Heterocyclization of o-(arylethynyl)arylhydrazines as a new procedure for the synthesis of substituted 1H-and 2H-indazoles and indoles

Article abstract of DOI:10.1023/A:1014071226473

Procedures for the preparation of 3-substituted 1H-and 2H-indazoles and 2-substituted indoles were developed based on cross-coupling of o-iodoarylhydrazines with copper acetylenides in pyridine or dimethylformamide. An alternative procedure for the synthesis of 3-substituted 1H-indazoles involves cyclocondensation of (2-chloroaryl)acetylenes with hydrazine hydrate in butanol.

Full text of DOI:10.1023/A:1014071226473

1268
Russian Chemical Bulletin, International Edition, Vol. 50, No. 7, pp. 1268—1273, July, 2001
Heterocyclization of o-(arylethynyl)arylhydrazines as a new procedure
for the synthesis of substituted 1H- and 2H-indazoles and indoles
T. A. Prikhodko and S. F. Vasilevsky«
Institute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Sciences,
3 ul. Institutskaya, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383 2) 34 2350. E-mail: vasilev@ns.kinetics.nsc.ru
Procedures for the preparation of 3-substituted 1H- and 2H-indazoles and 2-substituted
indoles were developed based on cross-coupling of o-iodoarylhydrazines with copper acetylenides
in pyridine or dimethylformamide. An alternative procedure for the synthesis of 3-substituted
1H-indazoles involves cyclocondensation of (2-chloroaryl)acetylenes with hydrazine hydrate
in butanol.
Key words: indazoles, isoindazoles, indoles, cross-coupling, o-iodoarylhydrazines,
o-chloroarylacetylenes, heterocyclization.
One of procedures for the synthesis of fused hetero-
cyclic compounds involves cyclization of ortho-func-
tionalized aryl- and hetarylacetylenes.1—3 Previously,
we have reported cyclocondensation of activated
(2-chloroaryl)acetylenes with hydrazine giving rise to
substituted 1H-indazoles4 and cross-coupling of (2-iodo-
aryl)hydrazines with terminal acetylenes or their copper
salts as a new procedure for the preparation of 2-sub-
stituted indoles.5
In the present study, we report the detailed experi-
mental conditions, characteristics of the compounds
synthesized, and some generalizations concerning these
cyclization reactions.
remained unconsumed even upon prolonged (34 h)
refluxing in n-bytanol. An attempt to carry out the
reaction of hydrazine hydrate with 2-chloro-5-nitrotolan
(60 h) was also unsuccessful.
In this connection, we examined cross-coupling
of 4-chloro-3-iodonitrobenzene (1) with aryl- and
hetarylacetylenes (2a—d) in the presence of the
PdCl2(PPh3)2—CuI system in Et3N (Scheme 1). The
reactions gave rise to (2-chloro-5-nitrophenyl)aryl-
acetylenes (3a—d) in 65—84% yields. Their physico-
chemical characteristics and spectral characteristics are
given in Tables 1 and 2, respectively.
Investigation into heterocyclization of (2-ethynyl-
aryl- and -hetaryl)hydrazines is very promising because
these compounds contain two nucleophilic centers in
the hydrazino group and the C≡C bond, which can be
subject to the attack by the N atoms. The target
(2-ethynylaryl- and -hetaryl)hydrazines can be prepared
by the reactions of (2-halogenoaryl- and -hetaryl)hydr-
azines with terminal alkynes as well as by cross-coupling
of the corresponding (2-chloroaryl- and -hetaryl)ace-
tylenes with hydrazine. We examined both these possi-
bilities. It should be noted that the first type of reactions
has not been studied previously. The second alternative
procedure has been mentioned only in the study6 con-
cerned with the reactions of 4-chlorophenylethynyl-
cinnolines with substituted hydrazines. In the latter
case, the expected ethynylarylhydrazines underwent cy-
clization to form pyrazole or pyrrole derivatives in
20—39% yields. No explanation for the fact that the
reactions followed different paths was provided. It is
needless to say that the use of highly reactive 4-chloro-
cinnoline did not allow one to make conclusions about
the scope and limitations of this cyclization reaction.
We performed systematic study of hydrazinolysis of
(2-chloroaryl)alkynes. It appeared that o-chlorotolan
Scheme 1
Cl
I
PdCl2(PPh3)2—CuI
H C C R
+
2a—d
NO2
1
R
Cl
NO2
3a—d
R = F-C6H4Br (a); F-C6H4NO2 (b);
Me
Cl
N
Me
(c);
(d)
N
N
Me
The reactions of compounds 3a—d with hydrazine
involved the replacement of the Cl atom and cyclization
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1210—1214, July, 2001.
