Transition metals in organic synthesis, part 100: 1 highly efficient palladium(II)-catalyzed oxidative cyclization to the 1,7,8-trioxygenated carbazole alkaloid murrayastine

Article abstract of DOI:10.1055/s-0031-1290968

Consecutive palladium-catalyzed C-N and C-C bond formation provides an efficient route to the 1,7,8-trioxygenated carbazole alkaloid murrayastine. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290968

1230▌
LETTER
1
letter
Transition Metals in Organic Synthesis, Part 100: Highly Efficient Palla-
dium(II)-Catalyzed Oxidative Cyclization to the 1,7,8-Trioxygenated Carba-
zole Alkaloid Murrayastine
Efficient Synthesis of Murrayastine
Laurent Huet, Ronny Forke, 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: 14.03.2012; Accepted after revision: 03.04.2012
7-oxygenated,13 6-oxygenated,14 2-oxygenated,15 2,7-di-
Abstract: Consecutive palladium-catalyzed C–N and C–C bond
oxygenated,15b 1,6-dioxygenated,16 2,6-dioxygenated,17
formation provides an efficient route to the 1,7,8-trioxygenated car-
and 1,7-dioxygenated carbazole alkaloids.18 Herein, we
describe a highly efficient palladium(II)-catalyzed oxida-
tive cyclization leading to the 1,7,8-trioxygenated carba-
bazole alkaloid murrayastine.
Key words: alkaloids, catalysis, cyclization, palladium
zole alkaloid murrayastine (1; Scheme 1).
In 1986, Furukawa et al. isolated murrayastine (1) from
Carbazole alkaloids have attracted a lot of interest due to
their broad range of useful biological activities.2–5 The
biogenesis of carbazole alkaloids in terrestrial plants pro-
ceeds via 3-methylcarbazole as parent compound.2,3 Sub-
sequent biogenetic transformations are oxygenation at
different positions, oxidation of the methyl group, prenyl-
ation and annulation of additional rings. Thus, the large
structural variety of naturally occurring carbazoles from
plants is generated from a key biogenetic precursor. Based
on the oxygenation pattern of the tricyclic carbazole alka-
loids, we have introduced a classification system for these
natural products.3
the stem bark of Murraya euchrestifolia Hayata collected
in Taiwan.19 The structural assignment for the natural
product was supported by synthesis (Scheme 1, approach
A). Goldberg–Ullmann coupling of the acetanilide 2 with
the bromoarene 3 was followed by hydrolysis of the am-
ide and palladium(II)-mediated cyclization to 1 (no yields
were given). We envisaged a synthesis via route B starting
from 3-bromoveratrole (4) and 2-methoxy-4-methylani-
line (5). This approach using our palladium(II)-catalyzed
oxidative cyclization of the intermediate N,N-diarylamine
as key step appeared to be much more promising.
We have developed efficient synthetic routes to highly
oxygenated carbazole alkaloids which are electron-rich
and thus, sensitive towards oxidation. Our iron-mediated
approach to carbazoles takes advantage of the activation
of the allylic C–H bonds in tricarbonyl(η4-cyclohexa-1,3-
diene)iron complexes.6 This route has been applied to the
synthesis of a broad range of carbazoles oxygenated at
different positions.7
Me
+
NHAc Br
MeO
A
OMe
OMe
Me
2
3
MeO
N
H
B
Me
MeO
OMe
+
In our palladium-catalyzed approach to carbazoles the
central biaryl C–C bond of the framework is generated in
a palladium(II)-catalyzed oxidative cyclization of an N,N-
diarylamine precursor.8 This process is based on the pal-
ladium(II)-mediated oxidative cyclization of N,N-diaryl-
amines originally reported by Åkermark in 1975.9
Although this process required stoichiometric amounts of
palladium(II) acetate, it has found several applications in
synthesis.10 In 1994, we have reported for the first time
that this cyclization becomes catalytic in palladium by re-
oxidation of palladium(0) to palladium(II) using a cop-
per(II) salt.11 Subsequently, the palladium(II)-catalyzed
cyclization was exploited for the synthesis of carbazole-
1,4-quinones.12 We also applied the palladium(II)-cata-
lyzed double C–H bond activation to the synthesis of
murrayastine (1)
H2N
MeO
Br
OMe
OMe
4
5
Scheme 1 Retrosynthetic analysis of murrayastine (1)
Regioselective ortho-bromination of guaiacol (6) using
the procedure of Pearson afforded 2-bromo-6-methoxy-
phenol (7; Scheme 2).20 Subsequent O-methylation led to
1-bromo-2,3-dimethoxybenzene (4). A preparation of 2-
methoxy-4-methylaniline (5) has been reported earlier.7h
The Buchwald–Hartwig coupling offers an easy access to
N,N-diarylamines.21 A brief study showed that using
SPhos or XPhos as ligand for the palladium(0)-catalyzed
coupling of 4 and 5 provided the best yields for the N,N-
diarylamine 8 (Table 1).22
SYNLETT 2012, 23, 1230–1234
Advanced online publication: 26.04.2012
DOI: 10.1055/s-0031-1290968; Art ID: ST-2012-B0240-L
© Georg Thieme Verlag Stuttgart · New York
Oxidative cyclization of compound 8 with stoichiometric
amounts of palladium(II) acetate in acetic acid as solvent
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Efficient Synthesis of Murrayastine
1231
amounts of the catalyst resulted in even higher turnover
numbers. However, increasing amounts of starting mate-
rial were recovered and the yield of 1 decreased signifi-
cantly (entries 9 and 10).
