Synthetic approach for constructing the 1-oxygenated carbazole core and its application to the preparation of natural alkaloids

Article abstract of DOI:10.1055/s-0032-1317175

An efficient synthetic approach for the construction of the 1-oxygenated carbazole core is described. The condensation of cyclohexane-1,2-diones with a series of anilines yielded the corresponding 2-anilinocyclohex-2-en-1-ones, followed by the one-pot aromatization/methylation process of the latter to provide N-aryl-2-methoxyanilines. A palladium(II)-catalyzed cyclization of these N-aryl-2-methoxyanilines afforded the desired 1-methoxycarbazole frame in high overall yields. This protocol was implemented for the total synthesis of the naturally occurring glycozolicine and 6-methoxymurrayanine.

Full text of DOI:10.1055/s-0032-1317175

PAPER
▌3327
paper
Synthetic Approach for Constructing the 1-Oxygenated Carbazole Core and
Its Application to the Preparation of Natural Alkaloids
Construction of the 1-Oxygenated Carbazole Core
Rafael Bautista, Alberto V. Jerezano, Joaquín Tamariz*
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala,
11340 México, D.F., Mexico
Fax +52(55)55866621; E-mail: jtamariz@woodward.encb.ipn.mx
Received: 26.06.2012; Accepted after revision: 08.08.2012
scaffold 2 or 3, which by subsequent dehydrogenation
Abstract: An efficient synthetic approach for the construction of
(and methylation) leads to the corresponding carbazoles 1
the 1-oxygenated carbazole core is described. The condensation of
(Scheme 1).5 The preparation of the hydrazone precursors
follows two methods: (1) the traditional acid-catalyzed
cyclohexane-1,2-diones with a series of anilines yielded the corre-
sponding 2-anilinocyclohex-2-en-1-ones, followed by the one-pot
aromatization/methylation process of the latter to provide N-aryl-2- condensation between cyclohexanone (4) and an arylhy-
drazine 5;6 or (2) the Japp–Klingemann reaction between
methoxyanilines. A palladium(II)-catalyzed cyclization of these N-
aryl-2-methoxyanilines afforded the desired 1-methoxycarbazole
frame in high overall yields. This protocol was implemented for the
total synthesis of the naturally occurring glycozolicine and 6-meth-
diazonium salt 6 and 2-formylcyclohexanone 7 leading to
hydrazone 8.6a,7
We previously described a general synthetic approach for
the preparation of the carbazole scaffold,8 on the basis of
a regioselective Diels–Alder reaction of exo-oxazolidin-
2-one dienes as the key step.9 This approach was recently
applied to the total synthesis of naturally occurring 1-
methoxycarbazoles, such as glycozolicine (1a), mukolidine
(1b), and mukoline (1c) (Figure 1).10 Since the success of
this strategy was due in part to the efficient palladium-cat-
alyzed cyclization reaction of a correctly functionalized
diarylamine,11 we herein attempted a new route for the
preparation of the 1-methoxycarbazole scaffold through
two alternative protocols (Scheme 2): (1) based on the de-
hydrogenation of intermediates 2 or 3 to afford 1 (Scheme
1),12 compounds 9 may be available precursors of 1 by a
palladium(II)-catalyzed cyclization of α-ketoenamines
11, as was carried out in a similar way with 2-(arylamino)-
1,4-benzoquinones13 or N-arylenaminones;1b and (2) di-
rect aromatization of intermediates 11 to furnish diaryl-
amines 10, followed by palladium(II)-catalyzed
cyclization to yield the desired carbazoles 1.
oxymurrayanine.
Key words: 1-methoxycarbazoles, α-ketoenamines, palladium(II),
cyclization, glycozolicine
Intense efforts have been focused on the development of
new and efficient synthetic routes for building the carba-
zole framework.1 The great interest in this framework is
due to the wide structural variety of these naturally occur-
ring alkaloids, and to their broad range of potent pharma-
cological activities, such as antimicrobial, anticancer,
antioxidant, antihypertensive, inhibitory platelet aggrega-
tion, cardiotonic, immunosuppressive, and antimicotic.1
In particular, diverse biological activity is exhibited by 1-
oxygenated carbazole alkaloids 1, extracted from leaves,
stem bark, and root of higher plant species of the genera
Clausena, Glycosmis and Murraya.2
Among the numerous protocols reported3 for the prepara-
tion of such compounds,1,4 the Fischer indolization strate-
gy has been useful for the construction of the tricyclic
R1
3
R1
R1
R2
R2
+
+
C
A
H2NHN
1
N
+
Cl– N2
OH
O
H
OMe
O
OMe
4
5
7
6
1
R2 = H
R2
R1
R1
R1
3
R2
N
N
1
H
N
H
N
H
O
OMe
O
8
2
3
Scheme 1 Fischer indolization approaches for the synthesis of carbazoles
SYNTHESIS 2012, 44, 3327–3336
Advanced online publication: 23.08.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317175; Art ID: SS-2012-M0545-OP
© Georg Thieme Verlag Stuttgart · New York

3328
R. Bautista et al.
PAPER
procedures were modified by using a stoichiometric
amount of palladium(II) acetate in acetonitrile or in cop-
per(II) acetate, but the expected ring closure, from 11a to
9a, did not take place.
R
N
H
OMe
Considering that these conditions mainly led to the forma-
tion of diarylamine 14a, we selected protocol (2) (Scheme
2) to build the carbazole framework. Although palladi-
um(II) acetate (30 mol%) was the most efficient catalyst
for dehydrogenation, giving rise to the desired diaryl-
amines 14, the latter were not stable enough under the re-
action and purification conditions to significantly increase
the yields. The use of other catalysts such as palladium on
carbon (5% or 10%), mercury(II) acetate, or 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone did not afford better
yields. Due to these shortcomings and taking into account
that most of the 1-oxygenated carbazoles are methylated,
we designed a one-pot, two-step procedure to carry out
both the dehydrogenation and methylation processes (Ta-
ble 2). Thus, the series 10a–e was prepared in high yields
(80–85%).
1a, R = Me
1b, R = CHO
1c, R = CH2OH
Figure 1 Glycozolicine (1a), mukolidine (1b), and mukoline (1c)
The preparation of 2-anilinocyclohex-2-en-1-ones 11a–e
was easily accomplished in high yields (82–95%) (Table
1) by the catalysis-free condensation of cyclohexane-1,2-
dione (13a) with a series of anilines 12a–e (Scheme 3).
