exo-2-oxazolidinone dienes in the total synthesis of the natural carbazoles, 6-methoxymurrayanine and clausenine

Article abstract of DOI:10.1055/s-2007-983741

A new application of exo-2-oxazolidinone dienes in the regioselective synthesis of natural carbazoles, 6-methoxymurrayanine (6) and clausenine (7), is described. The regioselective cycloaddition of novel diene 10 to acrolein by Lewis acid catalysis provid

Full text of DOI:10.1055/s-2007-983741

PAPER
1943
exo-2-Oxazolidinone Dienes in the Total Synthesis of the Natural Carbazoles,
6-Methoxymurrayanine and Clausenine
S
ynthesis of th
a
e
N
atural
C
b
arbazoles lo Bernal, Adriana Benavides, Rafael Bautista, Joaquín Tamariz*
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Prol.,
Carpio y Plan de Ayala, 11340 México, D. F. México
Fax +52(5)557296300/46211; E-mail: jtamariz@woodward.encb.ipn.mx
Received 21 February 2007
Another example of the biogenetic relationship between
Abstract: A new application of exo-2-oxazolidinone dienes in the
regioselective synthesis of natural carbazoles, 6-methoxymurraya-
nine (6) and clausenine (7), is described. The regioselective cy-
cloaddition of novel diene 10 to acrolein by Lewis acid catalysis
carbazoles could be found in the case of 6-methoxymur-
rayanine (6)10 and clausenine (7),1h in which the latter is
probably the natural precursor of 6. Interestingly, these
provided adduct 12, which after aromatization gave benzoxazolone carbazoles and the extracts from their natural sources dis-
play antifungal and antibacterial activities,1h,11 and, to the
best of our knowledge, the synthesis of 6 has not been pre-
14 as the key intermediate for the preparation of both carbazoles. A
straightforward and efficient synthesis of 7 was carried out by a pro-
cedure with no isolation of intermediates, starting from 14 and went
viously reported. With the aim of evaluating the versatili-
through a sequence of hydrogenation–hydrolysis–methylation and
Pd-cyclization to give the desired carbazole 7 in high overall yield.
ty of our methodology in the synthesis of C-ring
substituted carbazoles, we herein disclose the synthetic
Key words: carbazoles, 4,5-dimethylene-2-oxazolidinone dienes,
study for the preparation of natural carbazoles 6 and 712
6-methoxymurrayanine, clausenine, Diels–Alder reaction, decarbo-
nylation
(Figure 1).
MeO
R
6
3
Naturally occurring 1-oxygenated carbazoles have attract-
ed great interest due to their diverse and significant bio-
logical activity.1 These alkaloids are mainly extracted
from species of the genera Murraya and Clausena, and in
the case of 2- and 3-substituted families, their biogenesis
has been established.1c,d,2 For instance, murrayanine (1)1c,3
and mukonine (2)1g,2a arise from the in vivo oxidation of
murrayafoline A (3).1c,2b,4 Moreover, from the synthetic
viewpoint, the carbazole framework has been an attractive
target in the development of novel and efficient strategies
for the total synthesis of natural and unnatural carba-
zoles.1a,3a,5,6 We have described a general synthetic ap-
proach for the preparation of the carbazole scaffold,7 and
it has been applied in the total synthesis of carbazoles 1–
3.8 This strategy was based on the regioselective Diels–
Alder cycloaddition of the exo-2-oxazolidinone dienes 4,9
whose adducts 5 were transformed into the natural carba-
zoles in a short and efficient methodology (Scheme 1).
1
N
H
OMe
6, R = CHO
7, R = Me
Figure 1
Taking into account that carbazoles 6 and 7 have a meth-
oxy group at the C-6 position of their frame, the design of
the synthetic route included the preparation of diene 10,
which bears the desired substituent. The latter was ob-
tained as a white solid in moderate yield by reacting bu-
tane-2,3-dione (8) and 4-methoxyphenyl isocyanate (9),
according to the procedure previously described
(Scheme 2).9 In a similar strategy to that used for the prep-
aration of compounds 1 and 3 (Scheme 1),8b the A-ring of
carbazoles 6 and 7 was built through a regioselective
Diels–Alder addition of diene 10 to acrolein (11) under
Lewis acid catalysis (BF3·OEt2, –78 °C) at low tempera-
ture, which, after only 15 minutes of stirring, proceeded
until the complete disappearance of starting materials, to
give a mixture of isomeric adducts para/meta derivatives
12/13 in a high ratio (98:2). The desired product 12 was
obtained in high yield (93%) after purification by column
chromatography (Scheme 2). Highly regioselective
Diels–Alder cycloadditions of analogous exo-2-oxazolid-
inone dienes with electron-deficient dienophiles have also
been carried out under hydrophobic conditions.13 There-
fore, this reaction was conducted under a similar method-
ology (MeOH–H2O, 9:1) at room temperature for 18
hours. However, the regioselectivity was lower, since the
mixture 12/13 was obtained as an 85:15 ratio.