1066-5285/01/5007-1268 $25.00 ©ꢀ2001 Plenum Publishing Corporation

Russ.Chem.Bull., Int.Ed., Vol. 50, No. 7, July, 2001
1269
Heterocyclization of o-(arylethynyl)arylhydrazines
Table 1. Principal physicochemical characteristics of acety-
lenes 3a—d
Table 3. Principal physicochemical characteristics of
1H-indazoles 4a—d
Com- Yield M.p./°C
Found
Calculated
Molecular
formula
Com- Yield M.p./°C
pound (%) (solvent)
Found
Calculated
Molecular
formula
(%)
Cl
(%)
pound (%)
(solvent)
Ñ
H
Ñ
H
N
—
3a*
3b
65
77
84
112—113
(C6H6)
164—165
(C6H6)
140—141
(EtOH)
50.02 2.08 10.33 C14H7BrClNO2
49.96 2.10 10.53
55.73 2.29 11.44 C14H7ClN2O4
55.56 2.23 11.71
66.67 3.21 12.80 C14H9ClN2O2
61.66 3.33 13.00
4a*
4b
75
88
65
66
187—188 50.49 3.06
(C6H6) 50.62 3.03
213—214 56.10 3.33 19.04 C14H10N4O4
(Me2CO) 56.38 3.38 18.78
C14H10BrN4O2
3ñ
4ñ
218—219 62.84 4.70 21.04 C14H12N4O2
(EtOH) 62.68 4.51 20.88
3d
78 188.5—189.5 50.19 3.05 22.70 C13H9Cl2N3O2
(C6H6) 50.35 2.93 22.86
4d
243—244 50.66 4.17 11.91 C13H12ClN5O2
(EtOH) 51.07 3.96 11.60
* Found (%): Br, 23.80. Calculated (%): Br, 23.74.
* Found (%): Br, 23.90. Calculated (%): Br, 24.06.
Table 2. Spectral characteristics of acetylenes 3a—d
Table 4. Spectral characteristics of 1H-indazoles 4a—d
Com-
pound
IR,*
ν/cm
1H NMR,**
δ (J/Hz)
Com-
pound
IR,*
ν/cm
1H NMR,**
δ (J/Hz)
–1
–1
3a
1350, 1525 (NO2); 7.48 (d, 2 H, H(3´), H(5´),
4a
1330, 1480 (NO2); 4.39 (s, 2 H, CH2); 7.28 (d,
2210 (C≡C)
J3´,2´(5´,6´) = 7.0); 7.52 (d, 2 H,
H(2´), H(6´); 7.61 (d, 1 H, H(3),
J3,4 = 7.1); 8.14 (dd, 1 H, H(3),
J3,6 = 1.6); 8.43 (d, 1 H, H(6))
3260 (br., NH)
2 H, H(2´), H(6´),
J2´,3´(6´,5´) = 7.1); 7.48 (d,
1 H, H(3´), H(5´)); 7.55 (d,
1 H, H(6), J6,7 = 7.2); 8.31
(dd, 1 H, H(7), J7,4 = 1.5);
8.58 (d, 1 H, H(4));
3b
3c
1350, 1540 (NO2); 7.60—8.40 (m, 6 H, H arom.);
2215 (C≡C) 8.47 (d, 1 H, H(6), J3,6 = 1.5)
1350, 1540 (NO2); 2.60 (s, 3 H, CH3); 7.20—7.80
12.60 (br.s, 1 H, NH)
2225 (C≡C)
(m, 3 H, H(5), H (5´), H(6´));
8.10 (dd, 1 H, H(3), J3,4 = 7.0);
8.40 (d, 1 H, H(6), J3,6 = 1.5);
8.70 (d, 1 H, H(2´), J2´,5´ = 1.6)
4b
4c
1370, 1400, 1530, 4.64 (s, 2 H, CH2); 7.70—8.30
1570 (NO2);
3450 (br., NH)
(m, 6 H, C6H4NO2, H(6), H(7));
8.72 (d, 1 H, H(4), J4,7 = 1.6);
12.60 (br.s, 1 H, NH)
3d
1350, 1545 (NO2); 2.25 (s, 3 H, C—CH3); 3.95 (s,
1370, 1510 (NO2); 2.43 (s, 3 H, CH3); 4.45 (s,
2235 (C≡C)
3 H, N—CH3); 7.60 (d, 1 H,
H(3), J3,4 = 7.2, J3,6 = 1.7);
8.15 (d, 1 H, H(4));
3450 (br., NH)
2 H, CH2); 7.16 (d, 1 H, H(5´),
J5´,6´ = 7.0); 7.65 (d, 1 H, H(6´));
7.72 (d, 1 H, H(6), J6,7 = 7.2);
8.21 (dd, 1 H, H(7), J7,4 = 1.6);
8.55 (s, 1 H, H(2´)); 8.70 (d, 1 H,
H(4)); 12.70 (br.s, 1 H, NH)
8.42 (d, 1 H, H(6))
* Solutions in CHCl3; in the case of compound 3a, KBr pellets.
