Formylation dimethylformamide acetal

Reductive processes are sometimes useful for conversion of polyiodinated pyrroles into compounds with fewer iodine atoms. Sequential action of butyl-lithium and water reduced tetraiodopyrrole to a mixture of 2,3,4-triiodopyrrole (63%) and 2,3,5-triiodopyrrole (3%). Zinc and acetic acid was able to reduce the tetraiodo compound to 3,4-diiodopyrrole which was converted by butyl-lithium and then dimethylformamide into 3-formyl-... 

The reactivity of five-membered rings with one heteroatom to electrophilic reagents has been quantitatively compared. Table 1 shows that the rates of substitution for (a) formylation by phosgene and V,iV-dimethylformamide, (b) acetylation by acetic anhydride and tin(IV) chloride, and (c) trifluoroacetylation with trifluoroacetic anhydride (71AHC(13)235) are all in the sequence furan > tellurophene > selenophene > thiophene. Pyrrole is still more reactive as shown by the rate for trifluoroacetylation, by the relative rates of bromination of the 2-methoxycarbonyl derivatives (pyrrole > furan > selenophene > thiophene), and by the rate data on the reaction of the iron tricarbonyl-complexed carbocation [C6H7Fe(CO)3]+ (Scheme 5) (2-methylindole ss V-methylindole > indole > pyrrole > furan > thiophene (73CC540)). 

Vilsmeier formylation has attracted much attention as a route to cyclazines (see Section III,B,6). Jessep and Leaver have obtained the Vilsmeier salt 263 from 1 by using dimethylformamide and phosphoryl chloride at — 65°C, but the formylpyrrolizine was very unstable, and a second Vilsmeier reaction has not been achieved.128 The salt 263 could be converted to the 3,5-bisaldehyde equivalent 264a by treatment with dimethylthioformamide and acetic anhydride. Flitsch et al. prepared l-chloro-3H-pyrrolizine and treated it in situ at — 60°C with the Vilsmeier reagent to obtain the chloro derivative 259 of compound 263. 7 They also obtained the bis(dimethylaminomethylene) derivative 264b and, at room temperature, the tris(dimethylaminomethylene) derivative 265, which was hydrolyzed to give the dialdehyde 266. Reactions... 

To a stirred mixture of the above amine hydrochloride (55.0 g, 0.22 mole) and [[(2,4-dioxo-l-imidazolidinyl)imino]methyl]formyl chloride (42.0 g, 0.22 mole) was added a solution of 440 ml of dimethylformamide and 44 ml of pyridine. The mixture was stirred for 20 h and poured into 2 L of water. The solid was collected by filtration and washed with ethanol and ether to give 36.0 g (28%) of N-[2-(4-bromophenyl)-2-oxoethyl]-[[(2,4-dioxo-l-imidazolidinyl)-imino]methyl]formamide, melting point 267°-269°C (recrystallization from 2200 ml acetic acid). 

O-Formylation Acetic-formic anhydride. Formic acid. Formylimidazole. p-ToluenesuIfonyl chloride-Dimethylformamide. 

An alternative procedure is the reaction of A,A-dimethylformamide dimethyl acetal with diethyl cyanomethylphosphonate. In this case, the reaction proceeds spontaneously at room temperature to give the corresponding enaminophosphonate in high yield (95%, Scheme 6.15). Hydrolysis under basic conditions (2 M NaOH) at room temperature leads to diethyl 1-cyano-l-formyl-methylphosphonate in 83% yield in the enolic form exclusively. "... 

When substituted guanidines 21 are heated with formylation reagents, such as ethyl formate or dimethylformamide diethyl acetal, TV-mono- or TV,V -disubstituted 1,3,5-triazine-2,4-diamines are obtained.405a b Two reaction pathways are observed, but it is not possible to predict clearly which pathway will be followed. 

Further, enamines can be formylated by treatment with formic acid and acetic anhydride467 or with dimethylformamide and carbonyl chloride, the latter process being analogous to the Vilsmeier reaction and sometimes giving very good yields.471... 