Z
Z
O
N
O
N
O
O
N
H
OMe
Ph
Ph
4
1, Z = CHO
5
2, Z = CO2Me
3, Z = Me
Scheme 1
SYNTHESIS 2007, No. 13, pp 1943–1948
x
x.
x
x
.
2
0
0
7
Advanced online publication: 18.06.2007
DOI: 10.1055/s-2007-983741; Art ID: M01007SS
© Georg Thieme Verlag Stuttgart · New York

1944
P. Bernal et al.
PAPER
O
MeO
O
O
CHO
N
4
O
Et3N
+
Ar-NCO
+
5
dioxane
r.t., 24 h
40%
6
7
8
9, Ar = 4-MeOC6H4
10
11
BF3⋅OEt2
CH2Cl2
–78 °C
15 min
R
CHO
O
N
O
N
O
DDQ
+
O
O
O
C6H6, reflux
24 h
N
CHO
Ar
Ar
Ar
70%
98:2
14, R = CHO
15, R = Me
H2
12
13
Ar = 4-MeOC6H4
Scheme 2
The cyclohexene ring was aromatized by treating 12 with tion, to give carbazole 17 in 74% overall yield. Although
DDQ in benzene at reflux to furnish 2-(3H)-benzoxazo- Pd-promoted decarbonylation of aromatic aldehydes has
lone 14 in good yield. The latter might be the key interme- already been described,3a,15 under our conditions this pro-
diate for the preparation of both carbazoles 6 and 7, since cess is hitherto unknown.
the C-3 methyl group required in the structure of 7 could
In the case of 2-(3H)-benzoxazolone 15, the hydrolysis
be obtained by reduction of the formyl group of 14. There-
step was slower than that for 14, reacting only after five
fore, 2-(3H)-benzoxazolone 15 was prepared in an almost
hours with heating to 60 °C under the basic treatment to
give anilinophenol 18a (Scheme 4). It is likely that the
quantitative yield by the hydrogenation of 14 (Scheme 2).
Upon saponification of 14 under mild basic conditions electron-withdrawing effect of the formyl group enhances
(NaOH, EtOH–H2O, 25 °C, 1 h) diarylamine 16a was ob- the delocalization of the lone-pair of the nitrogen atom to-
tained in 85% yield (Scheme 3). The phenol group was wards the aromatic ring, increasing the reactivity of the
methylated by using methyl iodide in acetone and potassi- nucleophilic addition onto the carbonyl group of the car-
um carbonate as the base to give 16b in high yield. Final- bamate. Owing to the decomposition of compound 18a at
ly, efficient conversion of the latter into the desired room temperature, it was not possible for it to be fully
carbazole 6 was carried out by a Pd(II)-mediated cycliza- characterized. Thereby, once it was purified, compound
tion in good yield.6f,14 Spectroscopic data and melting 18a was O-methylated with MeI and K2CO3 to furnish de-
point of 6 were in agreement with those reported for the rivative 18b in high yield (94%, Scheme 4). Clausenine
natural product.10 It is worth noting that the efficacy of the (7) was prepared in 72% yield via the usual treatment with
last step depended on the reaction temperature. The trans- palladium acetate in acetic acid.
formation did not proceed at <80 °C, and was very slow at
80 °C (4 days). However, it turned out well (80%) when
With the aim of improving the synthesis of clausenine (7),
we investigated a straightforward and shorter methodolo-
the temperature is ranged between 90–110 °C. Unexpect-
gy, through a four-step procedure with no purification of
edly, when the temperature rises to 140–170 °C, not only
intermediates, starting from the key compound 14. Thus,
palladium-catalyzed hydrogenation of a mixture of 14 in
does the cyclization take place but also the decarbonyla-
CHO
MeO
CHO
O
N
Me
MeO
Me
i, ii
O
N
O
i, ii
O
N
H
N
H
Ar
OR
Ar
OR
14
16a, R = H
16b, R = Me
15
18a, R = H
18b, R = Me
MeO
R
MeO
Me
Pd(OAc)2
AcOH
Pd(OAc)2
AcOH
N
H
90–170 °C, 10–36 h
OMe
140 °C, 10 h
72%
N
H
OMe
6, R = CHO
17, R = H
7
Scheme 3 Reagents and conditions: i) NaOH, EtOH–H2O (2:1), r.t.,
6 h, 85%; ii) MeI, K2CO3, acetone, reflux, 3 h, 91%.
