A novel synthesis of N-protected carbazoles involving electrocyclization of in situ generated enamines

Article abstract of DOI:10.1016/j.tetlet.2005.04.016

A new route for the synthesis of carbazoles has been realized through the intermediacy of 2,3-divinylindoles involving an electrocyclization followed by aromatization.

Full text of DOI:10.1016/j.tetlet.2005.04.016

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4045–4048
A novel synthesis of N-protected carbazoles involving
electrocyclization of in situ generated enamines
Arasambattu K. Mohanakrishnan* and Ramalingam Balamurugan
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Received 9 March 2005; revised 30 March 2005; accepted 5 April 2005
Available online 20 April 2005
Abstract—A new route for the synthesis of carbazoles has been realized through the intermediacy of 2,3-divinylindoles involving an
electrocyclization followed by aromatization.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Ever since the first isolation of the carbazole alkaloid,
murrayanine1 organic chemists have been interested in
the synthesis of carbazole alkaloids due to their promis-
ing biological activities. In particular, many biomimetic
oxidation products of 3-methylcarbazole have been iso-
lated and their syntheses have been widely reported.2
Recently Kno¨lker and Reddy extensively reviewed the
synthesis of biologically active carbazole alkaloids.3
CO2Et
i) 5 eq. DMF.DMA
110 0C, 4 h
CO2Et
Me
X
CHO
N
N
ii) NaIO4 / DMF-H2O
SO2Ph
SO2Ph
2
1
Scheme 1.
Thermal electrocyclization methodology has been
widely used for the synthesis of carbazole based natural
products.4 Mohanakrishnan and Srinivasan outlined a
novel synthesis of phenylsulfonylcarbazoles involving
electrocyclization of N-phenylsulfonyl 2,3-divinylindoles
as the key step.5 Very recently syntheses of multifunc-
tional carbazoles6 have been reported involving either
cycloaddition or base mediated cyclization.
We presumed that the condensation of vinyl ester 1 with
DMF/DMA followed by oxidation using NaIO4 might
lead to aldehyde 2. However when 1 was reacted with
5 equiv of DMF/DMA at 110 ꢁC for 4 h followed by
treatment with NaIO4, aldehyde 2 was not obtained,
Scheme 1.
When 1 was reacted with DMF/DMA and the resulting
crude product was analyzed by mass spectrometry, the
presence of M+ ions at m/z 379, 365, 239 and 225, corre-
sponding to carbazoles 3a,b and 4a,b were observed,
Scheme 2.
In continuation of our interest in carbazole based alka-
loids we wanted to prepare the aldehyde 2. In this con-
nection, a survey of the literature revealed that CoeÕs
procedure has been widely utilized for the synthesis of
benzaldehydes, pyridine aldehydes, naphthaldehydes
and quinoline aldehydes.7–9 The enamine intermediates
involved in CoeÕs protocol have also been utilized for
the synthesis of indoles,10 azaindoles,11 quinolones12
etc. Very recently the acetals DMF/DMA, DMA/
DMA were used for formylation/acetylation of acetylenic
systems.13
R
R
N
N
H
SO2Ph
3a R = CO2Et
3b R = CO2Me
4a R = CO2Et
4b R = CO2Me
Keywords: Enamine; 2,3-Divinylindole; Electrocyclization; Carbazole.
*
Corresponding author. Tel.: +91 44 24451108; fax: +91 44
22352494; e-mail: mohan_67@hotmail.com
Scheme 2.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.016

