One-step construction of carbazoles by way of the palladium-catalyzed double N-arylation reaction and its application to the total synthesis of murrastifoline-A

Article abstract of DOI:10.1016/j.tet.2006.04.087

The one-step construction of N-substituted carbazoles by way of the Pd-catalyzed double N-arylation reaction of primary amines with 2,2′-dibromobiphenyl is described. Aryl and aliphatic amines including tert-butylamine and a protected glucopyranosylamine were effectively transformed into the corresponding N-substituted carbazoles. The first total synthesis of murrastifoline-A, a biscarbazole alkaloid, based on this methodology is also presented.

Full text of DOI:10.1016/j.tet.2006.04.087

Tetrahedron 62 (2006) 6792–6801
One-step construction of carbazoles by way of the palladium-
catalyzed double N-arylation reaction and its application
to the total synthesis of murrastifoline-A
*
Takafumi Kitawaki, Yoko Hayashi, Akiko Ueno and Noritaka Chida
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
Received 13 April 2006; revised 26 April 2006; accepted 28 April 2006
Available online 19 May 2006
Abstract—The one-step construction of N-substituted carbazoles by way of the Pd-catalyzed double N-arylation reaction of primary amines
with 2,20-dibromobiphenyl is described. Aryl and aliphatic amines including tert-butylamine and a protected glucopyranosylamine were
effectively transformed into the corresponding N-substituted carbazoles. The first total synthesis of murrastifoline-A, a biscarbazole alkaloid,
based on this methodology is also presented.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, Nozaki and co-workers reported a new synthetic
methodology; the Pd-catalyzed double N-arylation of pri-
mary amines with biphenyls possessing leaving groups
(Br, I, and OTf) at C-2 and 20.4 This method is an important
extension of the Buchwald–Hartwig N-arylation reaction,5
and proved to be an excellent protocol for the regioselective
construction of unsymmetrical multi-substituted carbazoles
in one-step. By this reaction, a variety of primary amines,
such as aryl amines and protected amines (O-alkyl carba-
mates) were successfully transformed into the corresponding
N-substituted carbazoles, however, lower yield has been
observed when an aliphatic primary amine (n-octylamine)
was employed as the substrate under the conditions using
Pd2(dba)3, t-Bu3P, and NaOt-Bu in toluene.4a The Nozaki
group also reported the successful synthesis of mukonine,
a carbazole alkaloid, using this novel methodology.4b
Carbazole alkaloids are known to show a wide range of
biological properties, such as antitumor, antibiotic, psycho-
tropic, antiinflammatory, and antihistaminic activities.1 Car-
bazoles are also useful organic materials, as they possess
photorefractive, photoconductive, and light-emitting proper-
ties. Due to the interesting and important properties of carba-
zoles, a number of methodologies for the construction of
the carbazole ring have been reported.2 Dehydrogenation of
tetrahydrocarbazoles prepared by the Fischer–Borsche syn-
thesis is one of the most classical methods.3a Coupling of
the metal-coordinated cyclohexadienylium ion with an elec-
tron-rich arylamine, followed by metal-mediated oxidative
cyclization and aromatization,3b the Pd(0) catalyzed intra-
molecular cyclization of 2-amino-20-halobiphenyl,3c and
the Pd(II) mediated oxidative cyclization of a diarylamine3d
have also been developed. Diels–Alder reaction,3e electro-
cyclic reaction,3f and acid catalyzed cyclization of keto-
sulfoxide3g are methods used for the construction from
indole derivatives. Cyclization of 2-arylacetanilides by the
action of Pd(OAc)2 and Cu(OAc)2 in the presence of O2,3h
and the anionic [4+2] cycloaddition of furoindolones3i
were reported in 2005. These methods, however, sometimes
encounter difficulties in controlling the regioselectivities
during the preparation of multi-substituted carbazoles.
Our group has an interest in the application of the
Buchwald–Hartwig N-arylation reaction to the natural prod-
ucts’ synthesis, and reported the first total synthesis of spica-
mycin,6 a novel nucleoside antibiotic possessing a unique
N-glycoside structure, by way of the Pd-catalyzed coupling
of a heptopyranosylamine with a protected 6-chloropurine
derivative.6a,d To extend the N-arylation methodology to
the synthesis of a variety of natural products, we have inde-
pendently studied the possibility of the Pd-catalyzed double
N-arylation reaction of primary amines with 2,20-dibromobi-
phenyl. In this paper, we report our results of the Pd-cata-
lyzed double N-arylation reaction, which generated N-aryl-,
N-alkyl-, and N-(glucopyranosyl)carbazoles in moderate
to high yields in one-pot reactions. The first total synthesis
Keywords: N-Substituted carbazole; Double N-arylation; One-pot synthesis;
Murrastifoline-A.
* Corresponding author. Tel./fax: +81 455661573; e-mail: chida@applc.
keio.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.087

T. Kitawaki et al. / Tetrahedron 62 (2006) 6792–6801
6793
Table 1. The double N-arylation of aniline (1a) with 2,20-dibromobiphenyl
(2)a
5
4
Pd catalyzed
double N-arylation
R
NH2
+
9
N
R
3
2
2'
Entry Pd Source Ligand Base
Time (h) Yield of 3a (%)b
8
1
1
Br Br
1
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)4
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
5
5
5
5
5
6
7
8
5
5
NaOt-Bu 14
79
84
69
62
85
82
51
22
42
32
R = aryl and
alkyl groups
2c
3
NaOt-Bu 24
NaOt-Bu 24
NaOt-Bu 24
NaOt-Bu 24
NaOt-Bu 24
NaOt-Bu 24
NaOt-Bu 13
2
N-substituted
carbazoles
4d
5
6
7
8
9
10
Me
3'
1'
OMe
9'N
Me
6
5
3
Cs2CO3
K3PO4
24
24
9
8
N
1
a
OMe
H
Reaction conditions: A mixture of 1a (1.0 equiv), 2 (1.1 equiv), Pd cata-
lyst (10 mol %), ligand (30 mol %), and base (3.0 equiv) in toluene was
heated at 120 ꢀC in a sealed tube.
Isolated yield after chromatographic purification.
Pd2(dba)3 (5 mol %), 5 (15 mol %).
Pd(OAc)2 (20 mol %), 5 (50 mol %).
murrastifoline-A (4)
b
c
d
Figure 1.
of murrastifoline-A (4), a biscarbazole alkaloid, utilizing
this methodology is also disclosed7 (Fig. 1).
N
Ph
3a
Pd2(dba)3
2. Results and discussion
ligand 5
PhNH2
(33%)
NaOt-Bu
toluene
2.1. Double N-arylation of aniline
1a
Br Br
60 °C, 14 h
The double N-arylation of aniline (1a) with 2,20-dibromobi-
phenyl8 (2) was first attempted under the conditions reported
by the Buchwald group for the N-arylation reaction of
primary amines5 with aryl halides after slight modification.
When a mixture of 1a (1 equiv) and 2 (1.1 equiv) in toluene
in the presence of Pd2(dba)3 (10 mol % to 1a), 2-(dicyclo-
hexylphosphino)biphenyl (5)5c (30 mol % to 1a), and
NaOt-Bu (3 equiv) was heated at 60 ꢀC for 14 h in a sealed
tube, the desired product, N-phenylcarbazole (3a) was iso-
lated in 33% yield (Scheme 1). A mixture of the mono N-
arylation products (9 and 10) was also obtained in 21% yield
2
X
NH
Ph
9 X = Br (19%)
10 X = H (2%)
Pd catalyst
ligand 5-8
1a
2
3a
base
toluene, 120 °C
(in a sealed tube)
see Table 1
ligands:
R2
1
(9:10¼10:1, determined by H NMR). To our delight, the
P(R1)2
R2
same reaction at higher temperature (120 ꢀC) significantly
improved the yield of the desired product, and carbazole
3a was obtained in 79% yield. In this case, a small amount
of the mono N-arylation products (9 and 10) were detected
by TLC, but could not be isolated. Although the Buchwald
group reported that the mono N-arylation of aniline with
20-chloroacetophenone proceeded in 81% yield with
Pd2(dba)3 (1 mol %) and ligand 5 (2 mol %),5c the double
N-arylation of aniline with 2 was found to be very slow
with less than 10 mol % Pd catalyst. It was also found that
the molar ratio of ligand/Pd2(dba)3 (2–3:1) was important
for higher yields of 3a. The dependence on the various reac-
tion parameters was then examined. For the ligands, 5 as
well as other dialkylphosphinobiaryls (6,5d 7,5c and 85e),
which have been reported by the Buchwald group being ex-
cellent ligands for the N-arylation, were tested. These results
are listed in Table 1, which showed that (i) Pd2(dba)3 was the
Pd source of choice (entries 2–4, when Pd(OAc)2 was em-
ployed, the formation of Pd metal precipitates was observed
during the course of the reaction), (ii) 5 and 2-(dicyclohex-
ylphosphino)-20,40,60-(triisopropyl)biphenyl (6) were effec-
tive ligands (entries 5–8), and (iii) the use of NaOt-Bu as
a base gave good results whereas Cs2CO3 or K3PO4 signifi-
cantly decreased the yields (entries 5, 9, and 10). As a result,
N-phenylcarbazole (3a) was obtained in 85% yield under the
conditions noted in entry 5.
