Reaction with formamides

Partially reduced derivatives have been obtained from o-aminopyridinemethanors (218 219) (75JAP(K)75157394), and partially reduced pyridines e.g. 220) have also furnished this type of derivative in reactions with formamide, guanidine and imidates <72JHC1113, 72JHC1123, 78CB2297). 

D. Reactions with Formamide, Guanidine, and Thiocai bamide. 199... 

Alkylpyrimidines were obtained in 59-70% yield from higher 1-dimethyl-amino- and l-methoxyalk-l-en-3-ynes (R = Me, Et, -Pr) by their reaction with formamide (70ZOR2374). The exception was l-methoxy-5,5-dimethylhex-l-en-3-yne, from which the pyrimidine was obtained in 45% yield only, which is related to steiic hindrance for the attack at the acetylene bond. 

Aldehydes can also be obtained from Grignard reagents by reaction with formamides, such as A-formylpiperidine. In this case, the initial adducts are stable and the aldehyde is not formed until hydrolysis during workup. 

Ready formation of pyrazolo[3,4-4 pyrimidines from reaction of 5-aminopyrazole -carboxylic acid derivatives is a well-established route to derivatives of this ring system. A recent application is the conversion of 286 into 288 by reaction with formamide and NIS 287 (Equation 40) <2002BML1687>. 

The oximes of 4,5,6,7-tetrahydrobenzo[6]thiophen-4-one and -7-one undergo the Beckmann rearrangement to give 146 354 451 and 147 (R = H),362 respectively. Compound 147 (R=C1) may be prepared similarly and by treating 2-chloro-4,5,6,7-tetrahydrobenzo[ ]thio-phen-7-one with ammonia in the presence of PPA.356 The oxime of 4,5,6,7 -tetrahydrobenzo [6]thiophene- 4-one affords 4-aminobenzo [6]-thiophene in a modified Leuckart reaction.241,355 The same oxime may be converted into 4-amino-4,5,6,7-tetrahydrobenzo[ ]thiophene by reduction with aluminum amalgam in methanol.452 The parent ketone also affords 4-amino-4,5,6,7-tetrahydrobenzo[6]thiophene on reaction with formamide at 165°, followed by acidic hydrolysis of the resulting 4-formylamino compound.355... 

For the synthesis of aldehydes, reactions with formamides are preferable (see Section 6.3), though modest yields have been reported in a few cases [A]. The other reactions can give good yields [A], as in the following procedure, but have been little exploited. 

In a series of theoretical calculations of addition to protonated formaldehyde it was also revealed that the intrinsic properties of the attacking nucleophile (X) are reflected in the bond energy of the X-CH2-OH+ intermediate (X = NH3 >H20 >HF >H2), and in the barrier for the subsequent 1,3-intramolecular proton transfer leading to water elimination [129]. In comparing different substituents X and Y, it was also found that for the same X,but different CH2Y+ ions the reactivity order is Y = NH2 [Pg.16]

Evidence for this reaction pathway came from the observations that the a-formamidoketone (6) could be isolated, and reaction with formamide converted it into the imidazole.67 Although, in theory, it is... 

Many water-insoluble ketones, aliphatic, aryl aliphatic, and heterocyclic, respond favorably to treatment with ammonium formate or formamide to form with subsequent hydrolysis the primary amines. A typical procedure for the synthesis of a-phenylethylamine (66%) from acetophenone and ammonium formate has been applied to many other ketones (65-84%). Nuclear alkoxyl, halo, and nitro groups are not disturbed. The reaction with formamide as the reducing agent is catalyzed by ammonium formate, ammonium sulfate, or magnesium chloride. ... 

The reaction with formamide requires a sensitizer such as benzophenone, and CONHj radicals are produced by hydrogen abstraction from the amide by the excited state of the ketone. With bromotrichloromethane 2 1 alkyne haloalkane adducts are produced as well as 1 1 adducts (equation 39). Extensive polymerization occurs, and peroxide-initiated reaction often gives better yields of simple products . 

