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Acta Chim. Slov. 1998, 45(4), pp. 455-462
1-ACYL-3-HYDROXY-1H-PYRAZOLES AND RELATED DERIVATIVES AS
USEFUL ACYLATING AGENTS*
Vladimir Kepe, Slovenko Poiane, and Marijan Kočevar
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5,
1000 Ljubljana, Slovenia
ABSTRACT
A general application of 1-acyl-3-hydroxy-1H-pyrazoles 5 as useful acylating agents for alcohols or phenols, amines and hydrazines is described. The use of a hydrazide for a direct acylation of an alcohol in the presence of 4-ethoxymethylene-2-phenyl-5(4H)-oxazolone (1) is also discussed.
Acylation is one of the fundamental reactions in organic chemistry and can be carried out by wide variety of reagents [1]. Acyl groups play an important role in the chemistry of biomolecules [2], they are fragments of important natural products, such as peptides [2-3] or modified peptide bond isosteres [4], they serve as protecting groups [5], etc. Pyrazole derivatives are important synthons and reagents in organic synthesis and have found applications as pharmaceuticals, agrochemicals, dyestuffs, etc. [6]. They can be obtained by various methods from different starting materials [6-9]. In a previous communication pyrazoles were described as relatively inert acylating agents, although their alcoholysis was dramatically accelerated under the influence of a strong acid or base [10]. On the other hand, 1-acyl-3-hydroxy-1 H-pyrazoles and related compounds
Dedicated to the memory of Professor Anton Šebenik.
456
have not been so often investigated, although several acetyl derivatives have been prepared and further studied [11-13]. Their potential as acylating N-acyl agents has not been described, but it was found that 3-acetoxy group in 3-acetoxy-1-acetyl-5-methyl-pyrazole has higher acetylating potential than its 1-acetyl group.
Recently, we have described a synthesis of 1-acyl-3-hydroxy-1H-pyrazoles 5 and related derivatives from ethoxymethyleneoxazolone derivative 1 and hydrazides or related derivatives 2 (Scheme 1) [6]. The method includes a migration of an acyl group in the intermediary-formed pyrazolone derivative 4 to yield the rearranged 1-acyl-3-hydroxy-1H-pyrazoles 5 in high yields. In contrast, in the reaction of the oxazolone derivative 1 with two equivalents of an appropriate hydrazine derivative the corresponding symmetrically N,N'-disubstituted hydrazines 6 were obtained together with the oxazolone derivative 7.
O:
O
t
Ph
EtO
"¦CI-k
1,4-Dioxane 0.5-2h reflux
R1CONHNHCOR1
R1CONHNH2 (2)
--------------------->•
1,4-Dioxane
2h rt + 2h reflux
2 R1CONHNH2
R1CO
O;
H NA NhUcH<^.
O.
-Ph
-N.
H M.
PhCONH
NH
"o
		COR1 l
		^Nn NNH
PhCONH O		4
		N
PhCONH
N
OH
Scheme 1
Here, we report a possibility of using pyrazole derivatives 5a-e as acylating agents. In contrast to the previous investigation of pyrazoles for such purposes [10], we wanted to explore the influence of an electron-rich hydroxy group on the acylating potential of pyrazole derivatives. When a mixture of equimolar amounts of the oxazolone derivative 1 and p-nitrophenylcarbohydrazide was heated for 30 h in a methanolic solution, we isolated the corresponding methyl p-nitrobenzoate (8) in 74% yield.
1

5
6
457
MeOH            _               _
1   + p-NOp-CfiH4-CONHNHp---------->¦   p-N<J2-C6H4-C<J2Me
D
 8
From the described reaction it is not clearly evident if pyrazole derivative is an
acylating agent, since the acyl group might also be transferred onto methanol in the intermediary step. For this reason, the reaction of the pyrazole 5c in methanol was carried out. It required a long heating period, but in the presence of an equimolar amount of sodium methoxide the reaction was over in 10 min at room temperature and we isolated methyl p-nitrobenzoate (8) in 72% yield (Scheme 2). Then we performed several reactions starting from equimolar amounts of the pyrazoles 5a-e and various derivatives of type 9 (Y = O, NH) in boiling 1,4-dioxane and the corresponding products of type 10 were obtained in 55-87% yield (Table 1). By this method the acyl groups were transferred from pyrazoles 5a-e to various amines, hydrazines, amino acid derivative and phenol yielding the corresponding amides, hydrazides or esters (11-18).