P(t-Bu)2
R2
5 R1 = Cy, R2 = H
6 R1 = Cy, R2 = i-Pr
7 R1 = t-Bu, R2 = H
8
Scheme 1. dba¼Dibenzylideneacetone, Cy¼cyclohexyl.
2.2. Double N-arylation of aliphatic amines
The successful preparation of N-phenylcarbazole (3a) by the
double N-arylation reaction led us to explore the reaction of
aliphatic primary amines with dibromobiphenyl 2 (Scheme 2
and Table 2).
Although ligands 5 and 6, which were found to be effective
for the reaction of aniline, gave less satisfactory results when
benzylamine was employed (entries 1 and 2), the use of
2-(di-tert-butylphosphino)binaphthyl (8) brought about a
significant improvement, giving the desired product, N-
benzylcarbazole (3b), in 60% yield (entry 4). The phosphine
group in 8 is more electron-rich and sterically bulky than that
in 5 and 6. These electronic and steric factors play an impor-
tant role in suppressing any undesired side reactions, such as

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T. Kitawaki et al. / Tetrahedron 62 (2006) 6792–6801
Pd2(dba)3
the product in good yield. For aliphatic primary amines with
ligand 5-8
sterically unencumbered structures, the use of ligand 8 gave
favorable results, whereas the use of ligand 6 proved to be
effective for the sterically hindered tert-butylamine (1g).
R
NH2
+
NaOt-Bu
toluene
N
R
3b-g
1b-g
Br Br
120 °C
(in a sealed tube)
2
see Table 2
2.3. Total synthesis of murrastifoline-A
b: R = Bn
Ph
O
BnO
O
O
We next tried to extend this methodology to the synthesis
of the structurally more complicated carbazole alkaloid,
murrastifoline-A (4). Murrastifoline-A was isolated by
Furukawa and co-workers from the root bark of Murraya
euchrestifolia (Rutaceae) collected in Taiwan.10 The struc-
ture elucidation study by spectral analyses revealed that
murrastifoline-A is a new biscarbazole possessing the di-
meric structure of 10-methoxy-30-methylcarbazole (murraya-
foline-A, murrastifoline-A numbering), where the nitrogen
in one carbazole unit (at the 90-position) is connected to a car-
bon atom at the 3-position of another carbazole unit. While
many monomeric carbazoles have been isolated from higher
plants,2 much attention has been recently focused on such
biarylic biscarbazole alkaloids11,12 due to their interesting
structures and expected biological activities. The C,N-
bonded biaryl biscarbazole structure found in 4 isveryunique
among the biscarbazole alkaloids,11 however, reports on the
synthetic approach to the C,N-bonded biaryl biscarbazoles
are limited.11d,12 In 2001, Bringmann disclosed the total syn-
thesis of murrastifoline-F, an isomer of murrastifoline-A (4)
in which the nitrogen in a carbazole unit at the 90-position is
bonded to another carbazole at C-5 (murrastifoline-A num-
bering), by the lead tetraacetate-mediated oxidative coupling
of 10-methoxy-30-methylcarbazole.12b
-MeO)C H CH -
c: R = (p
f: R =
g: R = t-Bu
6
4
2
OBn
d: R = n-C8H17
e: R = cyclohexyl
-
Scheme 2. Bn¼–CH2Ph.
Table 2. The double N-arylation of aliphatic amines with 2,20-dibromo-
biphenyl (2)a
Entry
Amine
Ligand
Product
Time (h)
Yield (%)b
1
2
3
4
5
6
1b
1b
1b
1b
1c
1d
1e
1fd
1g
1g
5
6
7
8
8
8
8
8
8
6
3b
3b
3b
3b
3c
3d
3e
3fe
3g
3g
13
13
13
13
13
24
24
24
13
13
20
9
42
60
71
67
80
52
17
42
7
8c
9
10
a
Reaction conditions: A mixture of 1 (1.0 equiv), 2 (1.1 equiv), Pd2(dba)3
(10 mol %), ligand (30 mol %), and NaOt-Bu (3.0 equiv) in toluene was
heated at 120 ꢀC in a sealed tube.
Isolated yield after chromatographic purification.
2 (300 mol % to 1f), Pd2(dba)3 (100 mol %), and 8 (300 mol %) at 60 ꢀC.
b-Anomer.
b
c
d
e
Obtained as an anomeric mixture (a/b¼1:1.7).
Our retrosynthetic analysis of murrastifoline-A (4) is shown
in Figure 2. The biscarbazole structure of murrastifoline-A
(4) could be constructed by the key double N-arylation of
the bottom-half segment, carbazolamine 12, with the top-
half segment, dibromobiphenyl derivative 11. For prepara-
tion of both the top and bottom segments (11 and 12), we
chose 2-amino-5-methylphenol (13) as the common starting
material.
the formation of unreactive Pd bis-amine complexes and/or
b-hydride elimination of the Pd-amido intermediates,5a,g in
the double N-arylation process. Compound 8 was also found
to work well for other aliphatic primary amines (entries 5–
7). It is important to note that the N-alkylcarbazoles, which
were prepared in poor yields under Nozaki’s conditions,4a
were obtained in moderate to good yields by the double
N-arylation reactions when 8 was employed as the ligand.
Under similar conditions, glucopyranosylamine derivative
1f, a structurally complex and chemically unstable amine,
could be converted into N-(glucopyranosyl)carbazole deriv-
ative 3f9 in 52% yield, although excess amounts of the Pd
catalyst and ligand 8 were required (entry 8). The reaction
of tert-butylamine (1g) with ligand 8 (entry 9), however, re-
sulted in a low yield of the desired product. It was found that
the use of ligand 6 instead of 8 produced a better result by
generating N-(tert-butyl)carbazole (3g) in moderate (42%)
yield (entry 10). The steric bulk of ligand 8 would prevent
the sterically hindered tert-butylamine from approaching
the catalyst. While the reasons for the better yield by the
double N-arylation of tert-butylamine with ligand 6 are not
clear, the effectual combination of the electronic (6 should
be electron richer than 5, but electron poorer than 8) and
steric (6 is smaller than 8) factors in 6 would contribute to
its effectiveness.
The synthesis of top-half segment (11) commenced from
the known O-tosylate (14),13 prepared from commercially
available 13 in 89% yield (Scheme 3). The conventional
iodination with N-iodosuccinimide (NIS) of 14 afforded 15
(69%), whose Suzuki–Miyaura cross-coupling reaction14 with
2-bromophenylboronic acid in the presence of Pd(PPh3)4
Me
5
3
OMe
2
Br
2'
Me
Br
double
N-arylation
5
top-half segment 11
4
+
OH
2
Me
H2N
6
3
NH2
13
9
N
SEM
8
1
Based on these experiments, it was shown that the double
N-arylation methodology is effective for the one-step syn-
thesis of various N-substituted carbazoles. For aniline, the
combination of Pd2(dba)3, NaOt-Bu, and ligand 5 provided
OMe
bottom-half segment 12
Figure 2. SEM¼–CH2OCH2CH2SiMe3.

T. Kitawaki et al. / Tetrahedron 62 (2006) 6792–6801
6795
in EtOH–benzene–2 M aqueous Na2CO3 cleanly afforded 16
in 99% yield. Sandmeyer reaction of 16 gave dibromobi-
phenyl 17 in 64% yield. In this reaction, the use of AcOH
as a co-solvent was essential for the effective diazotization.
The O-Ts protecting group in 17 was removed by basic
hydrolysis to give 18, whose O-methylation furnished the
top-half segment 11 in 59% yield from 17.
afforded 23. Although the attempted reduction of the nitro
function in 23 by catalytic hydrogenation (H2 in the presence
of 5% Pd on carbon) resulted in the formation of many un-
identified products, the treatment of 23 with NaBH2S3
cleanly provided the bottom-half segment 12 in 84% yield.