Since the direct cyclization of substrates analogous to
compounds 11 has been reported by palladium(II)-cata-
lyzed insertion,1b,13 we investigated the catalysis by palla-
dium(II) acetate in acetic acid under thermal conditions
(140 °C). Although the desired carbazole frame 9a was
not furnished when the reaction was carried out under
these conditions with 11a, a ca. 1:1 ratio of a mixture of
14a/15a was isolated (Scheme 3). Presumably, the cata-
lyst promoted the aromatization of the cyclohexenone
moiety of 11a to give 14a, while 15a was generated by de-
composition of 11a to aniline 12a, followed by acetyla-
tion due to the presence of acetic acid. The known
Finally, the palladium(II)-catalyzed cyclization of diaryl-
amines 10a–e was successfully carried out by following
the protocol originally developed by Knölker and co-
workers11b–d and optimized for the synthesis of natural
carbazoles 1a–c.10 In spite of different substituents in the
benzene ring, the conversion of the series 10a–e into the
R
R
N
H
N
H
OMe
O
1
9
+
R
R
R
N
H
O
N
H
OMe
O
NH2
O
10
11
12
13a
Scheme 2 Alternative protocols for the synthesis of carbazoles 1 starting from anilines 12 and cyclohexane-1,2-dione (13a)
ii
R = 4-Me
i
+
R
R
O
N
H
NH2
N
H
O
O
O
9a
13a
11a–e
12a–e
ii
R = 4-Me
+
N
H
NHAc
OH
14a 35%
15a 40%
Scheme 3 Reaction conditions: (i) 12 (1.78 mmol), 13 (1.78 mmol), toluene (150 mL), reflux, 12 h; (ii) Pd(OAc)2, AcOH, 140 °C.
Synthesis 2012, 44, 3327–3336
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Construction of the 1-Oxygenated Carbazole Core
3329
Table 1 Scope of the Reaction between Anilines 12a–e and Cyclohexane-1,2-diones 13a,ba
PhMe
R1
R1
+
reflux, 12 h
R2
O
R2
N
H
NH2
O
O
11a–g
12a–e
13a–b
Entry
Aniline
R1
Cyclohexene-1,2-dione
R2
Product
Yieldb (%)
N
H
1
12a
12b
4-Me
13a
13a
H
H
85
O
11a
MeO
N
H
2
4-OMe
95
O
11b
11c
N
H
3
4
5
6
12c
12d
12e
12a
3-Me
13a
13a
13a
13b
H
82
90
90
91
O
MeO
N
H
3-OMe
3-Cl-2-Me
4-Me
H
O
11d
Cl
N
H
H
O
11e
N
H
Me
O
11f
MeO
N
H
7
12b
4-OMe
13b
Me
92
O
11g
a Standard conditions: 12 (1.78 mmol), 13 (1.78 mmol), toluene (150 mL), reflux, 12 h.
b Isolated yields.
carbazole derivatives 1a,d–g proceeded well and in good the two possible isomers, 11f,g and 16a,b, the former
yields (70–78%) (Table 2). It is also noteworthy that gly- were obtained in high yield (Table 1, entries 6 and 7). This
cozolicine (1a) can be readily transformed into two natu- selectivity may be associated with the well-known behav-
ral carbazoles mukolidine (1b) and mukoline (1c)10 ior of secondary or sterically hindered amines in the pres-
(Figure 1).
ence of the non-symmetrical 2-methylcyclohexanone,
resulting in the formation of the more stable unsubstituted
enamine.14 Hence, enamine 11 should be more stable than
16, probably because the latter is destabilized by the inhi-
bition of the resonance between the nitrogen lone-pair and
the double bond (Scheme 4).
With the aim of evaluating the scope of this methodology
and of testing the regioselectivity of the formation step of
2-anilinocyclohex-2-en-1-ones 11, the non-symmetrical
cyclohexane-1,2-dione 13b was treated with anilines
12a,b under the same reaction conditions (Scheme 4). Of
© Georg Thieme Verlag Stuttgart · New York
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R. Bautista et al.
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Table 2 Scope of the Conversion of 2-Anilinocyclohexa-2-en-1-ones 11a–g into Carbazoles 1a,d–i
1) Pd(OAc)2, MeCN
80 °C, 24 h
R1
R1
R1
Pd(OAc)2, Cu(OAc)2
R2
N
H
R2
N
H
R2
2) K2CO2, MeI
acetone, reflux, 2 h
(Step 1)
DMF, MW (100 W)
130 °C, 70 min
(Step 2)
N
H
OMe
O
OMe
11a–g
10a–g
1a, d–i
Entry
Substrate
R1
R2
Step 1
Step 2
Product
Yielda (%) of 10 Product
Yieldb (%) of 1
1
2
11a
4-Me
H
H
10a
80
75
N
H
OMe
1a
MeO
11b
4-OMe
10b
85
77
N
H
OMe
OMe
1d
3
4
5
11c
11d
11e
3-Me
H
H
H
10c
10d
10e
80
72
78
70
N
H
1e
MeO
3-OMe
3-Cl-2-Me
83
N
H
OMe
1f
Cl
81
N
H
OMe
1g
6
7
11f
4-Me
Me
Me
10f
93
71
78
N
H
OMe
1h
MeO
11g
4-OMe
10g
86
N
H
OMe
1i
a Standard conditions: (1) 11 (0.86–1.24 mmol), Pd(OAc)2 (30 mol%), 80 °C, 24 h; (2) K2CO3 (1.5 equiv), MeI (2.0 equiv), reflux, 2 h; isolated
yields.
b Standard conditions: 10 (0.32–0.47 mmol), Pd(OAc)2 (10 mol%), Cu(OAc)2 (2.5 equiv), MW (100 W), 130 °C, 70 min; isolated yields.
Synthesis 2012, 44, 3327–3336
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Construction of the 1-Oxygenated Carbazole Core
3331
R
R
In summary, a short and efficient synthetic approach for
the construction of 1-methoxycarbazoles is described, in-
cluding the naturally occurring alkaloid glycozolicine
(1a). This approach was accomplished through a three-
step reaction sequence with high overall yields (47–62%),
starting from cyclohexene-1,2-diones 13a,b and the re-
spective anilines 12a–e, to provide α-ketoenamines 11a–
g. The latter proved to be easily available precursors for
conversion into diarylamines 10a–g, which were cyclized
to the desired carbazoles 1. A synthetic application of the
latter was also carried out by transforming 1d into the nat-
ural carbazole 1j by direct formylation. The use of this
methodology for the synthesis of further carbazole sys-
tems is currently under study and will be reported in due
course.
PhMe
+
reflux, 12 h
NH2
O
N
H
O
O
11f, R = Me
11g, R = OMe
12a, R = Me
12b, R = OMe
13b
R
and/or
N
H
O
16a, R = Me
16b, R = OMe
Scheme 4 Regioselective formation of α-ketoenamine 11g
The dehydrogenation of 11f,g proceeded efficiently to
give diarylamines 10f,g (Table 2, entries 6 and 7, step 1),
as well as the palladium(II)-catalyzed cyclization of the
latter, giving rise to the corresponding 2-methylcarba-
zoles 1h,i in good yields (Table 2, entries 6 and 7, step 2).
