Cross-coupling of 4,5,6,7-tetrahydroindole with functionalized haloacetylenes on active surfaces of metal oxides and salts

Article abstract of DOI:10.1134/S1070428010090186

Screening was performed of metal oxides (MgO, CaO, ZnO, BaO, Al ₂O₃, TiO₂, ZrO₂) and salts (CaCO₃, K₂CO₃, ZrSiO₄) as active surfaces for the reaction of ethynylation o

Full text of DOI:10.1134/S1070428010090186

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 9, pp. 1373−1377. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © L.N. Sobenina, D.N. Tomilin, O.V. Petrova, N. Gulia, K. Osowska, S. Szafert, A.I. Mikhaleva, B.A. Trofimov , 2010, published in
Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 9, pp. 1371−1375.
Dedicated to Full Member of the Russian Academy of Sciences
th
N.S. Zefirov on occasion of his 75 anniversary
Cross-Coupling of 4,5,6,7-Tetrahydroindole with Functionalized
Haloacetylenes on Active Surfaces of Metal Oxides and Salts
a
a
a
b
b
L. N. Sobenina , D. N. Tomilin , O. V. Petrova , N. Gulia , K. Osowska ,
c
a
a
S. Szafert , A. I. Mikhaleva , and B. A. Trofimov
aFaworsky Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
Irkutsk, 664033 Russia
e-mail: boris_trofimov@irioch.irk.ru
University of Wroclaw, Wroclaw, Poland
b
cWroclaw Research Center EIT+ Ltd., Poland
Received March 4, 2010
Abstract—Screening was performed of metal oxides (MgO, CaO, ZnO, BaO, Al O , TiO , ZrO ) and salts
2
3
2
2
(
CaCO , K CO , ZrSiO ) as active surfaces for the reaction of ethynylation of 4,5,6,7-tetrahydroindole with
3 2 3 4
ethyl bromopropynoate and bromobenzoylacetylene. It was established that Ca, Mg, Zn, and Ba oxides assist the
ethynylation of 4,5,6,7-tetrahydroindole, and their activity in the reaction with ethyl bromopropynoate considerably
exceeds that of aluminum oxide. The ethynylation is accompanied with the formation of intermediate E-2-(1-
bromoethenyl)-4,5,6,7-tetrahydroindole and side 1,1-di(4,5,6,7-tetrahydroindol-2-yl)ethenes and 1,1-di(4,5,6,7-
tetrahydroindol-2-yl)bromoethanes.
DOI: 10.1134/S1070428010090186
The regioselective functionalization of pyrroles
and indoles remains an urgent task in the chemistry of
heterocyclic compounds since these compounds are
structural fragments of numerous biologically active
natural substances and pharmaceuticals [1, 2]. A special
attention among the compounds of the pyrrole and indole
series is attracted by their ethynyl derivatives owing to
the rich chemistry of the acetylene function [3–7]. In this
connection considerable efforts are devoted to the devel-
opment of new effective procedures for the synthesis of
C-ethynylpyrroles and -indoles [8–12].
of aluminum oxide that did not require special catalysts,
bases, solvents, inert atmosphere, and which proceeded at
room temperature. The most promising for the use in this
reaction is the 4,5,6,7-tetrahydroindole that has become
the most available indole derivative due to the develop-
ment of the one-pot technology of its preparation from
cyclohexanone oxime and acetylene [18]. Being actually
an active pyrrole (namely, 2,3-dialkyl-substituted pyr-
role), 4,5,6,7-tetrahydroindole (I) unlike indole has the
most reactive position 2 thus providing a possibility of its
ethynylation just in this position opening the way to the
synthesis o f versatile 2-derivatives of 4,5,6,7-tetrahydro-
indole and by dehydrogenation, to 2-substituted indoles,
structural analogs of many important alkaloids [2, 19].
However the majority of the known methods of the
ethynylation of pyrrole ring requires the use of functional-
ized pyrroles and indoles as initial reagents [13].
We recently developed a new method of introduc-
tion of an acetylene substituent into the position 2 of
the pyrrole ring [14, 15] or the position 3 of the indole
ring [16, 17] based on the cross-coupling of pyrroles or
indoles with electrophilic haloacetylenes on the surface
Yet on the surface of the aluminum oxide the reac-
tion of 4,5,6,7-tetrahydroindole with haloacetylenes
occurs nonselectively: Along the expected 2-ethynyl-
4,5,6,7-tetrahydroindoles form the corresponding
2-(1-haloethenyl)-4,5,6,7-tetrahydroindoles, and also the
1
373

1374
SOBENINA et al.
products of the exchange in the latter of a halogen atom
with the molecule of the initial pyrrole, 1,1-di(4,5,6,7-
tetrahydroindol-2-yl)ethenes[14, 20].
triple bond of the benzoylbromoacetylene.
