Amines Acetic-formic anhydride

The hydroxyquinoline (39-2) provides the starting material for a quinolone that incorporates a hydrazine function. Reaction of (39-2) with 2,4-dintrophenyl O-hydroxylamine ether (41-1) in the presence of potassium carbonate leads to a scission of the weak N-O hydroxylamine bond by the transient anion from the quinolone the excellent leaving character of 2,4-dinitrophenoxide adds the driving force for the overall reaction, resulting in alkylation on nitrogen to form the hydrazine (41-2). The primary amine is then converted to the formamide (41-3) by reaction with the mixed acetic-formic anhydride. Alkylation of that intermediate with methyl iodide followed by removal of the formamide affords the monomethylated derivative (41-4). Chlorine at the 7 position is then displaced by A-methylpiperazine and the product saponified. There is thus obtained amifloxacin (41-6) [48]. 

Formylation. The anhydride formylates even unstable amines in an alcohol-free solvent in 80-100% yield. In no cases are even traces of trimethylacetamides detectable. Substantial amounts of acetamides can be formed when acetic formic anhydride is used. 

Acetic formic anhydride has been prepared by the reaction of formic acid with acetic anhydride2 3 and ketene,4,5 and of acetyl chloride with sodium formate.6 The present procedure is essentially that of Muramatsu.6 It is simpler than others previously described and gives better yields. It is easily adapted to the preparation of large quantities, usually with an increase in yield. Acetic formic anhydride is a useful intermediate for the formyl-ation of amines,3,7 amino acids,8,9 and alcohols,2,10 for the synthesis of aldehydes from Grignard reagents,11 and for the preparation of formyl fluoride.12... 

Tokitoh, N., Okazaki, R. A new method for deoxygenation of tertiary amine N-oxides with acetic formic anhydride. Chem. Lett. 1985,1517-1520. 

Formylation. See also Acetic-formic anhydride. Formic acid is a reactive acylal-ing agent for alcohols and amines and sometimes requires no catalyst or other solvent Cholic acid yields the triformyl derivative on being heated with 87% formic acid... 

Formylation of amines and alcohols. Behai,8 discoverer of the reagent, found that it reacts unidirectionally with simple alcohols to produce alkyl formates free from acetates. Hurd et al. J found that acetic-formic anhydride (prepared from formic acid and ketene) reacts quantitatively with aniline to give formanilide. Another study10 established that acetic-formic anhydride mixes endothermally with 2-nitro-2-methyl-l-propanol, exothermally with 2-nitro-2-methyl-l,3-propanediol, and displays no appreciable temperature effect with either 2-nitro-l-butanol or tris-(hydroxymethyl)-nitromethane. Formic esters are favored by avoiding a high reaction temperature and by not using sulfuric acid as catalyst. The mixed anhydride has been used for the preparation of formyl fluoride.11... 

CH3OH) across the carbon-carbon double bond of crotonic acid [( )-2-butenoic acid] followed by potassium bromide treatment of the initial adduct to yield the corresponding mercuric bromide and then the formation of 2-bromo-3-methoxybutanoic acid by the addition of bromine (Br2) to the latter. Acidification to the free acid, followed by amination (NH3), formylation with the equivalent of acetic-formic anhydride, hydrogen bromide (HBr) ether cleavage, and a final pH adjustment with ammonium hydroxide produced the desired amino acid. 

Chloral reacts with many amines to furnish formamido compounds and chloroform" but complexes often result from this reaction" . Formic acid alone will formylate certain anilines such as 3,4-dichloro-aniline" ". The addition of acetic anhydride improves reactivity" , presumably by the formation of acetic formic anhydride, but acetylation may then occur in preference to formylation. Huffman" has improved this method by preparing formic acetic anhydride before adding the amine . Oldh has described the use of formyl fluoride as a formylating agent. 

An efficient one-pot procedure for the iV-monomethylation of primary amines has been reported the method involves formylation with acetic formic anhydride followed by borane methyl sulphide reduction. The reaction sequence is applicable to even very weakly basic and sterically hindered amines, and the products are uncontaminated by over-alkylation. In addition, the transition-metal-catalysed j V-monoalkylation of amines by alcohols has been previously reported (c/. Vol. 6, p. 198) as a method to overcome problems associated with over-alkylation. A similar procedure for the preparation of unsymmetrical secondary (and tertiary) amines utilises a ruthenium catalyst, and is particularly suitable for the synthesis of cyclic amines. ... 