** In CDCl3.
4d
1330, 1510 (NO2); 2.75 (s, 3 H, C—CH3); 3.70 (s,
3400 (br., NH)
3 H, N—CH3); 4.45 (s, 2 H,
CH2); 7.65 (d, 1 H, H(6),
J6,7 = 9.0); 8.15 (dd, 1 H, H(7),
J7,4 = 2.2); 8.70 (d, 1 H, H(4));
12.50 (br.s, 1 H, NH)
giving rise to 3,5-disubstituted 1H-indazoles (4a—d)
(Scheme 2). Their physicochemical and spectral charac-
teristics are listed in Tables 3 and 4, respectively.
* KBr pellets.
** In (CD3)2CO; in the case of 4a, in CDCl3.
Scheme 2
NHNH2
C C R
We attribute the formation of the pyrazole ring
instead of the pyrrole ring to the higher nucleophilicity
of the terminal N atom of the hydrazino group and
polarization of the C≡C bond. The latter is caused by
the combined effect of the electron-withdrawing group
of the acetylenic fragment and the electron-donating
NHNH2 group as a result of which the α-carbon atom
of the C≡C bond acquires a partial positive charge.
Examination of the reaction of compound 3d with
piperidine as an example demonstrated that it began
with the replacement of the halogen atom to give exclu-
NH2NH2
3a—d
NO2
H
N
N
CH2R
O2N
4a—d

1270
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 7, July, 2001
Prikhodko and Vasilevsky
Scheme 4
sively 4-chloro-1,3-dimethyl-5-(5-nitro-2-piperidino-
phenylethynyl)pyrazole (5) (the yield was 94.3%)
(Scheme 3).
I
H C C
NO2
+
NHNH2
2b
Scheme 3
6
Me
Cl
C C
NO2
N
N
N
NHNH2
3d
+
H N
Me
8
CH2
NO2
NO2
5
N
N
Therefore, cyclocondensation of activated (2-chloro-
aryl)acetylenes with hydrazine hydrate affords 3-substi-
tuted 1H-indazoles and provides a new procedure for
the synthesis of these compounds. However, this proce-
dure has essential limitations associated with the neces-
sity of using both aryl halides and acetylenic compo-
nents containing only electron-withdrawing substitu-
ents. In addition, attempts to isolate intermediates, viz.,
(2-ethynylaryl)hydrazines, formed in cyclocondensation
of o-chloro-substituted arylacetylenes with NH2NH2
failed. Hence, there is no way of studying cyclization of
these intermediates as such depending on the reaction
conditions. However, it is known that the direction of
cyclization of (2-ethynylaryl)carbohydrazides, which also
bear two N atoms exhibiting different nucleophilicity,
can be controlled by the reaction conditions.7
H
7
to compound 11 due to substantial resinification
(Scheme 5).
Scheme 5
I
H C C
OMe
+
NHNHAc
9
10
C C
OMe
We suggested that an alternative procedure for the
synthesis of (2-ethynylaryl)hydrazines by the reactions
of (2-iodoaryl)hydrazines with terminal acetylenes or
their copper salts would make it possible not only to
isolate intermediates in the free form, but also to exam-
ine the direction of cyclization of (ethynylaryl)hydrazines
in the absence of electron-withdrawing substituents or
even in the presence of electron-donating substituents.
This could also help in gaing a better insight into the
influence of the internal (the nature of the substituents)
and external (cyclization conditions) factors on the
direction of heterocyclization, its scope, and limitations
and in performing the directed synthesis of not only
1H-indazoles but also other fused heterocyclic systems.
