Transition metals in organic synthesis, Part 87:1 An efficient palladium-catalyzed route to 2-oxygenated and 2,7-dioxygenated carbazole alkaloids - Total synthesis of 2-methoxy-3-methylcarbazole, glycosinine, clausine L, mukonidine, and clausin

Article abstract of DOI:10.1055/s-2008-1078508

Optimization of the palladium(II)-catalyzed oxidative cyclization of N,N-diarylamines opens up the way to an efficient synthesis of 2-oxygenated and 2,7-dioxygenated carbazole alkaloids including 2-methoxy-3-methylcarbazole, glycosinine, clausine L, mukon

Full text of DOI:10.1055/s-2008-1078508

1870
LETTER
Transition Metals in Organic Synthesis, Part 87:1 An Efficient Palladium-
Catalyzed Route to 2-Oxygenated and 2,7-Dioxygenated Carbazole Alkaloids
– Total Synthesis of 2-Methoxy-3-methylcarbazole, Glycosinine, Clausine L,
Mukonidine, and Clausine V
P
alladium-Cataly
o
ze
d
Route to
n
2-Oxygenat
n
ed and 2,7-D
y
ioxygenated
C
arba
F
zole
A
lkaloid
o
s
rke, Micha P. Krahl, Frank Däbritz, Anne Jäger, Hans-Joachim Knölker*
Department Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax +49(351)46337030; E-mail: hans-joachim.knoelker@tu-dresden.de
Received 7 April 2008
R
Abstract: Optimization of the palladium(II)-catalyzed oxidative
cyclization of N,N-diarylamines opens up the way to an efficient
synthesis of 2-oxygenated and 2,7-dioxygenated carbazole alka-
loids including 2-methoxy-3-methylcarbazole, glycosinine,
clausine L, mukonidine, and clausine V.
OH
N
H
2-hydroxy-3-methylcarbazole (1)
mukonal (2)
mukonidine (3)
R = Me
R = CHO
R = COOMe
Key words: alkaloids, antibiotics, catalysis, cyclizations, palladi-
um
R
Increasing interest in carbazole alkaloids can be attributed
to the useful biological activities found in this class of nat-
ural products.1–4 3-Methylcarbazole is the parent com-
pound for the biogenesis of carbazole alkaloids in
terrestrial plants.2 Oxygenation at different positions, oxi-
dation of the methyl group, prenylation, and annelation of
additional rings occur in vivo on further biogenetic trans-
formation. The 2-oxygenated and the 2,7-dioxygenated
carbazole alkaloids result from these biogenetic pathways
(Figure 1).
OMe
N
H
2-methoxy-3-methylcarbazole (4)
glycosinine (O-methylmukonal) (5)
clausine L (O-methylmukonidine) (6)
R = Me
R = CHO
R = COOMe
CHO
MeO
OMe
MeO
OR
It is interesting that various 2-oxygenated carbazole alka-
loids have been isolated from different parts of the Indian
medicinal plant Murraya koenigii.2 2-Hydroxy-3-methyl-
carbazole (1)5 has been obtained from the roots and
mukonal (2)6 from the stem bark of this plant, which is
also known as curry-leaf tree or in Hindi karipatta be-
cause the leaves of this tree provide the flavor for curry.
The isolation of mukonidine (3), has been reported
by Chakraborty in 1978 from the stem bark of Murraya
koenigii7 and by Wu in 1993 along with clausine L (O-
methylmukonidine) (6) from the Chinese medicinal plant
Clausena excavata.8 One year later, Bhattacharyya ob-
tained clausine L (6) also from the stem bark of Murraya
koenigii.9 Chakraborty’s assignment was supported by
synthesis from 2-hydroxycarbazole7,10 and from
mukonal.6 However, there has been some debate on the
structure of ‘Chakraborty’s mukonidine’ as the melting
point and the few spectroscopic data given (UV, IR, and
EI-MS)7 were not in agreement with those reported by
Wu.8 Bhattacharyya isolated 2-methoxy-3-methylcarba-
zole (4) from the petroleum ether extract of the seeds of
N
H
N
H
clausine V (9)
7-methoxymukonal (7)
7-methoxy-O-methylmukonal (8)
R = H
R = Me
Figure 1 2-Oxygenated and 2,7-dioxygenated carbazole alkaloids
Murraya koenigii.11 In 1990, Lange described the isola-
tion of O-methylmukonal (5) and 7-methoxy-O-methyl-
mukonal (8) from Murraya siamensis.12 Two years later,
Bhattacharyya obtained compound 5 from the dried roots
of Glycosmis pentaphylla and renamed it glycosinine.13 7-
Methoxymukonal (7) has been isolated from the root bark
of Clausena harmandiana14 and Murraya siamensis.12
The extracts of both plants are applied as folk medicine in
Thailand. Wu described the isolation of clausine V (9)
from the root bark of Clausena excavata.15 Clausine V (9)
is lacking the carbon substituent at C3, which most likely
has been lost in biogenesis via oxidation and decarboxy-
lation.
