether, and thioether, easily prepared from commercially available products, with 3.3 equiv of t-BuLi and further reaction with selected electrophiles gives rise to functionalized carbazole, dibenzofuran, and dibenzothiophene derivatives in a direct and regioselective manner. The process involves an anionic cyclization on a benzyne-tethered aryllithium intermediate.

Full text of DOI:10.1021/jo060911c

bearing neighboring electrophiles to afford overall aryne inser-
tion products5 and the construction of benzo-fused polycyclic
systems by the addition of a nucleophile that is part of an aryne
side chain. This last procedure, often called the benzyne
cyclization,6 has been extensively used for making four-, five-,
and six-membered rings. In this field, while intramolecular
additions of heteroatomic nucleophiles7 or stabilized carbanions8
to a benzyne is a well-developed synthetic procedure, the
generation and cyclization of benzyne-tethered organolithiums
remains a largely unexplored area and only few examples with
alkyllithiums have been reported.9 In this area, we have
described the intramolecular anionic cyclization of benzyne-
tethered vinyllithiums and its application to the synthesis of
4-functionalized indole derivatives.10 In this context, we envis-
aged that if we were able to prepare a o-lithiophenyl o-benzyne
amine, ether, or thioether, the subsequent intramolecular cy-
clization and further treatment with electrophiles would provide
the corresponding regioselectively functionalized carbazole,
dibenzofuran, or dibenzothiophene derivative (Scheme 1). This
approach would represent an efficient strategy for simultaneous
formation and regioselective functionalization of dibenzo-fused
five-membered heterocycles.
A Route to Regioselectively Functionalized
Carbazoles, Dibenzofurans, and
Dibenzothiophenes through Anionic Cyclization
of Benzyne-Tethered Aryllithiums
Roberto Sanz,*,† Yolanda Ferna´ndez,†,§
Ma Pilar Castroviejo,† Antonio Pe´rez,† and
Francisco J. Fan˜ana´s‡
Departamento de Qu´ımica, AÄ rea de Qu´ımica Orga´nica,
Facultad de Ciencias, UniVersidad de Burgos, Pza. Misael
Ban˜uelos s/n, 09001-Burgos, Spain, and Instituto UniVersitario
de Qu´ımica Organometa´lica “Enrique Moles”, UniVersidad de
OViedo, C/Julia´n ClaVer´ıa, 8, 33006-OViedo, Spain
rsd@ubu.es
ReceiVed May 2, 2006
Carbazoles, in view of incorporating an indole nucleus in their
moieties, are the core structures of numerous biologically active
compounds,11 and several carbazole derivatives are also widely
used as organic materials, due to their optical, electronic, and
charge-transport properties.12 Thus, a wide range of substituted
carbazoles have been prepared by different approaches, mainly
reductive cyclization of 2-nitrobiphenyls13 and Pd-catalyzed
The treatment of 2-fluorophenyl 2-iodophenylamines, ether,
and thioether, easily prepared from commercially available
products, with 3.3 equiv of t-BuLi and further reaction with
selected electrophiles gives rise to functionalized carbazole,
dibenzofuran, and dibenzothiophene derivatives in a direct
and regioselective manner. The process involves an anionic
cyclization on a benzyne-tethered aryllithium intermediate.
(4) For recent reports, see: (a) Iglesias, B.; Cobas, A.; Pe´rez, D.; Guitia´n,
E. Org. Lett. 2004, 6, 3557-3560. (b) Sato, Y.; Tamura, T.; Mori, M.
Angew. Chem., Int. Ed. 2004, 43, 2436-2440. (c) Jayanth, T. T.;
Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2005, 7, 2921-2924. (d) Liu,
Z.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 15716-15717.
(e) Jayanth, T. T.; Cheng, C.-H. Chem. Commun. 2006, 894-896.
(5) (a) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem.,
Int. Ed. 2002, 41, 3247-3249. (b) Tambar, U. K.; Stoltz, B. M. J. Am.