16
With both the top- and bottom-half segments in hand, the
crucial double N-arylation reaction was explored (Scheme
5). From the observations of the coupling reactions of aniline
with 2,20-dibromobiphenyl (Table 1), it was expected that
the use of 5 as the ligand would be the most effective for
the reaction. Indeed, when a mixture of segments 11 and
12 in toluene was heated at 120 ꢀC in the presence of
Pd2(dba)3, NaOt-Bu, and 5, the double N-arylation success-
fully took place to provide the desired N-protected biscarba-
zole 24 in 58% yield. It was found, as anticipated, the use of
ligands 6 and 8 gave less satisfactory results (28% yield with
6 and 23% yield with 8). Finally, the N-SEM group was re-
moved under acidic conditions to furnish murrastifoline-A
(4) in 94% yield. The spectral data of synthetic 4 were fully
identical with those of the natural product.10
B(OH)2
Me
Me
TsCl
Et3N
NIS
Br
13
CH2Cl2
Pd(PPh3)4
2 M aq. Na2CO3
benzene, EtOH
reflux
DMF
0 °C
I
OTs
OTs
0 °C
NH2
NH2
(89%)
(69%)
14
15
(99%)
Me
Me
5
NaNO2
CuBr
3 OR
conc. H2SO4
OTs
2
2'
AcOH
48% aq. HBr
r.t. to 80 °C
Br
NH2
Br
Br
16
(64%)
17 R = Ts
1 M aq. KOH
EtOH, reflux
(76%)
Me
18 R = H
3'
MeI, NaH
Pd2(dba)3 (20 mol%)
DMF, r.t.
1'
5 (60 mol%)
11 R = Me
OMe
(77%)
NaOt-Bu (3 eq.)
9'
Me
12
11
+
N
6
toluene
3
Scheme 3. Ts¼–SO2C6H4(p-Me).
120 °C, 24 h
in a sealed tube
9
N
R
8
(58%)
The bottom-half segment 12 was synthesized as shown in
Scheme 4. Thus, the Buchwald–Hartwig N-arylation5f of
14 with 4-bromonitrobenzene afforded diarylamine 19 in
81% yield. The treatment of 19 with excess Pd(OAc)2 in
AcOH induced the cyclization3d,13b to provide carbazole
20 in 53% yield. After protection of the nitrogen function
in 20 with the 2-trimethylsilylethoxymethyl (SEM) group
(86% yield), the product 21 was treated with NaOH in
MeOH-H2O to provide de-O-tosyl derivative 22 along with
its methyl ether 23 in 76 and 8% isolated yields, respectively.
Methyl ether 23 would be formed by the nucleophilic
aromatic substitution reaction of compound 21 with the
methoxide ion.15 The O-methylation of 22 quantitatively
OMe
24 R = SEM
4 M aq. HCl
EtOH-THF
reflux
4 R = H
(murrastifoline-A)
(94%)
Scheme 5.
3. Conclusion
In summary, we described the Pd-catalyzed double N-aryla-
tion reaction of primary amines with 2,20-dibromobiphenyls,
which provided N-substituted carbazoles in a one-step reac-
tion. By the choice of ligands, both the aryl and aliphatic
amines including tert-butylamine and an O-protected gluco-
pyranosylamine could be transformed into the correspond-
ing carbazoles. Based on this methodology, the first total
synthesis of murrastifoline-A (4) has been accomplished.
This synthesis fully confirmed the proposed structure of
the natural product and revealed that the double N-arylation
methodology is highly effective for the one-step construc-
tion of the structurally complex, unsymmetrical multi-
substituted carbazole derivatives.
O2N
Br
O2N
Me
5
OTs
O2N
Pd(OAc)2
14
2
AcOH
reflux
Pd2(dba)3
rac.-BINAP
NaOt-Bu
N
H
(53%)
19
(81%)
toluene, 120 °C
Me
Me
O2N
3
6
1 M aq. NaOH
MeOH
9
N
R
1
N
SEM
22: 76%
23: 8%
reflux
OTs
OR
20 R = H
22 R = H
SEMCl
MeI, NaH
DMF
4. Experimental
4.1. General
NaH, DMF
0 °C
(86%)
r.t.
21 R = SEM
23 R = Me
(100%)
NaBH2S3
THF
Melting points (mp) were determined on a Mitamura-riken
micro hot stage and are uncorrected. 1H NMR spectra
were measured with a JEOL JNM-Lambda 300 (300 MHz)
or a Varian MVX-300 (300 MHz) spectrometer, with
reflux
(84%)
12
Scheme 4. BINAP¼2,20-bis(diphenylphosphino)-1,10-binaphthyl.

6796
T. Kitawaki et al. / Tetrahedron 62 (2006) 6792–6801
1
tetramethylsilane as the internal standard for solutions in
CDCl3 at rt, unless otherwise noted. Chemical shifts are
reported as d values in ppm. 13C NMR spectra were taken
on a 75 MHz spectrometer. Mass spectra were measured
by a JEOL GC-Mate spectrometer with EI mode (70 eV),
unless otherwise noted. Optical rotations were measured
with a JASCO DIP-370 instrument with 1-dm tube and
mp 84–87 ꢀC; H NMR d 5.27 (s, 1H), 6.92 (ddd, J¼7.5,
7.2, <1 Hz, 1H), 6.99 (ddd, J¼7.8, 7.2, 1.5 Hz, 1H), 7.04
(dd, J¼7.5, <1 Hz, 1H), 7.15 (dd, J¼7.8, 1.7 Hz, 1H),
7.20–7.39 (m, 7H), 7.69 (dd, J¼7.7, 0.9 Hz, 1H); 13C
NMR d 116.6, 119.1, 120.5, 121.6, 124.6, 128.0, 129.0,
129.4, 129.5, 130.5, 130.8, 132.1, 133.3, 139.8, 141.0,
143.0; IR (neat) n 3010 cmꢁ1; MS m/z 325 [M+(81Br),
22%], 323 [M+(79Br), 20], 244 (81), 167 (32), 64 (100);
HRMS Calcd for C18H14N79Br (M+): 323.0310. Found:
values of [a]D are recorded in units of 10ꢁ1 deg cm2 gꢁ1
.
IR spectra were taken with a JASCO FTIR-200 spectro-
meter. Organic extracts were dried over anhydrous Na2SO4
and concentrated below 40 ꢀC under reduced pressure.
1
323.0311. Data for 10: Rf¼0.53 (toluene/hexane¼1:1); H
NMR d 5.52 (s, 1H), 6.83 (ddd, J¼7.3, 7.3, 1.2 Hz, 1H),
6.88–6.97 (m, 3H), 7.14–7.19 (m, 4H), 7.29–7.36 (m, 6H);
13C NMR d 117.6, 118.4, 121.2, 121.2, 127.6, 128.4,
129.0, 129.5, 131.0, 131.7, 139.2, 140.3, 143.5; IR (neat) n
3405 cmꢁ1; MS m/z 245 (M+, 100%), 167 (32); HRMS
Calcd for C18H15N (M+): 245.1204. Found: 245.1198.
˚
Solvents were dried over 3 A molecular sieves after dis-
tillation. Benzene, toluene, and DMF were distilled from
CaH2. MeOH was distilled from CaSO4 (DRIERITEÒ).
AcOH was distilled from Ac2O and KMnO4. EtOH (95%,
˚
dried over 3 A molecular sieves), Et2O (dehydrated), THF
(dehydrated, stabilizer free), and CH2Cl2 (dehydrated)
were purchased from Kanto Chemical Co., INC. For column
chromatography, Merck silica gel 60 (230–400 mesh)
was used, unless otherwise noted. For TLC analysis, Merck
precoated TLC plates (silica gel 60 F254 on glass plates,
0.25 mm) were used. For preparative TLC, Merck precoated
TLC plates (silica gel 60 F254 on glass plates, 0.5 mm)
were used.
4.2.3. N-Benzylcarbazole (3b)4b,18 (Table 2, entry 4). The
general procedure using 2-(di-tert-butylphosphino)bi-
naphthyl (8) gave N-benzylcarbazole (3b) (39.0 mg, 60%)
as a colorless solid: Rf¼0.53 (toluene/hexane¼1:1); mp
1
119–120 ꢀC (lit.4b mp 118–120 ꢀC); H NMR d 5.50 (s,
2H), 7.11–7.14 (m, 2H), 7.22–7.27 (m, 5H), 7.35 (d,
J¼7.3 Hz, 2H), 7.42 (dd, J¼7.3, 0.9 Hz, 2H), 8.13 (dd,
J¼7.6, 0.9 Hz, 2H); 13C NMR d 46.7, 109.0, 119.4, 120.5,
123.2, 126.0, 126.6, 127.6, 128.9, 137.3, 140.8; IR (KBr) n
3030, 2930, 1595, 1450 cmꢁ1; MS m/z 257 (M+, 100%),
166 (24), 109 (17), 91 (92); HRMS Calcd for C19H15N
(M+): 257.1204. Found: 257.1203. Anal. Calcd for
C19H15N$0.1H2O: C, 88.07; H, 5.91; N, 5.41%. Found: C,
88.08; H, 5.89; N, 5.40%.
4.2. General procedure for the double N-arylation
reaction (Tables 1 and 2)
Ar was bubbled into a mixture of amine (1) (0.250 mmol), di-
bromobiphenyl (2) (85.8 mg, 0.275 mmol), Pd2(dba)3 (22.9
mg, 0.0250 mmol), ligand (5, 6, 7 or 8) (0.0750 mmol), and
NaOt-Bu (72.1 mg, 0.750 mmol) in toluene (1 mL) for
15 min, unless otherwise noted. The mixture was then heated
at 120 ꢀC in a sealed tube for 13–24 h (see Tables 1 and 2).