In 1994, we described the synthesis of 2-methoxy-3-
methylcarbazole (4) by the iron-mediated arylamine cy-
clization with concomitant aromatization.16 Two years
later, we developed a molybdenum-mediated approach to
2-oxygenated carbazoles, which was applied to the syn-
thesis of 2-hydroxy-3-methylcarbazole (1), mukonal (2),
SYNLETT 2008, No. 12, pp 1870–1876
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Advanced online publication: 02.07.2008
DOI: 10.1055/s-2008-1078508; Art ID: G12108ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed Route to 2-Oxygenated and 2,7-Dioxygenated Carbazole Alkaloids
1871
Table 1 Oxidative Cyclization of 12 to 2-Methoxy-3-methylcarba-
zole (4).
2-methoxy-3-methylcarbazole (4), and glycosinine
(O-methylmukonal) (5).17 In 1997, an air-mediated oxida-
tive cyclization of the appropriate iron complex followed
by aromatization of the intermediate tricarbonyliron-coor-
Pd(OAc)2
Reoxidanta
–
Reaction conditionsb Yield (%)c
dinated 4a,9a-dihydro-9H-carbazole was used for the syn- 1.2 equiv
AcOH, reflux, 1.5 h
AcOH, reflux, 15h
AcOH, 90 °C, 21 h
PivOH, 90 °C, 3 h
48 (9)
thesis of mukonidine (3).18 However, these three routes
30 mol%
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
58 (–)
provided the carbazoles only in 10–30% overall yield.
30 mol%
56 (33)
63 (26)
We have been searching for more efficient routes to this
class of carbazoles. Recently, we described a short iron-
mediated synthesis of 2,7-dioxygenated carbazoles lead-
ing to 7-methoxy-O-methylmukonal (8) in three steps and
35% overall yield.19 Another palladium-catalyzed ap-
proach was used for the synthesis of 7-oxygenated carba-
zole alkaloids.20 In the present work, we report the
application of our palladium-catalyzed route to a highly
efficient synthesis of 2-oxygenated and 2,7-dioxygenated
carbazoles.
30 mol%
a An amount of 2.5 equiv of reoxidant was used.
b All reactions were carried out under an argon atmosphere.
c Value in parentheses: recovered starting material 12.
tion21 of iodobenzene (10) with 3-methoxy-4-methyl-
aniline (11) provided the diarylamine 12. Oxidative
cyclization of 12 in acetic acid at reflux with stoichiomet-
ric amounts of palladium(II) acetate22 afforded 2-meth-
oxy-3-methylcarbazole (4) in 48% yield (Table 1).23
Using 30 mol% of palladium(II) acetate and 2.5 equiva-
lents cupric acetate as reoxidant for palladium, the yield of
4 increased to 58%. Performing the reaction at 90 °C led
to less decomposition of 12. Finally, using pivalic acid as
solvent,24 the reaction provided 63% of 4 along with 26%
of recovered 12 and proceeded faster. Oxidation of 4 with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) led
quantitatively to glycosinine (5).23 The structural assign-
ment for glycosinine (5) has been additionally confirmed
by an X-ray crystal structure determination (Figure 2).25
Our present synthesis affords glycosinine (5) in three
steps and 45% overall yield. As a comparison, an elegant
synthesis of glycosinine (5) recently reported by St. Jean
Jr. and coworkers required four steps (50% overall
yield).4i We have shown previously, that ether cleavage
converts 2-methoxy-3-methylcarbazole (4) into 2-hy-
droxy-3-methylcarbazole (1) (78% yield) and glycosinine
(5) into mukonal (2) (81% yield).17
Me
Me
a
+
I
OMe
N
H
H2N
OMe
10
11
12
Me
CHO
c
b
OMe
OMe
N
N
H
H
2-methoxy-3-methylcarbazole (4)
glycosinine (5)
COOMe
COOMe
OH
e
d
OMe
N
H
N
H
clausine L (6)
mukonidine (3)
f
COOH
OMe
N
H
isomukonidine (13)
Scheme 1 Synthesis of 2-methoxy-3-methylcarbazole (4), glyco-
sinine (O-methylmukonal) (5), clausine L (6), mukonidine (3), and
isomukonidine (13). Reagents and conditions: a) 11 (1.1 equiv),
Pd(OAc)2 (9 mol%), BINAP (10 mol%), Cs2CO3 (1.6 equiv), toluene,
110 °C, 2 d (72%); b) Pd(OAc)2 (30 mol%), Cu(OAc)2 (2.5 equiv),
pivalic acid, 90 °C, 3 h (63% 4 and 26% 12); c) DDQ (2.2 equiv),
MeOH–H2O (17:1), 25 °C, 20 min (99%); d) MnO2 (25 equiv), KCN
(5 equiv), MeOH–H2O (15:1), 25 °C, 18 h (96%); e) BBr3 (2.2 equiv),
CH2Cl2, –78 °C to –4 °C, 1 h (95%); f) KOH (22 equiv), EtOH–H2O
(2:1), 50 °C, 4 h (85%).