4046
A. K. Mohanakrishnan, R. Balamurugan / Tetrahedron Letters 46 (2005) 4045–4048
CO2Et
NMe2
CO2Et
NMe2
2 eq. DMF.DMA
110 0C, 3 h
-NMe2
1
3a
N
N
SO2Ph
SO2Ph
Scheme 3.
The mechanism of formation of carbazole 3a can be
understood as the electrocyclization of an intermediate
enamine followed by aromatization, Scheme 3. The
formation of the remaining carbazoles 3b, 4a and b
would involve the secondary reaction of 3a with meth-
oxide ions. This was further confirmed by prolonging
the reaction period or by using excess of DMF/DMA,
when carbazoles 4a and b were the major products.
The formation of carbazole 3a also supported our
earlier observation5 that N-protection is essential for
smooth electrocyclization of 2,3-divinylindoles. Thus
the presence of the phenylsulfonyl group on the indole
nitrogen conveys typical triene character to the 2,3-
divinylindole system and thereby electrocyclization is
facilitated.
The enamine-based electrocyclization methodology was
then tested with a variety of 2-methyl-3-vinylindoles
and 3-methyl-2-vinylindoles 1–1h, and the results are
detailed in Table 1. Comparatively the reaction with
When the reaction was carried out using 2 equiv of
DMF/DMA for 3 h at 110 ꢁC, the carbazole 3a was
obtained as sole product in 73% yield, Scheme 3.
Table 1. Preparation of carbazoles using vinylindoles and N,N-dimethylformamide and N,N-dimethylacetamide dimethyl acetals
Entry
Vinylindoles14
Acetal
Carbazole15
Yield, % & (mp)
CO2Et
CO2Et
1
DMF/DMA
73 (180)
Me
SO2Ph
N
N
SO2Ph
3a
1
CO2Me
CO2Me
2
DMF/DMA
70 (188)
Me
SO2Ph
1b
N
N
SO2Ph
3b
CO2Et
CO2Et
Me
Me
SO2Ph
3
4
DMA/DMA
DMA/DMA
67 (174)
68 (171)
N
N
SO2Ph
3c
1
CO2Me
CO2Me
Me
Me
SO2Ph
1b
N
N
SO2Ph
3d
CO2Me
CO2Me
MeO
MeO
MeO
Me
SO2Ph
5
DMF/DMA
68 (183)
N
N
SO2Ph
3e
1c
CO2Me
Me
CO2Me
Me
MeO
6
7
DMA/DMA
DMF/DMA
55 (175)
65 (102)
N
N
SO2Ph
3f
SO2Ph
1c
CO2Me
CO2Me
CO2Me
N
N
CO2Me
SO2Ph
1d
PhO2S
3g

A. K. Mohanakrishnan, R. Balamurugan / Tetrahedron Letters 46 (2005) 4045–4048
4047
Table 1 (continued)
Entry
Vinylindoles14
Acetal
Carbazole15
Yield, % & (mp)
Me
CO2Me
CO2Me
8
9
DMF/DMA
0
N
N
SO2Ph
3h
SO2Ph
1e
MeO2C
CO2Me
CO2Me
CO2Me
CO2Me
DMF/DMA
DMF/DMA
65 (210)
62 (128)
N
N
SO2Ph
1f
SO2Ph
3i
MeO2C
MeO2C
CO2Me
10
Me
SO2Ph
1g
N
N
SO2Ph
3j
MeO2C
MeO2C
CO2Me
CO2Me
Me
11
12
DMA/DMA
DMF/DMA
53
Me
N
N
SO2Ph
SO2Ph
1g
3k
CO2Me
CO2Me
Ph
40 (182)
N
N
PhO2S
SO2Ph
1h
3l
2-methyl-3-vinylesters afforded the corresponding car-
bazoles in better yields (entries 1–7). The expected annul-
ation failed with 3-methyl-2-vinylindole 1e even under
forcing conditions (entry 8). However the annulation
was successful with 3-carbomethoxymethyl-2-vinylin-
dole 1f (entry 9). Hence the failure in the case of 1e
can be attributed to the relatively less acidic nature of
3-methyl group. The use of DMA/DMA instead of
DMF/DMA also led to the respective carbazoles in al-
most comparable yields (entries 3 and 4). But in two
cases, the yields of the carbazoles were relatively less
when DMA/DMA was employed (entries 6 and 11).
The annulation of 2-benzyl-3-vinylindole 1h led to the
isolation of 1-phenylcarbazole 3l in 40% yield (entry 12).
EtO2C
CO2Et
CO2Et
Me
Me
Me
S
5
6
EtO2C
Attempted annulations with substrates 5 and 6 were
unsuccessful even under vigorous conditions and the
starting materials were recovered unchanged. Similarly,
the attempted tris-annulation of 7 led only to the trans-
esterification product 8 in 30% yield, Scheme 4.
Me
MeO2C
Me
CO2Et
CO2Me
6 eq. DMF.DMA
Me
Me
Me
Me
110 0C, 4 h
CO2Et
It is noteworthy that in the case of 3-vinyl-2-methylpyr-
role 9, the expected bis-annulation was achieved but the
secondary reactions, namely cleavage of the phen-
ylsulfonyl groupand transesterification, could not be
CO2Me
7
8
Scheme 4.
R2
MeO2C
R2
R1
CO2Me
R1
4 eq. DMF.DMA
110 0C, 4 h
+
Me
Me
N
N
H
N
SO2Ph
SO2Ph
9
10 (15-20 %)
11 (10%)
R
1 & R2 = CO2Et, CO2Me
Scheme 5.

