Formamidine synthesis

The primary synthesis of alkoxypyrimidines is exemplified in the condensation of dimethyl malonate with O-methylurea in methanolic sodium methoxide at room temperature to give the 2-methoxypyrimidine (854) (64M207) in the condensation of diethyl phenoxymalonate with formamidine in ethanolic sodium methoxide to give the 5-phenoxypyrimidine (855) (64ZOB1321) and in the condensation of butyl 2,4-dimethoxyacetoacetate with thiourea to give 5-methoxy-6-methoxymethyl-2-thiouracil (856) (58JA1664). 

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. ... 

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>. 

Arginine is the formamidine donor for creatine synthesis (Figure 31-6) and via ornithine to putrescine, spermine, and spermidine (Figure 31-3) Arginine is also the precursor of the intercellular signaling molecule ni-... 

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-... 

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. 

Gawley and coworkers showed that oxazolines can be used in place of formamidines for asymmetric alkylations of tetrahydroisoquinolines. A number of substituted oxazolines were evaluated as chiral auxiliaries, and one derived from valinol was found to be optimal. Interestingly, the same enantiomer of valinol affords the opposite enantiomers of the substituted tetrahydroisoquinoline when incorporated into formamidine or oxazoline auxiliaries. An example is shown in Scheme 58, as applied to a synthesis of laudanosine and the morphinan 9-7 -0-methylflavinantine. ° ... 

Enamines and Formamidines. Enamines, prepared from methylpyridines, methyl-pyridazines, methylpyrimidines or methyltriazine, and A, A -dimethylformamide dimethylacetal or ferf-butoxybis(dimethylamino)methane, react with 2-phenyl-5(4//)-oxazolone 146 to afford the unsaturated 5(477)-oxazolones 199 and 201 that are intermediates in the synthesis of fused pyridones 200 and pyridotriazi-nones 202, respectively (Scheme 7.61). ... 

Despite the extensive use of microwave-enhanced reactions in order to effect syntheses, very little has been explored in the synthesis of thieno[3,2-i pyrimidines. One example of this newer technology being applied to heterocyclic systems involves the conversion of the formamidine 479 into 480 when treated with an amine under high-temperature microwave conditions (Equation 180) <20040L1523>. 

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. 

The scope of the synthesis is greatly widened by the preliminary preparation of the N-halogenoamidines (56), preferably in situ subsequent displacement of halogen by thiocyanate results in the formation of the desired 5-amino-1,2,4-thiadiazoles (58) in good yields (50-80%).6,79, 80 The use of formamidine affords the parent, 5-amino-1,2,4-thiadiazole (58 R = H) while use of AT-methylformamidine (59) leads to 5-imino-4-methyl-Zl4-1,2,4-thiadiazolines (60).81... 

A synthesis of the monoterpene alkaloid ( )-actinidine has been accomplished through the intramolecular cycloaddition of a substituted pyrimidine (81JCS(P1)1909). Condensation of the diester (756) with formamidine provided the pyrimidine precursor (757) which when heated at its melting point (203 °C) underwent cycloaddition with elimination of isocyanic acid to produce the pyridone (758). Conversion of the pyridone into the chloropyridine was effected with phosphoryl chloride. The chlorine atom was then removed by hydrogenoly-sis over palladium on charcoal to afford the racemic alkaloid (759 Scheme 175). 

Substituted amidines are of limited use in the synthesis of symmetric 1,3,5-triazines. Only formamidine or amidines bearing strongly electron withdrawing groups react readily. The proposed mechanism (59JA1466) resembles that of the trimerization of imidates (Scheme 87). 

Because formamidine hydrochloride is extremely deliquescent, considerable care must be exercised in its preparation if satisfactory results are to be achieved. Furthermore, formamidine hydrochloride cannot be used directly in most condensation reactions it must be treated first with a mole of base to liberate free formamidine. The same restriction applies to the metho-sulfate salt of formamidine in addition, complications in synthesis may be anticipated in this latter case because methyl hydrogen sulfate itself is an effective methylating agent.6... 

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). 

Meyers, A. I. Milot, G. a-Alkylation and stereochemistry of cis- and trans-decahydroqui-nolines mediated by the formamidine and Boc activating groups. Synthesis of pumiliotoxin C.J. Am. Chem. Soc. 1993, 335, 6652-6660. Elworthy, T. R. Meyers, A. I. The configurational stability of chiral lithio a-amino carbanions. The effect of Li-O vs Li-N complexa-tion. Tetrahedron 1994, 50, 6089-6096. 

Method I is based on reactions giving rise to the pyrimidine ring by N(3)-C(4) bond formation. Generally, cyclization is preceded by the formation of one more bond, for example, of C(2)-N(3). For instance, the reaction of formamidine 104 with MeNH2 provides a convenient approach to the synthesis of pyridothienopyrimidine 105 (1997KFZ18). 

As an intermediate in the synthesis of acetals, aldehydes, esters, formamidines, peptides and nitriles.. 

Chiral formamidines, derivatives of N-heterocycles in asymmetric synthesis 92T2589. 

Formamidines also activate secondary centres towards lithiation, and have been used extensively in the synthesis of the benzylisoquinolines, where the lithiation takes place at a benzylic position. Formamidines bearing chiral substituents (for example the serine-derived 85) allow the introduction of asymmetry at such centres.58... 

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