Formamides synthesis

In addition to the processes mentioned above, there are also ongoing efforts to synthesize formamide direcdy from carbon dioxide [124-38-9J, hydrogen [1333-74-0] and ammonia [7664-41-7] (29—32). Catalysts that have been proposed are Group VIII transition-metal coordination compounds. Under moderate reaction conditions, ie, 100—180°C, 1—10 MPa (10—100 bar), turnovers of up to 1000 mole formamide per mole catalyst have been achieved. However, since expensive noble metal catalysts are needed, further work is required prior to the technical realization of an industrial process for formamide synthesis based on carbon dioxide. 

This overall reaction is already carried out industrially via the intermediate forma-mide (HCONH2) which, together with the use of disparate operating conditions (high pressures and mild temperatures for formamide synthesis, vacuum and high temperatures for its decomposition), overcomes the unfavorable thermodynamics of... 

Formamide Process. The formamide process was developed by several companies, but in 2001 it was only used by BASF. The process involves the following steps 46 (1) methyl formate synthesis, (2) formamide synthesis, and (3) HCN formation/dehydration. 

Another formamide synthesis was described by Kiso 172) where DMF, HCONPrj and HCONHMe were prepared by treating the corresponding amines with CO2 and in the presence of a ruthenium(II)phosphine complex, e.g. RuHi(PPh3>4. 

It is convenient to combine these two synthetic approaches because they are formally similar. Both condense an a-functionalized ketone or aldehyde (C-4-C-5 synthon) with an amine or ammonia (N-1, N-3) and an aldehyde (C-2). "Die alternative Bredereck modification uses formamide as the source of the C-2-N-3 bond and of N-1. The older (Radziszewski or Weidenhagen) methods give 4-mono-, 4,5-di- and 2,4,5-trialkyl or -triaryl imidazoles the Bredereck formamide synthesis is largely restricted to the preparation of imidazoles with no 2 substituent. 

Bredereck s [456] reagent, dime- pyrazole thyl formamide synthesis dimethyl acetal (solvent 50 mh for 5 g resin)... 

These reactions are typified by Bredereck s formamide synthesis . This has been applied to the synthesis of 4,5-dimethylimidazole (as its formic acid complex) from acetoin and formamide <91JHC1819>. A similar reaction leads to 5-methylhistamine (243) <8lJHC83l>. 1-Hydroxyimidazoles are accessible in high yield from reaction of nitrosonium fluoroborate with acetonitrile and appropriate alkenes (Scheme 177) <84TL1319>. 

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),... 

Probably the most valuable advance in the field of oxazole syntheses has come from the methods developed by Bredereck and his co-workers.92-94 The so-called formamide synthesis of Bredereck et al. involves, especially in this case, the interaction of a-halo ketones with formamide and usually results in high yields of oxazoles (50-70%). 

While the base-catalyzed carbonylation of methanol yields methyl formate, a versatile intermediate for formic acid and formamide synthesis, the transition metal-catalyzed carbonylation involves C—C coupling, giving acetic acid derivatives as C2 oxygenates. 

Scheme 12.26 Formamide synthesis of chiral amines with loss of enantiopurity.

Figure 12.4 Formamide synthesis via methanol dehydrogenation proposed mechanism.

Dear readers please take notice Not once has the flask left the stirplate since the formamide and P2P reaction started up to the last point where MDA freebase was liberated. That s pretty damn convenient. Technically, the Leuckart reaction can continue as a one pot synthesis from the last part of P2P cleanup right up to final product. 

Ai,A/-bis(hydroxymethyl) formamide [6921-98-8] (21), which in solution is in equiUbrium with the monomethylol derivative [13052-19-2] and formaldehyde. With ben2aldehyde in the presence of pyridine, formamide condenses to yield ben2yhdene bisformamide [14328-12-2]. Similar reactions occur with ketones, which, however, requite more drastic reaction conditions. Formamide is a valuable reagent in the synthesis of heterocycHc compounds. Synthetic routes to various types of compounds like imida2oles, oxa2oles, pyrimidines, tria2ines, xanthines, and even complex purine alkaloids, eg, theophylline [58-55-9] theobromine [83-67-0], and caffeine [58-08-2], have been devised (22). 