Scheme 4 Reagents and conditions: i) NaOH, EtOH–H2O (5:2),
60 °C, 5 h, 83%; ii) MeI, K2CO3, acetone, reflux, 3 h, 94%.
Synthesis 2007, No. 13, 1943–1948 © Thieme Stuttgart · New York

PAPER
Synthesis of Natural Carbazoles
1945
cyanate (9; 5.30 g, 35.53 mmol) in dioxane (10 mL) was added over
a period of 30 min and stirring was continued for 24 h at r.t. The
mixture was filtered on Celite, the residue washed with CH2Cl2
(3 × 15 mL), and the solvent removed under vacuum. The residue
was purified by column chromatography over silica gel conditioned
with Et3N (10%) in hexane (30 g/g of crude) (hexane–EtOAc, 95:5),
to give 2.06 g (40%) of 10 as a white solid; Rf = 0.60 (hexane–
EtOAc, 4:1); mp 97–98 °C (hexane–EtOAc, 9:1).
the presence of KOH at room temperature for 12 hours,
followed by heating to reflux for 12 hours, yielded the
crude reaction mixture of phenol 18a. Then, successive
treatment of the latter with MeI and palladium acetate pro-
vided 7 in 75% overall yield (Scheme 5).
MeO
Me
CHO
O
IR (CH2Cl2): 1777, 1634, 1518, 1405, 1292, 1256, 1214, 1160,
1109, 988, 881, 832 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.75 (s, 3 H, CH3O), 4.20 (d,
J = 3.0 Hz, 1 H, H-6), 4.65 (d, J = 3.0 Hz, 1 H, H-6), 4.83 (d, J = 3.4
Hz, 1 H, H-7), 4.88 (d, J = 3.4 Hz, 1 H, H-7), 6.88–6.95 (m, 2 H,
ArH), 7.13–7.20 (m, 2 H, ArH).
13C NMR (75.4 MHz, CDCl3): d = 55.4 (CH3O), 84.4 (C-6), 86.8
(C-7), 114.9 (ArH), 125.3 (Ar), 128.2 (ArH), 139.2 (C-4), 148.8 (C-
5), 152.6 (C-2), 159.6 (Ar).
a
O
N
75%
N
H
OMe
Ar
14
7
Scheme 5 Reagents and conditions: (a) (i) H2/Pd/C (30 psi), KOH,
EtOH& ndash;H2O (7:3), r.t., 12 h; then reflux, 12 h; (ii) MeI, K2CO3,
acetone, reflux, 12 h; (iii) Pd(OAc)2, AcOH, 120 °C, 18 h.
MS (70 eV): m/z (%) = 217 (M+, 20), 186 (22), 158 (10), 146 (18),
142 (10), 130 (11), 121 (100), 103 (30), 91 (6), 77 (8).
HRMS (FAB): m/z [M+] calcd for C12H11NO3: 217.0739; found:
217.0742.
A partial synthesis of 7 from 6 by reduction of the alde-
hyde group was also attempted. When the process was
carried out by palladium-catalyzed hydrogenation of the
latter, 7 was obtained in 93% yield.
In summary, exo-2-oxazolidinone dienes have proved to
be efficient synthons in the total synthesis of natural car-
bazoles substituted in both A and C rings. Thus, naturally
occurring 6-methoxymurrayanine (6) and clausenine (7)
were prepared starting from a highly regioselective Diels–
Alder addition of diene 10 onto acrolein (11) in 40% and
36% overall yield, respectively. The 2-(3H)-benzoxazo-
lone 14 was used as the key intermediate not only for the
preparation of 6 via a three-step methodology, but also for
obtaining benzoxazolone 15, which was transformed into
7 following a similar procedure. Moreover, the latter was
obtained in 75% overall yield from 14 in a four-step reac-
tion sequence with no isolation of intermediates. There-
fore, these results represent a new approach for the
synthesis of clausenine (7), and the first total synthesis of
natural carbazole 6-methoxymurrayanine (6).
6-Formyl-3-(4-methoxyphenyl)-2,3,4,5,6,7-hexahydrobenzox-
azol-2-one (12)
To a stirred solution of 10 (1.57 g, 7.23 mmol) in anhyd CH2Cl2 (40
mL) at –78 °C under N2, were added dropwise 11 (0.49 g, 8.74
mmol) and BF3·OEt2 (0.021 g, 0.15 mmol), and the mixture was
stirred for 15 min at the same temperature. The mixture was washed
with a 5% aq solution of NaHCO3 (3 × 15 mL), 5% aq solution of
NH4NO3 (2 × 15 mL), and H2O (15 mL). The combined organic
layers were dried (Na2SO4) and the solvent was removed under vac-
uum, giving a mixture of 12/13 (98:2). The residue was purified by
column chromatography over silica gel (60 g, hexane–EtOAc, 3:2)
to give 1.84 g (93%) of 12 as a colorless oil; Rf = 0.34 (hexane–
EtOAc, 7:3).
