Intramolecular cyclocondensation

The cycloaddition between a nitrilimine 319 and an aroyl substituted heterocyclic ketene aminal 318 has been found to be stepwise, involving an initial nucleophilic addition of 318 to 319 followed by intramolecular cyclocondensation of the intermediate 320 providing fully substituted pyrazole 321 (Eq. 36) [92]. When Ar was the 2,4-dinitrophenyl group, the intermediate 320 was isolable and required forcing conditions (xylene, reflux, 10 h) to undergo cyclization ... 

Tandem cyclization from [5+1,6+0] atom fragments took place when 3-isothiocyanatobutyraldehyde was reacted with 2-aminobenzylamine 228 (X = NH) to give 229. Based on literature analogies the first step involves the attack of the most nucleophilic aliphatic amino group onto the isothiocyanate and then onto the aldehyde carbon to form 1-(n-aminobenzyl)-6-hydroxytetrahydropyrimidine-2-thione, which undergoes intramolecular cyclocondensation to 229 (Scheme 38) <2005BMC3185>. 

The synthesis of (6 5 6) fused heterocycles may involve one-pot double intramolecular cyclocondensations. A typical example of this reaction is the formation of amide intermediate 247 from 246, which further cyclizes to give pyridopurine derivative 248 (Scheme 13) <1995TL4249>. 

The construction of a tricyclic fused system can also be achieved by one-pot intermolecular/intramolecular cyclocondensations as exemplified by the reaction of functionalized amine 250 with isothiocyanate 251 to give 252 (Equation 33) <2005BMC3185>. 

When a solution of phenacyl halide 258 and excess tosyl hydrazide in methanol is heated to reflux, l-(tosylamido)-4-aryltriazole 261 is formed. The reaction proceeds presumably via dihydrazide derivative 259 that subsequently undergoes intramolecular cyclocondensation to triazoline 260. In the following step, the triazoline must be oxidized to the final triazole product 261. Mechanism of the oxidation is not quite clear, but the probable oxidant is the starting phenacyl halide, as a half of it is converted to the corresponding acetophenone tosylhydrazone that is isolated as the main side product of the reaction (Scheme 37) <2004H(63)1175>. 

Condensation of diazonium salts 1152 with activated nitriles provides hydrazones 1153. Treatment of hydrazones 1153 with hydroxylamine affords amidoximes 1154 in high yield. Upon heating with anhydrous sodium acetate in refluxing DMF, compounds 1154 undergo intramolecular cyclocondensation to provide 5-substituted 4-amino-2-aryl-277-1,2,3-triazoles 1155 in 75-85% yield (Scheme 190) <2006ARK(xv)53>. 

The literature is replete with synthetic methods to prepare 5-bromofurans. One of the more practical syntheses [10, 11] commenced with etherification of 4-bromophenol with bromoacetaldehyde diethyl acetal using either NaH in DMF or KOH in DMSO. Treatment of the resulting aryloxyacetaldehyde acetal with polyphosphoric acid (PPA) afforded 5-bromofuran in good yield via intramolecular cyclocondensation. However, cyclization of m-aryloxyacetaldehyde acetal 1 resulted in a mixture of two regioisomers, 6-bromofuran (2) and 4-bromofiiran (3). Finally, 7-bromofuran 5 can be prepared similarly using the intramolecular cyclocondensation of aryloxyacetaldehyde acetal 4 generated from etherification of 2-bromophenol with bromoacetaldehyde diethyl acetal. 

In another approach, the 3-[3 (2 -spirothiazolidin-4 -one)]quinazolin-4-one derivative 186 in the presence of sodium hydroxide in ethanol undergoes intramolecular cyclocondensation with the formation of the spirothiazolopyrazolo-quinazolinone 187 in moderate yield (Equation 82) <2001PS1>. 

The reaction of 2-aminobenzyl alcohol 376 with 2-chloro-4,5-dihydroimidazole afforded [2-(4,5-dihydro-177-imidazol-2-ylideneamino)phenyl]methanol hydrochloride 377, which upon treatment with carbon disulfide gave l-(477-3,l-benzoxazin-2-yl)imidazolidine-2-thione 378 (Scheme 71). The assumed reaction mechanism involved the initial formation of the dithiocarbamate 379, which underwent intramolecular nucleophilic addition to furnish the unstable thiazetidine 380. By nucleophilic attack of the hydroxy group on the carbon atom of the thiazetidine ring, thiocarbamate derivative 381 was formed, which gave the final 3,1-benzoxazine 378 by an intramolecular cyclocondensation with the evolution of H2S <2006H(68)687>. 

The indolizines constitute the core structure of many naturally occurring alkaloids, such as (-)-slaframine, (-)- dendroprimine, indalozin 167B and coniceine. There are a number of different routes to the synthesis of indolizines and they are most commonly synthesised by sequential N-quaternisation, intramolecular cyclocondensation reactions or the cycloaddition reaction of /V-acyl/alkyl pyridinium salts. 

Compounds with structure 80 can be synthesized by intra or intermolecular cyclization of substituted 3,4-diaminothieno[2,3-Z>]pyridines. For example, heating (A,A-dimethylaminomethylene)amines 82 affords tricyclic pyrimidine derivatives 83 via intramolecular cyclocondensation (1993KFZ40). 

The construction of a thieno[3,2-Z>]pyridine by pathway M involves the successive formation of the N(l)-C(2) and C(3)-C(4) bonds of the pyridine fragment. Various 3-aminothiophene-2-carboxylic acid derivatives are most often used as the starting reagents with 2C-components, which introduce carbon atoms C(2) and C(3) into the pyridine ring. For example, the reaction of amino ester 155 with dimethyl acetylenedicarboxylate (156) involves intramolecular cyclocondensation followed by hydrazinolysis to give derivatives of the new heterocyclic system thieno[2, 3 5,6] pyrido[2,3-<7]pyridazine (157) (1991JHC205, 1990SPH203). 

