Palladium-catalyzed synthesis of natural and unnatural 2-, 5-, and 7-oxygenated carbazole alkaloids from N-arylcyclohexane enaminones

Article abstract of DOI:10.3390/molecules180910334

A palladium-catalyzed synthesis of the carbazole framework is described, including the preparation of 2-, 5-, and 7-oxygenated natural and unnatural carbazole alkaloids. A series of N-arylcyclohexane enaminones, generated by condensation of cyclohexane-1,3-dione with diverse anilines, were aromatized by a Pd(0)-catalyzed thermal treatment to afford the corresponding diarylamines. The latter were submitted to a Pd(II)-catalyzed cyclization and methylation processes to provide the desired carbazoles, including clausine V. Following an inverse strategy, a new and short total synthesis of glycoborine is also reported.

Full text of DOI:10.3390/molecules180910334

Molecules 2013, 18, 10334-10351; doi:10.3390/molecules180910334
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Palladium-Catalyzed Synthesis of Natural and Unnatural
2-, 5-, and 7-Oxygenated Carbazole Alkaloids from
N-Arylcyclohexane Enaminones
Rafael Bautista, Pablo A. Montoya, Araceli Rebollar, Eleuterio Burgueño and Joaquín Tamariz *
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas,
Instituto Politécnico Nacional. Prol. Carpio y Plan de Ayala, México D.F. 11340, Mexico
* Author to whom correspondence should be addressed; E-Mail: jtamariz@woodward.encb.ipn.mx;
Tel.: +52-55-5729-6300 (ext. 62411); Fax: +52-55-5586-6621.
Received: 5 July 2013; in revised form: 5 August 2013 / Accepted: 12 August 2013 /
Published: 26 August 2013
Abstract: A palladium-catalyzed synthesis of the carbazole framework is described,
including the preparation of 2-, 5-, and 7-oxygenated natural and unnatural carbazole
alkaloids. A series of N-arylcyclohexane enaminones, generated by condensation of
cyclohexane-1,3-dione with diverse anilines, were aromatized by a Pd(0)-catalyzed thermal
treatment to afford the corresponding diarylamines. The latter were submitted to
a Pd(II)-catalyzed cyclization and methylation processes to provide the desired carbazoles,
including clausine V. Following an inverse strategy, a new and short total synthesis of
glycoborine is also reported.
Keywords: 2-oxygenated carbazoles; enaminones; palladium(II) cyclization; clausine V;
glycoborine
1. Introduction
Biologically active carbazole alkaloids, a family of natural products with a variety of molecular
structures, are isolated from higher order plants of the genera Clausena, Glycosmis, Micromelum, and
Murraya (Rutaceae), among other sources [1–5]. Specifically, a great number of 2-, 5-, 6-,
7-mono- and bis-oxygenated tricyclic carbazoles isolated from these genera [1–3] exhibit a broad
range of significant biological activities, including compounds with anti-tumor [6,7], antiplatelet
aggregative [8], antibiotic [6,9,10], anti-viral [11–13], anti-plasmodial [14], anti-convulsant [15],

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and sigma receptor antagonist [16,17] properties. Carbazole derivatives 1a–g are examples of these
natural alkaloids [8,18–23] (Figure 1).
Figure 1. Examples of naturally occurring 2-, 7-, and 2,7-oxygenated tricyclic carbazoles.
In spite of the large number of 2-, 5-, 6-, 7-mono- and bis-oxygenated tricyclic natural carbazoles
that have been isolated, the wide range of functional groups and substitution patterns that exists among
these compounds, and their important pharmacological activity, only recently a considerable number
of synthetic approaches for their efficient preparation have been published [1–3,24–36].
We recently described a general synthetic approach for the construction of 1-methoxycarbazoles,
including the naturally occurring alkaloid glycozolicine, which was accomplished with high overall
yields through a three-step reaction sequence [37]. Based on this approach, we describe herein a new
synthetic route for the preparation of 2-, 7-, and 2,7-oxygenated carbazoles 1. Starting from
cyclohexene-1,3-dione (2) and the respective anilines 3a–e, enaminones 4a–e were prepared (Scheme 1).
The latter were converted into diarylamines 5a–e and then cyclized to the desired carbazoles 1, via an
efficient Pd-catalyzed aromatization and cyclization sequence of reactions.
Scheme 1. Synthetic approach for the preparation of 2-oxygenated tricyclic carbazoles 1.
2. Results and Discussion
2.1. Synthesis of Diarylamines
The catalyst-free condensation of cyclohexane-1,3-dione (2) with anilines 3a–e provided 3-anilino-
2-cyclohexen-1-ones 4a–e in high yields (Table 1). However, the use of deactivated anilines, such as

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3-nitro- and 4-nitroanilines, failed to provide the desired enaminones, thus limiting this procedure to
anilines substituted with electron-donating groups. Applying our previous procedure for aromatization
using Pd(OAc)2 (30% mol) [37], derivatives 4a–b did not lead to the desired diarylamines 6a–b, but
instead furnished the carbazole frame compounds 7a–b in good yields (Scheme 2). Similar results via
Pd-mediated procedures have been reported for analogous substrates [1,38–41], which in turn have
been transformed into the 4-oxygenated carbazoles [42]. When using other catalysts, such as mercuric
acetate [43] and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) [44,45], diarylamines 6 were indeed
produced, but in very low yields (15%–20%).
Table 1. Scope of the reaction between cyclohexane-1,3-dione (2) and anilines 3a–e a.
Entry
3 (Ar)
4 (%) b
4a (92)
4b (95)
4c (90)
4d (93)
4e (96)
1
2
3
4
5
3a (C6H4-4-Me)
3b (C6H4-4-OMe)
3c (C6H4-3-Me)
3d (C6H4-3-OMe)
3e (C6H3-3,5-(OMe)2
a
Standard conditions: 2 (3.57 mmol), 3 (3.57 mmol), toluene (150 mL), reflux, 12 h.
b Isolated yields.
Scheme 2. Pd(II)-catalyzed treatment of 3-anilino-2-cyclohexen-1-ones 4a–b.
Due to the fact that the insertion of the aryl and cyclohexenone rings takes place via a
Pd(II)-catalyzed pathway [1,2,38–41,46], we chose a Pd(0)-mediated method for carrying out such an
aromatization. Initially, when 4b was treated with Pd/C (5%) at different concentrations (1–6 mol%)
with MeOH as the solvent and heating to 50–200 °C in a sealed vessel, diarylamine 6b was not
obtained and the starting material was recovered. However, the desired transformation was achieved
by increasing both the palladium(0) loading on charcoal (10%) (1.9%–5.7% mol) and the reaction
temperature (Table 2, entries 1–3). The use of the Pd(0)-mediated aromatization method for similar
substrates or carbazole derivatives in moderate to good yields has been reported [42,47–52]. Reagents
such as DDQ [44,45,53] and chloranil [54] have also been successfully applied to achieve analogous
conversions [43,55].
Although the preparation and purification of diarylamines 6a–b and 6d–e resulted in high yields
(Table 2, entries 3–4 and 6–7), the relative instability of these compounds under the conditions of the

