A one-pot direct iodination of the Fischer-Borsche ring using molecular iodine and its utility in the synthesis of 6-oxygenated carbazole alkaloids

Article abstract of DOI:10.1021/jo5025128

An efficient regioselective iodination of the Fischer-Borsche ring has been achieved using molecular iodine, in a one-pot synthesis. The acid-, metal-, and oxidant-free conditions of the present method are highly convenient and practical. Furthermore, the one-pot direct iodination process is extended to the concise synthesis of glycozoline, 3-formyl-6-methoxy-carbazole, and 6-methoxy-carbazole-3-methylcarboxylate natural alkaloids. This method has been proven to be tolerant to a broad range of functional groups, with good to excellent yields.

Full text of DOI:10.1021/jo5025128

Note
pubs.acs.org/joc
A One-Pot Direct Iodination of the Fischer−Borsche Ring Using
Molecular Iodine and Its Utility in the Synthesis of 6‑Oxygenated
Carbazole Alkaloids
Mahavir S. Naykode, Vivek T. Humne,* and Pradeep D. Lokhande*
Center for Advance Studies, Department of Chemistry, University of Pune, Pune-411007, India
S
* Supporting Information
ABSTRACT: An efficient regioselective iodination of the
Fischer−Borsche ring has been achieved using molecular
iodine, in a one-pot synthesis. The acid-, metal-, and oxidant-
free conditions of the present method are highly convenient
and practical. Furthermore, the one-pot direct iodination
process is extended to the concise synthesis of glycozoline, 3-
formyl-6-methoxy-carbazole, and 6-methoxy-carbazole-3-
methylcarboxylate natural alkaloids. This method has been
proven to be tolerant to a broad range of functional groups,
with good to excellent yields.
alogenated carbazoles are ubiquitous precursors found in
reports are known in the literature for the iodination of
carbazoles, such as IPy2BF4/TfOH,4 KI/KIO3/AcOH,5 I2/
Cu(OAc)2/PivOH/MW,6 CF3COOAg/ICl/CH3CN/AcOH,7
H
nature and bioactive substances.1 Significantly, halo-
carbazoles have been seen to be important in various studies
related to material science, such as in the evaluation of
photophysical properties of light-emitting carbazoles, in hole-
transport materials, conjugated polymers, intense luminescence,
organic light-emitting diodes, molecular glasses, and optoelec-
tronics devices.2
In general, the introduction of the halo-functionality in the
carbazole ring involves two steps: (i) the aromatization of the
Fischer−Borsche ring, followed by (ii) the halogenation process
(Figure 1). There are several known methods in the literature for
8
HI/H2O2, I2/NaIO4/H2SO4/EtOH, KI/NaIO4/H2SO4/
EtOH, I2/NaIO4/AcOH, I2/NaClO/EtOH, I2/HgO/EtOH,
and NIS/CHCl3.9 However, these methods require extra
oxidants, strong acids, long reaction time,4,5c and microwave
conditions,6,8 with several side products that are difficult to
separate. They also display poor regioselectivity. The literature
survey reveals that the direct iodination of carbazoles is more
difficult and most of the methods require the N-protection of
carbazoles, followed by iodination.4,5 Therefore, the develop-
ment of an oxidant-free protocol for the direct regioselective
iodination of tetrahydrocarbazole is highly desirable.
Over the past few decades, molecular iodine has been
employed for pharmaceutical and organic syntheses owing to
its ready availability as a reagent for organic transformations.10 In
continuation of our previous work devoted toward the
development of iodine-mediated transformations,11 we are
interested in developing an efficient protocol for the direct
one-pot iodination of tetrahydrocarbazoles using molecular
iodine. The present method has been carried out under acid-,
metal-, oxidant-free conditions, without the protection of N-
carbazole. It is seen to lead to a good regioselectivity. The
developed method has been extended to the total synthesis of
glycozoline (7), 3-formyl-6-methoxy-carbazole (8), and 6-
methoxy-carbazole-3-methylcarboxylate (9).
