A rapid assembly of furo[3,4-b]- and pyrrolo[3,4-b]carbazolones by domino wittig Diels-Alder reaction

Article abstract of DOI:10.1055/s-0030-1259695

Regioisomeric hexahydrofuro[3,4-b]carbazol-1-ones, hexahydropyrrolo[3,4-b] carbazol-1-ones, hexahydrofuro[3,4-b]carbazol-3-ones and hexahydropyrrolo[3,4-b] carbazol-3-ones were synthesized in 59% to 62% yields by domino Wittig Diels-Alder reactions from indole-3-carboxaldehyde and indole-2-carboxaldehyde and Wittig reagents. Further the corresponding carbazolelactones and carbazolelactams were obtained by oxidation with DDQ. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259695

LETTER
639
A Rapid Assembly of Furo[3,4-b]- and Pyrrolo[3,4-b]carbazolones by Domino
Wittig Diels–Alder Reaction
Rapid
A
ssemb
r
ly of Fu
a
b
]-
a
c
nd Pyrrolo[
h
3,4-
b
]carbaz
i
olone
s
Torney, Rupesh Patre, Santosh Tilve*
Department of Chemistry, Goa University, Goa 403206, India
Fax +91(832)2452886; E-mail: stilve@unigoa.ac.in
Received 21 December 2010
Dedicated to Prof. R. S. Mali on his 70th birthday
Abstract: Regioisomeric hexahydrofuro[3,4-b]carbazol-1-ones,
CHO
O
hexahydropyrrolo[3,4-b]carbazol-1-ones,
hexahydrofuro[3,4-
b]carbazol-3-ones and hexahydropyrrolo[3,4-b]carbazol-3-ones
were synthesized in 59% to 62% yields by domino Wittig Diels–
Alder reactions from indole-3-carboxaldehyde and indole-2-car-
boxaldehyde and Wittig reagents. Further the corresponding carba-
zolelactones and carbazolelactams were obtained by oxidation with
DDQ.
2
X
Ph2O
reflux
N
N
R
H
H
1
3
Key words: domino Wittig, Diels–Alder, furocarbazoles, pyrrolo-
carbazoles
O
X
N
H
A large number of substituted carbazole alkaloids have
been isolated1 from plants in last few decades. Both, natu-
ral and synthetic carbazoles display a wide range of bio-
logical activities which includes inhibition of CDK-5,
antitumor, psychotropic, anti-inflammatory, antimicrobi-
al, antihistamine, antibiotic, and antioxidative activities.2
Application of carbazoles in material science is also well
documented.3 Consequently, the development of regio-
selective synthesis4 of functionalized tetrahydrocarbazole
and carbazole scaffolds has gained paramount interest. A
plethora of reviews5 is available on the synthesis of carba-
zole alkaloids.
R
4
O
O
DDQ
X
X
N
H
N
H
R
R
6
5
X = O or NBn, R = H or Me
O
Ph3P
X
R
The ubiquitous presence of a lactone and a lactam unit in
many polycyclic antineoplastic agents6 prompted us to
undertake the synthesis of carbazolelactones and carba-
zolelactams. Further impetus was provided by the cyto-
toxicity exhibited by the recently isolated g-lactone
carbazole against human leukemia cell line.6a
Domino reactions7 are of current interest for the synthesis
of complex molecules. In continuation of our endeavors in
domino methodologies,8 we report herein a facile synthe-
sis of furo[3,4-b]carbazolones and pyrrolo[3,4-b]carbazo-
lones using domino Wittig–Diels–Alder reaction
sequence.9
R = H, X = O (2a) R = H, X = NBn (2c)
R = Me, X = O (2b) R = Me, X = NBn (2d)
Scheme 1 Synthesis of carbazolones using indole-3-carboxaldehyde
In this one-pot reaction first the Wittig reaction takes
place to form E unsaturated ester 3a, which under the re-
action conditions undergoes intramolecular Diels–Alder
reaction to form 4a, which then rapidly isomerizes to 5a
(Scheme 1).
The cis diastereomer was assumed to have arisen from the
syn transition state while the trans from the anti transition
state (Scheme 2). The formation of both the diastereomers
in equal proportion suggests that the energy barrier be-
tween the two transition states is negligible. Interestingly,
no dimeric product due to intermolecular Diels–Alder
reaction was observed though the conjugated double bond
in 3 can also behave as a dienophile. Compound 5a was
then easily oxidized with DDQ to the required furo[3,4-
b]carbazol-1-one. The success of this reaction prompted
us to condense phosphorane 2b with 1 to obtain a mixture
Thus, when indole-3-carboxaldehyde (1), was subjected
to domino Wittig Diels–Alder reaction protocol8e,10 with
phosphorane 2a a mixture of two diastereomers, cis- and
trans-3,3a,4,5,10,10a-hexahydro-1H-furo[3,4-b]carbazol-
1-one (5a) was obtained in 1:1 ratio (HPLC) in 60% yield.
SYNLETT 2011, No. 5, pp 0639–0642
x
x.
x
x.
2
0
1
1
Advanced online publication: 25.02.2011
DOI: 10.1055/s-0030-1259695; Art ID: G35110ST
© Georg Thieme Verlag Stuttgart · New York