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following cyclization reaction made it necessary to protect the phenol moiety. In order to achieve this
protection and taking into account that there are many naturally occurring methoxy-containing
oxygenated carbazoles, we decided to obtain the methylated derivatives 5a–e. For this purpose, we
employed a direct sequential procedure for the dehydrogenation and methylation of phenols 6 without
purification (Table 2, entries 3–7). Thus, the series of compounds 5a–e was prepared in high yields
(81%–87%).
Table 2. Conversion of 3-anilino-2-cyclohexen-1-ones 4a–e into diarylamines 6a–b, 6d–e and 5a–e a.
Entry
4 (R)
Pd/C (10%) (mol%) b
6 (%) c
6b (65)
6b (75)
6b (87)
6a (85)
(g)
5 (%) d
----
1e
2f
3
4b (4-OMe)
4b (4-OMe)
4b (4-OMe)
4a (4-Me)
1.9
3.8
5.7
5.7
5.7
5.7
5.7
----
5b (85)
5a (83)
5c (87)
5d (81)
5e (86)
4
5
4c (3-Me)
6
4d (3-OMe)
4e (3,5-(OMe)2
6d (84)
6e (88)
7
a
Standard conditions: (a) Preparation of diarylamines 6: 4 (0.81–1.00 mmol), Pd/C (10%), MeOH, 210 °C,
48 h; (b) Preparation of diarylamines 5a–e: Aromatization step: 4 (0.82–1.00 mmol), Pd/C (10%), MeOH,
210 °C, 24 h; Methylation step: 6 (1.0 mol equiv.), MeI (2.0 mol equiv.), K2CO3 (1.5 mol equiv.), acetone, reflux,
b
c
d
e
12 h. Calculated for Pd(0). Isolated yields. Isolated yields for the two steps. At 180 °C for 12 h.
f At 200 °C for 48 h. g Not isolated.
2.2. Synthesis of Carbazoles
The final cyclization step of diarylamines 5a–e was successfully carried out by following the
protocol originally developed by Knölker and coworkers [40,56,57], later applied by others [28,29],
and optimized in our syntheses of natural carbazoles [37,44]. Thus, the conversion of the series 5a–c
and 5e into the carbazole derivatives 1h–k resulted in good yields (80%–92%) (Table 3). It is
noteworthy that the cyclization of 5d provided clausine V (1d) in high yield (90%) [22,33].
With the aim of testing the utility of this methodology for the total synthesis of natural
7-oxygenated tricyclic carbazoles, we carried out the conversion of derivative 1h into clauszoline-K
(1f) and clauszoline-L (clausine C, 1g). Thus, upon applying the well-known procedure [58,59] for the
synthesis of these [32] and other natural carbazoles [44], carbazole 1h was treated with DDQ in a
mixture of MeOH/H2O/acetone (1:1:1) at room temperature for 45 min to give 1f in 70%
yield (Scheme 3).

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Table 3. Preparation of carbazoles 1d and 1h–k via Pd(II)-catalyzed cyclization of
diarylamines 5a–e a.
Entry
5 (R)
1
Isolated yield (%) b
1
5a (4-Me)
80
2
5b (4-OMe)
87
3
4
5c (3-Me)
82
90
5d (3-OMe)
5
5e (3,5-(OMe)2
92
a
Standard conditions: 5 (0.32–0.47 mmol), Pd(OAc)2 (10 mol%), Cu(OAc)2 (2.5 mol equiv.), DMF, MW
(100 W), 130 °C, 70 min. b Isolated yields.
Scheme 3. Preparation of natural carbazoles clauszoline-K (1f) and clauszoline-L (1g).
The latter was oxidized with a mixture of MnO2/KCN in MeOH [58] to furnish clauszoline-L (1g)
in almost quantitative yield. The spectral data of the products obtained agree with those described for
the natural [20,23] and synthetic [58] products.

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2.3. Total Synthesis of Glycoborine (Glycrophylamine, 9)
Recently, 5-methoxy-3-methylcarbazole (9) was isolated from the roots and branches of Glycosmis
macrophylla and named glycrophylamine. This compound showed cytotoxic activity against
NC1-H187 cancerigene cells [60]. However, the same carbazole had been isolated from Glycosmis
arborea a decade earlier, and named glycoborine. This was the first 5-oxygenated tricyclic natural
carbazole ever isolated [61]. Nowadays, three routes of synthesis have been developed for 9 based on
Fischer [61], Japp-Klingemann [62], and Cadogan cyclizations [33] as the key step. We herein
describe a new total synthesis of 9 starting from the key precursor tetrahydrocarbazole 7a (Scheme 4),
which was efficiently prepared from 4a (Scheme 2).
When a mixture of 7a, Pd/C (10%) (5.7% mol) and anhydrous MeOH was heated in a sealed vessel
to 270 °C for 48 h, 5-hydroxy-3-methylcarbazole (8) was isolated and then purified in good yield
(Scheme 4). Methylation of the latter under the usual reaction conditions provided the desired natural
carbazole 9, which was synthesized in four steps with high overall yield (53%). The spectral data of 9
agree with those described for the natural [60,61] and synthetic [33,62] products.
Scheme 4. Preparation of natural carbazole glycoborine (9).
All the structures of intermediates and products described in these synthetic sequences were
1
characterized by H- and 13C-NMR spectroscopy, with the help of 2D (HMQC and HMBC)
experiments and mass spectrometric techniques (MS and HRMS).
3. Experimental
3.1. General
Melting points (uncorrected) were determined with an Electrothermal capillary melting point
apparatus. IR spectra were recorded on a Perkin-Elmer 2000 spectrophotometer. 1H (300 or 500 MHz)
and 13C-NMR (75 or 125 MHz) spectra were recorded on Varian Mercury-300 or Varian VNMR
System instruments, with TMS as internal standard. Mass spectra (MS) and high-resolution mass
spectra (HRMS) were obtained, in electron impact (EI) (70 eV) mode, on Thermo-Finnigan Polaris Q
and Jeol JSM-GcMateII spectrometers, respectively. Microwave (MW) irradiation was performed on a
CEM MW reactor. Analytical thin-layer chromatography was carried out using E. Merck silica gel 60
F254 coated 0.25 plates, visualized by a long- and short-wavelength UV lamp. Flash column
chromatography was performed over Natland International Co. silica gel (230–400 mesh). All air
moisture sensitive reactions were carried out under nitrogen using oven-dried glassware. Toluene,
MeOH, and MeCN were freshly distilled over sodium and DMF over calcium hydride prior to use.
Acetone was dried by distillation after treatment with potassium permanganate. K2CO3 was dried
overnight at 200 °C prior to use. All other reagents were used without further purification.