However, the reaction of (2-iodophenyl)hydrazine
(6) with ð-nitrophenylacetylene (2b) under the standard
conditions of cross-coupling (PdCl2(PPh3)2—CuI, Et3N,
80 °C) afforded 3-substituted 1H-indazole (7) in 38%
yield (Scheme 4). We failed to isolate the expected
intermediate 8.
NHNHAc
11
This result can be assigned to lability of the starting
compound 9, the low reactivity of the halogen atom due
to the +M effect of the hydrazino group, and the lower
acidity of alkyne 10 compared to alkyne 2b (for 10,
pK = 29.7; for 2b, pK ≈ 26.9).8 Analogous results were
observed in the reactions of vic-iodoaminopyrazoles
with arylacetylenes whose pK 's are lower than 29. Com-
plications were circumvented with the use of acyl pro-
tection of the amino group and by performing the
synthesis accoding to the acetylenide procedure instead
of catalytic cross-coupling.9 We also used this approach
in the present study. Cross-coupling of iodide 9 with
copper phenyl- (12a), p-nitrophenyl- (12b), or p-meth-
oxyphenylacetylenide (12c) in DMF at 155 °C afforded
2-substituted indoles 14a—s, respectively, (in 30—73%
yields) instead of the expected intermediates 13a—c.
According to the data from 1H NMR spectroscopy,
indoles 14a—c existed in the tautomeric equilibrium
with 14´a—c (Scheme 6). The reaction involving sub-
strate 12b proceeded most smoothly.
We hypothesized that the introduction of an acyl
protective group into the hydrazine fragment would lead
to a decrease in its nucleophilicity and make it possible
to obtain the target intermediate. However, catalytic
cross-coupling of 2´-(2-iodophenyl)acetohydrazide (9)
with p-methoxyphenylacetylene (10) did not give rise
The fact that heterocyclization afforded the pyrrole
rather than the pyrazole ring is apparently associated

Russ.Chem.Bull., Int.Ed., Vol. 50, No. 7, July, 2001
1271
Heterocyclization of o-(arylethynyl)arylhydrazines
Scheme 6
C C
R
9
+
Cu C C
R
NHNHAc
12a—c
13a—c
CH2
N COMe
NO2
R
R
N
N
HN C Me
O
N C Me
OH
N
15
14a—c
14´a—c
R = H (a); F-NO2 (b); F-OMe (c)
Scheme 7
with the higher nucleophilicity of the amine N atom
compared to the amide N atom.
A different direction of cyclocondensation was ob-
served in the reaction of iodide 9 with acetylenide 12b
in pyridine giving rise to 2H-indazole (15) (30%), which
is apparently associated with the generation of a stron-
ger nucleophile, viz., of the N-anion, from the acidic
MåCONH group in the presence of the base (Py). An
attempt to perform condensation of iodohydrazine 9
with acetylenide 12c under analogous conditions was
unsuccessful due apparently to the opposite polarization
of the C≡C bond in intermediate 13c compared to 13b
and to the fact that no aromatic system can be formed.
Hydrazine 13b was synthesized from compounds 9
and 2b using catalytic cross-coupling at the temperature
below 80 °C (the yield was 68%).
C C
NO2
9 + 2b
NHNHCOMe
13b
K2CO3, BunOH
CuI, DMF
CH2
NO2
NO2
N
N
N
HNCOMe
We failed to prepare monosubstituted hydrazine by
removing acyl protection of 13b with the use of reflux-
ing in n-butanol in the presence of K2CO3 due to
cyclization of the target product to 1H-indazole 7 (48%).
In the absence of a base, no deacetylation of com-
pound 13b occurred and heterocyclization afforded in-
dole 14b in 75% yield (Scheme 7).
Thus, cyclocondensation of 2´-(2-iodophenyl)aceto-
hydrazide with p-nitrophenylacetylene in pyridine gave
rise to 2H-indazoles, whereas cyclocondensation in DMF
afforded 2-substituted indoles regardless of the character
of the substituents in copper arylacetylenides. The above
reactions provide a new procedure for the synthesis of
these compounds. Cross-coupling of (2-iodophe-
nyl)hydrazine or 2´-(2-iodophenyl)acetohydrazide with
p-nitrophenylacetylene was accompanied by hetero-
cyclization to form 3-substituted 1H-indazoles.
H
7
14b
FX-90Q spectrometer in CDCl3 and (CD3)2CO. TLC was
carried out on Silufol UV-254 plates.
