Regioselective synthesis of 1-hydroxycarbazoles via anionic [4+2] cycloaddition of furoindolones: A short synthesis of murrayafoline-A

Article abstract of DOI:10.1016/j.tetlet.2005.12.048

Suitably N-protected furoindolones react regioselectively with a variety of Michael acceptors in the presence of LDA to give 1-hydroxycarbazoles in a single-pot process and in good yields. The methodology has been applied to the synthesis of murrayafoline

Full text of DOI:10.1016/j.tetlet.2005.12.048

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1071–1075
Regioselective synthesis of 1-hydroxycarbazoles via anionic
[4+2] cycloaddition of furoindolones: a short
synthesis of murrayafoline-A
D. Mal,* B. Senapati and P. Pahari
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 8 November 2005; revised 1 December 2005; accepted 7 December 2005
Available online 27 December 2005
Abstract—Suitably N-protected furoindolones react regioselectively with a variety of Michael acceptors in the presence of LDA to
give 1-hydroxycarbazoles in a single-pot process and in good yields. The methodology has been applied to the synthesis of murraya-
foline-A.
Ó 2005 Elsevier Ltd. All rights reserved.
Carbazoles are ubiquitous structural subunits of numer-
ous naturally occurring compounds as well as synthetic
materials. Over the past four decades, a wide range of
biologically active carbazole alkaloids have been iso-
lated from plant sources. Many of these natural prod-
ucts display biological properties such as antitumor,
psychotropic, anti-inflammatory, antihistaminic, anti-
biotic and antioxidative activities.1 As synthetic materi-
als, many carbazole derivatives exhibit photoreactive,
photoconductive and light emitting properties.2 Carbaz-
oles have also been recognized as a useful scaffold in
anion binding studies.3 Consequently, the synthesis of
carbazoles has been a vigorously active area of study.4
regioselective routes to functionalized/substituted car-
bazoles from nitrogen substituted biaryls via a pyrrole
ring-formation approach and from benzene/indole
derivatives by the benzannulation approach or by ther-
mal electrocyclization methodology.5 Recently, Knolker
and Reddy extensively reviewed the synthesis of biolog-
ically active carbazole alkaloids.6 We now report a new
synthesis of 1-oxygenated carbazoles by benzannulation
of furoindolones with several Michael acceptors. This
methodology provides a simple and straightforward
regioselective route for the preparation of 1-oxygenated
multi-substituted carbazoles.
Our continued interest in the application of anionic
[4+2] cycloaddition7 of isobenzofuranones prompted
us to investigate the anionic reactivity of furoindolones
(Scheme 1) towards the synthesis of 1-hydroxy
carbazoles.
The conventional applications of electrophilic substitu-
tions of simple carbazoles are limited to the preparation
of 3- and 6-substituted carbazoles. Accordingly, consid-
erable efforts have been devoted to the development of
O
R
R
R
base
O
O
R
E
E
E
N
P
O
N
P
N
P
N
P
O
O
OH
E
P = Protecting group, E = Electron withdrawing group
Scheme 1. Proposed methodology for the synthesis of substituted carbazoles.
Keywords: Carbazole; Cycloaddition; Furoindolone; Murrayafoline-A.
*
Corresponding author. Tel.: +91 3222 283318; fax: +91 3222 282252; e-mail: dmal@chem.iitkgp.ernet.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.048

1072
D. Mal et al. / Tetrahedron Letters 47 (2006) 1071–1075
X
X
X
O
a,b or c
O
O
ref. 8
N
O
N
R
N
O
O
3
2
H
R
1
3a: R = COCMe3, X = H
3b: R = Me, X = H
3c: R = CH2Ph, X = H
3d: R = CH2Ph, X = OMe
2a: R = CO2Et, X = H
2b: R = SO2Ph, X = H
1a: X = H
1b: X = OMe
Scheme 2. Reagents and conditions: (a) n-BuLi, Me3COCl , dry THF, 71% for 3a; (b) LDA, MeI, dry THF, 84% for 3b; (c) K2CO3, PhCH2Cl, NaI,
dry acetone, 62% for 3c and 69% for 3d.
Table 1. Preparation of N-protected carbazoles using furoindolones and Michael acceptors
Entry
Furoindolone
Michael acceptor
Carbazole
Yield (%)
72
O
CO2Me
1
N
N
CO2Me
O
OH
OR
4
3b
Me
Me
Me
Me
CO2Me
2
3b
78 (5a)
76 (5b)
N
CO2Me
Me
5a: R = H
5b: R = Me
CN
OH
3
4
3b
3b
81
65
N
6
CN
Me
SO2Ph
OH
N
SO2Ph
7
Me
Me
OH
5
6
3b
55
64
CO2Me
Me
N
8
Me
O
CO2Me
OH
N
CO2Me
N
O
3c
9
Ph
Ph
Me
Me
CO2Me
N
R
7
3c
67 (10a)
81 (10b)
OH
CO2Me
AlCl3
10a:
R = CH2Ph
CH2Cl2
10b: R = H
CO2Me
COOMe
COOMe
8
9
3c
85
58
CO2Me
Me
N
OH
11
Ph
MeO
MeO
Me
O
CO2Me
N
N
O
CO2Me
OH
3d
12
Ph
Ph