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3.2. Synthesis and Characterization
3-(p-Tolylamino)cyclohex-2-en-1-one (4a) [63]. In a 250 mL, three necked, round-bottomed flask
equipped with a magnetic stirring bar, rubber septum, a water condenser and a Dean-Stark trap, under
N2 atmosphere, a mixture of 2 (0.400 g, 3.57 mmol) and 3a (0.382 g, 3.37 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 over silica gel (10 g/g of crude, hexane/EtOAc, 1:1) to give 4a (0.66 g, 92%)
as a pale yellow solid. Rf 0.15 (hexane/EtOAc, 1:1); mp 248–249 °C. IR (KBr): νmax 3214, 3029, 2937,
1
1573, 1512, 1361, 1311, 1245, 1183, 1141, 818 cm−1. H-NMR (500 MHz, CDCl3): δ = 1.98 (qu,
J = 6.5 Hz, 2H, H-5), 2.31 (br t, J = 6.5 Hz, 2H, H-6), 2.32 (s, 3H, CH3), 2.48 (t, J = 6.5 Hz, 2H, H-4),
13
5.48 (s, 1H, H-2), 6.99–7.03 (m, 2H, H-2′), 7.07–7.11 (m, 2H, H-3′), 7.12 (br s, 1H, NH). C-NMR
(125 MHz, CDCl3): δ = 20.9 (CH3), 21.8 (C-5), 29.5 (C-4), 36.4 (C-6), 99.0 (C-2), 124.0 (C-2′), 129.7
(C-3′), 135.3 (C-4′), 135.5 (C-1′), 163.1 (C-3), 198.1 (C-1). MS (70 eV): m/z (%) 201 (M+, 74), 184
(26), 173 (100), 144 (53), 130 (29), 106 (13), 91 (12), 77 (10). HRMS (EI): m/z [M+] calcd for
C13H15NO: 201.1154; found: 201.1156.
3-(4-Methoxyphenylamino)cyclohex-2-en-1-one (4b). Following the procedure described for 4a, using
2 (0.400 g, 3.57 mmol) and 3b (0.439 g, 3.57 mmol), 4b (0.74 g, 95%) was obtained as a pale yellow
solid. Rf 0.12 (hexane/EtOAc, 1:1); mp 166–167 °C [Lit. [64] 164–166 °C]. IR (KBr): νmax 3218,
1
3039, 2946, 1513, 1412, 1365, 1243, 1180, 1135, 1032, 834, 716 cm−1. H-NMR (500 MHz, CDCl3):
δ = 1.97 (qu, J = 6.5 Hz, 2H, H-5), 2.30 (t, J = 6.5 Hz, 2H, H-6), 2.47 (t, J = 6.5 Hz, 2H, H-4), 3.78 (s,
3H, CH3O), 5.34 (s, 1H, H-2), 6.80–6.84 (m, 2H, H-3′), 7.02–7.06 (m, 2H, H-2′), 7.13 (br s, 1H, NH).
13C-NMR (125 MHz, CDCl3): δ = 21.8 (C-5), 29.3 (C-4), 36.4 (C-6), 55.4 (CH3O), 98.6 (C-2), 114.4
(C-3′), 126.1 (C-2′), 130.8 (C-1′), 157.5 (C-4′), 164.0 (C-3), 198.0 (C-1). MS (70 eV): m/z (%) 217
(M+, 100), 200 (55), 189 (43), 174 (20), 160 (98), 146 (30), 130 (23), 117 (12), 77 (10). HRMS (EI):
m/z [M+] calcd for C13H15NO2: 217.1103; found: 217.1110.
3-(m-Tolylamino)cyclohex-2-en-1-one (4c). Following the procedure described for 4a, 4c (0.65 g,
90%) was obtained as a pale yellow oil from 2 (0.400 g, 3.57 mmol) and 3c (0.382 g, 3.57 mmol). Rf
0.15 (hexane/EtOAc, 1:1). IR (film): νmax 3256, 3066, 2959, 1546, 1453, 1360, 1244, 1185, 1136, 829,
1
795, 728 cm−1. H-NMR (500 MHz, CDCl3): δ = 1.98 (qu, J = 6.5 Hz, 2H, H-5), 2.29 (s, 3H, CH3),
2.32 (t, J = 6.5 Hz, 2H, H-6), 2.49 (t, J = 6.5 Hz, 2H, H-4), 5.55 (s, 1H, H-2), 6.91-6.95 (m, 2H, H-4′,
13
H-6′), 6.96 (br s, 1H, H-2′), 7.17 (t, J = 8.0 Hz, 1H, H-5′), 7.18 (br s, 1H, NH). C-NMR (125 MHz,
CDCl3): δ 21.3 (CH3), 21.8 (C-5), 29.6 (C-4), 36.4 (C-6), 99.3 (C-2), 120.9 (C-6′), 124.4 (C-2′), 126.2
(C-4′), 129.0 (C-5′), 138.0 (C-3′), 139.1 (C-1′), 162.9 (C-3), 198.3 (C-1). MS (70 eV): m/z (%) 201
(M+, 79), 184 (49), 173 (100), 158 (16), 144 (88), 130 (42), 106 (13), 91 (19), 77 (16). HRMS (EI):
m/z [M+] calcd for C13H15NO: 201.1154; found: 201.1160.
3-(3-Methoxyphenylamino)cyclohex-2-en-1-one (4d). Following the procedure described for 4a, using
2 (0.400 g, 3.57 mmol) and 3d (0.439 g, 3.57 mmol), 4d (0.72 g, 93%) was obtained as a pale yellow
solid. Rf 0.11 (hexane/EtOAc, 1:1); mp 126–127 °C [Lit. [64] 122.5–124 °C; [65] 126–128 °C]. IR
(KBr): νmax 3278, 3196, 3133, 2937, 1540, 1425, 1357, 1318, 1245, 1191, 1143, 1051, 871, 733 cm−1.
1H-NMR (500 MHz, CDCl3): δ 1.98 (qu, J = 6.5 Hz, 2H, H–5), 2.32 (t, J = 6.5 Hz, 2H, H–6), 2.50 (t,