After cooling, the mixturewas filtrated through a pad of silica
gel (3 g, toluene). The filtrate was concentrated to give a resi-
due, which was purified by column chromatography (silica
gel: 6 g, toluene/hexane) to afford carbazole 3.
4.2.4. N-(4-Methoxybenzyl)carbazole (3c)19 (Table 2,
entry 5). The general procedure using 2-(di-tert-butylphos-
phino)binaphthyl (8) gave N-(4-methoxybenzyl)carbazole
(3b) (51.2 mg, 71%) as a colorless solid: Rf¼0.32 (toluene/
hexane¼1:1); mp 122–123 ꢀC; 1H NMR d 3.73 (s, 3H), 5.46
(s, 2H), 6.78 (d, J¼8.6 Hz, 2H), 7.08 (d, J¼8.6 Hz, 2H), 7.24
(dd, J¼7.8, 7.4 Hz, 2H), 7.37 (d, J¼7.6 Hz, 2H), 7.42 (dd,
J¼7.6, 7.4 Hz, 2H), 8.12 (d, J¼7.8 Hz, 2H); 13C NMR
d 46.2, 55.4, 109.1, 114.3, 119.3, 120.5, 123.1, 125.9,
127.8, 129.4, 140.8, 159.1; IR (KBr) n 3050, 2835, 1595,
1460 cmꢁ1; LRMS m/z 287 (M+, 30%), 166 (11), 121
(100), 77 (12); HRMS Calcd for C20H17NO (M+):
287.1310. Found: 287.1300. Anal. Calcd for C20H17NO:
C, 83.59; H, 5.96; N, 4.87%. Found: C, 83.43; H, 5.95;
N, 4.85%.
4.2.1. N-Phenylcarbazole (3a)4a,17 (Table 1, entry 5). The
general procedure using 2-(dicyclohexylphosphino)bi-
phenyl (5) gave N-phenylcarbazole (3a) (51.9 mg, 85%) as
a colorless solid: Rf ¼0.37 (toluene/hexane¼1:5); mp 89–
1
90 ꢀC (lit.17 mp 89–90 ꢀC); H NMR d 7.23–7.31 (m, 2H),
7.37–7.41 (m, 4H), 7.42–7.48 (m, 1H), 7.54–7.62 (m, 4H),
8.14 (d, J¼7.8 Hz, 1H); 13C NMR d 109.9, 120.0, 120.4,
123.5, 126.0, 127.3, 127.6, 130.0, 137.9, 141.0; IR (KBr)
n 3020, 1595 cmꢁ1; MS m/z 243 (M+, 100%), 139 (12),
121 (9); HRMS Calcd for C18H13N (M+): 243.1048.
Found: 243.1040. Anal. Calcd for C18H13N: C, 88.86; H,
5.39; N, 5.76%. Found: C, 88.89; H, 5.32; N, 5.76%.
4.2.5. N-Octylcarbazole (3d)20 (Table 2, entry 6). The gen-
eral procedure using 2-(di-tert-butylphosphino)binaphthyl
(8) gave N-octylcarbazole (3d) (46.5 mg, 67%) as a colorless
1
syrup: Rf¼0.50 (toluene/hexane¼1:5); H NMR d 0.86 (t,
4.2.2. N-[2-(20-Bromobiphenyl)]aniline (9) and N-(2-
biphenyl)aniline (10)5e. The general procedure using
2-(dicyclohexylphosphino)biphenyl (5) at 60 ꢀC gave
N-phenylcarbazole (3a) (20.1 mg, 33%) and a mixture of
mono N-arylation products 9 and 10 (10:1, determined by
1H NMR, 16.8 mg, 21%). A small amount of the mixture
was separated by HPLC (Finepak SIL, JASCO Corp.,
J¼6.7 Hz, 3H), 1.24–1.40 (m, 10H), 1.86 (tt, J¼7.3,
7.3 Hz, 2H), 4.28 (t, J¼7.3 Hz, 2H), 7.21 (ddd, J¼7.6, 7.6,
1.2 Hz, 2H), 7.39 (dd, J¼7.8, 1.2 Hz, 2H), 7.45 (ddd,
J¼7.8, 7.6, 1.0 Hz, 2H), 8.09 (dd, J¼7.6, 1.0 Hz, 2H);
13C NMR d 14.2, 22.7, 27.4, 29.1, 29.3, 29.5, 31.9,
43.2, 108.8, 118.8, 120.5, 122.9, 125.7, 140.5; IR (neat)
n 3055, 2925, 1600, 1455 cmꢁ1; MS m/z 279 (M+, 79%),
245 (19), 180 (100); HRMS Calcd for C20H25N (M+):
279.1987. Found: 279.1982. Anal. Calcd for C20H25N: C,
85.97; H, 9.02; N, 5.01%. Found: C, 85.99; H, 8.93; N,
4.91%.
4.6 mm i.d., 250 mmL, EtOAc/hexane¼1:40, 1.0 mL minꢁ1
)
to provide compounds 9 (retention time 5.40 min) and 10
(retention time 6.95 min) in pure forms and for use as analyt-
ical samples. Data for 9: Rf ¼0.53 (toluene/hexane¼1:1);

T. Kitawaki et al. / Tetrahedron 62 (2006) 6792–6801
6797
4.2.6. N-Cyclohexylcarbazole (3e)21 (Table 2, entry 7).
The general procedure using cyclohexylamine (1e)
(0.0229 mL, 0.200 mmol), dibromobiphenyl (2) (68.6 mg,
0.220 mmol), Pd2(dba)3 (18.3 mg, 0.0200 mmol), 2-(di-tert-
butylphosphino)binaphthyl (8) (23.9 mg, 0.0600 mmol),
NaOt-Bu (57.7 mg, 0.600 mmol), and toluene (0.8 mL)
gave N-cyclohexylcarbazole (3e) (40.0 mg, 80%) as a color-
less solid: Rf¼0.53 (toluene/hexane¼1:5); mp 143–144 ꢀC
7.26–7.38 (m, 13H), 7.47–7.51 (m, 2H); 13C NMR d 67.3,
69.0, 75.2, 75.5, 82.1, 82.1, 86.8, 101.1, 126.1, 127.8,
127.9, 128.2, 128.3, 128.3, 128.4, 128.5, 129.0, 137.5,
138.3, 138.6; IR n 3400, 3335 cmꢁ1; MS m/z 447 (M+,
1%), 356 (2), 248 (37), 91 (100); HRMS Calcd for
C27H29NO5 (M+): 447.2046. Found: 447.2056. Anal. Calcd
for C27H29NO5: C, 72.46; H, 6.53; N, 3.13%. Found: C,
72.32; H, 6.55; N, 2.74%.
1
(lit.21 mp 143 ꢀC); H NMR d 1.31–1.61 (m, 3H), 1.82–
1.87 (m, 1H), 1.94–2.04 (m, 4H), 2.33–2.47 (m, 2H), 4.49
(tt, J¼12.3, 3.9 Hz, 1H), 7.20 (dd, J¼7.8, 7.6 Hz, 2H), 7.43
(ddd, J¼8.1, 7.6, 1.2 Hz, 2H), 7.56 (d, J¼8.1 Hz, 2H), 8.10
(dd, J¼7.6, 1.2 Hz, 2H); 13C NMR d 25.8, 26.7, 30.9, 55.5,
110.4, 118.6, 120.4, 123.4, 125.4, 139.8; IR (KBr) n 3055,
2920, 1590, 1455 cmꢁ1; MS m/z 249 (M+, 100%), 206 (43),
167 (92); HRMS Calcd for C18H19N (M+): 249.1517.
Found: 249.1517. Anal. Calcd for C18H19N: C, 86.70; H,
7.68; N, 5.62%. Found: C, 86.48; H, 7.60; N, 5.58%.