a
b
MeO
MeO
Br
MeO
Br
OH
OH
OMe
7
6
4
Murrayastine (1) has been fully characterized by its spec-
troscopic data,26 which were in good agreement with those
1
Me
reported for the natural product (UV, IR, H NMR and
c
d
MS).19 Although the natural product was described as col-
orless syrup,19 we have obtained murrayastine (1) as light
yellow crystals (mp 101–102 °C, with correct elemental
analysis).26 The structural assignment for murrayastine
(1) has been additionally confirmed by an X-ray crystal
structure determination (Figure 1).27
MeO
N
H
MeO
OMe
8
Me
CH2OPiv
+
MeO
MeO
N
H
N
MeO
OMe
MeO
OMe
H
murrayastine (1)
9
Scheme2 Palladium-catalyzed synthesis of murrayastine (1). Re-
agents and conditions: (a) Br2 (1 equiv), tert-BuNH2 (2 equiv),
CH2Cl2–toluene, –30 °C to r.t., 6 h (86%); (b) MeI (2 equiv), K2CO3
(3 equiv), acetone, 56 °C, 1.5 d (85%); (c) 5 (1.2 equiv), Pd(OAc)2 (7
mol%), XPhos (18 mol%), Cs2CO3 (1.4 equiv), toluene, 111 °C, 3 d
(95%); (d) Pd(OAc)2 (3 mol%), K2CO3 (5 mol%), HOPiv, 120 °C, air,
20 h (81% 1, 3% 9).
Table 1 Optimization of the Buchwald–Hartwig Coupling of Bro-
moarene 4 with Arylamine 5 to the Diarylamine 8a
Figure 1 Molecular structure of murrayastine (1) in the crystal
(ORTEP plot at the 50% probability level)
Ligandb
4 (%)c
Amount (mol%)
8, Yield (%)
BINAP
SPhos
XPhos
8
10
18
79
92
95
11
0
The best results [72–81% yield of murrayastine (1), en-
tries 5–8] have been obtained using 0.5–5 mol% of palla-
dium(II) acetate in pivalic acid at 120 °C. These
conditions afforded 3-(pivaloyloxymethyl)-1,7,8-trime-
thoxy-9H-carbazole (9) as a by-product (3–5% yield).28
Compound 9 obviously results from a palladium-cata-
lyzed pivaloyloxylation by C–H bond activation at the
methyl group and takes place subsequent to the oxidative
cyclization by twofold aryl C–H bond activation. To sup-
port this hypothesis, murrayastine (1) was treated with
palladium(II) acetate (3 mol%) and potassium carbonate
(7 mol%) in pivalic acid at 120 °C in the presence of air
for three days. These strong oxidizing conditions led
largely to decomposition (about 70%) but also afforded
compound 9 in 8% yield along with 22% of starting mate-
rial (1). If the same experiment was carried out without
palladium(II) acetate, murrayastine (1) was reisolated in
87% yield. Palladium(II)-catalyzed acetoxylations and
pivaloyloxylations have been reported previously.11,24c,29
However, to the best of our knowledge the present exam-
ple describes the first palladium(II)-catalyzed pivaloyl-
oxylation at the carbazole C-3 methyl group. We have
reported previously that donor-substituted electron-rich
carbazoles are readily decomposed by an excess of palla-
dium(II) acetate under the conditions of the oxidative cy-
clization.13,14 Therefore, in these cases the yields for the
oxidative cyclization achieved with only catalytic
3
a All reactions were carried out using Pd(OAc)2 (7 mol%) and Cs2CO3
(1.4 equiv) in toluene at reflux for 3 d.
