Formylation: a

In the presence of aluminum chloride and a small amount of cuprous haUde, a mixture of hydrogen chloride and carbon monoxide serves as a formyl a ting agent of aromatics (Gattermann-Koch reaction) (107) ... 

Whereas the above reactions are appHcable to activated aromatics, deactivated aromatics can be formylated by reaction with hexamethylenetetramine in strong acids such as 75% polyphosphoric acid, methanesulfonic acid, or trifluoroacetic acid to give saUcylaldehyde derivatives (117). Formyl fluoride (HCOF) has also been used as formyl a ting agent in the Friedel-Crafts reaction of aromatics (118). Formyl fluoride [1493-02-3] in the presence of BF was found to be an efficient electrophilic formyl a ting agent, giving 53% para-, 43% ortho- and 3.5% meta-tolualdehydes upon formylation of toluene (110). 

The most generally useful method for acylation or formyl a ti on of pyrroles is the Vil smeier-Ha ack reaction (32,33). The pyrrole is treated with the phosphoryl complex of A/ A -dialkjlamide and the intermediate imine salt is hydroly2ed. 

The important synthesis of pyrazoles and pyrazolines from aldazines and ketazines belongs to this subsection. Formic acid has often been used to carry out the cyclization (66AHQ6)347) and N-formyl-A -pyrazolines are obtained. The proposed mechanism (70BSF4119) involves the electrocyclic ring closure of the intermediate (587) to the pyrazoline (588 R = H) which subsequently partially isomerizes to the more stable trans isomer (589 R = H) (Section 4.04.2.2.2(vi)). Both isomers are formylated in the final step (R = CHO). 

Cyanoamidines such as (10) are converted into the more useful 2-formyl-A-norsteroids (11) by reduction with lithium in methylamine (buffered with ammonium acetate) followed by hydrolysis on hydrated alumina. This yields a mixture containing approximately 5 parts of the 2j5-aldehyde and 3 parts of the 2a-aldehyde (11). Both aldehydes are smoothly dehydrogenated by 2,3-dichloro-5,6-dicyanobenzoquinone in the presence of acid to the 2-formyl--A-iiorsteroids (12). ... 

Although crude cyanoamidine (10) can be used for many reactions, reduction to the 2-formyl-A-norsteroid (11) is most satisfactory when purified material is employed. The crude cyanoamidine is stirred for about 15 min with boiling toluene (120 ml/g of steroid) to effect dissolution, the hot solution is filtered quickly through fluted paper, and the filtrate is cooled and diluted with an equal volume of petroleum ether. The mixture is cooled for 0.5 hr in ice, affording from 25 g of crude material about 18 g of colorless 2a-(A-pyrrolidinylcyanoiminomethyl)-A-nor-5a-androstan-17 -ol (10) mp 252-255° (anal, sample mp 262-263°, from benzene-hexane 250 m ... 

Favorskii rearrangement, 159, 176 Formation of hetero-radicals, 238 2-Formyl-A-nor-5a-androstan-l 7 -oI, 415 2-Formyl-A-nor-5 a-androst-1 -en-17 S-ol, 416 6/3-Formyl-B-nor-5 -cholestane-3, 5 -dioI 3-acetate, 432... 

Chemical Name 0-2-deoxy-2-(methylamino)-o -L-glucopyranosyl-(1->2)-0-5-deoxy-3-C-formyl-a-L-lyxofuranosyl-(1->4)-N,N -bis(aminoiminomethyl)-D-streptamine... 

Additional P2 proline-containing PDF inhibitors have been reported in the patent literature by Dainippon and Questcor [95, 96]. The Dainippon examples disclosed contain an A-formyl-A-hydroxylamine group and possess good antibacterial activity against S. aureus, S. pneumoniae, Streptococcus pyogenes. Enterococcus faecium and M. catarrhalis [95]. The Questcor patent application describes various proline-containing hydroxamic acid inhibitors [96]. 

In 1975, SAR studies involving actinonin investigated an analogue in which the orientation of the Pl -P2 amide bond was reversed (13), but the compound was found to lack antibacterial activity. Since then, however, descriptions of some /i-aminohydroxamic acids and /i-amino-A-formyl-A-hydroxylamines as PDF inhibitors have appeared in the patent literature. Patent applications from Senju [97] and De Novo [98] pharmaceuticals cover Pl -P2 amides (14), ureas (15, 16) and sulfonamides (17). 

In the patent literature, Aventis has published a patent application covering hydroxamic acid containing macrocycles (39) with the same general template as the A-formyl-A-hydroxylamine macrocycles described above [114] and GlaxoSmithKline has published an application on macrocyclic PDF inhibitors containing a hydrazide scaffold (40) [115], No data has been published on these inhibitors to date. 

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