Amidines isonitriles

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. 

Hegarty and Chandler (17, 18) have found that secondary amines react with isonitriles 47 in the presence of AgCl at low temperature to give the iso-lable but thermodynamically unstable Z-amidines 50. This reaction is believed to occur via the formation of the metallated nitrilium intermediate... 

They are very unstable and must be generated at temperatures ranging between —100 and —120 °C, whereas lithiated amidines 683 can be kept in solution at —78 to — 20 °C989. Lithiated isonitriles 684 are also very unstable species990. 

Sulfonyl halides (e.g. benzenesulfonyl chloride) form adducts (11) with acid amides in an equilibrium reaction. From these adducts or via adducts of this type 0-sulfonated lactim ethers, isonitriles, adenine, nitriles, amidines, amidinium salts and formic acid esters were prepared. The adducts from DMF and chlorosulfonamides (12) can be used to prepare amidines or amidrazones. A/-Chlorosulfonylcarboxylic acid amides yield nitriles on treatment with DMF or other tertiary amides, presumably via an acid amide sulfonyl chloride complex (13 equation 3). ... 

The addition of amines to isonitriles, catalyzed by copper compounds, furnishes formamidines. The method has found further application, e.g. piperidine was added to benzeneisonitrile or to trimethylsi-lylmethaneisonitrile to give the amidine (321 Scheme 53). A -Sulfonylformamidines (322) were the... 

The six-coordinate tris(benzamidinates) [PhC(NSiMe3)2]3Ln also form 1 1 adducts with donor ligands such as THF, MeCN, or PhCN. In the case of ben-zonitrile, it was possible to isolate and structurally characterize two of these seven-coordinated nitrile-adducts. They are most readily isolated when the original preparation is directly carried out in the presence of one equivalent of benzonitrile (Scheme 15). The facile adduct formation with small donor molecules is yet another analogy between the tris(amidinates) and the tris(cyclopentadienyl) complexes, for which similar adducts with, for example, THF, nitriles or isonitriles are well established [6,7,17]. 

The same authors have broadened the scope of the solid-phase application of this reaction by employing different cyclic amidines instead of only the 2-aminopyridine nucleus and using a Wang resin-bound isonitrile ester [357]. In this paper the authors justified the use of catalytic PTS A instead of a carboxylic acid such as AcOH, because the latter would trigger a Passerini [342, 358] side reaction (Scheme 93). 

It has long been known that 1,3-azoles can be assembled from a component providing the two heteroatoms, for example a thioamide or an amidine, and an a-haloketone, A more recent route employs the interaction between the anion of an isonitrile and an aldehyde, thioaldehyde or imine. 

Matsumoto and co-workers reported in 1978 that simply heating a solution of 4-chlorobenzaldehyde (6), methyl a-isocyanoacetate (7), and piperidine (8) in MeOH led to the formation of an amidine (9) in about 50% yield (Scheme 5.6) [19]. The reaction is suggested to be initiated by the Knoevenagel condensation followed by a formal a-addition of the secondary amine to the isocyano group. It is evident from this work that the a-proton of a-isocyanoacetate 7 is relatively acidic and is readily deprotonated under even weakly basic conditions [20]. The nucleophilicity of the a-carbanion of the enolate 12 produced is apparently higher than that of the terminal divalent carbon of the isonitrile, thus initiating the overall reaction sequence by the Knoevenagel condensation. 

There seems to be no major limitation regarding the selection of aldehydes and isonitriles. For 2-aminoazenes, both heteroaromatic amidines and heteroaromatic guanidines participated in this novel 3CR. Flowever, aliphatic amidines were found to be inactive. Many variants have since been reported by different research groups, both academic and industrial, due to the medicinal importance of this family of heterocycles [68]. 

The [4+1] cycloaddition of 4,4-bis(trifluoromethyl)-l,3-diazabuta-1,3-diene 18, obtained by a reaction of hexafluoroacetone with an amidine in the presence of a dehydrating agent, to an isonitrile gives 5-(butylimino)-l-(2,6-dimethyl-phenyl)-2-phenyl-4,4-bis(trifluoromethyl)-2-imidazoline 19 in the form of Z and E isomers (92JFC(58)345) (Scheme 20). 

Copper salt catalyzed G-insertion of isonitriles, CO, or diazo compounds into NH-bonds of amines gives good yields of form-amidines, formamides, or N-alkylated products respectively Recently, the analogous C-insertion of isonitriles into OH-bonds of alcohols has been reported . A variety of compounds, otherwise difficult to obtain, such as certain carbodiimides, acylamidines, or isonitriles, can be prepared by H2S-elimination with acylchloro-formamidines . 

Scandium catalysts were often used in combinatorial organic synthesis. For library production of a-amino amidines, multicomponent reactions involving aldehydes, amines, and isonitriles (3CC Ugi condensation) were developed using Sc(OTf)3 as catalyst (Scheme 12.28). A set of amino amidines was synthesized by this method in good to excellent yields [63]. 

This researeh was extended to include non-symmetrical amidinate complexes of the same type with mixed Cp and Cp ligands, such as the cationic species [Cp Ru 2-PrN=C(Me)NPr )RuCp(L)] (138 L = none, NCMe, CNBu , PMc3 BF4 salts). For 138 (L = CNBu ), there is NMR evidence that the isonitrile ligand switches between the ruthenium centers. Coordinatively unsaturated intermediates play a key role in catalytic processes, and thus complexes 138 (L = none PFe salt) and 135 (PFe salt) were found to catalyze the atom-transfer radical cyclization of A7-allyl trichloroacetamides. It was discovered that the greater protection offered by the steric bulk of the Cp" ligand led to the superior performance of 135 (PF salt). ... 

Scheme 3.63 depicts a proposed mechanism where amine 164 and aldehyde react to generate the expected Pictet-Spengler product 202 via the iminium species 205. Evidence for the intermediate formation of 202 was observed through LC/MS monitoring, and the reaction with the protonated isonitrile 203 affords the final exocyclic amidine moiety 204. 

Medda F, Hulme C (2014) Exploiting the divalent nature of isonitriles a novel Picter-Spengler amidination process. Tetrahedron Lett 55 3328-3331. doi 10.1016/j.tetlet2014.04.043... 

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