Imines intramolecular cyclization with

Schering-Plough uses (S)-4-phenyl-2-oxazolidinone in the large-scale production of their cholesterol absorption inhibitor Zetia (ezetimibe) (11) (Scheme 23.l).40 2 Condensation of the alcohol 12 with imine 13 in the presence of a Lewis acid such as TiCl4 and tertiary amine base yields compound 14. Silylation followed by intramolecular cyclization with tetrabutylammonium fluoride (TBAF) yields the protected ezetimibe 15. Removal of the protecting groups is carried out with weak acid to afford Ezetimibe (11). 

Thiazolidones are another class of heterocycles that attract much attention because of their wide ranging biological activity [106], They are usually synthesized by three-component condensation of a primary amine, an aldehyde, and mercapto-acetic acid with removal, by azeotropic distillation, of the water formed [107]. The reaction is believed to proceed via imine formation then attack of sulfur on the imine carbon. Finally, an intramolecular cyclization with concomitant elimination of water occurs, generating the desired product. The general applicability of the reaction is limited, however, because it requires prolonged heating with continuous removal of water. To circumvent these difficulties and to speed up the synthesis, Miller et al. developed a microwave-accelerated three-component reaction for the synthesis of 4-thiazolidinones 63 [108]. In this one-pot procedure, a primary amine, an aldehyde, and mercaptoacetic acid were condensed in ethanol under MW conditions for 30 min at 120 °C (Scheme 17.44). The desired 4-thiazolidinones 63 were obtained in 55-91% yield. 

A range of imines derived from trifluoromethyl aryl ketones have been converted into heterocyclic products via intramolecular cyclization with loss of the CF3 group. For example, o-aminoimine (15), when treated with strong base, cyclizes to benzimidazole (16), with loss of trifluoromethyl anion. The corresponding o-phenols yield benzoxazoles, and examples using an external amine lead to aziridines. 

The Pictet-Spengler reaction is an acid-catalyzed intramolecular cyclization of an intermediate imine of 2-arylethylamine, formed by condensation with a carbonyl compound, to give 1,2,3,4-tetrahydroisoquinoline derivatives. This condensation reaction has been studied under acid-catalyzed and superacid-catalyzed conditions, and a linear correlation had been found between the rate of the reaction and the acidity of the reaction medium. Substrates with electron-donating substituents on the aromatic ring cyclize faster than the corresponding unsubstituted compounds, supporting the idea that the cyclization process is involved in the rate-determining step of the reaction. 

Furthermore, intramolecular cyclization of acyclic chiral imines, in which the imine and the enone groups are separated by alkyl chains, yield optically active cyclohexane and cyclopentane derivatives. /ra .v-l,2-Disubstitutcd carbocyclic compounds are exclusively or predominantly formed with diastereomeric ratios in the range 80 20 100 0, strongly dependent on the conditions used to induce cyclization, i.e. heat, pressure or Lewis acid (MgBr2) catalysis227. 

The intramolecular cyclization route to p-lactams still provides interest. P-Amino esters (obtained by a Reformatsky-type reaction of an imine and bromoacetates derived from chiral alcohols) are cyclized by the action Grignard reagents to 4-substituted P-lactams with impressive e.e. <96TL4095>. A similar approach through a Reformatsky-type reaction uses tricarbonyl(Ti -benzaldimine)chromium complexes and ultrasound <96T4849>. 3-Methyl-azetidin-2-ones (obtained from 3-amino-2-methylpropionates) have been resolved and their... 

Intramolecular process with rhodium catalyst has been described for the syntheses of indane, dihydroindoles, dihydrofurans, tetralins, and other polycyclic compounds. Wilkinson catalyst is efficient for the cyclization of aromatic ketimines and aldimines containing alkenyl groups tethered to the K z-position of the imine-directing group. 