However taking into account the fundamental dif-
ference in the reactivity of the 2-phenylpyrrole and the
4
,5,6,7-tetrahydroindole in some reactions [22, 23] and
In this study aiming at the increase in the efficiency
and selectivity of the synthesis of 2-ethynyl-4,5,6,7-
tetrahydroindoles we investigated in detail the cross-
coupling of 4,5,6,7-tetrahydroindole (Ia) with ethyl
bromopropynoate (IIa) and benzoylbromoacetylene (IIb)
on the surface of metal oxides (zinc, barium, calcium,
magnesium, titanium, and zirconium oxides) and salts
also the unlike reactivity of the benzoylbromoacetylene
and the ethyl bromopropynoate in the reaction of the
ethynylation of the pyrrole [14, 20] and indole [16, 17]
rings it was difficult to predict in advance which of the
cited active surfaces would be the most suitable for the
synthesis of 2-benzoylethynyl- or 2-ethoxycarbonylethy-
nyl-4,5,6,7-tetrahydroindoles.
(potassium and calcium carbonates, zirconium silicate).
The reactions were carried out at room temperature by
grinding equimolar quantities of reagents with solid metal
oxides or salts taken in 10-fold excess in the absence of
solvents. Depending on the nature of the active surface
compounds III–VI were obtained (Scheme 1). The
content of compounds III–VI in the reaction mixture
It actually proved that in contrast to the 2-phenylpyr-
role 4,5,6,7-tetrahydroindole (I) reacted with ethyl bro-
mopropynoate (IIa) on all mentioned active surfaces with
the formation of the corresponding ethynyl derivative
IIIa. Therewith the reaction mixtures obtained on the ox-
ides of calcium, barium, magnesium, and zinc contained
several times more 2-ethynyltetrahydroindole IIIa than
the product mixtures formed on the aluminum oxide. The
conversion of tetrahydroindole Ia on all studied surfaces
was close to 100% (unlike the analogous reactions of the
1
was determined from the H NMR spectra of samples
in CDCl taken from the reaction mixture after 0.5 h of
3
grinding (see the table).
The screening of the above series of metal oxides and
salts as active surfaces for the cross-coupling of pyrroles
with haloacetylenes was performed by an example of
reaction of 2-phenylpyrrole with benzoylbromoacety-
lene [21]. It was established that the oxides of calcium,
magnesium, zinc, and barium were efficient in the ethy-
nylation of the pyrrole ring whereas the silicon, titanium,
and zirconium oxides and salts (zirconium silicate and
calcium carbonate) specifically promoted the region- and
stereoselective addition of the 2-phenylpyrrole to the
2
-phenylpyrrole whose conversion was 46-100%).
For instance, the reaction mixture obtained with cal-
cium oxide contained 90% of ethynyltetrahydroindole
IIIa (see the table), whereas the 2-phenylpyrrole under
similar conditions reacted to the conversion not exceeding
2
9%, and the content of 2-ethynyl-5-phenylpyrrole was
in this case 19% [21].
Similar to the reaction on aluminum oxide, on the
mentioned active surfaces the cross-coupling is accom-
Scheme 1.
O
R
Active surface
+
Br
O
N
H
N
H
R
IIa, IIb
Ia
IIIa, IIIb
Br
Br
N
N
N
H
O
H
N
H
O
N
H
O
H
+
+
+
R
R
R
IVa, IVb
Va, Vb
VIa, VIb
R = OEt (a), Ph (b)
R = OEt (a), Ph (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

CROSS-COUPLING OF 4,5,6,7-TETRAHYDROINDOLE
1375
1
Monitoring by H NMR method of reaction between 4,5,6,7-tetrahydroindole (Ia) with ethyl bromopropynoate (IIa) or
benzoylbromoacetylene (IIb) (room temperature, 0.5 h)
Ethyl bromopropynoate (IIa)
Benzoylbromoacetylene (IIb)
Oxide or salt (active
surface)
Composition of reaction mixture, %
Ia
IIIa
IVa
Va
VIa
Ia
IIIb
IVb
Vb
VIb
MgO
CaO
0
0
0
0
0
0
0
0
0
0
0
84
90
61
87
27
16
20
13
100
24
17
14
8
2
2
0
0
10
0
0
0
0
0
0
0
0
0
0
62
80
50
55
67
0
14
8
0
12
0
14
0
ZnO
22
9
3
14
0
43
24
24
100
54
45
30
49
58
7
BaO
4
11
9
10
0
Al O (pH 9.3)
54
35
35
40
0
15
4
4
2
3
SiO2
TiO2
ZrO2
45
39
37
0
0
0
6
5
11
0
30
34
0
10
0
21
67
25
0
K CO
3
2
3
CaCO3
ZrSiO4
35
36
7
34
44
9
17
25
3
17
panied with the formation of 2-(1-bromoethenyl)-4,5,6,7-
tetrahydroindole (IVa) and di-(4,5,6,7-tetrahydroindol-
the nucleophilic addition of tetrahydroindole Ia to
intermediate 2-(1-bromoethenyl)-4,5,6,7-tetrahydro-
indole (IVa) (Scheme 3). In all cases the content of
2-(1-bromoethenyl)-4,5,6,7-tetrahydroindole (IVa) in the
reaction mixtures did not exceed 35–40%.