Substituents in a 1,4-quinone may be displaced by nucleophiles in the presence of strong bases an amidine supplies the necessary atoms for pyrimidine formation. When the amino and carbonyl functions are in peri positions, a doubly fused ring is formed by reaction with formamide. 

Chloraniformethan (1), introduced under the trade name Imugan , is one of these important fungicides. Its chemical composition is N-[2,2,2-trichloro-I-(3,4-dichloroaniIine)ethyl]formamide. Synthesis starts with chloral (2), which, in reaction with formamide (3) gives chloral-formamide [(2,2,2-trichloro-l-hydroxyethyl) formamide] (4). This reacts with 3,4-dichlorophenyl isocyanate (5) via the formation of the carbamic acid ester (6) as intermediate, to yield, after rapid carbon dioxide elminiation, the end-product (1) (Malz et ai, 1966., Dorker and Schrader, 1963),... 

Initially a-halo ketones (30) react with formamide to give iminoesters (31), which then either ring-close to the oxazoles (32) or decompose to form a-hydroxy ketones (33). The a-hydroxy ketones formed in this way react with excess formamide in the presence of liberated hydrogen halides or the added quantity of sulfuric acid to give a-formoxy ketones (34) which then yield the oxazoles (32) with formamide.10 95 On the other hand, a-hydroxy ketones and formamide in the absence of added sulfuric acid yield imidazoles (35) predominantly.92 Evidence for this reaction pathway came from the observations that a-formoxy ketones could be isolated, and reaction with formamide converted them into the oxazoles.94... 

In a variation94 of this procedure, acyloins themselves have been converted directly into 2-unsubstituted oxazoles by reaction with formamide and concentrated sulfuric acid at 100°-150o. The yields in this case, compared to overall yields of the two stages of the previous method, are either nearly the same or better. 

An additional heterocyclic ring fused to a (6 5 6) system can be constructed by a cyclocondensation reaction of an appropriately substituted tricyclic derivative with an external reagent. The NH2-CN functionality of (177) was transformed into a pyrimidine by the reaction with formamide <91H(32)895>, and cyclocondensation of the Ac-OH functionality in (178) with phenyl-hydrazine gave a pyrazole <9lH(32)90l>. A hydrazino derivative (179) was condensed with a carboxylic acid to give a 1,2,4-triazole in the reaction that involves an N-2 atom of (179) <88Ci(L)785>. 

Disubstituted-2-methyl-1,2,3-triazinium iodides 114a-c are demethylated to the triazines 17m,s,u by reaction with formamide and diammonium persulfate (Equation 92) < 1991H(32)2015>. This special case has already been mentioned in Section 9.01.5.6 together with the removal of 2-dicyanomethylene groups from the 1,2,3-triazinium dicyanomethylides 34 (R = H R, R = Me, Et, Ph) under the same conditions see also <1996CHEC-11(6)483>. Cycloadditions of 2-ethyl-1,2,3-triazinium tetrafluoroborates and 1,2,3-triazinium 2-dicyanomethylides have been treated in Section 9.01.5.7. 

The following section highlights some selected recent applications of the use of phosgene equivalents in the preparation of Vilsmeier-type chlorinated derivatives of amides and ureas. Thionyl chloride, carbonyl bromides, phosphorus oxychloride, phosgene, triphosgene, oxalyl chloride, and p-toluenesulfonyl chloride are all efficient oxophilic promoters capable of generating Vilsmeier-type chloro imi-nium ion intermediate 1770 by reaction with formamides, particularly dimethyl-formaraide, and ureas. 

A-Formylamines can be prepared by the Leuckart reaction, a reductive amination of carbonyl compounds by reaction with formamide and formic acid. Evidence for an unprecedented intramolecular transamidation in the mechanism of enantioselective Leuckart reaction of 2-norbornanone with a (l-norbornyl)acetamide is presented. ... 

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