Figure 2 Molecular structure of glycosinine (5) in the crystal
Further oxidation of glycosinine (5) with manganese di-
oxide in methanol in the presence of potassium cyanide26
provided clausine L (6), which on cleavage of the methyl
ether provided mukonidine (3) (mp 189 °C).1,23 The spec-
troscopic data of our synthetic mukonidine were in full
agreement with those reported by Wu.8 Ester cleavage of
clausine L (6) afforded isomukonidine (13), which may be
a potential structural alternative for ‘Chakraborty’s
The palladium-catalyzed construction of the carbazole
framework led to 2-methoxy-3-methylcarbazole (4) as
initial target (Scheme 1). Palladium(0)-catalyzed amina-
Synlett 2008, No. 12, 1870–1876 © Thieme Stuttgart · New York

1872
R. Forke et al.
LETTER
tate (78% yield of 17 and 12% of starting material 16).
Fine-tuning of the reaction conditions demonstrated that
at least in the present case the stoichiometric cyclization
in pivalic acid was not more efficient (Table 2). However,
the catalytic reaction was most efficient in pivalic acid as
solvent and provided after two hours of microwave heat-
ing at 130 °C 67% yield of 17 along with the regioisomer
18 (4% yield) and 7% of recovered 16.29 Treatment of 17
with in situ generated trimethylsilyl iodide30 resulted in a
selective cleavage of the triisopropylsilyl ether and af-
forded quantitatively the 7-hydroxycarbazole 19. Heating
with pyridinium chloride22d,31 provided 89% of the 2,7-di-
hydroxycarbazole 20 and 11% of 19.
Figure 3 Molecular structure of isomukonidine (13) in the crystal
mukonidine’. We found that the UV spectra of iso-
mukonidine (13) and mukonidine (3) are very similar.23
The melting point of isomukonidine (13) (226 °C) is
much higher as compared to mukonidine (168–170 °C)8
and closer to the value reported for ‘Chakraborty’s
mukonidine’ (245 °C).7 An X-ray analysis confirmed the
structural assignment for isomukonidine (13, Figure 3).27
Table 2 Oxidative Cyclization of 16 to Carbazole 17
Pd(OAc)2
1.1 equiv
1.1 equiv
10 mol%
15 mol%
20 mol%
Reoxidanta
–
Reaction conditionsb Yield (%)c
AcOH, Ar, 2 h
PivOH, Ar, 2 h
AcOH, air, 2 h
AcOH, air, 2 h
PivOH, air, 2 h
78 (12)
54 (40)
48 (28)
57 (21)
67 (7)
–
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
For the synthesis of 2,7-dioxygenated carbazoles with two
different oxygen substituents, we started from the triiso-
propylsilyl-protected building block 14 (Scheme 2).
Buchwald–Hartwig amination of 3-bromophenyl triiso-
propylsilyl ether (14) with 4-cyano-3-methoxyaniline
(15) led to the diarylamine 16. Oxidative cyclization of 16
a An amount of 2.5 equiv of reoxidant was used.
b All reactions were carried out by microwave heating at 130 °C.
with palladium(II) acetate afforded 3-cyano-7-triisopro- c Value in parentheses: Recovered starting material 16.
pylsilyloxy-2-methoxycarbazole (17) as major product
and the regioisomeric 3-cyano-7-triisopropylsilyloxy-4-
Reduction of 17 using diisobutylaluminum hydride at low
methoxycarbazole (18) as minor product (usually 4–6%
temperature32 afforded the aldehyde 21 (Scheme 3). Se-
yield). For the oxidative cyclization of 16 microwave
lective cleavage of the triisopropylsilyl ether with tetrabu-
heating at 130 °C was applied.28,29 The best result was ob-
tylammonium fluoride (TBAF) led to 7-hydroxy-O-
tained using stoichiometric amounts of palladium(II) ace-
CN
CN
a
+
TIPSO
Br
TIPSO
OMe
H2N
OMe
N
H
14
15
16
MeO
CN
CN
b
+
TIPSO
TIPSO
OMe
N
H
N
H
18
17
c
d
CN
CN
HO
OMe
HO
OH
N
H
N
H
19
20
Scheme 2 Synthesis of 3-cyano-2,7-dihydroxycarbazole (20). Reagents and conditions: a) 15 (1.2 equiv), Pd(OAc)2 (7 mol%), S-Phos (15
mol%), Cs2CO3 (1.65 equiv), toluene, 100 °C, 20 h (98%); b) Pd(OAc)2 (1.1 equiv), AcOH, MW: 130 °C, 2 h (78% 17 and 12% 16); c) NaI
(1.4 equiv), TMSCl (1 equiv), MeCN, 25 °C to 50 °C, 22 h (100%); d) pyridine·HCl (50 equiv), MW: 155 °C, 30 min (89% 20 and 11% 19).