Tetra-n-butylammonium octahydrotriborate [(Bu 4NXB,H8)] is a mild reagent which reduces aromatic and aliphatic ketones, aldehydes, and acid chlorides in high yield, and finally the formylation of functionalized primary aromatic and aliphatic amines with acetic formic anhydride followed by borane-methyl sulphide reduction in the same pot affords the corresponding iV-methylamines in excellent isolated yields. ... 

Nitromethane s. under H(PO H)JOH Acetic formic anhydride Formylation of amines s. 13, 442... 

Unsymmetric anhydrides that react selectively on one side are useful. Although formic anhydride is unstable above 10°C, acetic formic anhydride can be prepared by stirring sodium formate with acetyl chloride in ether (64% yield, bp 27-28°C) [22]. It is useful for the formylation of alcohols and amines. A stable solid formylating agent is the mixed anhydride prepared in 89% yield from p-methoxybenzoyl chloride and sodium formate catalyzed by a polymeric pyridine oxide [23]. Ethyl chlorofor-mate gives mixed anhydrides with various carboxylic acids which are then susceptible to nucleophilic substitution at the carboxylic carbonyl carbon. 

Mixed anhydrides of formic acid with higher homologous acids anhydride are well known and stable. BehaP prepared acetic-formic anhydride from acetic anhydride and formic acid, yielding a suitable formylating agent for the formylation of A/-formyl derivatives from the corresponding amines (Eq 1.8). 

Formylation Reactions. The problem with Acetic Formic Anhydride, the most commonly used formylating agent, is undesirable side reactions, particularly if there are acid sensitive functionalities in the compound. One of the best alternatives is to use pentafluorophenyl formate (7), an easily prepared and stable compound which reacts with N-nucleophiles in minutes at room temperature to yield the IV-formyl derivative (eq 5) (Table 3). Significantly, no reaction occurs with alcohols, thiols, or sterically hindered amines. 

Even though formic anhydride is not a stable compound (see p. 714), amines can be formylated with the mixed anhydride of acetic and formic acids (HCOO-COMe) °°° or with a mixture of formic acid and acetic anhydride. Acetamides are not formed with these reagents. Secondary amines can be acylated in the presence of a primary amine by conversion to their salts and addition of 18-crown-6. ° The crown ether complexes the primary ammonium salt, preventing its acylation, while the secondary ammonium salts, which do not fit easily into the cavity, are free to be acylated. 

Formylation of amines is performed with formic acid/acetic acid anhydride. The application of other mixed anhydrides with acetic acid as well as benzoic acid is less fovorable, because both possible amides will form in varying amounts. 

The formyl derivatives are obtained from the amines by the action of a mixture of 98% formic acid and acetic anhydride. It seems that either formic anhydride or a mixed anhydride of formic and acetic acid is formed as an intermediate and acts as the acylating agent. In some cases formyl derivatives were prepared via the aminolysis of ethyl formate or /-nitrophenyl formate . 

The desired pyridylamine was obtained in 69 % overall yield by monomethylation of 2-(aminomethyl)pyridine following a literature procedure (Scheme 4.14). First amine 4.48 was converted into formamide 4.49, through reaction with the in situ prepared mixed anhydride of acetic acid and formic acid. Reduction of 4.49 with borane dimethyl sulfide complex produced diamine 4.50. This compound could be used successfully in the Mannich reaction with 4.39, affording crude 4.51 in 92 % yield (Scheme 4.15). Analogous to 4.44, 4.51 also coordinates to copper(II) in water, as indicated by a shift of the UV-absorption maximum from 296 nm to 308 nm. 

Treatment of the tetralone oxime 2166 with iron powder in DMF in the presence of Me3SiCl 14 and a mixture of acetic anhydride and formic acid gives the N-for-myl amine 2167 in high yield [79]. co-Unsaturated alkoxyalkylazides such as 2168... 

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