3-Cyclobutene-l,2-diones

Ohno M, Eguchi S (2006) Directed Synthesis of Biologically Interesting Heterocycles with Squaric Acid (3,4-Dihydroxy-3-cyclobutene-l,2-dione) Based Technology. 6 1-37 Okino T (2006) Heterocycles from Cyanobacteria. 5 1-19... 

The coupling reaction of 75 with 3-(tributylstannyl)-3-cyclobutene-l,2-dione 2-ethylene acetal 83 is also catalyzed by PdCl2(PhCN)2, giving the benzo-... 

Tributylstannyl)-3-cyclobutene-1,2-diones and 4-methyl-3-(tributylstan-nyl)-3-cyclobutene-l,2-dione 2-ethylene acetals undergo the palladium/copper-catalyzed cross coupling with acyl halides, and palladium-catalyzed carbon-ylative cross coupling with aryl/heteroaryl iodides [45]. The coupling reaction of alkenyl (phenyl )iodonium triflates is also performed by a palladium/copper catalyst [46],... 

Fig. 12.1 Representative biological activities of the 3-cyclobutene-l, 2-dione scaffold.

The four-, five-, and six-membered analogs (178,180, and 182) were also obtained from the diprotonation of squaric acid (3,4-dihydroxy-3-cyclobutene-l,2-dione, 177), tri-O-protonation of croconic acid (4,5-dihydroxy-4-cyclopentene-l,2,3-trione, 179), and tetra-O-protonated rhodizonic acid (5,6-dihydroxy-5-cyclohexene-l,2,3,4-tetraone, 181), respectively. These ions were prepared in either Magic Acid (1 1 FSOsH-SbFs) or fluorosulfuric acid at low temperature and characterized by NMR. Ab initio/IGLO calculations showed that di-O-protonated squaric acid (178) is planar and aromatic, whereas the polyprotonated croconic and rhodizonic acids (180 and 182) have more carboxonium ion character, and no indication was obtained for any significant contributing homoaromatic structures. 

X-Ray crystal structure analyses of both squaric acid158 (3,4-dihydroxy-3-cyclobutene-l,2-dione) and the dianion159 are the usual benchmarks used in consideration of structural data of metal complexes. The relevant dimensions are shown in Table 9, from which it can be seen that there is substantial conjugation and C2 symmetry in the acid molecule while the dianion has DAh symmetry... 

Thermal electrocyclizations of perhalogenated 1,3-butadienes yield perhalogenated cyclobutenes which can be solvolysed to 3,4-dihydroxy-3-cyclobutene-l,2-dione ( squaric acid ) and its derivatives (G. Maahs, 1966 H. Knorr, 1978 A.H. Schmidt, 1978). Double CO extrusion from fused cyclobutenediones has been used to produce cycloalkynes, e.g., benzyne from benzocyclobutenedione by irradiation in an argon matrix (O.L. Chapman, 1973) and cycio-Cij, cyc(o-Cj4, etc. by laser desorption mass spectroscopy of appropriate precursors (see section 4.9.8). 

Directed Synthesis of Biologically Interesting Heterocycles with Squaric Acid (3,4-Dihydroxy-3-cyclobutene-l,2-dione)... 

Palladium(II)-copper(I) cocatalyzed couplings of several (/ ,/ -dialkylvinyl)phenyliodo-nium triflates with 4-isopropoxy-3-tri- -butylstannyl-3-cyclobutene-l,2-dione (71) in DMF at room temperature have recently been described (equation 259)157. As observed in earlier studies of Cu(I)- or Pd(II)-promoted reactions of vinyliodonium salts, the vinyl ligands are introduced with retention of configuration. Since iodobenzene is a byproduct of ligand coupling, the production of 3-phenyl-4-isopropoxy-3-cyclobutene-1,2-dione might also be expected. However, the (/ ,/ -dialkylvinyl)iodonium ions are much more reactive... 

A final example illustrates the use of squaric acid derivatives in enzyme inhibition. In an effort to discover potent inhibitors (of Yersinia PTPs and PTPIB) with reduced charge and thus improved bioavailabihty, Xie et al. (53) also studied the squaric acid motif as a nonhydrolyzable phosphotyrosine mimic. 3-aryl-4-hydroxy-3-cyclobutene-l,2-diones based on the... 

Figure 11.11. 3,4-Diamino-3-cyclobutene-l,2-diones redrawn from Ref. 34.

Many NMDA receptor antagonists have been synthesized that are based on the structure of glutamate, NMDA, and AMPA. Several 3,4-diamino-3-cyclobutene-l,2-dione derivatives (34) have been synthesized and found to be good inhibitors of the NMDA receptor (Fig. 

Kinney, W. A., Lee, N. E., Garrison, D. T, Podlesny, E. J., Jr, Simmonds, J. T, Bramlet, D., Notvest, R. R., Kowal, D. M., Tasse, R. P. Bioisosteric replacement of the a-amino carboxylic functionality in 2-amino-5-phosphonopentanoic acid yields unique 3,4-diamino-3-cyclobutene-l,2-dione containing NMDA antagonists. J. Med. Chem. 1992, 35, 4720-4726. 

The NANQUO02 crystal results from the aggregation of the 3,4-6i5(dimethy-lamino)-3-cyclobutene-l,2-dione neutral molecules. Each molecule presents... 

C. Gatti, E. May, R. Destro and F. Cargnoni, Fundamental properties and nature of C-H- -O interactions in crystals on the basis of experimental and theoretical charge densities. The case of 3,4-() s (dimethylamino)-3-cyclobutene-l,2-dione (DMACB) crystal, J. Phys. Chem. A106, 2707-2770 (2002). 

Figure 1.2.4 View along the a axis of one of the planes of the NANQUO02 crystal, the crystal of the 3,4-bis(dimethylamino)-3-cyclobutene-l,2-dione. The shortest C-H—O contacts are shown (the dotted lines, all in the 2.0-3.5 A range of distances). We have marked with a those contacts that are not bonds, as they do not present (3,-1) bond critical points.

Chlorobenzylidene chloride is hydrolysed by concentrated sulfuric acid in 5 hours at room temperature,531 and 4-chloro-3,3,4-trifluoro-l-phenyl-cyclo-butene gives 3-phenyl-3-cyclobutene-l,2-dione (75% yield) when treated with... 

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