Synthon ammonia

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Alternative conditions for reductive decyanations can be used. The allylic ether in compound 26, an intermediate in a total synthesis of (-)-roxaticin, was prone to reduction when treated with lithium in liquid ammonia. Addition of the substrate to an excess of lithium di-ferf-butylbiphenylide in THF at -78°C, and protonation of the alkyllithium intermediate provided the reduced product 27 in 63% yield, as a single diastereomer (Eq. 7). a-Alkoxylithium intermediates generated in this manner are configurationally stable at low temperature, and can serve as versatile synthons for carbon-carbon bond forming processes (see Sect. 4). 

Ph2P(NH2)NP(NH2)Ph2]+Cl, 19, which is prepared by the reaction of Ph2PCl3 and ammonia (136). This synthon has a preformed N-P-N-P-N unit and can be readily cyclized to a six or higher membered ring upon reaction with an appropriate reagent (137). An important application of the use of the Bezman s salt approach has been the synthesis of metallocyclophosphazenes of the type 20, which contain an early transition metal in the framework of the cyclophosphazene skeleton [Fig. 15(A)] (138). A modification of the Bezman s salt to design a chiral synthon allowed the synthesis of an optically pure cyclophosphazene (139). 

In practice, the equivalent synthon of 2 was l-cyano-4,5-dimethoxybenzocyclobutene 22 (Scheme 3.7) which on heating generates a reactive o-quinodimethane by a conrotatory electrocyclic ring opening process (Cf. Scheme 3.7) and reacts, at 150-160 °C, with the 3,4-dihydroisoquinoleine 23 to give 80-88%yield of 13-cyanoprotoberberine 24. A simple reductive decyanation with lithium in liquid ammonia in the presence of isopropyl alcohol afforded xylopinine (19) in 84.6% yield [19]. 

Cleavage by amines and ammonia seldom occurs (a) in a reaction under Chichibabin conditions [68DIS(B) 1303] and (b) with substrates like6-nitro-TP (91ZOR1100). Here the inherent C3-synthon is scavenged as imine 50 (Scheme 24). 

Oxazinium and -thiazinium cations are 67r-aromatic systems which readily react with nucleophiles at C-6. Ring opening is normally followed by recyclization so that a variety of heterocyclic systems are then formed. The behaviour of the oxygen and sulfur compounds are almost identical and so, as the latter are usually prepared from the former, it is not surprising that most attention has focussed on the reactions of 1,3-oxazinium species (72S333). These versatile synthons react with ammonia, for example, to give pyrimidines, while hydrazines afford pyrazoles and hydroxylamine produces isoxazoles (Scheme 20). 

Wan, Y.Q., Alterman, M., Larhed, M. and Hallberg, A., Formamide as a combined ammonia synthon and carbon monoxide source in fast palladium-catalysed aminocarbonylations of aryl halides, /. Comb. Chem., 2003, 5, 82-84. 

A C—N disconnection of a primary amine gives rise to the carbocation and amide anion synthons. It might be predicted therefore that treatment of an alkyl halide with ammonia (reagents equivalent to the above synthons) under pressure would constitute a suitable synthesis of a primary amine. In practice, however, the yield is poor since a mixture of all three classes of amines, together with some of the quaternary ammonium salt, is obtained, owing to more ready further alkylation of the sequentially formed products. 

Schnyder, A. Beller, M. Mehltretter, G. Nsenda, T. Studer, M. Indolese, A. F. Synthesis of primary aromatic amides by aminocar-bonylation of aryl halides using formamide as an ammonia synthon. /. Org. Chem. 2001, 66, 4311-4315. 

In the palladium-catalyzed allylic amination reaction, primary and secondary amines can be used as nucleophiles, whereas ammonia does not react. Therefore, many ammonia synthons have been developed, and a variety of protected primary allyl amines can now be prepared using azide, sulphonamide, phthalimide, di-f-butyl iminocarbonate ((Boc)2NLi), and dialkyl A-(rerr-butoxycarbonyl)phosphoramide anions as the nucleophile [20], An example of the use of ((Boc)2NLi) 30 as the amine nucleophile in the palladium-catalyzed allylic amination reaction is shown in Eq. (9). This reaction also illustrates the problem with the regioselectivity in the reaction as a mixture of the products 31-33 are obtained [21]. 