Molecules 2013, 18
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J = 6.5 Hz, 2H, H-4), 3.75 (s, 3H, CH3O), 5.59 (s, 1H, H-2), 6.66–6.70 (m, 2H, H-2′, H-6′), 6.72 (dm,
13
J = 8.0 Hz, 1H, H-4′), 7.16–7.21 (m, 1H, H-5′), 7.29 (br s, 1H, NH). C-NMR (125 MHz, CDCl3): δ
21.8 (C-5), 29.5 (C-4), 36.4 (C-6), 55.2 (CH3O), 99.6 (C-2), 109.7 (C-2′), 110.8 (C-6′), 116.0 (C-4′),
129.9 (C-5′), 139.4 (C-1′), 160.2 (C-3′), 162.7 (C-3), 198.4 (C-1). MS (70 eV): m/z (%) 217 (M+, 99),
200 (59), 189 (46), 160 (100), 146 (32), 130 (23), 117 (11), 77 (7). HRMS (EI): m/z [M+] calcd for
C13H15NO2: 217.1103; found: 217.1101.
3-(3,5-Dimethoxyphenylamino)cyclohex-2-en-1-one (4e). Following the procedure described for 4a,
with 2 (0.400 g, 3.57 mmol) and 3e (0.546 g, 3.57 mmol), 4e (0.85 g, 96%) was obtained as a pale
yellow solid. Rf 0.12 (hexane/EtOAc, 1:1); mp 139–140 °C. IR (KBr): νmax 3272, 2940, 1598, 1582,
1
1538, 1462, 1423, 1361, 1253, 1186, 1153, 1055, 824 cm−1. H-NMR (500 MHz, CDCl3): δ = 1.99
(qu, J = 6.5 Hz, 2H, H-5), 2.33 (t, J = 6.5 Hz, 2H, H-6), 2.49 (t, J = 6.5 Hz, 2H, H-4), 3.73 (s, 6H,
2CH3O), 5.64 (s, 1H, H-2), 6.24 (t, J = 2.0 Hz, 1H, H-4′), 6.30 (d, J = 2.0 Hz, 2H, H-2′, H-6′), 7.06
13
(br s, 1H, NH). C-NMR (125 MHz, CDCl3): δ = 21.8 (C-5), 29.6 (C-4), 36.4 (C-6), 55.3 (CH3O),
97.4 (C-4′), 100.2 (C-2), 102.1 (C-2′, C-6′), 139.9 (C-1′), 161.2 (C-3′, C-5′), 162.3 (C-3), 198.3 (C-1).
MS (70 eV): m/z (%) 247 (M+, 37), 230 (100), 219 (25), 190 (83), 160 (18), 135 (30), 120 (14), 77 (7).
HRMS (EI): m/z [M+] calcd for C14H17NO3: 247.1208; found: 247.1207.
3-(p-Tolylamino)phenol (6a). In a threaded ACE glass pressure tube with a sealed Teflon screw cap,
under N2 atmosphere, a mixture of 4a (0.20 g, 1.0 mmol) and Pd/C (10%) (0.060 g, 0.057 mmol) in
dry MeOH (2.5 mL) was stirred at 210 °C for 48 h. The solvent was removed under vacuum, and the
residue purified by column chromatography over silica gel (20 g/g of crude, hexane/EtOAc, 80:20), to
give 6a (0.168 g, 85%) as a pale grey solid. Rf 0.55 (hexane/EtOAc, 7:3); mp 81–82 °C [Lit. [66] 82 °C].
1
IR (film): νmax 3394, 1606, 1512, 1493, 1332, 1243, 1155, 969, 815, 766 cm−1. H-NMR (300 MHz,
CDCl3): δ = 2.27 (s, 3H, CH3), 5.58 (br s, 1H, NH), 6.31 (dd, J = 7.8, 2.1 Hz, 1H, H-4), 6.44 (t, J = 2.1 Hz,
1H, H-2), 6.51 (dd, J = 7.8, 2.1 Hz, 1H, H-6), 6.92–6.99 (m, 2H, H-2′), 6.99–7.07 (m, 3H, H-3′,
H-5). 13C-NMR (75.4 MHz, CDCl3): δ = 20.6 (CH3), 103.2 (C-2), 107.1 (C-4), 108.9 (C-6), 119.5
(C-2′), 129.8 (C-3′), 130.2 (C-5), 131.2 (C-4′), 139.7 (C-1′), 145.6 (C-1), 156.6 (C-3). MS (70 eV): m/z
(%) 199 (M+, 100), 183 (19), 170 (22), 154 (35), 128 (14), 91 (83), 65 (18). HRMS (EI): m/z [M+]
calcd for C13H13NO: 199.0997; found: 199.0998.
3-(4-Methoxyphenylamino)phenol (6b). Following the procedure described for 6a, with 4b (0.200 g,
0.92 mmol) and Pd/C (10%) (0.060 g, 0.057 mmol), 6b (0.172 g, 87%) was obtained as a pale grey
solid. Rf 0.50 (hexane/EtOAc, 8:2); mp 66–67 °C [Lit. [66] 67–68 °C]. IR (KBr): νmax 3379, 1601,
1
1526, 1504, 1459, 1291, 1239, 1174, 1110, 1027, 735 cm−1. H-NMR (300 MHz, CDCl3): δ = 3.79
(s, 3H, CH3O), 6.50 (br s, 1H, NH), 6.28 (ddd, J = 8.0, 2.4, 0.6 Hz, 1H, H-4), 6.37 (t, J = 2.4 Hz, 1H,
H-2), 6.44 (ddd, J = 8.0, 2.4, 0.6 Hz, 1H, H-6), 6.82–6.89 (m, 2H, H-3′), 7.04 (t, J = 8.0 Hz, 1H,
13
H-5), 7.04–7.10 (m, 2H, H-2′). C-NMR (75.4 MHz, CDCl3): δ = 55.5 (CH3O), 101.9 (C-2), 106.3
(C-4), 108.0 (C-6), 114.6 (C-3′), 122.9 (C-2′), 130.3 (C-5), 135.1 (C-1′), 146.9 (C-1), 155.4 (C-4′),
156.7 (C-3). MS (70 eV): m/z (%) 215 (M+, 100), 201 (6), 185 (7), 172 (5), 146 (4), 132 (5), 91 (11).
HRMS (EI): m/z [M+] calcd for C13H13NO2: 215.0946; found: 215.0952.

Molecules 2013, 18
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3-(3-Methoxyphenylamino)phenol (6d) [66]. Following the procedure described for 6a, with 4d (0.200
g, 0.92 mmol) and Pd/C (10%) (0.060 g, 0.057 mmol), 6d (0.166 g, 84%) was obtained as a purple oil.
1
Rf 0.51 (hexane/EtOAc, 8:2). IR (film): νmax 3411, 1645, 1489, 1156, 764 cm−1. H-NMR (300 MHz,
CDCl3): δ = 3.71 (s, 3H, CH3O), 5.76 (br s, 1H, NH), 6.38 (ddd, J = 8.1, 2.4, 0.9 Hz, 1H, H-4), 6.46
(dm, J = 7.8 Hz, 1H, H-4′), 6.54 (t, J = 2.4 Hz, 1H, H-2), 6.56–6.65 (m, 3H, H-2′, H-6, H-6′), 7.05 (t,
13
J = 8.1 Hz, 1H, H-5), 7.11 (t, J = 7.8 Hz, 1H, H-5′). C-NMR (75.4 MHz, CDCl3): δ = 55.1 (CH3O),
103.8 (C-2′), 104.6 (C-2), 106.3 (C-4′), 108.0 (C-4), 110.1 (C-6′), 110.7 (C-6), 130.0 (C-5′), 130.2
(C-5), 144.0 (C-1′), 144.3 (C-1), 156.6 (C-3), 160.3 (C-3′). MS (70 eV): m/z (%) 215 (M+, 26), 199
(21), 182 (25), 160 (31), 146 (45), 130 (25), 109 (23), 51 (100). HRMS (EI): m/z [M+] calcd for
C13H13NO2: 215.0946; found: 215.0952.
3-(3,5-Dimethoxyphenylamino)phenol (6e). Following the procedure described for 6a, with 4e (0.200 g,
0.81 mmol) and Pd/C (10%) (0.060 g, 0.057 mmol), 6e (0.174 g, 88%) was obtained as a yellow oil.
Rf 0.49 (hexane/EtOAc, 8:2). IR (film): νmax 3379, 2917, 1594, 1481, 1203, 1152, 1065, 821 cm−1.
1H-NMR (300 MHz, CDCl3): δ = 3.73 (s, 6H, 2CH3O), 5.74 (br s, 1H, NH), 6.07 (t, J = 2.1 Hz, 1H,
H-4′), 6.23 (d, J = 2.1 Hz, 2H, H-2′, H-6′), 6.39 (dd, J = 8.1, 2.4 Hz, 1H, H-4), 6.55 (dd, J = 2.4, 2.1
Hz, 1H, H-2), 6.62 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H, H-6), 7.08 (t, J = 8.1 Hz, 1H, H-5). 13C-NMR (75.4
MHz, CDCl3): δ = 55.3 (2CH3O), 93.2 (C-4′), 96.3 (C-2′, C-6′), 105.0 (C-2), 108.2 (C-4), 110.6
(C-6), 130.3 (C-5), 144.1 (C-1′), 144.7 (C-1), 156.6 (C-3), 161.4 (C-3′, C-5′). MS (70 eV): m/z (%) 245
(M+, 3), 154 (14), 153 (96), 125 (15), 124 (100), 94 (25), 92 (22). HRMS (EI): m/z [M+] calcd for
C14H15NO3: 245.1052; found: 245.1059.
3-Methoxy-N-(p-tolyl)aniline (5a) [67]. In a threaded ACE glass pressure tube with a sealed Teflon
screw cap, under N2 atmosphere, a mixture of 4a (0.20 g, 1.0 mmol) and Pd/C (10%) (0.060 g,
0.057 mmol) in dry MeOH (2.5 mL) was stirred at 210 °C for 24 h. After removing the solvent under
vacuum, K2CO3, (0.200 g, 1.45 mmol) and CH3I (0.281 g, 1.98 mmol) in dry acetone (20 mL) were
added, and the mixture was heated to reflux for 12 h. The solvent was removed under vacuum and the
residue purified by column chromatography over silica gel (20 g/g of crude, hexane/EtOAc, 90:10), to
give 5a (0.176 g, 83%) as a white solid. Rf 0.60 (hexane/EtOAc, 7:3); mp 49–50 °C. IR (KBr): νmax
3367, 1598, 1493, 1462, 1256, 1157, 1032, 950, 832, 774 cm−1. 1H-NMR (500 MHz, CDCl3): δ = 2.30
(s, 3H, CH3), 3.75 (s, 3H, CH3O), 6.00 (br s, 1H, NH), 6.42 (ddd, J = 8.5, 2.5, 0.5 Hz, 1H, H-4),
6.55-6.59 (m, 2H, H-2, H-6), 6.98–7.02 (m, 2H, H-2′), 7.06-7.10 (m, 2H, H-3′), 7.12 (tm, J = 8.5 Hz,
1H, H-5). 13C-NMR (125 MHz, CDCl3): δ = 20.7 (CH3), 55.1 (CH3O), 102.4 (C-2), 105.5 (C-4), 109.4
(C-6), 119.4 (C-2′), 129.8 (C-3′), 130.0 (C-5), 131.2 (C-4′), 140.0 (C-1′), 145.4 (C-1), 160.7
(C-3). MS (70 eV): m/z (%) 213 (M+, 100), 200 (23), 189 (24), 174 (21), 160 (39), 130 (11), 91 (12),
84 (9). HRMS (EI): m/z [M+] calcd for C14H15NO: 213.1154; found: 213.1153.
3-Methoxy-N-(4-methoxyphenyl)aniline (5b) [29]. Following the procedure described for 5a using 4b
(0.200 g, 0.92 mmol), Pd/C (10%) (0.055 g, 0.052 mmol), K2CO3 (0.190 g, 1.38 mmol) and MeI
(0.261 g, 1.84 mmol), 5b (0.179 g, 85%) was obtained as a white solid. Rf 0.55 (hexane/EtOAc, 7:3); mp
1
99–100 °C. IR (KBr): νmax 3400, 1597, 1509, 1460, 1239, 1157, 1035, 825, 768 cm−1. H-NMR
(300 MHz, CDCl3): δ = 3.75 (s, 3H, CH3O), 3.79 (s, 3H, CH3O), 6.51 (br s, 1H, NH), 6.38 (br dd,