D. Mal et al. / Tetrahedron Letters 47 (2006) 1071–1075
1073
Our previous study with N-ethoxycarbonyl derivative 2a
and N-phenylsulfonyl derivative 2b prepared from furo-
indolones 1a was fairly successful in providing a route to
indoloquinones.8 However, these synthons were not
reactive with Michael acceptors like acrylates and crot-
onates, thus eluding entry to simple carbazole deriva-
tives. Nevertheless, this study gave us an important
cue for further investigations. We observed that both
N-ethoxycarbonyl and N-phenylsulfonyl groups were
cleaved during the course of the reaction in the presence
of LDA at temperatures below ambient temperature.
We, therefore, decided to examine LDA-stable N-pro-
tection of compound 1a for the proposed cycloaddition
(Scheme 1).
For the access to 1,2,3-trisubstituted carbazoles, methyl
crotonate was reacted with 3b in the presence of LDA at
À78 °C and the desired product 5a was obtained in 78%
yield. To confirm its structure, it was converted to the O-
methyl derivative 5b. In striking contrast, ethyl cinna-
mate did not undergo annulation with 3b under similar
conditions. Both N-methylfuroindolone 3b and ethyl
cinnamate were recovered, after work-up of the reac-
tion. Similarly, methyl vinyl ketone and mesityl oxide
were not compatible for the reaction with 3b. Both
ketones were destroyed during the reaction. On the other
hand, cyano-containing and sulfone-containing Michael
acceptors (entries 3 and 4) underwent smooth annula-
tions with compound 3b. The reaction of 3b with methyl
methacrylate (entry 5) is noteworthy. It proceeded
through a cascade of reactions to give 1-hydroxy-2-
methylcarbazole 8.
Since the N-pivaloyl group of an indole is stable9 to
LDA below 40–45 °C, our initial studies began with
compound 3a (Scheme 2), which was readily prepared
in 71% yield from the parent furoindolone 1a by piva-
loylation with n-BuLi and pivaloyl chloride at À78 °C.
When compound 3a was treated with lithium diisopro-
pylamide (3.0 equiv), followed by methyl acrylate at
À78 °C and the resulting mixture worked-up in the
usual manner, the expected carbazole was not obtained.
Compound 1a was recovered in a substantial amount,
indicating that the pivaloyl group of 3a was removed
in the presence of LDA before the desired cycloaddition
could take place. We then proceeded to examine the
reactivity of N-methylfuroindolone 3b. This was pre-
pared in 84% yield from compound 1a by methylation
with LDA and iodomethane. Treatment of 3b with
LDA, followed by methyl acrylate gave, after work-
up, compound 4 in 72% yield. It was evident from this
result that the stability of the N-protection towards
LDA was crucial to the success of the benzannulation.
Although the Sammes annulation10 of phthalides is
known to involve the intermediacy of hydroxytetra-
lones, no such intermediate could be isolated from the
reaction with 3b. In order to generalize the observations,
we performed similar annulations with several Michael
acceptors for the preparation of N-protected carbazoles.
The results are summarized in Table 1.
In order to increase the utility of the products 4–8,
demethylation of the carbazole nitrogen of compound
8 was examined. The literature procedures11 tested on
8 resulted in formation of complex mixtures of products.
Consequently, we chose benzyl derivative 3c as an ann-
ulating agent. Annulation of compound 3c with methyl
acrylate in the presence of LDA gave compound 9 in
64% yield. We then carried out the same type of annula-
tion reaction with several Michael acceptors for the
preparation of N-benzylated carbazoles. Compound
3d, prepared from 1b also responded to the annulation
reaction with methyl crotonate and produced tetrasub-
stituted carbazole compound 12. We performed the N-
debenzylation of 10a with AlCl3 in dichloromethane to
give carbazole 10b in 81% yield.12
Having recognized the potential use of compound 10a in
the synthesis of murrayafoline-A 15, we proceeded as
shown in Scheme 3. For the crucial demethoxycarbonyl-
ation of 10a, different literature methods13 were investi-
gated. When subjected to aq NaOH, the reaction
stopped after hydrolysis of the ester group to the corre-
sponding acid derivative. The reaction of 10a with HBr
in AcOH returned the starting material even after
Me
Me
Me
Me2SO4, K2CO3
KOH, MeOH
CO2Me
reflux, 5 h
56%
Acetone, reflux
77%
N
N
N
OH
OMe
OH
Ph
Ph
Ph
10a
14
13
CF3CO2H
CF3SO3H (cat.)
Me
72%
O
Me
Me
N
OMe
Me
Single step
Ref. 16
Two steps
Ref. 15
N
H
N
H
N
H
OMe
O
16
15
17
OMe
murrayaquinone-A
murrayafoline-A
murrastifoline-F
Scheme 3. Synthesis of murrayafoline-A.