The intramolecular cyclization of l,2-dien-7-ynes and l,2-dien-6-ynes regiospecifically affords the corresponding titanacycles, which react with protons, carbon monoxide, aldehydes, or imines to give single products, as shown in Eqs. 9.56 and 9.57 [102], As the formation of titanacycles and their subsequent reaction with externally added reagents such as carbon monoxide (Eq. 9.56) or an aldehyde (or imine) (Eq. 9.57) proceeds with excellent chirality transfer, this represents a new method for synthesizing optically active cyclopentane derivatives from optically active allenes [102]. 

Scheme 29 describes a plausible mechanism for the formation of the products which fit the observed coulometric (n 0.45 F/mol) and preparative results. The intramolecular cyclization process involves a dimerization between a radical cation 52a and the ketene imine 52 to form the intermediate radical cation 52b which then cyclizes to the radical 52c which can abstract a hydrogen atom leading to 54 or can be further oxidized and transformed through a cyclization and deprotonation reaction to 53 which involves 1 F/mol. However, it seems that the [2 -1- 3]-cycloaddition between the parent compound 52 and the cation 52d giving rise to 55 is the fastest reaction as compared with the intramolecular cyclization of 52d to 53. This can also explain the low consumption of electricity. 

The reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

Radical cyclizations are often used in ring formations and are an effective methodology in the synthesis of piperidines. The intramolecular cyclization of an oxime ether, such as 63 onto an aldehyde or ketone gives a new entry into cyclic amino alcohols <99JOC2003, 99H(51)2711>. Similarly, reaction of a terminal acetylene with BujSnH generates a vinyl radical, which will cyclize with an imine moiety to give 3-methylenepiperidine <99TL1515>. The indolizidine alkaloid ipalbidine was prepared by a sulfur-controlled 6-exo-selective radical cyclization of an a/p/ia-phenylthio amide <99H(50)31>. 

Benzothiadiazines (158) are prepared by cyclization of the chlorohydrazones (212) on treatment with triethylamine (81JCS(Pl)2245). The reaction probably involves intramolecular nucleophilic attack by sulfur on a nitrile imine intermediate, since (212) does not cyclize on heating alone. Intramolecular aromatic sulfonation gives 1,2,4-benzothiadiazine 1,1-dioxides (214). Thus treatment of (213) with aluminum trichloride leads to cyclization with bond formation between sulfur and the aromatic ring (79JCS(P1)1043). 

Azomethine imine cycloadditions provide access to pyrazolidines, pyrazolines and pyrazoles. Intramolecular cyclizations were first reported in 1970.78 The main method for generation of azomethine im-ines involves reaction of a 1,2-disubstituted hydrazine with an aldehyde or an aldehyde precursor. 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

Dake s group84 published an interesting report in which AgOTf and cationic gold (I) complexes were compared for their use in the synthesis of the pyrrole scaffold. From (3-alkynyl ketones 66 (Scheme 5.29) and various primary amines 67, the imine intermediates JJ were formed in situ and the intramolecular cyclization produced various pyrroles 68. Both catalysts AgOTf (5 mol%) or Au(PPh3)OTf (5 mol%) were efficient, but the reaction proceeded more rapidly with silver catalysis. 

Similarly, the regio- and diastereoselective formation of azetidines can be accomplished through olefin insertion into the Zr-C bond of zirconaaziridines (Eq. 14). Cleavage of the Zr-C bond with I2 introduces an alkyl iodide functionality, which alkylates at nitrogen to result in intramolecular cyclization and the diastereoselective formation of azetidines, the products of the formal zirconium-mediated [2+2] reaction of an imine and an olefin. Hindered cyclic alkenes can also insert into the Zr-C bonds of zirconaaziridines to yield bi-cyclic products [55], albeit with low diastereoselectivity (2 1 for norbornene). 

A method to synthesize substituted imidazoles starts from 1,2-aminoalcohols 1081 via a four-step procedure, as demonstrated in Scheme 263. Oxidation of acylated alcohol 1082 leads to a ketone 1083, which is transformed into imine 1084. Activation of the amide bond with dehydrating agent PCls leads to intramolecular cyclization, providing... 

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