Cyclizations salts

This type of ring system appears as salt 215. Thus, the reaction of azauracils 213 with dibromopropane at 78-85°C gave bromopropyl derivatives 214, whereas at 110-120°C the cyclized salts 215 were formed (82MI7, 82MI8) (Scheme 47). 

When carbodiimides are used in a molar ratio of 2 1 with respect to the aminoalcohol, addition occurs on both functional groups with subsequent cyclization. Salts of amino alcohols react similarly. 

In other cases cyclization occurs more readily, and when 2-halogenopyridines react with 3-(2 -bromoethyl) indole, the cyclized salt, e.g. (110), results. ... 

The intramolecular reaction oF allcenes with various O and N functional groups offers useful synthetic methods for heterocycles[13,14,166]. The reaction of unsaturated carboxylic acids affords lactones by either exo- or endo-cyclization depending on the positions of the double bond. The reaction of sodium salts of the 3-alkenoic acid 143 and 4-alkenoic acid 144 with Li2PdCl4 affords mostly five-membcrcd lactones in 30-40% yields[167]. Both 5-hexe-noic acid (145) and 4-hexenoic acid (146) are converted to five- or six-mem-bered lactones depending on the solvents and bases[168]. Conjugated 2,4-pentadienoic acid (147) is cyclized with Li2PdCl4 to give 2-pyrone (148) in water[i69]. 

A variation of the Madelung cyclization involves installing a functional group at the o-methyl group which can facilitate cyclization. For example, a triphenylphosphonio substituent converts the reaction into an intramolecular Wittig condensation. The required phosphonium salts can be prepared by starting with o-nitrobenzyl chloride or bromide[9]. The method has been applied to preparation of 2-alkyl and 2-arylindoles as well as to several 2-alkenylindoles. Tabic 3.2 provides examples. 

A special application of the Japp-Klingemann/Eischer sequence is in the preparation of tryptamines from piperidone-3-carboxylate salts, a method which was originally developed by Abramovitch and Shapiro[2]. When the piperidone is subjected to Japp-Klingemann coupling under mildly alkaline conditions decarboxylation occurs and a 3-hydrazonopiperidin-2-one is isolated. Fischer cyclization then gives 1-oxotetrahydro-p-carbolines which can be hydrolysed and decarboxylated to afford the desired tryptamine. 

Addition of arylhydroxylamines to electrophilic allenes such as methyl propadienoate or l-methancsulfonyl-l,2-propadiene is another route to 0-vinyl derivatives[2]. The addition step is carried out by forming the salt of the hydroxylamine using NaH and the addition is catalysed with LiO CCFj. The intermediate adducts are cyclized by warming in formic acid. Yields are typically 80% or better. 

Gassman and co-workers developed a synthetic route from anilines to indoles and oxindoles which involves [2.3]-sigmatropic rearrangement of anilinosul-fonium ylides. These can be prepared from Ai-chloroanilines and ot-thiomcthyl-ketones or from an aniline and a chlorosulfonium salt[l]. The latter sequence is preferable for anilines with ER substituents. Rearrangement and cyclizalion occurs on treatment of the anilinosulfonium salts with EtjN. The initial cyclization product is a 3-(methylthio)indole and these can be desulfurized with Raney nickel. Use of 2-(methylthio)acetaldehyde generates 2,3-unsubstituled indoles after desulfurization[2]. Treatment of 3-methylthioindoles with tri-fiuoroacetic acid/thiosalieylie acid is a possible alternative to Raney nickel for desulfurization[3]. 

The action of ammonia on N-(5-aryl-l,3-oxathioI-2-ylidene) tertiary iminium salts (7) affords linear intermediates that cyclize to 2-amino-4-phenylthiazoles (Scheme 7) (45). 

Hydroxvthiazolium hydroxide inner salts (2) (X = 0) have been synthesized by an improved acetic-anhydride-triethylamine-caialyzed cyclization of N-substituied N-thiobenzovlalanines (Scheme 15) (23). 

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). 

Starting from 2-bromoethylamine hydrobromide and selenourea, Chu and Mautner (60) prepared the salt of 2-(aminoethyl)-selenopseudourea, which cyclizes upon heating in aqueous solution to give 2-aminoselenazoline (Scheme 58). 

Another interesting case is afforded by 2-alkyl-N-phenacyl or N-acetonylthiazolium salt (239), which in basic medium gives an intramolecular cyclization product. According to Reid et al. (502), this could... 

The cyclization of -halocarbonyl compounds is carried out with a great variety of reactants including thioamides, thioureas, their mono- or disubstituted derivatives, and salts and esters of monothiocar-bamic acid, leading to variously substituted thiazoles. 

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). 

N-Monosubstituted thioamides (96) have been cyclized with a-halocarbonyl compounds to give thiazolium salts (97) in excellent yields (89, 99. 102, 305, 722). 

The first step of the reaction involves the formation of the S-C bond with the elimination of a molecule of ammonium salt. The fact that it has been possible to isolate the acyclic intermediate (176), R = Me or Ph, would confirm this hypothesis, particularly when the reaction is carried out for a short time in the cold in ethereal solution (27, 82). These intermediates (176) can be cyclized quantitatively on standing or on being treated by hydrochloric acid. However, no evidence has been advanced concerning their structures. 

