Cyclocondensation with aldehydes

Few solid-phase syntheses of oxazoles have been reported (Table 15.17). The most general strategy is the dehydration of a-(acylamino) ketones (Entry 2, Table 15.17) or 2-(acylamino)phenols (Entry 1, Table 15.17). Oxazolidin-2-ones have been prepared by intramolecular nucleophilic cleavage of carbamates from insoluble supports (Entries 5 and 6, Table 15.17). Resin-bound 2-aminoethanols, which are accessible by nucleophilic ring-opening of oxiranes with amines, undergo cyclocondensation with aldehydes to yield oxazolidines [220,221]. These compounds are unstable towards acids, and can be released from the support only under neutral or basic reaction conditions. 

Cyclocondensations with aldehydes.2 The diene 1 reacts with aldehydes to give products of type 2 and/or 3, depending on the Lewis acid catalyst. With BF3 etherate, the rron.v-adduct 3 predominates, whereas with ZnCl2 catalysis the civ-adduct 2 is... 

Cyclocondensation with aldehydes (II, 332 333). The cyclocondcnsation of aldehydes with trimethylsilyloxydienes to provide 2.3-dihydro-4-pyroncs has been studied in the most detail with this diene. Two pathways base been identified. In reactions catalyzed by ZnCIi, MgBr, and a lanthanide shift reagent uch as Eu(fod), a pericyclic pathway is suggested by isolation of the initial cycloadduci 2 with the expected e/ir/o-seleetivity. In the presence of acid, this adduct is converted into a <7.v-2,3-dihydro-4-pyronc (3). Only traces of the /ra/i.v-isomer (4) arc formed. In coniiast, the BF,-catalyzed reaction results... 

Dihydrotriazinediones (149) were prepared when biurets (148) cyclocondensed with aldehyde acetals in the presence of boron trifluoride etherate <82JAP57145864>. Triazinetriones (150) were obtained if the biuret (148) was cyclized with diethyl carbonate (Scheme 43) <86GEP3516632>. 

The 4-phenylhydrazonoimidazolidin-2-ones (284) undergo cyclocondensation with aldehydes to give the corresponding 2-phenyl-3,5,6,7-tetrahydro-2/7-imidazo[5,l-c][l,2,4]triazol-5-ones (285) (Equation (79)) <83JHC189>. 

Wu and Sun have presented a versatile procedure for the liquid-phase synthesis of 1,2, ,4-tctrahydro-/i-carbolines [77]. After successful esterification of the MeO-PEG-OH utilized with Fmoc-protected tryptophan, one-pot cyclocondensations with various ketones and aldehydes were performed under microwave irradiation (Scheme 7.68). The desired products were released from the soluble support in good yields and high purity. The interest in this particular scaffold is due to the fact that the l,2,3,4-tetrahydro-/f-carboline pharmacophore is known to be an important structural element in several natural alkaloids, and that the template possesses multiple sites for combinatorial modifications. The microwave-assisted liquid-phase protocol furnished purer products than homogeneous protocols and product isolation/ purification was certainly simplified. 

The synthesis of 4,5-disubstituted triazoles shown in Scheme 208, carried out on a polymer support with microwave assistance, is based on a similar principle. In the first step, sulfinate 1248 is converted to sulfone 1249. Condensation with aldehydes provides vinyl sulfones 1250. Cyclocondensation of sulfones 1250 with sodium azide generates corresponding triazoline intermediates that eliminate sulfinate 1248 to provide triazoles 1251 in moderate to good yield <2006OL3283>. 

Similarly, Dang and co-workers reported the displacement of one chloride from pyrimidine 44 with various amines to give diaminopyrimidines 45 <00TL6559>. These compounds were then subjected to a FeCb-SiOz-promoted cyclocondensation with various aldehydes to produce trisubstituted purines 46 in moderate to good yields as potential adenosine regulating agents. 

Bis(bromomethyl)quinoxalines 263 was treated with aldehydes 264 to obtain 265 . Macrocyclization to 266 was completed by cyclocondensation of the aldehydes 265 with the appropriate diaminoalkanes. Elwahy used this chemistry to synthesize new macrocyclic ligands containing the quinoxaline subunit. 

A range of l,3-oxazolidin-4-ones (93) have been prepared by cyclocondensation of cyanohydrins, R R C(OH)CN, with aldehydes or ketones, R COR, under anhydrous strong acid conditions. The R groups used are mainly simple alkyl and aryl moieties, and the mechanism is discussed. 

When R2 substituent is flourocontaining alkyl group, the transformation 17 18 becomes hindered and its proceeding requires some special methods. For example, in [48] Biginelli-like cyclocondensations based on three-component treatment of 3-amino-l,2,4-triazole or 5-aminotetrazole with aldehydes and fluorinated 1,3-dicarbonyl compounds were investigated. It was shown that the reaction can directly lead to dihydroazolopyrimidines 20, but in the most cases intermediate tetrahydroderivatives 19 were obtained (Scheme 10). To carry out dehydration reaction, refluxing of tetrahydroderivatives 19 in toluene in the presence of p-TSA with removal of the liberated water by azeotropic distillation was used. The same situation was observed for the linear reaction proceeding via the formation of unsaturated esters 21. 

Cyclocondensation of 153 with aldehydes in DMF gave 154. The cycloaddition of 153 with isothiocyanates afforded 155 (77JCS(PI)765). Compound... 

Several types of cyclocondensation have been used to prepare imidazoles on insoluble supports (Figure 15.7). These include the condensation of 1,2-dicarbonyl compounds with aldehydes and amines, the 1,3-dipolar cycloaddition of iV-sulfonylimines to miinchnones, and the condensation of /V-acylated a-amino ketones with ammonia (Table 15.11). 

