Total synthesis of the natural carbazoles Murrayanine and Murrayafoline A, based on the regioselective Diels-Alder addition of exo-2-oxazolidinone dienes

Article abstract of DOI:10.1055/s-2004-831213

A new synthesis of the natural carbazoles Murrayanine (1) and Murrayafoline A (3) is described. The key step in the synthetic route involved the regioselective cycloaddition of the diene 4,5-dimethylene-3-phenyl-1,3- oxazolidin-2-one (4) to acrolein (6) c

Full text of DOI:10.1055/s-2004-831213

PAPER
2499
Total Synthesis of the Natural Carbazoles Murrayanine and Murrayafoline A,
Based on the Regioselective Diels–Alder Addition of exo-2-Oxazolidinone
Dienes
Total
S
ynthesis of
d
the
N
atural
C
r
arbazol
i
es
M
ur
a
r
ayanine an
n
d Murrayafo
a
line
A
Benavides, Javier Peralta, Francisco Delgado, Joaquín Tamariz*
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional., Prol. Carpio y Plan
de Ayala, 11340 México, Mexico
Fax +52(55)53963503; E-mail: jtamariz@woodward.encb.ipn.mx
Received 21 May 2004; revised 29 June 2004
Dedicated to Professor Pierre Vogel on the occasion of his 60th birthday
azolidinone diene 411,12 in a regioselective Diels–Alder
Abstract: A new synthesis of the natural carbazoles Murrayanine
cycloaddition.13 The adduct thus obtained (5) was hydro-
lyzed and aromatized in a single step to give the corre-
sponding arylphenylamine, which provided carbazole 2
(1) and Murrayafoline A (3) is described. The key step in the syn-
thetic route involved the regioselective cycloaddition of the diene
4,5-dimethylene-3-phenyl-1,3-oxazolidin-2-one (4) to acrolein (6)
catalyzed by Lewis acids at low temperature. Direct aromatization by palladium-promoted cyclization (Scheme 1).
of the substituted cyclohexene moiety of adduct 7, and further hy-
Following a methodology modified with respect to that
drolysis of the 2-oxazolidinone ring, proved to be a more efficient
designed for mukonine (2), we herein describe a total syn-
strategy than the opposite synthetic sequence for the preparation of
thesis of carbazoles 1 and 3, via a highly regioselective
cycloaddition of diene 4 to acrolein (6), which is a dieno-
phile not previously studied in Diels–Alder additions to
exo-2-oxazolidinone dienes.12
the corresponding arylphenylamines 14 and 18. Palladium-promot-
ed cyclization of the latter furnished the desired carbazoles 1 and 3
in high overall yields.
Key words: 4,5-dimethylene-2-oxazolidinone dienes, murraya-
nine, murrayafoline A, Diels–Alder, palladium acetate
CO2Me
CO2Me
O
N
O
Murrayanine (1)1 belongs to an extensive family of natu-
ral carbazoles mainly isolated from species of the genera
Murraya and Clausena, which are characterized by a
methoxy group at C-1 and a substituent at C-3.2 These al-
kaloids have attracted especial attention as a result of their
wide and significant biological activity.2a,3 Accordingly,
novel and efficient synthetic methodologies have been re-
ported in order to assemble the carbazole scaffold,4 lead-
ing to the total synthesis of natural carbazoles,5 among
them 1.6 It has been established that murrayanine (1) and
mukonine (2)7 biogenetically arise from the in vivo oxida-
tion of murrayafoline A (3) (Figure 1).2a,8 The latter has
been prepared by reduction of 1,1a,6c or 2,6a and by total
synthesis.6b,9
N
H
OMe
Ph
2
5
O
N
O
Ph
4
Scheme 1
Considering that the thermal Diels–Alder addition of di-
ene 4 to activated alkenes with electron-withdrawing
groups, such as methyl vinyl ketone12 and alkyl acry-
lates,10 yields a relatively low regioselectivity (para/meta,
ca. 74:26), we attempted to improve it by means of Lewis
acid catalysis at low temperature.12 Thus, the catalyzed
addition (BF3·OEt2, –78 °C) of diene 4 to acrolein (6) led
to a mixture of the para/meta regioisomers 7/8 in a high
ratio (98:2), and the desired adduct 7 was separated by
column chromatography (Scheme 2). When the cycload-
dition was carried out under thermal conditions (160 °C,
2.5 h) the ratio of 7 to 8 was lower (70:30).
We have recently described a total synthesis of 2,10
through a short strategy based on the use of the exo-2-ox-
Z
N
OMe
H
1, Z = CHO
2, Z = CO2Me
3, Z = CH3
The previously reported cascade method of hydrolysis of
the heterocyclic ring and aromatization of the cyclohex-
ene ring under basic conditions (NaOH–EtOH–H2O)13
failed to give the desired phenolic aniline 9 in good yield.
In addition, a complex mixture of products was obtained,
alcohol 10 among them, which has the phenyl arylamine
scaffold but the aldehyde group reduced.
Figure 1
SYNTHESIS 2004, No. 15, pp 2499–2504
Advanced online publication: 02.09.2004
x
x.
x
x
.