Melting points (uncorrected) were determined with an Electrother-
mal capillary melting point apparatus. IR spectra were recorded on
a Perkin-Elmer 2000 spectrophotometer. 1H (300 or 500 MHz) and
13C (75 or 125 MHz) NMR spectra were recorded on Varian Mer-
Experimental evidence supports the idea that the biogene- cury-300 or Varian VNMR System instruments, with TMS as inter-
nal standard. MS and HRMS were obtained in EI mode (70 eV)
mode on Thermo-Finnigan Polaris Q and on Jeol JSM-GcMateII
spectrometers, respectively. Microwave (MW) irradiation was per-
formed on a CEM MW reactor. Analytical TLC was carried out us-
tic routes for the formyl or carboxylic functionalized car-
bazoles at the A- and C-rings consist of an in vivo
oxidation of the corresponding methyl-substituted carba-
zoles.1c An example of this is the aforementioned transfor-
ing E. Merck silica gel 60 F254 coated 0.25 plates, visualized by a
mation of glycozolicine (1a) into the natural carbazoles
mukolidine (1b) and mukoline (1c) (Figure 1), which oc-
curs in the laboratory10 and probably in nature as well, via
an oxidative pathway. However, the direct Vilsmeier–
Haack formylation of the carbazole skeleton has seldom
been used as an approach for the synthesis of formyl, or
after a further oxidative step, of carboxylic carbazoles.15
This is probably due to the poor selectivity shown by this
procedure.16 However, we investigated the synthesis of
the naturally occurring carbazole 6-methoxymurrayanine
(1j),17 starting from the herein prepared 1d (Scheme 5), up
to now being reported only as an unnatural carbazole.4h,18
Thus, by treating the latter with a mixture of N,N-dimeth-
ylformamide/phosphoryl chloride, carbazole 1j was ob-
tained in 55% yield, recovering unreacted 1d (21%). The
spectral data of the obtained product agreed with those de-
scribed for the natural17 and synthetic18 products.
long- and short-wavelength UV lamp. Flash column chromatogra-
phy was performed over Natland International Co. silica gel (230–
400 mesh). All air moisture sensitive reactions were carried out un-
der N2 using oven-dried glassware. Toluene was freshly distilled
over Na, and CH2Cl2 over CaH2, prior to use. Acetone was dried by
distillation after treatment with KMnO4, followed by a second dis-
tillation over anhyd Na2SO4. K2CO3 was dried overnight at 200 °C
prior to use. All other reagents were used without further purifica-
tion.
2-(4-Tolylamino)cyclohex-2-en-1-one (11a); Typical Procedure
In a 250-mL, 3-necked, round-bottomed flask equipped with a mag-
netic stirring bar, rubber septum, water condenser, and Dean–Stark
trap, under N2, a mixture of 13a (0.20 g, 1.8 mmol) and 12a (0.19 g,
1.8 mmol) in dry toluene (150 mL) was stirred at reflux for 12 h.
The solvent was removed under vacuum, and the residue purified by
column chromatography (silica gel, 10 g/g of crude, hexane–
EtOAc, 98:2) to give 11a (0.30 g, 85%) as a pale yellow solid; mp
58–59 °C [Lit.19 58–59 °C]; Rf = 0.74 (hexane–EtOAc, 4:1).
IR (KBr): 3363, 2922, 1671, 1611, 1521, 1308, 1181, 1128, 804
cm–1.
MeO
1H NMR (500 MHz, CDCl3): δ = 2.00 (q, J = 6.5 Hz, 2 H, H5), 2.28
(s, 3 H, CH3Ar), 2.42 (dt, J = 6.5, 5.0 Hz, 2 H, H4), 2.55 (t, J = 6.5
Hz, 2 H, H6), 6.24 (br s, 1 H, NH), 6.31 (t, J = 5.0 Hz, 1 H, H3),
6.91–6.96 (m, 2 H, H2′), 7.04–7.10 (m, 2 H, H3′).
13C NMR (125 MHz, CDCl3): δ = 20.6 (CH3Ar), 23.0 (C5), 24.5
(C4), 37.7 (C6), 115.3 (C3), 119.4 (C2′), 129.7 (C3′), 130.8 (C4′),
136.8 (C2), 139.3 (C1′), 195.6 (C1).
MeO
CHO
DMF, POCl3
40 °C, 30 min
55%
N
H
N
H
OMe
OMe
1d
1j
Scheme 5 Synthesis of 6-methoxymurrayanine (1j) by formylation
of carbazole 1d
MS (70 eV): m/z (%) = 201 ([M+], 63), 186 (19), 172 (47), 144 (92),
130 (76), 118 (32), 91 (100), 77 (27), 65 (49), 54 (40).
HRMS (EI): m/z [M+] calcd for C13H15NO: 201.1154; found:
201.1153.
All the structures of intermediates and products described
in these synthetic sequences were characterized by 1H and
13C NMR spectroscopy, with the help of 2D (HMQC and
HMBC) experiments, and mass spectrometric techniques
(MS and HRMS).
2-(4-Methoxyphenylamino)cyclohex-2-en-1-one (11b)
Following the procedure for 11a, with 13a (0.20 g, 1.8 mmol) and
12b (0.22 g, 1.8 mmol), 11b (0.37 g, 95%) was obtained as a pale
yellow solid; mp 48–49 °C [Lit.19 48–49 °C]; Rf = 0.72 (hexane–
EtOAc, 4:1).
© Georg Thieme Verlag Stuttgart · New York
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3332
R. Bautista et al.
PAPER
IR (film): 3372, 1667, 1628, 1523, 1467, 1334, 1301, 1254, 1182,
1128, 1032, 820, 802 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.98 (q, J = 6.6 Hz, 2 H, H5),
2.33–2.41 (m, 2 H, H4), 2.53 (t, J = 6.6 Hz, 2 H, H6), 3.76 (s, 3 H,
CH3O), 6.10 (br s, 1 H, NH), 6.13 (t, J = 4.6 Hz, 1 H, H3), 6.79–6.86
(m, 2 H, H3′), 6.95–7.02 (m, 2 H, H2′).
13C NMR (75 MHz, CDCl3): δ = 23.0 (C5), 24.3 (C4), 37.6 (C6),
55.3 (CH3O), 113.9 (C3), 114.3 (C3′), 122.0 (C2′), 134.7 (C1′),
137.5 (C2), 154.7 (C4′), 195.5 (C1).
MS (70 eV): m/z (%) = 217 ([M+], 100), 202 (52), 188 (13), 160
(21), 146 (12), 134 (14), 117 (6), 92 (8), 77 (9).
