Unexpected results in the heterocyclization of 5-acetylenylpyrazole-4- carboxylic acid hydrazides under the influence of CuCl: Formation of a diazepinone and dehydrodimerization into the corresponding bis(pyrazolo[4,3-d] [1,2]diazepinone)

Article abstract of DOI:10.1016/j.tetlet.2005.04.127

The simple reaction of cyclization of hydrazides of vic-acetylenylbenzoic and acetylenylpyrazole carboxylic acid can lead to four different compounds: five-membered N-aminolactams, six-membered N-aminolactams, six-membered diazinones and diazepinones, but only the first three have been described. In this paper we report the unexpected formation of a bis(pyrazolo[4,3-d][1,2] diazepinone, the structure of which has been established by X-ray crystallography.

Full text of DOI:10.1016/j.tetlet.2005.04.127

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4457–4459
Unexpected results in the heterocyclization of 5-acetylenyl-
pyrazole-4-carboxylic acid hydrazides under the influence of
CuCl: formation of a diazepinone and dehydrodimerization
into the corresponding bis(pyrazolo[4,3-d][1,2]diazepinone)
Sergei F. Vasilevsky,a,* Elena V. Mshvidobadze,a Victor I. Mamatyuk,b
Galina V. Romanenkoc and Jose Elguerod,*
aInstitute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk,
Russian Federation
bInstitute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russian Federation
cInternational Tomography Center, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russian Federation
d
´ ´
Instituto de Quımica Medica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain
Received 1 February 2005; revised 27 April 2005; accepted 27 April 2005
Abstract—The simple reaction of cyclization of hydrazides of vic-acetylenylbenzoic and acetylenylpyrazole carboxylic acid can lead
to four different compounds: five-membered N-aminolactams, six-membered N-aminolactams, six-membered diazinones and diaz-
epinones, but only the first three have been described. In this paper we report the unexpected formation of a bis(pyrazolo[4,3-
d][1,2]diazepinone, the structure of which has been established by X-ray crystallography.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
three different paths.1,2 Benzene derivatives 1a under-
went cyclization into five-membered N-aminolactams
under the influence of a base (path a2 Scheme 1, KOH
in boiling ethanol), while pyrazole derivatives 1b gave
only six-membered N-aminolactam rings in the same
In previous reports, we have described that the intramo-
lecular cyclization of hydrazides of vic-acetylenylbenzoic
and acetylenylpyrazole carboxylic acid 1 occurs through
R
R
β2
N
N
β
α1
β1
R
α
N
N
H
H
O
= Ph (1a), Pz (1b)
R
α2
O
O
R
N
N
NH
2
H
NH
N
2
NH
1a, b
2
O
O
Scheme 1. The four possible routes of cyclization of hydrazides derived from acetylenylbenzoic (1a) and pyrazolecarboxylic (1b) acids.
Keywords: Pyrazolopyridines; Cross-coupling; Hetarylacetylenes; Heterocyclization.
*
Corresponding authors. Fax: +7 3832/307350 (S.F.V.); fax: +34 91 5644853 (J.E.); e-mail addresses: vasilev@ns.kinetics.nsc.ru;
iqmbe17@iqm.csic.es
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.127