The reaction probably proceeds through the S-cyanomethyl isothiouronium (238) salt, which can be isolated when the reaction is carried out in cold acetone. Cyclization takes place upon heating. 

The action of ammonia on N-(aryl-i,3-oxathiol-2-ylidine) tertiary im-inium salts (254) yields linear intermediates (255) that cyclize to 2-amino-4-phenyl thiazoles (256) on crystallization from acetic acid (Scheme 129) (730). 

Maddrell s salt Madelung cyclization Madopa Maduramicin... 

Diazo Coupling Reactions. Alkylphenols undergo a coupling reaction with dia2onium salts which is the basis for the preparation of a class of uv light stabilizers for polymers. The interaction of orxv i -nitrobenzenediazonium chloride with 2,4-di-/ r2 -butylphenol results in an azo-coupled product (30). Reduction of the nitro group followed by m situ cyclization affords the benzottiazole (31) (19). 

Reaction of (T)-(-)-2-acetoxysuccinyl chloride (78), prepared from (5)-mahc acid, using the magnesiobromide salt of monomethyl malonate afforded the dioxosuberate (79) which was cyclized with magnesium carbonate to a 4 1 mixture of cyclopentenone (80) and the 5-acetoxy isomer. Catalytic hydrogenation of (80) gave (81) having the thermodynamically favored aH-trans stereochemistry. Ketone reduction and hydrolysis produced the bicycHc lactone acid (82) which was converted to the Corey aldehyde equivalent (83). A number of other approaches have been described (108). 

Subsequent dehydrohalogenation afforded exclusively the desired (Z)-olefin of the PGI2 methyl ester. Conversion to the sodium salt was achieved by treatment with sodium hydroxide. The sodium salt is crystalline and, when protected from atmospheric moisture and carbon dioxide, is indefinitely stable. A variation of this synthesis started with a C-5 acetylenic PGF derivative and used a mercury salt cataly2ed cyclization reaction (219). Although natural PGI has not been identified, the syntheses of both (6R)- and (65)-PGl2, [62777-90-6] and [62770-60-7], respectively, have been described, as has that of PGI3 (104,216). 

In acid solution, the double bond of (203) is hydrogenated to the trans-fused sulfone (204). Presumably, this hydrogenation goes through a cis-fused intermediate that is rapidly epimerized to (204) under the acidic conditions of the reaction. Condensation of the sodium salt of 7,7-ethylenedioxy-3-oxooctanoate (205) with (204) produces (206). Cmde (206) is cyclized, hydroly2ed, and decarboxylated, producing the tricycHc compound (207). Hydrogenation of (207) followed by ketal hydrolysis and cyclization affords (208) in an overall yield of 35% from hydrindandione (203). 

The acid-instabihty of erythromycin makes it susceptible to degradation in the stomach to intramolecular cyclization products lacking antimicrobial activity. Relatively water-insoluble, acid-stable salts, esters, and/or formulations have therefore been employed to protect erythromycin during passage through the stomach, to increase oral bioavakabihty, and to decrease the variabiUty of oral absorption. These various derivatives and formulations also mask the very bitter taste of macroHdes. 

The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

Unsaturated hydrazones, unsaturated diazonium salts or hydrazones of 2,3,5-triketones can be used as suitable precursors for the formation of pyridazines in this type of cyclization reaction. As shown in Scheme 61, pyridazines are obtainable in a single step by thermal cyclization of the tricyanohydrazone (139), prepared from cyanoacetone phenylhydrazone and tetracyanoethylene (76CB1787). Similarly, in an attempted Fischer indole synthesis the hydrazone of the cyano compound (140) was transformed into a pyridazine (Scheme 61)... 

TL2733,82TL2737). The reaction proceeds through an aza-Cope rearrangement of the initially formed iminium salt, followed by intramolecular cyclization. 

Analogous open-chain precursors also lead readily to 1,3-dithiolylium salts. S-a-Oxoalkyl thioesters such as (20) on treatment with perchloric acid in glacial acetic acid and HaS undergo ready cyclization to the 1,3-dithiolylium perchlorate (22) (66AH0.7)39). The oxoalkyl dithioesters (21) are probably intermediates in this cyclization as they themselves undergo cyclization with warm 70% perchloric acid or sulfuric acid (80AHC(27)15l). 

Diaryl derivatives of the 1,3-oxathiolylium system (29) are prepared by acid-catalyzed cyclization of the /3-keto thioesters (28) which are readily prepared from thioacid salts (27)... 

The latter approach is illustrated by the conversion of the 2-thiazolethione (90) into the thiazolo[2,3-6]thiazolylium salt (92) by reaction with the a-halogenoketone. The intermediate (91) may be isolated, and strong acid was required to effect the final cyclization (77HC(30-1)1). A wide variety of [5,5] fused systems are prepared in this way, and variations of this approach are discussed in Chapter 4.36. 

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