640
P. Torney et al.
LETTER
of diastereomers of 5b which were directly converted into We next undertook the synthesis of carbazole lactones and
6b.
lactams regioisomeric to 6a–d using indole-2-carboxalde-
hyde 7. Thus, when 7 was subjected to similar reaction
conditions with 2a, a mixture of cis- and trans-
3a,4,10,10a-tetrahydro-1H-furo[3,4-b]carbazol-3(5H)-one
(10a) was obtained in 60% yield. Compound 10a was then
easily oxidized to 11a using DDQ (Scheme 3). The reac-
tion of 7 with phosphorane 2b, however, yielded an iso-
meric product 11b¢ in major amount. The formation of
11b¢ could be accounted from an allylic ester rearrange-
ment of the Wittig product intermediate prior to the Diels–
Alder reaction (as shown in Scheme 4).
Having synthesized the furocarbazolones 6a,b, our next
aim was to prepare the corresponding pyrrolocarbazolo-
nes, for which 1 was reacted with the phosphorane 2c un-
der similar reaction conditions. As expected a mixture of
cis and trans fused 2-benzyl-2,3,3a,4,10,10a-hexahydro-
pyrrolo[3,4-b]carbazol-1(5H)-one (5c) was formed which
on oxidation gave 6c. With phosphorane 2d, a mixture of
diastereomers of 5d was obtained, which on aromatization
gave the carbazolone 6d (Table 1).
Table 1 Product of Domino Wittig–Diels–Alder Reaction and Oxidation
Entry
Aldehyde Phosphorane Product 5/10
Yield (%)a Product 6/11
Yield (%)a
62
O
O
1
1
1
1
2a
2b
2c
5a
5b
5c
60
61
62
6a
6b
6c
O
O
N
H
N
H
O
O
2
3
59
15
O
O
N
H
N
H
O
O
NBn
NBn
N
H
N
H
O
O
4
5
1
7
2d
2a
5d
61
61
6d
11
59
NBn
NBn
N
H
N
H
O
O
10a
11a
N
H
N
H
O
O
O
O
N
H
N
H
b
b
O
O
6
7
2b
10b
57
11b
58b
+
+
O
O
N
N
H
H
O
b'
O
b'
NBn
NBn
7
8
7
7
2c
10c
10d
62
61
11c
11d
28
34
N
N
H
H
O
O
2d
NBn
NBn
N
H
N
H
O
O
a Isolated yield.
b The ratio of 11b/11b¢ (0.2:1.0) was determined by 1H NMR.
Synlett 2011, No. 5, 639–642 © Thieme Stuttgart · New York

