By cyclization

SUBSTITUTED BUTADIENES. The consequences of p-type orbitals rotations, become apparent when substituents are added. Many structural isomers of butadiene can be foiined (Structures VIII-XI), and the electrocylic ring-closure reaction to form cyclobutene can be phase inverting or preserving if the motion is conrotatory or disrotatory, respectively. The four cyclobutene structures XII-XV of cyclobutene may be formed by cyclization. Table I shows the different possibilities for the cyclization of the four isomers VIII-XI. These structmes are shown in Figure 35. 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

Another category Ic indole synthesis involves cyclization of a-anilino aldehydes or ketones under the influence of protonic or Lewis acids. This corresponds to retro.synthetic path d in Scheme 4.1. Considerable work on such reactions was done in the early 1960s by Julia and co-workers. The most successful examples involved alkylation of anilines with y-haloacetoacetic esters or amides. For example, heating IV-substituted anilines with ethyl 4-bromoacetoacetate followed by cyclization w ith ZnClj gave indole-3-acetate esterfi]. Additional examples are given in Table 4.3. 

A -(2 2-Diethoxyethyl)anilines are potential precursors of 2,3-unsubstituted indoles. A fair yield of 1-methylindole was obtained by cyclization of N-inethyl-M-(2,2-diethoxyethyl)aniline with BFj, but the procedure failed for indole itself[2], Nordlander and co-workers alkylated anilines with bromo-acetaldehyde diethyl acetal and then converted the products to N-trifliioro-acetyl derivatives[3]. These could be cyclized to l-(trifluoroacetyl)indoles in a mixture of trifluoroacetic acid and trifluoroacetic anhydride. Sundberg and... 

Mercapto-imida2oliuin inner salts have been reported to rearrange under the influence of hydrochloric acid, producing S-aminothiazolium chlorides (Scheme 25) (36). Their N-acylated derivatives are obtained by cyclization of N-thiobenzoyl alkylaminoacetonitriles, effected with acyl or sulfonyl halides (Scheme 26) (34, 35). 

Arylamino-2-chloroprop-2- enoic esters (72) obtained from 2-chloroaceto acetic ester (71) and arylamines, react with thiourea to yidd substituted 2-aminothiazoles (73), probably by initial nucleophilic substitution of the chloro atom of 72, followed by cyclization with loss of aniline (Scheme 33) (729). 

Thiazole acetic acids and their hotnologs can also be prepared by cyclization procedures 4-thiazole alkanoic acids and their salts were prepared by treating a thioamide with a -y-chloro- or 7-bromoacetoacetic or their a-alkyl derivatives (4, 10, 16, 22, 273, 275, 281, 640, 647, 695). 

Hydroxy-5-cyanothiazoles (817) were prepared by cyclizing Et02-CNHCSR (R = OEt, OBu, SEt, SCHjAr, OCHaAr) with a-chloro-acetonitrile (Scheme 145). 

The reactivity of alkylthiazoles possessing a functional group linked to the side-chain is discussed here neither in detail nor exhaustively since it is analogous to that of classical aliphatic and aromatic compounds. These reactions are essentially of a synthetic nature. In fact, the cyclization methods discussed in Chapter II lead to thiazoles possessing functional groups on the alkyl chain if the aliphatic compounds to be cyclized, carrying the substituent on what will become the alkyl side chain, are available. If this is not the case, another functional substituent can be introduced on the side-chain by cyclization and can then be converted to the desired substituent by a classical reaction. 

Haloalkylthiazoles are generally prepared by cyclization or from the corresponding hydroxyalkythiazole. They in turn can lead to numerous functional derivatives, such as aminoalkylthiazoles (33-42.50. 854), ethers... 

Hydroxyalkylthiazoles are also obtained by cyclization or from alkoxyalkyl-thiazoles by hydrolysis (36, 44, 45, 52, 55-57) and by lithium aluminium hydride reduction of the esters of thiazolecarboxylic acids (58-60) or of the thiazoleacetic adds. The Cannizzaro reaction of 4-thiazolealdehyde gives 4-(hydroxymethyl)-thiazole (53). The main reactions of hydroxyalkyl thiazoles are the synthesis of halogenated derivatives by the action of hydrobroraic acid (55, 61-63), thionyl chloride (44, 45, 63-66), phosphoryl chloride (52, 62, 67), phosphorus penta-chloride (58), tribromide (38, 68), esterification (58, 68-71), and elimination that leads to the alkenylthiazoles (49, 72). 

The amide can be prepared classically from the acid chloride or by ammonolysis of the ester, prepared directly by cyclization (15, 75, 78-80). 

The 4,5-dihalogenothiazoles are obtained by cyclization-halogenation reactions as show in scheme 12 (3). 2-Acetamido-4,5-diiodothiazole has been obtained by Hurd and Wehrmeister (80). The triiodothiazole can be prepared by iodination by molecular iodine of the mercuric complex of 2-iodothiazole following the Travagli method (81). 

