A synthetic approach to carbazoles using electrochemically generated hypervalent iodine oxidant

Article abstract of DOI:10.1016/j.tet.2010.11.015

Carbazoles were successfully synthesized by oxidative cyclization of the corresponding diaryl derivatives using electrochemically generated hypervalent iodine oxidant. Electron-withdrawing nitro and donating methoxy groups at the para position of the acetamide group interfered with cyclization. Glycozoline (8) was successfully synthesized in five steps with 50% overall yield.

Full text of DOI:10.1016/j.tet.2010.11.015

Tetrahedron 66 (2010) 9779e9784
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A synthetic approach to carbazoles using electrochemically generated hypervalent
iodine oxidant
*
Daichi Kajiyama, Keisuke Inoue, Yuichi Ishikawa, Shigeru Nishiyama
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 October 2010
Received in revised form 1 November 2010
Accepted 2 November 2010
Available online 6 November 2010
Carbazoles were successfully synthesized by oxidative cyclization of the corresponding diaryl derivatives
using electrochemically generated hypervalent iodine oxidant. Electron-withdrawing nitro and donating
methoxy groups at the para position of the acetamide group interfered with cyclization. Glycozoline (8)
was successfully synthesized in five steps with 50% overall yield.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
position of the acetamide groups, depending on the electron den-
sity of the substrates.13 A further literature search revealed micro-
In our previous synthetic investigation of biologically active
substances, we developed an electrochemically generated hyper-
valent iodine, which possesses comparable or superior properties
to commercially available oxidants, such as PIFA [Phenyliodine(III)
bis(trifluoroacetate)].1 Application of the oxidant to alkoxyamides
carrying aromatic moieties has provided ready accessibility to
quinolinone and azaspiro derivatives (Eq. 1).1
wave-enhanced Cadogan reaction using diaryls carrying a nitro
group (300 W, 15 min, then 210 ꢀC), and selenylation of diaryl
OH
In particular, the former was successfully converted into a series
of tetrahydropyrroloiminoquinone-class marine alkaloids.2 To fur-
ther pursue its scope and limitation as an oxidant, we developed an
oxidative cyclization approach to carbazole synthesis (Eq. 2, Fig. 1).
The relatively rigid tricyclic structure concomitant with bi-
ological activity3 prompted the development of a number of syn-
thetic methodologies, such as Pd(OAc)2-mediated cyclization of
diphenylamine,4 DielseAlder reaction,5 allene-mediated electro-
cyclic reaction,6 coupling of indole derivatives with unsaturated
ketones or Vilsmeier reagent,7 AlCl3-mediated cyclization of diaryl
amine phthalimide,8 oxidative iron-mediated arylamine cycliza-
tion,9 and radical cyclization of sulfonamide.10 However, we
adopted construction of carbazoles through a nitrenium ion in-
termediate or its equivalent. In addition to well-known nucleo-
philic substitution at the carbon adjacent to the nitrogen function
(Eq. 3),11 we carried out anodic oxidation of alkylated anilines,
which provided the iminium intermediates (Eq. 4), leading to
cyclized products.12 In contrast to these observations, direct nu-
cleophilic attack of the nitrogen atom, as in our previous approach,1
was expected to yield the corresponding carbazoles, although ox-
idation of acetanilide derivatives with PIFA caused introduction of
IC6H4 or CF3CO2 groups to the nitrogen function or to the para
COOMe
OMe
N
H
Clausamine E (cytotoxicity)
. 2000, , 125
63
J.Nat. Prod
OH
MeO
Me
OH
Me
N
H
Me
N
H
Carbazomycin B
(anti-inflammatory)
Siamenol (anti-HIV)
1980, , 683
J. Antibiot.
33
2000, , 427
63
J. Nat. Prod.
* Corresponding author. E-mail address: nisiyama@chem.keio.ac.jp (S. Nishiyama).
Fig. 1. Natural carbazoles.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.015

9780
D. Kajiyama et al. / Tetrahedron 66 (2010) 9779e9784
derivatives, followed by deselenylation.14 Our oxidant carrying the
CF3CH2O function as a ligand, instead of the CF3CO2 group of PIFA,
may provide simple and mild oxidation of diaryl derivatives,
without undesired side reactions, such as introduction of oxygen or
reagent onto the aromatic rings.
The substrates for oxidative cyclization were treated with an
oxidant solution produced by anodic oxidation of iodobenzene in
CF3CH2OH in advance (oxidant to substrate ratio¼3:1).