4458
S. F. Vasilevsky et al. / Tetrahedron Letters 46 (2005) 4457–4459
conditions (path b1). Isomerization of benzene deriva-
tives 1a under the action of copper(I) chloride in boiling
dimethylformamide afforded only the corresponding
condensed six-membered diazinones.1 Isomerization of
pyrazole derivatives 1b led both to diazinones and to
N-aminopyridones (paths: a1 and b1, Scheme 1).1,2
sequence of the +M-effect of the methoxy group.
Increasing the reaction time up to 30–35 h provided only
N-aminolactam 4b (yield 65%). However, the best route
to prepare 4b (70% yield) is to boil hydrazide 3b in the
presence of potassium hydroxide in ethanol.6 An unex-
pected result was obtained when hydrazide 3b was used
in a reaction of heterocyclization in the presence of
CuCl. Thus, hydrazide 3b in the presence of CuCl in
boiling dimethylformamide led to a bis(pyrazolo[4,3-
d][1,2]diazepinone 5b (50% yield).7 Cyclization of 1,3-di-
methyl-5-(p-methoxyphenyl)ethynylpyrazole-4-carbox-
ylic acid hydrazide (3b) occurred in a different way and
for the first time, we have found the fourth possibility of
Scheme 1 (path b2): the formation of a diazepinone ring.
Moreover, we have found that the final product has the
structure of a dehydrodimer (5b, Scheme 3).
Thus, only three compounds out of the four possible
cyclization products have been reported whereas forma-
tion of the diazepinone ring (path b2) has never been
observed.
2. Results and discussion
Taking into account that the nucleophilicity of the triple
bond depends markedly on its position on the pyrazole
ring, and that this can affect the course of the cycliza-
tion,2–4 we have continued our study of hydrazides
exploring the behavior of those derived from 5-acetyl-
enylpyrazole-4-carboxylic acid methyl ester (2a). This
isomer is characterized by the presence of the acetylenic
group in the lowest electron density 5-position and the
acyl hydrazide in the highest electron density 4-position.
Pyrazolo[4,3-d][1,2]diazepines are seldom found in the
literature, amongst the rare examples are two com-
pounds prepared by cycloaddition on 1,2-diazepines.8
The mechanism of formation of 5b is still unknown
but it probably involves a copper-mediated oxidative
coupling. The structure of 5b was established according
to the analytical and spectral data as well as from the
X-ray analysis (Fig. 1).9
We have found that the hydrazinolysis of 1,3-dimethyl-
5-(phenylethynyl)pyrazole-4-carboxylic acid methyl
ester (2a), even under the conditions of hydrazide prep-
aration (boiling 11 h with 80% hydrazine hydrate in
butanol) led to the cyclization product 4a (N-aminopyr-
idone) in 52% yield (Scheme 2). On the other hand, the
hydrazinolysis (15 h) of 1,3-dimethyl-5-(p-methoxyphen-
yl)ethynylpyrazole-4-carboxylic acid methyl ester (2b),
afforded a mixture of the desired hydrazide 3b (yield
33%)5 and the cyclization product (N-aminopyridone)
4b (yield 37%) (as a consequence of the higher nucleo-
philicity of the 5 position in the pyrazole ring) (Scheme
2). The decrease in the yield of lactam 4b can be a con-
Values of the corresponding bond lengths in the two 5b
molecules are practically the same. The seven-membered
cycles have the ÔbathÕ-conformation. Crystal packing is
formed by intermolecular hydrogen bonds. The starting
acetylenylpyrazole derivatives were obtained by cou-
pling the methyl ester of 1,3-dimethyl-5-iodopyrazole-
4-carboxylic acid with the corresponding copper(I)
acetylides in boiling dimethylformamide under argon
atmosphere. Yields of derivatives 2a and b are 60–70%.
In conclusion all four possibilities of Scheme 1 of the
hydrazides 1b have been observed. The direction of the
O
O
O
CH
NH
NH
3
2
NH
2
H C
3
H C
3
H C
3
O
BuOH
NH2NH2.H2O
N
+
R
N
N
N
C
C
C
N
C
N
N
R
R
CH
CH
CH
3
3
3
2 a, R =C H
3a,b
4a,b
6
5
b, R =p-OCH C H
6 4
3
Scheme 2. Hydrazinolysis of methyl esters 2a and b.
CH
N
3
N
O
H
H
H C
N
Ar
N
3
H C
N
3
O
N
H
NH
CuCl
DMF, 150 ˚C
OCH
2
N
N
C
H
C
N
N
O
Ar
CH
3
CH
H
3
3
N
H C
3
3b
Scheme 3. The unexpected formation of the pyrazolodiazepinone 5b.
5b, Ar = p-C H -OCH
6 4 3

