Double N-arylation of primary amines: Carbazole synthesis from 2,2′-biphenyldiols

Article abstract of DOI:10.1021/jo048472+

(Chemical Equation Presented) The double N-arylation of primary amines with 2,2′-biphenylylene ditriflates was investigated for the synthesis of multisubstituted carbazoles. Palladium complexes supported by 2-dicyclohexylphosphino-2′-methylbiphenyl or Xantphos [4,5- bis(diphenylphosphino)-9,9-dimethylxanthene] were found to be efficient catalysts for the reaction. The catalysts allow the use of anilines with an electron-donating or electron-withdrawing substituent and multisubstituted 2,2′-biphenylylene ditriflates as substrates. Ammonia equivalents, such as O-tert-butyl carbamate, are also employable as a nitrogen source to give the N-protected carbazoles which can easily give the corresponding N-unsubstituted carbazoles after deprotection. By using this methodology, a carbazole alkaloid, mukonine, is synthesized in 40% yield for five steps, in comparable efficiency to the recent precedents.

Full text of DOI:10.1021/jo048472+

Double N-Arylation of Primary Amines: Carbazole Synthesis from
2,2′-Biphenyldiols
Atsushi Kuwahara, Koji Nakano, and Kyoko Nozaki*
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
nozaki@chembio.t.u-tokyo.ac.jp
Received August 31, 2004
The double N-arylation of primary amines with 2,2′-biphenylylene ditriflates was investigated for
the synthesis of multisubstituted carbazoles. Palladium complexes supported by 2-dicyclohexyl-
phosphino-2′-methylbiphenyl or Xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] were
found to be efficient catalysts for the reaction. The catalysts allow the use of anilines with an
electron-donating or electron-withdrawing substituent and multisubstituted 2,2′-biphenylylene
ditriflates as substrates. Ammonia equivalents, such as O-tert-butyl carbamate, are also employable
as a nitrogen source to give the N-protected carbazoles which can easily give the corresponding
N-unsubstituted carbazoles after deprotection. By using this methodology, a carbazole alkaloid,
mukonine, is synthesized in 40% yield for five steps, in comparable efficiency to the recent
precedents.
Introduction
Conventional methodology for carbazole ring construc-
tion is briefly summarized below.3 The classical Fischer-
Borsche synthesis starts with appropriate cyclohexanone
arylhydrazones.3a From indole, cyclization via Diels-
Alder reaction or via ketosulfoxide was reported.4 Alter-
natively, cyclization of ortho-nitrogen-substituted bi-
phenyl via nitrene was developed.5 Recent development
of organometallic chemistry provided successful prece-
dents for metal-catalyzed synthesis of carbazole rings;
for example, the electrophilic addition of a cationic metal
dienyl complex to a multisubstituted aniline at the ortho
position of the nitrogen atom, followed by intramolecular
metal-catalyzed oxidative cyclization6 and the N-arylation
of an aniline by a haloarene followed by oxidative
cyclization.7,8
Carbazole derivatives are known as alkaloids from
plants, and many of these show antioxidative and bio-
logical activities, such as antitumor, psychotropic, anti-
inflammatory, antihistaminic, and antibiotic activities.1
Carbazole derivatives are also widely used as organic
materials, due to their photorefractive, photoconductive,
hole-transporting, and light-emitting properties.2 To
investigate the biological and physical properties of
carbazole derivatives, the introduction of substituents
onto a carbazole is essential. Because the standard
electrophilic substitution takes place mostly at the 3-, 6-,
and 9-positions of carbazole, the construction of the
carbazole ring itself from readily available synthons is
highly desired.
In our previous paper, we reported a new synthetic
methodology, the double N-arylation of primary amines
* Corresponding author. Phone and Fax: +81-3-5841-7261.
(1) (a) Chakraborty, D. P. The Alkaloids 1993, 44, 257. (b)
Chakraborty, D. P.; Roy, R. S. Prog. Chem. Org. Nat. Prod. 1991, 57,
71. (c) Tachibana, Y.; Kikuzaki, H.; Lajis, N. H.; Nakatani, N. J. Agric.
Food Chem. 2001, 49, 5589. (d) Sˇtolc, S. Life Sci. 1999, 65, 1943.
(2) Carbazole as materials (a) Zhang, Y.; Wada, T.; Sasabe, H. J.
Mater. Chem. 1998, 8, 809. (b) Grazulevicius, J. V.; Strohriegl, P.;
Pielichowski, J.; Pielichowski, K. Prog. Polym. Sci. 2003, 28, 1297. (c)
Thomas, K. R. J.; Lin, J. T.; Tao, Y.-T.; Ko, C.-W. J. Am. Chem. Soc.
2001, 123, 9404. (d) D´ıaz, J. L.; Dobarro, A.; Villacampa, B.; Velasco,
D. Chem. Mater. 2001, 13, 2528.
(3) (a) Gilchrist, T. L. Heterocyclic Chemistry; Pitman Publishing
Ltd.: London, 1985. (b) Sundberg, R. J. Comp. Heterocycl. Chem. II
1996, 2, 119-206. (c) Pindur, U. Chimia 1990, 44, 406. (d) Kno¨lker,
H. J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(4) (a) Moody, C. J. Synlett 1994, 681. (b) Bergman, J.; Pelcman, B.
Pure Appl. Chem. 1990, 62, 1967.
(5) So¨derberg, B. C. G. Curr. Org. Chem. 2000, 4, 727.
(6) Kno¨lker, H. J. Chem. Soc. Rev. 1999, 28, 151.
(7) (a) Lin, G.; Zhang, A. Tetrahedron Lett. 1999, 40, 341. (b)
Kno¨lker, H. J.; Kno¨ll, J. Chem. Commun. 2003, 10, 1170.