IR (CH2Cl2): 1753, 1709, 1611, 1513, 1445, 1400, 1300, 1248,
1166, 1114, 1028, 980, 833 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.86–2.02 (m, 1 H, H-5), 2.10–
2.22 (m, 1 H, H-5), 2.29–2.37 (m, 2 H, H-4), 2.68–2.81 (m, 2 H, H-
7), 2.81–2.88 (m, 1 H, H-6), 3.82 (s, 3 H, CH3O), 6.91–6.99 (m, 2
H, ArH), 7.19–7.23 (m, 2 H, ArH), 9.74 (s, 1 H, CHO).
Melting points (uncorrected) were determined with an Electrother-
mal capillary melting point apparatus. IR spectra were recorded on
13C NMR (75.4 MHz, CDCl3): d = 18.7 (C-4), 20.7 (C-7), 21.6 (C-
5), 45.5 (C-6), 55.5 (CH3O), 114.6 (ArH), 121.1 (C-3a), 126.3 (Ar),
126.7 (ArH), 132.8 (C-7a), 154.7 (C-2), 158.9 (Ar), 201.6 (CHO).
1
a PerkinElmer 1600 spectrophotometer. H and 13C NMR spectra
were recorded on a Varian Mercury (300 MHz) instrument, with
CDCl3 as the solvent and TMS as internal standard. Mass spectra
(MS) and high-resolution mass spectra (HRMS) were obtained, in
electron impact (EI) (70 eV) mode on Hewlett-Packard 5971A and
on Jeol JMS-AX 505 HA spectrometers, respectively. Analytical
TLC 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 N2 using oven-dried glassware. Dioxane,
benzene, and toluene were freshly distilled over sodium, and
CH2Cl2 and EtOAc over CaH2, prior to use. Acetone was dried by
distillation after treatment with 4Å molecular sieves. K2CO3 and
Li2CO3 were dried overnight at 120 °C prior to use. Et3N was fresh-
ly distilled from NaOH. All other reagents were used without fur-
ther purification.
MS (70 eV): m/z (%) = 273 (M+, 100), 245 (30), 217 (38), 188 (22),
173 (6), 160 (34), 147 (92), 133 (26), 121 (12), 92 (28), 77 (32).
HRMS (FAB): m/z [M+] calcd for C15H15NO4: 273.1001; found:
273.1000.
6-Formyl-3-(4-methoxyphenyl)-2,3-dihydrobenzoxazol-2-one
(14)
To a stirred solution of 12 (0.58 g, 2.12 mmol) in anhyd benzene (50
mL), at reflux under N2, was added dropwise a solution of DDQ
(1.06 g, 4.67 mmol) in anhyd benzene (40 mL) through a cannula,
and the mixture was stirred for 24 h at the same temperature. The
mixture was filtered on Celite, the solvent removed under vacuum,
and the residue purified by column chromatography over silica gel
(12 g, hexane–EtOAc, 9:1) to give 0.40 g (70%) of 14 as a white sol-
id; Rf = 0.31 (hexane–EtOAc, 7:3); mp 186–187 °C.
IR (CH2Cl2): 1762, 1709, 1696, 1612, 1518, 1455, 1382, 1360,
1305, 1284, 1259, 1160, 1034, 818 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.89 (s, 3 H, CH3O), 7.05–7.10
(m, 2 H, ArH), 7.12 (d, J = 8.1 Hz, 1 H, H-4), 7.40–7.48 (m, 2 H,
3-(4-Anisyl)-4,5-dimethylene-1,3-oxazolidin-2-one (10)
A mixture of 8 (2.04 g, 23.69 mmol) in anhyd dioxane (6 mL), Et3N
(4.79 g, 47.34 mmol) and Li2CO3 (2.5 g, 0.034 mol) was stirred at
r.t. under N2 for 30 min. Then, a solution of 4-methoxyphenyl iso-
Synthesis 2007, No. 13, 1943–1948 © Thieme Stuttgart · New York

1946
P. Bernal et al.
PAPER
ArH), 7.74 (dd, J = 8.1, 1.2 Hz, 1 H, H-5), 7.80 (d, J = 1.2 Hz, 1 H,
H-7), 9.97 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 55.6 (CH3O), 109.0 (C-4), 109.9
(C-7), 115.2 (ArH), 125.0 (Ar), 126.8 (ArH), 128.2 (C-5), 132.2 (C-
6), 136.9 (C-3a), 142.9 (C-7a), 153.3 (C-2), 159.9 (Ar), 190.3
(CHO).
MS (70 eV): m/z (%) = 269 (M+, 100), 254 (5), 224 (5), 210 (16),
182 (20), 154 (14), 92 (8), 77 (9).
