Cyclodimerization of indol-2-ylacetylenes. An example of intermolecular enyne-alkyne cycloaddition

Article abstract of DOI:10.1039/b009154p

The cyclodimerization of methyl 3-(indol-2-yl)-1-(phenylsulfonyl)acetylene that proceeded through an enzyme-alkyne cycloaddition to give 4-(indol-2-yl)carbazoles was discussed. The behaviour of indolyl-acetylenes bearing an electron-withdrawing group was

Full text of DOI:10.1039/b009154p

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Cyclodimerization of indol-2-ylacetylenes. An example of
intermolecular enyne–alkyne cycloaddition
Daniele Passarella,* Alessandra Giardini, Marisa Martinelli and Alessandra Silvani
1
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano,
Via Venezian 21, 20133 Milano, Italia. E-mail: Passarel@icil64.cilea.it
Received (in Cambridge, UK) 29th September 2000, Accepted 14th November 2000
First published as an Advance Article on the web 14th December 2000
Cyclodimerization of methyl 3-(indol-2-yl)propiolate 1 and 2-(indol-2-yl)-1-(phenylsulfonyl)acetylene 2 proceeds
through an enyne–alkyne cycloaddition to give 4-(indol-2-yl)carbazoles.
The enediynes and the enyne–allene cyclizations are receiving
great attention because of their involvement as key steps in the
activation of some natural antibiotics1 and show promise as
methods for the synthesis of polycyclic systems.2 Recently
intramolecular [4 ϩ 2]π cyclization of 1-en-3-ynes with alkynes
has been reported,3 and it provided a useful tool for the ready
construction of polycyclic aromatics. A small number of inter-
molecular cycloadditions of enynes with alkynes has been
described in the review literature.4
was obtained by a conventional procedure based on the in situ
elimination reaction of enol phosphate derived from a β-oxo
sulfone (Scheme 1). The acyl chloride 99 was converted into
Here we describe a cyclodimerization of indol-2-ylacetylenes
that could be considered an example of an enyne–alkyne
[4 ϩ 2]π cyclization. We discovered this type of reaction when
we studied the reactivity in Diels–Alder cycloaddition reactions
of methyl indol-2-ylpropiolate.5 In the reaction of 1 (SEM is
Scheme 1 Reagents and conditions: i: BuLi, Ϫ78 ЊC, CO2 (Ref. 6);
ii: SOCl2, 40 ЊC; iii: C6H5SO2CHLi2, Ϫ30 ЊC; iv: NaH, (EtO)2POCl, rt;
v: t-BuOK, Ϫ78 ЊC.
β-oxo sulfone 10 by reaction with the dianion of methyl
phenyl sulfone7 at Ϫ30 ЊC. Reaction of 10 with NaH in THF
followed by addition of diethyl chlorophosphate,8 gave the
corresponding enol phosphate.9 The in situ addition of a
solution of t-BuOK in THF at Ϫ78 ЊC leads to the elimination
product, 2-indol-2-yl-1-(phenylsulfonyl)acetylene 2 in 55%
yield. Compound 2 spontaneously underwent benzoannulation
just in the course of its purification affording the binary
compound 6. Heating compound 2 in toluene at 75 ЊC for
1 h we obtained 6 in 60% yield after purification. The NMR
spectra of 6 appeared complex but the spin systems of indole
and carbazole were easily detected.
To clarify the influence of the nature of the group present on
the acetylenic portion, compounds 3 and 4 were prepared.5
Compounds 3 and 4 did not give any cyclization products by
heating in toluene at 100 ЊC for 60 h. We deduced that the
presence of an electron-withdrawing group is necessary to
obtain products deriving from homo-benzoannulation.
We have described a particular behaviour of indolyl-
acetylenes 1 and 2 bearing an electron-withdrawing group.