However, BASF developed a two-step process (25). After methyl formate [107-31-3] became available in satisfactory yields at high pressure and low temperatures, its conversion to formamide by reaction with ammonia gave a product of improved quaUty and yield in comparison with the earlier direct synthesis. 

Two-Step Process. The significant advantage of the two-step process is that it only requkes commercial-grade methyl formate and ammonia. Thus the cmde product leaving the reactor comprises, in addition to excess starting materials, only low boiling substances, which are easily separated off by distillation. The formamide obtained is of sufficient purity to meet all quaUty requkements without recourse to the costiy overhead distillation that is necessary after the dkect synthesis from carbon monoxide and ammonia. 

The estimated capacity of formamide was approximately 100,000 t/yr worldwide in 1990. In 1993, there are only three significant producers BASE in Germany is the leading manufacturer. Smaller quantities of formamide are produced in the former Czechoslovakia (Sokolov) and Japan (Nitto) by direct synthesis from carbon monoxide and ammonia. Most of the formamide produced is utilized direcdy by the manufacturers. The market price for formamide (ca 1993) is about 2.00/kg. 

Aromatic and heterocycHc compounds are formylated by reaction with dialkyl- or alkylarylformamides in the presence of phosphoms oxychloride or phosgene (Vilsmeier aldehyde synthesis) (125). The Vilsmeier reaction is a Friedel-Crafts type formylation (126), since the intermediate cation formed by the interaction of phosphoms oxychloride with formamide is a typical electrophilic reagent. Ionic addition compounds of formamide with phosgene or phosphoms oxychloride are also known (127). 

The synthesis from phthalimide derivatives, eg, diimidophthalamide (or phthalimide [85-41-6]) is usually carried out in a solvent such as formamide. 

Oxazoles are also obtained by the reaction of a-halogenoketones (78) with primary amides (the Bliimlein-Lewy synthesis), and this method is particularly appropriate for oxazoles containing one or more aryl groups as in (79). Formamide may also be used in this process, resulting in a free 2-position in the oxazole, and when a urea derivative (80) is used, 2-aminooxazoles (81) are formed (80ZOR2185, 78IJC(B)1030, 78JIC264). Numerous applications of these procedures are described in Chapter 4.18. 

Finally, some results obtained from indazoles substituted in the carbocycle are of interest, even though in these cases the reaction does not involve the heterocyclic moiety (Section 4.04.2.3.2(ii)). For example, pyrazolo[3,4-/]- (566) and pyrazolo[4,3-/]-quinolines (567) have been obtained from aminoindazoles by the Skraup synthesis (76JHC899). Diethylethoxy-methylenemalonate can also be used to give (566 R = C02Et, R = OH) (77JHC1175). Pyrazolo-[4,3-/]- and -[4,3-g]-quinazolones (568) and (569) have been obtained from the reaction of formamide with 5-amino-4-methoxycarbonyl- and 6-amino-5-carboxyindazole, respectively (81CB1624). 

ATHERTON TODD Phosphoramidate Synihasis Synthesis of phosphoramidates from formamides and dialkyl phosphite. 

The product can be recrystallized readily from dimethyl-formamide to give yellow leaflets, m.p. 290-293°. However, it is pure enough to be used in the next step. This synthesis has also been applied to the preparation of l,4-bis-[4-( -tolyl)buta-dienyljbenzene (100%), l,4-bis-[4-(3-nitrophenyl)butadienyl]-benzene (56%), and l,4-bis-(3-methyl-4-phenylbutadienyl)ben-zene (87%). 

One approach is to uses solvent extraction with dimethyl formamide (DMF) to remove Cj acetylene and a C, acetylene-propadiene mixture from their steam cracked ethylene and propylene streams. The simple acetylene is sold as welding gas, and the C, stream is sold as starting material for chemical synthesis. 

The condensation of a vinylogous formamide with an enamine has been applied to an aza azulene synthesis (351). The point of attachment of the aldehyde to the enamine in condensations with indolenin derived poly-enamines was found to favor the second double bond (352,353). 

The Batcho-Leimgruber indole synthesis involves the condensation of o-nitrotoluene derivatives 1 with formamide acetals 2, followed by reduction of the trans-p-dimethylamino-2-nitrostyrene 3 which results to furnish indole derivatives represented by... 

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