Chem. Soc. 2005, 127, 5340-5341. (c) Yoshida, H.; Watanabe, M.; Ohshita,
J.; Kunai, A. Tetrahedron Lett. 2005, 46, 6729-6731. (d) Liu, Z.; Larock,
R. C. J. Am. Chem. Soc. 2005, 127, 13112-13113.
Chemistry of arynes provides a robust tool for synthetic
design and methodology.1 The recent reports concerned with
formation,2 synthetic applications,3 and in particular transition-
metal-catalyzed4 reactions of arynes illustrate the continued
interest in this area. Some of the most productive applications
of benzyne chemistry are their reactions with nucleophiles
(6) Introduced independently by Huisgen and Bunnet: (a) Huisgen, R.;
Sauer, J. Angew. Chem. 1960, 72, 91-108. (b) Bunnett, J. F.; Hrutfiord, B.
F. J. Am. Chem. Soc. 1961, 83, 1691-1697.
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3676. (b) Stanetty, P.; Krumpak, B. J. Org. Chem. 1996, 61, 5130-5133.
(c) Knight, D. W.; Little, P. B. J. Chem. Soc., Perkin Trans. 1 2001, 1771-
1777. (d) Fairhurst, R. A.; Janus, D.; Lawrence, A. Org. Lett. 2005, 7, 4697-
4700.
(8) (a) Iwao, M. J. Org. Chem. 1990, 55, 3622-3627. (b) Hoarau, C.;
Couture, A.; Deniau, E.; Grandclaudon, P. Synthesis 2000, 655-660 and
references therein.
† Universidad de Burgos.
‡ Universidad de Oviedo.
§ Present address: Ragactives, S.A., Parque Tecnolo´gico de Boecillo, 47151-
Boecillo, Valladolid, Spain.
(1) For reviews, see: (a) Biehl, E. R.; Khanapure, S. P. Acc. Chem. Res.
1989, 22, 275-281. (b) Kessar, V. S. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter
2.3. (c) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701-730. (d)
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6901.
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1211-1214. (b) Kitamura, T.; Yamane, M.; Inoue, K.; Todaka, M.; Fukatsu,
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(3) For recent applications, see: (a) Yoshida, H.; Fukushima, H.; Ohshita,
J.; Kunai, A. Angew. Chem., Int. Ed. 2004, 43, 3935-3938. (b) Hayes, M.
E.; Shinokubo, H.; Danheiser, R. L. Org. Lett. 2005, 7, 3917-3920. (c)
Lin, W.; Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 4258-
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M.; Cheng, M.-J.; Chu, S.-Y.; Cheng, C.-H. J. Am. Chem. Soc. 2006, 128,
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Lett. 1999, 40, 1049-1052. (b) Barluenga, J.; Fan˜ana´s, F. J.; Sanz, R.;
Ferna´ndez, Y. Chem.sEur. J. 2002, 8, 2034-2046.
(11) For a review, see: Knolker, H.-J.; Kethiri, R. R. Chem. ReV. 2002,
102, 4303-4428.
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2536. (b) Bouchard, J.; Wakim, S.; Leclerc, M. J. Org. Chem. 2004, 69,
5705-5711.
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10.1021/jo060911c CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/04/2006
J. Org. Chem. 2006, 71, 6291-6294
6291

SCHEME 1. Retrosynthetic Analysis of Functionalized
Dibenzo-Fused Five-Membered Heterocycles
SCHEME 2. Preparation of 2-Fluorophenyl 2-Halophenyl
Amines 3a-ca
reactions, such as intramolecular arylation of N,N-diaryl-
amines,14 cyclization of 2-arylacetanilides,15 oxidative cycliza-
tion of 3-(3′-alkenyl)indoles,16 or double N-arylation of primary
amines.17 Oxygen and sulfur analogues of carbazoles, such as
dibenzofurans18 and dibenzothiophenes,19 are also biologically
interesting due to their occurrence in a wide variety of
pharmaceutical and natural products possessing useful biological
activities. This has prompted the development of versatile and
regioselective synthetic routes to these compounds20 with
functional groups at specific positions, as well as interesting
synthetic transformations that use these substrates as starting
materials.21
In this paper, we wish to report a novel synthesis of
selectively functionalized carbazole, dibenzofuran, and diben-
zothiophene derivatives by anionic cyclization of benzyne-
tethered aryllithiums.