By cyclodimerization they produce 4-indolylcarbazoles 5 and
6 and even if they appear as byproducts, their formation
represents one of the few interesting examples of enyne–alkyne
intermolecular cycloaddition. Moreover the development of
new methods for the synthesis of functionalized carbazoles
is currently attracting chemists due to the discovery of many
carbazole alkaloids with varied biological activity.10
trimethylsilylethoxymethyl) with different dienophiles none of
the expected products were detected but only a compound
whose molecular weight induced us to take a dimeric structure
1
into account. The H NMR spectrum suggested a structure
incorporating two indole systems. The 1H–1H COSY permitted
us to assign the signals at δ 7.70 (d), 7.65 (d), 7.31 (t), 7.22 (t)
and 6.63 (s) to the 2-substituted indole moiety. The correlation
of the signals at δ 8.32 (s), 7.57 (d), 7.43 (t), 6.98 (t) and 6.80 (d)
confirmed not only the presence of a 2,3-disubstituted indole
but also of a carbazole portion. The presence of the signal at
δ 8.32 (s) indicated the 2,3,4-trisubstituted carbazole structure.
A complete spectroscopic analysis confirmed the structure 5
as deriving from the homocycloaddition of methyl indolyl-
propiolate that reacts as enyne and alkyne at the same time.
The formation of the product was observed when the reaction
temperature was raised to 100 ЊC and the starting material was
completely undetectable after 12 h. Then we prepared 2-(indol-
2-yl)-1-(phenylsulfonyl)acetylene 2 (PMBS is p-methoxyphenyl-
sulfonyl) where the electron-withdrawing sulfone group was
expected to improve the cyclodimerization rate, by activation of
the dienophile, providing a common and easily removable
functional group for further transformations. Compound 2
Experimental5
N-(2-Trimethylsilylethoxymethyl)-2,3-dimethoxycarbonyl-4-[N-
(2-trimethylsilylethoxymethyl)indol-2-yl]carbazole (5)
A mixture of 1 (100 mg, 0.3 mmol) and toluene (10 ml) were
heated at 100 ЊC for 12 h. After removal of the solvent and
DOI: 10.1039/b009154p
J. Chem. Soc., Perkin Trans. 1, 2001, 127–129
This journal is © The Royal Society of Chemistry 2001
127

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purification by chromatography (AcOEt–hexane 1:5) com-
pound 5 was isolated (65 mg, 65%). Oil. Rf 0.2 (AcOEt–hexane
1:5). 1H-NMR (CDCl3) δ 8.32 (1H, s), 7.70 (1H, d, J = 7.5 Hz),
7.65 (1H, d, J = 7.5 Hz), 7.57 (1H, d, J = 7.5 Hz), 7.43 (1H, t,
J = 7.5 Hz), 7.31 (1H, t, J = 7.5 Hz), 7.22 (1H, t, J = 7.5 Hz),
6.98 (1H, t, J = 7.5 Hz), 6.80 (1H, d, J = 7.5 Hz), 6.63 (1H, s),
5.84 (2H, s), 5.25 (2H, s), 4.00 (3H, s), 3.64 (3H, s), 3.60 (2H, t,
J = 7 Hz), 3.15 (2H, t, J = 7 Hz), 0.92 (2H, t, J = 7 Hz), 0.45
(2H, t, J = 7 Hz), 0.00 (9H, s), Ϫ0.30 (9H, s). 13C-NMR
(CDCl3) δ 169.1 (CO), 166.5 (CO), 142.4 (C), 139.5 (C), 137.6
(C), 134.6 (C), 129.5(C) , 128.4 (C), 127.9 (CH), 126.5 (C),
125.2 (C), 124.9 (C), 123.0 (CH), 122.4 (CH), 122.0 (C), 121.7
(CH), 121.0 (CH), 120.4 (CH), 112.1 (CH), 111.0 (CH), 109.5
(CH), 104.4 (CH), 74.1 (CH2), 72.6 (CH2), 66.5 (CH2), 66.0
(CH2), 52.7 (CH3), 52.4 (CH3), 17.8 (CH2), 17.6 (CH2), Ϫ1.4
(3CH3), Ϫ1.7 (3CH3). FABMS: 659 (M ϩ 1). Anal. calcd for
C36H46N2O6Si2: C 65.62, H 7.08, N 4.25. Found: C 65.74, H
7.23, N 4.33%.
