Unexpected cyclization route for o-ethynylbenzoic acids hydrazides in the presence of base

Article abstract of DOI:10.1007/s10593-009-0225-7

The reaction of o-ethynylbenzoic acids hydrazides with base has been studied. In the presence of a strong donor substituent (1,5-dimethylpyrazol-4- yl) it has been found that an unusual cyclization route occurs to give the corresponding benzopyridazinone

Full text of DOI:10.1007/s10593-009-0225-7

Chemistry of Heterocyclic Compounds, Vol. 45, No. 1, 2009
UNEXPECTED CYCLIZATION ROUTE FOR
o-ETHYNYLBENZOIC ACIDS HYDRAZIDES
IN THE PRESENCE OF BASE*
S. F. Vasilevsky1** and T. F. Mikhailovskaya1
The reaction of o-ethynylbenzoic acids hydrazides with base has been studied. In the presence of a
strong donor substituent (1,5-dimethylpyrazol-4-yl) it has been found that an unusual cyclization route
occurs to give the corresponding benzopyridazinone instead of the expected isoindolinone.
Keywords: arylacetylenes, benzopyridazinones, ethynylbenzoic acids esters, isoindolinones, hetero-
cyclization, cross coupling, reactions with hydrazine.
The high synthetic potential of polyfunctional aryl- and hetarylacetylenes ensures the unabated interest of
chemists in this class of compound. Vicinal functionally substituted aryl- and hetarylacetylenes are very convenient
synthons in the preparation of condensed heterocycles which are promising biologically active compounds [1].
In fact, a study of the reactivity of vicinal hydrazides of acetylenylbenzoic and pyrazolylcarboxylic
acids has shown that the presence of the α- and β-carbon atoms of the triple bond and the two nucleophilic
centers ("amine" and "amide" nitrogen atoms) in the hydrazide group guarantee many outcomes for their
reactions [2, 3]. Recent investigations of the heterocyclization of vic-acetylenylpyrazolecarboxylic acid
hydrazides led to the unexpected result that oxidative coupling of the molecule occurs along with formation of a
condensed diazepinone ring (which, in itself, was seen for the first time) [4].
In addition, the very limited number of previous investigations of aromatic series compounds does not
reveal the full picture of even the basic dependence of the heterocyclization route for unsaturated hydrazides.
Study of the cyclization of the vic-acetylenylbenzoic acid hydrazides series is limited to just two examples
[2, 3]. This circumstance, together with the marked effect of the nature of the substituent at the triple bond
carbon atom on the reaction course [4], led us to broaden the range of acetylenyl substituents in a series of
ortho-acetylenylbenzoic acids hydrazides.
The synthesis of the starting o-acetylenylbenzoates 1a,b was carried out by treating methyl o-iodo-
benzoate with the corresponding terminal alkynes under copper-palladium catalysis conditions [5] using the
system (Pd(PPh3)2Cl2, CuI, NEt3) in 67-97% product yield.
_______
* Dedicated to Academician B. A. Trofimov in his 70th jubilee.
** To whom correspondence should be addressed, e-mail: vasilev@kinetics.nsc.ru.
1Institute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Sciences,
Novosibirsk 630090, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 67-70, January, 2009. Original
article submitted May 25, 2008.
0009-3122/09/4501-0055©2009 Springer Science+Business Media, Inc.
55