2
0
0
4
DOI: 10.1055/s-2004-831213; Art ID: M03804SS
© Georg Thieme Verlag Stuttgart · New York

2500
A. Benavides et al.
PAPER
CHO
CHO
O
O
N
O
N
i
CHO
O
O
O
N
O
N
CHO
BF3⋅Et2O
69%
N
O
+
O
O
Ph
Ph
CHO
-78 °C, 10 min
7
13
Ph
Ph
97%
4
7
8
ii, iii
NaOH
EtOH/H2O
25 °C
12 h
R
(5:2)
CHO
iv
CHO
CH2OH
+
73%
N
N
H
H
OMe
OR
9, R = H (81%)
14, R = Me (95%)
N
H
N
H
1, R = CHO
15, R = CH2OH
OH
OH
9
10
Scheme 4 Conditions: i) DDQ, C6H6, reflux, 24 h. ii) NaOH,
EtOH–H2O (2.5:1), 25 °C, 1 h. iii) MeI, K2CO3, Me2CO, reflux, 3 h.
iv) Pd(OAc)2, AcOH, 160 °C, 12 h.
Scheme 2
In order to prevent the reduction of the carbonyl group,
compound 7 was protected with ethylene glycol to give 11
in high yield (Scheme 3). However, the basic hydrolysis
of 11 led to a complex mixture of products. From this mix-
ture compound 12, which decomposes rapidly, was isolat-
ed in low yield. It is noteworthy that the six-membered
ring did not undergo aromatization, suggesting that the
unusual aerial oxidation of the ring, likely promoted by
superoxide species,13 requires a highly enolizable sub-
strate to take place, as it is the case with those compounds
having carbonylic substituents at C-3 position of the car-
with the product of partial reduction, koenoline (15),6a,b in
a ca. 1:1 ratio. Furthermore, we were able to prepare 3 fol-
lowing a pathway analogous to that developed for 1
(Scheme 5). Thus, palladium-catalyzed hydrogenation of
13 yielded the methylated derivative 16 in high yield. By
successive hydrolysis of the latter, methylation of the phe-
nol intermediate 17, and intramolecular cyclization of the
arylphenylamine 18, carbazole 3 was obtained in 36%
overall yield.
bazole skeleton.10,13 Further attempts to promote aromati- In conclusion, we have demonstrated that the natural car-
zation by oxidation of 12 with chloramine-T14 or DDQ15 bazole murrayanine (1) can be prepared in five steps by a
were unsuccessful.
highly regioselective Diels–Alder addition reaction be-
tween the 2-oxazolidinone diene 4 and acrolein (6). Aro-
matization of the six-membered ring of adduct 7 allowed
us to carry out the hydrolysis of the oxazolidinone moiety
successfully leading to the arylphenylamine intermediate
9, under soft and efficient conditions. Natural carbazole 3,
which is the biogenetical precursor of 1, was also prepared
starting from 7 through a similar synthetic route, and in a
good overall yield.
O
CHO
O
N
O
N
O
ethylene glycol
O
O
p–TsOH
C6H6/CH2Cl2, 3:1
Ph
Ph
50 °C, 20 h
96%
7
11
O
O
NaOH
EtOH/H2O
(5:2)
50 °C
N
H
CH3
R
O
N
O
ii
O
12
N
H
Ph
OR
Scheme 3
13, R = CHO
16, R = CH3 (97%)
17, R = H (85%)
18, R = Me (93%)
iii
i
A one-step longer but more efficient methodology con-
sisted in the treatment of isomer 7 with DDQ in refluxing
benzene to aromatize the six-membered ring, furnishing
compound 13 in 69% yield (Scheme 4). Hydrolysis of 13
under mild basic conditions (NaOH, EtOH–H2O, 25 °C, 1
h) gave the arylphenylamine 9 in high yield. Then, meth-
ylation using MeI in acetone and K2CO3 (reflux, 3 h)
yielded 14 almost quantitatively.5c Finally, the coupling of
CH3
iv
71%
N
H
OMe
3
Scheme 5 Conditions: i) H2/Pd/C (30 psi), EtOAc, 25 °C, 6 h. ii)
NaOH, EtOH–H2O (5:2), 60 °C, 2 h. iii) MeI, K2CO3, Me2CO, reflux,
the aromatic rings of 14, promoted by palladium in acetic 3 h. iv) Pd(OAc)2, HOAc, 140 °C, 10 h.
acid,13,16 provided carbazole 1 in 38% overall yield
(Scheme 4), whose spectroscopic data matched those re-
ported for the natural product.1b
Melting points (uncorrected) were determined with an Electrother-
mal capillary melting point apparatus. IR spectra were recorded on
a Perkin-Elmer 1600 spectrophotometer. 1H and 13C NMR spectra
were recorded on Jeol GSX-270 (270 MHz), Varian Mercury (300
MHz), and Jeol-400 (400 MHz) instruments, in CDCl3 or acetone-
d6 as solvents and TMS as internal standard. MS and HRMS were
obtained, in electron impact (EI) (70 eV) and FAB (mNBA) modes,
Murrayafoline A (3) has been prepared by partial synthe-
sis from 1a by reduction of the aldehyde group.6c When
we investigated the reduction of 1 with zinc amalgam in
refluxing EtOH, natural carbazole 3 was obtained along
Synthesis 2004, No. 15, 2499–2504 © Thieme Stuttgart · New York

PAPER
Total Synthesis of the Natural Carbazoles Murrayanine and Murrayafoline A
2501
on a Hewlett-Packard 5971A and on a Jeol JMS-AX 505 HA spec-
trometers, respectively. Analytical TLC was carried out using E.