10.1021/jo048472+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/13/2004
J. Org. Chem. 2005, 70, 413-419
413

Kuwahara et al.
SCHEME 1. Double N-Arylation with
2,2′-Dihalobiphenyl
ylene ditriflates. Furthermore, the synthetic utility of the
double N-arylation methodology is demonstrated through
the total synthesis of mukonine, a carbazole alkaloid.
Results and Discussion
The Double N-Arylation of Anilines with 2,2′-
Biphenylylene Ditriflates. As substrates, 2,2′-biphen-
ylylene ditriflate and aniline were employed and the
reaction conditions were optimized (Table 1). The sub-
strates were mixed in toluene at 80 or 100 °C for 18 h in
the presence of Pd2(dba)3‚CHCl3, K3PO4, and various
ligands. The use of P(t-Bu)3 as a ligand, which was
effective for the reaction of 2,2′-dibromobiphenyl with
aniline in our previous study,9 resulted in no reaction
(entry 1). Similarly, Fu reported that the Suzuki-
Miyaura coupling of aryl triflate did not proceed by using
P(t-Bu)3.14 The use of P(cyclo-Hex)3, which was reported
to be effective for the Suzuki-Miyaura coupling of aryl
triflate,14 resulted in no reaction either (entry 2). Biphen-
ylphosphines (2-4)12a,15 were the ligands of choice (entries
3-7), and finally, the desired product, N-phenylcarbazole
(1a), was obtained in 92% yield using 2-dicyclohexylphos-
phino-2′-methylbiphenyl (3) at 100 °C (entry 6). Carbene
ligand 516 and bisphosphine ligand 617 were also effective
for the reaction, and especially with 6, the highest yield
of 97% was achieved (entries 8-10). The effect of base
was also examined. When Cs2CO3 or Na(O-t-Bu) was
employed instead of K3PO4, otherwise under the same
conditions as entry 6, the yield of N-phenylcarbazole
dropped to 50% or 14%, respectively, and biphenyldiol
was obtained as a byproduct in 22% or 50%, respectively.
The hydrolysis of triflate was also reported to occur when
nucleophilic strong base was employed.12a
Thus, using 3 as a ligand and K3PO4 as a base, the
reactions of substituted anilines and biphenyls were
examined (Scheme 3). Aniline with an electron-donating
or electron-withdrawing substitutent was employable.
Although the yield was not satisfactory, multi-substituted
carbazole 7 was also produced from 4,4′,5,5′,6,6′-hexa-
methyl-2,2′-biphenylylene ditriflate. It is noteworthy that
the methyl groups are introduced at the 2,4,5,7-positions
of carbazole, at which position, a simple electrophilic
substitution on carbazole does not take place.
The Double N-Arylation of Ammonia Equiva-
lents. Because most of the carbazole alkaloids have no
substituent on the nitrogen atom, we examined the
double N-arylation of ammonia and its equivalents.18 The
same reaction conditions as Table 1 were employed
unless otherwise stated. No reaction proceeded under
continuous ammonia flow at 95 °C for 5 h, and a complex
mixture was obtained when triphenylsilylamine was
employed.18a Further studies were carried out using
ammonia equivalents which are advantageous for labora-
tory handling (Table 2). N-Benzyl-protected carbazole
with 2,2′-dihalobiphenyls (Scheme 1).9 In contrast to
conventional carbazole-ring construction starting from
2-nitrogen-substituted biphenyls, the nitrogen atom is
derived from primary amines which are reacted with
biphenyl moieties in the double N-arylation strategy. We
disclosed that (1) various multisubstituted carbazoles can
be synthesized from the corresponding anilines and 2,2′-
dihalobiphenyls and that (2) the method is especially
effective for the synthesis of sterically crowded carba-
zoles, 2,2′-dicarbazolyl-1,1′-biaryls, which could not be
synthesized by the simple N-arylation of carbazole.
To synthesize multisubstituted carbazoles via the
double N-arylation, it is necessary to prepare the 2,2′-
dihalobiphenyls regioselectively.10 However, the cross-
coupling reaction,11 one of the most general and powerful
methods for the synthesis of unsymmetric biphenyls, is
not applicable to the regioselective synthesis of 2,2′-
dihalobiphenyls because it is difficult to distinguish one
of the two halogen atoms of 1,2-dihalobenzene upon its
coupling with an organometallic coupling partner (Scheme
1). As a solution for this problem, here we report our
successful usage of 2,2′-bis(trifluoromethanesulfonyloxy)-
biphenyls (2,2′-biphenylylene ditriflates), in place of 2,2′-
dihalobiphenyls, as the double N-arylation reagent
(Scheme 2).12 The 2,2′-biphenylylene ditriflates are readily
available from 2,2′-biphenyldiols which can be easily
prepared by the Suzuki-Miyaura cross-coupling13 of
o-halophenols with o-hydroxyphenylboronic acids. In
addition to primary amines, ammonia equivalents were
successfully utilized for the reaction with 2,2′-biphenyl-
(8) For other recent developments in carbazole synthesis, see: (a)
Smitrovich, J. H.; Davies, I. W. Org. Lett. 2004, 6, 533. (b) Rawat, M.;
Wulff, W. D. Org. Lett. 2004, 6, 329. (c) Duval, E.; Cuny, G. D.
Tetrahedron Lett. 2004, 45, 5411. (c) Witulski, B.; Alayrac, C. Angew.
Chem., Int. Ed. 2002, 41, 3281. (d) Bedford, R. B.; Cazin, C. S. J. Chem.