HRMS (EI): m/z [M+] calcd for C13H15NO2: 217.1103; found:
217.1109.
13C NMR (75 MHz, CDCl3): δ = 14.5 (CH3Ar), 23.0 (C5), 24.4
(C4), 37.6 (C6), 116.9 (C3), 118.7 (C6′), 123.3 (C4′), 126.7 (C5′),
128.1 (C2′), 135.3 (C3′), 136.8 (C2), 141.3 (C1′), 195.5 (C1).
MS (70 eV): m/z (%) = 237 ([M+ + 2], 35), 235 ([M+], 100), 220
(12), 206 (36), 178 (54), 164 (54), 144 (16), 117 (12), 89 (20).
HRMS (EI): m/z [M+] calcd for C13H14ClNO: 235.0764; found:
235.0760.
6-Methyl-2-(4-tolylamino)cyclohex-2-en-1-one (11f)
Following the procedure for 11a, with 13b (0.200 g, 1.59 mmol)
and 12a (0.170 g, 1.59 mmol), 11f (0.31 g, 91%) was obtained as a
pale yellow oil; Rf = 0.75 (hexane–EtOAc, 4:1).
IR (film): 3361, 1671, 1632, 1613, 1519, 1452, 1337, 1302, 1015,
809 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.21 (d, J = 7.0 Hz, 3 H, CH3-C6),
1.71–1.80 (m, 1 H, H5), 2.02–2.08 (m, 1 H, H5), 2.28 (s, 3 H,
CH3Ar), 2.37–2.47 (m, 2 H, H4), 2.47–2.54 (m, 1 H, H6), 6.24 (br
s, 1 H, NH), 6.26 (dd, J = 6.0, 3.0 Hz, 1 H, H3), 6.92–6.95 (m, 2 H,
H3′), 7.05–7.08 (m, 2 H, H2′).
13C NMR (75 MHz, CDCl3): δ = 15.5 (CH3C6), 20.6 (CH3Ar), 23.5
(C4), 31.0 (C5), 41.4 (C6), 114.5 (C3), 119.4 (C2′), 129.7 (C3′),
130.7 (C4′), 136.2 (C2), 139.5 (C1′), 198.4 (C1).
MS (70 eV): m/z (%) = 215 ([M+], 100), 200 (36), 186 (21), 172
(15), 144 (63), 130 (18), 118 (13), 91 (15), 77 (4).
HRMS (EI): m/z [M+] calcd for C14H17NO: 215.1310; found:
215.1312.
2-(3-Tolylamino)cyclohex-2-en-1-one (11c)
Following the procedure for 11a, with 13a (0.20 g, 1.8 mmol) and
12c (0.19 g, 1.8 mmol), 11c (0.29 g, 82%) was obtained as a pale
yellow oil; Rf = 0.74 (hexane–EtOAc, 4:1).
IR (KBr): 3341, 2913, 1675, 1605, 1534, 1492, 1450, 1312, 1176,
1126, 993, 876, 764, 691 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.00 (q, J = 6.6 Hz, 2 H, H5), 2.30
(s, 3 H, CH3Ar), 2.44 (dt, J = 6.6, 4.8 Hz, 2 H, H4), 2.54 (t, J = 6.6
Hz, 2 H, H6), 6.32 (br s, 1 H, NH), 6.40 (t, J = 4.8 Hz, 1 H, H3), 6.73
(br d, J = 7.2 Hz, 1 H, H6′), 6.83 (br s, 1 H, H2′), 6.81–6.88 (m, 1
H, H4′), 7.10–7.18 (m, 1 H, H5′).
13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3Ar), 22.8 (C5), 24.5
(C4), 37.6 (C6), 115.6 (C4′), 116.3 (C3′), 119.3 (C2′), 121.8 (C6′),
128.9 (C5′), 136.2 (C2), 139.0 (C3′), 141.8 (C1′), 195.5 (C1).
MS (70 eV): m/z (%) = 201 ([M+], 100), 186 (14), 172 (41), 158
(27), 144 (57), 130 (29), 118 (11), 91 (32), 77 (6), 65 (18).
HRMS (EI): m/z [M+] calcd for C13H15NO: 201.1154; found:
201.1155.
2-(4-Methoxyphenylamino)-6-methylcyclohex-2-en-1-one (11g)
Following the procedure for 11a, with 13b (0.200 g, 1.59 mmol)
and 12b (0.196 g, 1.59 mmol), 11g (0.34 g, 92%) was obtained as a
pale yellow oil; Rf = 0.73 (hexane–EtOAc, 4:1).
IR (film): 3362, 1670, 1630, 1512, 1460, 1297, 1241, 1035, 823
cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.21 (d, J = 6.6 Hz, 3 H, CH3),
1.66–1.82 (m, 1 H, H5), 1.99–2.10 (m, 1 H, H5), 2.35–2.44 (m, 2 H,
H4), 2.45–2.56 (m, 1 H, H6), 3.77 (s, 3 H, MeO), 6.10 (dd, J = 5.1,
4.2 Hz, 2 H, H3, NH), 6.80–6.89 (m, 2 H, H3′), 6.96–7.03 (m, 2 H,
H2′).
13C NMR (75 MHz, CDCl3): δ = 15.4 (CH3), 23.4 (C4), 31.1 (C5),
41.3 (C6), 55.4 (CH3O), 113.3 (C3), 114.4 (C3′), 122.1 (C2′), 135.0
(C1′), 137.1 (C2), 154.8 (C4′), 198.4 (C1).
MS (70 eV): m/z (%) = 231 ([M+], 100), 216 (39), 202 (24), 188
(17), 160 (22), 134 (16), 122 (7), 92 (7), 77 (6).
HRMS (EI): m/z [M – CH2]+ calcd for C13H15NO2: 217.1103; found:
217.1110.
2-(3-Methoxyphenylamino)cyclohex-2-en-1-one (11d)
Following the procedure for 11a, with 13a (0.20 g, 1.8 mmol) and
12d (0.22 g, 1.8 mmol), 11d (0.35 g, 90%) was obtained as a pale
yellow solid; mp 59–60 °C; Rf = 0.72 (hexane–EtOAc, 4:1).
IR (film): 3363, 2938, 1672, 1600, 1523, 1494, 1455, 1334, 1274,
1211, 1162, 1047, 764, 688 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.93–2.04 (m, 2 H, H5), 2.40–2.47
(m, 2 H, H4), 2.54 (dd, J = 7.5, 6.0 Hz, 2 H, H6), 3.76 (s, 3 H,
CH3O), 6.39 (br s, 1 H, NH), 6.44 (t, J = 4.8 Hz, 1 H, H3), 6.44–6.50
(m, 1 H, H6′), 6.57–6.66 (m, 2 H, H2′, H4′), 7.15 (t, J = 8.1 Hz, 2 H,
H5′).