4.2.8. 2,3-Di-O-benzyl-4,6-O-benzylidene-a- and b-D-
glucopyranosylcarbazole (3f) (Table 2, entry 8). Ar gas
was bubbled into a mixture of glucosylamine (1f) (20 mg,
0.0447 mmol), dibromobiphenyl (2) (42.0 mg, 0.135 mmol),
Pd2(dba)3 (41 mg, 0.0447 mmol), 2-(di-tert-butylphosphino)-
binaphthyl (8) (53.0 mg, 0.133 mmol), and NaOt-Bu
(12.9 mg, 0.134 mmol) in toluene (0.8 mL) for 15 min. The
reaction mixture was then heated at 60 ꢀC in a sealed tube
for 24 h. After cooling, the mixture was purified by column
chromatography (silica gel: 2 g, EtOAc/hexane¼1:40) to
afford an anomeric mixture of glucosylcarbazole (3f). The
mixture was separated by preparative TLC using EtOAc/
hexane¼1:8 as an eluent to give a-anomer (3fa)9 (5.1 mg,
19%) as a colorless syrup and b-anomer (3fb) (8.9 mg,
33%) as a colorless syrup. Data for 3fa: Rf¼0.23 (EtOAc/
4.2.7. 2,3-Di-O-benzyl-4,6-O-benzylidene-b-D-gluco-
pyranosylamine (1f). To a suspension of NaH (39 mg,
1.63 mmol) in DMF (2 mL) was slowly added 4,6-O-benzyl-
idene-b-D-glucopyranosylazide22 (120 mg, 0.409 mmol) at
0 ꢀC. After stirring at rt for 5 min, the reaction mixture
was cooled to 0 ꢀC. To this mixture was slowly added benzyl
bromide (0.15 mL, 1.26 mmol), and the mixture was stirred
at rt for 2 h. After addition of MeOH at 0 ꢀC, the reaction
mixture was diluted with EtOAc and washed with H2O
and brine. The organic layer was dried and concentrated to
give a residue, which was purified by column chromato-
graphy (silica gel: 6 g, EtOAc/hexane¼1:20) to afford
2,3-O-benzyl-4,6-O-benzylidene-b-D-glucopyranosylazide
(176 mg, 90%) as a white solid: Rf¼0.88 (EtOAc/tol-
uene¼1:2); mp 112 ꢀC; [a]D27 +69.5 (c 1.0, CHCl3); 1H
NMR d 3.36 (dd, J¼8.7, 8.4 Hz, 1H), 3.42 (ddd, J¼9.9,
9.6, 4.8 Hz, 1H), 3.64 (dd, J¼9.6, 9.3 Hz, 1H), 3.69 (dd,
J¼10.5, 9.9 Hz, 1H), 3.75 (dd, J¼9.3, 8.7 Hz, 1H), 4.32
(dd, J¼10.5, 4.8 Hz, 1H), 4.65 (d, J¼8.4 Hz, 1H), 4.77
and 4.92 (2d, J¼11.4 Hz, each 1H), 4.81 (s, 2H), 5.52 (s,
1H), 7.25–7.33 (m, 13H), 7.45–7.48 (m, 2H); 13C NMR
d 68.1, 68.4, 75.2, 75.7, 81.2, 81.3, 81.4, 90.6, 101.2,
126.0, 127.8, 128.0, 128.1, 128.3, 128.3, 128.4, 128.5,
129.1, 137.1, 137.7, 138.2; IR n 2115 cmꢁ1; MS m/z 473
(M+, 1%), 431 (1), 382 (18), 91 (100); HRMS Calcd for
C27H27N3O5 (M+): 473.1951. Found: 473.1960. Anal.
Calcd for C27H27N3O5: C, 68.48; H, 5.75; N, 8.87%.
Found: C, 68.51; H, 5.86; N, 8.64%.
1
hexane¼1:8); [a]D21 ꢁ14.5 (c 0.1, CHCl3); H NMR (C6D6)
d 3.50 (dd, J¼10.5, 10.2 Hz, 1H), 3.73 and 3.83 (2d,
J¼11.9 Hz, each 1H), 3.93 (br d, J¼1.8 Hz, 1H), 4.02–4.07
(m, 2H), 4.30 (dd, J¼10.5, 5.1 Hz, 1H), 4.42 and 4.53 (2d,
J¼12.2 Hz, each 1H), 4.60–4.71 (m, 1H), 5.39 (s, 1H), 6.47
(d, J¼1.8 Hz, 1H), 6.54 (d, J¼6.3 Hz, 2H), 6.81–6.90 (m,
4H), 7.11–7.36 (m, 11H), 7.65 (br d, J¼7.8 Hz, 4H), 8.03
(d, J¼7.5 Hz, 2H); IR (neat) n 3030, 2920, 1455 cmꢁ1; MS
m/z 597 (M+, 13%), 167 (23), 91 (100); HRMS Calcd for
C39H35NO5 (M+): 597.2515. Found: 597.2522. Data for
3fb: Rf¼0.20 (EtOAc/hexane¼1:8); [a]2D5 +31.7 (c 0.97,
CHCl3); 1H NMR d 3.35 (d, J¼10.0 Hz, 1H), 3.79 (m, 1H),
3.93 (dd, J¼10.5, 10.2 Hz, 1H), 4.00–4.08 (m, 2H), 4.06
(d, J¼10.0 Hz, 1H), 4.40 (dd, J¼8.8, 8.8 Hz, 1H), 4.46 (dd,
J¼10.5, 4.9 Hz, 1H), 4.83 (d, J¼11.2 Hz, 1H), 5.00 (d,
J¼11.2 Hz, 1H), 5.73 (s, 1H), 5.88 (d, J¼8.8 Hz, 1H), 6.34
(d, J¼7.6 Hz, 2H), 6.93 (dd, J¼7.6, 7.6 Hz, 2H), 7.05 (dd,
J¼7.6, 7.6 Hz, 1H), 7.28–7.64 (m, 16H), 8.09 (d, J¼7.6 Hz,
2H); 13C NMR d 68.9, 69.4, 75.2, 75.6, 78.8, 82.0, 82.4,
85.5, 101.5, 109.8, 112.8, 120.4, 126.2, 127.8, 127.9, 128.1,
128.2, 128.5, 128.6, 129.2, 136.7, 137.4, 138.5; IR (neat)
n 3030, 2875, 1455 cmꢁ1; MS m/z 597 (M+, 6%), 167 (12),
91 (100); HRMS Calcd for C39H35NO5 (M+): 597.2515.
Found: 597.2513.
To a solution of 2,3-O-benzyl-4,6-O-benzylidene-b-D-gluco-
pyranosylazide (136 mg, 0.287 mmol) in toluene (4 mL)
was added Lindlar catalyst (70 mg). The reaction mixture
was stirred for 12 h under H2 atmosphere (1 atm) at rt.
Then the catalyst was removed by filtration through Celite
and the filtrate was concentrated to give a residue, which
was recrystallized from EtOH to afford glucosylamine 1g
(98.5 mg, 76%) as a white solid: Rf¼0.34 (EtOAc/
toluene¼1:2); mp 111–112 ꢀC (decomp.); [a]D27 ꢁ38.7 (c
4.2.9. N-tert-Butylcarbazole (3g) (Table 2, entry 10). The
general procedure using 2-(dicyclohexylphosphino)-20,40,60-
triisopropylbiphenyl (6) gave N-(tert-butyl)carbazole (3g)
(23.6 mg, 42%) as a colorless solid: Rf¼0.38 (toluene/
1
hexane¼1:5); mp 122–123 ꢀC; H NMR d 2.00 (s, 9H),
7.19 (ddd, J¼7.8, 7.1, 0.7 Hz, 2H), 7.37 (ddd, J¼8.7, 7.1,
1.5 Hz, 2H), 7.86 (dd, J¼8.7, 0.7 Hz, 2H), 8.10 (dd,
J¼7.8, 1.5 Hz, 2H); 13C NMR d 31.2, 59.2, 113.9, 118.6,
120.0, 124.6, 125.2, 140.6; IR (KBr) n 3050, 2970, 1590,
1440 cmꢁ1; MS m/z 223 (M+, 17%), 167 (100), 140 (16);
HRMS Calcd for C16H17N (M+): 223.1361. Found:
223.1359. Anal. Calcd for C16H17N$0.1H2O: C, 85.37; H,
7.70; N, 6.22%. Found: C, 85.34; H, 7.63; N, 6.29%.
1
1.0, CHCl3); H NMR d 1.91 (br s, 2H), 3.21 (dd, J¼8.6,
8.6 Hz, 1H), 3.42 (ddd, J¼9.6, 9.3, 5.0 Hz, 1H), 3.65 (dd,
J¼9.3, 9.1 Hz, 1H), 3.71 (dd, J¼10.4, 9.6 Hz, 1H), 3.80
(dd, J¼9.1, 8.6 Hz, 1H), 4.22 (d, J¼8.6 Hz, 1H), 4.32 (dd,
J¼10.4, 5.0 Hz, 1H), 4.80 and 4.94 (2d, J¼11.4 Hz, each
1H), 4.84 and 4.92 (2d, J¼10.5 Hz, each 1H), 5.56 (s, 1H),

6798
T. Kitawaki et al. / Tetrahedron 62 (2006) 6792–6801
4.3. Synthesis of murrastifoline-A
4.3.4. 2,20-Dibromo-5-methyl-3-(4-toluenesulfonyloxy)-
1,10-biphenyl (17). To a solution of aminobromobiphenyl
16 (128 mg, 0.197 mmol) in AcOH (2.5 mL) was slowly
added NaNO2 (40.9 mg, 0.593 mmol) in concd H2SO4
(0.04 mL) at 0 ꢀC, then the mixture was stirred for 1 h at rt.
