1208 J . Org. Chem., Vol. 44, No. 8, 1979
Bellus
Syntheses of Squaric Acid, Its Monoorthoesters, and Related Derivatives via [2 21 Cycloadditions of Tetraalkoxyethylenes with Heterosubstituted Ketenes'
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Daniel BelluS Central Research Laboratories, Ciba-Geigy AG, CH-4002 Basel, Switzerland Received September 13, 1978
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Efficient syntheses of squaric acid are reported. The synthetic approach begins with the [2 21 cycloaddition reaction of tetraalkoxyethylenes with oxyketenes, which are produced in situ by triethylamine-promoted dehydrohalogenation of the corresponding acyl chlorides. The intermediately formed cyclobutanones undergo rapid enolization followed by esterification with the second equivalent of acid chloride to give the key compounds, the cyclobutenol esters 4a-e. Displacement-induced fragmentation of these esters, promoted by SiOz/triethylamine or basic AlZ03, yields smoothly the hitherto unknown monoorthoesters of squaric acid (5a-c). The acid hydrolyses of the cyclobutenol esters 4a,c and the orthoesters 5b,c, as well as the cyclobutenol esters 4d-f formed by similar [2 21 cycloadditions involving acetoxyketene and chloroketene, afford squaric acid (6) in high yields. When tetraalkoxyethylenes are reacted with in situ generated methylthioketene and phthalimidoketene, the corresponding cyclobutenol esters 4g and 4h are formed. However, 4g and 4h behave differently in subsequent reactions: 4g gives on acid hydrolysis the monomethyl thioester of squaric acid as the final product; 4h is stable toward SiOZhiethylamine, whereas attempted ethanolysis leads to ring-opened products 11 and 12.
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Squaric acid (6) is a deceptively simple organic molecule which has captured the imagination of chemists since its discovery by Cohen, Lacher, and Park in 1959.334Since then, many procedures have become available for the synthesis of 6. With one very recent exception,2 however, these include at least one laborious synthetic step, e.g., an autoclave reaction with fluorinated olefin^,^,^-^ the hydrolysis of halogenated cyclobutenes a t elevated temperatures by concentrated acids,5Jj+-11 a low-yield photochemical 12 21 cycloaddition,2J2or the electrochemical cyclotetramerization of carbon monoxide,13 or involve a curious starting material, di-tert b~toxyethyne.'~ As part of a program directed toward a study of biologically active derivatives of hydroxycyclobutenediones,l5 we looked for an easy new preparation of 6. In this paper we describe syntheses of some hitherto unknown derivatives of squaric acid, especially its monoorthoesters, and their smooth hydrolyses to 6. In addition, some related S and N derivatives will be described.
RO
OR
*
X-CH,COCI
f
Et,N
C,H
1
2
1
1
X-CH,COCI RO
RO
OR L
3
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4
30,/3'. E1,N
4
2, 01
ROH ( l o r XzSMeJ
RO
HO
5
= OCH3), thereby consuming another equivalent of acid chloride 2 (X = OCH3). The facile formation of 4a is understandable in light of the very rapid base-catalyzed enolization of cyclob~tanones.~~ When 2.1-2.2 equiv of the oxysubstituted acid chlorides 2 were used, the cyclobutenol esters 4a-c and the cyclobutene-1,2-diol diester 4d were formed in comparable yields (Table I), and tetraalkoxyethylenes 1 were no longer present in the reaction mixtures. Careful NMR analysis of crude 4a showed the presence of a minor component (less than 59/01,whose structure was as(5a) on signed as 2,3,4,4-tetramethoxy-2-cyclobuten-l-one the basis of its spectral properties (e.g., 6 4.11,characteristic for a CH30 group in position 3 of 3-methoxy-2-cyclobuten1 - 0 n e s ~ ~Spontaneous ~~). elimination of alcohol such as 3a 5a is a known side reaction of 3-alkoxy substituted cyclobutanones.17 The formation of 5a became a predominant, preparatively useful reaction when an ether solution of 4a was treated with a &fold weight excess of silica ge1/3% triethylamine system2 or basic alumina,26thus providing 5a in 80% yield (Table 11). Although no extensive optimization has been attempted, 5b and 5c were prepared in good yields after similar treatment with the SiOJEtsN system (eq 2). The tetraalkoxycyclobutenones 5a and 5c represent the first monoorthoesters of squaric acid, and 5b is the first mixed monoorthoester of squaric acid known so far.27Under identical experimental conditions, the cyclobutene-1,2-diol diester 4d underwent twofold displacement-induced fragmentation, initiated by cleavage of an ester group by some external nucleophilic species (eq 3). As a result, dimethyl squarate (8) was formed, presumably via intermediate cyclobutenone enol ester 7. Inspection of the data in Table I reveals that the outcome
Results and Discussion An interesting approach to highly oxidized cyclobutenes, discovered by R. W. Hoffmann,lGinvolves thermal [2 + 21 cycloaddition of tetramethoxyethylene (1, R = CH3) to electron deficient olefins and cumulenes followed by hydrolysis of the resulting tetramethoxycyclobutanes. By application of this procedure to [2 21 cycloadducts of tetraalkoxyethylenes with gaseous ketene,2J7as well as with in situ prepared alkyl-, vinyl-, and arylketenes, we recently made readily available a large number of the correspondingly substituted l-hydroxyl-cy~lobutene-3,4-diones.~~ As a continuation of our work in this area, we also studied the [2 21 cycloadditions of the now readily available tetraalkoxyethyleneszJ8with ketenes bearing substituents which would further raise the oxidation level of the resulting cyclobutanones. For this purpose, we chose meth~xyketene.'~ethoxyketene,20 acetoxyketene,21 chloroketene,Z1 methylthioketene,22 and phthalimidoketene,23 which were produced in situ by dehydrochlorination of the corresponding acid chlorides with triethylamine. Surprisingly, when tetramethoxyethylene (1, R = CH3) was allowed to react with 1 equiv of methoxyacetyl chloride (2, X = OCH3) in refluxing hexane in the presence of 1.1equiv of triethylamine, no cyclobutanone 3 (R = CH3, X = OCH3) was formed. Under these conditions, 50-55% of 1 (R = CH3) was unreacted and cyclobutenol ester 4a, bp 110 "C (0.015 mm), was isolated in 40% yield. 4a arises by esterification of the enol form of the primarily formed cyclobutanone 3 (R = CH3, X 0022-3263/79/1944-1208$01.00/00 1979 American Chemical Society
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J. Org. Chem., Vol. 44, No. 8, 1979 1209
Syntheses of Squaric Acid Table I. Tetraalkoxycyclobutenol Esters 4 from Reaction of Tetraalkoxyethylenes [ (RO)zC=C(OR)2] with Monosubstituted ]Ketenes (XHC=C=O), Produced In Situ from Ketene Precursors XCHzCOCl yield,
R
comDd 4a 4h 4c 4d 4 e!
4E 4g 4h
X
%
OCH3 OCH3 OCzH5 OCOCH3 121 C1 SCH3 phthalimido
69 86
bp (mm), "C 110 (0.015) oilb 125 (0.01) oilb oilb
82
82 b b 84 39
oilb
oilb 95-105d
a See eq 1 for reaction. See Experimental Section. Consists of 6696 4g and 18%5g. Melting point (dec).
r
Nu OMe
O-k-CH,OCOMe --+
1
Me'g