Figure 1. Synthesis of iodocarbazole from tetrahydrocarbazole.
the halogenation of carbazoles.3 However, the bromination and
chlorination processes involve the use of potentially hazardous
chemicals which are difficult to store and handle. Besides, the
combinations of different mineral acids and metal chlorides are
decomposed in the halogenation process, producing corrosive
side products, creating difficult separation and disposal problems
at the end. In this regard, iodination has been found to be the
preferable process over bromination and chlorination. Various
We commenced our strategy by the condensation of
commercially available phenyl hydrazine and cyclohexanone,
which were readily converted to the corresponding tetrahydro-
carbazole by the Fischer-indolization. We wished to study the
Received: November 3, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/jo5025128
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The Journal of Organic Chemistry
Note
a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
entry
iodine (mol %)
temp (°C)
time (h)
2
3
4
c
d
a
b
c
d
e
f
10
25
80
80
24
8
43
NR
NR
NR
NR
NR
NR
30
95
70
45
NR
30
50
93
60
50
80
10
10
6
50
110
110
110
110
e
100
125
150
ND
ND
ND
10
8
f
g
ND
93
a
b
Reaction was carried out with substrate 1a (1 mmol) and iodine (25 mol %) in DMSO (5 mL) at 110 °C. Isolated yield after column
c
d
e
f
chromatography. Starting substrate was recovered with product. NR indicates no reaction. ND indicates not determined. Product was confirmed
by NMR and HRMS.
a b
,
Scheme 1. Tandem One-Pot Synthesis of Various Iodocarbazoles
a
b
Reaction conditions: Substrate 4 (1 mmol), iodine (100 mol %) in DMSO at 110 °C Isolated yield after column chromatography
efficacy of a one-pot iodination process of tetrahydrocarbazole by
molecular iodine. First, when iodine (10−100 mol %) was added
to substrate 1, no remarkable change was observed at room
temperature. A catalytic amount of iodine was enough to initiate
the reaction at 80 °C (Table 1, entry a). When we increased the
amount of iodine (25 mol %), aromatic product (2) was isolated
in excellent yield (Table 1, entry b). This type of result was found
to be in line with our previous report.12 Further, by increasing the
amount of iodine (50 mol %), the mixture of aromatic and
monoiodinated products was obtained (Table 1, entry c).
Similarly, when 100 mol % of iodine was employed to substrate
1 at an elevated temperature (110 °C), the monoiodinated
B
DOI: 10.1021/jo5025128
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Note
carbazole was isolated with 93% yield (Table 1, entry e).
Additionally, when we investigated with 125 mol % of iodine
(Table 1, entry f), the mixture of mono- (60%) and di-
iodocarbazole (30%) was isolated. However, the addition of 150
mol % of iodine furnishes di-iodocarbazole as a sole product in
93% yield (Table 1, entry g). Herein, we successfully controlled
the formation of aromatic, mono- and di-iodocarbazoles under
optimal conditions. From these observations, it is clear that the
mol % of iodine and the temperature play important roles in the
process of one-pot direct iodination of tetrahydrocarbazole.
Compared with other solvents (DCE, CH3CN, DMF, PhOPh,
PhMe, and AcOH), DMSO was found to be a most suitable and
effective solvent for the iodination process.
(95%). In the next step, the iodo group of 6a was displaced by a
methoxy group using NaOMe/CuI21 in DMF at 120 °C, leading
to glycozoline (7) in 85% yield. Further, glycozoline (7)
undergoes the oxidative process when reacted with 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ)22 in methanol/water
medium, leading to the product 3-formyl-6-methoxy-carbazole
(8) in 90% yield. Thus, 3-formyl-6-methoxy-carbazole (8) was
obtained in three steps with 73% overall yield (Scheme 2).
Scheme 2. Concise Synthesis of Glycozoline and 3-Formyl-6-
a
methoxy-carbazole
With these optimized conditions, the substrate scope was
studied, as shown in Scheme 1. All substrates afforded the
corresponding products in good to excellent yield. The
iodination process appears to be invariant to the electron-rich
and electron-deficient substituents of the tetrahydrocarbazole.
We investigated the effect of electron-donating groups at the 3-
position of the tetrahydrocarbazole, and the resulting products
6a−c were isolated in good yield in shorter reaction times
(Scheme 1). When electron-withdrawing groups were put at the
3-position of tetrahydrocarbazole, a higher amount of molecular
iodine and a longer reaction time were required to complete the
iodination process (Scheme 1, entries 6d−h). This may be due to
the characteristic interactive behavior of iodine with the
carboxylic group.