Merck silica gel 60 F254 coated 0.25 plates, visualizing by long- and
short-wavelength UV lamps. Flash column chromatography was
performed on silica gel (230–400 mesh, Natland Int.). All air mois-
ture sensitive reactions were carried out under N2 using oven-dried
glassware. Benzene and xylene were freshly distilled over sodium,
and CH2Cl2 and EtOAc over CaH2, prior to use. Acetone was dried
by distillation after treatment with 4 Å molecular sieves. K2CO3 was
dried overnight at 120 °C prior to use. All other reagents were used
without further purification. Diene 4 was prepared as reported.12
13C NMR (75.4 MHz, CDCl3): d = 20.0 (C-4), 21.7 (C-7), 23.2 (C-
5), 38.1 (C-6), 65.1 [O(CH2)2], 105.6 (OCHO), 120.6 (C-3a), 124.9
(PhH), 127.4 (PhH), 129.3 (PhH), 134.0 (Ph), 134.5 (C-7a), 154.4
(C-2).
MS (70 eV): m/z = 287 (100) [M+], 259 (3), 226 (54), 215 (36), 171
(22), 158 (17), 130 (23), 117 (28), 77 (49), 73 (65).
HRMS (FAB): m/z [MH+] calcd for C14H18NO4: 288.1236; found:
288.1238.
6-Formyl-3-phenyl-2,3-dihydrobenzoxazol-2-one (13); Typical
Procedure
To a stirred solution of 7 (0.22 g, 0.90 mmol) in anhyd benzene (25
mL), at reflux under N2 atmosphere, a solution of DDQ (0.45 g, 1.98
mmol) in anhyd benzene (20 mL) was added dropwise through a
cannula, and the mixture was stirred for 24 h at the same tempera-
ture. The mixture was filtered on celite, the solvent was removed
under vacuum, and the residue was purified by column chromatog-
raphy over silica gel (7 g, hexane–EtOAc, 9:1), to give 13 (0.15 g,
69%) as a white solid; Rf 0.46 (hexane–EtOAc, 7:3); mp 161–162
°C.
6-Formyl-3-phenyl-2,3,4,5,6,7-hexahydrobenzoxazol-2-one (7);
Typical Procedure
Method A: To a stirred solution of 4 (0.20 g, 1.07 mmol) in anhyd
CH2Cl2 (6 mL), at –78 °C under N2 atmosphere, 6 (0.072 g, 1.28
mmol) and BF3·Et2O (0.003 g, 0.021 mmol) were added dropwise,
and the mixture was stirred for 10 min at the same temperature. The
mixture was washed with a 5% aq solution of NaHCO3 (2 × 15 mL),
5% aq solution of NH4NO3 (2 × 15 mL), and water (2 × 15 mL). The
combined organic layers were dried (Na2SO4) and the solvent was
removed under vacuum, giving a mixture of 7/8 (98:2). The residue
was purified by column chromatography over silica gel (8 g, hex-
ane–EtOAc, 3:2), to give 7 (0.24 g, 91%) as a white solid.
IR (CH2Cl2): 1759, 1704, 1598, 1448, 1379, 1354, 1279, 1163 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.20 (d, J = 8.0 Hz, 1 H, H-4),
7.47–7.63 (m, 5 H, PhH), 7.74 (dd, J = 8.0, 1.3 Hz, 1 H, H-5), 7.80
(d, J = 1.3 Hz, 1 H, H-7), 9.96 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 109.3 (C-4), 110.0 (C-7), 125.2
(PhH), 128.2 (PhH), 129.1 (C-5), 130.1 (PhH), 132.3 (Ar or Ph),
132.7 (Ph or Ar), 136.4 (Ph or Ar), 143.0 (C-7a), 152.9 (C-2), 190.3
(CHO).
MS (70 eV): m/z = 239 (82) [M+], 238 (49), 211 (16), 207 (37), 186
(36), 166 (25), 149 (16), 135 (86), 105 (45), 91 (24), 77 (100), 73
(30).
Method B: A mixture of diene 4 (0.10 g, 0.53 mmol), dienophile 6
(0.06 g, 1.07 mmol), and hydroquinone (0.003 g) in anhyd xylene
(4 mL), was placed in a threaded ACE glass pressure tube with a
sealed Teflon screw cap, under N2 atmosphere, and in the dark. The
mixture was stirred and heated to 160 °C for 2.5 h. The solvent was
removed under vacuum and the residue (7/8, 70:30) purified by col-
umn chromatography on silica gel (30 g/g of crude) (hexane–
EtOAc, 4:1), to give 7 (0.086 g, 66%) as a white solid; Rf 0.56 (hex-
ane–EtOAc, 1:1); mp 109–110 °C.
