Cyclic amidine

A -Imidazolines (294 Z = NH) are cyclic amidines and exhibit the characteristic resonance stabilization and high basicity. A -Oxazolines (294 Z = 0) are cyclic imino ethers, and A"-thiazolines (294 Z = S) are imino thioethers both are consequently easily hydrolyzed by dilute acid. 

Heating of diphenylcyclopropenone 67 with the cyclic amidine 68 in dimethoxyethane afforded the tricyclic compound 69 that upon heating... 

Catalytic hydrogenation of 2-cyano-l-(2-nitrophenyl)piperidines over Pearlman s catalyst in a low-pressure hydrogenator under 1 atm of hydrogen in dioxane gave cyclic amidine A -oxides 352 (01EJOC987). 

A catch and release synthesis of tetrazoles and cyclic amidines has been reported making use of solid-supported oximes [94]. When bound sulpho-nyloximes, obtained by reacting polymer supported sulfonyl chloride with oximes, were reacted with nucleophiles, tetrazoles or cychc amidines were obtained (Scheme 19). Alternatively, the use of TMS-CN affords imino nitriles, which have been used as intermediates for the preparation of indoles, 1,2,3,4-tetrahydropyridines, quinoxalines and benzimidazoles. 

Pyrimido[2,l- ][l,3]thiazinones 363 formed in low yield - instead of the targeted lactams 362 - on photoirradiation of the cyclic amidines 361 and the diazoketone 360 (Scheme 59). Under microwave conditions only 362 formed, which on photoirradiation decomposed <2005JOC334>. 

Chang et al. reported a mild tandem intramolecular hydroamination of yne amines to form an endo-adduct intermediate, which reacts with electron-deficient azides to produce cyclic amidines <06JA12366>. Selected examples of an interesting synthetic route to tropene derivatives 165 via a dual hydroamination strategy is shown below. This one-step reaction makes use of a palladium catalyst and takes place by sequential intermolecular hydroamination of cycloheptatriene with aryl, heteroaryl, and primary alkyl amines to generate intermediate 166, followed by transannular intramolecular hydroamination <06JA8134>. 

Amidines and cyclic amidines are also converted into 1,2,4-thiadiazoles by reaction with isothiocyanates, imino-sulfenyl chlorides, di- and trichloromethyl sulfenyl chlorides, and carbon disulfide in the presence of sulfur. Ureas, thioureas, guanidines, carbodiimides, and cyanimides react with chlorocarbonylsulfenyl chloride to produce 1,2,4-thiadiazol-5-one derivatives in another example of a type B synthesis <1996CHEC-II(4)307>. 

Cyclic Amidines are Potent iNOS Selective Inhibitors... 

N., A potent inhibitor of inducible nitric oxide synthase, ONO-1714, a cyclic amidine derivative, Biochem. Biophys. Res. Commun. 270 (2000), p.663-667... 

Coreactants, in microencapsulation, 16 444 Coreactive curing agents, 10 388-389, 392-411, 418. See also Curing agents amine functional, 10 392 401 carboxylic functional polyester and anhydride, 10 401—406 cyanate ester, 10 411 cyclic amidine, 10 410 isocyanate, 10 410 melamine-, urea-, and phenol-formaldehyde resins,... 

Cyclic 1,2-diketones, 24 594 Cyclic acrolein acetals, 2 271 Cyclic amidine curing agents, 10 410 Cyclic amidines, 10 412 Cyclic (aromatic disulfide) oligomers, 23 712... 

Some 2-amino derivatives (36) have been reported to show local anaesthetic, parasympathomimetic, long-lasting myorelaxant, brief hypotensive and mild antiarrhythmic activities [83]. Analogous cyclic amidines (37) with a 3-phenyl group were examined for potential hypoglycaemic agents [7]. Ten of 16 compounds showed weak to moderate activity in the rat. The most active compound was (37, R1 = OMe R2 = R3 = H, R4 = cyclopropyl), although it was less active than tolbutamide [84]. 

The simplest systems, and most closely related to the open chain systems discussed in the preceding section, are cyclic amidines, such as 2-iminopyrrolidine ([55], n = 3), 2-iminopiperidine ([55],n = 4) and their N-alkyl derivatives. Infrared spectra of their hydrochloride... 

The simplest systems containing two conjugated ring nitrogens are 2-imidazolines [77], which are cyclic amidines and give cations [78]. 

Cyclic amidines (213) react with chlorocarbonylsulfenyl chloride to give bicyclic 1,2,4-thia-diazoles. The product isolated from this reaction depends on the mode of addition. When (213) is added to chlorocarbonylsulfenyl chloride, 3-oxo derivatives (214) are isolated via the postulated intermediate (215). Addition of chlorocarbonylsulfenyl chloride to (213) leads to 5-oxo derivatives (216), via the proposed bis(intermediate) (217) (Scheme 47) <84CHEC-I(6)463). Cyclic amidines (213) have also been treated with 1-chloro-l-phenyliminomethanesulfenyl chloride (210) to afford 2>H-1,2,4-thiadiazoles (218). The other possible product from this reaction, the 2/7-isomer (219) has been shown to be unstable, rearranging to a benzothiazole. Heterocycles (213) which have been used in this transformation include 2-aminopyridine, 3-aminopyridazine, 2-aminobenzothiazole, 2-aminopyrimidine and 2-aminothiazole (Equation (33)) <86S1027>. 