13C NMR (75 MHz, CDCl3): δ = 22.7 (C5), 24.4 (C4), 37.5 (C6),
55.0 (CH3O), 104.1 (C2′), 105.8 (C6′), 110.8 (C4′), 117.2 (C3),
129.8 (C5′), 135.8 (C1′), 143.1 (C2), 160.3 (C3′), 195.4 (C1).
MS (70 eV): m/z (%) = 217 ([M+], 79), 188 (29), 174 (38), 160
(100), 146 (36), 130 (48), 117 (33), 92 (72), 77 (74), 64 (59), 54
(68).
HRMS (EI): m/z [M+] calcd for C13H15NO2: 217.1103; found:
217.1108.
2-Methoxy-N-(4-tolyl)aniline (10a); Typical Procedure
In a threaded ACE glass pressure tube with a sealed Teflon screw
cap, under N2, a mixture of 11a (0.250 g, 1.24 mmol) and Pd(OAc)2
(0.083 g, 0.37 mmol) in anhyd MeCN (2.5 mL) was stirred at 80 °C
for 24 h. The solvent was removed under vacuum, the residue mixed
with dry K2CO3 (0.26 g, 1.9 mmol) and MeI (0.352 g, 2.48 mmol)
in dry acetone (20 mL), and the mixture heated to reflux for 2 h. The
solvent was removed under vacuum and the residue purified by col-
umn chromatography (silica gel, 20 g/g of crude, hexane–EtOAc,
80:20), to give 10a (0.21 g, 80%) as a pale yellow oil;20 Rf = 0.65
(hexane–EtOAc, 7:3).
2-(3-Chloro-2-methylphenylamino)cyclohex-2-en-1-one (11e)
Following the procedure for 11a, with 13a (0.20 g, 1.8 mmol) and
12e (0.25 g, 1.8 mmol), 11e (0.38 g, 90%) was obtained as a white
solid; mp 63–64 °C; Rf = 0.75 (hexane–EtOAc, 4:1).
IR (film): 3411, 1599, 1518, 1458, 1297, 1242, 1114, 1028, 741
cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.31 (s, 3 H, CH3Ar), 3.89 (s, 3 H,
CH3O), 6.06 (br s, 1 H, NH), 6.81 (td, J = 7.5, 1.5 Hz, 1 H, H4), 6.85
(td, J = 7.5, 2.0 Hz, 1 H, H5), 6.87 (dd, J = 7.5, 2.0 Hz, 1 H, H3),
7.04–7.11 (m, 4 H, H2′, H3′), 7.20 (dd, J = 7.5, 1.5 Hz, 1 H, H6).
IR (KBr): 3384, 2951, 1664, 1631, 1568, 1508, 1461, 1435, 1335,
1302, 1120, 1008, 768 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.97–2.07 (m, 2 H, H5), 2.26 (s, 3
H, CH3Ar), 2.37–2.45 (m, 2 H, H4), 2.57 (dd, J = 7.2, 6.3 Hz, 2 H,
H6), 6.00 (t, J = 4.7 Hz, 1 H, H3), 6.12 (br s, 1 H, NH), 7.02–7.09
(m, 3 H, H4′, H5′, H6′).
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Construction of the 1-Oxygenated Carbazole Core
3333
13C NMR (125 MHz, CDCl3): δ = 20.7 (CH3Ar), 55.5 (CH3O),
110.2 (C3), 113.5 (C6), 119.1 (C4), 119.5 (C2′), 120.8 (C5), 129.7
(C3′), 130.9 (C4′), 133.7 (C1), 139.8 (C1′), 147.7 (C2).
MS (70 eV): m/z (%) = 213 ([M+], 90), 198 (36), 183 (100), 154
(25), 128 (8), 91 (7), 77 (8), 65 (7).
HRMS (EI): m/z [M+] calcd for C14H15NO: 213.1154; found:
213.1161.
3-Chloro-N-(2-methoxyphenyl)-2-methylaniline (10e)
Following the procedure for 10a, with 11e (0.250 g, 1.06 mmol),
Pd(OAc)2 (0.071 g, 0.32 mmol), K2CO3 (0.22 g, 1.6 mmol), and
MeI (0.30 g, 2.1 mmol), 10e (0.21 g, 81%) was obtained as a white
solid; mp 64–65 °C; Rf = 0.68 (hexane–EtOAc, 4:1).
IR (KBr): 3405, 1589, 1507, 1454, 1239, 1113, 1026, 732 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.32 (s, 3 H, CH3), 3.88 (s, 3 H,
CH3O), 5.89 (br s, 1 H, NH), 6.80–6.91 (m, 3 H, H3, H4, H5), 6.95
(dd, J = 5.7, 3.9 Hz, 1 H, H6), 7.00–7.07 (m, 2 H, H4′, H5′), 7.16–
7.21 (m, 1 H, H6′).
13C NMR (75 MHz, CDCl3): δ = 14.5 (CH3), 55.5 (CH3O), 110.4
(C3), 114.9 (C6), 118.0 (C6′), 119.9 (C4), 120.8 (C5), 123.0 (C4′),
126.8 (C5′), 127.6 (C2′), 133.3 (C1), 135.2 (C3′), 142.3 (C1′), 148.1
(C2).
MS (70 eV): m/z (%) = 247 ([M+], 100), 232 (5), 217 (16), 214 (18),
197 (91).
HRMS (EI): m/z [M+] calcd for C14H14ClNO: 247.0764; found:
247.0767.
2-Methoxy-N-(4-methoxyphenyl)aniline (10b)
Following the procedure for 10a, with 11b (0.200 g, 0.92 mmol),
Pd(OAc)2 (0.063 g, 0.28 mmol), K2CO3 (0.190 g, 1.38 mmol), and
MeI (0.261 g, 1.84 mmol), 10b (0.18 g, 85%) was obtained as a
white solid; mp 70–71 °C [Lit.21 71–72 °C]; Rf = 0.67 (hexane–
EtOAc, 4:1).
IR (KBr): 3379, 1601, 1526, 1239, 1174, 1110, 735 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.76 (s, 3 H, CH3O), 3.86 (s, 3 H,
CH3O), 5.97 (br s, 1 H, NH), 6.72–6.90 (m, 5 H, H3, H3′, H4, H5),
7.00–7.07 (m, 1 H, H6′), 7.07–7.15 (m, 2 H, H2′).
13C NMR (75 MHz, CDCl3): δ = 55.4 (2 CH3O), 110.1 (C3), 112.4
(C6), 114.5 (C3′), 118.4 (C4), 120.8 (C5), 122.6 (C2′), 134.9 (C1),
135.3 (C1′), 147.2 (C2), 155.2 (C4′).