HRMS (FAB): m/z [M+] calcd for C14H9NO3: 239.0582; found:
239.0578.
IR (CH2Cl2): 1757, 1711, 1597, 1503, 1395, 1360, 1273, 1166, 980
cm–1.
1H NMR (270 MHz, CDCl3): d = 1.79–1.94 (m, 1 H, H-5b), 2.04–
2.17 (m, 1 H, H-5a), 2.24–2.41 (m, 2 H, H-4), 2.59–2.75 (m, 2 H,
H-7), 2.75–2.86 (m, 1 H, H-6), 7.17–7.50 (m, 5 H, PhH), 9.68 (s, 1
H, CHO).
13C NMR (67.94 MHz, CDCl3): d = 18.9 (C-4), 20.5 (C-7), 21.5 (C-
5), 45.3 (C-6), 120.7 (C-3a), 124.9 (PhH), 127.5 (PhH), 129.2
(PhH), 133.1 (C-7a or Ph), 133.6 (Ph or C-7a), 154.2 (C-2), 201.5
(CHO).
3-Hydroxy-4-phenylaminobenzaldehyde (9); Typical Proce-
dure
A mixture of 13 (0.19 g, 0.79 mmol) and NaOH (0.16 g, 4.0 mmol)
in EtOH (9.4 mL) and H2O (3.8 mL) at 20 °C was stirred for 1 h.
The mixture was neutralized with 5% aq solution of HCl, and ex-
tracted 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 9 (0.137 g, 81%) as a yellow
solid; Rf 0.31 (hexane–EtOAc, 7:3); mp 116–117 °C.
MS (70 eV): m/z = 243 (94) [M+], 215 (51), 187 (20), 174 (19), 158
(26), 143 (28), 130 (37), 117 (100), 104 (22), 77 (97).
IR (CH2Cl2): 3456, 3375, 1665, 1597, 1529, 1451, 1317, 1247, 1175
cm–1.
1H NMR (300 MHz, CDCl3): d = 6.82 (br s, 1 H, NH), 7.08–7.14
(m, 1 H, PhH), 7.21–7.27 (m, 3 H, H-5, PhH), 7.29–7.40 (m, 3 H,
H-6, PhH), 7.63 (d, J = 1.8 Hz, 1 H, H-2), 8.25 (br s, 1 H, OH), 9.66
(s, 1 H, CHO).
13C NMR (75.4 MHz, CDCl3): d = 110.1 (C-2), 113.0 (C-5), 121.5
(PhH), 123.6 (PhH), 127.2 (C-6), 128.3 (C-1), 129.5 (PhH), 139.6
(C-4), 140.1 (Ph), 144.1 (C-3), 191.9 (CHO).
HRMS (FAB): m/z [MH+] calcd for C14H14NO3: 244.0974; found:
244.0973.
6-(1,3-Dioxolan-2-yl)-3-phenyl-2,3,4,5,6,7-hexahydrobenzox-
azol-2-one (11); Typical Procedure
A solution of 7 (0.50 g, 2.06 mmol), ethylene glycol (0.2 g, 3.2
mmol), and p-toluenesulfonic acid (few crystals), in an anhyd mix-
ture of benzene–CH2Cl2 (3:1) (10 mL), was stirred at 50 °C under
N2 atmosphere for 20 h. The mixture was treated with a 5% aq so-
lution of NaHCO3 until neutral, and was then 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), to give 11
(0.57 g, 96%) as a white solid; Rf 0.26 (hexane–EtOAc, 7:3); mp
145–146 °C.
MS (70 eV): m/z = 213 (100) [M+], 212 (65), 211 (40), 182 (21), 156
(12), 128 (19), 91 (14), 77 (25).
3-Methoxy-4-phenylaminobenzaldehyde (14); Typical Proce-
dure
A mixture of 9 (0.134 g, 0.63 mmol), MeI (0.27 g, 1.9 mmol) and
K2CO3 (1.3 g, 9.4 mmol) in anhyd acetone (10 mL) was heated to
60 °C for 3 h. The solvent was removed under vacuum, the residue
was 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 chro-
IR (KBr): 1757, 1713, 1497, 1400, 1148, 977 cm–1.
1H NMR (270 MHz, CDCl3): d = 1.48–1.68 (m, 1 H, H-5b), 1.96–
2.08 (m, 1 H, H-5a), 2.08–2.21 (m, 1 H, H-6), 2.24–2.48 (m, 3 H,
H-4, H-7), 2.52–2.65 (m, 1 H, H-7), 3.84–4.02 [m, 4 H, O(CH2)2],
4.81 (d, J = 4.7 Hz, 1 H, OCHO), 7.25–7.46 (m, 5 H, PhH).
Synthesis 2004, No. 15, 2499–2504 © Thieme Stuttgart · New York

2502
A. Benavides et al.
PAPER
matography over silica gel (30 g/g of crude, hexane–EtOAc, 9:1), to
give 14 (0.136 g, 95%) as yellow crystals; Rf 0.47 (hexane–EtOAc,
7:3); mp 114–115 °C.