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J = 7.8, 2.1 Hz, 1H, H-4), 6.44–6.51 (m, 2H, H-2, H-6), 6.83–6.89 (m, 2H, H-3′), 7.04–7.10 (m, 2H,
H-2′), 7.11 (t, J = 7.8 Hz, 1H, H-5). 13C-NMR (75.4 MHz, CDCl3): δ = 55.1 (CH3O-C3), 55.5
(CH3O-C4′), 101.1 (C-2), 104.6 (C-4), 108.2 (C-6), 114.6 (C-3′), 122.7 (C-2′), 130.0 (C-5), 135.3 (C-1′),
146.6 (C-1), 155.4 (C-4′), 160.7 (C-3). MS (70 eV): m/z (%) 229 (M+, 90), 216 (47), 214 (100), 186 (19),
171 (21), 142 (15), 115 (21). HRMS (EI): m/z [M+] calcd for C14H15NO2: 229.1103; found: 229.1111.
3-Methoxy-N-(m-tolyl)aniline (5c). Following the procedure described for 5a, with 4c (0.20 g,
1.0 mmol), Pd/C (10%) (0.060 g, 0.057 mmol), K2CO3 (0.200 g, 1.45 mmol) and MeI (0.281 g,
1.98 mmol), 5c (0.18 g, 87%) was obtained as a yellow oil. Rf 0.59 (hexane/EtOAc, 7:3). IR (film):
ν
max 3391, 1589, 1490, 1266, 1203, 1155, 1042, 765, 687 cm−1. 1H-NMR (300 MHz, CDCl3): δ = 2.31
(s, 3H, CH3), 3.77 (s, 3H, CH3O), 5.67 (br s, 1H, NH), 6.47 (br dd, J = 7.8, 2.4 Hz, 1H, H-4), 6.62-6.67
(m, 2H, H-2, H-6), 6.76 (br d, J = 7.2 Hz, 1H, H-4′), 6.88–6.94 (m, 2H, H-2′, H-6′), 7.12–7.20 (m, 2H,
13
H-5, H-5′). C-NMR (75.4 MHz, CDCl3): δ = 21.5 (CH3), 55.2 (CH3O), 103.2 (C-2), 105.9 (C-4),
110.2 (C-6), 115.4 (C-6′), 119.0 (C-2′), 122.1 (C-4′), 129.1 (C-5′), 130.0 (C-5), 139.2 (C-3′), 142.7
(C-1′), 144.6 (C-1), 160.6 (C-3). MS (70 eV): m/z (%) 213 (M+, 100), 200 (32), 189 (35), 174 (26), 160 (44),
130 (13), 92 (11), 77 (11). HRMS (EI): m/z [M+] calcd for C14H15NO: 213.1154; found: 213.1161.
bis(3-Methoxyphenyl)amine (5d) [26]. Following the procedure described for 5a, with 4d (0.20 g,
0.92 mmol), Pd/C (10%) (0.055 g, 0.052 mmol), K2CO3 (0.190 g, 1.38 mmol) and MeI (0.261 g,
1.84 mmol), 5d (0.171 g, 81%) was obtained as a white solid. Rf 0.55 (hexane/EtOAc, 7:3); mp
154–155 °C. IR (film): νmax 3393, 1592, 1490, 1270, 1207, 1155, 1040, 832, 760, 685 cm−1. 1H-NMR
(300 MHz, CDCl3): δ = 3.74 (s, 6H, 2CH3O), 5.78 (br s, 1H, NH), 6.47 (ddm, J = 8.1, 2.4 Hz, 2H, H-4,
13
H-4′), 6.61–6.68 (m, 4H, H-2, H-2′, H-6, H-6′), 7.14 (t, J = 8.1 Hz, 2H, H-5, H-5′). C-NMR (75.4
MHz, CDCl3): δ = 55.1 (2CH3O), 103.6 (C-2, C-2′), 106.3 (C-4, C-4′), 110.4 (C-6, C-6′), 130.0 (C-5,
C-5′), 144.1 (C-1, C-1′), 160.5 (C-3, C-3′). MS (70 eV): m/z (%) 229 (M+, 100), 217 (10), 200 (12),
189 (6), 170 (11), 160 (9), 154 (12), 142 (9), 115 (5). HRMS (EI): m/z [M+] calcd for C14H15NO2:
229.1103; found: 229.1104.
3,5-Dimethoxy-N-(3-methoxyphenyl)aniline (5e). Following the procedure described for 5a, with 4e
(0.200 g, 0.818 mmol), Pd/C (10%) (0.050 g, 0.047 mmol), K2CO3 (0.167 g, 1.21 mmol) and MeI
(0.230 g, 1.62 mmol), 5e (0.18 g, 86%) was obtained as a colorless oil. Rf 0.52 (hexane/EtOAc, 7:3).
IR (film): νmax 3735, 1590, 1541, 1457, 1203, 1150, 1057 cm−1. 1H-NMR (500 MHz, CDCl3): δ = 3.74
(s, 6H, 2CH3O), 3.76 (s, 3H, CH3O-3), 5.73 (br s, 1H, NH), 6.07 (t, J = 2.0 Hz, 1H, H-4), 6.24 (d,
J = 2.0 Hz, 2H, H-2, H-6), 6.49 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H, H-4′), 6.65 (t, J = 2.0 Hz, 1H, H-2′),
6.67 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H, H-6′), 7.15 (t, J = 8.0 Hz, 1H, H-5′). 13C-NMR (125 MHz, CDCl3):
δ = 55.1 (CH3O-3′), 55.2 (2CH3O), 93.3 (C-4), 96.2 (C-2, C-6), 104.2 (C-2′), 106.7 (C-4′), 111.0
(C-6′), 130.0 (C-5′), 144.0 (C-1), 144.9 (C-1′), 160.6 (C-3′), 161.6 (C-3, C-5). MS (70 eV): m/z (%)
259 (M+, 7), 257 (97), 242 (100), 214 (49), 199 (42), 184 (13), 156 (8), 128 (7). HRMS (EI): m/z [M+]
calcd for C15H17NO3: 259.1208; found: 259.1209.
2-Methoxy-6-methyl-9H-carbazole (1h). A mixture of 5a (0.100 g, 0.47 mmol), Pd(AcO)2 (0.0105 g,
0.047 mmol) and Cu(AcO)2 (0.211 g, 1.17 mmol) in dry DMF (0.5 mL), under N2 atmosphere, was
stirred and heated at 130 °C for 70 min under MW irradiation (100 W). The solvent was removed