Commun. 2002, 2310. (e) Kikugawa, Y.; Aoki, Y.; Sakamoto, T. J. Org.
Chem. 2001, 66, 8612. (f) Hagelin, H.; Oslob, J. D.; Åkermark, B. Chem.
Eur. J. 1999, 5, 2413.
(9) Nozaki, K.; Takahashi, K.; Nakano, K.; Hiyama, T.; Tang, H.-
Z.; Fujiki, M.; Yamagushi, S.; Tamao, K. Angew. Chem., Int. Ed. 2003,
42, 2051.
(10) (a) Gilman, H. J.; Gaj, B. J. J. Org. Chem. 1957, 22, 447. (b)
Yamato, T.; Hideshima, C.; Suehiro, K.; Tashiro, M.; Parakash, G. K.
S.; Olah, G. A. J. Org. Chem. 1991, 56, 6248. (c) Leroux, F.; Schlosser,
M. Angew. Chem., Int. Ed. 2002, 41, 4272.
(11) (a) Diedrich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 1998. (b) Miyaura, N. Cross-
Coupling Reaction. A Practical Guide; Springer-Verlag: Berlin, 2002.
(12) For reports on the N-arylation of amines with aryl triflates,
see: (a) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S.
L. J. Org. Chem. 2000, 65, 1158. (b) Singer, R. A.; Buchwald, S. L.
Tetrahedron Lett. 1999, 40, 1095. (c) Åhman, J.; Buchwald, S. L.
Tetrahedron Lett. 1997, 38, 6363. (d) Wolfe, J. P.; Åhman, J.; Sadighi,
J. P.; Singer, R. A.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367.
(e) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1264. (f) Louie,
J.; Driver, M. S.; Hamann, B. C.; Hartwig, J. J. Org. Chem. 1997, 62,
1268.
(14) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020.
(15) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(16) Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.; Hartwig,
J. F. Org. Lett. 2000, 2, 1423.
(17) Kranesburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995,
14, 3081.
(18) (a) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417. (b) Lee,
S.; Jørgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729.
(13) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
414 J. Org. Chem., Vol. 70, No. 2, 2005

Carbazole Synthesis via Double N-Arylation
SCHEME 2. Double N-Arylation with 2,2′-Biphenylylene Ditriflate
TABLE 1. Ligand Screening for the Double N-Arylation
of Aniline with 2,2′-Biphenylylene Ditriflatea
SCHEME 3. Double N-Arylation of Anilines with
2,2′-Biphenylylene Ditriflate
ligand
(mol %)
recovered
LC
entry
T (°C)
substrateb (%)
yieldc (%)
1
2
PtBu3 (10)
PCy3 (20)
2 (20)
80
80
83
96
39
8
not detected
not detected
a 2,2′-Biphenylylene ditriflate (0.50 mmol), aniline (0.60 mmol),
K3PO4 (1.4 mmol), Pd2(dba)3‚CHCl3 (0.0125 mmol), ligand 3 (0.050
mmol), toluene (1.5 mL), 100 °C. bIsolated yield. c4,4′,5,5′,6,6′-
Hexamethyl-2,2′-biphenylylene ditriflate (0.24 mmol), aniline (0.29
mmol), K3PO4 (0.67 mmol), Pd2(dba)3‚CHCl3 (0.012 mmol), ligand
3 (0.048 mmol), toluene (0.75 mL), 100 °C, 80 h.
3
80
18d
36d
78d
92
4
2 (20)
100
80
5
3 (20)
7
6
3 (20)
100
80
0
17
2
37
0
7
4 (20)
72d
50d
40d
97
8
5 (20)
80
9
6 (10)
80
TABLE 2. Double N-Arylation of Ammonia Equivalents
with 2,2′-Biphenylylene Ditriflatea
10
6 (10)
100
a Reaction conditions: 2,2′-biphenylylene ditriflate (0.40 mmol),
aniline (0.48 mmol), K3PO4 (2.8 equiv), Pd2(dba)3‚CHCl3 (0.020
mmol), ligand (0.040-0.080 mmol), toluene (1.2 mL), 80-100 °C,
18 h. Reaction times have not been minimized. b 2′-Hydroxybi-
phenyl-2-yl triflate and 2,2′-biphenyldiol are also included as a
recovered substrate because these two compounds were given by
hydrolysis of the substrate not only during the reaction, but also
after dilution with methanol for the preparation of LC sample.
c LC yields were estimated using phenanthrene as internal
standard; see the Experimental Section for details. d Biphenyl,
biphenylphenylamine, and other unidentified biproducts were also
detected.
entry
R
ligand (mol %) time (h) product yieldb (%)
1
2
3
4
5
6
Bn
3 (20)
6 (10)
3 (20)
6 (10)
3 (20)
6 (10)
24
72
18
64
18
67
8a
8b
8c
8c
8d
8d
41c
COMe
CO2Bn
CO2Bn
63 (15d)
33 (17d)
27 (25,d 10e)
65 (1d)
81
(8a) was obtained in 41% from benzylamine (entry 1).12a
By using Xantphos19,20 (6), N-acetylcarbazole (8b) was
obtained from acetamide20 in 63% yield accompanied by
deprotected carbazole in 15% yield (entry 2). The reaction
proceeded with O-benzyl carbamate,20 but the deprotec-
tion partially occurred, possibly due to the reductive
reaction conditions (entries 3 and 4). If the purpose of
the reaction is the direct production of N-unsubstituted
carbazole, the partial deprotection may not be a problem.