1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3 H, Me), 6.96–7.00 (m,
2 H, H-4, H-5), 7.11 (br s, 1 H, H-7), 7.39–7.47 (m, 1 H, PhH),
7.53–7.59 (m, 4 H, PhH).
IR (CH2Cl2): 3396, 3301, 1669, 1571, 1521, 1496, 1361, 1305,
1250, 1130, 1027 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.97 (s, 3 H, OMe), 6.74 (br s, 1
H, NH), 7.09–7.15 (m, 1 H, PhH), 7.23–7.26 (m, 3 H, H-5, PhH),
7.32–7.41 (m, 4 H, H-2, H-6, PhH), 9.76 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 55.7 (OMe), 107.7 (C-2), 110.1
(C-5), 121.5 (PhH), 123.7 (PhH), 127.8 (2C), 129.4 (PhH), 139.9,
140.3, 147.1 (C-3), 190.3 (CHO).
MS (70 eV): m/z = 227 (100) [M+], 212 (60), 183 (22), 154 (27), 129
(24), 77 (20).
HRMS (FAB): m/z [MH+] calcd for C14H14NO2: 228.1025; found:
228.1028.
1H NMR (300 MHz, Me2CO-d6): d = 2.40 (s, 3 H, Me), 6.99–7.07
(m, 2 H, H-4, H-5), 7.18 (br s, 1 H, H-7), 7.45–7.51 (m, 1 H, PhH),
7.57–7.67 (m, 4 H, PhH).
13C NMR (75.4 MHz, CDCl3): d = 21.4 (Me), 108.9 (C-4), 110.8 (C-
7), 124.3 (C-5), 124.8 (PhH), 128.1 (PhH), 128.7 (C-6), 129.7
(PhH), 133.4 (Ar or Ph), 133.7 (Ph or Ar), 142.8 (C-7a), 153.3 (C-
2).
13C NMR (75.4 MHz, Me2CO-d6): d = 20.7 (Me), 109.1 (C-4),
110.6 (C-7), 124.5 (C-5), 125.4 (PhH), 128.2 (PhH), 129.2 (C-6),
129.8 (PhH), 133.3 (Ar or Ph), 134.3 (Ph or Ar), 143.0 (C-7a), 152.9
(C-2).
MS (70 eV): m/z = 225 (100) [M+], 180 (70), 168 (16), 90 (5), 77
(34).
HRMS (FAB): m/z [MH+] calcd for C14H12NO2: 226.0868; found:
Murrayanine (1); Typical Procedure
A mixture of 14 (0.05 g, 0.22 mmol) and Pd(AcO)2 (0.074 g, 0.33
mmol) in glacial HOAc acid (3 mL), was placed in a threaded ACE
glass pressure tube with a sealed Teflon screw cap, under N2 atmo-
sphere, and in the dark. The mixture was stirred and heated to 160
°C for 12 h. The mixture was filtered, neutralized with aq sat. solu-
tion of NaHCO3, and extracted with EtOAc (2 × 15 mL). The organ-
ic layer was washed with brine (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), to give 1 (0.036 g, 73%) as a white solid; Rf 0.41 (hex-
ane–EtOAc, 7:3); mp 167–168 °C [Lit.1b 167–168 °C; 168 °C1a].
226.0871.
3-Methyl-2-phenylaminophenol (17); Typical Procedure
A mixture of 16 (0.07 g, 0.31 mmol) and NaOH (0.06 g, 1.5 mmol)
in a mixture of EtOH–H2O (5:2, 7 mL), previously deoxygenated by
N2 bubbling, was heated to 60 °C under stirring for 2 h. The solvent
was evaporated under vacuum, and the residue was dissolved in
EtOAc (20 mL) and washed with 5% aq solution of NH4Cl (2 × 15
mL), 5% aq solution of NaHCO3 (2 × 15 mL), and water (2 × 15
mL). The organic layer was dried (Na2SO4) and the solvent was 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 17 (0.053 g, 85%) as an orange oil; Rf
0.62 (hexane–EtOAc, 7:3).
IR (CH2Cl2): 3152, 1657, 1607, 1577, 1499, 1342, 1238, 1136 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.05 (s, 3 H, OMe), 7.32 (ddd, J =
7.7, 7.0, 1.3 Hz, 1 H, H-6), 7.46 (br s, 1 H, H-2), 7.48–7.51 (m, 2 H,
H-7, H-8), 8.10 (d, J = 7.7 Hz, 1 H, H-5), 8.18 (br s, 1 H, H-4), 8.70
(br s, 1 H, NH), 10.05 (s, 1 H, CHO).
1H NMR (300 MHz, Me2CO-d6): d = 3.07 (br s, 1 H, NH), 4.09 (s,
3 H, OMe), 7.29 (ddd, J = 7.8, 7.2, 0.7 Hz, 1 H, H-6), 7.47 (d, J =
1.2 Hz, 1 H, H-2), 7.49 (ddd, J = 8.4, 7.0, 0.9 Hz, 1 H, H-7), 7.67
(br d, J = 8.4 Hz, 1 H, H-8), 8.22 (br d, J = 7.8 Hz, 1 H, H-5), 8.36
(d, J = 1.2 Hz, 1 H, H-4), 10.06 (s, 1 H, CHO).
