Formamide, derivatives

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. 

With optically active formamide-derived aminocarbene complexes high enantioselectivity was observed in most cases (Table 5). This chemistry was used in the synthesis of 1-carbacephalathin and 3-ANA precursors (Eq. 9) [48], as well as the synthesis of a,a -disubstituted amino acids (Scheme 1) [49]. 

A similar rotational analysis has been done with formamide derivatives. It is known that thioformamide has a larger rotational barrier than formamide, which can... 

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-... 

The Jacobsen group has also shown that the recycling of the resin-bounded catalyst can be successfully performed [152,154]. Moreover, they have developed an efficient method for the hydrolysis of the aminonitrile into the corresponding amino acid. This method was apphed for the commercial production of optically active K-amino acids at Rhodia ChiRex (e.g. tert-leucine) the catalyst was immobihsed on a resin support (4 mol %, 10 cycles) and the intermediate hydrocyanation adduct was trapped by simply replacing TFAA with HCOOH/AC2O, for example. Highly crystalhne formamide derivatives were thus obtained in excellent yields (97-98% per cycle) with very high enantioselectivities (92-93% per cycle) [158]. 

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... 

Some studies seeking preferred conditions for this reaction have been made. Optimum yields are obtained when the amount of water present is appreciable, and it was noted that the rate of hydrogen evolution increases with increasing water content. A 75% formic acid system appears generally preferred. Under the reaction conditions examined by the submitters, olefins, ketones, esters, amides, and acids are inert, but nitro compounds are reduced to 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). 

It is therefore not possible to form the anti-amide 208 unless conformational changes at the nitrogen are allowed. It is however reasonable to make such an assumption for formamide-derived tetrahedral intermediates (cf p. 112). We can therefore analyze the cleavage of a tetrahedral conformer such as 213. This conformer can either give the anti or the syn-amide isomers (208 and 209) with stereoelectronic control. It is however not clear on that basis, why the formation of the less stable anti form 208 is favored. There must be another parameter in this case which is not known yet. 

Formamides derived from L-pipecolinic acid act as Lewis base organocatalysts for reduction of A-arylimines with trichlorosilane, giving yields and ees in the high 90s for a wide range of imine substrates.54... 

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. 

Compounds (20), (22), and their methyl derivatives can be synthesized from the appropriate thienyl formamide derivative, as illustrated in Equation (18) <76BSF883>. In analogous reactions, seleno[2,3-6]-, seleno[3,2-6]pyridine and their methyl derivatives can be prepared. 

A similar conformational analysis has been done with formamide derivatives, with secondary amides, and for hydroxamide acids. It is known that thioformamide has a larger rotational barrier than formamide, which can be explained by a traditional picture of amide resonance that is more appropriate for the thioformamide than formamide itself. Torsional barriers in a-keto amides have been reported, and the C—N bond of acetamides, thioa-mides, enamides carbamates (R2N—C02R), and enolate anions derived... 

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]. 

Figure4.1 Formamides derived from cyclic amino acids as catalysts forthe asymmetric reduction of imines.

Orienting experiments were carried out with the benzotriazole derivative 19a. Initially, the use of a substoichiometric amount (0.2 equiv) of DBNE in toluene afforded the N-(l-phenylpropyl)amide 20a in only 13% ee. In the presence of an equimolar mixture of 19a and DBNE 18, the amide 20a was isolated in 14% yield and 55% ee. It is important to note that no ethyl addition occurred at -78 °C. With 3 equiv of Et2Zn, and 1 equiv of DBNE, the amide 20a was isolated in 46% yield, and 76% ee. With these optimal conditions (>2 g of benzotriazole derivative, ca. 0.25 M), the reactivity of the other substrates 19b-g was examined. In these cases, the excess of Et2Zn was found to have no additional effect, and 2 equiv of Et2Zn was employed. With the exception of the formamide derivative 19f, all the other substrates afforded the corresponding amides 20b-e,g, with however a wide range of chemical yields (5-96%) and with moderate enan-tioselectivities (0-42% ee). The absence of selectivity observed for 19e was attributed to steric hindrance. 

The relationship between the formylation reactions carried out with formamide derivatives and the formation of ketones when using amides of other carboxylic acids has been pointed out. The method has not been as widely exploited as one might have expected. A -Methylacetamide and N,N-dimethylaceta-mide both give substituted acetophenones when they are allowed to interact with phosphoryl chloride in the presence of nucleophilic benzene derivatives. The initial product has to be hydrolyzed. Similarly, benzamide derivatives give substituted benzophenones as exemplified in equation (62). 

Formamide derivatives can sometimes be replaced with other amides, and examples include N,N-di-methylacetamide (DMA), V-methylpyrrolidone and VA -dimethylbenzamide. The resulting chloromethyleneiminium salts react with suitable nucleophiles yielding iminium salts, but self-condensation reactions are frequently encountered when proton loss from the iminium salt can occur. This is illustrated in Scheme 2 for DMA. 

A large number of acid chlorides have been used to convert formamide derivatives into their corresponding chloromethyleneiminium salts (13). These include POCI3 (the most popular), SOCI2, phosgene, oxalyl chloride and many others. 

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. 

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