As shown in Table 1, the oxidation reaction provided the cor-
responding carbazoles in 0e91% yields. A plausible reaction
mechanism is started by SN2 attack of the amide oxygen to the
oxidant to give the imidate-type intermediate, and subsequent
nucleophilic attack from the adjacent aromatic ring to achieve the
desired cyclization (Scheme 3). Detailed comparison of each entry
revealed that, in contrast to the symmetrical structure to give the
corresponding products in high yields (entries 1, 4, and 9), the
electron-donating effect of the MeO group to para and ortho posi-
tions gave cyclization at the appropriate positions (entries 2
and 12), and the MeO group adjacent to the diaryl bond interfered
2. Results and discussion
2.1. Oxidative cyclization of diaryl derivatives
Our synthesis was commenced by preparation of the diaryl
substrates by the SuzukieMiyaura reaction of the corresponding
borates 1aed and bromoacetanilides 2aed in the presence of Pd(0)
providing the corresponding diaryl derivatives 3aej (Scheme 2).
R
R
O
(eq. 1)
N
OMe
HN
OMe
O
N
OMe
O
O
Anodic
oxidation
I
in CF3CH2OH
R2
R1
R2
(eq. 2)
(eq. 3)
R1
NHAc
N
Ac
oxid.
Products
N
N
CO2R
CO2R
NHMe
N
oxid.
CH2
(eq. 4)
Products
Scheme 1.
R4
R4
R1
R5
R5
R3
Suzuki - Miyaura
coupling
R2
R3
B(OH)2
R2
R1
Br
NHAc
NHAc
1a
: R1= R2= H, R3= OMe
3a: R1= OMe, R2= R3= R4= R5= H (95%)
2a
: R4= R5= H
3b
1b: R1= R3= H, R2= OMe
: R2= OMe, R1= R3= R4= R5= H (74%)
2b: R4= OMe, R5= H
2c: R4= NO2, R5= H
3c
1c
: R3= OMe, R1= R2= R4= R5= H (89%)
: R2= R3= H, R1= OMe
1d
3d: R1= R2= R3= R4= R5= H (60%)
: R1= R2= R3= H
2d
: R4= H, R5= OMe
3e
: R4= OMe, R1= R2= R3= R5= H (76%)
3f
: R2= R4= OMe, R1= R3= R5= H (84%)
3g: R4= NO2, R1= R2= R3= R5= H (93%)
3h
: R2= OMe, R4= NO2, R1= R3= R5= H (23%)
3i
: R5= OMe, R1= R2= R3= R4= H (88%)
3j: R2= R5= OMe, R1= R3= R4= H (90%)
Scheme 2. Synthesis of the diaryls 3.

D. Kajiyama et al. / Tetrahedron 66 (2010) 9779e9784
9781
Table 1
Cyclization of the diaryls
with smooth coupling, leading to the product in moderate
yield (entry 3).
R5
R4
Upon introduction of functional groups to the para position of
the acetamide group, neither electron-donating nor -withdrawing
group effected the desired cyclization, but complex mixtures were
produced (entries 5e8), although nitro groups did not cause
marked consumption of the starting materials (entries 7e8). The
resonance effect of the aromatic substituents to the nitrogen
function was different from the stabilization of the imidate in-
termediate by the MeO group (Eq. 1, Scheme 1). On the other hand,
the MeO group at the meta position of the acetamide group, which
had no direct resonance effect on the acetamide moiety, provided
no undesired reaction pathway, leading to the corresponding
products (entries 9e12).
Upon comparison of reactivity with PIFA, the electrochemically
generatedoxidant relativelyafforded clear reaction of 3i to 4i even at
ambient temperature (97% conversion yield, 43 h, entry 9), whereas
PIFA at the same temperature gave a complex mixture. At 0 ꢀC with
PIFA, the cyclic products were produced in 47% yield (5 h, entry 10).
When reacted at ꢁ20 ꢀC for 48 h, the PIFA conditions gave 4i in 63%
yield, although the reaction was stopped at this stage (entry 11).
R4
R3
R5
AcN
PhI(OCH2CF3)2
R4
R3
R5
R2
R1
R2
R1
R2
R1
N
TFE
NHAc
Ac
3
4
5
Entry
Diaryls (3)
Yields, %b
3a
4
5
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
0
28
0
17
0
20
56
88
15
0
91
0
40 (59)
24 (33)
42
0
0
0
0
0
0
0
0
0
73 (88)
0
0
0
3g
3h
3i
0
9
83 (97)
47
32 (63)
44 (48)
10
11
12
3ic
3id
3j
49
8
40 (44)
a
Recovered starting materials.
b
c
In parentheses are conversion yields.