4048
A. K. Mohanakrishnan, R. Balamurugan / Tetrahedron Letters 46 (2005) 4045–4048
´
Maury, O.; Guegan, J.-P.; Dupau, P.; Toupet, L.; Bozec,
H. L. Synthesis 2003, 4, 577–583.
controlled; a mixture of products 10 and 11 was ob-
tained in low yields, Scheme 5. Use of less than 4 equiv
of DMF/DMA led to the formation of vinylindoles as
mono annulated products.
9. Riesgo, E. C.; Jin, X.; Thummel, R. P. J. Org. Chem. 1996,
61, 3017–3022.
10. Caron, S.; Vazquez, E. J. Org. Chem. 2003, 68, 4104–4107.
11. Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem.
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13. Lee, K. Y.; Lee, M. J.; Gowrisankar, S.; Kim, J. N.
Tetrahedron Lett. 2004, 45, 5043–5046.
In conclusion, we have developed a convenient proce-
dure for the synthesis of functionalized carbazoles
involving electrocyclization methodology based on in
situ generated enamine intermediates. The further appli-
cation of this methodology to the synthesis of carbazole-
containing natural products is in progress.
14. The starting vinylesters are prepared via the Wittig
reaction of the corresponding aldehydes.
15. All the carbazoles 3a–l gave satisfactory spectral and
analytical data. Typical experimental procedure for 3a: to a
stirred solution of vinyl ester (0.5 g, 1.35 mmol) in dry
DMF (1.5 mL), DMF/DMA (322 mg, 2.71 mmol) was
added. The reaction mixture was heated at 110 ꢁC under
N2 for 3 h. It was then poured into 2% aq HCl (15 mL)
and extracted with CHCl3 (2 · 20 mL). The combined
extracts were washed with water (10 mL) and brine
(10 mL) and dried (Na2SO4). Removal of solvent followed
by column chromatographic purification (silica gel,
EtOAc–hexane 1:5) afforded carbazole 3 as a colourless
solid (0.38 g, 73%).
Acknowledgements
We thank UGC, New Delhi (F.12-140/2001 SR-1) for
the financial support. R.B. thanks the UGC for fellow-
ship. Financial support to the Department by DST-
FIST is also acknowledged.
References and notes
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1
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J = 6.84 Hz, 2H), 7.32–7.39 (m, 2H), 7.45–7.49 (m, 2H),
7.81–7.83 (d, J = 7.32 Hz, 2H), 7.91–7.93 (d, J = 7.84 Hz,
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For 3d: mp171 ꢁC; IR (KBr) mmax: 1720, 1369, 1172 cmÀ1
.
1H NMR (300 MHz, CDCl3): d 2.83 (s, 3H), 3.96 (s, 3H),
7.28–7.50 (m, 5H), 7.84–7.94 (m, 3H), 8.23 (s, 1H), 8.30–
8.33 (d, J = 8.17 Hz, 1H), 8.51 (s, 1H). 13C NMR
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8.33–8.35 (d, J = 8.8 Hz, 1H), 8.56 (s, 1H). MS (EI) m/z
(%): 396 (80), 254 (100), 240 (46). Elemental Anal. Calcd
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63.69; H, 4.39; N, 3.94.
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