HRMS (FAB): m/z [M+] calcd for C15H11NO4: 269.0688; found:
269.0691.
mixture was stirred and heated to 90 °C for 36 h in the dark. The
mixture was diluted with toluene (10 mL) and the solvent was re-
moved under vacuum. This procedure was repeated twice. The res-
idue was purified by column chromatography over silica gel (30 g/
g of crude, hexane–EtOAc, 9:1), to give 0.033 g (80%) of 6 as a
white solid; Rf = 0.69 (hexane–EtOAc, 7:3); mp 230–232 °C [Lit.10
mp 231–233 °C].
IR (CH2Cl2): 3150, 1657, 1609, 1582, 1496, 1442, 1328, 1260,
1221, 1142, 1031, 847, 709 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.95 (s, 3 H, CH3O), 4.07 (s, 3 H,
CH3O), 7.12 (dd, J = 8.7, 2.4 Hz, 1 H, H-7), 7.43 (d, J = 8.7 Hz, 1
H, H-8), 7.44 (br s, 1 H, H-2), 7.57 (d, J = 2.4 Hz, 1 H, H-5), 8.17
(s, 1 H, H-4), 8.51 (br s, 1 H, NH), 10.04 (s, 1 H, CHO).
13C NMR (75.4 MHz, CDCl3): d = 55.8 (CH3O), 56.0 (CH3O),
103.1 (C-5), 103.2 (C-2), 112.2 (C-8), 116.1 (C-7), 120.6 (C-4),
123.5 (C-4a), 124.2 (C-5a), 129.8 (C-3), 134.1 (C-8a), 134.7 (C-1a),
146.1 (C-1), 154.7 (C-6), 191.8 (CHO).
MS (70 eV): m/z (%) = 255 (M+, 57), 240 (100), 212 (52), 184 (61),
169 (17), 154 (4), 141 (9).
HRMS (FAB): m/z [M+] calcd for C15H13NO3: 255.0895; found:
255.0892.
3-Hydroxy-4-(4-methoxyphenylamino)benzaldehyde (16a)
A mixture of 14 (0.23 g, 0.86 mmol) and 0.17 g (4.3 mmol) of
NaOH in EtOH (12.5 mL) and H2O (6 mL) at 20 °C was stirred for
6 h. The mixture was neutralized with 5% aq solution of HCl, and
extracted with CH2Cl2 (2 × 15 mL). The organic layer was dried
(Na2SO4) and the solvent was removed under vacuum. The residue
was purified by column chromatography over silica gel (30 g/g of
crude, hexane–EtOAc, 9:1) to give 0.18 g (85%) of 16a as a yellow
solid; Rf = 0.44 (hexane–EtOAc, 7:3); mp 184–185 °C.
IR (CH2Cl2): 3353, 1662, 1596, 1515, 1454, 1348, 1242, 1167 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.72 (s, 3 H, CH3O), 6.56 (br s, 1
H, NH), 6.90–6.97 (m, 2 H, ArH), 6.98 (d, J = 8.1 Hz, 1 H, H-5),
7.15–7.23 (m, 2 H, ArH), 7.28 (dd, J = 8.1, 2.1 Hz, 1 H, H-6), 7.42
(d, J = 2.1 Hz, 1 H, H-2), 7.50 (br s, 1 H, OH), 9.68 (s, 1 H, CHO).
13C NMR (75.4 MHz, CDCl3): d = 55.5 (s, CH3O), 110.1 (C-2),
112.0 (C-5), 114.7 (ArH), 124.7 (ArH), 127.0 (C-1), 128.1 (C-6),
132.6 (Ar), 141.5 (Ar), 143.4 (C-3), 156.7 (Ar), 190.7 (CHO).
1,6-Dimethoxy-9H-carbazole (17)
Following the method of preparation of 6, a mixture of 16b (0.04 g,
0.16 mmol) and Pd(AcO)2 (0.043 g, 0.19 mmol) in glacial AcOH
(2.5 mL) was stirred and heated to 140 °C for 24 h or to 170 °C for
10 h to give 0.026 g (74%) of 17 as a white solid; Rf = 0.61 (hexane–
EtOAc, 7:3); mp 118–120 °C.
IR (CH2Cl2): 3406, 1616, 1579, 1481, 1463, 1394, 1294, 1256,
1213, 1175, 1025, 800, 738 cm–1.
MS (70 eV): m/z (%) = 243 (M+, 13), 242 (100), 227 (5), 211 (44),
198 (20), 182 (4), 170 (9), 128 (11), 121 (5), 77 (8).
HRMS (FAB): m/z [M+] calcd for C14H13NO3: 243.0895; found:
243.0885.