Nevertheless, from a synthetic viewpoint, obtaining the
t
CO2 Bu
CO2 Bu
t
a Reaction conditions: 2,2′-biphenylylene ditriflate (0.50 mmol),
amine (0.60 mmol), K3PO4 (2.8 equiv), Pd2(dba)3‚CHCl3 (0.025
mmol), ligand (0.05-0.10 mmol), xylene (1.5 mL, entries 1, 2 and
4) or toluene (1.0-1.5 mL, entries 3, 5 and 6), 100 °C. b Isolated
yield. c At 120 °C. d N-H carbazole. e N-benzylcarbazole.
product in its perfectly protected form is also significant.
Finally, using O-tert-butyl carbamate,21 N-protected car-
bazole 8d was obtained in 81% yield (entry 6).
Xantphos (6) seems to be a superior ligand to o-
biphenylphosphine 3 for the double N-arylation of car-
bamate in the following point. The reaction proceeded fast
(19) Harris, M. C.; Geis, O.; Buchwald, S. L. J. Org. Chem. 1999,
64, 6019.
(20) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101.
J. Org. Chem, Vol. 70, No. 2, 2005 415

Kuwahara et al.
SCHEME 4. Total Synthesis of Mukonine
SCHEME 5. Comparison of the Double N-Arylation with Some of Precedents
with 3, and the desired product was obtained in 65% yield
after 18 h at 100 °C (entry 5). At this stage, the starting
material was almost consumed, and byproducts such as
biphenyl resulting from reduction were produced. Re-
cently, Bergman and Ellman reported that P(cyclo-Hex)3
behaves as a hydride source in their rhodium-catalyzed
arylation of an imidazole with a halobenzene.22 Similarly,
the dicyclohexylphosphino group of 3 may have worked
as a hydride source in the present reaction. On the other
hand, the reaction was slow with 6, and it took 67 h to
consume the starting material. However, the desired
product, N-Boc-carbazole, was the only isolable major
product in this case (entry 6).
tisubstituted carbazole, is an alkaloid from the Indian
curry-leaf tree (Murraya koenigii).1 Taking advantage of
the easy availability of the corresponding biphenyldiol,
we synthesized mukonine (13) via the double N-arylation
starting from methyl vanillate and the pinacol ester of
2-hydroxyphenylboronic acid, the total yield being 40%
for five steps (Scheme 4). Bromination23 of methyl vanil-
late followed by the Suzuki-Miyaura coupling with the
pinacol ester of 2-hydroxyphenylboronic acid gave biphen-
yldiol 10. The coupling reaction was slow in toluene, a
nonpolar solvent, presumably due to the coordination of
the hydroxyl group to the catalyst.13,24 The yield was
improved when DMF, a polar solvent, was employed.
Biphenyldiol 10 was converted to the corresponding
Synthesis of Mukonine by the Double N-Aryla-
tion Methodology. Mukonine [1-methoxy-3-(methoxy-
carbonyl)carbazole], which is an unsymmetrically mul-
(23) (a) Shepherd, J. A.; Poon, W. W.; Myles, D. C.; Clarke, C. F.
Tetrahedron Lett. 1996, 37, 2395. (b) Wriede, U.; Fernandez, M.; West,
K. F.; Harcourt, D.; Moore, H. W. J. Org. Chem. 1987, 52, 4485.
(24) (a) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 57, 207.
(b) Zhuravel, M. A.; Nguyen, S. T. Tetrahedron Lett. 2001, 42, 7925.
(c) Nishimura, M.; Ueda, M.; Miyaura, N. Tetrahedron 2002, 58, 5779.
(21) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K.
H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575.
(22) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A.
Org. Lett. 2004, 6, 35.
416 J. Org. Chem., Vol. 70, No. 2, 2005

Carbazole Synthesis via Double N-Arylation
dried 20-mL Schlenk tube containing a magnetic stirring bar
was charged with Pd2(dba)3‚CHCl3 (13 mg, 0.0125 mmol),
2-dicyclohexylphosphino-2′-methylbiphenyl (3) (18 mg, 0.050
mmol), 2,2′-biphenylylene ditriflate (230 mg, 0.50 mmol), and
K3PO4 (300 mg, 1.4 mmol). The tube was evacuated and
backfilled with argon, and then aniline (55 µL, 0.60 mmol) and
toluene (1.5 mL) were added through the septum via syringe.
After being degassed by freeze-pump-thaw cycles, the mix-
ture was stirred at 100 °C under argon until the ditriflate was
consumed as judged by TLC analysis. The reaction mixture
was allowed to cool to ambient temperature, diluted with
dichloromethane (40 mL), and transferred to a separatory
funnel. The mixture was washed with water (10 mL), and the
aqueous phase was extracted with ethyl acetate (20 mL × 3).
The combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
crude residue was purified by silica gel column chromatogra-
phy with hexane (Rf 0.33) as an eluent to give 1a (107 mg,
0.44 mmol, 88%) as a white solid. The structure was identified
on the basis of the 1H and 13C NMR spectral data of the
commercially available N-phenylcarbazole: 1H NMR (CDCl3)
δ 8.17-8.13 (m, 2H), 7.63-7.55 (m, 4H), 7.49-7.45 (m, 1H),
7.42-7.39 (m, 4H), 7.31-7.27 (m, 2H); 13C NMR (CDCl3) δ
140.9, 137.7, 129.8, 127.4, 127.1, 125.9, 123.3, 120.3, 119.9,
109.7.