However, when we studied the effect of the disubstitution
pattern of tetrahydrocarbazole 5 for the iodination process,
surprisingly, regioselective iodination was obtained. The careful
analysis of products 6i−l shows that regioselective iodination
takes place at the 1-position of tetrahydrocarbazole (Scheme 1).
The disappearance of the doublets at 7.26−7.53 ppm and the
formation of a characteristic peak at 7.68 ppm in 1H NMR and at
76.1 ppm in 13C NMR analysis support the regioselective
iodination at the 1-position of tetrahydrocarbazole.
a
Reagents and conditions: (a) Iodine (1 equiv), DMSO, 110 °C, 6 h,
95%; (b) NaOMe, CuI, DMF, 120 °C, 12 h, 85%; (c) DDQ, MeOH/
H2O (16:1), rt, 16 h, 90%.
The careful survey of the literature shows that the total
synthesis of 6-methoxy-carbazole-3-methylcarboxylate (9) was
started from the methyl derivative, which subsequently oxidized
to the carboxylate group. To the best of our knowledge, there are
no reports documented in the literature for the direct use of the
carboxylate functionality. In this context, herein, we report the
concise synthesis of 9 from the direct use of the ester group as a
starting substrate 5c. In our approach, we started with 5c, which,
upon one-pot iodination by molecular iodine, gave 6-iodo-
carbazole-3-methylcarboxylate (6c) at 90% yield. This product
was treated with NaOMe/CuI21 in DMF at 120 °C and gave 6-
methoxy-carbazole-3-methylcarboxylate (9) in two steps with
72% overall yield (Scheme 3).
To exemplify the power of the one-pot iodination process, we
carried out a concise synthesis of biologically active 6-oxygenated
carbazole alkaloids, such as glycozoline (7), 3-formyl-6-methoxy-
carbazole (8), and 6-methoxy-carbazole-3-methylcarboxylate
(9). Glycozoline was first isolated from the root bark of
Glycosmis pentaphylla,13 and later, it was found in Murraya
koenigii,14 Glycosmis arborea,15 Glycosmis mauritiana,16 Clausena
lansium,17 and in the roots of the West African tree Zanthoxylum
lemairi.18 It exhibits antibiotic and antifungal properties. The 3-
formyl-6-methoxy-carbazole (8) and 6-methoxy-carbazole-3-
methylcarboxylate (9) were isolated from the roots of Clausena
lansium.19 Later, 3-formyl-6-methoxy-carbazole (8) was also
isolated from the stem bark of Micromelum hirsutum and showed
antituberculosis (TB) activity against the H37Rv strain of
Mycobacterium tuberculosis in vitro.20 Accordingly, we prepared
a synthetic plan to accomplish a series of 6-oxygenated carbazole
alkaloids using molecular iodine. A key step of our route is the
one-pot synthesis of iodocarbazoles from the tetrahydrocarba-
zoles using molecular iodine.
Our synthetic strategy for the construction of 6-oxygenated
carbazole alkaloids started from the Fischer−Borsche process.
The appropriate substrates 5a and 5c were prepared by
condensation of the commercially available phenyl hydrazine
and cyclohexanone under reflux condition. When 3-methyl-
tetrahydrocarbazole (5a) was subjected to stoichiometric
amounts of molecular iodine (one-fold) in DMSO at 110 °C,
3-methyl-6-iodo-carbazole (6a) was isolated in excellent yield
Scheme 3. Concise Synthesis of 6-Methoxy-carbazole-3-
methylcarboxylate
a
a
Reagents and conditions: (a) Iodine (1 equiv), DMSO, 110 °C, 6 h,
90%; (b) NaOMe, CuI, DMF, 120 °C, 12 h, 80%.
In conclusion, we have developed a simple, efficient, and direct
process of iodination of tetrahydrocarbazoles using molecular
iodine in one-pot. This protocol is equally compatible with
electron-deficient and electron-rich groups and affords the
desired iodocarbazole in acceptable to excellent yield with good
regioselectivity. The application of this method has been
successfully extended to the total synthesis of natural products
to provide glycozoline (overall yield 61% in two steps), 3-formyl-
6-methoxy-carbazole (overall yield 55% in three steps), and 6-
methoxy-carbazole-3-methylcarboxylate (overall yield 63% in
two steps).