b BINAP = 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl, SPhos =
2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, XPhos = 2-dicy-
clohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
c Reisolated starting material (4).
gave murrayastine (1) in only 36% yield and led largely to
decomposition (Table 2, entry 1). Using 10 mol% of pal-
ladium(II) acetate and 2.5 equivalents of copper(II) ace-
tate either in acetic acid, or with a few drops of DMF and
microwave heating,23 led to similar yields of the natural
product and left some unchanged starting material (entries
2 and 3). Performing the palladium(II)-catalyzed (10
mol%) cyclization in dioxane at reflux afforded murrayas-
tine (1) in up to 51% yield (entry 4). In pivalic acid as sol-
vent at 120 °C and with air as reoxidant for the
palladium,15b,24 the turnover of the oxidative cyclization
was much better (entries 5–10). Using 3 mol% of palladi-
um(II) acetate gave the best result (81% of 1, turnover
number: 28).25 With just 0.5 mol% of the palladium cata-
lyst, the yield of murrayastine (1) was still 72% corre-
sponding to a turnover number of 154 (entry 8). Lower
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1230–1234

1232
L. Huet et al.
LETTER
Table 2 Results for the Palladium(II)-Catalyzed Oxidative Cyclization of the Diarylamine 8 to Murrayastine (1)
Recovered 8 (%)a
Yield (%) of 9
TONb
Entry Pd(OAc)2
Reaction conditions
Yield (%) of 1
1
2
3
120 mol%
10 mol%
10 mol%
HOAc, reflux, Ar, 2 h
36
27
31
–
–
–
–
–
HOAc, 2.5 equiv Cu(OAc)2, reflux, air, 24 h
33
61
2.7
3.1
MW, 2.5 equiv Cu(OAc)2, DMF,c air, 2 h
dioxane, 2.5 equiv Cu(OAc)2, reflux, air, 48 h
HOPiv, 0.1 equiv K2CO3, 120 °C, air, 20 h
HOPiv, 0.05 equiv K2CO3, 120 °C, air, 20 h
HOPiv, 0.03 equiv K2CO3, 120 °C, air, 2 d 4 h
HOPiv, 0.02 equiv K2CO3, 120 °C, air, 4 d
HOPiv, 0.01 equiv K2CO3, 120 °C, air, 3 d 4 h
HOPiv, 0.01 equiv K2CO3, 120 °C, air, 6 d
4
5
10 mol%
5 mol%
51
79
81
75
72
47
23
34
–
5.1
16.8
28
–
5
6
3 mol%
traces
18
3
7
1 mol%
4
79
8
0.5 mol%
0.25 mol%
0.10 mol%
16
5
154
188
230
9
23
traces
traces
10
38
a Recovered starting material 8.
b Turnover number for the catalytically active palladium(II) species based on all products formed by palladium(II)-catalyzed oxidative cycliza-
tion (1 and 9).
