Convenient synthesis of bis(3-indolyl)-acetylene via Sonogashira coupling

Article abstract of DOI:10.1080/00397910601133631

We describe the synthesis of bis(3-indolyl)acetylene 6 via a Pd-catalyzed cross-coupling reaction of iodoindole 8 and 3-indolylacetylene 9, followed by deprotection of 14 to furnish 6. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601133631

Synthetic Communicationsw, 37: 829–837, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601133631
Convenient Synthesis of Bis(3-indolyl)-
acetylene via Sonogashira Coupling
Sudipta Roy and Gordon W. Gribble
Department of Chemistry, Dartmouth College, Hanover, NH, USA
Abstract: We describe the synthesis of bis(3-indolyl)acetylene 6 via a Pd-catalyzed
cross-coupling reaction of iodoindole 8 and 3-indolylacetylene 9, followed by depro-
tection of 14 to furnish 6.
Keywords: (indolyl)acetylenes, iodoindoles, Pd-catalyzed reaction
Bis(3-indolyl)acetylenes (1) constitute a potentially important class of
molecules because of their possible use as building blocks in heterocycle
synthesis. The phenyl analog of 1, diphenylacetylene (2, tolan), has been
widely used in organic synthesis. Huang and Larock have extensively
utilized the triple bond of 2 in the palladium-catalyzed synthesis of substituted
phenanthrenes, indenones, b-naphthylamines, indoles, naphthalenes, b- and
g-carbolines, coumarins, isocoumarins, a-pyrones, fluorenes, tetraarylolefins,
carbazoles, isoquinolines, dihydroisoquinolines, pyridines, benzofurans, and
benzopyrans.[1] Takahashi et al. used 2 in the zirconium-mediated synthesis
of substituted pyridines, pyridones, iminopyridines, and arylcyclobutanes
and palladium-catalyzed synthesis of pentasubstituted fulvenes.[2] Satoh
et al. demonstrated the palladium-catalyzed synthesis of highly substituted
1,3-butadienes and rhodium-catalyzed synthesis of 2,3-diphenyl-1-
indenones using 2.[3] Tobisu et al. have used 2 for the ruthenium-catalyzed
synthesis of functionalized g-butyrolactones.[4] Chang et al. also used 2
in cobalt- and nickel-catalyzed synthesis of substituted indenol, indenes,
and substituted cyclobutenes.[5] Diphenylacetylene (2) was also used by
others to synthesize various substituted heterocycles.[6] However, bis(3-
Received in the USA July 23, 2006
Address correspondence to Gordon W. Gribble, Department of Chemistry,
Dartmouth College, Hanover, NH 03755, USA. E-mail: ggribble@dartmouth.edu
829

830
S. Roy and G. W. Gribble
Scheme 1.
indolyl)acetylenes are relatively unexplored, and only one synthesis of this
class of molecules has been reported to date.
The aforementioned sole synthesis of 6 was reported by Kamenskii and
coworkers; they obtained an 8% yield of the desired product from 3-indolyl
skatyl ketone (1,2-di-1H-indol-3-yl-ethanone, 5) (Scheme 1).[7] Their
synthesis of 5 involved the use of highly unstable indole-3-acetyl chloride
(3), which needs to be used immediately after preparation from indole-3-
acetic acid. The indolyl Grignard 4 was generated from indole and ethylmag-
nesium bromide.
A direct synthesis of 1 (R, R0 ¼ SO2Ph) involving a Sonogashira reaction
as the key step in which two indole fragments are combined seemed very
attractive. Toward this goal, we synthesized 3-iodo-1-(phenylsulfonyl)indole
(8) and 3-ethynyl-1-(phenylsulfonyl)indole (9). The known 3-iodo-1-(phenyl-
sulfonyl)indole (8) was prepared from indole in 61% yield via iodination
followed by N-protection (Scheme 2).
To synthesize 3-ethynyl-1-(phenylsulfonyl)indole (9), we protected
3-formylindole (10) with the phenylsulfonyl group to give 11, which was
then converted to 12 using the Corey–Fuchs procedure (Scheme 3).[8]
Scheme 2.

Synthesis of Bis(3-indolyl)acetylene
831
Scheme 3.
Dibromide 12 was first treated with lithium hexmethyldisilazide (LiHMDS) to
generate bromoalkyne 13, which was subjected to the next reaction without any
further purification. Treatment of crude bromoalkyne 13 with sec-BuLi gave the
alkyne 9 in 60% yield in two steps.[9] Alkyne 9 can also be prepared from 12
directly using two equivalents of n-BuLi albeit in lower yield.
Having the required components in hand, we coupled them using a
Sonogashira reaction with Pd(PPh3)4 as the catalyst in the presence of
Scheme 4.