Arnold and his colleagues have applied the combination of dimethylformamide with phosgene or phosphoryl chloride also to formylation of aliphatic compounds such as acetals,844,845 ketals,846 vinyl ethers,844,845,847 and ketones848,849 (see also Ziegenbein and his co-workers850). Vinyl ethers afford 2-alkyl-3-(dialkylamino) derivatives of acrylaldehyde 844... 

In the still more 7t-deficient 1,2,3-triazole series (see 20), several 4-amino-5-formyl derivatives resisted both direct acylation and acetal formation. A successful alternative was to form intermediates with side chains conjugated to the nucleus. For example, 1- and 2-methyl-, as well as 3-benzyl-4-amino-l,2,3-triazole-5-aldehydes reacted with a cold mixture of dimethylformamide and phosphoryl chloride to give excellent yields of, e.g., 3-benzyl-4-dimethyl-aminomethyleneamino-l,2,3-triazole-5-aldehyde (84). This was converted to 9-benzyl-8-azapurine (see 21) in excellent yield by refluxing in methanolic ammonium acetate.87 In a variation of this reaction, an imidate (85) replaced the amidine (84) as intermediate. Thus, 4-amino-l-methyl-l,2,3-triazole-5-aldehyde and triethyl orthoacetate, refluxed for 2 hr, gave an excellent yield of 4-ethoxyethylideneamino-l,2,3-triazole-5-aldehyde (85), cyclized, by stirring in cold ethanolic ammonia, to 2,7-dimethyl-8-azapurine (good yield).87... 

The Vilsmeier reaction has attracted some attention as a route to cyclazines. 3H-pyrrolizine (1) gave the Vilsmeier salt (19a) on treatment with dimethylformamide and phosphoryl chloride at — 60°C. A second formylation to (20a) was achieved by treatment of (19a) with dimethyl-thioformamide and acetic anhydride <80JCS(P1)1319>. Similar products were obtained from a chloro-formylation of the ketone (3a) the Vilsmeier reaction at — 50°C gave the salt (19b) in 65% yield. From a reaction at 0 °C, 91 % of the trisubstituted derivative (21) was obtained, which was hydrolysed... 

Condensation of syn- or anti-27 with hydrazine afforded new pyrazole derivatives 28 with a stereodefined and protected amino diol side chain [64]. The preparation of push-pull substituted unsaturated monosaccharide derivatives and their use in the synthesis of nucleoside analogs have been reviewed [65]. Thus, the 2-formyl pentose glycals were transformed to the corresponding acyclo-C-nucleosides 29 [66]. Similarly, the benzy-lated 2-formylglycals reacted with hydrazine derivatives to afford the substituted l,2,4-tri-0-benzyl-lC-(lH-pyrazol-4-yl)-D-tetritols the deprotection of which was achieved with Pd/H2 to yield the lC-( 1-methyl-lH-pyrazol-4-yl)-D-tetritols [67]. 3-0-Benzyl-6-deoxy-l,2-0-isopropylidene-o -D-xylo-hept-5-ulofuranurono-nitrile was reacted with f, N-dimethylformamide dimethyl-acetal in THF to furnish the (E)-3-0-benzyl-6-deoxy-6-dimethyl-aminometh-ylene-l,2-0-isopropylidene-Q -D-xylo-hept-5-ulofuranurono-nitrile as a major product, and on treatment with carbon disulfide and methyl iodide under basic conditions afforded 3-0-benzyl-6-deoxy-l,2-0-isopropylidene-6-[bis(methylsulfanyl)methylene]-a-D-xylo-hept-5-ulofuranurono-nitrile. Further reaction with hydrazines yielded the reversed pyrazole-C-nucleoside analogs [68]. 

The hydrazone and iViV-dimethylformamide dimethyl acetal give the hetero-substituted azine (CFj)]C N N CH-NMe2. Treatment of the hydrazone with triethyl orthoformate-P3O3 followed by aqueous work-up causes hydrolysis of the initial product (CF C N N CH OEt to the formyl draivative (CP3)3C N NH CHO. 

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