2
-yl)-ethene (Va) (Scheme 1), and the former is an
intermediate compound.
The side product of the reaction, 1,1-di(4,5,6,7-
tetrahydroindol-2-yl)ethene (Va) resulting from the
replacement of the bromine atom in intermediate IV by
the molecule of tetrahydroindole Ia (Scheme 2) formed
always in negligible amounts.
Scheme 3.
Ia
IVa, IVb
VIa, Vib
Scheme 2.
Ia
Tetrahydroindole Ia reacted with benzoylbromoacety-
lene (IIb) on the studied metal oxides less actively and
less selectively than with ethyl bromopropynoate (IIa)
IVa, IVb
Va, Vb
_HBr
(see the table). The only exception is the aluminum oxide:
In its presence the content of 2-(benzoylethynyl)-4,5,6,7-
tetrahydroindole (IIIb) in the reaction mixture is 2.5 times
higher than the content of 2-ethynyltetrahydroindole IIIa
obtained under similar conditions from ethyl bromopro-
pynoate (IIa). The only surface exceeding in this respect
that of the aluminum oxide is the surface of the calcium
oxide. On the titanium and zirconium oxides and on
the calcium carbonate tetrahydroindole Ia reacted with
acetylene derivative IIb giving a mixture of 2-(bromo-
ethenyl)- (IVb) and 2-ethynyl-4,5,6,7-tetrahydroindoles
As was formerly reported [24] in the presence of the
potassium carbonate under the studied reaction conditions
4
(
,5,6,7-tetrahydroindole Ia with ethyl bromopropynoate
IIa) selectively formed 2-ethynyl-4,5,6,7-tetrahydroin-
dole (IIIa).
On the surface of silicon, titanium, zirconium oxides
and salts (calcium carbonate and zirconium silicate)
the ethynylation occurred to a low yield (13–24%,
see the table). The main product of these reactions is
unstable di(4,5,6,7-tetrahydroindol-2-yl)bromoethane
(IIIb). Besides in the reaction products obtained on these
active surfaces compound VIb was detected.
(
VIa). This compound was previously shown [20] to
form without involvement of the active surface by
The only active surface assisting the region- and ste-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

1376
SOBENINA et al.
reoselective addition of tetrahydroindole Ia to the triple
bond of benzoylbromoacetylene (IIb) was silicon oxide
Ethynylation of 4,5,6,7-tetrahydroindole (Ia) with
haloacetylenes on active surfaces. Equimolar amounts
of 4,5,6,7-tetrahydroindole (Ia) and haloacetylene IIa or
IIb were thoroughly ground for 5 min at room tempera-
ture in a porcelain mortar with an oxide or a salt taken
in 10-fold excess with respect to the overall amount of
reagent. The reaction mixture was kept for 25 min more
(see the table).
The potassium carbonate, the most selective and ef-
ficient in the reaction of tetrahydroindole Ia ethynylation
with ethyl bromopropynoate (IIa), acts nonselectively in
the reaction with acetylene IIb: Some part of the reaction
intermediate bromoethenyltetrahydroindole IVb remains
in the reaction mixture. Yet the increase in the reaction
duration to 1 h or the use of potassium carbonate 2-fold
amount made it possible to carry out this reaction ma-
terially selectively and to isolate ethynylpyrrole IIIb in
1
and was analyzed by H NMR. To this end a weighed
portion (100–120 mg) of the reaction mixture was washed
with CDCl . The ratio of the reaction products was de-
3
termined by the integral intensity of signals of the H3
proton of the tetrahydroindole ring of compounds IIIa
3
(
6.49 ppm) and IIIb (6.61 ppm); H and H protons of
6
4
6% yield. Analogously from N-methyl- and N-benzyl-
,5,6,7-tetrahydroindoles we obtained the corresponding
a
compounds IVa (6.66 and 6.05 ppm) and IVb (6.84 and
3
3’
7
.10 ppm); H , H , and H protons of compounds Va
ethynyltetrahydroindoles VII, VIII in 68–71% yield
a
(
6.29, 6.41, and 5.56 ppm) and Vb (6.62, 6.56 and 6.50
(Scheme 4).