832
S. Roy and G. W. Gribble
catalytic CuI. To our delight, the desired compound 14 was produced in 86%
yield (Scheme 4). Compound 14 can be conveniently deprotected by 2.5 M
NaOH (aq) in ethanol to furnish the unprotected compound 6 in 70% yield
(85% yield based on recovered starting material).
In summary, we describe a convenient synthesis of phenylsulfonyl-
protected and unprotected bis(3-indolyl)acetylenes. The chemistry of these
internal alkynes is ongoing in our laboratory and will be reported in due course.
EXPERIMENTAL
Melting points were determined with a Mel-Temp Laboratory Device apparatus
and are uncorrected. IR spectra were recorded on a Perkin-Elmer 600 series
FTIR spectrophotometer. 1H and 13C NMR spectra were recorded on either a
Varian XL-300 or a 500 Fourier transform NMR spectrometer. Both low-
and high-resolution mass spectra were carried out at the Mass Spectrometry
Laboratory, School of Chemical Sciences, University of Illinois at Urbana–
Champaign. Elemental analyses were performed by Atlantic Microlab Inc.,
Norcross, GA. All experiments were performed under a nitrogen atmosphere.
Anhydrous THF and CH2Cl2 were prepared on a solvent purification
system. All other solvents (analytical grade) including anhydrous solvents
and reagents were used as received.
3-Iodo-1-(phenylsulfonyl)indole (8)
To a stirred solution of indole (1.76 g, 15 mmol) in DMF (25 mL) at rt, freshly
powdered KOH (88%, 2.10 g, 33 mmol) was added. The mixture was stirred at
rt for 1 h. Then a solution of iodine (3.88 g, 15.3 mmol) in DMF (25 mL) was
added dropwise. After the addition was complete, the solution was stirred at rt
for 2 h. It was then poured into ice-cold water (400 mL) containing aqueous
ammonium hydroxide (10 mL) and sodium metabisulfite (1g). The solid pre-
cipitate was allowed to settle, filtered, washed well with ice-cold water, air-
dried, and redissolved in dichloromethane (50 mL). Freshly powdered NaOH
(1.8 g, 45 mmol) and tetra-n-butylammonium hydrogen sulfate (0.25 g,
0.75 mmol) were added. After stirring the mixture for 15 min at rt, benzenesul-
fonyl chloride (2.3 mL, 18 mmol) was added dropwise and stirred for 6 h. The
reaction mixture was then washed with brine (50 mL), water (3 ꢀ 50 mL), and
then again with brine (50 mL). The organic phase was dried (MgSO4) and con-
centrated in vacuo. The residue was dissolved in minimum amount of dichlor-
omethane and subjected to purification by column chromatography on silica gel
(petroleum ether–ether 4:1) followed by recrystallization from ethyl acetate–
hexanes to yield the desired product (3.51 g, 61%) as a colorless solid: mp
1
127–1298C (lit.[10] 125–1278C): H NMR (CDCl3): d 7.97–7.99 (m, 1H),

