Formamidine acetate

Formamidine acetate [3473-63-0] M 104.1, m 159-161"(dec), 164 (dec), pK j( 12. Unlike the hydrochloride, the acetate salt is not hygroscopic. It is recrystd from a small volume of acetic acid, by addition of EtOH and the crysts are washed with EtOH then Et20 and dried in a vac. [Taylor, Ehrhart and Karanisi Org Synth 46 39 7966.]... 

These thiazoles are of specific interest in that they display exceptional pharmacological properties. Additionally, the unsaturated 2-aminonitrile functionality of the above thiazoles is recognized for its versatile functionality and therefore for its ensuing significance in the synthesis of heterocycles. The synthetic utility of thiazoles 13a-f is illustrated by the reactions of the unsaturated 2-aminonitrile functionality in compounds 13b and 13c with formamidine acetate, resulting in the thiazolopyrimidines 14a and 14c respectively. The synthesis of this relatively rare family of heterocycles provides a route into structurally similar bioactive compounds. ... 

Because silylation with HMDS 2/TCS 14 in acetonitrile at ambient temperature converts the unreactive a-chloroketone moiety of 743 into an /Z-mixture of reactive alkyl 4-chloro-3-trimethylsilyloxycrotonates 746a, b [230, 231] which can be isolated and distilled, if humidity is excluded, silylation of 743a, b in the presence of ami dine salts such as 745 gives the desired ethyl or methyl imidazole(4,5)-acetates 748a, b via IMz and 747b. The reaction of formamidine acetate with 746a,b affords 745 (with R=H) in up to 70% yield [232, 233] (Scheme 5.79). As side reactions one must, e.g., take into account the reaction of 746 with ammonia to give 755 which subsequently dimerizes to the pyrazine 756, as discussed in Section 5.5.3. 

Two methods are available for the synthesis of 8-C-gly-cosyladenines. A particularly mild method consists in the treatment of 5-amino-4-cyano-2-C-glycosylimidazoles, such as 289a, with formamidine acetate.214 In this way, Igolen and coworkers208,209,211 prepared the C-nucleosides 296 and 299. An alternative synthetic approach to this class of compound involves the treatment of a 2,5-anhydrohexonic acid (such as 15 or 129) with 4,5,6-triaminopyrimidine, followed by cyclization to the nitrogen he-... 

Likewise 3-amino-2-cyano-4-(3-methoxyphenyl)-A -carboethoxypyrrole is converted into 7-(3-methoxyphenyl)-pyrrolo[3,2- pyrimidin-4-one by, first decarboxylation, and then cyclization in refluxing formic acid <2006BMCL2091>. Replacing the 3-methoxyphenyl group on the pyrrole with a reduced pyrrole (a mimic of a ribofuranose ring) leads to a 4-aminopyrrolo[3,2- pyrimidine when treated with formamidine acetate <2006BMCL2662>. 

Cycloaddition of 2-amino-3-cyano-4,5,6-trisubstituted pyridine 360 with formamidine acetate in the presence of diglyme produced the 4-pyridopyrimidinylamine 361 as its hydrochloride salt (Equation 30) <2000USP6030969>. 

Cyclocondensation of ethyl 2-aminonicotinate in presence of HC(OEt)3 and various primary amines gave 22 3-substituted pyrido[2,3-,7]pyrimidin-4(377)-ones 371 <1995PHA719>. Fourteen 3,5,7-triarylpyrido[2,3-r7]pyrimi-dine-2,4(l/7,37/)-diones 372 have been prepared from the reaction of either 2-amino-3-cyano-4,6-diarylpyridines or the 3-carboxamido products of alcoholic KOH hydrolysis, with aryl isocyanates better yields were obtained from the amides <1995IJB740>. 4-Aminopyrido[2,3- pyrimidin-5(8//)-one 158 was synthesized by treatment of 2-amino-3-cyano-4-methoxypyridine with trimethylsilyl iodide to give the corresponding pyridin-4(177)-one, which was refluxed with formamidine acetate in ethoxyethanol to effect the cyclization <2000JME3704>. 

Cyclization of either nicotinic acid derivatives 597 by heating with neat formamide (170°C/16h) <2004TL3737> or 598 with formamidine acetate in ethanol (100°C/20h) <2004TL3737> gave the correspondingpyrido[4,3-<7 pyrimidin-4(3//)-one derivatives 599 and 600 (Equation 49). 

The synthesis of 6-substituted derivatives 626 was achieved via reaction of 2-substituted-5-aminopyridine-4-car-boxylic acids and formamidine acetate in boiling 2-methoxyethanol <1996J(P1)2221>. The pyrido[3,4- lpyrimidinone 628 was prepared by amination of the thioureido derivative 627 with diisopropylamine followed by cyclization in boiling DMF <2004FRP2846657>. Pyridine 627 was prepared from the corresponding 3-amino derivative with ethoxycarbonyl isothiocyanate in DMF. 