3
ppm); H , CH COPh, 7-CH of the cyclohexane ring of
2
2
Thus new active surfaces were found (calcium, mag-
compounds VIa (7.06, 3.90, and 3.20 ppm) and VIb
nesium, barium, and zinc oxides) permitting the efficient
and regioselective introduction of a functional acetylene
substituent into the position 2 of the tetrahydroindole
skeleton without solvent and specially added transition
metal compounds.
(7.15, 4.64, and 3.20 ppm).
Reaction of 4,5,6,7-tetrahydroindole (Ia), 1-methyl-
and 1-benzyl-4,5,6,7-tetrahydroindoles (Ib, Ic) with
benzoylbromoacetylene (IIb) on K2CO3. General pro-
cedure. A mixture of 1 mmol of tetrahydroindole Ia–Ic
and 1 mmol of acetylene derivative IIb was thoroughly
ground for 5 min at room temperature in a porcelain
mortar with 10-fold excess of potassium carbonate. The
mixture self-heated to 30°C and acquired bright yellow
color that further became brown. The reaction mixture
was kept for 1 h and then treated with water. The separated
crystals were filtered off, dried to the constant weight,
and the ethynyltetrahydroindoles IIIb, VII, VIII were
purified by column chromatography on aluminum oxide
The effect of the nature of the active surfaces and
the structure of the haloacetylene (ethyl bromopropyno-
ate and benzoylbromoacetylene) was studied on the
content in the reaction mixtures of intermediate E-2-(1-
bromoethenyl)-4,5,6,7-tetrahydroindoles IVa, IVb and
the side products 1,1-di-(4,5,6,7-tetrahydroindol-2-yl)
ethenes Va, Vb and 1,1-di-(4,5,6,7-tetrahydroindol-2-yl)
bromoethanes VIa, VIb.
EXPERIMENTAL
(eluent hexane).
IR spectra of compounds were recorded on a spectro-
Spectral characteristics of 2-benzoylethynyl-4,5,6,7-
tetrahydroindole (IIIb) were reported in [14].
–
1
photometer Bruker IFS-25 in the region 400–4000 CM
from pellets with KBr. H and 13C NMR spectra were
1
2-Benzoylethynyl-1-methyl-4,5,6,7-tetrahydroin-
dole (VII). Yield 0.179 g (68%). Orange crystals, mp
registered on a spectrometer Bruker DPX 400 [operating
1
13
–1
frequencies 400.13 ( H) and 100.6 ( C) MHz], solvent
116–117°C. IR spectrum, ν, cm : 2156 (C≡C), 1608
1
CDCl , internal reference HMDS.
(C=O). H NMR spectrum, δ, ppm: 1.73 m (2H, 5-CH ),
3
2
Scheme 4.
O
K CO
2 3
+
Br
O
N
R
N
R
20°C, 1 h
Ph
Ph
IIb
R = H (Ia, IIIb), Me (Ib, VII), Bn (Ic, VIII).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010
_
Ia Ic
IIIb, VII, VIII

CROSS-COUPLING OF 4,5,6,7-TETRAHYDROINDOLE
1377
8
. Matsumoto, S., Kobayashi, T., and Ogura, K., Heterocycles,
1
7
.83 m (2H, 6-CH ), 2.49 m (2H, 4-CH ), 2.55 m (2H,
2 2
3
2005, vol. 66, p. 319.
-CH ), 3.63 s (3H, NMe), 6.62 s (1H, H ), 7.47 m (2H,
2
m
p
o
9. Kitano, Y., Suzuki, T., Kawahara, E., and Yamazaki, T.,
H COPh), 7.57 m (1H, H COPh), 8.14 m (2H, H
COPh). 1 C NMR spectrum, δ, ppm: 22.5, 22.7, 22.9,
3
Bioorg. Med. Chem., 2007, vol. 17, p. 5863.
2
3.1 (4,5,6,7-CH ), 31.2 (NMe), 90.0 (C≡), 96.7 (≡C),
10. Soley, R., Albericio, F., and Alvarez, M., Synthesis, 2007,
2
3
4
2
5
o
p. 1559.