Synlett 2008, No. 12, 1870–1876 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Route to 2-Oxygenated and 2,7-Dioxygenated Carbazole Alkaloids
1873
CN
CHO
a
TIPSO
OMe
TIPSO
OMe
N
H
N
H
17
21
CHO
b
HO
OMe
N
H
22
Scheme 3 Synthesis of 7-hydroxy-O-methylmukonal (22). Reagents and conditions: a) DIBAL (2.5 equiv), CH2Cl2, –78 °C, 3 h (78% 21 and
14% 17); b) TBAF (1.5 equiv), DMF, 0 °C, 5 min (85%).
a
+
MeO
Br
MeO
N
H
OMe
H2N
OMe
23
24
25
b
MeO
OMe
N
H
clausine V (9)
Scheme 4 Synthesis of clausine V (9). Reagents and conditions: a) 24 (1.4 equiv), Pd(OAc)2 (6 mol%), BINAP (6 mol%), Cs2CO3 (1.3 equiv),
toluene, 110 °C, 2 d (100%); b) Pd(OAc)2 (1.2 equiv), AcOH, 117 °C, 50 min (67%).
methylmukonal (22), a regioisomer of 7-methoxy- In conclusion, we have developed a highly efficient syn-
mukonal (7).
thesis of 2-oxygenated and 2,7-dioxygenated carbazole
alkaloids via a sequence of palladium(0)-catalyzed ami-
nation and palladium(II)-catalyzed cyclization by double
C–H bond activation. According to our recent findings,34
the carbazoles described above could be of interest due to
their potential as anti-TB agents.
Finally, we applied our method to a short synthesis of
clausine V (9) (Scheme 4).33 Buchwald–Hartwig amina-
tion of 3-bromoanisole (23) with m-anisidine (24) afford-
ed di(3-methoxyphenyl)amine (25). Using stoichiometric
amounts of palladium(II) acetate, the oxidative cycliza-
tion led to clausine V (9) in 67% yield. The best results for
the catalytic process were achieved with 10 mol% of pal-
ladium(II) acetate and of the reoxidant, either copper(II)
or manganese(III) acetate, under oxygen (Table 3). Our
synthesis provides clausine V (9) in two steps and 67%
overall yield.
References and Notes
(1) Part 86: Forke, R.; Jäger, A.; Knölker, H.-J. Org. Biomol.
Chem. 2008, 6, in press.
(2) For some comprehensive reviews, see: (a) Chakraborty, D.
P.; Roy, S. In Progress in the Chemistry of Organic Natural
Products, Vol. 57; Herz, W.; Grisebach, H.; Kirby, G. W.;
Steglich, W.; Tamm, C., Eds.; Springer: Wien, 1991, 71.
(b) Chakraborty, D. P. In The Alkaloids, Vol. 44; Cordell, G.
A., Ed.; Academic Press: New York, 1993, 257.
Table 3 Oxidative Cyclization of 25 to Clausine V (9)
Pd(OAc)2
1.2 equiv
10 mol%
10 mol%
10 mol%
Reoxidanta
–
Reaction conditionsc Yield (%)
(c) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102,
4303. (d) Knölker, H.-J. Top. Curr. Chem. 2005, 244, 115.
(e) Knölker, H.-J.; Reddy, K. R. In The Alkaloids, Vol. 65;
Cordell, G. A., Ed.; Academic Press: Amsterdam, 2008, 1.
air, 50 min
air, 9 h
67
37
49
47
Cu(OAc)2
Cu(OAc)2
O2, 9 h
b
Mn(OAc)3
O2, 6 h
a An amount of 10 mol% of reoxidant was used.
b Mn(OAc)3·2 H2O.
c All reactions were carried out in AcOH at reflux.
Synlett 2008, No. 12, 1870–1876 © Thieme Stuttgart · New York