13C NMR (75.4 MHz, CDCl3): d = 55.7 (OMe), 103.4 (C-2), 111.5
(C-8), 120.4 (C-4), 120.6 (C-5, C-6), 123.5 (C-4a or C-5a), 123.6
(C-5a or C-4a), 126.6 (C-7), 130.0 (C-1a or C-3), 134.0 (C-3 or C-
1a), 139.4 (C-8a), 146.0 (C-1), 191.9 (CHO).
IR (CH2Cl2): 3372, 1598, 1502, 1457, 1411, 1308, 1238, 1177,
1154, 799, 749, 693 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.30 (s, 3 H, Me), 5.05 (br s, 1 H,
OH), 5.93 (br s, 1 H, NH), 6.64–6.74 (m, 3 H, H-4, PhH), 6.79–6.87
(m, 2 H, H-6, PhH), 7.02 (d, J = 8.1 Hz, 1 H, H-3), 7.14–7.22 (m, 2
H, PhH).
13C NMR (75.4 MHz, CDCl3): d = 21.2 (Me), 115.2 (PhH), 115.8
(C-6), 119.8 (C-3 or PhH), 121.5 (PhH or C-3), 125.8 (C-4), 129.3
(PhH), 137.1 (C-2, C-5), 146.2 (Ph), 151.7 (C-1).
MS (70 eV): m/z = 199 (100) [M+], 184 (10), 170 (11), 154 (16), 128
(10), 122 (8), 107 (4), 93 (25), 77 (28).
13C NMR (75.4 MHz, Me2CO-d6): d = 55.5 (OMe), 103.5 (C-2),
112.1 (C-8), 119.9 (C-4), 120.4 (C-6), 120.7 (C-5), 123.6 (C-5a),
123.8 (C-4a), 126.6 (C-7), 130.4 (C-3), 140.5 (C-1a or C-8a), 140.6
(C-8a or C-1a), 146.6 (C-1), 191.4 (CHO).
MS (70 eV): m/z = 225 (100) [M+], 210 (62), 182 (11), 154 (51), 139
(11), 126 (18).
HRMS (FAB): m/z [M+] calcd for C13H13NO: 199.0997; found:
199.0994.
(2-Methoxy-4-methylphenyl)phenylamine (18); Typical Proce-
dure
A mixture of 17 (0.07 g, 0.35 mmol), MeI (0.15 g,1.06 mmol), and
K2CO3 (0.73 g, 5.29 mmol) in anhyd acetone (10 mL) was heated to
reflux for 3 h. The solvent was removed under vacuum, the residue
was 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 chro-
matography over silica gel (2.1 g, hexane–EtOAc, 9:1), under N2
pressure, to give 18 (0.07 g, 93%) as an orange oil; Rf 0.77 (hexane–
EtOAc, 7:3).
HRMS (FAB): m/z [M+] calcd for C14H11NO2: 225.0790; found:
225.0789.
6-Methyl-3-phenyl-2,3-dihydrobenzoxazol-2-one (16); Typical
Procedure
A mixture of 13 (0.23 g, 0.96 mmol) and 10% Pd/C (0.23 g, 0.22
mmol) in EtOAc (25 mL) at 20 °C and under an H2 atmosphere (30
psi) was stirred for 6 h. The mixture was filtered on celite, the sol-
vent was removed under vacuum, and the residue was purified by
flash column chromatography over silica gel (6.3 g, hexane–EtOAc,
9:1), under N2 pressure, to give 16 (0.21 g, 97%) as a white solid; Rf
0.68 (hexane–EtOAc, 7:3); mp 90–91 °C.
IR (CH2Cl2): 3411, 2927, 1596, 1521, 1498, 1462, 1409, 1315,
1259, 1156, 1129, 1036, 804, 747, 693 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.32 (s, 3 H, Me), 3.86 (s, 3 H,
MeO), 5.99 (br s, 1 H, NH), 6.66–6.75 (m, 2 H, H-3, H-5), 6.89 (t,
J = 7.2 Hz, 1 H, PhH), 7.05–7.14 (m, 2 H, PhH), 7.20 (d, J = 7.7 Hz,
1 H, H-6), 7.22–7.30 (m, 2 H, PhH).
IR (CH2Cl2): 1773, 1597, 1503, 1455, 1374, 1347, 1273, 1202,
1162, 986 cm–1.
Synthesis 2004, No. 15, 2499–2504 © Thieme Stuttgart · New York

PAPER
Total Synthesis of the Natural Carbazoles Murrayanine and Murrayafoline A
2503
13C NMR (75.4 MHz, CDCl3): d = 21.1 (Me), 55.5 (OMe), 111.6
(C-3), 115.8 (C-6), 117.6 (PhH), 120.4 (PhH), 120.8 (C-5), 129.2
(PhH), 129.9 (C-1 or C-4), 130.1 (C-4 or C-1), 143.4 (Ph), 148.6 (C-
2).
MS (70 eV): m/z = 213 (100) [M+], 198 (78), 183 (36), 170 (28), 154
(16), 128 (11), 77 (20).
