Dimethyl squarate

An unusual synthesis of ( )-septicine (866) from dimethyl squarate (878) exploits rearrangement of a 4-(l-pyrrolo)cyclobutenone 879 to the indolizine-5,8-dione 880, presumably via a ketene intermediate formed by electrocyclic ring opening of 879 (Scheme 113) (584). Partial reduction of 880 yielded the 4-hydroxypyridone 881, the triflate ester of which was deoxygenated with a palladium(II)-formic acid system to yield the l,2,3,5-tetrahyi oindolizin-5-one 882. Mild reduction with aluminum hydride completed the synthesis of ( )-866 in an excellent overall yield of 27% from 878. 

This methodology has been extended to 4-alkynyl-4-(propargyloxy)cyclobutcnones,2 formed by addition of lithium acetylides to dimethyl squarate (3) followed by treatment of the 1,2-adducts with propargyl iodides. These products (4) when heated at 135° rearrange to methylenebcnzofurans (5), which isomcrizc in an acidic medium to benzofurans (6). 

DIMETHYL SQUARATE AND ITS CONVERSION TO 3-ETHENYL-4-METHOXYCYCLOBUTENE-1,2-DIONE AND 2-BUTYL-6-ETHENYL-5-M ETHOXY-1,4-BENZOQUINONE (3-Cyclobutene-1,2-dione, 3-ethenyl-4-methoxy- and 2,5-cyclohexadiene-1,4-dione, 5-butyl-3-ethenyl-2-methoxy- from 3-cyclobutene-1,2-dione, 3,4-dimethoxy-)... 

B. 3-Ethenyl-4-methoxycyctobutene-1,2-dione (2). A 2-L, flame-dried, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and nitrogen bubbler is charged with 10.0 g (70.4 mmol) of dimethyl squarate, 1, and 1 L of dry tetrahydrofuran (THF) (Note 19). The stirred solution is cooled in a dry ice-acetone bath at -78°C, and 39.0 mL (91.7 mmol) of vinyllithium (2.35 M) (Notes 20 and 21) is added via syringe in four portions to the dimethyl squarate solution. After the addition is complete, the yellow solution is stirred for 2 hr (Note 22), whereupon 14.8 mL (105 mmol) of trifluoroacetic anhydride (Note 23) is added dropwise via syringe. The... 

The synthesis of dimethyl squarate as outlined here is a general method that can be employed for the synthesis of a variety of other alkyl squarates.4... 

A 1-mL aliquot is taken from the reaction flask and 2 drops of trifluoroacetic anhydride (Note 23) is added. The solution is then checked against dimethyl squarate by TLC (7/3 hex/EtOAc). If dimethyl squarate, 1, is present an additional 5 mL (11.75 mmol) of vinyllithium is added. The solution is allowed to stir for 20 min and the above procedure is repeated until there is no evidence of dimethyl squarate. 

Dimethyl squarate has recently been used for the versatile and regiospecific synthetic routes to highly substituted benzo- and naphthoquinones and related aromatic compounds.3... 

Two other syntheses of dimethyl squarate have been reported.2 One such method involves the formation of the disilver salt of squaric acid followed by treatment with methyl iodide. This process, unfortunately, is laborious as well as costly. The other synthesis involves the reaction of squaric acid with diazomethane. This reaction not only gives a lower yield, but is inherently unsuited for large scale preparations. The synthesis presented here provides a convenient and inexpensive route to the preparation of dimethyl squarate, and is also suitable for large scale synthesis.4 One should take precautions when synthesizing or using dialkyl squarates, particularly dimethyl squarate, since they are known to cause severe contact dermatitis.5 Thus, all procedures should be carried out in the hood and protective clothing and gloves should be worn. 

Dimethyl squarate Cyclobutenedione, dimethoxy- (8) 3-Cyclobutene-1,2-dione, 3,4-dimethoxy- (9) (5222-73-1)... 

ETHENYL-4-METHOXYCYCLOBUTENE-l,2-DIONE. This procedure also provides a convenient method for the preparation of DIMETHYL SQUARATE, an important intermediate. The synthesis of (lR, 6S, 7S )-4-(tert-BUTYLDIMETHYLSILOXY)-6-(TRIMETHYLSILYL)BICYCLO-[5.4.0JUNDEC-4-EN-2-ONE is representative of a general protocol for the construction of cycloheptenones by a [3 + 4] annulation. The method features the addition of a lithium enolate to an acryloyl silane to give a 1,2-adduct that undergoes a novel sequence of a concerted Brook rearrange-ment/cyclopropanation and an anionic oxy-Cope rearrangement. 

This type of cyclization has also seen extensive use toward quickly accessing complex multi-ring systems. In recent work by Moore, alkyne 144 was lithiated and added to dimethyl squarate (145). The resulting cyclobutenone 146 was refluxed at 132°C in chlorobenzene to produee benzophenanthridine derivative 147 in a good yields (Scheme 26) [48]. 

DIMETHYL SQUARATE AND ITS CONVERSION TO 3-ETHENYL-4-METHOXYCYCLOBUTENE-1,2-DIONE AND 2-BUTYL-6-ETHENYL-5-METHOXY-1.4-BENZOQUINONE... 

---