a Reagents and conditions: (a) Cs2CO3 (1.4 equiv), Pd2(dba)3 (3 mol
%), BINAP (4.5 mol %), 1-Br-2-NO2C6H4 (1 equiv), toluene, 100 °C, 16
h; (b) (1) n-BuLi (1 equiv), THF, -50 to 20 °C, 1 h; (2) 1-Cl-2-NO2C6H4
(1.5 equiv), THF, -78 to reflux, 12 h; (c) KBH4 (7 equiv), CuCl (3 equiv),
MeOH, 20 °C, 30 min; (d) (1) NaNO2 (1.1 equiv), H2SO4, 0 °C, 30 min;
(2) KI (1.3 equiv), 0 °C to reflux, 30 min; (e) (1) NaH (1.5 equiv), DMF,
0 °C, 30 min; (2) MeI (1.3 equiv), DMF, 0 to 20 °C, 1 h.
To develop a route to prepare functionalized carbazoles
according to our retrosynthetic analysis (Scheme 1), we needed
to synthesize 2-fluorophenyl 2-halophenylamines 3. Thus, the
starting compounds 3a,b were easily prepared from com-
mercially available o-halonitrobenzenes and 2-fluoroaniline in
a three-step sequence, as shown in Scheme 2. First, Pd/BINAP-
catalyzed amination22 of o-bromonitrobenzene with N-methyl-
2-fluoroaniline using cesium carbonate as base gave rise in good
yield to tertiary amine 1a (Scheme 2). Amine 1b was prepared
by deprotonation of N-(3-dimethylaminopropyl)-2-fluoroaniline
with n-BuLi in THF and subsequent alkylation with o-
chloronitrobenzene.23 In a second step, reduction of the nitro
group into an amino group yielded diamines 2a,b in high yields.
This process was carried out with potassium borohydride in the
presence of copper(I) chloride.24 In the last step, diazotation
and further displacement by iodide25 afforded the desired iodo
SCHEME 3. Synthesis of 4-Functionalized Carbazoles 4
derivatives 3a,b in moderate to good yields (Scheme 2).
Alternatively, related N-(2-bromophenyl)-N-(2-fluorophenyl)-
methylamine 3c could be prepared in two steps from com-
mercially available 2-bromoaniline and 2-bromofluorobenzene.
Their Pd/BINAP-catalyzed coupling in the same conditions as
above22 afforded N-(2-bromophenyl)-2-fluoroaniline though in
a modest yield. This diarylamine was easily alkylated in almost
quantitative yield with NaH/MeI in DMF (Scheme 2). On the
basis of the starting materials, we obtained comparable overall
yields from both routes.
Once we had prepared amines 3, we investigated the best
conditions to generate the targeted benzyne-tethered aryllithium.
We found that treatment of 3a or 3c with 3.3 equiv of t-BuLi
in THF at low temperature and further warming to 0 °C afforded
after hydrolysis 9-methyl-9H-carbazole 4a in good yield (Scheme
3 and Table 1). We have also observed that the addition of only
2 equiv of t-BuLi gave rise to selectively iodine- or bromine-
lithium exchange. The formation of the carbazole skeleton could
be explained through an intramolecular anionic 5-exo-dig
(14) Campeau, L.-C.; Thansandote, P.; Fagnou, K. Org. Lett. 2005, 7,
1857-1860. Larock and Liu have reported a two-step synthesis of carbazoles
and dibenzofurans by the cross-coupling of o-iodoanilines or phenols with
arynes, followed by Pd-catalyzed intramolecular cyclization: Liu, Z.;
Larock, R. C. Org. Lett. 2004, 6, 3739-3741.