EXPERIMENTAL SECTION
Representative Procedure for the Synthesis of Iodocarba-
zoles by Molecular Iodine (5a−l). A mixture of iodine (742 mg, 2.92
■
C
DOI: 10.1021/jo5025128
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The Journal of Organic Chemistry
Note
mmol) and substituted tetrahydrocarbazole 5a−l (500 mg, 2.92 mmol)
in DMSO (5 mL) was stirred at 110 °C for 8 h. The progress of the
reaction was monitored by thin-layer chromatography (PMA was used
to strain). The reaction mixture was poured in an ice cold saturated
solution of sodium thiosulfate and kept at 0 °C overnight. The solid
product was separated out. The crude product was purified by column
chromatography using n-hexane/ethyl acetate (100:1) as eluent to
afford iodocarbazoles 6a−l.
(s, 1H), 8.09 (s, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 6.0 Hz, 1H),
7.49 (d, J = 9.0 Hz, 1H), 7.30 (m, 1H); 13C NMR (75 MHz, CDCl3): δ
141.2, 138.9, 135.5, 129.5, 128.9, 127.2, 125.3, 120.7, 113.1, 111.5, 111.1,
102.5, 83.2; MS (70 ev) m/z: 317 (M+), HRMS (ESI-qTOF) Calcd for
C13H7IN2 [M + H]+, 318.9726: found 318.9722.
3-Chloro-6-iodo-9H-carbazole (6g).25 733 mg (92%) as a white
solid, mp 184−186 °C (lit.25 mp 181−182 °C); IR (ν cm−1): 3395,
3032, 1600, 1496, 1427; 1H NMR (300 MHz, DMSO-d6): δ 11.56 (s,
D2O exchange, 1H), 8.57 (s, 1H), 8.27 (s, 1H), 7.66 (d, J = 9.0 Hz, 1H),
7.50 (d, J = 9.0 Hz, 1H), 7.41 (t, J1 = 3.0 Hz, J2 = 9.0 Hz, 1H), 7.37 (t, J1 =
3.0 Hz, J2 = 9.0 Hz, 1H); 13C NMR (75 MHz, DMSO-d6): δ 139.2,
138.0, 134.0, 129.1, 125.9, 124.2, 123.2, 122.3, 120.1, 113.5, 112.4, 81.6;
MS (70 ev) m/z: 326 (M+), HRMS (ESI-qTOF) Calcd for C12H7ClIN
[M + H]+, 327.9384: found 327.9390.
3-Iodo-9H-carbazole (3).23 811 mg (95%) as a white solid, mp 188−
192 °C (lit.23 mp 191 °C); IR (ν cm−1): 3398, 3040, 1598, 1498, 1440;
1H NMR (300 MHz, DMSO-d6): δ 11.21 (s, D2O exchange, 1H),
8.31(s, 1H), 7.96 (d, J = 9.0 Hz, 1H), 7.47 (dd, J1 = 3.0 Hz, J2 =3.0 Hz,
1H), 7.33 (d, J = 6.0 Hz, 1H), 7.26 (d, J = 6.0 Hz, 1H), 7.21 (t, J1 = 3.0
Hz, J2 = 6.0 Hz, 1H), 7.00 (t, J1 = 6.0 Hz, J2 = 6.0 Hz, 1H); 13C NMR (75
MHz, DMSO-d6): δ 139.6, 138.6, 133.2, 128.5, 126.1, 125.0, 121.0,
120.5, 118.8, 113.3, 110.9, 81.2; MS (70 ev) m/z: 292 (M+), HRMS
(ESI-qTOF) Calcd for C12H8IN [M + H]+, 293.9774: found 293.9770.
3,6-Diiodo-9H-carbazole (4).24 1.139 g (93%) as a white solid, mp
200−202 °C; IR (ν cm−1): 3400, 3040, 1600, 1498, 1445; 1H NMR (300
MHz, DMSO-d6): δ 11.54 (s, D2O exchange, 1H), 8.57 (s, 2H), 7.65 (d,
J = 9.0 Hz, 2H), 7.35 (d, J = 6.0 Hz, 2H); 13C NMR (75 MHz, DMSO-
d6): δ 138.7, 133.9, 129.1, 123.7, 113.4, 81.8; MS (70 ev) m/z: 418 (M+),
HRMS (ESI-qTOF) Calcd for C12H7I2N [M + H]+, 419.8740: found
419.8742.