Such one-atom synthons are normally ammonia or a primary or secondary amine. The following examples are therefore classified according to the type of five-atom cosynthon used ... 

Since Nl and N4 are always provided by ammonia or an amine, examples in this small but significant category are classified according to the nature of the C—C synthons (which are identical in all examples reported recently). 

Enamines are also involved in the classical Hantzsch synthesis, which is usually performed by annulation of an enamine intermediate derived from ammonia and a suitable /3-ketoester or an equivalent 1,3-diketo synthon, with an a-haloketone. A new development is the adaptation of this reaction to solid-phase conditions <1998TL2381>. Heating of the /3-aminoacrylonitrile 276 with the ketone 277 gave a decent yield of the pyrrole 278 (Equation 85), a member of a series of similar compounds which were synthesized using this approach <1997S530>. An additional solid-phase variant of the Hantzsch synthesis provided a set of pyrrole-/3-carboxamide derivatives <1998BML2381>. 

A fluorous imine reagent (3), also commercially available, was introduced by Herr as an ammonia equivalent in the Buchwald-Hartwig amination of aryl bromides, iodides, and triflates (Reaction Scheme 9)3 In this case, the problem of introducing a primary amine was solved by the use of (3) as a synthon for ammonia. 

It is convenient to combine these two synthetic approaches because they are formally similar. Both condense an a-functionalized ketone or aldehyde (C-4-C-5 synthon) with an amine or ammonia (N-1, N-3) and an aldehyde (C-2). "Die alternative Bredereck modification uses formamide as the source of the C-2-N-3 bond and of N-1. The older (Radziszewski or Weidenhagen) methods give 4-mono-, 4,5-di- and 2,4,5-trialkyl or -triaryl imidazoles the Bredereck formamide synthesis is largely restricted to the preparation of imidazoles with no 2 substituent. 

Tosylmethyl isocyanide (TosMIC) (75 R = H), a versatile reagent in synthesis, can also be used as an acyl anion equivalent. For instance symmetrical and unsymmetrical diketones were prepared by using this TosMIC synthon (equation 40). Ketones are homologated to enones by alkylating the condensation product derived from TosMIC, followed by acid hydrolysis (Scheme 46). 1-Isocyano-l-tosyl-l-alkenes (76), formed by the reaction of TosMIC with an aldehyde or ketone, react with a primary amine or ammonia to give 1,5-disubstituted (or 5-monosubstituted) imidazoles in high yield (Scheme 47). ... 

It is also possible to introduce a nitrogen function using these types of process 0-tosylation then t-butylamine as a synthon for ammonia leads to 2-aminopyridines and oxalyl chloride, together with a secondary amide, produces 2-amino-pyridine amides. ... 

Vinamidinium (R2NCH=CR CH=N R2) salts (best as non-hygroscopic hexafluorophosphates) will serve as synthons for substituted malondialdehydes in these syntheses this is one case in which the intermediate is known.Using hydroxylamine instead of ammonia leads to A-oxides. The vinamidinium salts are available by reaction of the relevant substituted acetic acid (R CH2C02H) with phosphorus oxychloride and dimethylformamide. ... 

An example of a ring closure of type 95 is provided by the conversion of compound 120 into the dihydrothiazinone 121 in the presence of sodium hydride.88 The derivative 120 was prepared by treating the salt 119 with l-bromo-2-chloroethane. The salt 119, which is a versatile synthon (Section V,C,2,b), was generated as a stable species by the reduction of the dihydrothiazinone 80a with sodium in liquid ammonia followed by the addition of one molar equivalent of ammonium chloride. Although the overall yield of the product 121 was low (24%) in the above case, the synthesis is of considerable potential. 

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