Domino Wittig-Diels Alder reaction: Synthesis of carbazole lignans

Article abstract of DOI:10.1016/j.tetlet.2016.04.038

A convenient two step protocol for the synthesis of carbazole lignans involving Domino Wittig reaction/Diels Alder reaction followed by aromatization with DDQ is described. The main step of this protocol involves interaction between 2- or 3-indolecarboxyaldehydes and cinnamyl 2-(triphenylphosphoranylidene)acetates.

Full text of DOI:10.1016/j.tetlet.2016.04.038

Accepted Manuscript
Domino Wittig - Diels Alder reaction: synthesis of carbazole lignans
Santosh G. Tilve, Prachi S. Torney, Rupesh E. Patre, Durga P. Kamat,
Bikshandarkoil R. Srinivasan, Fedor I. Zubkov
PII:
S0040-4039(16)30388-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.038
TETL 47538
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
17 February 2016
6 April 2016
12 April 2016
Please cite this article as: Tilve, S.G., Torney, P.S., Patre, R.E., Kamat, D.P., Srinivasan, B.R., Zubkov, F.I., Domino
Wittig - Diels Alder reaction: synthesis of carbazole lignans, Tetrahedron Letters (2016), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2016.04.038
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Graphical Abstract
Domino Wittig - Diels Alder reaction:
Leave this area blank for abstract info.
synthesis of carbazole lignans
Santosh G. Tilve, Prachi S. Torney, Rupesh E. Patre, Durga P. Kamat, Bikshandarkoil R. Srinivasan and Fedor
I. Zubkov

1
Tetrahedron Letters
Domino Wittig - Diels Alder reaction: synthesis of carbazole lignans
a,
a
a
a
a
Santosh G. Tilve , Prachi S. Torney , Rupesh E. Patre , Durga P. Kamat , Bikshandarkoil R. Srinivasan
b
and Fedor I. Zubkov
a
Department of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India
Department of Organic Chemistry, Peoples’ Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow, 117198, Russian Federation
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convenient two step protocol for the synthesis of carbazole lignans involving Domino Wittig
reaction / Diels Alder reaction followed by aromatization with DDQ is described. The main step
of this protocol involves interaction between 2- or 3-indolecarboxyaldehydes and cinnamyl 2-
(triphenylphosphanylidene)acetates.
Available online
2
016 Elsevier Ltd. All rights reserved.
Keywords:
Domino reaction
Wittig reaction
Diels Alder reaction
Aromatization
Lignans
1
Furanone moiety fused to a cyclic framework is a structural feature found in many biologically active compounds. For example
2
podophyllotoxin (1) a naturally occurring lignan is a drug used in the treatment of cancer. Taiwanin C (2a) and justicidin E (2b) are
3
two naturally occurring naphthalene lignans where furanone ring is fused with the aromatic ring. When one of the aromatic rings in the
lignan skeleton is replaced by a heterocycle it is usually termed as heterolignan. Azatoxin (3a) and 8’-azaphyllotoxin (3b) are two
1
n
4
successfully designed and synthesized potent azalignans. Isoelliptoxin (3c) is an indole analogue of deoxypodophyllotoxin (Figure 1).
5
Heterolignans are of interest due to their potential biological activities and efforts are ongoing to synthesize them. In continuation of
our interest in domino Wittig - Diels Alder reaction sequence, we report herein synthesis of a series of indole lignans.
6
Figure 1. Structures of some naturally occurring lignans.
Thus, when indole-2-carboxyaldehyde 4 was subjected to domino Wittig - Diels Alder reaction protocol with phosphorane 6a, a
7
mixture of two diastereomers 8a and 8b was obtained in 9:1 ratio in 63% yield (Scheme 1). The major isomer 8a was obtained as a
white solid while the minor was a viscous oil. We could not unambiguously decide the nature of the geometry of the two isomers based
on their NMR data. Recourse was taken to single crystal X-ray diffraction analysis in the case of solid 8a which afforded suitable
8
crystals for structure determination (Figure 2).
—
——

Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@stilve@unigoa.ac.in

2
Tetrahedron
Scheme 1. Domino Wittig reaction Diels-Alder reaction protocol
In this one pot sequence first the Wittig reaction takes place to form the (E)-unsaturated ester 7, which undergoes [4+2]
cycloaddition either in syn or anti mode (Figure 3) followed by rapid isomerization to give a mixture of 8a and 8b. The formation of
both the diastereoisomers in unequal proportion suggests that the energy barrier between the two transition states is different and favors
the anti transition state. It was observed that the diastereoisomer in which the six and five membered rings are trans fused to each other
was formed in more proportion than the cis fused one, as indicated by the orientation of the protons attached at C10A and C3A (Fig. 2).
Figure 2. Crystal structure for 8a. Displacement ellipsoids have been drawn at 50% probability level and H atoms are shown as small spheres
of arbitrary radii.
Figure 3. Transition state involved in Diels-Alder reaction.
Having successfully synthesized the tetrahydrocarbazole lignan skeleton 8, the synthesis of its analogues 9-11 was undertaken. The
required phosphoranes 6b-d were prepared from the corresponding cinnamyl alcohols (Scheme 2). These phosphoranes were then
condensed with 4 to obtain 9-11 (Scheme 3) in moderate to good yields. The tetrahydrocarbazole lactones were then aromatized using
DDQ to carbazole lignans 12a-d in good yields (Table 1). A one pot procedure was attempted for the direct preparation of 12a by
refluxing a mixture of 4, 6a and 10% Pd-C in diphenyl ether. However the product 12a was obtained in mere 32% yield. Hence the two-
step protocol was preferred.