MS (70 eV): m/z (%) = 229 ([M+], 23), 214 (17), 179 (28), 170 (26),
154 (23), 130 (13), 77 (100), 51 (34).
HRMS (EI): m/z [M+] calcd for C14H15NO2: 229.1103; found:
229.1103.
2-Methoxy-3-methyl-N-(4-tolyl)aniline (10f)
Following the procedure for 10a, with 11f (0.200 g, 0.93 mmol),
Pd(OAc)2 (0.062 g, 0.28 mmol), K2CO3 (0.192 g, 1.39 mmol), and
MeI (0.264 g, 1.86 mmol), 10f (0.196 g, 93%) was obtained as a
pale yellow solid; mp 68–69 °C; Rf = 0.74 (hexane–EtOAc, 4:1).
IR (KBr): 3400, 1603, 1588, 1518, 1474, 1328, 1251, 1207, 1001,
767 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.30 (s, 3 H, CH3-C3), 2.31 (s, 3
H, CH3-C4′), 3.75 (s, 3 H, CH3O), 6.04 (br s, 1 H, NH), 6.66 (dd,
J = 8.0, 1.0 Hz, 1 H, H4), 6.88 (t, J = 8.0 Hz, 1 H, H5), 7.03–7.06
(m, 2 H, H2′), 7.07 (dd, J = 8.0, 1.0 Hz, 1 H, H6), 7.08–7.11 (m, 2
H, H3′).
13C NMR (125 MHz, CDCl3): δ = 15.9 (CH3-C3), 20.7 (CH3-C4′),
59.6 (CH3O), 112.9 (C6), 119.4 (C2′), 121.7 (C4), 124.1 (C5), 129.8
(C3′), 131.0 (C3), 131.1 (C4′), 137.3 (C1), 140.0 (C1′), 146.9 (C2).
2-Methoxy-N-(3-tolyl)aniline (10c)
Following the procedure for 10a, with 11c (0.200 g, 0.99 mmol),
Pd(OAc)2 (0.067 g, 0.30 mmol), K2CO3 (0.210 g, 1.52 mmol), and
MeI (0.280 g, 1.97 mmol), 10c (0.17 g, 80%) was obtained as a pale
yellow oil;22 Rf = 0.65 (hexane–EtOAc, 4:1).
IR (film): 3409, 1585, 1523, 1493, 1243, 1115, 1028, 741 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.30 (s, 3 H, CH3), 3.85 (s, 3 H,
CH3O), 6.01 (br s, 1 H, NH), 6.75 (dm, J = 7.5, 1.6 Hz, 1 H, H4′),
6.82–6.90 (m, 3 H, H3, H4, H5), 6.93–6.98 (m, 2 H, H2′, H6′), 7.16
(dd, J = 8.7, 7.5 Hz, 1 H, H5′), 7.27–7.32 (m, 1 H, H6).
MS (70 eV): m/z (%) = 227 ([M+], 100), 212 (26), 197 (62), 168
(11), 154 (4), 77 (5).
13C NMR (125 MHz, CDCl3): δ = 21.5 (CH3), 55.5 (CH3O), 110.4
(C3), 114.6 (C6), 115.5 (C2′), 119.2 (C6′), 119.7 (C4), 120.7 (C5),
121.9 (C4′), 129.0 (C5′), 133.0 (C1), 139.0 (C3′), 142.6 (C1′), 148.1
(C2).
MS (70 eV): m/z (%) = 213 ([M+], 100), 198 (42), 183 (98), 154
(26), 128 (8), 91 (6), 65 (8).
HRMS (EI): m/z [M+] calcd for C15H17NO: 227.1310; found:
227.1307.
2-Methoxy-N-(4-methoxyphenyl)-3-methylaniline (10g)
Following the procedure for 10a, with 11g (0.200 g, 0.87 mmol),
Pd(OAc)2 (0.058 g, 0.26 mmol), K2CO3 (0.178 g, 1.29 mmol), and
MeI (0.247 g, 1.74 mmol), 10g (0.18 g, 86%) was obtained as a pale
yellow oil; Rf = 0.65 (hexane–EtOAc, 4:1).
HRMS (EI): m/z [M+] calcd for C14H15NO: 213.1154; found:
213.1163.
IR (film): 3351, 1603, 1515, 1471, 1327, 1242, 1168, 1037, 997,
827, 774 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.29 (s, 3 H, CH3), 3.75 (s, 3 H,
CH3O), 3.76 (s, 3 H, CH3O), 5.98 (br s, 1 H, NH), 6.60 (d, J = 7.2
Hz, 1 H, H4), 6.80–6.94 (m, 4 H, H3′, H5, H6), 7.05–7.13 (m, 2 H,
H2′).
13C NMR (75 MHz, CDCl3): δ = 15.8 (CH3), 55.4 (CH3O), 59.4
(CH3O), 111.5 (C6), 114.5 (C3′), 120.9 (C4), 122.5 (C2′), 124.1
(C5), 130.8 (C3), 135.3 (C1′), 138.4 (C1), 146.1 (C2), 155.1 (C4′).
2-Methoxy-N-(3-methoxyphenyl)aniline (10d)
Following the procedure for 10a, with 11d (0.200 g, 0.92 mmol),
Pd(OAc)2 (0.063 g, 0.28 mmol), K2CO3 (0.190 g, 1.38 mmol), and
MeI (0.261 g, 1.84 mmol), 10d (0.175 g, 83%) was obtained as a
pale yellow oil;23 Rf = 0.67 (hexane–EtOAc, 4:1).
IR (film): 3401, 1591, 1494, 1461, 1245, 1156, 1028, 743 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.76 (s, 3 H, CH3O), 3.85 (s, 3 H,
CH3O), 6.14 (br s, 1 H, NH), 6.47 (ddd, J = 8.5, 2.0, 1.0 Hz, 1 H,
H4′), 6.69–6.73 (m, 2 H, H2′, H6′), 6.82–6.91 (m, 3 H, H3, H4, H5),
7.16 (t, J = 7.5 Hz, 1 H, H5′), 7.30–7.34 (m, 1 H, H6).
MS (70 eV): m/z (%) = 243 ([M+], 100), 228 (54), 213 (19), 197
(64), 184 (19), 168 (7), 154 (6).
13C NMR (125 MHz, CDCl3): δ = 55.1 (CH3O), 55.5 (CH3O), 103.9
(C2′), 106.3 (C4′), 110.5 (C3), 110.8 (C6′), 115.3 (C6), 120.1 (C4),
120.7 (C5), 129.9 (C5′), 132.6 (C1), 144.1 (C1′), 148.4 (C2), 160.6
(C3′).
MS (70 eV): m/z (%) = 229 ([M+], 100), 217 (10), 200 (12), 189 (6),
170 (11), 154 (12), 142 (9), 115 (5), 77 (4).