Synthesis of Bis(3-indolyl)acetylene
833
7.90–7.92 (m, 2H), 7.72 (s, 1H), 7.55–7.58 (m, 1H), 7.45–7.48 (m, 2H), 7.38–
7.41 (m, 2H), 7.31–7.34 (m, 1H); 13C NMR (CDCl3): d 138.0, 134.5, 134.3,
132.6, 129.8, 129.6, 127.0, 125.9, 124.2, 122.2, 113.5, 67.4.
1-(Phenylsulfonyl)indole-3-carbaldehyde (11)
To a stirred solution of commercially available 3-formylindole (Aldrich,
5.81 g, 40 mmol) in dichloromethane (50 mL) at 08C, freshly powdered
NaOH (4.64 g, 116 mmol) and tetra-n-butylammonium hydrogen sulfate
(0.54 g, 1.6 mmol) were added. The mixture was stirred at the same tempera-
ture for 15 min, and then a solution of benzenesulfonyl chloride (6.2 mL,
48 mmol) in dichloromethane (5 mL) was added dropwise. The mixture was
stirred at 08C for 1 h and then at rt for 2 h. Water (100 mL) was added to
the reaction mixture. The separated organic layer was washed with water
(3 ꢀ 100 mL) and brine (100 mL) and dried (Na2SO4). The solvent was evap-
orated, and the residue was purified by recrystallization from dichloro-
methane–hexanes to yield 11 (10.95 g, 96%) as a white solid: mp 156–
1
1588C (lit.[11] 156–1578C); H NMR (CDCl3): d 10.11 (s, 1H), 8.26–8.27
(m, 2H), 7.96–7.99 (m, 3H), 7.06–7.63 (m, 1H), 7.50–7.53 (m, 2H), 7.40–
7.44 (m, 1H), 7.36–7.39 (m, 1H); 13C NMR (CDCl3): d 185.5, 137.5,
136.4, 135.4, 134.9, 129.9, 127.3, 126.6, 126.4, 125.3, 122.8, 122.7, 113.4.
3-(2,2-Dibromoethenyl)-1-(phenylsulfonyl)indole (12)
To a stirred solution of carbon tetrabromide (6.63 g, 20 mmol) in dichloro-
methane (75 mL) at 08C, triphenylphosphine (10.5 g, 40 mmol) was added in
portions. After stirring the mixture at the same temperature for 1 h, a solution
of 11 (2.85 g, 10 mmol) in dichloromethane (35 mL) was added dropwise.
The mixture was stirred at 08C for an additional 5 h and then poured into
hexanes (500 mL) with vigorous stirring. Stirring was continued for 1 h. The
precipitate was filtered off and washed thoroughly with hexanes
(3 ꢀ 100 mL). The combined filtrate was concentrated in vacuo, and the
residue was purified by column chromatography on silica gel (hexanes–ethyl
acetate 9:1) to yield 12 (4.27 g, 97%) as a white solid: mp 160–1628C; IR
(thin film): 1446, 1366, 1175, 1132, 1093, 971, 756 cm21; 1H NMR (CDCl3):
d 8.32 (s, 1H), 8.01–8.03 (m, 1H), 7.92–7.94 (m, 2H), 7.52–7.58 (m, 3H),
7.45–7.49 (m, 2H), 7.36–7.40 (m, 1H), 7.28–7.31 (m, 1H); 13C NMR
(CDCl3): d 138.0, 134.3, 134.2, 129.6, 129.5, 127.1, 127.0, 126.9, 125.7,
125.1, 123.9, 119.1, 117.7, 113.8, 90.7; LRMS (EI): m/z 441, 400, 300
(100%), 221, 194, 140, 113, 77; HRMS (EI): m/z calcd. for C16H11NO2SBr2:
438.8877, found: 438.8886. Anal. calcd. for C16H11NO2SBr2: C, 43.56; H,
2.51; N, 3.18; S, 7.27; Br, 36.23. Found: C, 43.72; H, 2.42; N, 3.35; S, 7.30;
Br, 36.43.

834
S. Roy and G. W. Gribble
3-Ethynyl-1-(phenylsulfonyl)indole (9)
Using LiHMDS followed by sec-BuLi
To a stirred solution of 12 (2.21 g, 5 mmol) in THF (40 mL) at 2788C, lithium
bis(trimethylsilyl)amide (11 mL, 1 M solution in THF, 11 mmol) was added
dropwise. After the addition was complete, the reaction mixture was stirred
at the same temperature for 30 min and then quickly quenched by the rapid
addition of saturated aqueous ammonium chloride solution (75 mL). It was
extracted with ethyl acetate (3 ꢀ 50 mL) and dried (Na2SO4). The solvent
was evaporated, and the solid residue was subjected to prolonged drying.
After complete drying, it was redissolved in THF (40 mL), cooled to 2788C,
and sec-butyllithium (5.4 mL, 1.4 M in cyclohexane, 7.5 mmol) was added
dropwise. The mixture was stirred at 2788C for 15 min, and then saturated
aqueous NH4Cl solution was rapidly added. The mixture was extracted with
ethyl acetate (2 ꢀ 50 mL) and dried (Na2SO4). The solvent was evaporated,
and the residue was purified by column chromatography on silica gel (dichloro-
methane–hexanes 1:1) to furnish the desired product (0.84 g, 60% in two steps)
as a yellowish brown solid.
Using n-BuLi
To a stirred solution of 12 (0.13 g, 0.3 mmol) in tetrahydrofuran (3 mL) at
2788C, n-butyllithium (0.26 mL, 2.5 M in hexanes, 0.65 mmol) was added
dropwise. The mixture was stirred at the same temperature for 1 h, then
allowed to warm to rt, and stirred for 45 min. The reaction was quenched by
the dropwise addition of cold water and extracted with n-pentane (50 mL).
The organic phase was washed with brine (100 mL) and dried (Na2SO4). The
solvent was evaporated, and the residue was purified by column chromato-
graphy (dichloromethane–hexanes 1:1) to yield 9 (31 mg, 37%) as a
yellowish brown solid: mp 83–858C; IR (thin film): 3287, 1446, 1374, 1177,
1
1132, 1097, 967, 745 cm21; H NMR (CDCl3): d 8.00 (d, 1H, J ¼ 8.3 Hz),
7.92 (d, 2H, J ¼ 7.8 Hz), 7.81 (s, 1H), 7.66 (d, 1H, J ¼ 7.8 Hz), 7.56 (t, 1H,
J ¼ 7.1 Hz), 7.47 (t, 2H, J ¼ 7.6 Hz), 7.38 (t, 1H, J ¼ 7.6 Hz), 7.32 (t, 1H,
J ¼ 7.6 Hz), 3.28 (s, 1H); 13C NMR (CDCl3): d 137.9, 134.4, 134.2, 130.9,
130.1, 130.0, 129.6, 127.1, 125.9, 124.1, 120.7, 113.7, 104.5, 81.9, 75.0;
LRMS (EI): m/z 281 (Mþ), 140 (100%), 113, 77; HRMS (EI): m/z calcd.
for C16H11NO2S: 281.0510, found: 281.0502.
1-(Phenylsulfonyl)-3-[[1-(phenylsulfonyl)indolyl]ethynyl]indole (14)
To a mixture of alkyne 9 (0.17 g, 0.6 mmol), iodoindole 8 (0.19 g, 0.5 mmol),
Pd (PPh3)4 (24 mg, 0.02 mmol), and cuprous iodide (2 mg, 0.01 mmol) in
anhydrous DMF (2 mL), triethylamine (1.4 mL, 10 mmol) was added. The