2.2. Synthesis of glycozoline (8)
PIFA as an oxidant at 0 ꢀC.
d
PIFA as an oxidant at ꢁ20 ꢀC.
Glycozoline (8), the antibacterial and antifungal carbazole iso-
lated from the roots of Glycosmis pentaphylla (Retz.) DC, was syn-
thesized to confirm availability of the electrochemically generated
hypervalent iodine oxidant, although synthesis of this carbazole
natural product has been reported.15 The synthesis was started by
bromination of p-toluidine, followed by N-acetylation to give the
acetanilide 5 in high overall yield (Scheme 4). The SuzukieMiyaura
coupling with the corresponding borate 1b under standard condi-
tions provided the diaryl 6 in 78% yield. The key oxidation using the
electrochemicallygenerated oxidant (ca. 3 equiv.molto 6) proceeded
smoothly to give the carbazole 7 in 87% yield. To confirm its effec-
tiveness, the diaryl 6 was also exposed to PIFA at 0 ꢀC, and to anodic
oxidation under constant potential electrolytic conditions (anode:
glassy carbon beaker; cathode: platinum wire; potential: 1.44 V;
concentration: 0.25 mM; supporting salt: LiClO4). The former pro-
duced 7 in 58% yield, while anodic oxidation gave no desired prod-
uct, but a polymeric mixture. Finally, abstraction of the N-protecting
group under alkaline conditions, gave 8 in quantitative yield, and all
of spectroscopic data of the synthetic sample were superimposable
on the reported data.15,16 Consequently, the synthesis of glycozoline
(8) was accomplished in 50% overall yield from p-toluidine.
R1
R1
CH3
N
O
NHAc
OCH2CF3
3
I
Ar
R1
4
N
Ac
Scheme 3. A plausible reaction mechanism.
Scheme 4. Synthesis of glycozoline (8).

9782
D. Kajiyama et al. / Tetrahedron 66 (2010) 9779e9784
3. Conclusion
by silica gel column chromatography (hexane/EtOAc¼3/1) to give
45.0 mg of 3b (74%)18 1H NMR
:
d
8.27 (d, 1H, J¼8.0 Hz), 7.41e7.34
Oxidative cyclization of the phenyl acetanilide derivatives using
our electrochemically generated hypervalent iodine oxidant pro-
vided the corresponding carbazoles in moderate to good yields. The
reactivity was affected by substitution pattern in both aromatic
rings. Application of this methodology to synthesis of natural
products was successfully demonstrated to provide glycozoline (8)
in good overall yield. Further investigation is required to un-
derstand the scope and limitations of the electrochemically gen-
erated oxidant.
(m, 2H), 7.26e7.23 (m, 2H), 7.16 (dd, 1H, J¼7.6, 7.2 Hz), 6.95 (dd, 2H,
J¼8.4, 2.7 Hz), 6.89 (s, 1H), 3.83 (s, 3H), 2.02 (s, 3H); 13C NMR
d
168.5, 160.3, 139.7, 134.9, 132.2, 130.3, 130.1, 128.7, 124.5, 121.7,
121.6, 115.0, 113.8, 55.6, 24.9.
4.3.1.2. N-(30,5-Dimethoxybiphenyl-2-yl)acetamide (3f). IR (film)
2938, 2835, 1662 cmꢁ1
;
1H NMR
d
8.03 (d, 1H, J¼9.2 Hz), 7.38
(dd,1H, J¼8.0, 7.6 Hz), 7.00 (br s,1H), 6.95e6.91 (m, 3H), 6.89 (d,1H,
J¼2.0 Hz), 6.80 (d, 1H, J¼2.8 Hz), 3.83 (s, 3H), 3.80 (s, 3H), 2.00
(s, 3H); 13C NMR
d 168.2, 159.9, 156.3, 139.5, 134.2, 129.9, 127.7,
4. Experimental
4.1. General
123.9, 121.2, 115.2, 114.5, 113.6, 113.4, 55.5, 55.3, 24.3. ESI-HRMS
calcd for C16H18NO3 272.1287 (MþþH), found, m/z 272.1282.