1, 3-Dichloro-6-iodo-9H-carbazole (6h). 640 mg (88%) as a white
solid, mp 164−168 °C; IR (ν cm−1): 3400, 3033, 1590, 1495, 1429; 1H
NMR (300 MHz, DMSO-d6): δ 11.30 (s, D2O exchange, 1H), 8.60 (s,
1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.48 (d, J = 9.0
Hz, 1H); 13C NMR (75 MHz, DMSO-d6): δ 140.3, 138.2, 135.8, 129.9,
125.7, 123.8, 123.2, 122.1, 120.4, 120.0, 113.0, 81.0; MS (70 ev) m/z:
360 (M+), HRMS (ESI-qTOF) Calcd for C12H6Cl2IN [M + H]+,
361.8994: found 361.8996.
3-Chloro-1-iodo-6-methyl-9H-carbazole (6i). 685 mg (88%) as a
white solid, mp 92−96 °C; IR (ν cm−1): 3398, 3032, 1600, 1498, 1429;
1H NMR (300 MHz, DMSO-d6): δ 11.27 (s, D2O exchange, 1H), 8.24
(s, 1H), 8.05 (s, 1H), 7.74 (s, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.48 (dd, J =
9.0 Hz, 1H), 2.50 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 140.3,
138.1, 135.7, 129.8, 125.7, 123.8, 123.2, 122.0, 120.3, 120.0, 113.0, 76.0,
20.3; MS (70 ev) m/z: 340 (M+), HRMS (ESI-qTOF) Calcd for
C13H9ClIN [M + H]+, 341.9540: found 341.9536.
3-Iodo-6-methyl-9H-carbazole (6a).12 788 mg (95%) as a brown
solid, mp 188−190 °C (lit.12 mp 189 °C); IR (ν cm−1): 3400, 3030,
1595, 1492, 1430; 1H NMR (300 MHz, CDCl3): δ 8.34 (s, D2O
exchange, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.87 (s, 1H), 7.62 (d, J = 9.0 Hz,
1H), 7.40 (s, 1H), 7.30 (t, J1 = 3.0 Hz, J2 = 12.0 Hz, 1H), 7.19 (t, J1 = 3.0
Hz, J2 = 6.0 Hz, 1H), 2.51 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 144.0,
142.9, 138.1, 133.5, 133.2, 132.4, 130.2, 126.6, 124.8, 117.6, 115.4, 85.6,
26.1; MS (70 ev) m/z: 306 (M+), HRMS (ESI-qTOF) Calcd for
C13H10IN [M + H]+, 307.9930: found 307.9933.
1-Iodo-6-methyl-9H-carbazole-3-methylcarboxylate (6j). 653 mg
(87%) as a white solid, mp 185−190 °C; IR (ν cm−1): 3386, 3034, 1720,
1
1600, 1450, 1260; H NMR (300 MHz, DMSO-d6): δ 11.45 (s, D2O
3-Iodo-6-methoxy-9H-carbazole (6b). 707 mg (88%) as a white
solid, mp 152−158 °C; IR (ν cm−1): 3382, 3060, 1613, 1485, 1454; 1H
NMR (300 MHz, CDCl3): δ 11.0 (s, D2O exchange, 1H), 8.09 (s, 1H),
7.97 (s, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.52 (d, J
= 9.0 Hz, 1H), 7.42 (d, J = 6.0 Hz, 1H), 3.88 (s, 3H); 13C NMR (75
MHz, CDCl3): δ 151.6, 139.8, 134.0, 125.8, 123.8, 122.6, 119.9, 118.8,
114.8, 111.7, 103.0, 82.3, 54.4; MS (70 ev) m/z: 322 (M+), HRMS (ESI-
qTOF) Calcd for C13H10INO [M + H]+, 323.9879: found 323.9882.