Synthesis of Bis(3-indolyl)acetylene
835
reaction mixture was stirred at rt for 20 h. It was then poured into 0.1 M HCl
(100 mL) and extracted with ethyl acetate (2 ꢀ 50 mL). The combined
organic phase was washed with water (50 mL), brine (50 mL), and dried
(Na2SO4). The solvent was evaporated, and the residue was dissolved in a
minimum amount of dichloromethane, purified by column chromatography
(hexanes–ethyl acetate ¼ 2:1), and followed by recrystallization from ethyl
acetate to furnish 14 (0.23 g, 86%) as a white solid: mp 249–2518C (dec);
1
IR (thin film): 1446, 1372, 1175, 1128, 980, 748 cm21; H NMR (DMSO-
d6): d 8.34 (s, 2H), 8.07–8.10 (m, 4H), 8.02 (d, 2H, J ¼ 8.1 Hz), 7.71–7.78
(m, 4H), 7.60–7.65 (m, 4H), 7.37–7.50 (m, 4H); 13C NMR (DMSO-d6): d
136.5, 135.1, 133.5, 130.0, 129.8, 126.9, 126.0, 124.4, 120.3, 113.5, 104.2,
84.6; LRMS (EI): m/z 536 (Mþ), 400, 395, 383, 277, 254, 242, 141, 127,
115, 73 (100%); HRMS (EI): m/z calcd. for C30H20N2O4S2: 536.0865,
.
found: 536.0850. Anal. calcd. for C30H20N2O4S2 1/6H2O: C, 66.77; H,
3.80; N, 5.19; S, 11.88. Found: C, 66.50; H, 3.64; N, 5.10; S, 11.71.
Extensive drying did not remove the water present in the sample, which
1
was found to be present in the H NMR spectrum.
3-[(Indolyl)ethynyl]indole (6)
To a stirred solution of 14 (107 mg, 0.2 mmol) in ethanol (3 mL), 2.5 M
NaOH (0.8 mL, 2 mmol) were added. The mixture was stirred for 48 h.
Water (25 mL) was added. It was extracted with ether (2 ꢀ 50 mL). The
aqueous layer was acidified with 1 N HCl (25 mL) and extracted with ethyl
acetate (25 mL). The combined organic phase was dried (Na2SO4) and
purified by column chromatography on silica gel (dichloromethane) to yield
6 (36 mg, 70%) as a white solid (24 mg, 22% of the starting material was
recovered): mp 253–2558C (dec) (lit.[7] 268–2708C, dec); IR (thin film):
1
3383, 742 cm21; H NMR (DMSO-d6): d 11.44 (s, 2H), 7.71 (s, 2H), 7.66–
7.68 (m, 2H), 7.44–7.46 (m, 2H), 7.17–7.21 (m, 2H), 7.12–7.15 (m, 2H);
13C NMR (DMSO-d6): d 135.4, 128.6, 128.1, 122.1, 119.8, 118.9, 112.0,
97.3, 84.2; LRMS (EI): m/z 256 (100%), 236, 199, 128, 77; HRMS (EI):
m/z calcd. for C18H12N2: 256.1001, found: 256.1004.
ACKNOWLEDGMENTS
This investigation was supported in part by the donors of the Petroleum Research
Fund (PRF), administered by the American Chemical Society, and Wyeth.
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Synthesis of Bis(3-indolyl)acetylene
837
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