1074
D. Mal et al. / Tetrahedron Letters 47 (2006) 1071–1075
Van Dijken, A.; Bastiaansen, J. A. M.; Kiggen, N. M. M.;
Langeveld, B. M. W.; Rothe, C.; Monkman, A.; Bach, I.;
Stoessel, P.; Brunner, K. J. Am. Chem. Soc. 2004, 126,
7718–7727; (c) Thomas, K. R.; Lin, J. T.; Tao, Y. T.; Ko,
C. W. J. Am. Chem. Soc. 2001, 123, 9404–9411; (d)
Kawamura, Y.; Yanagida, S.; Forrest, S. R. J. Appl. Phys.
2002, 92, 87–93.
extended reflux and a similar outcome was obtained
when 10a was treated with DBU in toluene at reflux.
Finally, we achieved demethoxycarbonylation of 10a with
concentrated KOH solution in methanol to give 13 in
moderate yield. The low yield may be attributed to the
sensitivity of 1-hydroxy-3-methylcarbazole 13 to aerial
decomposition during its isolation. Compound 13 was
converted to the O-methyl derivative 14 (77%) by reflux-
ing with a mixture of K2CO3 and Me2SO4 in acetone. It
was observed that compound 14 was stable and easy to
handle with respect to 13. However, debenzylation of
compound 14 proved problematical. A wide range of
literature methods14 were investigated for the debenz-
ylation but without success. Finally, debenzylation
was successfully accomplished by refluxing N-benzyl-
murrayafoline-A (14) in TFA with a catalytic amount
of TfOH for 20–25 min to produce 15. This synthesis
of 15 is a formal synthesis of murrayaquinone-A 1615
and murrastifoline-F 17,16 as they have both been
previously reported from compound 15.
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In conclusion, the anionic [4+2] cycloaddition of furoin-
dolones has been introduced as a regioselective route for
synthesizing 1-oxygenated carbazoles. Further applica-
tions of this methodology for the synthesis of other
highly substituted carbazoles and biscarbazoles are
underway.
Acknowledgements
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Financial support from the CSIR and DST, New Delhi
is gratefully acknowledged. B.S. and P.P. acknowledge
the receipt of their Senior Research Fellowships from
the CSIR, New Delhi.
8. Mal, D.; Senapati, B. K.; Pahari, P. Synlett 2005, 994–996.
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12. Selected data: Compound 3b: Mp: 147 °C; FT-IR: 1747,
1
1571, 1456, 1321. H NMR (200 MHz, CDCl3): d 7.64 (d,
1H, J = 8.2); 7.40–7.50 (m, 2H); 7.15–7.30 (m, 1H); 5.39
(s, 2H); 3.95 (s, 3H); 13C NMR (50 MHz, CDCl3):
d 163.82, 144.33, 133.87, 128.65, 126.17, 121.07, 120.18,
111.30, 66.98, 30.03; (one signal could not be identified
due to overlapping). HRESIMS (m/z): 188.0709, calcd for
C11H9NO2: 188.0712.
1
Compound 4: Mp: 99 °C. H NMR (200 MHz, CDCl3): d
11.68 (s, 1H); 8.04 (d, 1H, J = 7.8); 7.50–7.66 (m, 3H);
7.40 (d, 1H, J = 8.1); 7.21–7.24 (m, 1H); 4.23 (s, 3H); 3.97
(s, 3H); 13C NMR (50 MHz, CDCl3): d 171.96, 150.80,
142.29, 128.58, 128.52, 126.42, 122.15, 120.86, 119.48,
119.22, 110.96, 109.09, 107.71, 52.11, 31.94; ESIMS
[M+H]+: 256.0979, [MÀOMe]+: 224.0728.
Compound 10a: Mp: 123 °C; 1H NMR (200 MHz,
CDCl3): d 12.34 (s, 1H); 8.03 (d, 1H, J = 7.8); 7.36–7.45
(m, 3H); 7.15–7.26 (m, 6H); 5.94 (s, 2H); 4.00 (s, 3H); 2.68
(s, 3H); 13C NMR (50 MHz, CDCl3): d 173.46, 151.92,
150.75, 142.20, 138.94, 130.71, 128.47, 127.56, 127.07,
126.99, 126.48, 122.22, 120.93, 119.37, 113.79, 109.83,
108.18, 52.0, 48.45, 24.57; HRESIMS (m/z): 346.1442
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