PurpurogaHin (5), a red-brown to black mordant dye, forms from electrolytic and other mild oxidations of pyrogaHol (1). The reaction is beHeved to proceed through 3-hydroxy-(9-benzoquinone (2) and 3-hydroxy-6-(3,4,5-trihydroxyphenyl)-(9-benzoquinone (3). The last, in the form of its tautomeric triketonic stmcture, represents the vinylogue of a P-diketone. Acid hydrolysis leads to the formation of (4), foHowed by cyclization and loss of formic acid... 

The pyrazole ring is resistant to oxidation and reduction. Only ozonolysis, electrolytic oxidations, or strong base can cause ring fission. On photolysis, pyrazoles undergo an unusual rearrangement to yield imidazoles via cleavage of the N —N2 bond, followed by cyclization of the radical iatermediate to azirine (27). 

The principal pathway for the decomposition of aspartame begins with the cleavage of the ester bond, which may or may not be accompanied by cyclization (Eig. 2). The resultant diketopipera2ine and/or dipeptide can be further hydroly2ed into individual amino acids (qv). 

When dihydromyrcene is treated with formic acid at higher temperatures (50°C) than that required to produce dihydromyrcenol and its formate, an unexpected rearrangement occurs to produce a,3,3-trimethylcyclohexane methanol and its formate (106). The product is formed by cyclization of dihydromyrcene to the cycloheptyl carbonium ion, which rearranges to give the more stable cyclohexyl compound (107). The formate ester, a,3,3-trimethylcyclohexane methanol formate [25225-08-5] (57) is a commercially avaUable product known as Aphermate. 

Enantioselective addition of hydrogen cyanide to hydroxypivaldehyde (25), catalyzed by (lf)-oxynittilase, afforded (R)-cyanohydrin (26) in good optical yield. Acid-catalyzed hydrolysis followed by cyclization resulted in (R)-pantolactone in 98% ee and 95% yield after one recrystallization (56). 

Aminophenols. Reaction of chloroformate with aminophenols (qv) also takes place at the more reactive amino group selectively. Thus (9-aminophenol [95-55-6] gives benzoxazolone [59-49-4] by cyclization of the intermediate carbamate (31). 

Another positive-working release by cyclization, illustrated by equation 5, starts with an immobile hydroquinone dye releaser (8), where R = alkyl and X is an immobilizing group. Cyclization and dye release take place in alkaU in areas where silver haUde is not undergoing development. In areas where silver haUde is being developed, the oxidized form of the mobile developing agent oxidizes the hydroquinone to its quinone (9), which does not release the... 

Hydroxycoumarin [1076-38-6] can be synthesized by cyclization of acetyl methyl salicylate. It is a coumatin metaboHte occurring in spoiled hay. Derivatives of 4-hydroxycoumarin such as dicoumarol [66-76-2] warfarin [81-81-2] cyclocoumarol [518-20-7] ethylbis—coumaracetate [548-00-5] and bis-4-hydroxycoumarin [25892-93-7] are synthetic blood anticoagulants (see Blood, coagulants and anticoagulants). 

When an acetylamino group is attached at an ortho position the replacement of chlorine is followed by cyclization. For example, 4-acetylamino-5-chloro-l-phenylpyridazin-6(lH)-one is converted with hydrogen sulfide in DMF to 2-methyl-6-phenylthiazolo[4,5- f]pyridazin-7(6//)-one (116). 

In some instances, ring contraction is accompanied by cyclization to indole derivatives. For example, l-aryl-6-oxo-l,4,5,6-tetrahydropyridazines with a carboxyl or methyl group at position 3 give indoles when treated with an ethanolic solution saturated with hydrogen chloride or in the presence of BF3 etherate. 

Various 4-aminopteridine 3-oxides have recently been obtained by cyclization of 2-amino-3-cyanopyrazine derivatives (81H(15)293). 

Reaction of thiazoles with DMAD illustrates the overall reaction and the rearrangements which may be encountered. Thiazole or 2-methylthiazole (411 R=H and Me, respectively) in DMF reacted with DMAD to give an initial 1,4-dipolar species (412). Reaction with a second DMAD gave the 1 2 molar adduct, presumably (413). Ring opening to (414), followed by cyclization in the alternative mode, resulted in the formation of (415), the structure of which (R = Me) was established by X-ray analysis (78AHC(23)263) (see also Chapter 4.19). 

The synthetic potential of nitrenes is more readily apparent in the synthesis of ring-fused systems (81AHC(28)309), which can be accomplished by cyclization onto a heteroatom or onto an adjacent ring, the latter having the possibility of reaction at carbon or at a heteroatom. 

Acyl-4-aminoisoxazoles have been prepared by cyclization of a-(acylmethoxy-imino)nitriles in the presence of lithium hydroxide (equation 44) (80LA1623). 

This class was first reported in 1924 and was formed 62HC(17)l) by cyclization of a-bromo-/3-aryl-y-nitroketones. The direct synthesis by oxygenation of 2-isoxazolines has not been reported. To date only 3-substituted derivatives have been prepared. Aryl-nitromethanes react with nitrostilbene to form isoxazoline A-oxide by a nitrile ion displacement (Scheme 138) <62HC(17)1, 68TL3375). 

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