3-Iodo-6,8-dimethyl-9H-carbazole (6c). 685 mg (85%) as a yellow
solid, mp 137−140 °C; IR (ν cm−1): 3390, 3026, 1598, 1485, 1415; 1H
NMR (300 MHz, CDCl3): δ 10.07 (s, D2O exchange, 1H), 7.47 (s, 1H),
7.31 (s, 1H), 7.28 (s, 1H), 7.17 (d, J = 6.0 Hz, 1H), 6.72 (d, J = 6.0 Hz,
1H), 2.55 (s, 3H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 143.9,
142.5, 141.3, 138.9, 136.8, 133.2, 129.9, 128.6, 126.2, 123.6, 122.2, 82.0,
20.6, 15.0; MS (70 ev) m/z: 321 (M+), HRMS (ESI-qTOF) Calcd for
C14H12IN [M + H]+, 322.0087: found 322.0090.
6-Iodo-9H-carbazole-3-methylcarboxylate (6d). 689 mg (90%) as
a white solid, mp 220−224 °C; IR (ν cm−1): 3386, 1717, 1600, 1450,
1258; 1H NMR (300 MHz, DMSO-d6): δ 11.80 (s, D2O exchange, 1H),
8.80 (s, 1H), 8.63 (s, 1H), 7.98 (dd, J1 = 3.0 Hz, J2 = 3.0 Hz, 1H), 7.66
(dd, J1 = 3.0 Hz, J2 = 3.0 Hz, 1H), 7.52 (d, J = 6.0 Hz, 1H), 7.35 (d, J = 6.0
Hz, 1H), 3.84 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 167.3, 143.0,
139.9, 134.8, 129.8, 127.8, 125.6, 123.5, 121.5, 120.8, 114.3, 111.5, 83.2,
52.3; MS (70 ev) m/z: 350 (M+), HRMS (ESI-qTOF) Calcd for
C14H10INO2 [M + H]+, 351.9834: found 351.9842.
exchange, 1H), 8.72 (s, 1H), 8.07 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.68
(s, 1H), 7.61 (d, J = 9.0 Hz, 1H), 3.88 (s, 3H), 2.44 (s, 3H); 13C NMR
(75 MHz, DMSO-d6): δ 166.6, 142.5, 140.4, 135.7, 130.6, 126.8, 122.9,
122.7, 122.4, 120.4, 120.3, 111.4, 76.1, 51.6, 20.3; MS (70 ev) m/z: 364
(M+), HRMS (ESI-qTOF) Calcd for C15H12INO2 [M + H]+, 365.9991:
found 365.9993.
1-Iodo-6-methyl-9H-carbazole-3-carbonitrile (6k). 648 mg (82%)
as a brown solid, mp 218−224 °C; IR (ν cm−1): 3400, 3040, 2222, 1600,
1482, 1454; 1H NMR (300 MHz, DMSO-d6): δ 11.58 (s, D2O exchange,
1H), 8.59 (s, 1H), 8.00 (s, 1H), 7.72 (dd, J1 = 3.0 Hz, J2 = 3.0 Hz, 1H),
7.68 (s, 1H), 7.62 (d, J = 6.0 Hz, 1H), 2.40 (s, 3H); 13C NMR (75 MHz,
DMSO-d6): δ 142.3, 141.0, 137.0, 131.4, 129.4, 126.6, 123.3, 122.7,
121.2, 120.9, 113.2, 101.2, 76.9, 21.0; MS (70 ev) m/z: 331 (M+),
HRMS (ESI-qTOF) Calcd for C14H9IN2 [M + H]+, 332.9883: found
332.9887.
1-Iodo-6-methyl-9H-carbazole-3-carboxylic Acid (6l). 634 mg
(83%) as a brown solid, mp 240−244 °C; IR (ν cm−1): 3400, 3045,
1600, 1495, 1450, 1265; 1H NMR (300 MHz, DMSO-d6): δ 12.20 (s,
D2O exchange, 1H), 11.41 (s, D2O exchange, 1H), 8.66 (s, 1H), 8.01 (s,
1H), 7.97 (dd, J = 6.0 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J = 6.0 Hz, 1H),
2.39 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 168.4, 143.0, 141.0,
136.3, 131.0, 127.8, 123.6, 123.4, 122.9, 122.0, 121.0, 111.8, 76.7, 20.9;
MS (70 ev) m/z: 350 (M+), HRMS (ESI-qTOF) Calcd for C14H10INO2
[M + H]+, 351.9828: found 351.9832.