Pyridine, DMF, and triethylamine, which were purchased
from Lancaster, as well as benzene and chloroform (both of
analytical grade) were used without additional purifica-
tion. 4-Chloro-3-iodonitrobenzene (1),10 terminal acetylenes
2a—d,11—14 and copper arylacetylenides 12a—c
15
were pre-
pared according to known procedures.
Aryl(2-chloro-5-nitrophenyl)acetylenes (3a—d) (general
procedure). A solution of 4-chloro-3-iodonitrobenzene10
(1) (10 mmol), terminal acetylene 2a—d (10—15 mmol),
Pd(PPh3)2Cl2 (40 mg), and CuI (20 mg) in a 1 : 3 mixture of
Et2NH (or Et3N) and benzene was stirred under in an atmo-
sphere of Ar at 25—80 °C for 4—11 h until the starting iodide 1
disappeared (TLC control). After completion of the reaction,
the mixture was diluted with ether and filtered through a small
layer of Al2O3. The filtrate was concentrated in vacuo. The
residue was chromatographed on a 4½5-cm column with SiO2
using benzene as the eluent. The yields and physicochemical
characteristics of compounds 3a—d are given in Table 1. The
1H NMR spectral data are listed in Table 2.
Experimental
The IR spectra were recorded on UR-20 and Specord-IR
instruments. The 1H NMR spectra were measured on a JEOL
3-Substituted 5-nitro-1H-indazoles (4a—d) (general pro-
cedure). Compound 3a—d (2—5 mmol) was refluxed with a

1272
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 7, July, 2001
Prikhodko and Vasilevsky
2—5-fold excess of NH2NH2•H2O in BunOH (5—10 mL) for
1—6 h until the starting chloride disappeared (TLC control).
The solvent was evaporated and the residue was passed through
a small layer of Al2O3 using ether and CHCl3 as the eluents.
The yields and physicochemical characteristics of compounds
H(3) and H(3´)); 6.9—8.1 (m, 8 H, H arom.). Found (%):
C, 72.85; H, 5.62; N, 10.22. C17H16N2O2. Calculated (%):
C, 72.84; H, 5.75; N, 9.99. IR (CHCl3), ν/cm–1: 1040 (OCH3);
1705 (C=O); 3250, 3390 (br., NH, OH).
C. A mixture of iodide 9 (2.8 g, 0.01 mol), acetylenide 12b
(2.3 g, 0.0112 mol), and Py (50 mL) was refluxed under a
stream of Ar for 1.5—2 h. After completion of the reaction
(TLC control), the solvent was blown off with air and a
solution of the residue in CHCl3 was filtered through a layer of
Al2O3 (4½5 cm, CHCl3 as the eluent). The filtrate was washed
with an aqueous solution of NH3 (until the blue color disap-
peared) and water and then dried with Na2SO4. The solution
was chromatographed on SiO2 (5½6 cm, benzene as the eluent)
three times and 2-acetyl-3-(p-nitrobenzyl)-1H-indazole (15)
was isolated in a yield of 0.47 g (15.2%), m.p. 123—125 °C
(from EtOAc). 1H NMR (CDCl3), δ: 2.75 (s, 3 H, CH3); 4.41
(s, 2 H, CH2); 7.3—7.6 (m, 5 H, H(3´), H(5´), H(4), H(5),
H(6)); 8.17 (d, 2 H, H(2´), H(6´), J2´,6´ = 11.25 Hz); 8.46 (d,
1 H, H(7), J7,6 = 8.4 Hz). Found (%): C, 64.92; H, 4.32;
N, 14.11. C16H13N3O3. Calculated (%): C, 65.08; H, 4.44;
N, 14.23. IR (CHCl3), ν/cm–1: 1350, 1330 (sh), 1530 (NO2);
1720, 1710 (sh) (C=O).