4.3.1.3. N-(30-Methoxy-5-nitrobiphenyl-2-yl)acetamide (3h). IR
IR spectra were recorded on a JASCO Model A-202 spectropho-
tometer. 1H NMR and 13C NMR spectra were obtained on JEOL JNM
AL-400, JEOL JNM ECX-400, and JEOL JNM a-400 spectrometers in
(film) 3400, 2939, 2836, 1707 cmꢁ1; 1H NMR
d 8.65 (d, 1H, 9.1 Hz),
8.22 (dd,1H, J¼9.1, 2.5 Hz), 8.12 (d,1H, J¼2.5 Hz), 7.52 (br s,1H), 7.46
(dd, 1H, J¼8.4, 7.6 Hz), 7.03 (ddd, 1H, J¼8.4, 2.5, 2.5 Hz), 6.95 (ddd,
1H, J¼7.6, 2.5, 1.5 Hz), 6.89 (dd, 1H, J¼2.5, 1.5 Hz), 3.86 (s, 3H), 2.07
a deuteriochloroform (CDCl3) solution using tetramethylsilane as
an internal standard, otherwise stated. High-resolution mass
spectra were obtained on JEOL JMS-700 (FAB) or Waters LCT Pre-
mier XE (ESI). Preparative and analytical TLC were carried out on
silica gel plates (Kieselgel 60 F254, E. Merck AG, Germany) using UV
light and/or 5% phosphomolybdic acid in ethanol for detection.
Preparative reversed phase TLC was carried out using Silica gel 60
RP-18 F254S, Merck. Kanto Chemical silica 60N (spherical, neutral,
(s, 3H); 13C NMR
d 168.3, 160.5, 143.0, 140.6, 136.9, 131.4, 130.7,
125.3, 124.2, 120.9, 119.9, 114.7, 114.6, 55.4, 24.9. ESI-HRMS calcd for
C15H15N2O4 287.1032 (MþþH), found, m/z 287.1012.
4.3.1.4. N-(30,4-Dimethyoxybiphenyl-2-yl)acetamide (3j). IR (film):
2938, 2835, 1675 cmꢁ1
;
1H NMR
d
8.02 (s, 1H), 7.38 (dd, 1H, J¼8.4,
7.6 Hz), 7.26 (br s, 1H), 7.14 (d, 1H, J¼8.4 Hz), 6.94e6.91 (m, 2H), 6.87
63e210 mm) was used for column chromatography. All reactions
(s, 1H), 6.72 (dd, 1H, J¼6.8, 2.4 Hz), 3.85 (s, 3H), 3.83 (s, 3H), 2.03
were carried out under an argon atmosphere, unless otherwise
noted. When necessary, solvents were dried prior to use. Dry tet-
rahydrofuran (THF) and dry diethyl ether (Et2O) were purchased
from Kanto Chemical Co., Inc. Other anhydrous solvents were also
obtained through activated commercially available alumina col-
(s, 3H); 13C NMR
d 168.1, 160.1, 159.5, 139.3, 135.7, 130.5, 130.0, 124.0,
121.5, 114.9, 113.2, 110.4, 106.0, 55.4, 55.2, 24.7. ESI-HRMS: calcd for
C16H18NO3 272.1287 (MþþH), found, m/z 272.1294.
4.4. Cyclization of diaryl ethers
ꢀ
umn, and stored over MS4A under an argon atmosphere.
4.4.1. Typical procedure of the oxidative cyclization. Electrochemical
method: A solution of iodobenzene (89.3 mg, 0.437 mmol) in TFE
(25 mL) containing LiClO4 (133 mg, 1.25 mmol) was electrolyzed
(CCE at 0.3 mA/cm2, 2.5 F/mol, a glassy carbon beaker as an anode,
4.2. Synthesis of bromoacetanilides
The bromoacetanilides used in this investigation were known
compounds.17 We synthesized them as follows.
ꢀ
a platinum wire as a cathode). After electrolysis, MS4A (3 g) was
To a stirred solution of 1-bromo-4-methoxy-2-nitrobenzene
(294.5 mg, 1.27 mmol) in EtOH (5 mL) and AcOH (5 mL) was added
iron powder (284.5 mg, 5.08 mmol) and refluxed at 100 ꢀC for 1 h.
The mixture was cooled to room temperature and diluted with
water. The mixture was neutralized with K2CO3 and extracted with
EtOAc. The organic layer was dried (Na2SO4) and evaporated to give
added to the mixture. After 10 min, the substrate 3i (33.8 mg,
0.14 mmol) was added. After being stirred for 48 h, was partitioned
between H2O and EtOAc. The organic layer was dried (Na2SO4) and
evaporated. The residue was chromatographed on preparative
TLC (hexane/EtOAc¼3/1) to give 27.7 mg of 4i (83%) and 5.1 mg of
20 (15%).