c Microwave heating with five drops of DMF.23
amounts of palladium(II) are considerably higher than
those of the stoichiometric reaction. Thus, low concentra-
tions of palladium(II) prevent decomposition of the carba-
zole already generated under the conditions of the
oxidative cyclization. The present synthesis of a highly
electron-rich trioxygenated carbazole represents a strong
support for this conclusion. At the same time, donor-sub-
stituted N,N-diarylamines like 8 cyclize very readily in the
presence of palladium(II) which is attributed to the high
reactivity towards initial electrophilic attack by palladi-
um(II) and subsequent cyclopalladation to the pallada-
cycle 10 followed by reductive elimination leading to
murrayastine (1; Scheme 3). Such palladacycles have
been proposed as intermediates of this process many years
ago.9,30 Recently, we have isolated and characterized for
the first time a palladacycle intermediate of this type from
a palladium(II)-catalyzed oxidative cyclization of an
N,N-diarylamine.1
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MeO
N
H
MeO
OMe
10
Scheme 3 Intermediate diaryl palladium(II) complex 10 proposed
for the oxidative cyclization to murrayastine (1)
Carbazoles are of strong current interest due to their po-
tential as antimicrobial agents.31 The present synthesis
provides murrayastine (1) in two steps and 77% yield
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© Georg Thieme Verlag Stuttgart · New York

LETTER
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(22) Characteristic spectroscopic data for the diarylamine 8: pale
yellow solid; mp 78 °C. IR (ATR): n= 3413, 3003, 2968,
2931, 2854, 2836, 1601, 1586, 1498, 1478, 1464, 1447,
1421, 1401, 1336, 1297, 1251, 1220, 1190, 1165, 1134,
1082, 1037, 993, 916, 934, 838, 808, 773, 739 cm–1. 1H
NMR (500 MHz, CDCl3): δ = 2.33 (s, 3 H), 3.857 (s, 3 H),
3.863 (s, 3 H), 3.88 (s, 3 H), 5.90 (br s, 1 H), 6.46 (m, 1 H),
6.72–6.73 (m, 2 H), 6.92 (d, J = 2.4 Hz, 1 H), 6.93 (s, 1 H),
7.28 (d, J = 8.3 Hz, 1 H). 13C NMR and DEPT (125 MHz,
CDCl3): δ = 21.20 (Me), 55.60 (Me), 55.78 (Me), 60.23
(Me), 103.44 (CH), 107.98 (CH), 111.78 (CH), 117.50 (CH),
120.80 (CH), 123.85 (CH), 129.38 (C), 130.90 (C), 137.46
(C), 138.01 (C), 149.64 (C), 153.00 (C). MS (EI): m/z (%) =
273 (72) [M+], 258 (7), 243 (8), 227 (100), 184 (11). Anal.
Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.33; H, 6.87; N, 5.13.
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203.
(25) Experimental Procedure for the Palladium(II)-
Catalyzed Oxidative Cyclization to Murrayastine (1):
The diarylamine 8 (200 mg, 0.732 mmol), K2CO3 (5.4 mg,
0.039 mmol) and pivalic acid (500 mg) were placed in a 10-
mL test tube. The mixture was heated at 120 °C under air and
recrystallized Pd(OAc)2 (5.0 mg, 0.022 mmol) was added.
After 20 h of vigorous stirring at 120 °C in the presence of
air, the reaction mixture was cooled to r.t. The residue was
dissolved in EtOAc and washed several times with a sat.
solution of K2CO3 and then with brine. After extraction with
EtOAc, the combined organic layers were dried over
Na2SO4. Removal of the solvent and flash chromatography
(pentane–CH2Cl2–EtOAc, gradient elution from 40:5:1 to
18:5:1) on silica gel provided murrayastine (1; yield: 160
mg, 81%) and 3-(pivaloyloxymethyl)-1,7,8-trimethoxy-9H-
carbazole (9; yield: 9.4 mg, 3%).
(26) Characteristic spectroscopic data for murrayastine (1): light
yellow crystals; mp 101–102 °C. UV (MeOH): λmax = 223,
245, 253, 297, 321, 334 nm. IR (ATR): n=3398, 3343,
3247, 2955, 2921, 2851, 1633, 1583, 1498, 1462, 1440,
1418, 1383, 1344, 1281, 1250, 1221, 1209, 1179, 1134,
1088, 1065, 1031, 1021, 971, 935, 819, 781 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 2.51 (s, 3 H), 3.97 (s, 3 H), 3.99 (s,
3 H), 4.02 (s, 3 H), 6.69 (s, 1 H), 6.86 (d, J = 8.5 Hz, 1 H),
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(f) Ito, C.; Nakagawa, M.; Wu, T.-S.; Furukawa, H. Chem.
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(12) (a) Knölker, H.-J.; Fröhner, W. J. Chem. Soc., Perkin Trans.
1 1998, 173. (b) Knölker, H.-J.; Reddy, K. R.; Wagner, A.
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© Georg Thieme Verlag Stuttgart · New York
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7.38 (s, 1 H), 7.65 (d, J = 8.5 Hz, 1 H), 8.22 (br s, 1 H). 13
C
(C), 133.89 (C), 134.22 (C), 145.46 (C), 150.20 (C), 178.50
(C=O). MS (EI): m/z (%) = 371 (55) [M+], 270 (100).
