Amidines phosphorus

Fusion of an additional heterocyclic ring onto that already present in the benzodiazepines has led to some medicinal agents with considerable activity. Treatment of an intermediate like 15 with phosphorus pentasulfide affords the corresponding thio-amide (37). Condensation of this intermediate with acetyl hydra-zide affords triazolam )37). The same agent can be prepared by reaction of the amidine, 38, ° with acetylhydrazide. ... 

Fusion of an additional heterocyclic ring onto a benzodiazepine is well known to considerably increase potency. This increase in potency is apparently maintained when the benzene ring is replaced by thiophene. Thiophene aminoketone 161 is converted to the benzodiazepine analogue 164 via chloroacetamide 162 and then glycine derivative 163 by the same sequence as that used in the benzene series. Treatment of the product 164 with phosphorus pentasulfide gives the thio-amide 165 reaction of that intermediate with hydrazine leads to the amino amidine 166. Conden-... 

An n.m.r. study of the permutational isomerisations within a series of amidium fluorophosphates (133) has revealed an irregular mechanism with dissociation of the P-N and also the P-0 bonds of the bidentate ligands and the formation of five-coordinate intermediates (134)61. Reversible intramolecular migrations of pentaco-ordinate phosphorus in the N-C-N triad of amidines (e.g. 135, 136,... 

Conversion of an amide a thioamide enhances the reactivity of that function since it favors the enol form and provides a better leaving group for addition-elimination reactions (mercaptide vs. hydroxide). Thioamides obtained by treatment of diazepi-none such as (15-1) or (16-1) with phosphorus pentasulhde provide starting materials for further modihcation of the benzodiazepine nucleus. (More recently developed reagents such as Lawesson s Reagent or hw(tricyclohexyltin) sulhde provide more convenient methods for that transformation.) Thus, reaction of the thioamide (15-2) with (9-allylhydroxylamine leads directly to the amidine, probably via an addition-elimination sequence of the thioenol tautomer of (15-2). There is thus obtained the antianxiety agent uldazapam (15-3) [17]. 

The preparation of the A -desmethyl analogue, amoxapine (39-7), illustrates an alternate approach in which the oxygen ether linkage is formed last. Reaction of the imidazolide (39-2) from 2,4-dichlorobenzoic acid (39-1) and carbonyldiimidazole with ort/zo-aminophenol (39-3) gives the benzamide (39-4). This is then converted to its imino chloride (39-5) with the ubiquitous phosphorus oxychloride. Treatment of the product with piperazine leads to the amidine (39-6), probably by an addition-elimination sequence. Copper catalyzed displacement of chlorine by phenoxide closes the ring there is thus obtained amoxapine (39-7) [40]. 

Scheme 28 outlines Eschenmoser s model corrin synthesis. The enamide (310) was treated with KCN to give (311), and this gave the thiolactam (312) when treated with phosphorus pentasulfide. Benzoyl peroxide oxidation yielded the disulfide (313), and in the presence of the enamide (310) this gave the bicyclo thio-bridged compound (314). Sulfur extrusion, by this time a standard procedure (Scheme 22), provided the vinylogous amidine (315)... 

The kinetics and mechanism of the phosphorus-catalysed dimerization of acrylonitrile to give 1,4-dicyanobut-l-ene and 2,4-dicyanobut-l-ene have been studied.114 The reactions of aryhminodimagnesium (138) with //-substituted p-cyanobenzophenones, l-cyano-9-fluorenenone, o-, m-, and p-dicyanobcnzcnes, and o-, m-, and p-nitrobenzonitriles have been examined.115 The effect of pressure on the reaction of 3 -methyl- l-(4-tolyl)triazene (139) and benzoic acid in chloroform and acetonitrile has been studied.116 The effect of acids on the rate of urethane formation from alcohols and isocyanates in the presence of alkyltin carboxylates has been examined.117 A Hammett a value has been reported for the amidine group N=CHNMe2 and used for the prediction of the basicity of sites in bifunctional amidines.118... 

This method is capable of extension to the preparation of other N,N -disubstituted amidines.5 In some preparations it may be advantageous to remove phosphorus oxychloride by distillation under reduced pressure before addition of the amine. The method is not wholly satisfactory for preparation of N,N -di-arylformamidines, which are better made by the orthoformic ester method.6 During preparation of diphenylacetamidine considerable gluey material formed by decomposition of the intermediate N-phenylacetimidochloride 7 is an impediment to the isolation of the product.8 This amidine is better prepared by the method of Sen and Ray.9... 

Another method of building up the physostigmine ring system was devised by the same authors who devised the first (35). In this method, the pyrrolo ring was closed by reaction of an appropriately amino-substituted oxindole (XV) with phosphorus pentoxide to yield the cyclic amidine XVI, which was subsequently reduced to XVII and then methylated to give a product claimed to be dl-esermethole (characterized as the methopicrate). 

The dehydrating agent in the case of the guanidines is HFA itself phosphorus oxychloride has to be used to effect ring closure in the case of the amidines (52). An intermediate 1 1 adduct 111 can be isolated, which, in addition to the formation of llOd and IlOe, on dehydration reacts with the aromatic system to yield 3,4-dihydrochinazolines 112 (52). 

Carbodiimides also insert into Ta—N bonds in a mixed tantalium amido/imido complex. Pentacoordinated phosphoranes, such as 413, react with DCC or diisopropylcarbodi-imide to give hexacoordinate phosphorus amidinates 414 ... 