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under vacuum by adding toluene, and the azeotropic distillation was continued until no solvent
remained. The residue was purified by column chromatography over silica gel (10 g/g of crude,
hexane/EtOAc, 95:5), to give 1h (0.079 g, 80%) as a white solid. Rf 0.60 (hexane/EtOAc, 7:3); mp
1
226–227 °C [Lit. [32] 227–228 °C]. IR (film): νmax 3392, 1659, 1026, 826, 764, 687 cm−1. H-NMR
(500 MHz, DMSO-d6/acetone-d6, 3:7): δ = 2.46 (s, 3H, CH3), 3.86 (s, 3H, CH3O), 6.76 (dd, J = 8.4,
2.4 Hz, 1H, H-3), 6.99 (d, J = 2.4 Hz, 1H, H-1), 7.11 (dd, J = 8.2, 1.5 Hz, 1H, H-7), 7.33 (d,
J = 8.2 Hz, 1H, H-8), 7.78 (br s, 1H, H-5), 7.91 (d, J = 8.4 Hz, 1H, H-4), 10.6 (br s, 1H, NH).
13C-NMR (125 MHz, DMSO-d6/acetone-d6, 3:7): δ = 21.2 (CH3), 55.4 (CH3O), 95.0 (C-1), 108.1
(C-3), 110.8 (C-8), 117.2 (C-4a), 119.6 (C-5), 121.1 (C-4), 124.0 (C-4a), 125.9 (C-7), 128.0 (C-6),
139.0 (C-8a), 142.4 (C-9a), 159.5 (C-2). MS (70 eV): m/z (%) 211 (M+, 100), 196 (51), 168 (76), 139
(10), 86 (6). HRMS (EI): m/z [M+] calcd for C14H13NO: 211.0997; found: 211.0994.
2,6-Dimethoxy-9H-carbazole (1i). Following the procedure described for 1h, with 5b (0.100 g, 0.44
mmol), Pd(AcO)2 (0.0099 g, 0.044 mmol) and Cu(AcO)2 (0.198 g, 1.1 mmol), 1i (0.086 g, 87%) was
obtained as a white solid. Rf 0.55 (hexane/EtOAc, 7:3); mp 162–163 °C [Lit. [29] 163–164 °C]. IR
1
(KBr): νmax 3398, 1626, 1491, 1465, 1284, 1221, 1202, 1162, 1029, 820 cm−1. H-NMR (300 MHz,
CDCl3): δ = 3.85 (s, 3H, CH3O), 3.86 (s, 3H, CH3O), 6.75 (dd, J = 8.4, 2.4 Hz, 1H, H-3), 6.92 (dd,
J = 8.7, 2.5 Hz, 1H, H-7), 6.95 (d, J = 2.4 Hz, 1H, H-1), 7.31 (d, J = 8.7 Hz, 1H, H-8), 7.51 (d,
J = 2.5 Hz, 1H, H-5), 7.89 (d, J = 8.4 Hz, 1H, H-4), 9.90 (br s, 1H, NH). 13C-NMR (75.4 MHz,
CDCl3): δ = 53.9 (CH3O), 54.3 (CH3O), 93.3 (C-1), 101.2 (C-5), 106.6 (C-3), 110.0 (C-8), 112.0
(C-7), 115.9 (C-4a), 119.7 (C-4), 122.7 (C-4b), 133.8 (C-8a), 141.1 (C-9a), 152.8 (C-6), 158.0 (C-2).
MS (70 eV): m/z (%) 227 (M+, 100), 212 (86), 184 (69), 169 (28), 141 (19), 114 (7). HRMS (EI): m/z
[M+] calcd for C14H13NO2: 227.0946; found: 227.0951.
2-Methoxy-7-methyl-9H-carbazole (1j). Following the procedure described for 1h, with 5c (0.100 g,
0.47 mmol), Pd(AcO)2 (0.0105 g, 0.047 mmol) and Cu(AcO)2 (0.211 g, 1.17 mmol), 1j (0.081 g, 82%)
was obtained as a white solid. Rf 0.61 (hexane/EtOAc, 7:3); mp 162–163 °C [Lit. [68] 280 °C]. IR
1
(film): νmax 3399, 1654, 1047, 1025, 995, 827, 766 cm−1. H-NMR (500 MHz, DMSO-d6/acetone-d6,
3:7): δ = 2.46 (s, 3H, CH3), 3.85 (s, 3H, CH3O), 6.75 (dd, J = 8.5, 2.5 Hz, 1H, H-3), 6.95 (dd, J = 8.3,
1.0 Hz, 1H, H-6), 6.99 (d, J = 2.5 Hz, 1H, H-1), 7.25 (br s, 1H, H-8), 7.84 (d, J = 8.3 Hz, 1H, H-5),
13
7.88 (d, J = 8.5 Hz, 1H, H-4), 10.7 (br s, 1H, NH). C-NMR (125 MHz, DMSO-d6/acetone-d6, 3:7):
δ = 21.4 (CH3), 54.9 (CH3O), 94.2 (C-1), 106.9 (C-3), 110.3 (C-8), 116.1 (C-4a), 118.4 (C-5), 119.6
(C-6), 119.9 (C-4), 120.2 (C-4b), 133.1 (C-7), 140.0 (C-8a), 140.8 (C-9a), 157.8 (C-2). MS (70 eV):
m/z (%) 211 (M+, 100), 196 (58), 168 (66), 139 (10), 86 (6). HRMS (EI): m/z [M+] calcd for
C14H13NO: 211.0997; found: 211.1000.
2,7-Dimethoxy-9H-carbazole (Clausine V, 1d). Following the procedure described for 1h, with 5d
(0.100 g, 0.44 mmol), Pd(AcO)2 (0.0099 g, 0.044 mmol) and Cu(AcO)2 (0.198 g, 1.10 mmol), 1d
(0.089 g, 90%) was obtained as a white solid. Rf 0.56 (hexane/EtOAc, 7:3); mp 229–230 °C [Lit. [22]
228–230 °C]. IR (KBr): νmax 3382, 2927, 1608, 1575, 1502, 1457, 1322, 1265, 1233, 1160, 1118, 1026,
1
825, 805 cm−1. H-NMR (300 MHz, DMSO-d6/acetone-d6, 3:7): δ = 3.85 (s, 6H, 2CH3O), 6.75 (dd,
J = 8.4, 2.4 Hz, 2H, H-3, H-6), 6.99 (d, J = 2.4 Hz, 2H, H-1, H-8), 7.85 (d, J = 8.4 Hz, 2H, H-4, H-5),