1H NMR (300 MHz, CDCl3): d = 3.90 (s, 3 H, CH3), 3.97 (s, 3 H,
CH3O), 6.85 (dd, J = 8.0, 0.8 Hz, 1 H, H-2), 7.04 (dd, J = 8.8, 2.4
Hz, 1 H, H-7), 7.12 (t, J = 8.0 Hz, 1 H, H-3), 7.31 (d, J = 8.8 Hz, 1
H, H-8), 7.52 (d, J = 2.4 Hz, 1 H, H-5), 7.62 (dd, J = 8.0, 0.8 Hz, 1
H, H-4), 8.14 (br s, 1 H, NH).
13C NMR (75.4 MHz, CDCl3): d = 55.4 (CH3O), 56.0 (CH3O),
103.1 (ArH), 105.7 (ArH), 111.6 (ArH), 112.7 (ArH), 115.0 (ArH),
119.3 (ArH), 124.0 (C-4a or C-5a), 124.3 (C-5a or C-4a), 130.6 (C-
1a), 134.1 (C-8a), 145.7 (C-1), 153.8 (C-6).
MS (70 eV): m/z (%) = 227 (M+, 84), 212 (100), 197 (16), 184 (22),
169 (7), 153 (7), 141 (26), 113 (11).
HRMS (FAB): m/z [M+] calcd for C14H13NO2: 227.0946; found:
227.0941.
3-Methoxy-4-(4-methoxyphenylamino)benzaldehyde (16b)
A mixture of 16a (0.08 g, 0.33 mmol), MeI (0.14 g, 0.99 mmol), and
K2CO3 (0.68 g, 4.93 mmol) in anhyd acetone (25 mL) was heated to
60 °C for 3 h. The solvent was removed under vacuum, the residue
dissolved in EtOAc (15 mL), and washed with brine (2 × 15 mL).
The organic layer was dried (Na2SO4) and the solvent was removed
under vacuum. The residue was purified by column chromatogra-
phy over silica gel (30 g/g of crude, hexane–EtOAc, 9:1) to give
0.077 g (91%) of 16b as a pale yellow oil; Rf = 0.83 (hexane–
EtOAc, 7:3).
IR (CH2Cl2): 3391, 1669, 1591, 1513, 1461, 1358, 1294, 1256,
1126, 1032, 752 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.82 (s, 3 H, CH3O), 3.96 (s, 3 H,
CH3O), 6.57 (br s, 1 H, NH), 6.90–6.99 (m, 3 H, H-5, ArH), 7.15–
7.22 (m, 2 H, ArH), 7.29 (dd, J = 8.1, 1.8 Hz, 1 H, H-6), 7.37 (d,
J = 1.8 Hz, 1 H, H-2), 9.73 (s, 1 H, CHO).
13C NMR (75.4 MHz, CDCl3): d = 55.5 (CH3O), 55.7 (CH3O),
107.4 (C-2), 109.2 (C-5), 114.7 (ArH), 125.0 (ArH), 127.0 (C-1),
128.2 (C-6), 132.4 (Ar), 141.9 (Ar), 146.6 (C-3), 156.8 (C-10),
190.3 (CHO).
3-(4-Methoxyphenyl)-6-methyl-2,3-dihydrobenzoxazol-2-one
(15)
A mixture of 14 (0.20 g, 0.74 mmol) and 10% Pd/C (0.14 g, 0.13
mmol) in EtOAc (20 mL) at 20 °C and under H2 (30 psi) was stirred
for 6 h. The mixture was filtered on Celite, the solvent removed un-
der vacuum, and the residue purified by column chromatography
over silica gel (6.0 g, hexane–EtOAc, 9:1) under N2 pressure, to
give 0.186 g (98%) of 15 as a white solid; Rf = 0.76 (hexane–EtOAc,
7:3); mp 173–175 °C.
IR (CH2Cl2): 1768, 1612, 1517, 1446, 1383, 1303, 1254, 1162,
1028, 983 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.41 (s, 3 H, CH3), 3.87 (s, 3 H,
CH3O), 6.88 (d, J = 8.1 Hz, 1 H, H-4), 6.97 (br d, J = 8.1 Hz, 1 H,
H-5), 7.01–7.08 (m, 2 H, ArH), 7.10 (br s, 1 H, H-7), 7.41–7.49 (m,
2 H, ArH).
MS (70 eV): m/z (%) = 257 (M+, 70), 242 (100), 211 (80), 198 (40),
171 (36), 148 (30), 79 (10).
HRMS (FAB): m/z [M+] calcd for C15H15NO3: 257.1052; found:
257.1049.