A number of aromatic amidines have been readily obtained by boiling a primary or secondary amine with a substituted amide in a solution of phosphorus trichloride. Several aliphatic amides undergo a similar condensation with amines and phosphorus oxychloride. An imino chloride, RC(C1)=NR, is an intermediate in this process. N-Phenylbenzarnidine, CsHsC(NHC6Hs)= NH, is obtained by the action of methanolic ammonia on... 

These compounds have been prepared in two ways from 3-amino-l,2,4-triazines. In the first case, the aminotriazine is converted into the amidine (359) with iV,iV-dimethylfor-mamide or -acetamide acetal. Reaction of the amidine with hydroxylamine produces the amidoxime (360) and cyclization with phosphorus oxychloride forms the desired bicyclic product (361) (77JOC1018). Also, the desired ring system can be synthesized by treating 3-amino-l,2,4-triazines with acetonitrile in the presence of aluminum chloride to afford the acetamidines (362) which, in one case (R = = Me), can be transformed into... 

X -systems, and other low coordination phosphorus species, in particular phosphenium ions, R2P , and phosphinidenes, RP . The reactions of phosphenium ions with isocyanides, 1,3-dienes and o-quinones, and amidines, have been investigated. The coordination chemistry of phosphenium ions also continues to stimulate interest.The thermal decomposition of phosphirene and phosphirane P-complexes provides a new approach for the synthesis of terminal phosphinidene complexes, e.g., (180), which can be trapped with a variety of reagents. Evidence of the formation of surface phosphinidene intermediates has been adduced in the heterogeneous dechlorination of alkyldi-chlorophosphines by magnesium metal at 600K. ... 

A still unresolved problem is the structure of the often used adducts from phosphorus trihalides and carboxylic acid amides, which might be described by the formulae (8) or (9). With the aid of in situ generated adducts of acid amides and PX3 amidines, isonitriles, quinazolinones, alkyl chlorides, aminomethylenediphosphonic acids, carbamoyl halides, triformylaminomethane, 1,3,4-oxadia-zoles, sulfides (from sulfoxides), nitriles (from primary nitro compounds)" and bromoqui-nolines (from methoxyquinolines)" have been prepared. 

The preferred bases include triethylamine, amidines, and guanidines. Dehydration of the carbamate has been done with phosphorus trichloride, phosphorus oxytrichloride, phosphorus pentoxide, acetic anhydride, benzenesulfonic acid anhydride, o-sulfobenzoic anhydride (2.14), or other similar compounds. 

The acaricidal properties of N,N-dimethyl-N -(4-chloro-2-methylphenyl) form-amidine (chlorphenamidine, 13) have been described by Dittrich (1966). The compound is prepared by the condensation of 4-chIoro-2-methylaniiine and dimethyl formamide with phosphorus oxychloride (Arndt and Steinhausen, 1963). 

An anilide and urethane react together under the influence of phosphorus pentoxide on heating in xylene to form a 4-quinazolinone (620) (Scheme 98). The reactive intermediate for the cyclization reaction is the ethoxycarbonyl amidine (619) . 

Benzoxazoles. - Both o- and m-halogenobenzanilides (413) are converted into the amidines (415) by potassium amide in liquid ammonia these are formed by aryne cyclization to 2-phenylbenzoxazole (414) and subsequent aminoly-sis." The conversion of acetophenone oxime into 2-methylbenzoxazole by the action of phosphorus oxychloride involves a Beckmann rearrangement. Pyrolysis of aryl azidoformates, ArOaCNa, gives benzoxazol-2-ones. The azide (416) is converted into the benzoxazole (417) on heating. The... 

H. Bredereck and his co-workers857 858 have prepared a number of amidines in good yield when using phosphorus oxychloride in benzene ... 

TV1,/V1 -Dimethyl-/V2-phenylformamidine A mixture of dimethylformamide (27.4 g) and anhydrous benzene (50 ml) at 20-25° was treated, with stirring and exclusion of moisture, with phosphorus oxychloride (23.1 g) in anhydrous benzene (50 ml) dropwise, and then left overnight at room temperature. On the next day aniline (11.6 g) in anhydrous benzene (40 ml) was dropped in at approximately 35°, while the yellow oil that separated was kept in suspension by rapid stirring. Stirring was continued for a further 3-4 h, after which the supernatant benzene was decanted and the residue was kneaded with anhydrous benzene (50 ml) the benzene was decanted and the kneading and decantation were repeated. To convert this material into the free base it was dissolved in ice-water, the solution was covered with a layer of the equal amount of benzene, and the mixture was made strongly alkaline with cold 2n sodium hydroxide solution. The mixture was shaken, the benzene layer was separated, and the aqueous phase was extracted twice more with benzene. The benzene solutions were united, dried over potassium carbonate, and evaporated. The residue was purified by distillation in a vacuum, giving the amidine, b.p. 119-122°/10 mm, D20 1.5955 (15.6g, 85%). 

When ureas are used as the amide component, guanidines are formed analogously.858 If the amine component contains a suitably reactive group, the amidine may on occasions react further to give a heterocycle for instance, benzothiazole is obtained in 85% yield from o-aminothiophenol, dimethylformamide, and phosphorus oxychloride.859... 

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