MI1). The proposed route involves photoisomerization of DAMN to 9, followed by addition of another mole of HCN to give adenine. Adenine can also be prepared by oligomerization of HCN in liquid ammonia in 24% yield and from DAMN and formamidine acetate in 55% yield (72USP3671649). In a definitive paper, Shuman et al. show that 10, as well as 9, is an intermediate to adenine in the nonphotochemical route (Scheme 3) (79JOC4532). 

Formamidine acetate (117) reacts with the pyrrole (118) in refluxing ethoxyethanol to give the pyrrolopyrimidine (119) which has been converted into the antibiotics toyocamycin, sangivamycin and tubercidin (Section 3.09.5) (69JA2102). A reaction with carbon disulfide... 

Different substrates have been tested under the following conditions 300 ml stainless steel autoclave 0.25 moles of substrate 2.0 g Raney nickel (60% in water) 1.5 g (0.014 moles) of formamidine acetate 120 ml methanol temperature 80°C H2 pressure 12 bar, 1500 rpm. 

The halonitro compounds and the methanol used were of purum or pract. quality from Fluka. The amidine derivatives (in the form of their salts) were purchased from Fluka or Aldrich (purum or pract.). The N,N-dialkyl-formamidine acetates were prepared by analogy to a published procedure (ref. 8) from cyanamide and used as isolated (containing ca. 10% ammonium acetate). 

Some results of this inhibitor screening are summarized in Table 1. It is immediately clear that formamidine acetate and its N-alkylated derivatives are good dehalogenation inhibitors. The selectivity achieved is comparable to that of dicyandiamide while the hydrogenation time observed is considerably lower. Compared to the unmodified system, the other inhibitors do not show a significantly improved selectivity but have a positive effect on the activity. 

Reaction time time and chemoselectivity for the hydrogenation of different substrates (formamidine acetate Raney nickel methanol 80°C 12 bar)... 

Figures 2a-d show plots of catalyst potential and substrate concentration (GLC) versus hydrogen consumption for the hydrogenation with formamidine acetate (a), with dicyandiamide (b), with guanidine acetate (c) and without modifier (d). This type of presentation allows to standardize and to compare reactions with different reaction times, which are indicated at the upper edge of the graphs. As expected by analogy with the results reported for the unmodified nickel catalysts (ref.9), no dehalogenation is observed as long as either nitro compounds or partially reduced intermediates are present in solution.

Amidine derivatives are effective dehalogenation inhibitors for the chemoselective hydrogenation of aromatic halonitro compounds with Raney nickel catalysts. The best modifiers are unsubstituted or N-alkyl substituted formamidine acetates and dicyandiamide which are able to prevent dehalogenation even of very sensitive substrates. Our results indicate that the dehalogenation occurs after the nitro group has been completely reduced i.e. as a consecutive reaction from the halogenated aniline. A possible explanation for these observations is the competitive adsorption between haloaniline, nitro compound, reaction intermediates and/or modifier. The measurement of the catalyst potential can be used to determine the endpoint of the desired nitro reduction very accurately. 

As the temperature decreases gradually, vigorous refluxing is observed (Note 4). Formamidine acetate starts to crystallize from the boiling mixture after 20-30 minutes. The ammonia flow is continued until no further decrease in temperature is observed (Note 5). The mixture is cooled to room temperature, the precipitate collected by filtration and washed thoroughly with SO ml. of absolute ethanol. The yield of colorless formamidine acetate is 53.0-55.8 g. (83.8-88.2%), m.p. 162-164° (Note 6). Evaporation of the mother liquor under reduced pressure followed by chilling gives a small additional amount of product (1.0-2.2 g.) (Note 7). 

By contrast, formamidine acetate is not hygroscopic and no particular care need be taken to protect it from atmospheric moisture. Furthermore, formamidine acetate can be used directly without prior treatment with base in syntheses requiring free formamidine.8,7-10 Finally, this preparation of formamidine is by far the simplest and most convenient yet reported it obviates the necessity of using either toxic (hydrogen cyanide) or cumbersome (Raney nickel) reagents, and the method can be adapted to the preparation of N,N -disubstituted formamidines by substitution of primary amines for ammonia.11... 

Among the important reagents for which preparative procedures are given are 2,2 -bipyridine (by nickel directed and catalyzed dehydrogenation of pyridine p. 5), formamidine acetate (p. 39), phenyltrichloromethylmercury (p. 98), and trimethyl- and triethyloxonium fluoroborate (pp. 120, 113). The preparation of palladium catalyst ( Lindlar ) for the selective reduction of acetylenes is described (p. 89), as is the use of di-phenyliodonium-2-carboxylate, as a precursor of benzyne in the synthesis of 1,2,3,4-tetraphenylnaphthalene (p. 107). 

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