1874
R. Forke et al.
LETTER
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(23) Characteristic Spectroscopic Data of the 2-Oxygenated
and 2,7-Dioxygenated Carbazole Alkaloids
2-Methoxy-3-methylcarbazole (4)
Colorless crystals; mp 221 °C (lit.11 223 °C). UV (MeOH):
l
max = 230, 237, 257, 264 (sh), 301, 331 nm. IR (ATR):
n = 3402, 2992, 2919, 2851, 1631, 1609, 1496, 1455, 1340,
1304, 1230, 1194, 1175, 1139, 1109, 1038, 1014, 1003, 885,
819, 766, 749, 725 cm–1. 1H NMR (500 MHz, acetone-d6):
d = 2.32 (s, 3 H), 3.89 (s, 3 H), 7.02 (s, 1 H), 7.12 (t, J = 7.8
Hz, 1 H), 7.27 (t, J = 7.8 Hz, 1 H), 7.43 (d, J = 7.8 Hz, 1 H),
7.82 (s, 1 H), 7.97 (d, J = 7.8 Hz, 1 H), 10.05 (br s, 1 H). 13
C
NMR and DEPT (125 MHz, acetone-d6): d = 16.87 (CH3),
55.68 (CH3), 93.35 (CH), 111.27 (CH), 116.73 (C), 118.95
(C), 119.43 (CH), 119.79 (CH), 121.94 (CH), 124.14 (C),
124.60 (CH), 140.61 (C), 140.74 (C), 158.20 (C). MS (EI):
m/z (%) = 211 (100) [M+], 210 (11), 196 (77), 180 (7), 168
(25), 167 (35), 166 (10). Anal. Calcd (%) for C14H13NO: C,
79.59; H, 6.20; N, 6.63. Found: C, 79.12; H, 6.64; N, 6.13.
Glycosinine (O-Methylmukonal) (5)
Colorless crystals; mp 196–198 °C (lit.12 189.0–189.5 °C,
lit.13 185 °C). UV (MeOH): lmax = 235, 243 (sh), 276, 295,
351 nm. IR (ATR): n = 3323, 2922, 2851, 1664, 1603, 1575,
1487, 1460, 1436, 1412, 1381, 1345, 1328, 1309, 1259,
1244, 1200, 1169, 1145, 1030, 974, 917, 901, 854, 841, 764,
744, 724 cm–1. 1H NMR (500 MHz, acetone-d6): d = 4.02 (s,
3 H), 7.16 (s, 1 H), 7.22 (t, J = 7.8 Hz, 1 H), 7.37 (t, J = 7.8
Hz, 1 H), 7.49 (d, J = 7.8 Hz, 1 H), 8.14 (d, J = 7.8 Hz, 1 H),
8.51 (s, 1 H), 10.46 (s, 1 H), 10.66 (br s, 1 H). 13C NMR and
DEPT (75 MHz, acetone-d6): d = 56.32 (CH3), 93.78 (CH),
111.89 (CH), 117.95 (C), 119.58 (C), 120.74 (CH), 120.95
(CH), 121.35 (CH), 124.38 (C), 126.37 (CH), 141.61 (C),
146.43 (C), 162.37 (C), 188.57 (CHO). MS (EI): m/z
(%) = 225 (100) [M+], 224 (26), 210 (9), 209 (14), 208 (22),
196 (8), 180 (21), 179 (42), 168 (21), 154 (28). Anal. Calcd
(%) for C14H11NO2: C, 74.65; H, 4.92; N, 6.22. Found: C,
74.77; H, 4.98; N, 6.19.
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(12) Ruangrungsi, N.; Ariyaprayoon, J.; Lange, G. L.; Organ, M.
G. J. Nat. Prod. 1990, 53, 946.
(13) Jash, S. S.; Biswas, G. K.; Bhattacharyya, S. K.;
Bhattacharyya, P.; Chakraborty, A.; Chowdhury, B. K.
Phytochemistry 1992, 31, 2503.
(14) Chaichantipyth, C.; Pummangura, S.; Naowsaran, K.;
Thanyavuthi, D.; Anderson, J. E.; McLaughlin, J. L. J. Nat.
Prod. 1988, 51, 1285.
Clausine L (6)
Colorless crystals; mp 172–173 °C (lit.8 133–135 °C; lit.9
204–205 °C). UV (MeOH): lmax = 235, 241, 269, 282 (sh),
319, 333 nm. IR (ATR): n = 3264, 2951, 2922, 2852, 1690,
1632, 1608, 1574, 1486, 1462, 1427, 1392, 1348, 1313,
1278, 1239, 1201, 1163, 1115, 1082, 1035, 979, 950, 909,
875, 825, 789, 775, 766, 750, 727 cm–1. 1H NMR (500 MHz,
acetone-d6): d = 3.85 (s, 3 H), 3.92 (s, 3 H), 7.15 (s, 1 H),
7.20 (t, J = 7.8 Hz, 1 H), 7.35 (t, J = 7.8 Hz, 1 H), 7.49 (d,
J = 7.8 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 8.54 (s, 1 H),
10.53 (br s, 1 H). 13C NMR and DEPT (75 MHz, acetone-d6):
d = 51.77 (CH3), 56.44 (CH3), 94.85 (CH), 111.83 (CH),
113.76 (C), 116.97 (C), 120.47 (CH), 120.63 (CH), 124.19
(C), 124.99 (CH), 126.00 (CH), 141.53 (C), 144.70 (C),
159.83 (C), 167.45 (C=O). MS (EI): m/z (%) = 255 (100)
[M+], 240 (5), 224 (89), 209 (18), 194 (9), 181 (7), 166 (14),
153 (15), 139 (11). HRMS: m/z calcd for C15H13NO3 [M+]:
255.0895; found: 255.0889.