Synthesis of Glycozoline (7) and 6-Methoxy-carbazole-3-
methylcarboxylate (9).21 In a 100 mL round-bottom flask, substrate
6a (0.100 g, 0.325 mmol), CuI (0.123 g, 0.651 mmol), and DMF (10
mL) were added to a solution of NaOMe, prepared from metallic
sodium (0.149 g, 6.5 mmol) and absolute MeOH (1.5 mL). The
reaction mixture was refluxed (maintain the temperature of oil bath at
120 °C) for 12 h under an argon atmosphere. After the completion of
reaction, EtOAc (30 mL) was added to the reaction mixture and the
insoluble materials were filtered through Celite and washed with EtOAc.
The filtrate was washed with brine, dried over Na2SO4, and
concentrated. The residue was chromatographed on a column of silica
gel using n-hexane/EtOAc (100:2) to give 7 (0.058 g, 85%) as a brown
powder.
6-Iodo-9H-carbazole-3-carboxylic Acid (6e). 666 mg (85%) as a
brown solid, mp 254−260 °C; IR (ν cm−1): 3400, 3043, 1603, 1490,
1450, 1260; 1H NMR (300 MHz, DMSO-d6): δ 12.52 (s, D2O exchange,
1H), 11.68 (s, D2O exchange, 1H), 8.72 (s, 1H), 8.54 (s, 1H), 7.93 (d, J
= 9.0 Hz, 1H), 7.59 (d, J = 6.0 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.29 (d,
J = 9.0 Hz, 1H); 13C NMR (75 MHz, DMSO-d6): δ 167.8, 142.3, 139.4,
134.1, 129.1, 127.5, 125.1, 123.0, 121.4, 120.9, 113.7, 110.7, 82.4; MS
(70 ev) m/z: 336 (M+), HRMS (ESI-qTOF) Calcd for C13H8INO2 [M
+ H]+, 337.9672: found 337.9668.
6-Iodo-9H-carbazole-3-carbonitrile (6f). 673 mg (83%) as a brown
solid, mp 186−190 °C; IR (ν cm−1): 3400, 3045, 2225, 1600, 1485,
1450; 1H NMR (300 MHz, CDCl3): δ 8.87 (s, D2O exchange, 1H), 8.37
D
DOI: 10.1021/jo5025128
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Glycozoline or 3-Methoxy-6-methyl-carbazole (7).12 58 mg (85%)
as a brown solid, mp 182−184 °C (lit.12 mp 181−183 °C); IR (ν cm−1):
3400, 3035, 1580, 1485, 1454; 1H NMR (300 MHz, CDCl3): δ 10.8 (s,
D2O exchange, 1H), 7.71 (s, 1H), 7.52 (s, 1H), 6.77−7.23 (m, 3H), 6.58
(d, J = 9.0 Hz, 1H), 3.73 (s, 3H), 2.51 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 152.9, 138.4, 134.7, 130.8, 126.4, 119.3, 114.1, 110.7, 110.2,
109.3, 102.2, 99.3, 55.3, 22.5; MS (70 ev) m/z: 211 (M+), HRMS (ESI-
qTOF) Calcd for C14H13NO [M + H]+, 212.1069: found 212.1065.
6-Methoxy-carbazole-3-methylcarboxylate (9).26 116 mg (80%) as
a white solid, mp 150−152 °C (lit.26b mp 147−149 °C); IR (ν cm−1):
3395, 1780, 1670, 1550, 1430, 1258; 1H NMR (300 MHz, DMSO-d6): δ
11.80 (s, D2O exchange, 1H), 8.80 (s, 1H), 8.64 (s, 1H), 7.99 (dd, J = 6.0
Hz, 1H), 7.66 (dd, J = 6.0 Hz, 1H), 7.52 (d, J = 6.0 Hz, 1H), 7.35 (d, J =
6.0 Hz, 1H), 3.84 (s, 6H); 13C NMR (75 MHz, DMSO-d6): δ 167.0,
142.8, 139.4, 134.6, 129.8, 127.8, 125.3, 123.5, 121.5, 121.0, 115.8, 113.7,
111.3, 55.3, 52.3; MS (70 ev) m/z: 255 (M+), HRMS (ESI-qTOF)
Calcd for C15H13NO3 [M + H]+, 256.0968: found 256.0972.
Markina, N. A.; Larock, R. C. J. Org. Chem. 2012, 77, 11153. (e) Liu, C.-
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Pharm. Bull. 1993, 41, 2096.