(29) For examples, see: (a) Raposo, M. M. M.; Oliveira-Campos,
A. M. F.; Shannon, P. V. R. J. Chem. Res., Synop. 1997, 354.
(b) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2004, 126, 9542. (c) Gu, R.; Van Hecke, K.; Van
Meervelt, L.; Toppet, S.; Dehaen, W. Org. Biomol. Chem.
2006, 4, 3785. (d) Zheng, X.; Song, B.; Xu, B. Eur. J. Org.
Chem. 2010, 4376. (e) Jiang, H.; Chen, H.; Wang, A.; Liu,
X. Chem. Commun. 2010, 7259. (f) Chernyak, N.; Dudnik,
A. S.; Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2010,
132, 8270. (g) Huang, C.; Chernyak, N.; Dudnik, A. S.;
Gevorgyan, V. Adv. Synth. Catal. 2011, 353, 1285.
(h) Wang, L.; Xia, X.-D.; Guo, W.; Chen, J.-R.; Xiao, W.-J.
Org. Biomol. Chem. 2011, 9, 6895. (i) Emmert, M. H.;
Cook, A. K.; Xie, Y. J.; Sanford, M. S. Angew. Chem. Int.
Ed. 2011, 50, 9409; Angew. Chem. 2011, 123, 9581.
(30) For reviews, see: (a) Becalli, E. M.; Broggini, G.; Martinelli,
M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318.
NMR and DEPT (125 MHz, CDCl3): δ = 21.90 (Me), 55.46
(Me), 56.77 (Me), 60.85 (Me), 106.10 (CH), 107.12 (CH),
112.21 (CH), 115.50 (CH), 119.57 (C), 124.79 (C), 128.09
(C), 129.58 (C), 133.84 (C), 134.21 (C), 145.24 (C), 149.99
(C). MS (EI): m/z (%) = 271 (100) [M+], 256 (46), 213 (46),
170 (19). Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32; N,
5.16. Found: C, 71.04; H, 6.51; N, 4.90.
(27) Crystal data for murrayastine (1): C16H17NO3, crystal size:
0.25 × 0.24 × 0.23 mm3, M = 271.31 g mol–1, orthorhombic,
space group: Pbca, λ = 0.71073 Å, a = 9.158(1), b =
11.517(1), c = 26.488(3) Å, V = 2793.8(5) Å3, Z = 8, Dcalcd
=
1.290 g cm–3, μ = 0.089 mm–1, T = 198(2) K, θ range = 3.23–
27.00°; reflections collected: 23879, independent: 3044 (Rint
= 0.0611), 189 parameters. The structure was solved by
direct methods and refined by full-matrix least-squares on
F2; final R indices [I > 2σ(I)]: R1 = 0.0566, wR2 = 0.1022;
maximal residual electron density: 0.198 e Å–3. CCDC
870640 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
(b) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem.
Int. Ed. 2009, 48, 9792; Angew. Chem. 2009, 121, 9976.
(c) You, S.-L.; Xia, J.-B. Top. Curr. Chem. 2010, 292, 165.
(d) Han, W.; Ofial, A. R. Synlett 2011, 1951. (e) Yeung,
C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
www.ccdc.cam.uk/data_request/cif.
(28) Characteristic spectroscopic data for 3-(pivaloyloxymethyl)-
1,7,8-trimethoxy-9H-carbazole (9): yellow solid. 1H NMR
(600 MHz, CDCl3): δ = 1.24 (s, 9 H), 3.98 (s, 3 H), 4.01 (s,
3 H), 4.02 (s, 3 H), 5.25 (s, 2 H), 6.85 (s, 1 H), 6.89 (d, J =
8.5 Hz, 1 H), 7.57 (s, 1 H), 7.68 (d, J = 8.5 Hz, 1 H), 8.36 (br
s, 1 H). 13C NMR and DEPT (150 MHz, CDCl3): δ = 27.20
(3 × Me), 38.79 (C), 55.55 (Me), 56.77 (Me), 60.89 (Me),
67.18 (CH2), 105.95 (CH), 106.51 (CH), 112.74 (CH),
115.64 (CH), 119.48 (C), 124.54 (C), 128.32 (C), 129.73
(f) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(31) (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.; 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, 374.
Synlett 2012, 23, 1230–1234
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