R2YH (9)
5a 5b 5c 5d 5e
R1
Me
Ph
p-NO2-Ph
Th
Py
Th = 2-Thienyl Py = 4-Pyridinyl
R2Y"COR1   +   7 10
p-NO2-C6H4-CO2Me
Et02CCH2NHCOPh        HOCH2CH2NHCOPh 12                                     13
PhC02Ph     PhNHCO-^     )-N02
N
~N
PhNHNHCOMe
11
CONHNHCOPh
14
15
16
S
17
O
,CONHCH2Ph     l^     I N
COPy
18
Scheme 2
For the synthesis of products 12 and 15 triethylamine was used as a catalyst. All other products were obtained after a short heating period of time in reasonable yields. With ethanolamine as a substrate, a selective N-acylation occurred to yield product 13.
5
8
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The separation of the products of type 10 from the pyrazolone derivative 7 was achieved by an alkaline water solution of the crude material from which the products separated or were extracted with a mixture of chloroform and 1,4-dioxane and finally purified by column chromatography.
Table 1. Reaction Conditions and Yields of Compounds 11-18
Entry	Pyrazole 5	Substrate 9	Conditions	Acylated	Yield
	(2 mmol) 5a	(2 mmol)	(dioxane, D) 2 h	Product 11	(%)
1		PhNHNH2			67
2	5b	EtO2CCH2NH2	2 ha	12	59
3	5b	HOCH2CH2NH2	1 h	13	74c
4	5b	Pyrazinyl-CONHNH2	2 h	14	84d
5	5b	PhOH	4 ha	15	55
6	5c	PhNH2	2 hb	16	77
7	5d	PhCH2NH2	2 h	17	87
8	5e	Morpholine	1 h	18	72
aEt3N was added as a catalyst. bDue to solubility problems DMF was used as a solvent. cYield after isolation by column chromatography. dIsolation by work-up with 1 M NaOH, followed by filtration.
In conclusion, we have demonstrated the use 1-acyl-3-hydroxy-1H-pyrazoles as a convenient source of an acyl unit. The whole method starting from hydrazides represents a possible way of an activation of hydrazides, which are known as poor donors of acyl units due to their high resonance stability. The main advantages of this method are easily available and cheap chemicals, relatively mild reaction conditions and a simple work-up.
EXPERIMENTAL
Melting points were determined on a Kofler micro hot stage and are uncorrected. Thin-layer chromatography was carried out on Fluka silica gel TLC-cards. Column chromatography   was   carried   out   on   Fluka   silica   gel   60   (220-440   mesh).   4-
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Ethoxymethylene-2-phenyl-5(4H)-oxazolone (1) [14], 2-pyrazinecarbohydrazide [15] and 2-(benzoylamino)acetohydrazide [16] were prepared as described in the literature. 1,4-Dioxane was purified as described [17]. All other compounds and reagents were used as received from commercial suppliers (Fluka, Aldrich).
Preparation of Methyl 4-Nitrobenzoate (8).
Method A. A mixture of oxazolone 1 (0.436 g, 2 mmol) and 4-nitrobenzohydrazide (0.363 g, 2 mmol) was refluxed in methanol (10 mL) for 30 hours. The product was isolated by column chromatography on silica gel (ethyl acetate-petroleum benzine, 1:1). Yield 0.268 g (74%) of a white solid, which was identical with commercially available ester; mp 94-96 °C (lit [18] mp 94-95 °C).
Method B. Pyrazole 5c (0.704 g, 2 mmol) was dissolved in a freshly prepared 1 M solution of NaOMe in methanol (2 mL). The reaction was completed in 10 min (TLC evidence), methanol was removed under reduced pressure and methyl 4-nitrobenzoate was isolated by column chromatography (ethyl acetate-petroleum benzine, 1:1). Yield 0.261 g (72%) of a white solid.
General Procedure for Reactions of Pyrazoles 5 with Nucleophilic Reagents 9.