2´-[2-(Nitrophenylethynyl)phenyl]acetohydrazide (13b). A
mixture of iodide 9 (3.0 g, 0.0108 mol), p-nitrophenylacetylene
2b 18 (2.0 g, 0.013 mol), (Ph3P)2PdCl2 (80 mg), and CuI
(40 mg) was refluxed in a mixture of Et3N (6 mL) and benzene
(40 mL) under an atmosphere of Ar for 12 h. The reaction
mixture was filtered through a layer of SiO2 (3½3 cm, CHCl3 as
the eluent), the solvent was distilled off, and the residue was
twice chromatographed on SiO2 (4½7 cm, PhCH3 and CHCl3
as the eluents; 4½12 cm, CHCl3 as the eluent). Compound 13b
was isolated in a yield of 2.1 g (67.7%), m.p. 165—166 °C (from
EtOH—C6H6). 1H NMR (CDCl3), δ: 2.15 (s, 3 H, CH3);
6.8—7.62 (m, 6 H, H(3), H(4), H(5), H(6), H(2´), H(6´));
8.20 (d, 2 H, H(3´), H(5´), J3´,5´ = 8.6 Hz). Found (%):
C, 64.61; H, 4.24; N, 14.43. C16H13N3O3. Calculated (%):
C, 65.08; H, 4.44; N, 14.23. IR (CHCl3), ν/cm–1: 1350 and
1530 (NO2); 1710 (C=O); 2220 (C≡C); 3450 (br., NH).
1-Acetamido-2-(4-nitrophenyl)indole (14b). A. A mixture
of compound 13b (0.88 g, 0.003 mol), CuI (200 mg), and DMF
(40 mL) was heated under a stream of Ar at 120 °C for 8 h. The
reaction mixture was filtered through a layer of Al2O3 (2.5½4 cm,
CHCl3 as the eluent), the solvent was distilled off, and the
residue was chromatographed on SiO2 (2.5½4 cm, CHCl3 as
the eluent). Compound 14b was obtained in a yield of 0.39 g.
Preparative chromatography on SiO2 afforded an additional
amount of product 14b (0.25 g); the total yield was 72.7%, m.p.
287.5—288.5 °C (from EtOH). 1H NMR (CDCl3, 50 °C),
δ: 1.52 and 2.22 (both s, 3 H, =C(OH)CH3 and COCH3); 6.83
and 6.95 (both s, 1 H, H(3) and H(3´)); 7.2—8.45 (m,
8 H, H arom.). Found (%): C, 65.13; H, 4.51; N, 14.05.
C16H13N3O3. Calculated (%): C, 65.08; H, 4.44; N, 14.23.
IR (CHCl3), ν/cm–1: 1340, 1510 (NO2); 1680 (C=O); 3200,
3380 (br., NH, OH).
1
4a—d are given in Table 3. The H NMR spectral data are
listed in Table 4.
4-Chloro-1,3-dimethyl-5-(5-nitro-2-piperidinophenyl-
ethynyl)pyrazole (5). A solution of chloride 3d (0.3 g,
0.001 mmol) and piperidine (0.9 g, 0.001 mol) in BunOH
(10 mL) was heated at 90—100 °C for 5 h (TLC control). Then
the reaction mixture was cooled and the precipitate of com-
pound 5 (0.15 g) that formed was filtered off. The mother
liquor was concentrated, the residue was washed with ether,
and an additional amount of compound 5 was obtained (0.18 g);
the total yield was 0.33 g (94.3%). After recrystallization from
EtOH, the yield was 0.22 g (62.9%), m.p. 113—114 °C.
1H NMR, (CDCl3), δ: 1.75 (m, 6 H, C(CH2)3C); 2.35 (s, 3 H,
CCH3); 3.45 (m, 4 H, CH2NCH2); 3.95 (s, 3 H, NCH3); 6.95
(dd, 1 H, H(3), J3,4 = 8.0 Hz, J3,6 = 1.5 Hz); 8.15 (d, 1 H,
H(4)); 8.40 (d, 1 H, H(6)). Found (%): C, 60.05; H, 5.44;
Cl, 9.64. C18H19ClN4O2. Calculated (%): C, 60.25; H, 5.34;
Cl, 9.88. IR (KBr), ν/cm–1: 1330, 1540 (NO2); 2220 (C≡C).
(2-Iodophenyl)hydrazine (6) was prepared from o-iodoaniline
in 68% yield according to procedures reported previously.16,17
Hydrazine 6 was subjected to acylation without purification.
2´-(2-Iodophenyl)acetohydrazide (9). Ac2O (11 mL,
0.1165 mol) was added portionwise to a solution of hydrazine 6
(12.15 g, 0.052 mol) in dry benzene (80 mL). The crystals that
precipitated were filtered off and washed with hexane. Com-
pound 9 was obtained in a yield of 12.78 g (89.2%), m.p.
179—180.5 °C (from benzene). 1H NMR (CDCl3), δ: 2.10 (s,
3 H, CH3); 6.10—7.75 (m, 4 H, C6H4). Found (%): C, 35.30;
H, 3.45; I, 45.11. C8H9IN2O. Calculated (%): C, 34.80; H, 3.29;
I, 45.97. IR (CHCl3), ν/cm–1: 1695 (C=O); 3300 (br.),
3435 (NH).