HRMS (EI): m/z [M+] calcd for C15H17NO2: 243.1259; found:
243.1266.
1-Methoxy-6-methyl-9H-carbazole (Glycozolicine, 1a); Typical
Procedure
A mixture of 10a (0.106 g, 0.50 mmol), Pd(OAc)2 (0.011 g, 0.05
mmol), and Cu(OAc)2 (0.22 g, 1.2 mmol) in dry DMF (0.5 mL), un-
der N2, was stirred and heated at 130 °C for 70 min under micro-
wave irradiation (100 W). The solvent was removed under vacuum
HRMS (EI): m/z [M+] calcd for C14H15NO2: 229.1103; found:
229.1107.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3327–3336

3334
R. Bautista et al.
PAPER
and the residue purified by column chromatography (silica gel, 10
g/g of crude, hexane–EtOAc, 95:5), to give 1a (0.079 g, 75%) as a
white solid; mp 145–146 °C [Lit.10 145–146 °C; Lit.6c 137–138 °C;
Lit.7a 150 °C]; Rf = 0.60 (hexane–EtOAc, 7:3).
MS (70 eV): m/z (%) = 227 ([M+], 100), 212 (40), 184 (65), 169
(23), 149 (37), 141 (26), 77 (13).
HRMS (EI): m/z [M+] calcd for C14H13NO2: 227.0946; found:
227.0949.
1,6-Dimethoxy-9H-carbazole (1d)
2-Chloro-8-methoxy-1-methyl-9H-carbazole (1g)
Following the procedure for 1a, with 10e (0.10 g, 0.4 mmol),
Pd(OAc)2 (0.009 g, 0.04 mmol), and Cu(OAc)2 (0.18 g, 1.0 mmol),
1g (0.07 g, 70%) was obtained as a white solid; mp 98–99 °C; Rf =
0.63 (hexane–EtOAc, 7:3).
Following the procedure for 1a, with 10b (0.100 g, 0.44 mmol),
Pd(OAc)2 (0.0099 g, 0.044 mmol), and Cu(OAc)2 (0.2 g, 1.1 mmol),
1d (0.076 g, 77%) was obtained as a white solid;4h mp 118–119 °C
[Lit.18a 118–120 °C]; Rf = 0.62 (hexane–EtOAc, 7:3).
IR (KBr): 3416, 1615, 1578, 1482, 1459, 1429, 1298, 1259, 1217,
1175, 1031, 796, 737 cm–1.
IR (KBr): 3439, 1580, 1506, 1432, 1323, 1256, 1130, 1059, 1014,
774, 730 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.60 (s, 3 H, CH3), 4.03 (s, 3 H,
CH3O), 6.90 (d, J = 8.0 Hz, 1 H, H7), 7.16 (t, J = 8.0 Hz, 1 H, H6),
7.23 (d, J = 8.0 Hz, 1 H, H3), 7.62 (d, J = 8.0 Hz, 1 H, H5), 7.79 (d,
J = 8.0 Hz, 1 H, H4), 8.16 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): δ = 14.1 (CH3), 55.5 (CH3O), 105.9
(C7), 112.8 (C5), 118.1 (C2), 118.7 (C4), 120.3 (C6), 120.8 (C3),
121.8 (C4a), 124.5 (C4b), 129.9 (C8a), 131.0 (C1), 139.3 (C9a),
145.7 (C8).
MS (70 eV): m/z (%) = 245 ([M+], 3), 230 (11), 202 (27), 179 (26),
167 (27), 140 (25), 91 (10), 77 (100), 51 (40).
HRMS (EI): m/z [M+] calcd for C14H12ClNO: 245.0607; found:
245.0607.
1H NMR (500 MHz, CDCl3): δ = 3.90 (s, 3 H, CH3O-C6), 3.96 (s,
3 H, CH3O-C1), 6.85 (br d, J = 7.5 Hz, 1 H, H2), 7.04 (dd, J = 8.5,
2.5 Hz, 1 H, H7), 7.11 (t, J = 7.5 Hz, 1 H, H3), 7.30 (d, J = 8.5 Hz,
1 H, H8), 7.51 (d, J = 2.5 Hz, 1 H, H5), 7.62 (d, J = 7.5 Hz, 1 H,
H4), 8.13 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): δ = 55.4 (CH3O-C1), 56.0 (CH3O-
C6), 103.2 (C5), 105.7 (C2), 111.6 (C8), 112.7 (C4), 115.0 (C7),
119.3 (C3), 124.0 (C4b), 124.3 (C4a), 130.6 (C9a), 134.1 (C8a),
145.7 (C1), 153.8 (C6).
MS (70 eV): m/z (%) = 227 ([M+], 100), 212 (48), 196 (4), 184 (80),
169 (30), 141 (33), 126 (7), 77 (23).
HRMS (EI): m/z [M+] calcd for C14H13NO2: 227.0946; found:
227.0950.
1-Methoxy-2,6-dimethyl-9H-carbazole (1h)
1-Methoxy-7-methyl-9H-carbazole (1e)
Following the procedure for 1a, with 10f (0.100 g, 0.44 mmol),
Pd(OAc)2 (0.0099 g, 0.044 mmol), and Cu(OAc)2 (0.197 g, 1.09
mmol), 1h (0.07 g, 71%) was obtained as a white solid; mp 159–158
°C; Rf = 0.65 (hexane–EtOAc, 7:3).
Following the procedure for 1a, with 10c (0.106 g, 0.50 mmol),
Pd(OAc)2 (0.011 g, 0.05 mmol), and Cu(OAc)2 (0.226 g, 1.25
mmol), 1e (0.076 g, 72%) was obtained as a white solid; mp 172–
173 °C [Lit.24 172.6–176.4 °C]; Rf = 0.61 (hexane–EtOAc, 7:3).
IR (KBr): 3329, 1604, 1572, 1515, 1487, 1284, 1228, 1085, 1006,
800 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.46 (s, 3 H, CH3-C2), 2.50 (s, 3
H, CH3-C6), 3.93 (s, 3 H, CH3O), 6.99 (d, J = 8.0 Hz, 1 H, H3), 7.20
(dd, J = 8.3, 1.5 Hz, 1 H, H7), 7.30 (d, J = 8.3 Hz, 1 H, H8), 7.66 (d,
J = 8.0 Hz, 1 H, H4), 7.79 (s, 1 H, H5), 8.07 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 15.7 (CH3-C2), 21.4 (CH3-C6),
60.3 (CH3O), 110.4 (C8), 115.7 (C4), 120.1 (C5), 122.3 (C3), 123.5
(C4a), 124.1 (C4b), 126.8 (C7), 128.7 (C6), 134.0 (C9a), 137.7
(C8a), 143.1 (C1).