The reaction mixture was slowly added to CuBr (85.1 mg,
0.593 mmol) in 47 wt % aqueous HBr solution (1.7 mL) at
80 ꢀC, and stirred for 1.5 h at 80 ꢀC. After cooling, the reac-
tion mixture was extracted with Et2O and washed succes-
sively with 1 M aqueous NaOH solution, saturated aqueous
NaHCO3 solution, and brine. The organic layer was dried
and concentrated to give a residue, which was purified by
column chromatography (silica gel: 15 g, EtOAc/petroleum
ether¼1:20) to afford dibromobiphenyl 17 as white crystals:
Rf ¼0.43 (EtOAc/petroleum ether¼1:5); mp 163 ꢀC; 1H
NMR d 2.05 (s, 3H), 2.46 (s, 3H), 6.62 (s, 1H), 7.09 (s,
1H), 7.20 (d, J¼6.9 Hz, 2H), 7.26–7.43 (m, 4H), 7.65 and
7.81 (2dd, J¼8.1, <1 Hz, each 1H); 13C NMR d 21.4, 21.9,
118.8, 120.2, 123.5, 124.0, 128.1, 128.8, 129.7, 130.5,
130.8, 133.5, 139.9, 141.5, 143.3, 150.0; IR (neat) n 2920,
1600, 1580 cmꢁ1; MS m/z 498 [M(81Br2)+, 14%], 496
[M(81Br,79Br)+, 24], 494 [M(79Br2)+, 12], 416 (22), 414
(18), 343 (12), 341 (23), 339 (12), 335 (23), 155 (100);
HRMS Calcd for C20H16O739Br2S (M+): 493.9187. Found:
493.9183.
4.3.1. 4-Toluenesulfonic acid 2-amino-5-methylphenyl
ester13 (14). To a solution of 2-amino-5-methylphenol (13,
3 g, 24.4 mmol) in CH2Cl2 (45 ml) were added Et3N
(3.74 ml, 26.8 mmol) and TsCl (5.11 g, 26.6 mmol) at
0 ꢀC. After stirring at 0 ꢀC for 15 min, the reaction mixture
was extracted with CHCl3 and washed with H2O. The
organic layer was dried and concentrated to give a residue,
which was recrystallized from Et2O to afford tosylate 14
(6.04 g, 89%) as a brown solid: Rf ¼0.23 (EtOAc/petroleum
ether¼1:5); mp 81–82 ꢀC (lit.13b 81–82 ꢀC); 1H NMR d 2.15
(s, 3H), 2.46 (s, 3H), 3.64 (br s, 2H), 6.61 and 6.83 (2d,
J¼8.0 Hz, each 1H), 6.66 (s, 1H), 7.33 and 7.78 (2d,
J¼8.3 Hz, each 2H); MS m/z 277 (M+, 41%), 122 (100),
94 (89); HRMS Calcd for C14H15NO3S (M+): 277.0773.
Found: 277.0773. Anal. Calcd for C14H15NO3S: C, 60.63;
H, 5.45; N, 5.05%. Found: C, 60.46; H, 5.42; N, 4.83%.
4.3.2. 4-Toluenesulfonic acid 2-amino-3-iodo-5-methyl-
phenyl ester (15). To a solution of tosylate 14 (2.00 g,
7.21 mmol) in DMF (40 mL) was slowly added NIS
(1.78 g, 7.93 mmol) at 0 ꢀC. The reaction mixture (protected
fromlight)was stirredfor3 h atrt, thendilutedwithEt2O, and
washed with 30 wt % of aqueous Na2S2O3 solution and brine.
The organic layer was dried and concentrated to give a resi-
due, which was purified by column chromatography (silica
gel: 60 g, EtOAc/petroleum ether¼1:7) to afford iodide 15
(2.01 g, 69%) as an orange solid: Rf ¼0.45 (EtOAc/petroleum
ether¼1:5); mp 141–142 ꢀC; 1H NMR d 2.13 (s, 3H), 2.47 (s,
3H), 4.06 (br s, 2H), 6.69 (s, 1H), 7.34 (s, 1H), 7.35 and 7.78
(2d, J¼8.3 Hz, each 2H); 13C NMR d 19.9, 21.8, 84.6, 123.7,
128.5, 129.0, 130.0, 132.6, 135.2, 137.7, 138.4, 145.9; IR
(neat) n 3460 cmꢁ1; MS m/z 403 (M+, 18%), 248 (100), 121
(12); HRMS Calcd for C14H14NO3IS (M+): 402.9739.
Found: 402.9741. Anal. Calcd for C14H14NO3IS: C, 41.70;
H, 3.50; N, 3.47%. Found: C, 41.93; H, 3.66; N, 3.26%.
4.3.5. 2,20-Dibromo-5-methyl-1,10-biphenyl-3-ol (18). To
a solution of tosylate 17 (47.8 mg, 0.0963 mmol) in EtOH
(4 mL) was added 1 M aqueous KOH solution (0.3 mL) at
rt. The reaction mixture was heated at reflux for 1 h. After
cooling, the mixture was extracted with Et2O and washed
with 10 wt % aqueous citric acid solution and brine. The
organic layer was dried and concentrated to give a residue,
which was purified by column chromatography (silica gel:
3 g, Et2O/petroleum ether¼1:10) to afford hydroxybiphenyl
18 (25 mg, 76%) as a light yellow oil; Rf ¼0.48 (EtOAc/
1
petroleum ether¼1:5); H NMR d 2.33 (s, 3H), 5.62 (s,
1H), 6.65 (d, J¼1.7 Hz, 1H), 6.90 (d, J¼1.7 Hz, 1H),
7.21–7.28 (m, 2H), 7.40 (ddd, J¼7.5, 7.5, 1.2 Hz, 1H),
7.66 (dd, J¼7.5, 1.2 Hz, 1H); 13C NMR (75 MHz) d 21.2,
108.7, 116.0, 123.5, 123.6, 127.3, 129.5, 130.9, 132.7,
138.8, 141.9, 142.3, 152.2; IR (neat) n 3500 cmꢁ1; MS m/z
344 [M(81Br2)+, 49%], 342 [M(81Br,79Br)+, 100], 340
[M(79Br2)+, 51], 263 (58), 261 (58), 182 (93); HRMS
Calcd for C13H10O79Br2 (M+): 339.9099. Found: 339.9102.
4.3.3. 2-Amino-20-bromo-5-methyl-3-(4-toluenesulfonyl-
oxy)-1,10-biphenyl (16). To a solution of Pd(PPh3)4
(22.8 mg, 0.0198 mmol) in benzene (1 mL) was added iodide
(15) (200 mg, 0.495 mmol) in benzene (5 mL) under Ar.
Then, 2 M aqueous Na2CO3 solution (1.9 mL, 3.96 mmol)
and 2-bromophenylboronic acid (120 mg, 0.595 mmol) in
EtOH (2.4 mL) were added to the mixture. The reaction mix-
ture was heated at reflux for 2 h under vigorous stirring. After
cooling, the mixture was diluted with Et2O and washed with
brine. The organic layer was dried and concentrated to give
a residue, which was purified by column chromatography
(silica gel: 10 g, EtOAc/hexane¼1:10) to afford biphenyl
16 (213 mg, 99%) as a pale yellow syrup; Rf ¼0.37 (EtOAc/
petroleum ether¼1:5); 1H NMR d 2.22 (s, 3H), 2.44 (s, 3H),
3.42 (s, 2H), 6.72 and 6.91 (2d, J¼1.2 Hz, each 1H), 7.22
(2ddd, J¼8.4, 7.5, 1.2 Hz, each 1H), 7.31 and 7.79 (2d,
J¼8.4 Hz, each 2H), 7.36 (dd, J¼7.5, 1.2 Hz, 1H), 7.63
(dd, J¼8.4, 1.2 Hz, 1H); 13C NMR d 20.2, 21.6, 122.8,
123.7, 126.8, 127.7, 128.4, 128.7, 129.0, 129.4, 129.6,
131.4, 132.5, 132.9, 134.5, 136.7, 138.7, 145.3; IR (neat)
n 3480 cmꢁ1; MS m/z 433 [M(81Br)+, 11%], 431 [M(79Br)+,
11], 278 (58), 276 (59), 197 (100); HRMS Calcd for
C20H18NO831BrS (M+): 433.0170. Found: 433.0169. Anal.
Calcd for C20H18NO3BrS: C, 55.56; H, 4.20; N, 3.24%.
Found: C, 55.33; H, 4.28; N, 3.02%.
4.3.6. 2,20-Dibromo-3-methoxy-5-methyl-1,10-biphenyl
(11). To a solution of hydroxylbiphenyl 18 (4.7 mg,
0.0137 mmol) in DMF (0.5 mL) were added NaH (1.1 mg,
0.0275 mmol) and MeI (1.7 mL, 0.0275 mmol) at 0 ꢀC.