(15) Wu, T.-S.; Huang, S.-C.; Wu, P.-L.; Kuoh, C.-S.
Phytochemistry 1999, 52, 523.
(16) Knölker, H.-J.; Bauermeister, M. J. Indian Chem. Soc. 1994,
71, 345.
(17) Knölker, H.-J.; Goesmann, H.; Hofmann, C. Synlett 1996,
737.
(18) (a) Knölker, H.-J.; Wolpert, M. Tetrahedron Lett. 1997, 38,
533. (b) Knölker, H.-J.; Wolpert, M. Tetrahedron 2003, 59,
5317.
(19) Kataeva, O.; Krahl, M. P.; Knölker, H.-J. Org. Biomol.
Chem. 2005, 3, 3099.
(20) Krahl, M. P.; Jäger, A.; Krause, T.; Knölker, H.-J. Org.
Biomol. Chem. 2006, 4, 3215.
(21) (a) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
(b) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131.
Mukonidine (3)
Colorless crystals; mp 189 °C (lit.8 168–170 °C; lit.10
188 °C). UV (MeOH): lmax = 235, 243, 270 (sh), 276 (sh),
284, 325, 338 nm. IR (ATR): n = 3347, 2952, 2922, 2852,
Synlett 2008, No. 12, 1870–1876 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Route to 2-Oxygenated and 2,7-Dioxygenated Carbazole Alkaloids
1875
1644, 1627, 1582, 1481, 1464, 1432, 1373, 1363, 1329,
1258, 1236, 1189, 1165, 1118, 1093, 1014, 991, 949, 898,
(s, 1 H). 13C NMR and DEPT (125 MHz, acetone-d6):
d = 56.26 (CH3), 93.69 (CH), 98.04 (CH), 110.15 (CH),
117.14 (C), 118.49 (C), 119.25 (C), 119.79 (CH), 121.49
(CH), 143.23 (C), 146.54 (C), 157.47 (C), 161.59 (C),
188.56 (CHO). Anal. Calcd (%) for C14H11NO3: C, 69.70; H,
4.60; N, 5.81. Found: C, 69.89; H, 4.84; N, 5.44.
Clausine V (9)
871, 821, 784, 762, 740, 719 cm–1. 1H NMR (500 MHz,
acetone-d6): d = 4.00 (s, 3 H), 6.93 (s, 1 H), 7.20 (t, J = 7.8
Hz, 1 H), 7.36 (t, J = 7.8 Hz, 1 H), 7.47 (d, J = 7.8 Hz, 1 H),
8.09 (d, J = 7.8 Hz, 1 H), 8.62 (s, 1 H), 10.52 (br s, 1 H),
11.07 (s, 1 H). 13C NMR and DEPT (75 MHz, acetone-d6):
d = 52.60 (CH3), 97.70 (CH), 105.95 (C), 111.79 (CH),
117.85 (C), 120.58 (CH), 120.89 (CH), 123.41 (CH), 124.30
(C), 126.51 (CH), 141.96 (C), 146.62 (C), 161.62 (C),
172.22 (C=O). MS (EI): m/z (%) = 241 (46) [M+], 209 (100),
181 (20), 153 (33), 126 (10), 104 (10).
Colorless crystals; mp >270 °C (decomp.) (lit.15 228–
230 °C; lit.33 272–274 °C). UV (MeOH): lmax = 224 (sh),
227, 231, 236 (sh), 238, 259, 311, 319 nm. IR (ATR):
n = 3378, 2937, 2837, 1607, 1573, 1502, 1453, 1323, 1263,
1230, 1198, 1156, 1118, 1025, 934, 823, 803, 728 cm–1. 1H
NMR (500 MHz, acetone-d6): d = 3.84 (s, 6 H), 6.76 (dd,
J = 8.5, 2.2 Hz, 2 H), 6.98 (d, J = 2.2 Hz, 2 H), 7.84 (d,
J = 8.5 Hz, 2 H), 10.07 (br s, 1 H). 13C NMR and DEPT (125
MHz, acetone-d6): d = 55.66 (2 CH3), 95.55 (2 CH), 108.37
(2 CH), 117.97 (2 C), 120.59 (2 CH), 142.27 (2 C), 159.11
(2 C). MS (EI): m/z (%) = 227 (100) [M+], 212 (92), 184
(19), 169 (17), 141 (6). Anal. Calcd (%) for C14H13NO2: C,
73.99; H, 5.77; N, 6.16. Found: C, 73.55; H, 6.16; N, 6.68.
(24) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
16496.