The condensation reaction of cyclic amidines with trichloromethylsulfenyl chloride yields sul-fenamides, which afford 5-arylimino-l,2,4-thiadiazolines on treatment with aromatic amines <84CHEC-I(6)463>. An example of this type of reaction starting from 2-amino-4-arylthiazoles (271) affords 3/f-thiazolo[2,3-c]-l,2,4-thiadiazoles (272), via the sulfenamide (270) (Scheme 60) <88IJC(B)501>. 

There are five possible dihydropyrimidine forms, although most of the known dihydropyrimidines have either the 1,2- 491 or the tautomeric 1,4- 492 or 1,6-dihydro structures 493 <1986H(24)1433>. Of the three possible tetra-hydropyrimidine forms, the most commonly found is the 1,4,5,6-tetrahydro- or cyclic amidine structure 498. 

Reduced pyrimidines are much less stable toward hydrolysis than the fully conjugated analogs, and this is often used synthetically to produce amino acids and diamines. The BH3 reduction of cyclic amidines (1,4,5,6-tetrahydropyr-imidines) to hexahydropyrimidines, and their subsequent hydrolysis was mentioned above <1999JFIC105>, but there are many more examples. For instance, m-cyclobutane /5-amino acids 544 can be prepared from the cyclobutane derivatives 542 formed by the [2-F2] photocycloaddition reaction between uracil and ethylene <2002TL6177, 2004TL7095, 2006SL1394>. 

The aza-Diels-Alder reaction of a variety of amino-aza-heterocycles to yield cyclic amidines and isothioureas has been reported <1996TL2619>. 

The schemes for preparing imidazolines take advantage of the fact that this heterocyclic system in effect consists simply of a cyclic amidine of ethylenediamine. Thus, treatment of the iminoether (81-1) from phenylacetonitrile with ethylenediamine can be envisaged to result in the initial displacement of ethoxide to give a transient intermediate such as (81-2) internal addition-elimination by the remaining side chain... 

A few scattered examples of hexahydro- and octahydro-l,3-diazocines have been reported, mainly in the context of studies on the effect of chain length on the cyclization of diamines. Reaction of the N- aryl-iV - aroyldiamines (194) with polyphosphoric ester gives the cyclic amidines (195) (77JCS(P2)2068). Yields of the diazocines (195 n =5) were about 40%, compared to 90% for the 1,3-diazepine (195 n =4). The basicities of the products decrease in the order of ring size 6 7>8 5, lower basicity reflecting non-planarity of the amidine system. 

Imoto, M., Iwanami, T., Akabane, M. (Suntory Ltd.) Use of cyclic amidine compounds as nicotinic acetylcholine receptor modulators, WO0181334 (2001). 

The condensation of 1,4-diamines with a variety of carboxylic acid derivatives, e.g. imidate esters, orthoformic esters, /V-ethoxycarbonylthioamides (77JOC2530), nitriles and ethoxyacetylene, produces the cyclic amidine linkage —N = C(R)NH— (67AHC(8)2l, p. 40). Cyclic ureas, —NHC(0)NH—, have been similarly produced using carbonyl chloride, A, A -carbonyldi imidazole, carbon monoxide, thiocarbonyl chloride or carbon disulfide (67AHC(8)21, p. 38). 

Support-bound 1,2-diamines can be readily converted into imidazolidinones by treatment with carbonyl diimidazole [128,129]. The required diamines have been prepared on cross-linked polystyrene by reduction of peptides bound to MBHA resin with borane. Similarly, bicyclic imidazolines have been prepared from triamines and thiocarbonyl diimidazole (Entry 10, Table 14.3). Dehydration of polystyrene-bound monoacyl ethylene-1,2-diamines yields 4,5-dihydroimidazoles (cyclic amidines, Entry 5, Table 13.18). Several groups have reported the synthesis of 2-aminoimidazol-4-ones from resin-bound amino acid derivatives (e.g., Entry 6, Table 15.11). Most of these compounds are, however, unstable, and slowly decompose if dissolved in DMSO (Jesper Lau, private communication). 

Non-cyclic amidines (120 of Scheme 44) react as ambident nucleophiles in the reactions with TNB in DMSO forming198 the two zwitterionic intermediates 121 and 122 of Scheme 44, when the nucleophilic centre is the nitrogen or the carbon atom, respectively. 121 and 122 are in equilibrium with unprotonated forms. Some 122 cr-complexes were isolated as crystalline solids. In 122, a further nucleophilic attack is carried out by the C=NH group and this forms a met a bridged compound (123) in protonated or unprotonated forms198. 

These results can be readily explained. For instance, the reaction of cyclic amidine 214 with hydroxide ion in water must give first the tetrahedral intermediate 220, which after appropriate proton transfer (+22U can only give the aminoamide 216 with stereoelectronic control. In order to form the lactam 21ji, intermediate 220 must undergo a conformational change to intermediate 222 followed by an appropriate proton transfer (+223). Since lactam 218 is not observed under kinetically controlled conditions, the conformational change 220 222 cannot compete with the breakdown of 220 via 221. Lactam 21 8 is then slowly formed from aminoamide 216 na intermediate 222. 

Edwards, P. D., et al., Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity and high ligand efficiency. J Med Chem, 2007, 50, 5912-5925. 

Alder, R. W. Sessions, R. B. Synthesis of medium-ring bicyclic diamines by the alkylation and cleavage of cyclic amidines. Tetrahedron Lett. 1982, 23, 1121-1124. 

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