ditriflate 11, which was subjected to the double N-
arylation with O-tert-butyl carbamate. Using Xantphos
(6) as the ligand, the desired product, N-Boc-mukonine
(12), was obtained in 70% yield. Deprotection of the Boc
group by trifluoroacetic acid provided mukonine (13)
quantitatively. The total yield of 40% for five steps is
comparable to the recent precedents with high efficien-
cies, such as (1) Horner-Emmons reaction of 3-indole-
carbaldehyde followed by the intramolecular cyclization,
46% yield for six steps,25 (2) Stobbe condensation of
3-indolecarbaldehyde with dimethyl succinate followed
by the intramolecular cyclization, 32% yield for three
steps,26 and (3) electrophilic substitution of aniline
derivative by tricarbonylcyclohexadienylium iron followed
by oxidative intramolecular coupling, 33% for two steps.27
Conclusion
Here, we report that 2,2′-biphenylylene ditriflates,
easily prepared by the Suzuki-Miyaura coupling of
o-halophenols with o-hydroxyphenylboronic acids, were
effectively utilized for the double N-arylation of primary
amines as well as O-tert-butyl carbamate, an ammonia
equivalent. The synthesis of mukonine, a carbazole
alkaloid, was also demonstrated.
As shown in Scheme 5, the carbazole synthesis via
cyclization of nitrobiphenyls or oxidative coupling of
diarylamines inherently gives regioisomers. In contrast,
the double N-arylation strategy can selectively provide
each of the isomers. Thus, the double N-arylation may
be advantageous for the regioselective synthesis of multi-
subsutituted carbazole.28 Considering the recent remark-
able advances in the Suzuki-Miyaura cross-coupling and
in the Buchwald-Hartwig N-arylation, the double N-
arylation with 2,2′-biphenylylene ditriflates will provide
a powerful tool for the synthesis of unsymmetrically
multi-substituted carbazoles.
N-(p-Methoxyphenyl)carbazole (1b). A crude material
was prepared from 2,2′-biphenylylene ditriflate (230 mg, 0.50
mmol) and p-methoxyaniline (74 mg, 0.60 mmol) according to
the procedure described above. Purification of the crude
product by silica gel column chromatography with hexane/
ethyl acetate (10/1, Rf 0.39) as an eluent gave 1b (130 mg, 0.47
mmol, 95%) as a white solid: mp 147-149 °C (hexane/ethyl
acetate ) 10/1); 1H NMR (CDCl3) δ 8.14 (ddd, J ) 7.7, 1.2, 0.8
Hz, 2H), 7.45 (d, J ) 9.0 Hz, 2H), 7.40 (ddd, J ) 8.2, 7.0, 1.0
Hz, 2H), 7.33 (ddd, J ) 8.2, 1.0, 0.8 Hz, 2H), 7.27 (ddd, J )
7.7, 7.0, 1.0 Hz, 2H), 7.11 (d, J ) 9.0 Hz, 2H), 3.92 (s, 3H); 13
C
NMR (CDCl3) δ 158.8, 141.3, 130.3, 128.6, 125.8, 123.1, 120.2,
119.6, 115.0, 109.7, 55.6. Anal. Calcd for C19H15NO: C, 83.49;
H, 5.53. Found: C, 83.54; H, 5.75.
N-[p-(Trifluoromethyl)phenyl]carbazole (1c). Crude
material was prepared from 2,2′-biphenylylene ditriflate (230
mg, 0.50 mmol) and p-(trifluoromethyl)aniline (78 µL, 0.60
mmol) according to the procedure described above. Purification
of the crude product by silica gel column chromatography with
hexane/dichloromethane (10/1, Rf 0.50) as an eluent and
recycling preparative GPC gave 1c (141 mg, 0.45 mmol, 91%)
as a white solid: mp 165-167 °C (CHCl3); 1H NMR (CDCl3) δ
8.15 (d, J ) 7.8 Hz, 2H), 7.88 (d, J ) 8.3 Hz, 2H), 7.73 (d, J )
8.3 Hz, 2H), 7.46-7.41 (m, 4H), 7.32 (ddd, J ) 7.8, 5.6, 2.5
Hz, 2H); 13C NMR (CDCl3) δ 141.1, 140.3, 129.2 (q, JC-F ) 33.4
Experimental Section
Ligand Screening by HPLC Analysis. A flame-dried 20-
mL Schlenk tube containing a magnetic stirring bar was
charged with Pd2(dba)3‚CHCl3 (21 mg, 0.020 mmol), ligand
(0.040-0.080 mmol), 2,2′-biphenylylene ditriflate (180 mg, 0.40
mmol), and K3PO4 (240 mg, 1.12 mmol). The tube was
evacuated and backfilled with argon, and then aniline (44 µL,
0.48 mmol) and toluene (1.2 mL) were added through the
septum via syringe. After the mixture was degassed by freeze-
pump-thaw cycles, the mixture was stirred at 80 or 100 °C
for 18 h under argon. The reaction mixture was cooled to
ambient temperature and diluted with methanol, followed by
addition of phenanthrene as internal standard. The crude
mixture was analyzed by HPLC (methanol/water ) 76.5/23.5,
1.2 mL/min). Retention times (min) of major products were as
follows: aniline, tR ) 3.0; 2,2′-biphenyldiol, tR ) 3.8; 2-hydroxy-
2′-(trifluoromethansulfonyloxy)biphenyl, tR ) 6.0; toluene, tR
Hz), 127.09 (q, JC-F ) 3.8 Hz), 127.03, 126.2, 123.9 (q, JC-F
)
269.9 Hz), 123.7, 120.6, 120.5, 109.5. Anal. Calcd for C19H12-
NF3: C, 73.31; H, 3.89. Found: C, 73.20; H, 4.17.