262.5 mg of a bromide: 1H NMR
d
(CD3OD) 7.18 (d, 1H, J¼8.4 Hz),
PIFA method at 0 ꢀC: To a solution of 3i (24.5 mg, 0.101 mmol) in
TFE (5 mL) was added PIFA (86.8 mg, 0.201 mmol) at 0 ꢀC. After
being stirred at the same temperature for 6 h, the reaction mixture
was diluted with H2O and extracted with EtOAc. The organic layer
was dried (Na2SO4) and evaporated. The residue was chromato-
graphed on preparative TLC (hexane/EtOAc¼3/1) to give 11.3 mg of
4i (47%).
6.39 (d, 1H, J¼2.8 Hz), 6.16 (dd, 1H, J¼8.4, 2.8 Hz), 4.88 (s, 2H), 3.69
(s, 3H).
A solution of the bromide (252.9 mg, 1.25 mmol) in Ac2O (3 mL)
was stirred overnight The solvent was evaporated, and the residue
was purified by silica gel flash chromatography (hexaneeEtOAc¼
5:1) to give 307.6 mg of 2b (quant.): 1H NMR
d 8.06 (s, 1H), 7.60
(br s, 1H), 7.38 (d, 1H, J¼8.0 Hz), 6.56 (d, 1H, J¼8.0 Hz), 3.80 (s, 3H),
PIFA method at ꢁ20 ꢀC: Compound 3i was reacted at ꢁ20 ꢀC for
48 h with the oxidant (73 mg, 0.17 mmol) to give 4i (6.4 mg, 32%), as
well as 3i (10.1 mg, 49%).
2.22 (s, 3H).
4.3. Synthesis of diaryl ethers
Compound 4i: IR (film) 2937, 2834, 1693 cmꢁ1 1H NMR
; d 8.04
(d, 1H, J¼7.8 Hz), 7.91 (m, 1H), 7.88 (d, 1H, J¼1.7 Hz), 7.84 (d, 1H,
4.3.1. Typical Procedure of the SuzukieMiyaura coupling to com-
pound 4. 4.3.1.1. N-(30-Methoxybiphenyl-2-yl)acetamide (3b). To a
solution of 2a (54.0 mg, 0.25 mmol) in MeCN (10 mL) and H2O
(0.5 mL) were added 1b (41.8 mg, 0.28 mmol), K2CO3 (52.1 mg,
0.38 mmol), and Pd(PPh3)4 (29.1 mg, 0.025 mmol): the mixture was
refluxed at 100 ꢀC under Ar. After being reacted at the same tem-
perature overnight, the mixture was cooled to room temperature,
then diluted with H2O and extracted with EtOAc. The organic layer
was dried (Na2SO4) and evaporated. The crude product was purified
J¼8.6 Hz), 7.41e7.33 (m, 2H), 6.98 (dd, 1H, J¼8.6, 2.3 Hz), 3.92
(s, 3H), 2.86 (s, 3H); 13C NMR
d 170.1, 159.7, 140.0, 138.3, 126.6,
125.8, 123.6, 120.1, 119.7, 119.1, 115.7, 111.3, 101.9, 55.7, 27.7. ESI-
HRMS: calcd for C15H14NO2 240.1025 (MþþH), found, m/z
240.1022.
4.4.1.1. 1-(2-Methoxy-9H-carbazol-9-yl)ethanone (4a). IR (film):
2938, 2834, 1692 cmꢁ1; 1H NMR
(m, 1H), 7.85 (d, 1H, J¼1.5 Hz), 7.81 (d, 1H, J¼8.2 Hz), 7.40e7.31
d
8.01 (d, 1H, J¼7.8 Hz), 7.88e7.87

D. Kajiyama et al. / Tetrahedron 66 (2010) 9779e9784
9783
(m, 2H), 6.96 (dd, 1H, J¼8.2, 2.3 Hz), 3.91 (s, 3H) 2.83 (s, 3H); 13C
0.41 mmol) in TFE (25 mL) containing LiClO4 (133 mg, 1.3 mmol)
was electrolyzed (CCE at 0.3 mA/cm2, 2.5 F/mol). After electrolysis,
MS4A (3 g) was added to the mixture. After 10 min, 6 (34.8 mg,
0.14 mmol) was added. After overnight, the mixture was parti-
tioned between H2O and EtOAc. The organic layer was dried
(Na2SO4) and evaporated. The residue was chromatographed on
preparative TLC to give 30.0 mg of 7 (87%).
NMR
d 170.1, 159.6, 139.9, 138.3, 126.6, 125.8, 123.6, 120.0, 119.6,
ꢀ
119.0, 115.6, 111.2, 101.9, 55.6, 27.6. ESI-HRMS: calcd for C15H14NO2
240.1025 (MþþH), found, m/z 240.1034.
