Derivatization of Squaric Acid to 4Hydroxy2Cyclobutenone Skeleton

Squaric acid itself is almost useless for this aim because of its intrinsic aromatic stability and difficult solubility in organic solvents. Instead, its esters 5 are the most convenient compounds from which derivatization reactions start. While acid 1 and its esters are now commercially available, (cf. 1 is now produced on a commercial basis by Kyowa Hakkou Kogyo Co. Japan [27]). The esterification method for 1 is improved [28] and preparation of dimethyl squarate 5 (R = CH3) is recorded in Organic Synthesis [29].

There are several approaches for derivatization of squaric acid (1). The traditional major route relies on the nucleophilic reaction of the eligible esters 5 with organolithium and organomagnesium reagents; their addition to 5 is known to be sufficiently selective to give 1,2-addition products 6 (4-substituted 4-hydroxy-2-cyclobutenones) from the former and 1,4-addition products 7 (3-substituted cyclobutene-1,2-diones) from the latter [30]. When acid-catalyzed rearrangement of 6 to form 7 with one combined substituent (R1) at C-3 is followed by the repeated nucleophilic addition to combine another substituent (R2), this series of reactions gives rise to 2,4-doubly substituted 4-hydroxy-2-cyclobutenone 8 [31,32]. Trisubstituted 4-hydroxy-2-cyclobutenone 11 can be prepared via acetal intermediates 9 and 10 [33] (Scheme 1).

Organotin and copper species are also used for the derivatization of 5 by cross-coupling reactions (typically shown as 5 ^ 12 ^ 13) [34-38]. The a-carbanion generated at the position adjacent to cyclobutenedione ring is a different derivatization route via nucleophilic addition (14 ^ 15 ^ 16) [39] (Scheme 2).

The derivatization method is compensated by the electrophilic addition reaction using organosilicon reagents [40-43]. Thus, the squaric acid family of derivatives, e.g., dichloride 17, methyl ester chloride 18, amide chloride 19, and diester 5 are the partners of the reactions with allylsilanes, silyl enol ethers, and silyl ketene acetals (Scheme 3). In this case, 1,2- and 1,4-addition to 20 and 21, respectively, are regulated by the substitution pattern of unsat-urated organosilanes, kind of Lewis acid catalysts, and the reactivity of acid derivatives. The less congested is the reaction site, the more preferable is 1,2-




S R1Li

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