(15) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560-14561.
(16) Kong, A.; Han, X.; Lu, X. Org. Lett. 2006, 8, 1339-1342.
(17) Nozaki, K.; Takahashi, K.; Nakano, K.; Hiyama, T.; Tang, H.-Z.;
Fujiki, M.; Yamaguchi, S.; Tamao, K. Angew. Chem., Int. Ed. 2003, 42,
2051-2053.
(18) (a) Sargent, M. V.; Stransky, P. O. Dibenzofurans. In AdVances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: London,
1984; Vol. 35, pp 2-81. (b) Jones, K. Sci. Synth. 2001, 10, 131-153.
(19) Andrews, M. D. Sci. Synth. 2001, 10, 211-263.
(20) For recent reports about the synthesis of dibenzofurans, see: (a)
Wu, M.-J.; Lee, C.-Y.; Lin, C.-F. Angew. Chem., Int. Ed. 2002, 41, 4077-
4079. (b) Serra, S.; Fuganti, C. Synlett 2003, 2005-2008. (c) Goel, A.;
Dixit, M.; Verma, D. Tetrahedron Lett. 2005, 46, 491-493.
(21) Cho, Y.-H.; Kina, A.; Shimada, T.; Hayashi, T. J. Org. Chem. 2004,
69, 3811-3823.
(22) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144-1157.
(23) Secondary N-alkyl-2-fluoroanilines were prepared by alkylation of
2-fluoroaniline; see ref 10b. Although in lower yield, amine 1a could also
be prepared by treatment of the lithium amide of N-methyl-2-fluoroaniline
with o-chloronitrobenzene in THF at reflux.
(24) He, Y.; Zhao, H.; Pan, X.; Wang, S. Synth. Commun. 1989, 19,
3047-3050.
(25) Scott, T. L.; So¨derberg, B. C. G. Tetrahedron 2003, 59, 6323-
6332.
6292 J. Org. Chem., Vol. 71, No. 16, 2006

TABLE 1. Preparation of Functionalized Carbazoles 4 from
Amines 3a-c
SCHEME 4. Synthesis of 1-Functionalized Dibenzofurans
10 and Dibenzothiophenes 11a
yielda
(%)
entry amine
R
E+
product
E
1
2
3
4
5
6
7
8
3a Me
MeOH
Ph2S2
Br(CH2)2Br
PhNCO
Et2CO
4a
4b
4c
4d
4e
4f
H
SPh
Br
CONHPh
Et2C(OH)
H
79
64
70
71
74
70
61
3a Me
3a Me
3c Me
3c Me
3b (CH2)3NMe2 MeOH
3b (CH2)3NMe2 Bu3SnCl
3b (CH2)3NMe2 p-TolCHO
4g
4h
SnBu3
p-TolC(H)OH 58
a Isolated yield based on starting amines 3.
cyclization on the benzynic intermediate 5, which is generated
by consecutive halogen-lithium exchange, abstraction of the
proton ortho to the fluorine atom, and elimination of lithium
fluoride, affording in this way a regioselectively lithiated
carbazole derivative 6 (Scheme 3).26 The intermediacy of 6 was
confirmed by its quenching with selected electrophiles and
isolation of 4-functionalized carbazoles 4b-e (Scheme 3 and
Table 1, entries 2-5). With the starting amine 3b, we found
that its double lithiation took place under the same reaction
conditions as the parent amines 3a,c. It is interesting to note
that even the occurrence of a potentially metalating directing
group, such as the dimethylamino, did not represent any
difficulty and, in fact, a good yield of the desired product was
obtained. So, treatment of 3b with 3.3 equiv of t-BuLi from
-78 to 0 °C and further addition of electrophiles afforded the
corresponding 4-functionalized carbazoles 4f-h in similar yields
as those reported for carbazoles obtained from 3a,c (Scheme 3
and Table 1, entries 6-8). The easy preparation of N-(3-
dimethylaminopropyl)carbazole derivatives 4f-h following this
methodology should be remarked as compounds with related
structures are very useful products in medicinal chemistry.27
Using this anionic benzyne cyclization methodology, it has been
possible to further functionalize the cyclized product by reaction
with electrophilic reagents, and so the introduction at C4 of a
bromine (4c) or a tri-n-butylstannyl group (4g) is particularly
useful for, for example, further transformations via Pd-catalyzed
coupling reactions. Moreover, the most reactive positions for
electrophilic substitution in carbazoles are the 3 and 6 positions,
para to the nitrogen atom, and to a lesser extent, the 1 and 8
positions,28 and therefore, the regioselective introduction of
substituents at the 4 position still remains an attractive objective
in carbazole chemistry.29
a Reagents and conditions: (a) o-ClC6H4NO2 (1.5 equiv), Cu2O (1.5
equiv), pyridine, 20 °C to reflux, 12 h; (b) Fe (3 equiv), HCl/EtOH, reflux,
6 h; (c) (1) NaNO2 (1.1 equiv), H2SO4, 0 °C, 30 min; (2) KI (1.3 equiv),
0 °C to reflux, 30 min.