Isomukonidine (13)
Colorless crystals; mp 226 °C (decomp.) (‘Chakraborty’s
mukonidine’, lit.7 245 °C). UV (EtOH): lmax = 235, 241,
269, 278 (sh), 281, 320, 334 nm. IR (ATR): n = 3206, 3180,
2922, 2851, 1702, 1625, 1608, 1582, 1492, 1459, 1439,
1357, 1328, 1303, 1246, 1224, 1192, 1159, 1078, 1024,
1010, 968, 914, 874, 819, 778, 764, 751, 716 cm–1. 1H NMR
(500 MHz, acetone-d6): d = 4.13 (s, 3 H), 7.24 (t, J = 7.8 Hz,
1 H), 7.27 (s, 1 H), 7.39 (t, J = 7.8 Hz, 1 H), 7.51 (d, J = 7.8
Hz, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 8.77 (s, 1 H), 10.62 (br s,
1 H), 10.88 (br s, 1 H). 13C NMR and DEPT (125 MHz,
acetone-d6): d = 57.08 (CH3), 94.56 (CH), 111.62 (C),
111.88 (CH), 118.10 (C), 120.72 (CH), 120.84 (CH), 123.97
(C), 126.24 (CH), 126.37 (CH), 141.58 (C), 145.02 (C),
158.90 (C), 166.56 (C=O). MS (EI): m/z (%) = 241 (100)
[M+], 226 (5), 224 (9), 194 (5), 182 (11), 168 (6), 154 (14),
153 (6). Anal. Calcd (%) for C14H11NO3: C, 69.70; H, 4.60;
N, 5.81. Found: C, 69.84; H, 4.81; N, 5.92.
(25) Crystal Data for Glycosinine (5)
C14H11NO2, crystal size: 0.34 × 0.21 × 0.09 mm3, M =
225.24 g mol–1, monoclinic, space group: P21/c, l = 0.71073
Å, a = 11.235 (1), b = 13.717 (1), c = 7.259 (2) Å,
b = 106.38 (1)°, V = 1073.3 (3) Å3, Z = 4, Dcalcd = 1.394
g cm–3, m = 0.094 mm–1, T = 198 (2) K, q range = 3.28–
30.00°; reflections collected: 26896, independent: 3108
(Rint = 0.0999), 159 parameters. The structure was solved by
direct methods and refined by full-matrix least-squares on
F2; final R indices [I > 2s(I)]: R1 = 0.0514, wR2 = 0.1018;
maximal residual electron density: 0.273 e Å–3. CCDC-
686500 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.uk/data_request/cif.
3-Cyano-7-hydroxy-2-methoxycarbazole (19)
Colorless crystals; mp 251–252 °C. UV (MeOH):
lmax = 220, 244, 282, 322, 336 nm. IR (ATR): n = 3529,
3385, 3364, 3324, 3205, 2923, 2841, 2219, 1612, 1574,
1474, 1450, 1429, 1400, 1357, 1322, 1283, 1263, 1243,
1202, 1143, 1115, 1026, 954, 899, 845, 819, 810, 721 cm–1.
1H NMR (500 MHz, acetone-d6): d = 3.97 (s, 3 H), 6.79 (dd,
J = 8.4, 2.1 Hz, 1 H), 6.94 (d, J = 2.1 Hz, 1 H), 7.14 (s, 1 H),
7.89 (d, J = 8.4 Hz, 1 H), 8.21 (s, 1 H), 8.47 (br s, 1 H), 10.45
(br s, 1 H). 13C NMR and DEPT (125 MHz, acetone-d6):
d = 56.43 (CH3), 93.45 (C), 94.23 (CH), 97.72 (CH), 110.21
(CH), 116.10 (C), 118.26 (C), 118.47 (C), 121.41 (CH),
125.36 (CH), 142.88 (C), 144.55 (C), 157.40 (C), 159.90
(C). Anal. Calcd (%) for C14H10N2O2: C, 70.58; H, 4.23; N,
11.76. Found: C, 70.99; H, 4.71; N, 11.30.
(26) (a) Manganese dioxide (precipitated, active) from Merck
(art. 805958). (b) Corey, E. J.; Gilman, N. W.; Ganem, B. E.
J. Am. Chem. Soc. 1968, 90, 5616. (c) Knölker, H.-J.
J. Prakt. Chem. 1995, 337, 75.
(27) Crystal Data for Isomukonidine (13)
C14H11NO3, crystal size: 0.32 × 0.29 × 0.28 mm3,
M = 241.24 g mol–1, monoclinic, space group: C2/c,
l = 0.71073 Å, a = 16.423 (3), b = 7.5231 (15), c = 18.548
(4) Å, b = 96.25 (3)°, V = 2278.1 (8) Å3, Z = 8, Dcalcd = 1.407
g cm–3, m = 0.100 mm–1, T = 298 (2) K, q range = 3.13–
30.02°; reflections collected: 34016, independent: 3328
(Rint = 0.0590), 168 parameters. The structure was solved by
direct methods and refined by full-matrix least-squares on
F2; final R indices [I > 2s(I)]: R1 = 0.0430, wR2 = 0.1125;
maximal residual electron density: 0.316 e Å–3. CCDC-
686501 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.uk/data_request/cif.