C-Alkylation of 1,1-enediamines takes place readily when they are treated with electrophilic olefins including a,/ -unsaturated aldehydes, ketones and carboxylic acid derivatives. Primary and secondary 1,1-enediamines usually lead to fused heterocyclic products due to the simultaneous intramolecular cyclocondensation between the amino and the carbonyl groups of the initially formed adducts. 

In contrast to these results, intramolecular cyclocondensation of the amino group with the carbonyl carbon takes place following the addition step in the reaction between... 

In contrast to benzenesulfonyl azide, the reaction between 8 and aryl azides gives only a small amount of 226. Instead, highly substituted triazoles 228 are formed as the major products176,177. When 4-nitrophenyl azide is used, the reaction furnishes 228 exclusively. It has been believed that the reaction involves two competitive pathways and benzoyl-substituted 1,1-enediamines 8 act mainly as nucleophiles rather than as 1,3-dipolarophiles toward aryl azides. Consequently, they add to the azide group and, following intramolecular cyclocondensation, give products 228. Only in the case of unfavorable electronic factors does 1,3-cycloaddition reaction to give 226 take place (Scheme 13)177. 

The mechanistic rationale of the Cl sequence provides reactive intermediates such as enones and elusive allenols (vide supra) that can be exploited even in a domino sense, if a suitable trapping functionality is present. For the synthesis of heterocycles two bimolecular sequences have been elaborated. One is terminated by an intramolecular cyclocondensation with an amino group, which is unprotected and carried through the sequence to trap the evolving enone functionality. The other exploits the generation of a vinyl allene intermediate, which is captured by an intramolecularly tether dienophile in the sense of a (4+2)-cycloaddition. 

In all cases, intermediate 3-thiocyanato-2-alkenal arylimine 56 was not isolated, it reacted further by intramolecular cyclocondensation to salts 30a,c,e,i and 57-64 (90DDP275459, 92JPR25, Scheme 16). In order to establish the structure of salts 57, an X-ray analysis was performed for salt 57 (R = 4-MeO) (98ZK331). In Table 1 are... 

Aryl-4,5,6,7-tetrahydro-l,2-benzisothiazolium salts 121 were synthesized by intramolecular cyclocondensation of unstable intermediates 2-thiocyanato-4,5,6,7-tet-rahydro-l,2-benzaldehyde-phenylimines 120. This is a convenient novel method for their production (95JPR175, 96JPR424, 96T783, 99HCA685, Scheme 40). The list of salts 121 is given in Table 7. 

S-T h i ocy a n a to v i n y 1 aide h y des 119 were also versatile C3S building blocks in the synthesis of acceptor substituted 2-amino-isothiazolium salts 131 and 132 by intramolecular cyclocondensation of thiocyanatovinylaldehyde hydrazones 129 (93TL1909). The alternative cyclization route to 1,2,3-thiadiazines was not observed. Alicyclic aldehydes 119 reacted with benzhydrazides (R = ArCO) to unstable benzhydrazones 129 (R = ArCO) that cyclized spontaneously to 130 (R = ArCO). The imines 130... 

If a co-carbalkoxy group is present in the starting linear compound instead of the halogen atom, a similar procedure allows synthesis of 2,6-dioxo-l,2-azaphosphina-nes 124 by intramolecular cyclocondensation of amidophosphonic ester 125 [167],... 

Compound (41) was prepared from 3-hydroxy-6-methylpyridine by sequential benzylation, N-quaternization with PhCOCHjBr, and intramolecular cyclocondensation <82JCR(S)245>. A series... 

The intramolecular cyclocondensation of 1-(2-hydroxylaminoethyl) cytosine (90) gave pyrim-ido[2,l-c][l,2,4]oxadiazines (91) and (92) (Scheme 8) <71JCS(C)867>. The attempted esterification of aminooxy acetic acid intermediate (94) led by ring closure to (18) (Scheme 9) <70H(22)1879>. Some of the biologically active pyrimido[2,3-Z ][l,3,5]thiadiazines (9 were obtained from pyrimido-2-thiones (96) and A -aryl-AT-chloromethylcarbamoylchlorides (95) (Equation (18)) <83FRP2512450). 

Less common are literature examples in which mechanochemical reaction was carried out at elevated temperature. Naimi-Jamal reported the heating of double-walled ball-mill beaker equipped with fittings for circulating water at 96°C (boiling water as circulant) [45]. One-pot solvent-free synthesis of pyrano[2,3-d]pyrimidine-2,4(lFf,3F0-diones 154 was achieved by simply ball milling a stioichiometric mixture of an aromatic aldehyde, malononitrile, and barbituric acid, without addition of solvent and catalyst (Scheme 2.53). Quantitative yields were obtained (Table 2.47) and products generally did not require purification, the solid products were just dried at 80°C in vacuum and recrystaUized, if necessary. Reaction presumably takes place by initial Knoevenagel condensation of aromatic aldehyde with malononitrile to afford the intermediate Michael acceptor, which subsequently reacts with barbituric acid. Tautomerization of Michael adduct is followed by intramolecular cyclocondensation and another tautomerization to afford pyrano[2,3-d]pyrimidine-2,4(177,37f)-diones 154. 

Alkane-2,6-diones give 3-alkylcyclohex-2-enones only by a kinetically controlled intramolecular cyclocondensation process promoted by a lithium dialk-ylamide in ether. ... 

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