TABLE 2. Preparation of Functionalized Dibenzofurans 10 and
Dibenzothiophenes 11
starting
product
yielda
(%)
entry
E+
product
E
1
2
3
4
5
6
7
8
9
9a
9a
9a
9a
9a
9b
9b
9b
9b
ClCO2Et
Ph2S2
p-TolCN
PhNCO
Et2CO
MeOH
Ph2S2
Br(CH2)2Br
p-TolCHO
10a
10b
10c
10d
10e
11a
11b
11c
11d
CO2Et
SPh
p-TolCO
CONHPh
Et2C(OH)
H
SPh
Br
p-TolC(H)OH
67
61
62
63
55
79
78
76
75
a Isolated yield based on starting products 9.
with 2-fluorophenol or 2-fluorothiophenol, respectively, in the
presence of copper(I) oxide and pyridine30 afforded diaryl ether
7a and thioether 7b in good yields (Scheme 4). The reduction
of the nitro groups was carried out with Fe in HCl giving rise
to the corresponding amino derivatives 8a,b. Finally, their
diazotation and further displacement by iodide25 allowed the
preparation of the required compounds 9a,b in overall good
yields (Scheme 4). Reaction of 9a,b in the same conditions as
described above for amines 3, that is, addition of 3.3 equiv of
t-BuLi at -78 °C, warming to 0 °C, and trapping with selected
electrophiles, afforded 1-functionalized dibenzofurans 10 and
dibenzothiophenes 11 in good yields (Scheme 4 and Table 2).
Again, a benzyne-tethered aryllithium 12 accounts for the
regioselective functionalization of the final heterocycles. These
results illustrate the usefulness of this methodology for the
synthesis of dibenzofurans and dibenzothiophenes functionalized
at C1, which are difficult to prepare in isomerically pure form
using classical organic chemistry.
After the synthesis of carbazoles by the described method,
we turned our attention to the possibility of applying this
methodology for the preparation of related dibenzofurans and
dibenzothiophenes starting from the corresponding 2-fluorophe-
nyl ether 9a and thioether 9b. The synthesis of these compounds
is shown in Scheme 4, and so, treatment of o-chloronitrobenzene
(26) Treatment of N-(2-bromophenyl)-2-fluoroaniline with 4.3 equiv of
t-BuLi only gave rise to deprotonation and bromine-lithium exchange.
Subsequent cyclization was not observed.
In summary, we have developed a practical and efficient route
to regioselectively functionalized carbazoles and related diben-
zofurans and dibenzothiophenes. The starting materials (2-
fluoroanilines, 2-fluorophenol, 2-fluorothiophenol, and o-ha-
lonitrobenzenes) are commercially available or can be easily
made. The key step is the selective formation of a benzyne-
(27) (a) Windholz, M., Budavari, S., Blumetti, R. F., Otterbein, E. S.,
Eds. The Merck Index: An Encyclopedia of Chemicals, Drugs and
Biologicals; Merck & Co., Inc.: Rathway, NJ, 1983. (b) Katritzky, A. R.;
Rachwal, S.; Rachwal, B. J. Org. Chem. 1994, 59, 5206-5214.