A pyrazole 5 (2 mmol) was added to a solution of a nucleophile 9 (2 mmol) in dioxane (4 mL) and the reaction mixture was refluxed for 1-4 hours. The mixture was cooled, then chloroform (8 mL) and water (2 mL) were added. The pH value of the water layer was adjusted to 13 with 1 M NaOH in order to dissolve pyrazolone 7 in water. The layers were separated and the water layer was extracted with a mixture of chloroform (8 mL) and dioxane (4 mL). Organic layers were collected, washed with water (5 mL), dried over Na2SO4 and evaporated under reduced pressure. The products (with the exception of 14) were purified by column chromatography and were obtained as TLC-pure compounds. Reaction conditions and yields of products 11-18 are given in Table 1.
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The following products were obtained by the General Procedure:
N-(2,3-Dihydro-3-oxo-1H-pyrazol-4-yl)benzamide (7).
This compound can be isolated from the water layer by acidification to pH 5 with acetic acid and filtration of the resulting solid; mp 205-206 °C (lit [14] mp 204-205 °C).
N'-Phenylacetohydrazide (11).
This compound was prepared by refluxing pyrazole 5a and phenylhydrazine for 2 h. Yield 0.201 g (67%) of a white solid; mp 125-127 °C (lit [19] mp 129 °C).
Ethyl 2-(benzoylamino)acetate (12).
This compound was prepared by refluxing pyrazole 5b and glycine ethyl ester hydrochloride in the presence of triethylamine (0.6 mL, 4.3 mmol) for 2 h. Yield 0.245 g (59%) of a white solid; mp 59-60 °C (lit [20] mp 60.5 °C).
N-(2-Hydroxyethyl)benzamide (13).
This compound was prepared by refluxing pyrazole 5b and 2-aminoethanol for 1 h. It was isolated by column chromatography on silica gel (chloroform-methanol, 5:1). Yield 0.244 g (74%) of a beige solid; mp 56-59 °C (lit [21] mp 58 °C).
N'-(2-Pyrazinylcarbonyl)benzohydrazide (14).
This compound was prepared by refluxing pyrazole 5b and 2-pyrazinecarbohydrazide for 2 h. The reaction mixture was cooled, water (5 mL) was added and the pH value was adjusted to 10 with 1 M NaOH. The resulting solid was filtered off and washed with 1,4-dioxane. Yield 0.407 g (84%) of a white solid; mp 217-219 °C (lit [22] mp 217 °C).
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Phenyl benzoate (15).
This compound was prepared by refluxing pyrazole 5b, phenol and triethylamine (0.3 mL, 2.1 mmol) for 4 h. Yield 0.218 g (55%) of a white solid; mp 67-69 °C (lit [23] mp 70 °C).
N-Phenyl-4-nitrobenzamide (16).
This compound was prepared by refluxing pyrazole 5c and aniline in DMF for 2 h. DMF was evaporated under reduced pressure, 1,4-dioxane (4 mL) was added and the product was isolated as described in the General Procedure. Yield 0.360 g (77%) of a yellowish solid; mp 219-220 °C (lit [24] mp 218 °C).
N-Benzyl-2-thiophenecarboxamide (17).
This compound was prepared by refluxing pyrazole 5d and benzylamine in 1,4-dioxane for 2 h. Yield 0.378 g (87%) of white crystals; mp 117-120 °C (lit [25] mp 119.5-120.5 °C).
4-(4-Pyridinylcarbonyl)morpholine (18).
This compound was prepared by refluxing pyrazole 5e and morpholine for 1 h. Yield 0.276 g (72%) of a white solid; mp 73-74 °C (lit [26] mp 75-76 °C).
ACKNOWLEDGMENT
We thank the Ministry of Science and Technology for the financial support.
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POVZETEK
Opisana je splošna metoda za uporaba 1-acil-3-hidroksi-1 H-pirazolov 5 kot primernih acilirnih sredstev za alkohole ali fenole, amine in hidrazine. Opisan je tudi primer uporabe hidrazida ob prisotnosti 4-etoksimetilen-2-fenil-5(4H)-oxazolona (1) za neposredno aciliranje alkohola.