Guanidine intermediates

When o-aminocarbonitriles 48 (R2 = R3 = Me) or 52 were reacted with jY-arylcyanamides in the presence of dry hydrogen chloride gas followed by aqueous workup, a mixture of 2-amino-3-aryl-4-iminothieno[2,3-d]-pyrimidines 65d and the corresponding thieno[2,3-d]pyrimidin-4(3//)-ones 66b was isolated. The formation of the latter as a minor product for each derivative was rationalized to proceed via the guanidine intermediate 67, which hydrolyzed through a Ritter-type reaction and then cyclized during workup (93JHC435). 

Highly nitrogenous heterocycles such as l,2,4-triazolo-l,3,5-triazines have been shown to rearrange upon treatment with excess base. 5,7-Bis(dimethylamino)-3-(methylthio)-l,2,4-triazolo[4,3-a][l,3,5]triazine 51 was isomerized to 53 via isolatable guanidine intermediate 52 in the presence of excess anhydrous dimethylamine, pyrrolidine or aniline in absolute ethanol at 85 This reaction was also shown to go forward under acidic conditions, although a mixture of 52 and 53 was recovered in the process. 

Moura S, Pinto E (2010) Synthesis of cyclic guanidine intermediates of anatoxin-a(s) in both racemic and enantiomerically pure forms. Synlett 967-969. doi 10.1055/s-0029-1219559... 

Starting from dipeptide loaded MBHA resin643 and after exhaustive reduction with the borane-THF method, triamine 644 was treated with Dde-OH in DMF or Trt-Cl along with DIEA in DCM DMF (9 1) to protect the primary amine in 645 (Scheme 9.75). Treatment of this with 10 equiv of BrCN under N2 in DCM gave the guanidine intermediate 646, which... 

The required triamino-4(3H)-pyrimidinone is prepared in three steps starting from guanidine [50-01-1] (14) (26). Condensation with methylcyanoacetate [105-34-0] (15) under basic conditions, followed by nitrosation of the intermediate [56-06-4] (16), gives... 

The 6-methyl derivative (98, R = Me) was an important intermediate in the synthesis of analogs (e.g., 183) of folic acid. Korte has shown that 2-aminopyrido[3,2-guanidine carbonate with 3-aminopicolinic acid and that treatment of the same acid with ammonium thiocyanate or potassium cyanate yields the thioureido and ureido derivatives (100, X = S and X = 0). In contrast to the pyrido[2,3-d]pyrimidine system bsoth of these compounds could be cyclized by heat and the latter (100, X = O) is a likely intermediate in the synthesis of the dione (98) by the fusion with urea. 

In a similar way, 3-amino-1,2,4-triazino[6,5-c]quinoline 4-oxides 127 were synthesized by the reaction of 4-chloro-3-nitroquinoline 128 with guanidine, followed by the cyclization of intermediate arylguanidines under basic conditions (81JHC1537). 

The guanidine function, when attached to an appropriate lipophilic function, often yields compounds that exhibit antihypertensive activity by means of their peripheral sympathetic blocking effects. Attachment of an aromatic ring via a phenolic ether seems to fulfill these structural requirements. Alkylation of 2,6-dichlorophenol with bromochloroethane leads to the intermediate, 58. Alkylation of hydrazine with that halide gives 59. Reaction of the hydrazine with S-methylthiourea affords the guanidine, guanoclor (60). ... 

An early application of this reaction to the preparation of barbiturates starts by the condensation of the ketone, I21, with ethyl cyanoacetate by Knoevenagel condensation. Alkylation of the product (122) with ethyl bromide by means of sodium ethoxide affords 123. Condensation of this intermediate with guanidine in the presence of sodium ethoxide gives the diimino analog of a barbiturate (124). Hydrolysis affords vinbarbital (111). > ... 

Reaction of 2,3-dichlorobenzoyl chloride with cyanide ion leads to the corresponding benzoyl cyanide (141). Condensation of that reactive intermediate with aminoguanidine 142 leads to the hydrazone-like product 143. Treatment with base results in addition of one of the guanidine amino groups to the nitrile function and formation of the 1,2,4-triazine ring. The product, lamo-trigine (144), is described as an anticonvulsant agent [31]. 

The 5-methyl-5-ethyloxazolidine-2,4-dione may be prepared by reacting methyl ethyl ketone with sodium cyanide and with ammonium thiocyanate followed by desulfurization. This intermediate may also be prepared by condensing a-hydroxy-a-methylbutyramide with ethyl chlorocarbonate or by condensing ethyl a-hydroxy-a-methylbutyrate with urea. Another method described (Traube and Aschar, Ber., 46, 2077-1913) consists in the condensation of ethyl a-hydroxy-a-methylbutyrate with guanidine followed by hydrolysis. 

The reaction of N-amino heterocycles 759 and 760 with diaryl carbodii-mide gave triazolotriazine 761 in good yield. In some cases the intermediate guanidines are isolated which by thermal or basic treatment cyclized (86H3363 89H1607) to neutral or mesoionic compounds. 

As yet, a number of experiments have failed to convert ureas 205 such as N-phenylurea or imidazolin-2-one by silylation amination with excess amines R3NHR4 such as benzylamine or morpholine and excess HMDS 2 as well as equivalent amounts of NH4X (for X=C1, I) via the silylated intermediates 206 and 207 in one reaction step at 110-150°C into their corresponding guanidines 208 with formation of NH3 and HMDSO 7 [35] (Scheme 4.13). This failure is possibly due to the steric repulsion of the two neighbouring bulky trimethylsilyl groups in the assumed activated intermediate 207, which prevents the formation of 207 in the equilibrium with 206. Thus the two step Rathke-method, which demands the prior S-alkylation of 2-thioureas followed by amination with liberation of alkyl-mercaptans, will remain one of the standard syntheses of guanidines [21, 35a,b,c]. 

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