3-Cyano-2,7-dihydroxycarbazole (20)
Colorless crystals; mp >260 °C (decomp.). UV (MeOH):
lmax = 220, 244, 277, 282, 323, 337 nm. IR (ATR): n = 3349,
3315, 2921, 2851, 2218, 1613, 1475, 1448, 1420, 1393,
1326, 1283, 1216, 1190, 1145, 987, 953, 882, 844, 822, 806,
789, 752, 724 cm–1. 1H NMR (500 MHz, acetone-d6):
d = 6.77 (dd, J = 8.4, 2.1 Hz, 1 H), 6.91 (d, J = 2.1 Hz, 1 H),
7.05 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 8.16 (s, 1 H), 8.46 (br
s, 1 H), 9.44 (br s, 1 H), 10.29 (br s, 1 H). 13C NMR and
DEPT (125 MHz, acetone-d6): d = 92.51 (C), 97.62 (CH),
97.82 (CH), 110.06 (CH), 116.31 (C), 118.45 (C), 118.80
(C), 121.34 (CH), 124.87 (CH), 143.15 (C), 144.93 (C),
157.49 (C), 157.92 (C).
(28) Sridharan, V.; Martín, M. A.; Menéndez, J. C. Synlett 2006,
2375.
7-Hydroxy-O-methylmukonal (22)
Light yellow crystals; mp >240 °C (decomp.). UV (MeOH):
(29) Experimental Procedure for the Microwave-Assisted
Palladium(II)-Catalyzed Oxidative Cyclization
The diarylamine 16 (400 mg, 1.01 mmol), Pd(OAc)2 (46.3
mg, 0.21 mmol), Cu(OAc)2 (458 mg, 2.52 mmol), and
pivalic acid (4.7 g) were heated in a 10 mL microwave vessel
for 2 h at 130 °C. The reaction mixture was extracted with a
sat. solution of K2CO3 until the aqueous layer showed no
further blue color. The aqueous layer was extracted with
Et2O and the combined organic layers were dried with
lmax = 223, 242, 284 (sh), 300, 348 nm. IR (ATR): n = 3384,
3310, 2920, 2846, 1655, 1603, 1583, 1498, 1469, 1400,
1364, 1320, 1236, 1199, 1157, 1104, 1036, 953, 921, 907,
860, 842, 817, 800, 745, 735 cm–1. 1H NMR (500 MHz,
acetone-d6): d = 3.99 (s, 3 H), 6.79 (dd, J = 8.4, 2.1 Hz, 1 H),
6.94 (d, J = 2.1 Hz, 1 H), 7.08 (s, 1 H), 7.92 (d, J = 8.4 Hz,
1 H), 8.35 (s, 1 H), 8.45 (br s, 1 H), 10.41 (br s, 1 H), 10.44
Synlett 2008, No. 12, 1870–1876 © Thieme Stuttgart · New York

1876
R. Forke et al.
LETTER
MgSO4. Removal of the solvent in vacuum and flash
chromatography (PE–Et2O, gradient elution from 4:1 to 1:1)
of the crude product on SiO2 provided 3-cyano-7-triiso-
propylsilyloxy-4-methoxycarbazole (18) (yield 17.0 mg,
4%) as colorless crystals (mp 141–143 °C), then the
diarylamine 16 (yield 28.2 mg, 7%) as colorless crystals,
and, as the most polar fraction, 3-cyano-7-triisoprop-
ylsilyloxy-2-methoxycarbazole (17) (yield 266.0 mg, 67%)
as colorless crystals (mp 180–181 °C).
(32) Winterfeldt, E. Synthesis 1975, 617.
(33) For a previous synthesis, see: Hsieh, B. R.; Litt, M. H.
Macromolecules 1985, 18, 1388.
(34) (a) Choi, T. A.; Czerwonka, R.; Fröhner, W.; Krahl, M. P.;
Reddy, K. R.; Franzblau, S. G.; Knölker, H.-J.
ChemMedChem 2006, 1, 812. (b) Choi, T. A.; Czerwonka,
R.; Knöll, J.; Krahl, M. P.; Reddy, K. R.; Franzblau, S. G.;
Knölker, H.-J. Med. Chem. Res. 2006, 15, 28. (c) Choi, T.
A.; Czerwonka, R.; Forke, R.; Jäger, A.; Knöll, J.; Krahl, M.
P.; Krause, T.; Reddy, K. R.; Franzblau, S. G.; Knölker,
H.-J. Med. Chem. Res. 2008, 17, DOI: 10.1007/s00044-007-
9073-0.
(30) Olah, G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra, R.
J. Org. Chem. 1979, 44, 1247.
(31) Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 249.
Synlett 2008, No. 12, 1870–1876 © Thieme Stuttgart · New York

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