4.4.1.2. 1-(3-Methoxy-9H-carbazol-9-yl)ethanone (4b). IR (film)
2938, 2835, 1687 cmꢁ1 1H NMR
; d 8.17e8.14 (m, 2H), 7.95 (d, 1H,
J¼8.6 Hz), 7.49e7.44 (m, 2H), 7.37 (dd, 1H, J¼8.0, 7.2 Hz), 7.05 (dd,
PIFA method: To a solution of 6 (15.8 mg, 0.061 mmol) in TFE
(5 mL) was added PIFA (52.4 mg, 0.12 mmol) at 0 ꢀC. After being
stirred at the same temperature for 5 h, the mixture was parti-
tioned between H2O and EtOAc. The organic layer was dried
(Na2SO4) and evaporated. The residue was chromatographed on
preparative TLC (hexane/EtOAc¼3/1) to give 9.0 mg of 7 (58%).
1H, J¼8.6, 2.4 Hz), 3.93 (s, 3H), 2.86 (s, 3H); 13C NMR
d 169.6, 156.4,
139.0, 133.1, 128.3, 127.3, 126.4, 123.4, 119.8, 117.2, 116.2, 114.8, 103.1,
55.7, 27.6. ESI-HRMS calcd for C15H14NO2 240.1025 (MþþH), found,
m/z 240.1012.
4.4.1.3. 1-(1-Methoxy-9H-carbazol-9-yl)ethanone (5b). IR (film)
Compound 7: IR (film) 2937, 1687 cmꢁ1 1H NMR
; d 8.15 (d, 1H,
2931, 2837, 1700 cmꢁ1; 1H NMR
d
8.28 (d, 1H, J¼8.1 Hz), 7.95 (d, 1H,
J¼8.9 Hz), 8.00 (d, 1H, J¼8.9 Hz), 7.74 (s, 1H), 7.41 (d, 1H, J¼2.4 Hz),
J¼7.6 Hz), 7.64 (d, 1H, J¼7.6 Hz), 7.47 (dd, 1H, J¼7.8, 7.8 Hz), 7.35 (dd,
7.27 (d, 1H, J¼8.9 Hz), 7.03 (dd, 1H, J¼8.9, 2.4 Hz), 3.93 (s, 3H), 2.83
2H, J¼7.8, 7.6 Hz), 7.01 (d,1H, J¼8.1 Hz), 4.00 (s, 3H), 2.58 (s, 3H); 13C
(s, 3H), 2.51 (s, 3H); 13C NMR
d 169.4, 156.3, 137.1, 133.3, 133.0,
NMR
d
172.9, 148.0, 140.1, 129.1, 127.8, 127.6, 125.2, 124.5, 123.2,
128.4, 127.3, 126.5, 119.9, 117.3, 115.8, 114.6, 103.0, 55.7, 27.4, 21.1.
ESI-HRMS: calcd for C16H16NO2 254.1181 (MþþH), found, m/z
254.1190.
119.6, 115.0, 112.7, 109.3, 55.6, 27.2. ESI-HRMS calcd for C15H14NO2
240.1025 (MþþH), found, m/z 240.1023.
4.4.1.4. 1-(4-Methoxy-9H-carbazol-9-yl)ethanone (4c). IR (film)
4.5.3. Glycozoline (8). A solution of 7 (13.5 mg, 0.053 mmol) in
MeOH (9 mL) and H2O (3 mL) in the presence of KOH (90 mg
1.6 mmol) was heated at 80 ꢀC for 18 h. The solution was partitioned
between H2O and EtOAc. The organic layer was dried (Na2SO4) and
evaporated to give 11.2 mg of 30 (quant.), mp 179e180 ꢀC from
hexane/CHCl3 (lit.16 181e182 ꢀC): IR (KBr) 3399, 2938, 1495,
2938, 2837, 1694 cmꢁ1; 1H NMR
d
8.34 (dd, 1H, J¼6.8, 1.2 Hz), 8.21
(d, 1H, J¼8.4 Hz), 7.80 (d, 1H, J¼8.4 Hz), 7.47e7.36 (m, 3H), 6.87 (d,
1H, J¼8.0 Hz), 4.07 (s, 3H), 2.88 (s, 3H); 13C NMR
d 170.2, 155.7,
139.8, 137.9, 127.9, 126.3, 125.6, 123.7, 123.2, 115.5, 115.3, 108.7,
104.9, 55.5, 27.7. ESI-HRMS calcd for C15H14NO2 240.1025 (MþþH),
found, m/z 240.1021.