Molecules 2013, 18
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10.81 (br s, 1H, NH). 13C-NMR (75.4 MHz, DMSO-d6/acetone-d6, 3:7): δ = 54.9 (2CH3O), 94.6 (C-1,
C8), 107.3 (C-3, C-6), 116.8 (C-4a, C-4b), 119.7 (C-4, C-5), 141.4 (C-8a, C-9a), 157.9 (C-2, C-7). MS
(70 eV): m/z (%) 227 (M+, 77), 212 (100), 184 (42), 169 (54), 153 (13), 141 (27), 114 (5). HRMS (EI):
m/z [M+] calcd for C14H13NO2: 227.0946; found: 227.0946.
2,4,7-Trimethoxy-9H-carbazole (1k). Following the procedure described for 1h, with 5e (0.101 g, 0.39
mmol), Pd(AcO)2 (0.0087 g, 0.039 mmol) and Cu(AcO)2 (0.175 g, 0.97 mmol), 1k (0.092 g, 92%) was
obtained as a white solid. Rf 0.20 (hexane/EtOAc, 7:3); mp 167–168 °C. IR (KBr): νmax 3383, 1617,
1580, 1510, 1453, 1428, 1260, 1213, 1149, 1119, 1032, 803 cm−1. 1H-NMR (500 MHz,
CDCl3/acetone-d6, 7:3): δ = 3.83 (s, 6H, 2CH3O), 3.98 (s, 3H, CH3O), 6.27 (d, J = 1.3 Hz, 1H, H-3),
6.46 (d, J = 1.3 Hz, 1H, H-1), 6.76 (dd, J = 8.5, 2.2 Hz, 1H, H-6), 6.82 (d, J = 2.2 Hz, 1H, H-8), 7.99
(d, J = 8.5 Hz, 1H, H-5), 9.32 (br s, 1H, NH). 13C-NMR (125 MHz, CDCl3/acetone-d6, 7:3): δ = 54.7
(CH3O), 54.9 (CH3O), 55.0 (CH3O), 86.7 (C-1), 90.2 (C-3), 94.0 (C-8), 106.0 (C-4a), 107.0 (C-6),
116.1 (C-4b), 121.7 (C-5), 139.7 (C-8a), 141.3 (C-9a), 155.2 (C-4), 156.8 (C-7), 158.7 (C-2). MS
(70 eV): m/z (%) 257 (M+, 39), 247 (36), 230 (100), 219 (24), 214 (22), 190 (82), 176 (21), 160 (19),
117 (7). HRMS (EI): m/z [M+] calcd for C15H15NO3: 257.1052; found: 257.1052.
7-Methoxy-9H-carbazole-3-carbaldehyde (Clauszoline-K) (1f). A mixture of 1h (0.030 g, 0.14 mmol)
and DDQ (0.129 g, 0.57 mmol) in acetone/MeOH/H2O (1:1:1) (10 mL) was stirred at 25 °C for 45 min.
The solvent was removed under vacuum and the residue purified by column chromatography over
silica gel (10 g/g of crude, hexane/EtOAc, 8:2), to give 1f (0.022 g, 70%) as a white solid. Rf 0.25
(hexane/EtOAc, 8:2); mp 184–185 °C [Lit. [32] 183–186 °C]. IR (KBr): νmax 3296, 1670, 1604, 1570,
1479, 1322, 1237, 1160, 1026, 821 cm−1. 1H-NMR (500 MHz, DMSO-d6/CDCl3, 3:7): δ = 3.88 (s, 3H,
CH3O), 6.84 (dd, J = 8.5, 2.0 Hz, 1H, H-6), 7.00 (d, J = 2.0 Hz, 1H, H-8), 7.51 (d, J = 8.0, 1H, H-1),
7.83 (dd, J = 8.0, 1.0 Hz, 1H, H-2), 7.96 (d, J = 8.5 Hz, 1H, H-5), 8.45 (s, 1H, H-4), 10.05 (s, 1H,
CHO), 11.40 (br s, 1H, NH). 13C-NMR (125 MHz, DMSO-d6/CDCl3, 3:7): δ = 54.0 (CH3O), 93.8
(C-8), 107.6 (C-6), 109.5 (C-1), 115.0 (C-4b), 119.7 (C-5), 121.3 (C-4), 121.8 (C-4a), 124.1 (C-2),
126.9 (C-3), 140.8 (C-8a), 142.6 (C-9a), 158.0 (C-7), 190.2 (CHO). MS (70 eV): m/z (%) 225 (M+,
40), 210 (28), 180 (72), 167 (97), 160 (44), 146 (30), 130 (32), 115 (28), 77 (29), 51 (100). HRMS
(EI): m/z [M+] calcd for C14H11NO2: 225.0790; found: 225.0796.
Methyl 7-methoxy-9H-carbazole-3-carboxylate (Clauszoline-L, Clausine C) (1g). A mixture of 1f
(0.200 g, 0.89 mmol), MnO2 (0.20 g, 2.3 mmol), and KCN (0.028 g, 0.43 mmol) in MeOH (10 mL)
was stirred at 25 °C for 24 h. The solvent was removed under vacuum and the residue purified by
column chromatography over silica gel (10 g/g of crude, hexane/EtOAc, 8:2), to give 1g (0.22 g, 97%)
as a white solid. Rf 0.29 (hexane/EtOAc, 8:2); mp 194–195 °C [Lit. [20] 195–197 °C; [32] 195 °C; [33]
194–195 °C]. IR (KBr): νmax 3288, 1698, 1605, 1439, 1327, 1259, 1195, 1159, 1094, 815, 728 cm−1.
1H-NMR (500 MHz, acetone-d6): δ = 3.88 (s, 3H, CH3O), 3.91 (s, 3H, CH3O), 6.88 (dd, J = 8.5, 2.0
Hz, 1H, H-6), 7.08 (d, J = 2.0 Hz, 1H, H-8), 7.51 (d, J = 8.5, 1H, H-1), 7.99 (dd, J = 8.5, 1.5 Hz, 1H,
13
H-2), 8.09 (d, J = 8.5 Hz, 1H, H-5), 8.69 (d, J = 1.5 Hz, 1H, H-4), 10.80 (br s, 1H, NH). C-NMR
(125 MHz, acetone-d6): δ = 51.8 (CH3O), 55.7 (CH3O), 95.7 (C-8), 109.6 (C-6), 110.9 (C-1), 117.4
(C-4b), 121.6 (C-5), 121.9 (C-4a), 122.1 (C-4), 123.9 (C-3), 126.4 (C-2), 143.0 (C-8a), 144.0 (C-9a),