S. F. Vasilevsky et al. / Tetrahedron Letters 46 (2005) 4457–4459
4459
Figure 1. View of two crystallographically independent molecules of 5b and numbering scheme.
7. Experimental procedure for the cycloisomerization of
hydrazides in the presence of copper(I) chloride for
example: hydrazide (3b), 0.3 g (1.0 mmol), 0.08 g of
copper(I) chloride in 5 mL of dimethylformamide were
boiled 4 h under argon atmosphere. The reaction mixture
was cooled and poured into chloroform and was washed
with aqueous ammonium hydroxide. The chloroform
solution was dried over sodium sulfate and filtered through
alumina (0.5 · 1 cm), and the solvent was evaporated under
reduced pressure. The product was crystallized from
ethanol, yield 5b 0.15 g (50.0%), mp. 350–350.5 ꢁC (EtOH).
reaction depends on the mutual arrangement of the acet-
ylene and the acylhydrazino groups, the nature of the
substituent attached to the acetylenic fragment and the
condensation conditions.
Acknowledgement
This work was supported by CRDF (NO-008-XI).
IR, m/cmꢀ1(KBr): 1662 (C@O); 3439 (NH); 13C–1H NMR,
3
References and notes
0
dH (DMSO-d6): 2.30 (s, 6H, CH3, J8H–8H = 10.3 Hz;
1JC–H = 136.6 Hz); 3.39 (s, 6H, NCH3); 3.78 (s, 6H,
OCH3); 5.58 [s, 2H, H(8)]; 6.93 [PhOCH3: m, 4H, H
(3,5)]; 7.54 [PhOCH3: m, 4H, H (2,6)]; 11.19 (s, 2H, 5-NH);
dC (DMSO-d6): 12.84 (q, CH3); 34.28 [d, C8, 1J13C-
1. Vasilevsky, S. F.; Pozdnyakov, A. V.; Shvartsberg, M. S.
Izv. Akad. Nauk SSSR, Ser. Khim. 1985, 1367; Bull. Acad.
Sci. USSR, Div. Chem. Sci. 1985, 34, 1250.
2. Vasilevsky, S. F.; Mshvidobadze, E. V.; Elguero, J. J.
Heterocycl. Chem. 2002, 39, 1229.
H(8) = 136.6 Hz, J13C-H(80) = 5.9 Hz]; 35.26 (q, NCH3);
2
55.26 (q, OCH3); 111.02 (s, C3a); 114.11 (d, Cm); 128.37 (d,
Co); 128.69 (s, Ci); 138.25 (s, C8a); 148.99 (s, C3); 150.46 (s,
C7); 160.84 (s, Cp); 161.86 (s, C4). The values for the JHH
3. Tretyakov, E. V.; Knight, D. W.; Vasilevsky, S. F. J. Chem.
Soc., Perkin Trans. 1 1999, 3721.
3
4. Vasilevsky, S. F.; Tretyakov, E. V.; Elguero, J. Synthesis
and Properties of Acetylenic Derivatives of Pyrazoles, in
Adv. Heterocycl. Chem. 2002, 82, 1.
constants for 8-H were obtained from the splitting of the
13CH satellites for this signal in the 1H NMR spectrum, and
so was the value J13C–1H = 136.6 Hz. Attribution of the
1
5. Full spectroscopic and analytical data have been obtained
for all the compounds reported herein. For example,
hydrazide of 1,3-dimethyl-5-(p-methoxyphenyl)ethynylpy-
razole-4-carboxylic acid methyl ester (3b): IR, m/cmꢀ1
(KBr): 2210 (C„C); 1648 (C@O); 3250, 3435 (NH, NH2).
1H NMR, dH (DMSO-d6): 2.27 (s, 3H, CCH3); 3.80 (s, 3H,
NCH3); 3.83 (s, 3H, OCH3); 4.11 (s, 2H, NH2); 6,99
[PhOCH3: m, 2H, H (2,6)]; 7.84 [PhOCH3: m, 2H, H (3,5)];
10.45 (s, 1H, NH).
signals in the 13C NMR spectrum were made on the basis of
the information obtained from the mono-resonance and 2D
correlation spectra 13C–1H at direct and remote spin–spin
coupling constants. Anal. Calcd for C30H30N8O4: C, 63.59;
H, 5.34; N, 19.78. Found: C, 62.89; H, 5.32; N, 19.53.
8. Gesche, P.; Klinger, F.; Streith, J.; Strub, H. Tetrahedron
Lett. 1980, 21, 4507; Gesche, P.; Klinger, F.; Muller, W.;
¨
Streith, J.; Strub, H.; Sustmann, R. Chem. Ber. 1985, 118,
4682.
9. Crystal data for 5b: C30H30N8O4, FW = 566.62, crystals are
6. Experimental procedure for the cycloisomerization of
hydrazides in the presence of potassium hydroxide: hydra-
zide of pyrazole carboxylic acid 3b, 0.2 g (0.7 mmol) and
0.1 g of KOH were boiled in 5 mL of ethanol for 2 h (TLC
control: Silufol). The solvent was distilled under reduced
pressure, the precipitate was dissolved in benzene and
filtered through alumina (1.5 · 1 cm), then the benzene
was distilled under reduced pressure. The product was
crystallized from ethanol, yield 4b 0.14 g (70.0%), mp 213–
215 ꢁC (EtOH), IR, m/cmꢀ1 (KBr): 1679 (C@O); 3436
monoclinic, P21, a = 8.029(5), b = 25.916(14), c = 14.222(9)
3
˚
˚
A, b = 101.147(12)ꢁ, V = 2904(3) A , Z = 4, Dcalcd
=
=
1.296 g/cmꢀ3
, , total of 9441 (hmax
l = 0.090 mmꢀ1
23.31ꢁ), 7538 unique (Rint = 0.0795), 2654 (F > 4rF), 870
parameters. Goof = 0.704, R1 = 0.0572, wR2 = 0.0842
(I > 2rI), R1 = 0.1635, wR2 = 0.1086 (all data), largest diff.
peak 0.141 e Aꢀ3. CCDC 254372 contains the supplemen-
˚
tary crystallographic data for this paper. These data can be
obtained free of charge via the internet at www.ccdc.
cam.ac.uk/conts/retrieving.html (or from Cambridge Crys-
tallographic Data Center, 12 Union Road, Cambridge
CB21EZ, UK. Fax: (+44) 1223 336 033; or deposit@
ccdc.cam.ac.uk.
1
(NH2); H NMR, dH (CDCl3): 2.41 (s, 3H, CH3); 3.72 (s,
3H, NCH3); 3.87 (s, 3H, OCH3); 4.67 (s, 2H, NH2); 6,96
[PhOCH3: m, 2H, H (2,6)]; 8.00 [PhOCH3: m, 2H, H (3,5)];
7.34 [s, 1H, H(7)].