Formamide derivatives amines

Furfuryl dimethyl amine is first produced. This may conveniently be accomplished by employing the Leuckart synthesis known to those skilled in the art, which involves the use of an aldehyde or a ketone, and formate of ammonia or an amine, or corresponding formamide derived by dehydration of formate of ammonia or an amine. 

The Leuckart-Wallach reaction is the oldest method of reductive amination of carbonyl compounds. It makes use of formamide, formic acid or ammonium formate at high temperature. The final product is a formamide derivative, which can be converted to an amine by reduction or hydrolysis. The method has been applied to the preparation of 1,2-diamines with a norbornane framework, which are interesting rigid analogues of 1,2-diaminocyclohexanes. As a matter of fact, starting from N-acetyl-2-oxo-l-norbornylamine 222, the diamide 223 was obtained with excellent diastereoselectivity and then converted to the M-methyl-N -ethyl derivative 224 by reduction with borane [ 104] (Scheme 34). On the other hand, when the reac-... 

Ihnat and coworkers substituted the primary amine group with a series of gradually increasing alkyl amides 113-119, aromatic amides 120 and 121, succinamide 122 and methylsulfonamide 123 with a systematic increase in partition coefficient (octanoFwater), to increase permeability while retaining iron-chelating ability. The formamide derivative... 

Metal-Nitrogen Compounds The cobalt catalyzed reaction of primary and secondary amines with carbon monoxide leads to the formation of formamide derivatives. Dimethylamine, for example, gives iV,i T-dimethvlformamide in 60% yield (90, 91). Very likely cobalt-nitrogen compounds are intermediates which undergo a CO insertion and then reduction. The following mechanism has been suggested for the reaction (90). 

The unique transformation of formamides to ureas was reported by Watanabe and coworkers [85]. In place of carbon monoxide, formamide derivatives are used as a carbonyl source. The reaction of formanilide with aniline was conducted in the presence of a catalytic amount of RuCl2(PPh3)3 in refluxing mesitylene, leading to N,AT-diphenylurea in 92% yield (Eq. 56) [85]. They proposed that the catalysis starts with the oxidative addition of the formyl C-H bond to the active ruthenium center. In the case of the reaction of formamide, HCONH2, with amines, two molecules of the amine react with the amide to afford the symmetrically substituted ureas in good yields. This reaction evolves one molecule of NH3 and one molecule of H2. 

Since CIgSiH is known to be activated by DMF and other Lewis bases to effect hydrosilylation of imines (Scheme 4.2) [8], it is hardly surprising that chiral formamides, derived from natural amino adds, emerged as prime candidates for the development of an asymmetric variant of this reaction [8]. It was assumed that, if successful, this approach could become an attractive altemative to the existing enzymatic methods for amine production [9] and to complement another organo catalytic protocol, based on the biomimetic reduction with Hantzsch ester, which is being developed in parallel [5]. 

While A-carboxybiotin is responsible for transfer of the carboxyl group, biotin derivatives are not involved in the transfer of more reduced one-carbon units. The next lowest oxidation state at carbon involves the transfer of an aldehyde carboxyl —HC=0. This is equivalent to substitution for the hydroxyl group of formic acid. The leaving group in this case is a derivative of tetrahydrofolate, which contains the carbon as a formamide derivative. Amide resonance is a powerful factor in maintaining the C-N bond. Rotation of the carboxyl out of the plane of the amine will weaken the bond by disruption of resonance. 

McElwee-White and Gerack have developed a metal-free procedure for carbonylation of benzylamines 912 in methanol in the presence of NaI04, producing formamide derivatives 913 in good to excellent yields (Scheme 3.373) [1361]. Secondary amines can also be formylated under these conditions to give respective formamides in 51-58% yields. Labeling experiments have established that CO is the source of the formyl carbonyl, while its hydrogen is derived from the protic solvent. 