Reactions of hydrazide 9 with copper phenyl- (12a),
p-nitrophenyl- (12b), and p-methoxyphenylacetylenides (12c).
A. A mixture of iodide 9 (2.76 g, 0.01 mol), copper
phenylacetylenide (1.7 g, 0.01 mol) (12a), and DMF (20 mL)
was refluxed under a stream of Ar for 5 h. After completion of
the reaction, the mixture was poured into water (50 mL) and
extracted with CHCl3 (6½50 mL). The extract was washed with
an aqueous solution of NH3 and water, dried with Na2SO4, and
filtered through a layer of Al2O3 (4½4 cm, CHCl3 as the
eluent). The solvent was distilled off. The residue was twice
chromatographed on SiO2 (4½7 cm, PhCH3 as the eluent) and
crystallized from PhCH3 with activated carbon. 1-Acetamido-
2-phenylindole (14a) was obtained in a yield of 0.43 g (17.2%),
1
m.p. 216—217 °C (from EtOAc). H NMR (CDCl3), δ: 1.55
and 2.10 (s, 3 H, =C(OH)Me and COCH3); 6.65 and 6.75
(both s, 1 H, H(3) and H(3´)); 7.10—8.25 (m, 9 H, C6H4 and
C6H5). Found (%): C, 76.28; H, 5.57; N, 11.39. C16H14N2O.
Calculated (%): C, 76.78; H, 5.64; N, 11.19. IR (CHCl3),
ν/cm–1: 1710 (C=O); 3230, 3400 (br., NH, OH).
B. A mixture of iodide 9 (0.7 g, 0.0025 mol), acetylenide
12b (0.6 g, 0.0029 mol), and DMF (20 mL) was refluxed under
a stream of Ar for 3 h. The reaction mixture was diluted with
water (50 mL) and extracted with CHCl3. The extract was
washed with an aqueous solution of NH3 and water and then
dried with Na2SO4. After removal of the solvent, the residue
was passed through a layer of SiO2 (2½4 cm, CHCl3 as the
eluent), the solvent was distilled off, and the residue was
recrystallized from EtOH. Compound 14b was obtained in a
yield of 0.56 g (74.7%), m.p. 280—283 °C. Its 1H NMR
spectrum is identical with that of compound 14b prepared
from 13b.
B. A mixture of iodide 9 (2.8 g, 0.01 mol), acetylenide 12c
(2.2 g, 0.0112 mol), and DMF (25 mL) was refluxed under a
stream of Ar for 7 h. After completion of the reaction, the
mixture was filtered through a layer of SiO2 (2½5 cm, CHCl3 as
the eluent), the solution was concentrated to dryness, and the
residue was chromatographed on SiO2 (3.5½22 cm, benzene
and CHCl3 as the eluents). 1-Acetamido-2-(p-methoxy-
phenyl)indole (14c) was obtained in a yield of 1.15 g (41.07%),
1
m.p. 193—194 °C (from EtOAc). H NMR (CDCl3), δ: 1.53
and 2.12 (both s, 3 H, =C(OH)Me and COCH3); 3.83 and 3.85
(both s, 3 H, OCH3 and OCH3´); 6.55 and 6.65 (both s, 1 H,

Russ.Chem.Bull., Int.Ed., Vol. 50, No. 7, July, 2001
1273
Heterocyclization of o-(arylethynyl)arylhydrazines
3-(4-Nitrobenzyl)indazole (7). A. A solution of hydrazine 6
(3.29 g, 0.014 mol), phenylacetylene 2b (2.65 g, 0.018 mol),
(Ph3P)2PdCl2 (60 mg), and CuI (30 mg) in a mixture of Et3N
(20 mL) and benzene (50 mL) was refluxed under an atmo-
sphere of Ar for 4.5 h. After completion of the reaction, the
mixture was diluted with ether and twice filtered through a
layer of SiO2 (3½7 cm, ether as the eluent), the solvent was
distilled off, and the residue was chromatographed on SiO2
(4.5½13 cm, benzene and ether as the eluents) three times.
Compound 7 was obtained in a yield of 1.34 g (38.3%), m.p.
117—118 °C (from a benzene—hexane mixture). 1H NMR
(CDCl3), δ: 4.45 (s, 2 H, CH2); 7.0—8.2 (m, 8 H, H arom.);
10.6 (br.s, 1 H, NH). Found (%): C, 66.44; H, 4.49; N, 16.32.
