Formamidines production

In many cases, the a-haloketone does not appear to be an intermediate in this reaction, since reagents such as sulfur trioxide, sulfuric, or 60% nitric add lead to 2-aminothiazole but with lower yields (11 to 43%). Formamidine disulfide [-S-C(=NH)NH2]2, a product of the oxidation of thiourea, seems to be the intermediate in this reaction, since upon treatment with ketones, it gives 2-aminothiazole (604). However, the true mechanism of this reaction has not yet been completely elucidated. 

Typically, an acetanilide (1 mol. equiv.) was treated with the Vilsmeier reagent generated from POCI3 (7 mol. equiv.) and V,V-dimethylformamide (DMF, 2.5 mol. equiv.) at 75 °C for 4 - 20 h. The reaction products were readily obtained by filtration after pouring the reaction mixture onto ice-water minor reaction products were isolated after basification of the filtrate. A variety of acetanilides were studied under these optimised reaction conditions and some significant observations were noted. Activated acetanilides 3 [e.g. R = 4-Me (70%), 4-OMe (56%)] reacted faster and in better yield to give quinolines 4 than other strongly deactivated systems 3 [e.g. R = 4-Br (23%), 4-Cl (2%), 4-NO2 (0%)] — in these cases, formamidines 5 and acrylamides 6 were the major reaction products. 

However, Sahasrabudhey thinks that the compound formed from 5-amino-1,2,3,4-thiatriazole does not have the composition CSN2H3CI, but (CSN2H4C1)2, and is in fact the dihydrochloride of formamidine disulfide, the oxidation product of thiourea. This con-... 

The heavy alkaline earth metals Ca, Sr, and Ba react with 2 equivalents of NJ -bis(2,6-diisopropylphenyl)formamidine in the presence of bis(pentafluorophenyl)-mercury to afford the bis(formamidinato) species as THF adducts in good to moderate yield (Scheme 23). When the same reactions are carried out in a 1 1 molar ratio, N-p-tetrafluorophenyl-N,N -bis(2,6-diisopropylphenyl)formamidine is isolated as the sole product in all cases (Scheme 23). Other substituted N -bis(aryl)formamidinate complexes of the heavy alkaline earth metals were synthesized accordingly. ... 

Continuing his studies on the metallation of tetrahydro-2-benzazepine formamidines, Meyers has now shown that the previously unsuccessful deprotonation of 1-alkyl derivatives can be achieved with sec-butyllithium at -40 °C <96H(42)475>. In this way 1,1-dialkylated derivatives are now accessible. The preparation of 3//-benzazepines by chemical oxidation of 2,5- and 2,3-dihydro-l/f-l-benzazepines has been reported <96T4423>. 3Af-Diazepines are also formed by rearrangement of the 5//-tautomers which had been previously reported to be the products of electrochemical oxidation of 2,5-dihydro-lAf-l-benzazepine <95T9611>. The synthesis and radical trapping activities of a number of benzazepine derived nitrones have been reported <96T6519, 96JBC3097>. 

Finally, Odom and co-workers reported a titanium-catalyzed three-component coupling between primary amines, alkynes, and isonitriles for the preparation of a, 3-unsaturatcd /3-iminoamines in good yields (Scheme 35).121 Beside the three-component coupling product, an. V,.V-disubstituted formamidine and an imine were also identified as minor... 

Needless to say, it would be interesting to apply the same type of chemistry described in Figure 2 for the methylcarbamate esters to the synthesis of derivatives of the formamidine insecticides. However, additional work with the formamidines, particularly those related to chlordimeform, has been discouraged because of the mutagenic and carcinogenic potential of the aryla-mine metabolic products. 

The mechanism of this sequence is enlightening when contrasted with the mechanism of the formamidine auxiliary (Scheme 56). Scheme 59a illustrates the results of some deprotonation-alkylation experiments on deuteriated diastereomers. ° ° Two features of the product of these experiments were examined the diastereomer ratio and the percent deuterium incorporation. The deuterium incorporation in the product reveals that there is a preference for removal of the -proton. When deuterium is in the -position, this selectivity is opposed by the isotope effect, and the product has about half the original deuterium remaining. When deuterium is in the a-position, the selectivity for the -proton (imposed by the chiral auxiliary) and the isotope effect act in concert, and virtually all the... 

Isoindole is an interesting precursor for successive alkylations at the a- and a -positions because both are benzylic. Oxazoline ° and formamidine auxiliaries have been used to accomplish the a,a -dialkylation to give a C2-symmetric amine. The C2-symmetric amine products are envisioned as possible tools for a variety of asymmetric processes. The diastereoselectivity of the second alkylation is enhanced by the presence of the stereocenter formed in the first alkylation (Scheme 61). ° Several other electrophiles were evaluated with the formamidine auxiliary. ... 

Reaction between 79 and formamidine (Scheme 25) gave not 5-methyl-adenine (105), but a rearranged product (106). MINDO/3 calculations show that the two rings in 105 deviate considerably from coplanarity, with loss of conjugation and introduction of strain. Computed bond distances and... 

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>. 

Diphenylacetylene has also been reacted with iodouracil 431 having a formamidine moiety under similar conditions to afford the dehydrogenated product 432 and the deaminated product 433 via intermediates 435 and 436, respectively. The selectivity increased in the presence of lithium chloride, whereby 93% of 432 with a trace amount of 433 were obtained. The lithium cation prevents the insertion of palladium into intermediate 434 to form intermediate 436, which is necessary to form 433. The reaction of 431 with asymmetric acetylenes in the presence of lithium chloride afforded the dehydrogenated pyridopyrimidines 437 and 439. However, reaction of 422 with acetylenic compounds in the absence of lithium chloride afforded the deaminated pyridopyrimidines 438 and 440 (Equation 37) <2000TL5899>. 

N-Pbenyl-N -f Nitropbenyh-formamidine, yel crysts (from toluene St then from ale), mp 181—85° was obtd when p-nitroaniline ethyl-N-phenylformami date, [HC( N.C6H5)OC2H5] were heated in a distilling flask at 180° for 2 hrs, and the mixt poured while hot intp dry toluene, pptg the product which was collected and recrystd... 

A typical example of the reaction of isocyanates with formamidines is shown in equation (92). Alkyl isocyanates can react in a similar way, but there can be mixed products formed under certain circumstances, as in the reaction of methyl isocyanate with N,N- dialkyl-N 1-arylformamidines (166). The predicted product (167 equation 93) is formed except when AT,AT-dimethyl-N-arylformamidines are used. In the latter case a mixture of (168) and (169) is formed (equation 94). The mechanism of the formation of (169) is shown in Scheme 104 (73HCA776). 

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). 

Trimethyl si lyl-Lo-acetonitrile has been shown to be highly versatile in the presence of cuprous chloride. Amines lead to formamidines through the insertion into their N-H bond whereas alcohols lead to desilylation products (see Section VLB).292... 

Treatment of compound (192) with sodium hydroxide in DMSO gives the pyrimidine (196). It is most likely that this product (1%) is formed via addition of water to the C=N bond adjacent to the benzoyl group (Scheme 12). This affords the formamidine (193) which undergoes benzylic-like rearrangement to the acid (194) which cyclizes (194) - (195). Decarboxylation and N—N bond cleavage in the pyrazole moiety gives the final isolable product (196) <83CPB395i>. 

A variety of amidines react with nitromalonaldehyde in presence of Triton B or piperidine, to form the 5-nitropyrimidines 116 [Eq. (37)].106-110 Yields range from 30 to 90%. Acetamidine gives a very poor yield of the nitropyrimidine and formamidine does not give any isolable product. 

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