6-Methoxymurrayanine (6)
A mixture of 16b (0.04 g, 0.16 mmol) and Pd(AcO)2 (0.043 g, 0.19
mmol) in glacial AcOH (2.5 mL) was placed in a threaded ACE
glass pressure tube with a sealed Teflon screw cap under N2. The
13C NMR (75.4 MHz, CDCl3): d = 21.4 (CH3), 55.5 (CH3O), 108.7
(C-4), 110.7 (C-7), 114.9 (ArH), 124.2 (C-5), 126.1 (Ar), 126.5
Synthesis 2007, No. 13, 1943–1948 © Thieme Stuttgart · New York

PAPER
Synthesis of Natural Carbazoles
1947
(ArH), 129.2 (C-3a), 133.1 (C-6), 142.7 (C-7a), 153.6 (C-2), 159.2
(Ar).
MS (70 eV): m/z (%) = 255 (M+, 100), 240 (7), 210 (8), 196 (27),
168 (22), 154 (4), 77 (8).
HRMS (FAB): m/z [M+] calcd for C15H13NO3: 255.0895; found:
the dark. The mixture was filtered, neutralized with 5% aq solution
of NaOH, and extracted with EtOAc (20 mL). The organic layer
was washed with 5% aq solution of NH4Cl (2 × 15 mL) and H2O
(2 × 15 mL), dried (Na2SO4), and the solvent was removed under
vacuum. The residue was purified by column chromatography over
silica gel (30 g/g of crude, hexane–EtOAc, 9:1) under N2 pressure
to give 0.025 g (72%) of 7 as a pale yellow powder.
255.0894.
Method C: A mixture of 14 (0.1 g, 0.37 mmol), a solution of KOH
(0.083 g, 1.48 mmol) in EtOH–H2O (7:3, 10 mL), and 10% Pd/C
(0.1 g, 0.093 mmol) at 20 °C and under H2 (30 psi) was stirred for
12 h, and then heated to reflux for 12 h. The mixture was filtered on
Celite, and the residue was washed with EtOH (3 × 15 mL). The so-
lution was neutralized with aq HCl (39%). The solvent was re-
moved under vacuum, the residue dissolved in CH2Cl2 (10 mL), and
H2O (5 mL) was added. The aqueous layer was washed with CH2Cl2
(3 × 10 mL), the combined organic layers were dried (Na2SO4), and
the solvent was removed under vacuum. The residue was dissolved
in acetone (15 mL), then K2CO3 (0.13 g, 0.93 mmol) and MeI (0.26
g, 1.85 mmol) were added, and the mixture was heated to reflux for
12 h. The mixture was filtered on Celite, the solvent removed under
vacuum, and the residue mixed in a threaded ACE glass pressure
tube with a sealed Teflon screw cap with Pd(AcO)2 (0.17 g, 0.76
mmol) in glacial AcOH (2 mL) under N2. The mixture was stirred
and heated to 120 °C for 18 h in the dark. The mixture was diluted
with toluene (15 mL) and the solvent was removed under vacuum.
This procedure was repeated twice. The residue was purified by col-
umn chromatography over silica gel (20 g/g of crude, hexane–
EtOAc, 9:1) to give 0.067 g (75%) of 7 as a pale yellow solid; Rf =
0.47 (hexane–EtOAc, 7:3); mp 149–150 °C (acetone–hexane, 9:1)
(Lit.1h mp 150 °C).
2-(4-Methoxyphenylamino)-5-methylphenol (18a)
A mixture of 15 (0.08 g, 0.31 mmol) and 0.125 g (3.13 mmol) of
NaOH in a solution of EtOH–H2O (5:2, 8 mL), previously deoxy-
genated by bubbling N2, was heated to 60 °C under N2 for 5 h. The
solvent was evaporated under vacuum, the residue dissolved in
EtOAc (25 mL) and washed with 5% aq solution of NH4Cl (2 × 15
mL), 5% aq solution of NaHCO3 (2 × 15 mL), and H2O (2 × 15
mL). The organic layer was dried (Na2SO4) and the solvent re-
moved under vacuum. The residue was purified by column chroma-
tography over silica gel (30 g/g of crude, hexane–EtOAc, 9:1) under
N2 pressure to give 0.06 g (83%) of 18a as an orange oil; Rf = 0.42
(hexane–EtOAc, 7:3).
IR (CH2Cl2): 3365, 1511, 1458, 1292, 1235, 1178, 1112, 1034, 806
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.31 (s, 3 H, CH3), 3.76 (s, 3 H,
CH3O), 4.93 (br s, 1 H, OH), 5.88 (br s, 1 H, NH), 6.60–6.88 (m, 6
H, H-4, H-6, ArH), 6.99 (d, J = 8.1 Hz, 1 H, H-3).