C14H11N3O2. Calculated (%): C, 66.40; H, 4.38; N, 16.59.
IR (CHCl3), ν/cm–1: 1350 and 1530 (NO2); 3480 (br., NH).
When the reaction was carried out at 20 °C (8 h), 80.8% of the
starting p-nitrophenylacetylene remained unconsumed.
B. A mixture of acetylhydrazine 13b (1.0 g, 0.0034 mol),
K2CO3 (200 mg), and BunOH (20 mL) was refluxed for 2 h,
the solvent was distilled off, and the residue was chromato-
graphed on SiO2 (2.5½3.5 cm, CHCl3 as the eluent). After
recrystallization, compound 7 was isolated in a yield of 0.27 g.
The mother liquor was chromatographed on SiO2 (1.5½7 cm,
PhCH3 and CHCl3 as the eluents) to obtain an additional
amount of product 7 (0.21 g); the total yield was 48.0%, m.p.
113—114 °C (from a benzene—hexane mixture). The 1H NMR
spectrum of the resulting compound is identical with that of
compound 7 prepared from hydrazine 6 and phenylacetylene 1b.
3. E. V. Tretyakov, D. W. Knight, and S. F. Vasilevsky,
J. Chem. Soc., Perkin Trans. 1, 1999, 3721.
4. S. F. Vasilevsky and T. A. Prikhodko, Mendeleev Commun.,
1996, 3, 98.
5. T. A. Prikhodko and S. F. Vasilevsky, Mendeleev Commun.,
1998, 4, 149.
6. D. E. Ames and D. Bull, Tetrahedron, 1982, 38, 383.
7. S. F. Vasilevskii, A. V. Pozdnyakov, and M. S. Shvartsberg,
Izv. Akad. Nauk SSSR, Ser. Khim., 1985, 1367 [Bull. Acad.
Sci. USSR, Div. Chem. Sci., 1985, 34, 1250 (Engl. Transl.)].
8. M. I. Terekhova, E. S. Petrov, S. F. Vasilevskii, M. S.
Shvartsberg, and V. F. Ivanov, Izv. Akad. Nauk SSSR, Ser.
Khim., 1984, 923 [Bull. Acad. Sci. USSR, Div. Chem. Sci.,
1984, 33, 850 (Engl. Transl.)].
9. E. V. Tretyakov, D. W. Knight, and S. F. Vasilevsky,
J. Chem. Soc., Perkin Trans. 1, 1999, 3713.
10. Beilstein Handbuch der Organischen Chemie, Springer, Ber-
lin, 1930, 5, 133.
11. L. Brandsma, S. F. Vasilevsky, and H. D. Verkruijsse,
Application of Transition Metal Catalysts in Organic Syn-
thesis, Springer-Verlag, Heidelberg—Berlin—New York,
1998, 220.
12. N. A. Bumagin, A. B. Ponomaryov, and I. P. Beletskaya,
Synthesis, 1984, 728.
13. A. N. Kost, P. B. Terent´ev, and T. Zavada, Dokl. Akad.
Nauk SSSR, 1960, 130, 326 [Dokl. Chem., 1960 (Engl.
Transl.)].
14. A. I. Belov, M. I. Terekhova, E. S. Petrov, S. F. Vasilevsky,
and M. S. Shvartsberg, Izv. Akad. Nauk, Ser. Khim., 1992,
507 [Bull. Russ. Acad. Sci., Div. Chem. Sci., 1992, 41, 398
(Engl. Transl.)].
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 95-03-
08928a).
15. R. D. Stephens and C. E. Castro, J. Org. Chem., 1963,
28, 3313.
16. M. Hunsberger, E. R. Shaw, J. Fugger, R. Ketcham, and
D. Lednicer, J. Org. Chem., 1956, 21, 394.
17. E. Votocek, V. Ettel, and M. B. Koppova, Bull. Soc. Chim.
Fr., 1926, 39, 278.
References
1. S. F. Vasilevsky and E. V. Tretyakov, Lieb. Ann. Chem.,
1995, 775.
18. N. A. Bumagin, A. B. Ponomaryov, and I. P. Beletskaya,
Synthesis, 1984, 728.
2. M. S. Shvartsberg, I. D. Ivanchikova, and S. F. Vasilevsky,
Tetrahedron Lett., 1994, 35, 2077.
Received December 9, 2000