(1H, t, J = 7.5 Hz), 7.15 (1H, t, J = 7.5 Hz), 6.77 (1H, s), 5.63
(2H, s), 3.60 (2H, s), 3.55 (2H, t, J = 7.5 Hz), 2.43 (6H, s), 0.91
(2H, t, J = 7.5 Hz), Ϫ0.05 (9H, s). 13C-NMR (CH, CH2, CH3)
(CDCl3) δ 123.3, 120.7 (2C), 110.3, 108.7, 73.1, 65.6, 48.6, 44.1
(2C), 17.8, Ϫ1.5 (3C).
N-(p-Methoxyphenylsulfonyl)indole-2-carboxylic acid (8)
1-(p-Methoxyphenylsulfonyl)indole 7 (2 g, 7 mmol) was
dissolved in THF (20 ml). The solution was cooled at Ϫ78 ЊC
and BuLi (3.62 ml, 9 mmol) was added dropwise. The reaction
mixture was maintained at rt for 5 min and then cooled at
Ϫ78 ЊC. Solid CO2 (1.5 eq.) was added. The solution was then
allowed to reach room temperature. The mixture was poured
into aqueous NaHCO3; the organic phase was separated and
the aqueous phase was acidified (HCl 5 M) and extracted with
CH2Cl2. Amorphous solid. Yield: 62%. 1H-NMR (CDCl3)
δ 8.17 (1H, d, J = 8 Hz), 8.02 (2H, AAЈ part of AAЈBBЈ
system), 7.60 (1H, d, J = 8 Hz), 7.48 (1H, t, J = 8 Hz), 7.37 (1H,
s), 7.31 (1H, t, J = 8 Hz), 6.93 (2H, BBЈ part of AAЈBBЈ
system), 3.80 (3H, s). 13C-NMR (CDCl3) δ 163.8, 163.6, 138.7,
131.1, 130.3, 129.8 (2C), 127.9, 127.2, 124.1, 122.6, 118.5, 115.5,
114.1 (2C), 55.6. Anal. calcd. for C16H13NO5S: C 58.00, H 3.96,
N 4.23. Found: C 58.19, H 4.01, N 4.31%.
N-(p-Methoxyphenylsulfonyl)-2,3-bis(phenylsulfonyl)-4-[N-(p-
methoxyphenylsulfonyl)indol-2-yl]carbazole (6)
A mixture of 2 (100 mg, 0.22 mmol) and toluene (10 ml) were
heated at 75 ЊC for 1 h. After removal of the solvent and purifi-
cation by chromatography (AcOEt–hexane 3:2) compound 6
was isolated (60 mg, 60%). Oil. Rf 0.3 (hexane–AcOEt 2:3).
1H-NMR (CDCl3) δ 9.80 (1H, s), 8.30 (1H, d, J = 7.5 Hz), 8.10
(1H, d, J = 7.5 Hz), 8.00–7.91 (3H, m), 7.98 (1H, d, J = 7.5 Hz),
7.68 (2H, d, J = 7 Hz), 7.60–7.51 (4H, m), 7.46–7.30 (4H, m),
7.22 (2H, d, J = 7 Hz), 7.10 (2H, d, J = 8 Hz), 6.92 (2H, d, J = 8
Hz), 6.62 (1H, t, J = 7.5 Hz), 6.26 (1H, s), 6.19 (2H, d, J = 8
Hz), 5.90 (1H, d, J = 7.5 Hz), 3.80 (3H, s), 3.60 (3H, s).