After stirring at 0 ꢀC for 45 min, the reaction mixture was
quenched with MeOH. The mixture was extracted with
Et2O and washed with saturated aqueous NaHCO3 solution
and brine. The organic layer was dried and concentrated to
give a residue, which was purified by column chromato-
graphy (silica gel: 0.4 g, EtOAc/petroleum ether¼1:50) to
give methoxybiphenyl (11) (3.7 mg, 77%) as a colorless
oil; Rf ¼0.66 (EtOAc/petroleum ether¼1:5); 1H NMR
d 2.01 (s, 3H), 3.27 (s, 3H), 6.32 (d, J¼1.6 Hz, 2H), 6.54
(d, J¼1.6 Hz, 1H), 6.78 (ddd, J¼7.5, 7.4, 1.8 Hz, 1H),
6.96 (ddd, J¼7.4, 7.3, 1.2 Hz, 1H), 7.10 (dd, J¼7.3,
1.8 Hz, 1H), 7.48 (dd, J¼7.5, 1.2 Hz, 1H); 13C NMR
d 21.3, 55.7, 110.7, 112.3, 123.9, 124.1, 127.2, 129.3,

T. Kitawaki et al. / Tetrahedron 62 (2006) 6792–6801
6799
131.3, 132.9, 138.0, 143.1, 144.0, 156.6; IR (neat) n 2940,
solid: Rf ¼0.37 (EtOAc/petroleum ether¼1:5); 1H NMR
d ꢁ0.13 (s, 9H), 0.84 (t, J¼7.6 Hz, 2H), 2.43 (s, 3H), 2.48
(s, 3H), 3.49 (t, J¼7.6 Hz, 2H), 5.89 (s, 2H), 6.87 (s, 1H),
7.38 (d, J¼7.7 Hz, 2H), 7.57 (d, J¼8.6 Hz, 1H), 7.82 (s,
1H), 7.83 (d, J¼7.7 Hz, 2H), 8.38 (dd, J¼8.6, 2.0 Hz, 1H),
8.93 (d, J¼2.0 Hz, 1H); 13C NMR d ꢁ1.4, 17.7, 21.2, 21.9,
66.2, 74.0, 110.4, 117.1, 119.7, 122.2, 122.3, 122.9, 126.7,
128.8, 130.1, 131.4, 131.7, 132.7, 135.1, 141.9, 144.7,
146.2; IR (neat) n 1520, 1330 cmꢁ1; MS m/z 526 (M+,
27%), 468 (11), 313 (26), 261 (25), 73 (100); HRMS Calcd
for C26H30N2O6SSi (M+): 526.1594. Found: 526.1558.
1580 cmꢁ1
;
MS m/z 358 [M(81Br2)+, 49%], 356
[M(81Br,79Br)+, 100], 354 [M(79Br2)+, 51], 277 (77), 275
(79), 196 (43), 181 (42), 165 (22); HRMS Calcd for
C14H12O729Br2 (M+): 353.9255. Found: 353.9254.
4.3.7. 4-Toluenesulfonic acid 5-methyl-2-[(4-nitrophenyl)-
amino]phenyl ester (19). Ar gas was bubbled into a mixture
of amine (14) (125 mg, 0.450 mmol), 4-bromonitrobenzene
(137 mg, 0.678 mmol), Pd2(dba)3 (82 mg, 0.0895 mmol),
rac.-BINAP (168 mg, 0.269 mmol), and NaOt-Bu (64.5 mg,
0.671 mmol) in toluene (5 mL) for 15 min. The reaction
mixture was then heated at 120 ꢀC in a sealed tube for 15 h.
After cooling, the mixture was filtered through Celite. The
filtrate concentrated to give a residue, which was purified by
column chromatography (silica gel: 15 g, EtOAc/petroleum
ether¼1:10) to afford diarylamine 19 (233 mg, 81%) as a yel-
low solid; Rf ¼0.31 (EtOAc/petroleum ether¼1:5); mp 108–
4.3.10. N-[2-(Trimethylsilyl)ethoxymethyl]-3-methyl-6-
nitrocarbazol-1-ol (22). To a solution of tosylate 21
(38.3 mg, 0.0727 mmol) in MeOH (3.8 mL) was added
1 M aqueous NaOH solution (0.2 mL). The reaction mixture
was heated at reflux for 1 h. After cooling, the products were
extracted with Et2O and the organic layer was washed with
10 wt % aqueous citric acid solution and brine, and then
dried. Removal of the solvent gave a residue, which was
purified by column chromatography (silica gel: 2.5 g,
EtOAc/petroleum ether¼1:10) to give hydroxycarbazole
22 (20.6 mg, 76%) as a yellow solid and methoxycarbazole
23 (2.2 mg, 8%) as a yellow solid. Data for 22: Rf¼0.28
(EtOAc/petroleum ether¼1:5); mp 172 ꢀC; 1H NMR
d ꢁ0.04 (s, 9H), 1.02 (t, J¼8.4 Hz, 2H), 2.50 (s, 3H), 3.73
(t, J¼8.4 Hz, 2H), 5.81 (s, 2H), 6.94 (s, 1H), 7.43 (d,
J¼9.0 Hz, 1H), 7.51 (s, 1H), 7.73 (s, 1H), 8.36 (dd, J¼9.0,
2.3 Hz, 1H), 8.93 (d, J¼2.3 Hz, 1H); 13C NMR d ꢁ1.4,
18.0, 21.5, 66.8, 74.2, 108.4, 113.0, 117.1, 117.6, 122.0,
123.7, 126.0, 128.6, 133.5, 141.4, 142.8, 143.8; IR (neat) n
3240, 1520, 1320 cmꢁ1; MS m/z 372 (M+, 6%), 314 (14),
254 (23), 75 (100); HRMS Calcd for C19H24N2O4Si (M+):
372.1505. Found: 372.1508.
1
109 ꢀC; H NMR d 2.31 (s, 3H), 2.32 (s, 3H), 6.34 (br s,
1H), 6.68 (d, J¼8.4 Hz, 2H), 7.00 (s, 1H), 7.08 and 7.25
(2d, J¼7.5 Hz, each 1H), 7.16 (d, J¼7.7 Hz, 2H), 7.65 (d,
J¼7.7 Hz, 2H), 8.03 (d, J¼8.4 Hz, 2H); 13C NMR d 21.0,
21.8, 113.8, 123.4, 125.1, 126.0, 128.4, 128.8, 129.9, 130.2,
132.0, 135.8, 140.0, 141.7, 146.0, 149.6; IR (neat) n 3380,
1500, 1325 cmꢁ1; MS m/z 398 (M+, 36%), 243 (100), 226
(38), 197 (57); HRMS Calcd for C20H18N2O5S (M+):
398.0937. Found: 398.0937.
4.3.8. 3-Methyl-6-nitro-1-(4-toluenesulfonyloxy)carba-
zole (20). To a solution of diarylamine 19 (142 mg,
0.355 mmol) in AcOH (14 mL) was added Pd(OAc)2
(319 mg, 1.42 mmol) at rt. The reaction mixture was heated
at reflux for 5 h. After cooling, the mixture was filtered
through a pad of Celite. The filtrate was extracted with
Et2O and washed with H2O, saturated aqueous NaHCO3
solution, and brine. The organic layer was dried and concen-
trated to give a residue, which was purified by column chro-
matography (silica gel: 14 g, EtOAc/petroleum ether¼1:7)
to afford carbazole 20 (75 mg, 53%) as a yellow solid:
Rf ¼0.23 (EtOAc/petroleum ether¼1:5); mp 224–225 ꢀC;
1H NMR d 2.41 (s, 3H), 2.47 (s, 3H), 6.71 (s, 1H), 7.35 (d,
J¼8.3 Hz, 2H), 7.47 (d, J¼9.0 Hz, 1H), 7.78 (d, J¼8.3 Hz,
2H), 7.80 (s, 1H), 8.37 (dd, J¼9.0, 2.0 Hz, 1H), 8.94 (br s,
1H), 8.94 (d, J¼2.0 Hz, 1H); 13C NMR d 21.4, 21.9,
111.1, 117.6, 119.9, 122.0, 122.5, 122.8, 126.4, 128.8,
130.1, 131.5, 131.6, 131.9, 134.3, 141.6, 143.2, 146.3; IR
(neat) n 3370, 1520, 1320 cmꢁ1; MS m/z 396 (M+, 10%),
348 (11), 330 (31), 241 (34), 197 (100); HRMS Calcd for
C20H16N2O5S (M+): 396.0780. Found: 396.0780.