Treatment of the ethynylbenzoates 1a,b with hydrazine hydrate in ethanol showed significant
differences in both reactivity and reaction path.
OMe
OMe
N
NH2
CONHNH2
O
3
2a
N
N
Me
N
N
Me
R
Me
KOH
EtOH
H2NNH2
EtOH
Me
N
NH
COOMe
O
1a,b
4
CONHNH2
2b
1,2 a R = p-MeOC6H4, b R = 1,5-dimethylpyrazol-4-yl
Heating the (p-methoxyphenyl)ethynylbenzoate 1a with hydrazine hydrate in ethanol did not stop at the
stage of intermediate formation of hydrazide 2a but immediately gave the cyclization product 3 in 67% yield.
Support for a 5- rather than a 6-membered N-aminolactam was based on the different values of the CO
stretching vibrations in the IR spectra of these isomers [6]. It is known that increased strain on going from the
6- to the 5-membered ring brings about an increase in νCO by 30-35 cm-1. In known δ-lactams the stretching
vibrational frequency for the CO group (νCO) is 1660-1680 cm-1 while in γ-lactams it is not less than
1695-1700 cm-1. The value of νCO in the IR spectrum of compound 3 of 1706 cm-1 fully agrees with the
assignment of an amino-substituted γ-lactam structure for 3.
In the case of a 4-pyrazolyl residue (having a strong +M-effect) the intermediate acetylenylhydrazide 2b
(85%) was separated. If the former formation of the N-aminolactam 3 is in agreement with our previous data
[2, 3] then formation of the open form (hydrazide 2b) in high yield and without traces of the proposed
N-aminolactam is observed for the first time.
Since the hydrazide 2b appears to be inert towards hydrazine the cyclization was carried out by selecting
the more powerful base of KOH in alcohol. The result of the reaction proved unexpected, the main product
being the benzopyridazinone 4 in 70% yield. It should be noted that acetylenic derivatives of benzoic and
pyrazolecarboxylic acid hydrazides gave only the γ- and δ-N-aminolactams in the presence of hydrazine hydrate
or KOH base, i.e. attack of the amide nitrogen atom always occurs at a triple bond carbon atom. Such a route
fully agrees with that expected since the reaction is carried out with a strong base, in fact the attacking agent is
the N-anion formed from the amide fragment of the hydrazide group.
In addition, according to our data [2, 3], the formation of a diazinone ring (as in the case of compound 4)
for both benzene and pyrazole derivatives occurs only in neutral media in the presence of CuI, i.e. when the
amine nitrogen atom is a stronger nucleophiles than the amide nitrogen atom. The novelty of the reaction
reported in this work relates to the formal formation of the benzopyridazinone 4 as the product of attack of the
α-carbon atom of the triple bond by the amine nitrogen atom (a less powerful nucleophile than the N-anion) in
the presence of KOH with subsequent prototropic isomerization. It is likely that the formation of the diazinone
occurs via a rearrangement. The mechanism of this reaction is currently being studied by quantum-chemical
methods.
56