N-Phenyl-2,3,4,5,6,7-hexamethylcarbazole (7). Accord-
ing to the procedure described above, a reaction mixture of
Pd2(dba)3‚CHCl3 (12 mg, 0.012 mmol), 3 (18 mg, 0.048 mmol),
K3PO4 (140 mg, 0.67 mmol), 4,4′,5,5′,6,6′-hexamethyl-2,2′-
biphenylylene ditriflate (130 mg, 0.24 mmol), and aniline (26
µL, 0.29 mmol) in toluene (0.75 mL) was stirred at 100 °C for
80 h. Purification of the crude product by silica gel column
chromatography with hexane/ethyl acetate (30/1, Rf 0.20) as
an eluent and recycling preparative GPC gave 7 (26 mg, 0.078
mmol, 33%) as a white solid: mp 192-194 °C (CHCl3); 1H
NMR (CDCl3) δ 7.60-7.57 (m, 2H), 7.49-7.44 (m, 3H), 6.93
(s, 2H), 2.77 (s, 6H), 2.34 (s, 6H), 2.34 (s, 6H); 13C NMR (CDCl3)
δ 140.3, 138.1, 134.2, 130.1, 129.7, 128.1, 127.3, 127.1, 122.0,
107.6, 22.3, 21.7, 15.8. Anal. Calcd for C24H25N: C, 88.03; H,
7.70. Found: C, 87.86; H, 7.90.
) 7.3; 2,2′-biphenylylene ditriflate, tR ) 11.5; biphenyl, tR
12.2; phenanthrene tR ) 18; N-phenylcarbazole, tR ) 37.
)
N-Phenylcarbazole (1a): General Procedure for the
Double N-Arylation of Amine with Ditriflate. A flame-
(25) Bringmann, G.; Tasler,; S.; Endress, H.; Peters, K.; Peters, E.-
M. Synthesis 1998, 10, 1501.
(26) Brenna, E.; Fugatani, C.; Serra, S. Tetrahedron 1998, 54, 1585.
(27) (a) Kno¨lker, H. J.; Bauermeister, M. Tetrahedron 1993, 49,
11221. (b) Kno¨lker, H. J.; Wolpert, M. Tetrahedron 2003, 59, 5317.
(28) For examples of regioselectivity in the substituted carbazole
synthesis, see: Bouchard, J.; Wakim, S.; Leclerc, M. J. Org. Chem.
2004, 69, 5705 and refs 4a and 8a,d.
N-Benzylcarbazole (8a).29,30 According to the procedure
described above, a reaction mixture of Pd2(dba)3‚CHCl3 (26 mg,
(29) Bonesi, S. M.; Ponce, M. A.; Erra-Balsells, R. J. Heterocycl.
Chem. 2004, 41, 161.
J. Org. Chem, Vol. 70, No. 2, 2005 417

Kuwahara et al.
0.025 mmol), 3 (36 mg, 0.10 mmol), K3PO4 (300 mg, 1.4 mmol),
2,2′-biphenylylene ditriflate (230 mg, 0.50 mmol), and benzyl-
amine (63 µL, 0.60 mmol) in xylene (1.5 mL) was stirred at
120 °C for 24 h. Purification of the crude product by silica gel
column chromatography with hexane/dichloromethane (5/1, Rf
0.37) gave 8a (52 mg, 0.20 mmol, 41%) as a white solid: mp
118-120 °C (hexane/dichloromethane ) 5/1, lit.30 mp 117 °C);
1H NMR (CDCl3) δ 8.14 (ddd, J ) 7.8, 1.2, 0.7 Hz, 2H), 7.43
(ddd, J ) 8.2, 7.0, 1.2 Hz, 2H), 7.37 (br t, J ) 8.2 Hz, 2H),
7.28-7.22 (m, 5H), 7.16-7.13 (m, 2H), 5.53 (s, 2H); 13C NMR
(CDCl3) δ 140.6, 137.1, 128.7, 127.4, 126.4, 125.8, 123.0, 120.4,
119.2, 108.9, 46.5. Anal. Calcd for C19H15N: C, 88.68; H, 5.88.
Found: C, 88.41; H, 6.15.
degassed by freeze-pump-thaw cycles, the mixture was
stirred at 120 °C for 49 h under argon. The reaction mixture
was allowed to cool to ambient temperature and then was
concentrated under reduced pressure. The resulting residue
was dissolved in dichloromethane (50 mL) and saturated
aqueous ammonium chloride (20 mL) and transferred into a
separatory funnel. After the organic phase was separated, the
aqueous phase was extracted with ethyl acetate (40 mL × 4).
The combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by silica gel column chroma-
tography with hexane/2-propanol (10/1, Rf 0.17) to give almost
pure 10. Further purification by silica gel column chromatog-
raphy with chloroform/methanol (40/1, Rf ) 0.25) as an eluent
afforded the desired biphenyldiol (640 mg, 2.3 mmol, 66%) as
a white solid: mp 144-145 °C (chloroform); IR (CHCl3) 1713
cm-1; 1H NMR (CDCl3) δ 7.74 (d, J ) 2.0 Hz, 1H), 7.60 (d, J )
2.0 Hz, 1H), 7.35-7.30 (m, 2H), 7.08-7.04 (m, 2H), 6.66 (bs,
1H), 5.98 (bs, 1H), 4.02 (s, 3H), 3.90 (s, 3H); 13C NMR (CDCl3)
δ 166.6, 153.4, 146.3, 145.8, 131.1, 129.8, 126.4, 124.3,
124.0, 123.0, 121.3, 117.7, 110.8, 56.5, 52.2. Anal. Calcd for
C15H14O5: C, 65.69; H, 5.15. Found: C, 65.41; H, 5.23.