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160.5 (C-2), 167.9 (CO2Me). MS (70 eV): m/z (%) 255 (M+, 100), 240 (22), 224 (44), 212 (61), 196
(38), 181 (33), 153 (67), 126 (15), 84 (20), 51 (21). HRMS (EI): m/z [M+] calcd for C15H13NO3:
255.0895; found: 255.0900.
6-Methyl-2,3-dihydro-1H-carbazol-4(9H)-one (7a). In a threaded ACE glass pressure tube with a
sealed Teflon screw cap, under N2 atmosphere, a mixture of 4a (0.10 g, 0.5 mmol) and Pd(AcO)2
(0.034 g, 0.15 mmol) in dry MeCN (2.5 mL) was stirred at 80 °C for 24 h. The solvent was removed
under vacuum and the residue purified by column chromatography over silica gel (20 g/g of crude,
hexane/EtOAc, 80:20), to give 7a (0.077 g, 78%) as a white solid. Rf 0.15 (hexane/EtOAc, 1:1); mp
281–282 °C [Lit. [69] 280–282 °C]. IR (film): νmax 3154, 2934, 1615, 1469, 1406, 1375, 1213, 1183,
1122, 1070, 1016, 797 cm−1. 1H-NMR (300 MHz, DMSO-d6): δ = 2.09 (qu, J = 6.3 Hz, 2H, H-2), 2.38
(s, 3H, CH3), 2.41 (t, J = 6.3 Hz, 2H, H-3), 2.93 (t, J = 6.3 Hz, 2H, H-1), 6.97 (br d, J = 8.1 Hz, 1H,
H-7), 7.27 (d, J = 8.1 Hz, 1H, H-8), 7.77 (br s, 1H, H-5), 11.75 (br s, 1H, NH) 13C-NMR (75.4 MHz,
DMSO-d6): δ = 21.2 (CH3), 22.7 (C-1), 23.4 (C-2), 37.8 (C-3), 111.1 (C-8), 111.4 (C-4a), 120.1 (C-5),
123.7 (C-7), 124.7 (C-4b), 130.2 (C-6), 134.1 (C-8a), 152.2 (C-9a), 192.8 (C-4). MS (70 eV): m/z (%)
199 (M+, 100), 198 (45), 183 (13), 170 (11), 154 (20), 128 (8), 91 (40).
6-Methoxy-2,3-dihydro-1H-carbazol-4(9H)-one (7b). Following the procedure described for 7a, with
4b (0.100 g, 0.46 mmol) and Pd(AcO)2 (0.0309 g, 0.138 mmol), 7b (0.08 g, 80%) was obtained as a
white solid. Rf 0.13 (hexane/EtOAc, 1:1); mp 252–253 °C [Lit. [70] 250–254 °C]. IR (KBr): νmax 3416,
1
1578, 1482, 1459, 1259, 1217, 1175, 1031, 796, 780 cm−1. H-NMR (300 MHz, DMSO-d6): δ = 2.09
(qu, J = 6.3 Hz, 2H, H-2), 2.41 (t, J = 6.3 Hz, 2H, H-3), 2.92 (t, J = 6.3 Hz, 2H, H-1), 3.76 (s, 3H,
CH3O), 6.77 (dd, J = 8.7, 2.7 Hz, 1H, H-7), 7.28 (d, J = 8.7 Hz, 1H, H-8), 7.45 (d, J = 2.7 Hz, 1H, H-5),
11.74 (br s, 1H, NH) 13C-NMR (75.4 MHz, DMSO-d6): δ = 22.8 (C-1), 23.4 (C-2), 37.7 (C-3), 55.2 (CH3O),
102.4 (C-5), 111.6 (C-7), 111.7 (C-4a), 112.2 (C-8), 125.2 (C-4b), 130.5 (C-8a), 152.3 (C-9a), 155.1
(C-6), 192.8 (C-4). MS (70 eV): m/z (%) 215 (M+, 2), 155 (37), 153 (100), 127 (12), 125 (35), 90 (23).
6-Methyl-9H-carbazol-4-ol (8). In a threaded ACE glass pressure tube with a sealed Teflon screw cap,
under N2 atmosphere, a mixture of 7a (0.20 g, 1.0 mmol) and Pd/C (10%) (0.060 g, 0.057 mmol) in
dry MeOH (2.5 mL) was stirred at 270 °C for 48 h. The solvent was removed under vacuum and the
residue purified by column chromatography over silica gel (20 g/g of crude, hexane/EtOAc, 80:20), to
give 8 (0.168 g, 85%) as a white solid. Rf 0.30 (hexane/EtOAc, 7:3); mp 125–126 °C. IR (film): νmax
1
3404, 1615, 1589, 1455, 1341, 1297, 1267, 1047, 803, 752, 724 cm−1. H-NMR (500 MHz, CDCl3):
δ = 2.52 (s, 3H, CH3), 5.38 (br s, 1H, OH), 6.53 (d, J = 8.5 Hz, 1H, H-3), 6.95 (d, J = 8.5 Hz, 1H, H-1),
7.17–7.22 (m, 2H, H-2, H-7), 7.26 (t, J = 8.5 Hz, 1H, H-8), 7.89 (br s, 1H, NH), 8.06 (br s, 1H, H-5).
13C-NMR (125 MHz, CDCl3): δ = 21.4 (CH3), 103.3 (C-1), 104.9 (C-3), 109.7 (C-8), 111.6 (C-4a),
122.5 (C-4b), 122.7 (C-5), 126.3 (C-2 or C-7), 126.4 (C-7 or C-2), 129.0 (C-6), 137.0 (C-8a), 141.7
(C-9a), 151.8 (C-4). HRMS (EI): m/z [M+] calcd for C13H11NO: 197.0841; found: 197.0844.
5-Methoxy-3-methyl-9H-carbazole (Glycoborine, Glycrophylamine, 9). A mixture of 8 (0.150 g,
0.76 mmol), MeI (0.216 g, 1.52 mmol) and K2CO3 (0.157 g, 1.14 mmol) in dry acetone (10 mL) was
heated to reflux for 2 h. The solvent was removed under vacuum and the residue purified by column
chromatography over silica gel (10 g/g of crude, hexane/EtOAc, 95:5), to give 9 (0.151 g, 94%) as a

Molecules 2013, 18
10347
white solid. Rf 0.35 (hexane/EtOAc, 8:2); mp 133–134 °C [Lit. [33] 154–156 °C; [60] 132–134.6 °C; [61]
155–156 °C; [62] 135 °C]. IR (KBr): νmax 3402, 1586, 1508, 1458, 1346, 1261, 1103, 804, 719 cm−1.
1H-NMR (500 MHz, CDCl3): δ = 2.52 (s, 3H, CH3), 4.06 (s, 3H, CH3O), 6.64 (d, J = 8.0 Hz, 1H, H-6),
6.97 (d, J = 8.0 Hz, 1H, H-8), 7.18 (dd, J = 8.0, 1.2 Hz, 1H, H-2), 7.24 (d, J = 8.0 Hz, 1H, H-1), 7.29
(t, J = 8.0 Hz, 1H, H-7), 8.00 (br s, 1H, NH), 8.11 (br s, 1H, H-4). 13C-NMR (125 MHz, CDCl3):
δ = 21.4 (CH3), 55.3 (CH3O), 100.1 (C-6), 103.5 (C-8), 109.5 (C-1), 112.4 (C-4b), 122.8 (C-4a), 122.9
(C-4), 126.1 (C-2), 126.4 (C-7), 128.8 (C-3), 136.9 (C-9a), 141.2 (C-8a), 156.2 (C-5). HRMS (EI): m/z
[M+] calcd for C14H13NO: 211.0997; found: 211.0995.
4. Conclusions
In this work, a short and efficient synthetic route for the construction of 2-, 5-, and 7-oxygenated
carbazole alkaloids including natural clausine V (1d) is described. As the key steps, this approach
includes a palladium(0)-catalyzed aromatization and a palladium(II)-catalyzed cyclization to provide
the 2- and 7-oxygenated tricyclic carbazole framework. In the case of the natural 5-oxygenated
carbazole glycoborine (glycrophylamine, 9), the palladium-catalyzed sequence was inverted, with
cyclization performed before aromatization. The preparation of natural carbazoles clauszoline-K (1f)
and clauszoline-L (1g) was also carried out by transformation of carbazole 1h. This methodology is
currently being applied to the synthesis of diverse carbazoles, and the results will be reported in due course.
Acknowledgments
We thank Professors Francisco Delgado and Gerardo Zepeda for their help in spectrometric
analyses, and Bruce A. Larsen for reviewing the use of English in the manuscript. J.T. acknowledges
SIP/IPN (Grants 20110172, 20120830, and 20130686) and CONACYT (Grants 83446 and 178319) for
financial support. R.B., P.A.M., and A.R. thank CONACYT for awarding them graduate scholarships,
and SIP/IPN (PIFI) for scholarship complements. J.T. and E.B. are fellows of the EDI-IPN and
COFAA-IPN programs.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 4a–e, 5a, 5d, 5e, 1d, 1f–g, 1h–i, and 1k are available
from the authors.
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