Synthesis of 3-Formyl-6-methoxy-carbazole (8).22 In a 100 mL
round-bottom flask, substrate 7 (100 mg, 0.473 mmol) was treated with
DDQ (537 mg, 2.36 mmol) in MeOH/H2O (16:2) at room
temperature for 4 h, and the progress of the reaction was monitored
by thin-layer chromatography. The solvent was evaporated in vacuum.
The crude product was purified through column chromatography using
n-hexane/ethyl acetate to give 8 with 90% yield.
3-Formyl-6-methoxy-carbazole (8).22 95 mg (90%) as a white solid,
mp 134−138 °C (lit.26b mp 135−136 °C); IR (ν cm−1): 3210, 3040,
1680, 1600, 1530, 1482, 1454; 1H NMR (300 MHz, CDCl3): δ 11.08 (s,
D2O exchange, 1H), 10.11 (s, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.30 (d, J
= 9.0 Hz, 1 H), 7.24 (d, J = 6.0 Hz, 1H), 6.97 (d, J = 6.0 Hz, 1H), 6.92 (d,
J = 9.0 Hz, 1H), 3.94 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 181.8,
138.7, 137.5, 133.8, 129.0, 128.0, 127.0, 125.6, 123.8, 120.2, 119.1, 112.5,
110.5, 52.3; MS (70 ev) m/z: 225 (M+), HRMS (ESI-qTOF) Calcd for
C14H11NO2 [M + H]+, 226.0862: found 226.0865.
(15) Chakravarty, A. K.; Sarkar, T.; Masuda, K.; Shiojima, K.
Phytochemistry 1999, 50, 1263.
ASSOCIATED CONTENT
■
(16) Rastogi, K.; Kapil, R. S.; Popli, S. P. Phytochemistry 1980, 19, 945.
(17) Li, W.-S.; McChesney, J. D.; El-Feraly, F. S. Phytochemistry 1991,
30, 343.
(18) Adesina, S. K.; Olugbade, T. A.; Akinwusi, D. D.; Bergenthal, D.
Pharmazie 1997, 52, 720.
S
* Supporting Information
Characterization data including 1H and 13C NMR spectra. This
material is available free of charge via the Internet at http://pubs.
acs.org.
(19) (a) Li, W.-S.; McChesney, J. D.; El-Feraly, F. S. Phytochemistry
1991, 30, 343. (b) Wu, S.-L.; Li, W.-S. Chin. Pharm. J. 1999, 51, 227.
(20) Ma, C.; Case, R. J.; Wang, Y.; Zhang, H.-J.; Tan, G. T.; Hung, N.
V.; Cuong, N. M.; Franzblau, S. G.; Soejarto, D. D.; Fong, H. H. S.; Pauli,
G. F. Planta Med. 2005, 71, 261.
(21) Kikugawa, Y.; Aoki, Y.; Sakamoto, T. J. Org. Chem. 2001, 66, 8612.
(22) Forke, R.; Krahl, M. P.; Krause, T.; Schlechtingen, G.; Knolker,
H.-J. Synlett 2007, 268.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: vivekhumne@rediffmail.com (V.T.H.).
*E-mail: pdlokhande@chem.unipune.ac.in (P.D.L.).
Notes
■
The authors declare no competing financial interest.
(23) Mohanakrishnan, A. K.; Prakash, C.; Ramesh, N. Tetrahedron
2006, 62, 3242.
(24) Wu, Y.; Guo, H.; James, T. D.; Zhao, J. J. Org. Chem. 2011, 76,
5685.
(25) Pielichowski, J.; Kyziol, J. J. Polym. Sci., Polym. Lett. Ed. 1974, 12,
257.
(26) (a) Guney, T.; Lee, J. J.; Kraus, G. A. Org. Lett. 2014, 16, 1124.
(b) Li, W.-S.; McChesney, J. D.; El-Feraly, F. S. Phytochemistry 1991, 30,
343.
ACKNOWLEDGMENTS
■
V.T.H. is thankful to CSIR, New Delhi, India, for the award of a
senior research fellowship, and M.S.N. is thankful to UGC, New
Delhi, India, for the award of a junior research fellowship. We
thank Dr. Kumar Vanka, NCL, Pune, for helpful discussions.
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E
DOI: 10.1021/jo5025128
J. Org. Chem. XXXX, XXX, XXX−XXX