N-(4-Methoxyphenyl)-N-(2-methoxy-4-methylphenyl)amine
(18b)
A mixture of 18a (0.045 g, 0.20 mmol), MeI (0.084 g, 0.59 mmol),
and K2CO3 (0.407 g, 2.95 mmol) in anhyd acetone (10 mL) was
heated to reflux for 3 h. The solvent was removed under vacuum,
the residue dissolved in EtOAc (15 mL), and was washed with brine
(2 × 15 mL). The organic layer was dried (Na2SO4) and the solvent
was removed under vacuum. The residue was purified by column
chromatography over silica gel 30 g/g of crude, hexane–EtOAc,
9:1) under N2 pressure to give 0.045 g (94%) of 18b as a pale yellow
oil; Rf = 0.57 (hexane–EtOAc, 7:3).
IR (CH2Cl2): 3416, 2930, 1583, 1462, 1393, 1304, 1266, 1214,
1146, 1037, 944, 828 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.52 (s, 3 H, CH3), 3.91 (s, 3 H,
CH3O), 3.98 (s, 3 H, CH3O), 6.71 (br s, 1 H, H-2), 7.03 (dd, J = 8.7,
2.3 Hz, 1 H, H-7), 7.32 (d, J = 8.7 Hz, 1 H, H-8), 7.43 (br s, 1 H, H-
4), 7.49 (d, J = 2.3 Hz, 1 H, H-5), 8.01 (br s, 1 H, NH).
13C NMR (75.4 MHz, CDCl3): d = 21.9 (CH3), 55.4 (CH3O), 56.0
(CH3O), 103.0 (C-5), 107.5 (C-2), 111.6 (C-8), 112.3 (C-4), 114.8
(C-7), 123.9 (C-4a), 124.2 (C-5a), 128.8 (C-1a), 129.0 (C-3), 134.4
(C-8a), 145.4 (C-1), 153.6 (C-6).
IR (CH2Cl2): 3349, 2934, 1614, 1513, 1461, 1400, 1339, 1243,
1156, 1131, 1035, 809, 773, 647 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.30 (br s, 3 H, CH3), 3.79 (s, 3 H,
CH3O), 3.87 (s, 3 H, CH3O), 5.83 (br s, 1 H, NH), 6.64 (ddd, J = 8.0,
1.7, 0.8 Hz, 1 H, H-5), 6.69 (br d, J = 1.7 Hz, 1 H, H-3), 6.81–6.89
(m, 2 H, ArH), 6.96 (d, J = 8.0 Hz, 1 H, H-6), 7.04–7.12 (m, 2 H,
ArH).
MS (70 eV): m/z (%) = 241 (M+, 94), 226 (100), 211 (9), 198 (20),
183 (7), 168 (8), 155 (18), 120 (16), 77 (4).
HRMS (FAB): m/z [M+] calcd for C15H15NO2: 241.1103; found:
241.1099.
13C NMR (75.4 MHz, CDCl3): d = 21.0 (CH3), 55.50 (CH3O), 55.55
(CH3O), 111.3 (C-3), 113.4 (C-6), 114.5 (ArH), 120.9 (C-5), 121.8
(ArH), 128.6 (C-1 or C-4), 132.1 (C-4 or C-1), 136.1 (Ar), 147.7 (C-
2 or Ar), 154.8 (Ar or C-2).
Acknowledgment
We thank Fernando Labarrios and Fabiola Jiménez for his help in
spectrometric measurements. J.T. acknowledges DEPI/IPN (Grants
20030147, 20040123, 20050151, 20060583) and CONACYT
(Grants 32273E and 43508Q) for financial support. A.B. and P.B.
thank CONACYT for the award of a graduate scholarship. R.B.
thanks SNI/CONACYT for a scholarship. A.B. and P.B. also thank
CGPI/IPN (PIFI) and Ludwig K. Hellweg Foundation for scholar-
ship awards. J.T. is a fellow of the EDI-IPN and COFAA-IPN pro-
grams.
MS (70 eV): m/z (%) = 243 (M+, 100), 228 (74), 213 (12), 197 (65),
184 (19), 168 (6), 156 (5), 121 (9), 92 (4), 77 (9).
HRMS (FAB): m/z [M+] calcd for C15H17NO2: 243.1259; found:
243.1264.
Clausenine (7)
Method A: A mixture of 6 (0.025 g, 0.098 mmol) and 10% Pd/C
(0.018 g, 0.017 mmol) in EtOAc (10 mL) at 20 °C (30 psi) was
stirred under H2 for 6 h. The mixture was filtered on Celite, the sol-
vent removed under vacuum, and the residue was purified by flash
column chromatography over silica gel (3.0 g, hexane–EtOAc, 9:1)
under N2 pressure to give 0.022 g (93%) of 7 as a pale yellow solid.
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Synthesis 2007, No. 13, 1943–1948 © Thieme Stuttgart · New York