1458 cmꢁ1; 1H NMR
d
7.83 (s, 1H), 7.81 (s, 1H), 7.53 (d, 1H, J¼2.5 Hz),
7.30 (d, 1H, J¼8.2 Hz), 7.29 (d, 1H, J¼8.9 Hz), 7.22 (d, 1H, J¼8.2 Hz),
4.4.1.5. 1-(2,6-Dimethoxy-9H-carbazol-9-yl)ethanone (4j). IR (film)
7.05 (dd, 1H, J¼8.9, 2.5 Hz), 3.93 (s, 3H), 2.52 (s, 3H); 13C NMR
2938, 2834, 1685 cmꢁ1; 1H NMR
d
7.96 (d, 1H, J¼8.8 Hz), 7.86 (s, 1H),
7.79 (d, 1H, J¼8.4 Hz), 7.35 (d, 1H, J¼2.4 Hz), 6.98e6.94 (m, 2H), 3.92
(s, 3H), 3.91 (s, 3H), 2.83 (s, 3H); 13C NMR
169.7, 159.8, 156.4, 140.5,
d 153.7, 138.5, 134.7, 128.3, 127.1, 123.6, 123.4, 120.1, 114.8, 111.2,
110.4, 103.0, 56.0, 21.3. ESI-HRMS: calcd for C14H14NO 212.1075
d
(MþþH), found, m/z 212.1072.
132.8, 127.7, 120.1, 119.7, 116.6, 113.0, 111.1, 102.7, 102.0, 55.7, 55.7,
27.5. ESI-HRMS: calcd for C16H16NO3 270.1130 (MþþH), found, m/z
270.1118.
Acknowledgements
This work was supported financially by the Scientific Research C,
High-Tech Research Center Project for Private Universities Match-
ing Fund (2006e2011), and Scientific Research on Priority Arias
‘Advanced Molecular Transformations of Carbon Resources’ from
MEXT.
4.4.1.6. 1-(1,7-Dimethoxy-9H-carbazol-9-yl)ethanone(5j). IR (film):
1
2938, 2837, 1619 cmꢁ1; H NMR
d
7.86 (d, 1H, J¼1.8 Hz), 7.80 (d, 1H,
J¼8.2 Hz), 7.53 (dd, 1H, J¼8.2, 1.8 Hz), 7.31 (dd, 1H, J¼7.8, 7.8 Hz),
6.96e6.92 (m, 2H), 3.98 (s, 3H), 3.91 (s, 3H), 2.57 (s, 3H); 13C NMR
d
173.2, 160.1, 147.9, 141.4, 129.2, 128.3, 124.7, 120.2, 118.6, 112.0, 112.0,
108.1, 99.2, 55.6, 55.5, 27.1. ESI-HRMS: calcd for C16H16NO3 270.1130
(MþþH), found, m/z 270.1118.
References and notes
1. (a) Amano, Y.; Nishiyama, S. Tetrahedron Lett. 2006, 47, 6505; (b) Amano, Y.;
Inoue, K.; Nishiyama, S. Synlett 2008, 134; (c) Amano, Y.; Nishiyama, S. HET-
EROCYCLES 2008, 75, 1997.
4.5. Synthesis of glycozoline (8)
2. Inoue, K.; Ishikawa, Y.; Nishiyama, S. Org. Lett. 2010, 12, 436.
3. For instance antimicrobial activity, see Chakraborty, D. P.; Das, K. C.; Das, B. P.;
Chowdhury, B. K. Trans. Bose Res. Inst. 1975, 38, 1.
4.5.1. N-(30-Methoxy-5-methylbiphenyl-2-yl)acetamide (6). To
a
solution of 5 (177.0 mg, 0.78 mmol)19 in MeCN (10 mL) and H2O
(0.5 mL) were added 1b (141.0 mg, 0.93 mmol),20 K2CO3 (160.8 mg,
1.17 mmol), and Pd(PPh3)4 (45.0 mg, 0.038 mmol); the mixture was
refluxed at 100 ꢀC under Ar. After being refluxed at the same
temperature for 6 h, the mixture was cooled to room temperature,
and partitioned between H2O and EtOAc. The organic layer was
dried (Na2SO4) and evaporated. The crude product was purified by
silica gel column chromatography (hexane/EtOAc¼4/1) to give
150.8 mg of 6 (78%): IR (film) 3267, 2938, 2834, 1664 cmꢁ1; 1H NMR
€
4. (a) Chowdhury, B. K.; Jha, S. Synth. Commun. 2001, 31, 1559; (b) Knolker, H.-J.;
€
Frohner, W. J. Chem. Soc., Perkin Trans. 1 1998, 173.