2,2′-Bis(trifluoromethansulfonyloxy)-3-methoxy-5-
(methoxycarbonyl)biphenyl (11). Biphenyldiol 10 (160 mg,
0.59 mmol), pyridine (140 µL, 1.8 mmol), and dichloromethane
(2.0 mL) were placed in a 20-mL Schlenk tube. To this solution
was slowly added trifluoromethanesulfonic acid anhydride (240
µL, 1.4 mmol) at 0 °C. The reaction mixture was allowed to
warm slowly to 20 °C and then stirred for 7 h. After the volatile
materials were removed under reduced pressure, the resulting
residue was dissolved in ethyl acetate (20 mL) and washed
with 1 M aqueous HCl (10 mL), water (10 mL), and brine (10
mL). The organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude residue was
purified by silica gel column chromatography with hexane/2-
propanol (10/1, Rf 0.40) to afford 11 (310 mg, 0.57 mmol, 97%)
as a white solid: mp 104-105 °C (hexane/2-propanol ) 10/1);
IR (CHCl3) 1726 cm-1; 1H NMR (CDCl3) δ 7.80 (d, J ) 2.0 Hz,
1H), 7.73 (d, J ) 2.0 Hz, 1H), 7.57 (ddd, J ) 2.4, 6.8, 8.2 Hz,
1H), 7.52-7.47 (m, 2H), 7.43 (d, J ) 8.2 Hz, 1H), 4.04 (s, 3H),
3.95 (s, 3H); 13C NMR (CDCl3) δ 165.3, 151.6, 146.6, 139.4,
132.4, 131.1, 130.5, 130.4, 128.54, 128.48, 124.8, 121.8, 118.3
(q, JC-F ) 319 Hz), 118.1 (q, JC-F ) 319 Hz), 114.3, 56.8, 52.7;
HRMS-FAB+ (m/z) M+ calcd for C17H12F6O9S2 537.9827, found
537.9832.
N-tert-Butoxycarbonyl-1-methoxy-3-(methoxycarbon-
yl)carbazole (12). A flame-dried 20-mL Schlenk tube con-
taining a magnetic stirring bar was charged with Pd2(dba)3‚
CHCl3 (31 mg, 0.030 mmol), 6 (35 mg, 0.060 mmol), ditriflate
11 (160 mg, 0.30 mmol), O-tert-butyl carbamate (42 mg, 0.36
mmol), and K3PO4 (210 mg, 0.96 mmol). The tube was
evacuated and backfilled with argon, and then xylene (0.9 mL)
was added. After the mixture was degassed by freeze-pump-
thaw cycles, the mixture was stirred at 100 °C for 64 h under
argon. The reaction mixture was allowed to cool to ambient
temperature and then diluted with dichloromethane (40 mL).
The resulting mixture was washed with saturated aqueous
ammonium chloride (10 mL), and the aqueous phase was
extracted with ethyl acetate (20 mL × 4). The combined
organic layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography with hexane/
ethyl acetate (12/1, Rf 0.12) as an eluent to afford 12 (75 mg,
0.21 mmol, 70%) as a white solid: mp 127-130 °C (hexane/
ethyl acetate ) 12/1); IR (CHCl3) 1715 cm-1; 1H NMR (CDCl3)
δ 8.34 (d, J ) 0.9 Hz, 1H), 8.08 (d, J ) 8.3 Hz, 1H), 8.01 (d, J
) 7.8 Hz, 1H), 7.67 (s, 1H), 7.50 (t, J ) 7.8 Hz, 1H), 7.37 (t, J
) 7.6 Hz, 1H), 4.04 (s, 3H), 3.98 (s, 3H), 1.65 (s, 9H); 13C NMR
(CDCl3) δ 167.3, 150.2, 148.0, 140.4, 131.0, 127.7, 127.6, 125.7,
125.0, 123.0, 120.1, 114.7, 114.2, 109.8, 83.7, 55.8, 52.2, 27.9;
HRMS-FAB+ (m/z) M+ calcd for C20H21NO5 355.1420, found
355.1413.
N-Acetylcarbazole (8b).29 According to the procedure
described above, a reaction mixture of Pd2(dba)3‚CHCl3 (26 mg,
0.025 mmol), 6 (29 mg, 0.050 mmol), K3PO4 (300 mg, 1.4
mmol), 2,2′-biphenylylene ditriflate (230 mg, 0.50 mmol), and
acetamide (36 mg, 0.61 mmol) in xylene (1.5 mL) was stirred
at 100 °C for 72 h. Purification of the crude product by silica
gel column chromatography with hexane/dichloromethane (2/
1, Rf 0.20) gave 8b (66 mg, 0.31 mmol, 63%) as a white solid:
mp 69-71 °C (hexane/dichloromethane ) 2/1); IR (CHCl3) 1693
cm-1; 1H NMR (CDCl3) δ 8.20 (br d, J ) 8.5 Hz, 2H), 7.98 (ddd,
J ) 7.5, 1.4, 0.6 Hz, 2H), 7.47 (ddd, J ) 8.5, 7.5, 1.4 Hz, 2H),
7.38 (dt, J ) 7.5, 1.0 Hz, 2H), 2.87 (s, 3H); 13C NMR (CDCl3)
δ 170.1, 138.6, 127.3, 126.4, 123.6, 119.8, 116.2, 27.7. Anal.
Calcd for C14H11NO: C, 80.36; H, 5.30. Found: C, 80.53; H,
5.50.