References
(1) (a) Chakraborty, D. P.; Barman, B. K.; Bose, P. K.
Tetrahedron 1965, 21, 681. (b) Li, W.-S.; McChesney, J.
D.; El-Feraly, F. S. Phytochemistry 1991, 30, 343.
(c) Bhattacharyya, P.; Chakraborty, D. P. Phytochemistry
1973, 12, 1831.
HRMS (FAB): m/z [M+] calcd for C14H15NO: 213.1143; found:
213.1154.
(2) (a) Fiebig, M.; Pezzuto, J. M.; Soejarto, D. D.; Kinghorn, A.
D. Phytochemistry 1985, 24, 3041. (b) Bhattacharyya, P.;
Chakraborty, D. P. In Prog. Chem. Org. Nat. Prod., Vol. 52;
Herz W., Grisebach H., Kirby G. W., Tamm C., Springer
Verlag: Wien, 1987, 159. (c) Wu, T.-S.; Huang, S.-C.; Wu,
P.-L.; Kuoh, C.-S. Phytochemistry 1999, 52, 523.
(d) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102,
4303.
Murrayafoline A (3);6a,b Typical Procedure
A mixture of 18 (0.04 g, 0.19 mmol) and Pd(AcO)2 (0.05 g, 0.22
mmol) in glacial HOAc acid (2.5 mL), was placed in a threaded
ACE glass pressure tube with a sealed Teflon screw cap, under N2
atmosphere, and in the dark. The mixture was stirred and heated to
140 °C for 10 h. The mixture was filtered, neutralized with aq sat.
solution of NaHCO3, and extracted with EtOAc (2 × 20 mL). The
organic layer was washed with a 5% aq solution of NH4Cl (2 × 15
mL), and water (2 × 15 mL), then dried (Na2SO4), and the solvent
was removed under vacuum. The residue was purified by column
chromatography over silica gel (1.2 g, hexane–EtOAc, 9:1), under
N2 pressure, to give 3 (0.028 g, 71%) as a pale pink oil; Rf 0.67 (hex-
ane–EtOAc, 7:3).
(3) (a) Chakraborty, D. P. Planta Med. 1980, 39, 97. (b) Wu,
T.-S.; Chan, Y.-Y.; Liou, M.-J.; Lin, F.-W.; Shi, L.-S.; Chen,
K.-T. Phytother. Res. 1998, 12, S80. (c) Bringmann, G.;
Ledermann, A.; Holenz, J.; Kao, M.-T.; Busse, U.; Wu, H.
G.; François, G. Planta Med. 1998, 64, 54. (d) Wu, T.-S.;
Huang, S.-C.; Wu, P.-L.; Teng, C.-M. Phytochemistry 1996,
43, 133. (e) Chakraborty, A.; Chowdhury, B. K.;
Bhattacharyya, P. Phytochemistry 1995, 40, 295.
(4) (a) Knölker, H.-J.; Fröhner, W. J. Chem. Soc., Perkin Trans.
1 1998, 173. (b) Knölker, H.-J.; Wolpert, M. Tetrahedron
Lett. 1997, 38, 533. (c) Scott, T. L.; Söderberg, B. C. G.
Tetrahedron Lett. 2002, 43, 1621. (d) Majumdar, K. C.;
Das, U.; Kundu, A. K. Synth. Commun. 1998, 28, 1593.
(e) Chakraborty, A.; Saha, C.; Podder, G.; Chowdhury, B.
K.; Bhattacharyya, P. Phytochemistry 1995, 38, 787.
(f) Beccalli, E.; Marchesini, A.; Pilati, T. Tetrahedron 1996,
52, 3029. (g) Knölker, H.-J.; Bauermeister, M.; Pannek, J.-
B.; Wolpert, M. Synthesis 1995, 397. (h) Lee, C.-Y.; Lin,
C.-F.; Lee, J.-L.; Chiu, C.-C.; Lu, W.-D.; Wu, M.-J. J. Org.
Chem. 2004, 69, 2106.
IR (CH2Cl2): 3418, 2923, 1588, 1503, 1452, 1393, 1335, 1305,
1263, 1231, 1135, 1038, 828, 747 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.53 (s, 3 H, Me), 3.98 (s, 3 H,
OMe), 6.73 (br s, 1 H, H-2), 7.19 (ddd, J = 7.8, 6.6, 1.5 Hz, 1 H, H-
7), 7.33–7.45 (m, 2 H, H-6, H-8), 7.47 (s, 1 H, H-4), 8.01 (d, J = 8.1
Hz, 1 H, H-5), 8.16 (br s, 1 H, NH).