4.3.11. N-[2-(Trimethylsilyl)ethoxymethyl]-1-methoxy-3-
methyl-6-nitro-carbazole (23). To a solution of hydroxy-
carbazole 22 (13.6 mg, 0.0365 mmol) in DMF (1.3 mL)
were added NaH (1.8 mg, 0.0750 mmol) and MeI (5 mL,
0.080 mmol) at 0 ꢀC. After stirring for 50 min at 0 ꢀC, the
reaction was quenched by addition of MeOH. The mixture
was diluted with Et2O and washed with saturated aqueous
NaHCO3 solution and brine. The organic layer was dried
and concentrated to give a residue, which was purified by
column chromatography (silica gel: 2 g, EtOAc/petroleum
ether¼1:50) to give methoxycarbazole 23 (14.1 mg, 100%)
as a light yellow solid: Rf ¼0.51 (EtOAc/petroleum ether¼
1:5); mp 113 ꢀC; 1H NMR d ꢁ0.11 (s, 9H), 0.87 (t,
J¼7.8 Hz, 2H), 2.54 (s, 3H), 3.57 (t, J¼7.8 Hz, 2H), 4.02
(s, 3H), 6.05 (s, 2H), 6.85 (s, 1H), 7.53 (s, 1H), 7.57 (d,
J¼8.6 Hz, 1H), 8.34 (dd, J¼8.6, 2.4 Hz, 1H), 8.93 (d,
J¼2.4 Hz, 1H); 13C NMR d ꢁ1.3, 18.0, 21.9, 55.7, 65.9,
74.7, 110.1, 110.8, 113.2, 117.3, 121.6, 123.5, 125.1,
129.1, 132.0, 141.5, 144.4, 146.8; IR (neat) n 1515,
1330 cmꢁ1; MS m/z 386 (M+, 12%), 309 (7), 75 (100);
HRMS Calcd for C20H26N2O4Si (M+): 386.1662. Found:
386.1658.
4.3.9. N-[2-(Trimethylsilyl)ethoxymethyl]-3-methyl-6-
nitro-1-(4-toluenesulfonyloxy)carbazole(21).Toasolution
of carbazole 20 (779 mg, 1.96 mmol) in DMF (40 mL) was
added NaH (70.7 mg, 2.95 mmol) at 0 ꢀC. After stirring
at 0 ꢀC for 1 h, to the mixture was added 2-(trimethylsilyl)
ethoxymethyl chloride (SEMCl) (0.42 mL, 2.39 mmol) and
the mixture was stirred at 0 ꢀC for 1.5 h. After addition of
MeOH, the mixture was diluted with EtOAc and washed
successively with water, saturated aqueous NaHCO3 solu-
tion, and brine. The organic layer was dried and concentrated
to give a residue, which was purified by column chro-
matography (silica gel: 50 g, EtOAc/hexane¼1:7) to afford
SEM protected carbazole 21 (884 mg, 86%) as a yellow
4.3.12. N-[2-(Trimethylsilyl)ethoxymethyl]-8-methoxy-6-
methyl-carbazol-3-amine (12). To a solution of nitrocarba-
zole 23 (18.0 mg, 0.0466 mmol) in THF (1.0 mL) at 0 ꢀC
was added a THF solution of NaBH2S316 [prepared by stir-
ring a mixture of NaBH4 (11 mg, 0.279 mmol) and sulfur

6800
T. Kitawaki et al. / Tetrahedron 62 (2006) 6792–6801
(31 mg, 0.978 mmol) in THF (0.8 mL) under Ar at rt for
40 min] under Ar. The reaction mixture was heated at reflux
for 30 min. After cooling, the products were extracted with
Et2O and the organic layer was washed with H2O and 1 M
aqueous NaOH solution, and then dried. Removal of the sol-
vent left a residue, which was purified by column chromato-
graphy (silica gel: 2 g, EtOAc/petroleum ether¼1:3) to give
carbazolamine 12 (13.9 mg, 84%) as a light yellow oil:
7.62 (s, 1H), 7.66 (d, J¼8.4 Hz, 1H), 8.09 (d, J¼2.1 Hz,
1H), 8.13 (d, J¼8.1 Hz, 1H), 10.45 (s, 1H); 13C NMR (ace-
tone-d6) d 21.7, 21.9, 55.9, 56.1, 108.8, 110.7, 111.1, 111.7,
113.4, 113.4, 120.2, 120.5, 120.8, 123.9, 124.0, 125.1, 126.0,
126.4, 126.6, 129.9, 130.0, 130.1, 130.4, 132.0, 140.0, 144.0,
146.7, 147.8; IR (neat) n 3420 cmꢁ1; MS m/z 420 (M+, 6%),
270 (14), 252 (2), 58 (100); HRMS Calcd for C28H24N2O2
(M+): 420.1838. Found: 420.1838.
1
Rf¼0.08 (EtOAc/petroleum ether¼1:5); H NMR d ꢁ0.12
(s, 9H), 0.85 (t, J¼8.1 Hz, 2H), 2.49 (s, 3H), 3.20–3.80 (br
s, 2H), 3.53 (t, J¼8.1 Hz, 2H), 3.97 (s, 3H), 5.95 (s, 2H),
6.72 (s, 1H), 6.87 (dd, J¼8.4, 2.1 Hz, 1H), 7.31 (d,
J¼2.1 Hz, 1H), 7.36 (d, J¼8.4 Hz, 1H), 7.37 (s, 1H); 13C
NMR d ꢁ1.3, 18.0, 21.8, 55.5, 65.1, 74.3, 105.8, 109.1,
110.9, 112.8, 115.8, 124.5, 125.0, 128.6, 129.2, 136.0,
139.7, 146.7; IR (neat) d 3350, 2950 cmꢁ1; MS m/z 356
(M+, 14%), 239 (11), 226 (15), 149 (17), 75 (100); HRMS
Calcd for C20H28N2O2Si (M+): 356.1920. Found: 356.1922.
Acknowledgements
We thank Professor H. Furukawa (Meijo University,
Nagoya, Japan) for providing us with spectral data of natural
murrastifoline-A. We also thank Professor K. Nozaki (The
University of Tokyo, Tokyo, Japan) for valuable discussions
on the double N-arylation reaction. This work was partially
supported by Grant-in-Aid for the 21st Century COE
program ‘KEIO LCC’ from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
4.3.13. 10,8-Dimethoxy-30,6-dimethyl-9-[2-(trimethylsilyl)
ethoxymethyl]-3,90-bi-9H-carbazole (N-SEM-murra-
stifoline-A) (24). Ar gas was bubbled into a mixture of di-
bromobiphenyl11(17.2 mg,0.0483 mmol),carbazolamine12
(15.2 mg, 0.0426 mmol), Pd2(dba)3 (7.8 mg, 0.0085 mmol),
2-(dicyclohexylphosphino)biphenyl (5) (9.2 mg, 0.0262
mmol), and NaOt-Bu (8.2 mg, 0.0852 mmol) in toluene
(0.6 mL) for 10 min. The reaction mixture was then heated
at 120 ꢀC in a sealed tube for 24 h. After cooling, the mixture
was purified by column chromatography (silica gel: 2 g,
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in the twist-boat conformation. This intriguing conformation
in 3fa was also supported by the molecular mechanics calcula-
tion of the model compound, in which 2,3-di-O-benzyl ethers
in the real system are replaced with 2,3-di-O-methyl ethers.
The most stable conformer of the model compound generated
by a Monte Carlo conformational search performed with
MacroModel (version 6.0) using MM2* force field and
observed NMR data are shown below (some hydrogens are
removed for clarity).
ˆ
16. (a) Lalancette, J. M.; Freche, A.; Monteux, R. Can. J. Chem.
1968, 46, 2754–2757; (b) Lalancette, J. M.; Freche, A.;
ˆ
´
Brindle, J. R.; Laliberte, M. Synthesis 1972, 526–532; (c)
Panek, J. S.; Xu, F.; Rondon, A. C. J. Am. Chem. Soc. 1998,
´
120, 4113–4122.
17. Steinhoff, G. W.; Henry, M. C. J. Org. Chem. 1964, 29, 2808–
2809.
18. Bonesi, S. M.; Ponce, M. A.; Erra-Balsells, R. J. Heterocycl.
Chem. 2004, 41, 161–171.
NOE
6
O
19. Miki, Y.; Hachiken, H.; Kashima, Y.; Sugimura, W.; Yanase, N.
Heterocycles 1998, 48, 1–4.
20. Brunner, K.; Dijken, A. V.; Borner, H.; Bastiaansen, J. J. A. M.;
¨
Kiggen, N. M. M.; Langeveld, B. M. W. J. Am. Chem. Soc.
4
5
O
1
N
2
3
J1,2 = 1.8 Hz
J2,3 = 0 Hz
O
J5,6ax = 10.2 Hz
J5,6eq = 5.1 Hz
2004, 126, 6035–6042.
21. Waters, W. A.; White, J. E. J. Chem. Soc. C 1968, 740–
Such a conformation flip of an aldohexose unit has been also ob-
servedfor K-252d, a naturally occurring indolo[2,3-a]carbazole
glycoside; see: Yasuzawa, T.; Iida, T.; Yoshida, M.; Hirayama,
745.
22. Chong, P. Y.; Petillo, P. A. Org. Lett. 2000, 2, 2113–
2116.