110.7 (C ), 119.4 (C ), 119.8 (C ), 128.4 (C ), 129.0 (C
m
p
i
COPh), 133.3 (C COPh), 136.1 (C COPh), 137.3 (C
COPh), 177.1 (C=O). Found, %: C 81.77; H 6.42; N 5.13.
C H NO. Calculated, %: C 82.10; H 6.51; N 5.32.
11. Knight, D.W., Rost, H.C., Sharland, Ch.M., and
Singkhonrat, J., Tetrahedron Lett., 2007, vol. 48, p. 7906.
18
17
12. Nikitin, E.B., Nelson, M.J., and Lightner, D.A., J. Hetero-
cyclic, Chem., 2007, vol. 44, p. 739.
2
-Benzoylethynyl-1-benzyl-4,5,6,7-tetrahydroin-
dole (VIII). Yield 0.241 g (71%). Light-yellow crystals,
13. Trofimov, B.A. and Sobenina, L.N., Target in Heterocyclic
Systems, 2009, p. 13.
–
1
mp 106–107°C. IR spectrum, ν, cm : 2163 (C≡C), 1622
1
(
C=O). H NMR spectrum, δ, ppm: 1.71 m (2H, 5-CH ),
14. Trofimov, B.A., Stepanova, Z.V., Sobenina, L.N., Mikha-
leva, A.I., and Ushakov, I.A., Tetrahedron Lett., 2004,
vol. 45, p. 6513.
2
1
7
.77 m (2H, 6-CH ), 2.45 m (2H, 4-CH ), 2.52 m (2H,
2 2
3
-CH ), 5.23 s (2H, NCH ), 6.70 s (1H, H ), 7.08 m (2H,
2
2
o
m,p
H CH Ph), 7.31–7. 51 m (6H, H CH Ph, COPh),
15. Trofimov, B.A., Sobenina, L.N., Stepanova, Z.V., Deme-
nev,A.P., Mikhaleva,A.I., Ushakov, I.A., Vakul’skaya, T.I.,
and Petrova, O.V., Zh. Org. Khim., 2006, vol. 42, p. 1348.
2
2
.97 m (2H, H COPh). 13C NMR spectrum, δ, ppm:
2.9, 23.0, 23.2, 23.4 (4,5,6,7-CH ), 48.5 (NCH ), 90.0
o
7
2
2
2
3
4
2
(
C≡), 96.6 (≡C), 111.3 (C ), 120.3 (C ), 120.7 (C ),
16. Sobenina, L.N., Demenev, A.P., Mikhaleva, A.I.,
Ushakov, I.A., Vasil’tsov, A.M., Ivanov, A.V., and Trofi-
mov, B.A., Tetrahedron Lett., 2006, vol. 47, p. 7139.
5
p
m
1
26.7 (C ), 127.8 (C CH Ph), 128.7 (C CH Ph), 129.1
2 2
o
o
p
(C CH Ph), 129.3 (C COPh), 133.6 (C COPh), 136.2
2
i
i
(C COPh), 137.6 (C CH Ph), 177.5 (C=O). Found, %:
17. Petrova, O.V., Sobenina, L.N., Ushakov, I.A., and Mikha-
2
C 84.57; H 6.42; N 4.03. C H NO. Calculated, %:
leva, A.I., Zh. Org. Khim., 2008, vol. 44, p. 1512.
2
4
21
C 84.92; H 6.24; N 4.13.
18. Trofimov, B.A., Mikhaleva, A.I., Shmidt, E.Yu., Ryapo-
lov, O.A., and Platonov, V.B., RF Patent 2297410, 2007;
Byull. Izobr., 2007, no. 11.
The study was carried out under a financial support
for the scientific schools of the President of the Russian
Federation (grant NSh 3230-2010.3) and of the Russian
Foundation for Basic Research (grant no. 09-03-00064).
Slawomir Szafert is grateful to the Polish Committee
for Scientific Research for the financial support (grants
no. 204 140 31/3236 and 204 151138).
1
2
2
9. Hesse, M., Alkaloids Nature’s Curse or Blessing, VHCA
Verlag, (Helvetica Chimica Acta, Zurich, Switzerland).
Weinheim, Germany: Willey-VCH, 2002, p. 413.
0. Trofimov, B.A., Sobenina, L.N., Demenev, A.P., Stepano-
va, Z.V., Petrova, O.V., Ushakov, and I.A., Mikhaleva,A.I.,
Tetrahedron Lett., 2007, vol. 48, p. 4661.
1. Trofimov, B.A., Sobenina, L.N., Stepanova, Z.V.,
Vakul’skaya, T.I., Kazheva, O.N., Aleksandrov, G.G.,
Dyachenko, O.A., and Mikhaleva,A.I., Tetrahedron, 2008,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010