Numerous solid-phase preparations of quinazolinones have been reported. The main synthetic strategies used are summarized in Figure 15.16. Quinazolin-2,4-diones can be prepared from anthranilic acid derived ureas or from N-(alkoxycarbonyl)-anthranilamides. These reactions have been performed on insoluble supports either in such a way that the cyclized product remains linked to the support, or such that it is simultaneously cleaved from the support upon ring formation. Quinazolin-4-ones can be prepared by cyclocondensation of anthranilamides with aldehydes, orthoesters [342], or other carboxylic acid derivatives [343]. The selection of examples listed in Table 15.29 illustrates the variety of substitution patterns accessible by means of these cyclizations. 

Cyclocondensation of aldehydes with silyloxydienes (12, 312). The stereoselectivity of this reaction depends not only on the catalyst but also on the solvent as summarized in equation (I) for reactions with l-methoxy-2-methyl-3-trialkylsi-lyloxy-l,3-pentadienes la and lb.8... 

The same authors have also reported the synthesis of 2-amino quinolines46, Scheme 5.28. Secondary amines were reacted with aldehydes to form enamines subsequent addition of 2-azidobenzophenones initially forms triazoline intermediates, which undergo a thermal rearrangement and intermolecular base-catalysed cyclocondensation to produce 2-amino quinolines. The reactions were run at 180°C for 10 min (the time includes 3 min required for enamine formation) to give the products in 57-100% yields. 

Appropriately substituted hydroxy amides and ureas can be used instead of diamines. Thus, acid-catalyzed cyclocondensation of iV-carbamoyl prolinols 137 (R1 = H, (CH2)3) (Scheme 27) with aldehydes RCHO (R = Ph, 2-MeOC6H4, 2-naphthyl, etc.) stereoselectively afforded a series of pyrroldine-fused oxadiazepinones 46 (Scheme 5) <1990CPB2627, 1990H(30)287, 1996LA927>. Similar heterocyclization of 4-(2-hydroxyethylthio)-2-azetidinone with acetone dimethyl acetal was used in the synthesis of azetidinone-fused oxathiazepanes of type 33 (X = S) (Figure 4) <1980JA2039>. 

Cyclocondensation of dioxygenated 1,3-dienes with aldehydes. In the presence of ZnCl2 in benzene or BP3 etherate in ether, this diene 1 undergoes cyclization with a wide variety of aldehydes to afford 2,3-dihydro-y-pyrones (equation I). The products... 

According to the classical Hantzsch synthesis of pyridine derivatives, an a,(5-unsaturated carbonyl compound is first formed by Knoevenagel condensation of an aldehyde with a P-dicarbonyl compound. The next step is a Michael reaction with another equivalent of the P-dicarbonyl compound (or its enamine) to form a 1,5-diketone, which finally undergoes a cyclocondensation with ammonia to give a 1,4-dihydropyridine with specific symmetry in its substitution pattern. 

S. J. Danishefsky, J. F. Kerwin, and S. Kobayashi, Lewis acid catalyzed cyclocondensation of functionalized dienes with aldehydes, J. Am. Chem. Soc., 104 (1982) 358-360. 

Condensation of 1,2-diketones with aldehydes in the presence of NH4OH constitutes an efficient approach towards trisubstituted imidazoles. Impressively, under dielectric heating conditions (180 °C), the cyclocondensation reaction required merely 5 min to go to completion [39]. Moreover, analytically pure products were easily isolated from the reaction mixture by a neutralization-filtration sequence. The high speed of the reaction combined with the ease of product isolation rendered the cyclocondensation especially suitable for the generation of imidazole libraries (Scheme 15). 

Benzoin 23 could be used instead of benzil 22, provided that the microwave-assisted cyclocondensation is performed on inorganic support (silica gel or alumina) under solvent-free conditions [40]. A related diversity-oriented approach towards imidazoles utilized the cyclocondensation of unsymmetrical keto-oximes with aldehydes in the presence of NH4OAc [41] (Scheme 16). Hydroxyimidazoles 24 were formed in the cyclization step and... 

The synthesis of the C9-C15 subunit 64 commenced with the cyclocondensation of aldehyde 67 and diene 68 to provide dihydropyrone 66 (Scheme 16) [118]. A Luche reduction [119, 120] and acid-mediated Ferrier rearrangement gave lactol 69 [121], installing the 03-04 (Z)-trisubstituted olefin. A further five steps... 

Cyclocondensation with carbonyl compounds. This diene undergoes condensation with both aldehydes and ketones in the presence of 1 cquiv. of zinc chloride or BF, etherate to afford unstable orthoester adducts, whii h are hydrolyzed to 8-lactones (equation I). The europium(lll) catalysts Eu(fod), and the chiral Eu(hfc), are also excellent catalysts,... 

Likewise, pyrroles are accessible if in the last cyclocondensation step a primary amine is applied. Therefore, upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, after subsequent Stetter reaction with aldehydes 92 in presence of catalytic amounts of thiazolium salt 93, and after addition of primary amines 96 or ammonium chloride and glacial acetic acid, the 1,2,3,5-tetrasubstituted or 2,3,5-trisubstituted pyrroles 97 are obtained in good yields in a one-pot procedure (Scheme 52) [259, 260]. 

Aldehydes and siloxydienes undergo cyclocondensation with Bp3-Et20 to form pyranones (Eq. 58) [104]. The stereoselectivity is influenced by the solvent. 

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