5. (a) Beccalli, E. M.; Marchesini, A. Tetrahedron 1996, 52, 3029; (b) Moody, C. J.
Synlett 1994, 681; (c) Jackson, P. M.; Moody, C. J.; Mortimer, R. J. J. Chem. Soc.,
Perkin Trans. 1 1991, 2941; (d) Jackson, P. M.; Moody, C. J. Synlett 1990, 521; (e)
Moody, C. J.; Shah, P. J. Chem. Soc., Perkin Trans. 1 1989, 2463.
6. (a) Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S. Tetrahedron
2000, 56, 5807; (b) Choshi, T.; Sada, T.; Fujimoto, H.; Nagayama, C.; Sugino, E.;
Hibino, S. J. Org. Chem. 1997, 62, 2535; (c) Choshi, T.; Sada, T.; Fujimoto, H.;
Nagayama, C.; Sugino, E.; Hibino, S. Tetrahedron Lett. 1996, 37, 2593.
7. Bergman, J.; Pelcman, B. Tetrahedron 1988, 44, 5215.
d
8.08 (d, 1H, J¼8.0 Hz), 7.37 (dd, 1H, J¼8.4, 8.0 Hz), 7.17 (d, 2H,
J¼6.4 Hz), 7.06 (s, 1H), 6.93 (d, 2H, J¼8.0 Hz), 6.88 (s, 1H), 3.83
(s, 3H), 2.34 (s, 3H), 2.01 (s, 3H); 13C NMR
168.1, 159.9, 139.6, 133.9,
8. Kikugawa, Y.; Aoki, Y.; Sakamoto, T. J. Org. Chem. 2001, 66, 8612.
€
€
€
9. (a) Knolker, H.-J.; Frohner, W.; Reddy, K. R. Eur. J. Org. Chem. 2003, 740;
€
(b) Knolker, H.-J.; Hopmann, T. Tetrahedron 2002, 58, 8937; (c) Knolker, H.-J.;
d
€
€
€
Frohner, W. Tetrahedron Lett. 1999, 40, 6915; (d) Knolker, H.-J.; Frohner, W.
Tetrahedron Lett. 1997, 38, 4051; (e) Knolker, H.-J.; Schlechtingen, G. J. Chem. Soc.,
Perkin Trans. 1 1997, 349; (f) Knolker, H.-J. Synlett 1992, 371; (g) Knolker, H.-J.;
Hopmann, T. Synlett 1995, 981; (h) Knolker, H.-J.; Bauermeister, M. J. Chem. Soc.,
132.2, 132.0, 130.4, 129.9, 128.9, 121.8, 121.2, 114.6, 113.4, 55.2, 24.4,
20.7. ESI-HRMS: calcd for C16H18NO2 256.1338 (MþþH), found, m/z
256.1335.
€
€
€
€
Perkin Trans. 1 1989, 1468.
10. Clive, D. L. J.; Etkin, N.; Joseph, T.; Lown, J. W. J. Org. Chem. 1993, 58, 2442.
11. Shono, T. Electroorganic Chemistry as a New Tool in Organic Synthesis; Spinger:
Berlin, 1984.
4.5.2. 1-(3-Methoxy-6-methyl-9H-carbazol-9-yl)ethanone
(7). Electrochemical method: A solution of iodobenzene (84.5 mg,

9784
D. Kajiyama et al. / Tetrahedron 66 (2010) 9779e9784
12. Nishiyama, S.; Iida, Y.; Hino, S.; Yamamura, S. Electrochim. Acta 1997, 42, 1943.
13. Itoh, N.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. J. Org. Chem. 2002, 67, 7424.
14. Crich, D.; Rumthao, S. Tetrahedron 2004, 60, 1513.
18. Tsang, W. C. P.; Munday, R. H.; Brashe, G.; Zheng, N.; Buchwals, S. L. J. Org. Chem.
2008, 73, 7063.
19. Das, B.; Venkateswarku, K.; Majhi, A.; Eddaiah, V.; Reddy, K. R. J. Mol. Catal. A:
15. Chakraborty, D. P. Phytochemistry 1969, 8, 769.
Chem. 2007, 267, 30.
16. Chakraborty, D. P. Tetrahedron Lett. 1966, 6, 661.
17. Duane, E. R.; Stille, J. K. J. Org. Chem. 1989, 54, 5856.
20. Tang, S.; Liu, M.; Gu, C.; Zhao, Y.; Lu, P.; Lu, D.; Liu, L.; Shen, F.; Yang, B.; Ma, Y. J.
Org. Chem. 2008, 73, 4212.