Amidine intermediates

In the reactions of cis- and rrans-2-aminomethyl-l-cyclohexanol or -1-cycloheptanol or cis- and trans-2-hydroxymethyl-l-cyclohexylamine or -1-cycloheptylamine with ethyl 4-chlorobenzimidate, the stereo- and regio-isomeric derivatives and homologs 164 and 165 were prepared (79T799). The amidine intermediate 166 of the benzimidate ring closure was also... 

For the cis azetidinones 315, the first step is the formation of an amidine intermediate, followed by ring enlargement with transamidation [96-H(42)625]. The preceding amidine structure was revealed by TLC on silica gel when the formation of derivatives 316 was investigated (89MI1). 

Presumably an amidine intermediate is involved which undergoes intramolecular cyclization by nucleophilic attack on the carbonyl function to yield the pyrimidine. 

An entire series of heterocyclizations is based on a-cyano-/3,/3-bis(acetyl)enamines (84JOC4696). When treated with weak bases, compounds 28 give amidine intermediates (29), which undergo cyclization yielding five-membered ring derivatives (30). The subsequent hydrolysis of 30 affords high yields of pyrrolinones (31). 

Base-catalyzed trimerizations are facile also for example, trifluoromethyl cyanide trimer-izes in the presence of ammonia, presumably through the formation of the amidine intermediate (139 Scheme 77) (67JOC231). Similarly, perfluoro-n-propyl cyanide forms the 1,3,5-triazine in the presence of sodium methoxide, probably via the imidate (140 Scheme 78) (52JA5633). 

Arylation of piperidine by Ni-catalyzed coupling of aryl nitriles proceeds in good yield. An amidine intermediate is suggested <03S1643>. 

A mixture of the triazoline (10 mmol) and triethyl phosphite (20 ml) is refluxed (10-30h) under an inert atmosphere. When the amidine intermediate is no longer detectable (TLC, 40% ethyl acetate-cyclohexane) the solution is rotary evaporated, and the crude residue is chromatographed on a silica gel column using the same solvent as for TLC. The first fraction (minor) is unchanged amidine the second fraction contains the benzimidazole (2) in 60-95% yield. 

Thioamides can serve as surrogates for isothiocyanates in the Marckwald synthesis. For example, reaction of a-amino acetals 1278 with thioamides 1277 in the presence of HgClz affords amidine intermediates, which cyclize to form imidazoles under acidic conditions. This method has been applied to synthesize a variety of sugar imidazoles (Scheme 324) <2005HCA10, 2004HCA3035, 2004HCA719, 2000TA435>. 

Makino et al. described a pathway to quinazolinones utilizing a resin-bound amine, treatment of which with 2-methoxycarbonyl phenylisothiocyanate formed resin 147, which subsequently cydized in the presence of TFA to form the quina-zohnone core structure 151 [190]. Quinazoline alkaloids have been synthesized by cychzation of amidine intermediate 148 [191]. A two-step reaction on a sohd support involving cyclocondensation of ethyl oxalate 149 with benzamide and subsequent cleavage employing trimethylsilyl iodide also provided a quinazohne [192]. 

When 4//-l,3-benzothiazine-4-thiones react with propargylamine imidazoles form in 53-72% yields by way of an amidine intermediate <87LA103>. Oxidation of the dehydration product of creatine gives creatone (205) with concurrent Dimroth rearrangement (Scheme 138) <82BCJ1912, 87BCJ4115>. 

Malononitrile (in THE at 20-25 °C overnight) and cyanoacetamide (in water at 20-25 °C for 5 days) react with pteridines, e.g. I, to give pyrido[2,3-6]pyrazines, e.g. 2, by addition across the 3,4-bond followed by scission of that bond and a nitrogen-eliminating recyclization. The intermediate of the reaction with cyanoacetamide can be isolated by addition of aqueous sodium hydroxide. Because the product from malononitrile can be generated under anhydrous conditions, it can be concluded that the reaction takes place by a concerted cyclization of the amidine intermediate with elimination of hydrogen cyanide, rather than via a pyridazinamine which could arise by hydrolysis of this amidine (cf. similar reactions in other fused pyrimidine series).56,64-66... 

The first step in the ring closure of carboxamide 107 (R=NH2) with imidates is the formation of an amidine intermediate, with subsequent nucleophilic attack of the imino group of the amidine on the carbonyl group this takes places with loss of the carboxamide iV-substituent [117]. This observation formed the basis of a simple synthesis of CHINOIN 143 enantiomers. From carboxamides 39 and 40 with ethyl m-chlorobenzimidate, 109 and 110 were obtained in high enantiomeric purity. The absolute configurations were determined by hydrolysis of 109 and 110 to the corresponding amino acid, which was identified by HPLC [79]. 

Comparative results have been obtained in the synthesis of 3H-quinazolin-4-one [100]. The fusion of anthranilic acid with formamide led to the formation of an o-amidine intermediate and usually proceeded by intramolecular cyclization (Eq. 15) ... 

Using a somewhat different C-H functionalization approach to benzimidazoles, Punniyamurthy and co-workers have explored the conversion of A -benzyl bisarylhydrazones to 2-aryl-A -benzyl-benzimidazoles. This conversion is optimally achieved using stoichiometric Cu(OTf)2 in toluene at 110 °C. (This transformation was also reported using catalytic Cu(OTf)2 (20 mol%) under an oxygen atmosphere, albeit in lower yield). This reaction likely proceeds via a copper-amidine intermediate analogous to the intermediate accessed by Brasche and Buchwald in their direct intramolecular arylation of iV-aryl amidines. 

A metal-free protocol for amination of azoles has recently been reported [98]. It includes two steps (1) the ring opening of benzoxazoles or oxadiazoles on heating with secondary aliphatic amines and (2) oxidative ring closure of the resulting amidines on their treatment with (diacetoxyiodo)benzene as oxidant within a short time at room temperature (Scheme 41). The same process can also be performed as a one-pot synthesis without isolation of the amidine intermediate. 

Amination of benzoxazoles and 1,3,4-oxadiazoles with secondary amines in the presence of Brpnsted or Lewis acid and 2,2,6,6-tetramethylpiperidine-Af-oxoammonium tetrafluoroborate (TEMPO BF4 ) as oxidant has also been reported [99]. The reaction is supposed to proceed via the acyclic amidine intermediate, which is converted into the corresponding 2-aminoazole through stepwise... 

Later, Wagh et al. developed a facile and metal-free protocol to prepare various 2-arylaminobenzoxazoles 177 through IBX-promoted oxidative ring closure of amidine intermediate 176 (Scheme 44) [62],... 

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