N-(Benzyloxycarbonyl)carbazole (8c).31 According to the
procedure described above, a reaction mixture of Pd2(dba)3‚
CHCl3 (26 mg, 0.025 mmol), 6 (29 mg, 0.050 mmol), K3PO4
(300 mg, 1.4 mmol), 2,2′-biphenylylene ditriflate (230 mg, 0.50
mmol), and O-benzyl carbamate (91 mg, 0.60 mmol) in xylene
(1.5 mL) was stirred at 100 °C for 64 h. Purification of the
crude product by silica gel column chromatography with
hexane/ethyl acetate (30/1, Rf 0.34) gave 8c (40 mg, 0.12 mmol,
27%) as a white solid. mp 85-86 °C (hexane/ethyl acetate )
30/1, lit.31 mp 74 °C); IR (CHCl3) 1724 cm-1; 1H NMR (CDCl3)
δ 8.31 (d, J ) 7.8 Hz, 2H), 7.99 (d, J ) 7.8 Hz, 2H), 7.56 (d, J
) 6.9 Hz, 2H), 7.48-7.35 (m, 7H), 5.58 (s, 2H); 13C NMR
(CDCl3) δ 152.3, 138.2, 135.2, 128.8, 128.7, 128.6, 127.2, 126.0,
123.4, 119.6, 116.3, 68.7. Anal. Calcd for C20H15NO2: C, 79.72;
H, 5.02. Found: C, 79.51; H, 5.20.
N-(tert-Butoxycarbonyl)carbazole (8d).32 According to
the procedure described above, a reaction mixture of Pd2(dba)3‚
CHCl3 (26 mg, 0.025 mmol), 6 (29 mg, 0.050 mmol), K3PO4
(300 mg, 1.4 mmol), 2,2′-biphenylylene ditriflate (230 mg, 0.50
mmol), and O-tert-butyl carbamate (70 mg, 0.60 mmol) in
toluene (1.2 mL) was stirred at 100 °C for 67 h. Purification
of the crude product by silica gel column chromatography with
hexane/ethyl acetate (20/1, Rf 0.40) gave 8d (108 mg, 0.40
mmol, 81%) as a colorless oil. The structure was identified on
the basis of the 1H and 13C NMR spectral data:32 1H NMR
(CDCl3) δ 8.31 (br d, J ) 8.4 Hz, 2H), 7.99 (ddd, J ) 7.7, 1.4,
0.7 Hz, 2H), 7.47 (ddd, J ) 8.4, 7.3, 1.4 Hz, 2H), 7.35 (dt, J )
7.5, 1.0 Hz, 2H), 1.77 (s, 9H); 13C NMR (CDCl3) δ 151.1, 138.5,
127.0, 125.7, 122.9, 119.5, 116.2, 83.8, 28.4.
3-Methoxy-5-methoxycarbonyl-2,2′-biphenyldiol (10).
A flame-dried 80-mL Schlenk tube containing a magnetic
stirring bar was charged with Pd(PPh3)4 (190 mg, 0.16 mmol),
2-bromophenol 9 (914 mg, 3.5 mmol), and K3PO4 (2.7 g, 13
mmol). The tube was evacuated and backfilled with argon, and
then the pinacol ester of 2-hydroxyphenylboronic acid (950 µL,
4.2 mmol) in DMF (9.5 mL) was added. After the mixture was
(30) Dell, S.; Lozanov, M. E.; Shieh, W.-C. N-Alkylation of Indole
Derivatives. U.S. Patent 2,004,059,131, March 25, 2004.
(31) Barth, H.; Steiner, K.; Schneider, S.; Bayer, U.; Westermayer,
M.; Wolfsperger, U.; Betche, H.-J. Method of Producing Heterocylic
Carbamates from Aza-heterocyclic Compounds and Carbon Dioxide.
U.S. Patent 6,566,533, May 20, 2003.
(32) Diep, V.; Dannenberg, J. J.; Franck, R. W. J. Org. Chem. 2003,
68, 7907.
418 J. Org. Chem., Vol. 70, No. 2, 2005

Carbazole Synthesis via Double N-Arylation
Mukonine (13).26,27a To a solution of N-Boc-mukonine (12,
27 mg, 0.077 mmol) in dichloromethane (2.6 mL) was slowly
added 0.1% trifluoroacetic acid anhydride in trifluoroacetic acid
(0.23 mL) at 0 °C. The reaction mixture was stirred for 15 min
at 0 °C and additionally stirred for 2 h at 20 °C. After the
volatile materials were removed under reduced pressure, the
resulting residue was purified by silica gel column chroma-
tography with hexane/ethyl acetate (3/1, Rf 0.39) to afford
mukonine (19 mg, 0.075 mmol, 97%) as a white solid. The
structure was identified based on the 1H and 13C NMR spectral
data:26,27a 1H NMR (CDCl3) δ 8.48 (dd, J ) 1.1, 0.6 Hz, 1H),
8.47 (bs, 1H), 8.10 (m, 1H), 7.60 (d, J ) 1.1 Hz, 1H), 7.49 (ddd,
J ) 8.1, 1.3, 0.8 Hz, 1H), 7.46 (ddd, J ) 8.1, 6.8, 1.1, 1H), 7.28
(ddd, J ) 8.1, 1.3, 0.8 Hz, 1H), 4.07 (s, 3H), 3.98 (s, 3H); 13C
NMR (CDCl3) δ 168.0, 145.0, 139.5, 132.9, 126.3, 123.7, 123.6,
121.9, 120.7, 120.3, 116.2, 111.2, 106.7, 55.7, 52.0.
Acknowledgment. We are grateful to Prof. Koji
Araki, Dr. Toshiki Mutai, and Mr. Isao Yoshikawa (The
University of Tokyo) for the HRMS analysis. K. Nozaki
gratefully acknowledges Yamada Science Foundation for
financial support.
Supporting Information Available: 1H and 13C NMR
spectra for compounds 11 and 12. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO048472+
J. Org. Chem, Vol. 70, No. 2, 2005 419