13C-NMR (CDCl3) δ 164.6, 163.4, 143.9, 142.3, 141.0, 140.2,
140.0, 139.6, 138.5, 136.4, 135.9, 132.9, 132.4, 131.5, 130.2,
129.3 (4C), 129.2 (2C), 129.5, 129.0, 128.7 (2C), 128.6, 128.3
(2C), 128.1, 126.6, 125.3, 124.4, 123.9, 123.4, 122.9, 121.5,
120.5, 114.9 (2C), 114.6, 114.2, 113.4 (2C), 111.4, 55.8, 55.4.
FABMS: 903 (M ϩ 1). HREIMS calcd. for C46H34N2O10S4
902.1096. Found 902.1123.
1-[N-(p-Methoxyphenylsulfonyl)indol-2-yl]-2-(phenylsulfonyl)-
ethanone (10)
Carboxylic acid 8 (1.4 g, 4.3 mmol) was dissolved in SOCl2
(2 ml). After 4 hours at 40 ЊC the excess of SOCl2 was removed
under reduced pressure and the product 9 was directly used for
the subsequent step. Methyl phenyl sulfone (625 mg, 4 mmol)
was dissolved in THF (5 ml). The mixture was cooled to Ϫ30 ЊC
and BuLi (3.6 ml, 9 mmol) was added dropwise. After 30 min a
solution of 9 (1.28 g, 3.7 mmol) in THF was added. After 1 h
the solution was poured into a saturated solution of NH4Cl and
extracted with CH2Cl2. The organic phase was washed with
brine. The crude β-keto sulfone was purified by flash chroma-
tography (hexane–AcOEt 2:1). Amorphous solid. Yield: 50%.
Rf 0.28 (hexane–AcOEt 2:1). IR (CHCl3) ν/cmϪ1 3040, 1685,
1
1590. H-NMR (CDCl3) δ 8.02 (1H, d, J = 8 Hz), 7.85 (2H,
1-[N-(2-Trimethylsilylethoxymethyl)indol-2-yl]-2-phenyl-
acetylene (3)
AAЈ part of AAЈBBЈ system), 7.65–7.20 (8H, m), 7.10 (1H, s),
6.75 (2H, BBЈ part of AAЈBBЈ system), 4.80 (2H, s), 3.75
(3H, s). 13C-NMR (CDCl3) δ 181.9, 164.3, 139.1, 133.5, 132.9,
131.5, 131.4, 129.2, 128.9 (3C), 127.5 (3C), 127.2, 124.5, 123.2,
121.5, 116.0, 114.0 (2C), 66.9, 55.7. Anal. calcd. for
C23H19NO6S2: C 58.83, H 4.08, N 2.98. Found: C 58.91, H 4.18,
N 3.01%.
2-Iodo-N-SEMindole (460 mg, 1.2 mmol) was dissolved in
CH3CN (10 ml). CuI (10 mg, 0.053 mmol), Pd(PPh3)4 (32 mg,
0.028 mmol), phenylacetylene (0.154 ml, 1.4 mmol) and Et3N
(1.5 ml) were added. The solution was stirred for 6 h at 40 ЊC
and for 12 h at room temperature. The mixture was poured into
a saturated NaCl solution and extracted with AcOEt. The
crude mixture was purified by flash chromatography (CH2Cl2–
hexane 1:5). Yield: 42%. Oil. 1H-NMR (CDCl3) δ 7.60 (1H, d,
J = 7.5 Hz), 7.58–7.54 (2H, m), 7.49 (1H, d, J = 7.5 Hz), 7.42–
7.36 (3H, m), 7.28 (1H, t, J = 7.5 Hz), 7.17 (1H , t, J = 7.5 Hz),
6.87 (1H, s), 5.71 (2H, s), 3.61 (2H, t, J = 8 Hz), 0.92 (2H, t,
J = 8 Hz), Ϫ0.08 (9H, s). 13C-NMR (CDCl3) δ 132.0, 126.2,
123.5, 123.3, 122.7, 118.4 (2C), 117.5, 116.8, 115.8 (3C), 105.3,
103.8, 90.4, 75.8, 68.0, 60.6, 12.7, Ϫ1.5 (3C).