Optically active amines can also be generated directly from ketones with ammonium formate in a catalytic version of the Leuckart-Wallach reaction (Equation 15.89). The imine is derived from the ammonia generated from the ammonium formate, and the reducing equivalent is derived from the formate. In the presence of the [Ru(BINAP)Cl2]2 catalyst, the amine and formamide were formed as the major products. After hydrolysis of the formamide, the amine was isolated in high yield and ee. 

Kantlehner et reported the formylation of (hetero)aromatic compounds including unsubstituted and alkyl-substituted aromatics, aromatic ethers, tertiary aromatic amines, fused aromatic rings and thiophenes using new formylating agents (Scheme 1.1) based on formamide derivatives in the presence of Lewis acids. 

Secondary amines do not give the expected /V-TBDMS derivatives under the conditions normally used for similar alcohol protection (Chapter 14). Instead, /V-formamides are produced (3) in good yield through a DMF-derived Vilsmeier intermediate. 

Pr)4, " borohydride-exchange resin,and formic acid. When the last is used, the process is called the Wallach reaction. Conjugated aldehydes are converted to alkenyl-amines with the amine/silica gel followed by reduction with zinc borohydride.In the particular case where primary or secondary amines are reductively methylated with formaldehyde and formic acid, the method is called the Esch-weiler-Clarke procedure. It is possible to use ammonium (or amine) salts of formic acid, " or formamides, as a substitute for the Wallach conditions. This method is called the Leuckart reaction,and in this case the products obtained are often the N-formyl derivatives of the amines instead of the free amines. Primary and secondary amines can be iV-ethylated (e.g., ArNHR ArNREt) by treatment with NaBH4 in acetic acid. Aldehydes react with aniline in the presence of Mont-morillonite KIO clay and microwaves to give the amine. Formaldehyde with formic acid converts secondary amines to the N-methyl derivative with microwave irradiation. 

Whereas condensation of a-hydroxy ketones such as benzoin and acetoin on heating with formamide [240] or ureas in acetic acid [239, 242] to form imidazoles such as 769 or 770 is a well known reaction, only two publications have yet discussed the amination of silylated enediols, prepared by Riihlmann-acyloin condensation of diesters [241], by sodium, in toluene, in the presence of TCS 14 [241, 242]. Thus the silylated acyloins 771 and higher homologues, derived from Riihl-... 

Reductive alkylation can also be accomplished by heating carbonyl compounds at 150-250° with 4-5 mol of ammonium formate, formamide, or formates or formamides prepared by heating primary on secondary amines with formic acid at 180-190° (Leuckart reaction) [322]. An excess of85-90% formic acid is frequently used. Formyl derivatives of primary or secondary amines are sometimes obtained as products and have to be hydrolyzed to the corres-... 

Reactions involving the [4 + 1 + 1] principle, an example of which is shown in equation (136), are rather uncommon and of strictly limited utility [3 + 2 + 1] and [2 + 2 + 2] processes, on th,e other hand, are well known. Representative [3 + 2+1] three-bond formation processes are given in equations (137)—(141), from which it can be seen that the common situation is where ammonia, a substituted amine or formamide constitutes the one-atom fragment. Many [2 + 2 + 2] atom fragment syntheses are known and some are familiar reactions. Thus, the cobalt(I)-catalyzed condensation of nitriles and isocyanates with alkynes gives pyridines and 2-pyridones, often in excellent yield (e.g. equation 142), while the cyclotrimerizations of nitriles, imidates, isocyanates, etc., are well established procedures for the synthesis of 1,3,5-triazine derivatives (e.g. equation 143). Further representative examples are given in equations (144)-(147), and the reader is referred to the monograph chapters for full discussion of these and other [2 + 2 + 2] processes. Examination of the... 

USP482361). Compound 184 is converted into the pyrazolo[4,3- /]-pyrimidine derivative 185 by formamide. Amines convert 184 into carboxamide 186, which affords 187 upon treatment with formamide (78MI1). Reduction of 181 in the presence of formic acid gives the pyrazole derivative 183, which when treated with DMF affords the pyrazolo[4,3-d]pyrimidine derivative 182 (81USP4822361 83FES369). 

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]. 

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