1H NMR (300 MHz, Me2CO-d6): d = 2.48 (s, 3 H, Me), 3.97 (s, 3 H,
OMe), 6.82 (d, J = 0.9 Hz, 1 H, H-2), 7.14 (ddd, J = 7.8, 7.1, 1.1 Hz,
1 H, H-6), 7.35 (ddd, J = 8.2, 7.1, 1.2 Hz, 1 H, H-7), 7.49 (s, 1 H,
H-4), 7.54 (ddd, J = 8.1, 1.1, 0.6 Hz, 1 H, H-8), 8.03 (dd, J = 7.8,
0.6 Hz, 1 H, H-5), 10.29 (br s, 1 H, NH).
(5) (a) Pindur, U. Chimia 1990, 44, 406; and references cited
therein. (b) Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron
1998, 54, 1585. (c) Choshi, T.; Sada, T.; Fujimoto, H.;
Nagayama, C.; Sugino, E.; Hibino, S. J. Org. Chem. 1997,
62, 2535. (d) Knölker, H.-J.; Schlechtingen, G. J. Chem.
Soc., Perkin Trans. 1 1997, 349. (e) Knölker, H.-J.; Baum,
E.; Hopfmann, T. Tetrahedron Lett. 1995, 36, 5339.
(f) Knölker, H.-J.; Reddy, K. R. Heterocycles 2003, 60,
1049. (g) Scott, T. L.; Söderberg, B. C. G. Tetrahedron
2003, 59, 6323.
13C NMR (75.4 MHz, CDCl3): d = 21.9 (Me), 55.4 (OMe), 107.6
(C-2), 110.9 (C-8), 112.5 (C-4), 117.3 (C-1a), 119.1 (C-6), 120.4
(C-5), 123.5 (C-4a or C-5a), 124.2 (C-5a or C-4a), 125.4 (C-7),
129.4 (C-3), 139.4 (C-8a), 145.3 (C-1).
13C NMR (75.4 MHz, Me2CO-d6): d = 21.3 (Me), 55.1 (OMe),
107.8 (C-2), 111.5 (C-8), 112.4 (C-4), 116.9 (C-1a), 118.8 (C-6),
120.2 (C-5), 123.4 (C-4a or C-5a), 124.3 (C-5a or C-4a), 125.4 (C-
7), 128.9 (C-3), 140.4 (C-8a), 145.9 (C-1).
MS (70 eV): m/z = 211 (100) [M+], 196 (84), 180 (10), 168 (77), 167
(6) (a) Bringmann, G.; Tasler, S.; Endress, H.; Peters, K.; Peters,
E.-M. Synthesis 1998, 1501. (b) Knölker, H.-J.;
Bauermeister, M. Tetrahedron 1993, 48, 11221.
(c) Chakraborty, D. P.; Chowdhury, B. K. J. Org. Chem.
1968, 33, 1265.
(72), 139 (13), 115 (6), 84 (5).
HRMS (FAB): m/z [M+] calcd for C14H13NO: 211.0997; found:
211.0991.
(7) For a recent synthesis of 2, see: Knölker, H.-J.; Wolpert, M.
Tetrahedron 2003, 59, 5317.
Acknowledgment
We are grateful to Dr. Hugo A. Jiménez-Vázquez for reviewing the
manuscript. We thank Fernando Labarrios for his help in spectro-
metric measurements. J. T. acknowledges DEPI/IPN (Grants
200410, 20030147, and 20040123) and CONACYT (Grants 32273-
E and 43508-Q) for financial support. A. B. thanks CONACYT for
a graduate scholarship awarded. A. B. thanks CGPI/IPN (PIFI) and
Ludwig K. Hellweg Foundation for scholarship complements. J. T.
and F. D. are fellows of the EDI-IPN and COFAA-IPN programs.
(8) (a) Chowdhury, B. K.; Chakraborty, D. P. Phytochemistry
1971, 10, 1967. (b) Chowdhury, B. K.; Chakraborty, D. P.
Chem. Ind. 1969, 549. (c) Chakraborty, D. P.;
Bhattacharyya, P.; Roy, S.; Bhattacharyya, S. P.; Biswas, A.
K. Phytochemistry 1978, 17, 834.
(9) Bringmann, G.; Ledermann, A.; François, G. Heterocycles
1995, 40, 293.
(10) Zempoalteca, A.; Tamariz, J. Heterocycles 2002, 57, 259.
(11) Hernández, R.; Sánchez, J. M.; Gómez, A.; Trujillo, G.;
Aboytes, R.; Zepeda, G.; Bates, R. W.; Tamariz, J.
Heterocycles 1993, 36, 1951.
(12) Mandal, A. B.; Gómez, A.; Trujillo, G.; Méndez, F.;
Jiménez, H. A.; Rosales, M. J.; Martínez, R.; Delgado, F.;
Tamariz, J. J. Org. Chem. 1997, 62, 4105.
(13) Mandal, A. B.; Delgado, F.; Tamariz, J. Synlett 1998, 87.
Synthesis 2004, No. 15, 2499–2504 © Thieme Stuttgart · New York

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A. Benavides et al.
PAPER
(14) Padmavathi, V.; Sumathi, R. P.; Reddy, K. V.; Reddy, A. S.;
Reddy, D. B. Synth. Commun. 2000, 30, 4007.
(16) Åkermark, B.; Eberson, L.; Jonsson, E.; Pettersson, E. J.
Org. Chem. 1975, 40, 1365.
(15) Walker, D.; Hiebert, J. D. Chem. Rev. 1967, 67, 153.
Synthesis 2004, No. 15, 2499–2504 © Thieme Stuttgart · New York