MS (70 eV): m/z (%) = 225 ([M+], 100), 210 (92), 184 (20), 182
(35), 167 (18), 152 (5), 140 (5), 77 (3).
HRMS (EI): m/z [M+] calcd for C15H15NO: 225.1154; found:
225.1155.
IR (KBr): 3404, 1618, 1577, 1504, 1436, 1322, 1260, 1243, 1101,
1027, 809, 776, 723 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.48 (s, 3 H, CH3Ar), 3.96 (s, 3 H,
CH3O), 6.84 (d, J = 8.0 Hz, 1 H, H2), 7.03 (br d, J = 8.0 Hz, 1 H,
H6), 7.12 (t, J = 8.0 Hz, 1 H, H3), 7.16 (br s, 1 H, H8), 7.62 (d,
J = 8.0 Hz, 1 H, H4), 7.90 (d, J = 8.0 Hz, 1 H, H5), 8.10 (br s, 1 H,
NH).
13C NMR (125 MHz, CDCl3): δ = 22.0 (CH3), 55.4 (CH3O), 105.5
(C2), 111.0 (C8), 112.6 (C4), 119.6 (C3), 120.1 (C5), 120.9 (C6),
121.4 (C4b), 124.4 (C4a), 129.6 (C9a), 135.8 (C7), 139.6 (C8a),
145.6 (C1).
MS (70 eV): m/z (%) = 211 ([M+], 100), 196 (72), 168 (85), 153
(12), 139 (13), 115 (6), 77 (13).
HRMS (EI): m/z [M+] calcd for C14H13NO: 211.0997; found:
211.0990.
1,6-Dimethoxy-2-methyl-9H-carbazole (1i)
Following the procedure for 1a, with 10g (0.100 g, 0.41 mmol),
Pd(OAc)2 (0.0092 g, 0.041 mmol), and Cu(OAc)2 (0.187 g, 1.03
mmol), 1i (0.077 g, 78%) was obtained as a white solid; mp 167–
168 °C; Rf = 0.62 (hexane–EtOAc, 7:3).
1,7-Dimethoxy-9H-carbazole (1f)
Following the procedure for 1a, with 10d (0.100 g, 0.44 mmol),
Pd(OAc)2 (0.0099 g, 0.044 mmol), and Cu(OAc)2 (0.20 g, 1.1
mmol), 1f (0.077 g, 78%) was obtained as a white solid; mp 164–
165 °C [Lit.25 164–166 °C]; Rf = 0.62 (hexane–EtOAc, 7:3).
IR (film): 3382, 1572, 1488, 1461, 1439, 1291, 1211, 1173, 1028,
1005, 806 cm–1.
IR (KBr): 3431, 1630, 1577, 1503, 1445, 1382, 1320, 1262, 1245,
1192, 1157, 1095, 1011, 825, 778 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.46 (s, 3 H, CH3), 3.91 (s, 3 H,
CH3O-C6), 3.93 (s, 3 H, CH3O-C1), 6.99 (d, J = 7.8 Hz, 1 H, H3),
7.03 (dd, J = 8.9, 2.3 Hz, 1 H, H7), 7.31 (d, J = 8.9 Hz, 1 H, H8),
7.49 (d, J = 2.3 Hz, 1 H, H5), 7.66 (d, J = 7.8 Hz, 1 H, H4), 8.09 (br
s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 15.7 (CH3), 56.0 (CH3O-C6), 60.3
(CH3O-C1), 103.0 (C5), 111.4 (C8), 114.6 (C7), 115.7 (C4), 122.1
(C3), 123.6 (C4a), 124.4 (C4b), 126.9 (C2), 134.0 (C9a), 134.3
(C8a), 143.1 (C1), 153.8 (C6).
1H NMR (500 MHz, CDCl3): δ = 3.87 (s, 3 H, CH3O-C7), 3.98 (s,
3 H, CH3O-C1), 6.83 (dd, J = 7.5, 0.5 Hz, 1 H, H2), 6.84 (dd,
J = 8.5, 2.5 Hz, 1 H, H6), 6.90 (d, J = 2.5 Hz, 1 H, H8), 7.12 (t,
J = 7.5 Hz, 1 H, H3), 7.57 (d, J = 7.5, 1 H, H4), 7.89 (d, J = 8.5 Hz,
1 H, H5), 8.17 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): δ = 55.5 (CH3O-C1), 55.6 (CH3O-
C7), 94.8 (C8), 105.0 (C2), 108.3 (C6), 112.2 (C4), 117.6 (C4b),
119.8 (C3), 121.2 (C5), 124.5 (C4a), 129.6 (C9a), 140.5 (C8a),
145.4 (C1), 159.0 (C7).
MS (70 eV): m/z (%) = 241 ([M+], 93), 226 (100), 211 (12), 198
(19), 183 (20), 167 (16), 154 (17), 127 (6), 77 (3).
Synthesis 2012, 44, 3327–3336
© Georg Thieme Verlag Stuttgart · New York

PAPER
Construction of the 1-Oxygenated Carbazole Core
3335
HRMS (EI): m/z [M+] calcd for C15H15NO2: 241.1103; found:
241.1112.
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3-Formyl-1,6-dimethoxy-9H-carbazole (6-Methoxymurraya-
nine) (1j)
In a 25-mL, 2-necked, round-bottomed flask equipped with a mag-
netic stirring bar, rubber septum, and water condenser, under N2, a
mixture of dry DMF (0.472 g, 6.47 mmol) and POCl3 (0.050 g, 0.33
mmol) was stirred at 0 °C for 20 min. Afterward, a soln of 1d (0.050
g, 0.22 mmol) in dry DMF (0.5 mL) was added, and the mixture
stirred at r.t. for 10 min, then at 40 °C for 30 min. The mixture was
poured into H2O (2 mL) and 2 M aq NaOH soln was added until
neutral. The organic layer was purified by column chromatography
(silica gel, 20 g/g of crude, hexane–EtOAc, 9:1) to give 1j (0.031 g,
55%) as a pale yellow solid; mp 231–233 °C [Lit.17 231–233 °C;
Lit.18a 230–232 °C]; Rf = 0.69 (hexane–EtOAc, 7:3).
Acknowledgment
We thank Professors Eleuterio Burgueño and Francisco Delgado for
his help in spectrometric analyses, and Bruce A. Larsen for review-
ing the English in the manuscript. J.T. acknowledges SIP/IPN
(Grants 20100236, 20110172 and 20120830) and CONACYT
(Grant 83446) for financial support. R.B. and A.V.J. thank CONA-
CYT for awarding them graduate scholarships, and SIP/IPN (PIFI)
for scholarship complements. J.T. is a fellow of the EDI-IPN and
COFAA-IPN programs.
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http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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