EXPERIMENTAL
1H NMR spectra were taken on a Bruker AV-300 instrument (300 MHz) using CDCl3 with TMS as
internal standard and IR spectra on a Vector 22 instrument as a film (compound 1b) or as KBr tablets
(compounds 2b, 3, 4). Melting points were measured on a Koffler stage. High resolution mass spectra were
taken on a Finnigan MAT 8200 instrument (EI, 70 eV). Elemental analysis was performed on a Carlo Erba
(Italy) model 1106 CHN analyzer. Commercially available PdCl2(PPh3)2 and 2-methyl-3-butyn-2-ol were
obtained from the Aldrich company.
Methyl 2-[(1,5-dimethyl-1H-pyrazol-4-yl)ethynyl]benzoate (1b). Methyl o-iodobenzoate (1.31 g,
5 mmol), CuI (0.01 g, 0.1 mmol), Pd(PPh3)2Cl2 (0.02 g, 0.06 mmol), PPh3 (0.04 g, 0.3 mmol), triethylamine
(3.0 ml, 4.35 g, 43 mmol), and (1,5-dimethyl-4-pyrazolyl)acetylene (0.72 g, 6 mmol) were added successively
with stirring to benzene (30 ml) in a stream of argon. The mixture was held under an argon stream for 5 h
40 min at 80ºC. Monitoring of the reaction was carried out by TLC (chloroform). At the end of the reaction the
mixture was cooled to 25ºC, filtered through a layer of aluminium oxide (20×20 mm) and SiO2 (10×20 mm),
washed initially with benzene (2×5 ml) and then ethyl acetate (3×5 ml), and the solvent was distilled off. The
20
product was dried in a desiccator over KOH to give the product 1b (1.51 g, 97%) with nD 1.6195. IR
1
spectrum, ν, cm-1: 1728.4 (C=O), 2209.6 (C≡C). H NMR spectrum, δ, ppm (J, Hz): 2.46 (3H, s, CH3); 3.82
(3H, s, NCH3); 3.94 (3H, s, OCH3); 7.32 (1H, t, J = 7.5, H-5); 7.52 (1H, t, J = 6.2, H-4); 7.58-7.59 (2H, m, H-3,
Hpyrazole); 7.94 (1H, d, J = 7.9, H-6). Mass spectrum, m/z: 254.1049 [M]. C15H14N2O2. Calculated M 254.1046.
Found, %: C 71.22; H 5.53; N 11.22. C15H14N2O2. Calculated, %: C 70.85; H 5.55; N 11.02.
Methyl 2-[(4-methoxyphenyl)ethynyl]benzoate (1a) was prepared similarly to 1a, yield 2.5 g (95%),
mp 65-67ºC (hexane) (mp 67-69ºC [7]).
2-[(1,5-Dimethyl-1H-pyrazol-4-yl)ethynyl]benzohydrazide (2b). Hydrazine hydrate (80%, 0.21 g,
4.2 mmol) was added to a solution of ester 1b (0.72 g, 2.8 mmol) in ethanol (5 ml) and was refluxed for 8 h 35
min (TLC monitoring). The mixture was cooled to 25ºC and the precipitate formed was filtered off and
recrystallized from ethyl acetate (7 ml) to give the product (0.61 g, 85%) with mp 109-110ºC. IR spectrum, ν,
1
cm-1: 1641.2 (C=O), 2204.2 (C≡C). H NMR spectrum, δ, ppm (J, Hz): 2.39 (3H, s, CH3); 2.72 (2H, s, NH2);
3.81 (3H, s, NCH3); 7.35-7.55 (3H, m, H-3,4,5arom); 7.58 (1H, s, Hpyrazole); 7.98 (1H, d, J = 8.0, H-6); 8.53 (1H, s,
NH). Mass spectrum, m/z: 254.1157 [M]. C14H14N4O. Calculated: M 254.1167. Found, %: C 66.62; H 5.75;
N 10.37. C14H14N4O2. Calculated, %: C 66.13; H 5.55; N 22.02.
2-Amino-3-(4'-methoxybenzylidene)isoindolin-1-one (3). Hydrazine hydrate (80%, 0.4 g, 10 mmol)
was added to a solution of ester 1a (1 g, 3.8 mmol) in ethanol (5 ml) and was refluxed for 14 h 50 min
(monitoring by TLC, CH2Cl2–AcOEt, 1:1). The mixture was cooled to 25ºC and the precipitate formed was
filtered off and recrystallized from ethanol (25 ml) to give the product 3 (0.67 g, 67%) with mp 140-141ºC. IR
1
spectrum, ν, cm-1: 1641.2 (C=O), 2204.2 (C≡C). H NMR spectrum, δ, ppm (J, Hz): 3.78 (3H, s, OCH3); 4.35
(2H, s, NH2); 6.65 (1H, s, =CH); 6.85 (2H, d, J = 8.7, H o,o'-Ph); 7.65 (2H, d, J = 8.7, H m, m'-Ph); 7.65-7.84
(4H, m, H-4,5,6,7). Mass spectrum, m/z 266.1048 [M]. C16H14N2O2. Calculated: M 266.1050. Found, %:
C 72.05; H 5.46; N 10.52. C16H14N2O2. Calculated, %: C 72.16; H 5.30; N 10.52.
4-[(1,5-Dimethyl-1H-pyrazol-4-yl)methyl]phthalazin-1(2H)-one (4) KOH (60 mg, 110 mmol) was
added to a solution of hydrazide 2b (100 mg, 39 mmol) in ethanol (5 ml) and the product was refluxed for 15 h
(monitoring by TLC, AcOEt). The mixture was cooled to 25ºC and the precipitate formed was filtered off and
recrystallized from ethanol to give the product 4 (70 mg, 70%) with mp 236-238ºC. IR spectrum, ν, cm-1: 1675
(C=O). 1H NMR spectrum, δ, ppm: 2.21 (3H, s, CH3); 3.73 (3H, s, NCH3); 4.03 (2H, s, CH2); 7.70-7.85 (4H, m,
H-5,6,7,8); 9.93 (1H, s, NH). Mass spectrum, m/z: 254.1155 [M]. C14H14N4O. Calculated: M 254.1167. Found,
%: C 66.42; H 5.63; N 22.23. C14H14N4O. Calculated, %: C 66.13; H 5.55; N 22.20.
This work was carried out with the financial support of the grant RUX0-008-NO-06/BP2M08, Russian
Fund for Basic Research No. 07-03-00048a and with the integrated grant No 54 and Chemical Service Center of
the Siberian Branch of the Russian Academy of Sciences.
57

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