1-[N-(p-Methoxyphenylsulfonyl)indol-2-yl]-2-phenylsulfonyl-
acetylene (2)
NaH (40 mg, 1.1 mmol) was suspended in THF (5 ml). A
solution of 10 (400 mg, 0.92 mmol) in THF (10 ml) was added
dropwise at rt. After 30 minutes, diethyl chlorophosphate (0.12
ml, 1.1 mmol) was added dropwise. After 4 h the solution was
cooled at Ϫ78 ЊC and t-BuOK (134 mg, 1.2 mmol) in THF (5
ml) was added slowly. The mixture was poured into aqueous
NH4Cl and extracted with AcOEt. The crude product 2 (228
mg, 55%) was purified by flash chromatography (hexane–
AcOEt 1:1). Yellow oil. Rf 0.4 (hexane–AcOEt 1:1). IR
(CHCl3) ν/cmϪ1 3060, 2100, 1590, 1375, 1165; 1H-NMR
(CDCl3) δ 8.22 (1H, d, J = 8 Hz), 8.20–7.43 (5H, m), 7.80
(2H, AAЈ part of AAЈBBЈ system), 7.65 (1H, d, J = 8 Hz), 7.50
(1H, t, J = 8 Hz), 7.28 (1H, t, J = 8 Hz), 7.16 (1H, s), 6.85
(2H, BBЈ part of AAЈBBЈ system), 3.80 (3H, s). 13C-NMR
(CDCl3) δ 163.4, 139.9, 137.3, 135.9, 134.3, 131.4, 129.3 (2C),
129.9 (2C), 129.0 (2C), 128.0, 127.6, 127.0, 124.3, 122.2, 114.8,
114.6 (2C), 85.1, 65.3, 55.3. HREIMS calcd. for C23H17NO5S2:
451.0548. Found 451.1165.
3-[N-(2-Trimethylsilylethoxymethyl)indol-2-yl]prop-2-ynyl-
N,N-dimethylamine (4)
2-Iodo-N-SEMindole (460 mg, 1.2 mmol) was dissolved in
CH3CN (10 ml). CuI (10 mg, 0.053 mmol), Pd(PPh3)4 (32 mg,
0.028 mmol), 1-dimethylaminoprop-2-yne (0.150 ml, 1.4 mmol)
and Et3N (1.5 ml) were added. The solution was stirred for 6 h
at 40 ЊC and for 12 h at room temperature. The mixture was
poured into a saturated NaCl solution and extracted with
AcOEt. The crude mixture was purified by flash chroma-
tography (hexane–AcOEt 1:1). Yield: 38%. Oil. 1H-NMR
(CDCl3) δ 7.57 (1H, d, J = 7.5 Hz), 7.47 (1H, d, J = 7.5 Hz), 7.28
128
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4 R. P. Johnson, Chem. Rev., 1989, 89, 1111.
5 D. Passarella, G. Lesma, M. Deleo, M. Martinelli and A. Silvani,
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6 The corresponding carboxylic acid 8 was prepared by reaction of
1-(p-methoxyphenylsulfonyl)indole 7 with BuLi and CO2 at Ϫ78 ЊC.
See: D. A. Shirley and P. A. Roussel, J. Am. Chem. Soc., 1953, 75,
375. The subsequent reaction of 8 with SOCl2 gave acyl chloride 9.
7 M. W. Thomsen, B. M. Handwerker, S. A. Katz and R. B. Belser,
J. Org. Chem., 1988, 53, 906.
8 J. W. Lee and D. Y. Oh, Synlett, 1990, 290.
9 T. Bottin-Strzalko, J. Corset, F. Froment, M. Pouet, J. Seyden-Piume
and M. Simmonin, J. Org. Chem., 1980, 45, 1270.
10 D. P. Chakraborty, in The Alkaloids, Chemistry and Pharmacology,
ed. G. A. Cordell, Academic Press, New York, 1993, vol. 44,
p. 257.
Acknowledgements
This work was supported by Ministero dell’Università e della
Ricerca Scientifica e Tecnologica (MURST).
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