(28) Joule, J. A. In AdVances in Heterocyclic Chemistry; Katritzky, A.
R., Ed.; Academic Press: Orlando, FL, 1984; Vol. 35, pp 83-198.
(29) (a) Lee, C.-Y.; Lin, C.-F.; Lee, J.-L.; Chiu, C.-C.; Lu, W.-D.; Wu,
M.-J. J. Org. Chem. 2004, 69, 2106-2110. (b) Zhao, J.; Larock, R. C.
Org. Lett. 2005, 7, 701-704.
(30) Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65, 6319-6337.
J. Org. Chem, Vol. 71, No. 16, 2006 6293

evaporated under reduced pressure. The crude product was purified
by column chromatography (eluent: hexane) on silica gel to afford
4c (0.182 g, 70%) as a white solid: mp 97-99 °C; 1H NMR (400
MHz, CDCl3) δ 8.79 (d, J ) 8.0 Hz, 1H), 7.56-7.52 (m, 1H),
7.41-7.29 (m, 5H), 3.80 (s, 3H); 13C NMR (100.6 MHz, CDCl3)
δ 141.9 (C), 140.9 (C), 126.2 (CH), 126.0 (CH), 122.9 (CH), 122.5
(CH), 122.2 (C), 121.3 (C), 118.9 (CH), 116.6 (C), 108.2 (CH),
107.2 (CH), 29.0 (CH3); EI-LRMS m/z 261 (M+ + 2, 100), 259
(M+, 100); IR (KBr) 2924, 1600, 1464 cm-1. HRMS calcd for
C13H10BrN, 258.9997; found, 259.9989. Anal. Calcd for C13H10-
BrN: C, 60.02; H, 3.87; N, 5.38. Found: C, 60.13; H, 3.88; N,
5.36.
tethered aryllithium followed by an intramolecular anionic
cyclization and further trapping of the resulting organolithium
with several electrophiles. This strategy allows the synthesis of
carbazoles, dibenzofurans, and dibenzothiophenes substituted
at positions which are difficult to functionalize by traditional
methods. We believe that this methodology constitutes a
synthetically competitive alternative to the existing strategies
for the construction of this kind of regioselectively substituted
dibenzo-fused heterocycles.
Experimental Section
General Procedure for the Synthesis of 4-Functionalized
Carbazoles 4, 1-Functionalized Dibenzofurans 10, and Diben-
zothiophenes 11. Synthesis of 4-Bromo-9-methyl-9H-carbazole
(4c; Table 1, Entry 3). t-BuLi (2.2 mL of a 1.5 M solution in
pentane, 3.3 mmol) was added to a solution of amine 3a (0.327 g,
1 mmol) in THF (8 mL) at -78 °C. The resulting solution was
stirred for 20 min at this temperature, and then, the reaction mixture
was allowed to warm to 0 °C and stirred for 30 min. After cooling
to -78 °C, 1,2-dibromoethane (0.225 g, 1.2 mmol) was added
dropwise, and stirring continued at low temperature for further 30
min. The reaction mixture was then allowed to warm to room
temperature, quenched with water, and extracted with EtOAc (3 ×
20 mL). The combined organic layers were dried (Na2SO4) and
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia and FEDER (CTQ2004-08077-C02-02/BQU) for
financial support. M.P.C. thanks the Ministerio de Educacio´n
y Ciencia for a MEC-FPU predoctoral fellowship. Many thanks
are due to Dr. F. Rodr´ıguez (Universidad de Oviedo) for helpful
comments.
Supporting Information Available: Typical experimental
procedures and spectroscopic details for all compounds and a copy
of 1H and 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO060911C
6294 J. Org. Chem., Vol. 71, No. 16, 2006