LETTER
Rapid Assembly of Furo[3,4-b]- and Pyrrolo[3,4-b]carbazolones
641
For obtaining hexahydropyrrolo[3,4-b]carbazol-3-ones, 7
was treated with phosphorane 2c,d. With phosphorane 2c,
a mixture of diastereomers (cis- and trans-fused) of 2-
benzyl-1,2,3a,4,10,10a-hexahydropyrrolo[3,4-b]carbazol-
3(5H)-one (10c) was formed. Phosphorane 2d provided
the corresponding 2-benzyl-4-methyl-1,2,3a,4,10,10a-
hexahydropyrrolo[3,4-b]carbazol-3(5H)-one (10d). The
compounds 10c and 10d were aromatized to obtain 11c
and 11d, respectively.
O
O
O
H
O
H
H
N
H
N
H
R
R
cis-fused products
syn TS
O
O
O
H
In conclusion we have demonstrated that the functional-
ized tetrahydrocabazoles can be rapidly assembled using
domino Wittig and Diels–Alder reaction protocol. During
this sequence, Wittig reaction, intramolecular Diels–
Alder reaction and isomerization take place in a domino
fashion.
O
H
N
R
H
N
H
R
trans-fused products
anti TS
Scheme 2 Transition states involved in Diels–Alder reaction.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
R
2
X
Ph2O
reflux
Acknowledgment
CHO
N
N
H
H
O
We thank IISc, Bangalore, for HRMS facility, NIO, Goa for spec-
tral analysis and UGC and DST, New Delhi, for the financial sup-
port.
8
7
R
References and Notes
X
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11
X = O or NBn, R = H or Me
Scheme 3 Synthesis of carbazolones using indole-2-carboxaldehyde
O
2b
CHO
O
N
H
Ph2O, reflux
N
H
12
7
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11b'
Scheme 4 Probable mechanism for the formation of 11b¢
Synlett 2011, No. 5, 639–642 © Thieme Stuttgart · New York

642
P. Torney et al.
LETTER
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(10) General Procedure for the Tandem Wittig–Diels–Alder
Reaction for Preparation of Tetrahydrocarbazole
Lactones (5a,b/10a,b) and Tetrahydrocarbazole
Lactams (5c,d/10c,d): A solution of indole carboxaldehyde
1/7 (1 mmol) and phosphorane 2a–d (1.5 mmol) in diphenyl
ether (10 mL) was refluxed under nitrogen atmosphere for
2–8 h. The crude mixture was subjected to column
chromatography over silica gel and diphenyl ether was
removed using hexanes as eluent. Further elution with
30–40% EtOAc and hexanes afforded the corresponding
g-lactones 5a,b/10a,b and g-lactams 5c,d/10c,d.
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General Procedure for Aromatization Using DDQ: A
mixture of tetrahydrocarbazoles 5a–d/10a–d (1 mmol) and
DDQ (3 mmol) in dioxane (10 mL) was refluxed for 8 h. The
reaction mixture was allowed to cool to ambient temperature
and filtered. The filtrate was then concentrated under
reduced pressure. The resulting residue was dissolved in
EtOAc (20 mL) and washed with 2 N NaOH (20 mL) and
H2O (20 mL). The organic phase was dried over anhyd
Na2SO4 and concentrated under reduced pressure. The
resulting residue on purification using flash chromatography
with hexanes–EtOAc (70:30) gave the oxidized products
6a–d/11a–d.
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Y.; Nijsiri, R.; Hiroshi, F. J. Nat. Prod. 2009, 72, 1202.
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Dalla Via, L. Chem. Med. Chem. 2009, 4, 363.
3,5-Dihydro-1H-furo[3,4-b]carbazol-1-one (6a): 1H NMR
(300 MHz, DMSO): d = 5.46 (s, 2 H), 7.21 (t, J = 7.8 Hz, 1
H), 7.49 (t, J = 7.8 Hz, 1 H), 7.53 (d, J = 8.1 Hz, 1 H), 7.62
(s, 1 H), 8.30 (d, J = 7.8 Hz, 1 H), 8.66 (s, 1 H), 11.78 (s, 1
H). 13C NMR (300 MHz, DMSO): d = 69.85, 104.29, 111.83,
116.03, 118.12, 120.10, 121.47, 122.56, 124.50, 127.28,
141.27, 144.40, 144.85, 171.69. HRMS: m/z [M + Na] calcd
for C14H9O2N: 246.0531; found: 246.0524.
(c) Poljakova, J.; Eckschlager, T.; Hrabeta, J.; Hrebackova,
J.; Smutny, S.; Frei, E.; Martinek, V.; Kizek, R.; Stiborova,
M. Biochem. Pharmacol. 2009, 77, 1466. (d) Romero, M.;
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