3
Scheme 2. Synthesis of phosphoranes 6a-d from cinnamyl alcohols.
Scheme 3. Synthesis of lignans 12a-d.
Scheme 4. Synthesis of lignans 17a-d.
After successfully synthesizing the carbazole lignans 12a-d, the two-step protocol was evaluated for the synthesis of isomeric
carbazole lignans 17a-d. Thus indole-3-carboxyaldehyde 5 was condensed with the phosphoranes 6a-d to obtain tetrahydrocarbazoles
13-16, which were then oxidized with DDQ to provide the carbazole lignans 17a-d (Scheme 4, Table 1).
Table 1. Tetrahydrocarbazole (8-11; 13-16) - carbazole (12, 17) lignans.
Ratio
Entry
Products
Total yield (%)
DDQ aromatized product
Yield (%)
(
a/b)
a
1
8a/8b
9/1
63
75
82
59
62
60
76
56
12a
12b
12c
12d
17a
17b
17c
17d
60
78
83
58
61
60
79
56
b
2
9a/9b
10/1
3
10a/10b
11a/11b
13a/13b
14a/14b
15a/15b
16a/16b
Traces of b
a
4
7/3
5
Traces of b
Traces of b
Traces of b
Traces of b
6
7
8
a
Isolated ratio.
Ratio based on H NMR.
b
1
In conclusion, we have demonstrated that isomeric carbazole lignans can be conveniently assembled by domino Wittig - Diels Alder
reaction sequence followed by aromatization with DDQ.
Acknowledgments
We thank Indian Institute of Science, Bangalore for providing the HRMS facility. D.P. Kamat acknowledges University Grants
Commission, New Delhi for the award of Senior Research Fellowship.
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General Procedure for the preparation of substituted cinnamyl phosphoranes 6a-d:
A solution of substituted cinnamyl alcohol (1 mmol) and pyridine (1 mmol) in dry chloroform (20 mL) was cooled to 0 °C. Bromoacetyl bromide (1
mmol) was added dropwise with stirring over a period of 15 min. The mixture was stirred for 1 h at 0 °C and further at room temperature for 1 h. To
the reaction mixture, water (20 mL) was added and extracted with chloroform (2 × 25 mL). The organic layer was washed with 2N HCl (2 × 15 mL),
sat. sodium bicarbonate (2 × 20 mL) and finally with water (20 mL). The chloroform layer was dried over anhyd. sodium sulfate. Evaporation of the
solvent under vacuum gave crude cinnamyl 2-bromoacetate which was as such used for the next reaction. The solution of cinnamyl 2-bromoacetate (1
mmol) and triphenylphosphine (1.05 mmol) in dry toluene (20 mL) was stirred overnight at room temperature. The salt formed was filtered and
dissolved in methanol (5 mL). To this water (20 mL) and toluene (40 mL) was added, followed by addition of 2N sodium hydroxide solution with
stirring to phenolphthalein end point. The toluene layer was separated and the aqueous layer was extracted with toluene (2 × 20 mL). The toluene
layer was dried over anhyd. sodium sulfate and the solvent removed under vacuum to give substituted cinnamyl (triphenylphosphoranylidene)acetate.
General procedure for the preparation of tricyclic γ- lactones 8-11 and 13-16:
A solution of indolecarboxaldehyde (1 mmol) and phosphorane 6a-d (1.5 mmol) in diphenyl ether (10 mL) was refluxed for 1-2 h. The crude mixture
was subjected to column chromatography over silica gel using hexanes to remove diphenyl ether first and further elution with 30-50% ethyl acetate in
hexanes to afford diastereomeric γ-lactones.
General procedure for the preparation of indole based heterolignans 12a-d and 17a-d
A mixture of tetrahydrolignans (1 mmol) and DDQ (2.5 mmol) in dioxane (10 mL) was refluxed for 2 h. The reaction mixture was allowed to cool to
ambient temperature and filtered. The filtrate was then concentrated under reduced pressure and resulting residue was dissolved in ethyl acetate (50
mL) and washed with sat. sodium bicarbonate (2 × 10 mL) and water (2 × 10 mL). The organic layer was dried over anhyd. sodium sulfate and
concentrated under reduced pressure. The resulting residue on purification using flash chromatography with hexanes/ethyl acetate gave the oxidized
products.
8
.
Crystal data for 8a: C20H17NO , M = 303.35, monoclinic, space group P 2 /c, a = 12.879(3) Å, b = 6.2881(14) Å, c = 19.076(4) Å, β = 93.163(4)º, V
2
1
3
3
-
1
=
1542.5(6) Å , Z = 4, ρcalcd = 1.306 Mg/m , F(000) = 640, µ = 0.084 mm , R = 0.0417, wR = 0.1141, GOF = 1.050 for 2717 reflections with I > 2σ
(
I). www.ccdc.cam.ac.uk/conts/retrieving.html Crystallographic data (excluding structure factors) for the structure of 8a reported herein have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 1453376. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1 EZ, UK. (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Supplementary Material
1
13
Supplementary data (experimental procedures and characterization data, copies of H, C NMR spectra and structure protocol of 8a)
associated with this article can be found, in the online version, at

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Highlights


Synthesis of new heterolignans employing indole heterocycle.
Versatile Domino Wittig reaction - Diels Alder reaction strategy for the synthesis of isomeric carbazole
lignans.

Efficient and regioselective construction of carbazole lactones.