A short and efficient synthesis of furo[2,3-b]indoles

Article abstract of DOI:10.1016/j.tetlet.2010.06.068

Application of Wittig olefination-Claisen rearrangement protocol for the short synthesis of furo[2,3-b]indoles is described.

Full text of DOI:10.1016/j.tetlet.2010.06.068

Tetrahedron Letters 51 (2010) 4494–4496
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A short and efficient synthesis of furo[2,3-b]indoles
*
Mukund G. Kulkarni , Sanjay W. Chavhan, Mayur P. Desai, Yunnus B. Shaikh, Dnyaneshwar D. Gaikwad,
Attrimuni P. Dhondge, Ajit S. Borhade, Vijay B. Ningdale, Deekshaputra R. Birhade, Nagorao R. Dhatrak
Department of Chemistry, University of Pune, Ganeshkhind, Pune 411 007, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Application of Wittig olefination–Claisen rearrangement protocol for the short synthesis of furo
[2,3-b]indoles is described.
Received 11 May 2010
Revised 10 June 2010
Accepted 15 June 2010
Available online 18 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
a complex mixture of products. Most likely the sensitive 1,4-di-alde-
hyde functionality is getting affected under the reaction conditions.
Fused heterocyclic rings arepresent aspartial structures indiverse
natural products. For this and other reasons, since long ago, synthesis
of fused heterocyclic ring systems such as pyrrolo-indoles,1 carbaz-
oles,2 furo-indoles, etc. is a matter of interest for chemists.
Reduction of the nitro group under basic conditions using NaSH,59
generated from the mixture of sodium sulfite and sodium bicarbon-
ate in the presence of methanol, was carried out, which avoided the
side reactions. From this reaction, furo[2,3-b]indole (4a) was iso-
lated directly in good yield (Table 1).
The furo[2,3-b]indole ring system is at the core of many natural
products.3–8 Due to the biological activity9–13 associated with this
ring system and its derivatives and its use as a synthetic interme-
diate in the synthesis of numerous alkaloids, several methods have
been reported for the synthesis of this ring system.14–47 In spite of
this voluminous work, even today construction of this ring system
is an attractive goal for demonstrating the efficacy of newer syn-
thetic protocols. The Wittig olefination–Claisen rearrangement
protocol developed in our laboratory48,49 has been applied exten-
sively in the total syntheses of natural products50–52 and heterocy-
clic compounds.53–57 We herein describe the successful application
of Wittig olefination–Claisen rearrangement protocol58 in a four-
step synthesis of furo[2,3-b]indoles.
After the successful preparation of furoindole (4a), the general-
ity of this method was studied. For this purpose, substituted o-ni-
tro benzaldehydes were used. All these compounds smoothly
reacted under the above reaction conditions to give the corre-
sponding furo[2,3-b]indoles (4b–g) in good yields (Table 1).
In conclusion, herein we have developed a short and efficient
synthesis of furo[2,3-b]indole, with good overall yield, by using
Wittig olefination–Claisen rearrangement methodology.
2. Experimental section
2.1. General procedure for the Wittig reaction
Reaction of o-nitro benzaldehyde (1a) with allyloxymethylene
triphenylphosphorane, under optimized reaction conditions50 gave
allyl vinyl ether (2a) in good yield (Scheme 1). The 1H NMR spec-
trum showed that the allyl vinyl ether (2a) was an inseparable
mixture of E- and Z-isomers. All attempts to separate the E- and
Z-isomers did not materialize, but the ratio of these isomers was
determined from NMR spectrum (Table 1).
The Claisen rearrangement of the allyl vinyl ether (2a) was
effected by heating it in refluxing anhydrous xylene to give the cor-
responding4-pentenal (3a) in good yield. Double bond of 4-pentenal
(3a) was ozonolyzed to get the di-aldehyde. This di-aldehyde, being
found to be unstable and acid sensitive, was used as such for the next
step. The attempted reduction of the nitro group in (3a) to the amine
using Ra–Ni/H2 or Pd/C–H2 in methanol ended up in the formation of
To a stirred and cooled (0 °C) suspension of allyloxy methylen-
etriphenylphosphonium salt (1.2 equiv) and aldehyde (1.0 equiv)
in dry THF was added potassium tertiary butoxide (1.2 equiv) in
a dropwise manner. After addition, the mixture was further stirred
for 40–45 min at 0 °C (TLC check). Then it was diluted with water
and extracted with ether (3 Â 50 ml). The combined ether layer
was washed with water, dried over anhydrous sodium sulfate,
and concentrated under reduced pressure. The crude product was
purified by column chromatography using hexane/ethyl acetate
(98:1) solvent system to get allyl vinyl ethers (2a–g) in good yields.
The E- & Z-isomers were inseparable and hence were carried for-
ward for further reactions as such.
2.2. General procedure for the Claisen rearrangement
* Corresponding author. Tel.: +91 020 25601394; fax: +91 020 25691728.
E-mail addresses: mgkulkarni@chem.unipune.ernet.in, ochem@chem.unipu-
ne.ernet.in (M.G. Kulkarni).
The inseparable mixture of E- and Z-allyl vinyl ethers (2a–g)
was dissolved in dry xylene and the resulting reaction mixture
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.068

M. G. Kulkarni et al. / Tetrahedron Letters 51 (2010) 4494–4496
4495
R4 CHO
O
R4
R4
R4
R3
R2
R3
R2
R3
R2
CHO
NO2
R3
R2
O
ii
iii
iv
i
N
H
NO2
R1
NO2
R1
R1
R1
4a-g
3a-g
1a-g
2a-g
Scheme 1. Reagents and conditions: (i) Ph3P+CH2OCH2CH@CH2ClÀ (1.2 equiv), t-BuOÀNa+ (1.2 equiv), dry THF, 0 °C, 40–45 min; (ii) dry xylene, reflux, 5–7 h; (iii) O3, Dry
DCM, Me2S, 0 °C 20 min; (iv) Na2S (2 equiv), NaHCO3, methanol, reflux 12 h.
was heated at 144 °C for 5–7 h (TLC check). Xylene was removed
under reduced pressure; the crude product was directly loaded
on a silica gel column using 1–2% of ethyl acetate/hexane system
as an eluent to get pure 4-pentenals (3a–g).
to effect the reduction of intermediate ozonoide to get di-aldehyde.
As the di-aldehyde was found to be unstable it was used as such for
the next reaction without purification.
2.4. General method for the reductive cyclization
2.3. General method for the ozonolysis
Two equivalents of sodium sulfide was dissolved in a minimum
amount of water then sodium bicarbonate was added to it until the
solution became saturated. The reaction mixture was cooled at 0 °C
and methanol was added slowly to the reaction mixture, sodium
carbonate got precipitated. The reaction mixture was filtered. To
The 4-pentenals (3a–g) were dissolved in dry DCM and the
reaction mixture was cooled at 0 °C. Through a stirred and cooled
reaction mixture, ozone gas was passed for about 20 min (TLC
check). After completion of the reaction, excess of Me2S was added
Table 1
Wittig olefination–Claisen rearrangement protocol for the synthesis of furo[2,3-b]indoles
Sr. No.
Aldehydes
Allyl vinyl ethers
% Yield (Z:E) 2a–g
4-Pentenals
% Yield 3a–g
Furo[2,3-b]indoles
% Yield 4a–g
CHO
O
1a
75 (1:2.03)
70 (1:1.04)
83
84
NO2
N
H
79
MeO
MeO
CHO
NO2
MeO
O
1b
1c
N
H
MeO
78
MeO
MeO
CHO
NO2
MeO
MeO
O
N
71 (1:0.78)
84
H
Br
Cl
Br
75
MeO
MeO
CHO
NO2
MeO
MeO
O
O
N
1d
1e
80 (1:0.45)
71 (1:0.85)
80
85
H
Cl
77
MeO
MeO
CHO
NO2
MeO
MeO
N
H
OMe
OMe
76
Br
Br
MeO
MeO
CHO
NO2
MeO
MeO
O
1f
72 (1:1.04)
72 (1:1.56)
83
82
N
H
OMe
OMe
78
CHO
NO2
O
O
O
O
O
1g
N
H
78

4496
M. G. Kulkarni et al. / Tetrahedron Letters 51 (2010) 4494–4496
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Acknowledgments
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thank CSIR, New Delhi for the financial support.
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