Cyclization with carbonyls

Replacement of carbonyl by sulfonyl led to the benzo-2,l,3-thiadiazin-4-one 2,2-dioxide ring system, in particular bentazon (7) (68SAP6705164). It can be synthesized by reaction of 2-aminobenzoic acid, or ester, with isopropylsulfamoyl chloride, followed by cyclization with carbonyl chloride in the case of the acid, or sodium hydroxide in the case of the ester. 

The most frequently used method of this type is the reaction of hydrazones (247) with diazonium compounds to afford formazans (248). These can be cyclized with carbonyl compounds in the presence of acid to yield verdazylium cations (252) which are reduced under basic conditions to give the verdazyls (253) which can be further reduced to the tetrahydro-l,2,4,5-tetrazines (254). The formazans (248) can be alkylated and the alkylfor-mazans (249) cyclized by heating or treatment with a base to form the tetrahydrotetrazines (250). It is not necessary to isolate the alkylated compounds (249) the complete reaction (248-250) can be carried out at room temperature in the presence of barium oxide or hydroxide in DMF. Oxidation of (250) provides a synthesis of verdazyls (251) (see Section 2.21.3.4.2). 

The use of diazocarbonyl compounds in the synthesis of O-bridged systems is the approach of choice. There are a few main synthetic strategies of bridged framework building based on this approach tandem cyclization with carbonyl ylide formation/cycloaddition, tandem cyclization with 0x0-nium ylide formation/sigmatropic shift, intramolecular cyclopropanation, and cyclization with single bond insertion. 

A combination of palladium-ene cyclization with carbonylation reactions is particularly attractive since it permits the stereoselective formation of four carbon-carbon bonds in a single process. In this reaction, 7r-allylpalladium complex 47 (Scheme 11) is formed from allyl carbonate 46 and Pd(0), and it is then converted into vinylpalladium complex 48 via palladium-ene cyclization. Carbonylation of 48 gives bicyclic compound 49, which is further reacted with carbon monoxide to give carboxylic acid 50. 

Yoo achieved the syntheses of a-kainic acid (63) and a-allokainic acid (64) using Pd-ene cyclization with carbonylation (Scheme 14). " ° Cyclization of 65 with Pd(dba)2,... 

Other interesting regioselective reactions are carried out within the synthesis of nitrofurantoin. Benzaidehyde semicarbazone substitutes chlorine in chloroacetic ester with the most nucleophilic hydrazone nitrogen atom. Transamidation of the ester occurs with the di-protic outer nitrogen atom. Only one nucleophilic nitrogen atom remains in the cyclization product and reacts exclusively with carbonyl compounds. 

An unusual reaction was reported in which 2-(4-pyridyl)-4-carboxyethylthiazole (50) prepared from thioisonicotinamide (49) and ethylbromopyruvate (48) was converted to 51, which upon treatment with KNCS in the presence of NaHCOj gave 52 (618). This was again cyclized with 48 to yield 2-(4-pyridyI)-4-(4-ethoxycarbonyl-2-thiazolyl hydrazino-carbonyl)thiazole (S3) (Scheme 24). 

Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

The mechanism of the original Knorr pyrrole synthesis entails in situ reduction of the oxime moiety to an amine, condensation with the second carbonyl compound, and cyclization with loss of a second molecule of water to give a pyrrole for example, 10 + 11 to 12. Several studies have demonstrated that different pathways and pyrrole products obtain depending on the substrates. 

We have previously discussed that keto-aldehydes react with anilines first at the aldehyde carbon to form the aldimine. Subsequent condensation with another aniline formed a bis-imine or enamino-imine. The aniline of the ketimine normally cyclizes on the aldimine (24 —> 26). Conversely, cyclization of the aldimine could be forced with minimal aniline migration to the ketimine using PPA (30 —> 31). The use of unsymmetrical ketones has not been thoroughly explored a few examples are cited below. One-pot enamine formation and cyclization occurred when aniline 48 was reacted with dione 49 in the presence of catalytic p-TsOH and heat. Imine formation occurred at the less-hindered ketone, and cyclization with attack on the reactive carbonyl was preferred. ... 

Stereoselectivity in the condensation reaction of 2-arylethylamines with carbonyl compounds to give 1,2,3,4-tetrahydroisoquinoline derivatives was somewhat dependent on whether acid catalysis or superacid catalysis was invoked. Particularly in the cases of 2-alkyl-N-benzylidene-2-phenethylamines, an enhanced stereoselectivity was observed with trifluorosulfonic acid (TFSA) as compared with the weaker acid, trifluoroacetic acid (TFA). Compound 43 was cyclized in the presence of TFA to give modest to good transicis product ratios. The analogous compound 44 was cyclized in the presence of TFSA to give slightly improved transicis product ratios. 

An elegant synthesis of both isothiazole and 3-methylisothiazole has been reported by Wille and his co-workers.This depends on the cyclization with liquid ammonia of the cis form of the addition product 14 which is obtained from the appropriate acetylenic carbonyl... 

The aminobutynones 342 contain a push-pull system with a strongly electron-withdrawing carbonyl group therefore, they show electrophilic properties. Cyclizations with their participation proceed differently from those with ynamines (91UK103 00UK642) and acetylenic ketones (73UK511). 

So far, only reactions in which the internal nucleophile is tethered to the nitrogen atom of the A -acyliminium ion have been discussed, however, cyclizations with nucleophiles attached to other positions are also possible. If the nucleophile is connected to the carbon atom adjacent to the carbonyl group, bridged azabicycloalkane derivatives are obtained in high yield by using the more reactive allyl- or propargylsilanes. 

Carbonyl-ene reactions can be carried out in combination with other kinds of reactions. Mixed acetate acetals of y,8-enols, which can be prepared from the corresponding acetate esters, undergo cyclization with nucleophilic capture. When SnBr4 is used for cyclization, the 4-substituent is bromine, whereas BF3 in acetic acid gives... 

Nickel(O) complexes are extremely effective for the dimerization and oligomerization of conjugated dienes [8,9]. Two molecules of 1,3-butadiene readily undergo oxidative cyclization with a Ni(0) metal to form bis-allylnickel species. Palladium(O) complexes also form bis-allylpalladium species of structural similarity (Scheme 2). The bis-allylpalladium complexes show amphiphilic reactivity and serve as an allyl cation equivalent in the presence of appropriate nucleophiles, and also serve as an allyl anion equivalent in the presence of appropriate electrophiles. Characteristically, the bis-allylnickel species is known to date only as a nucleophile toward carbonyl compounds (Eq. 1) [10,11],... 

Stepanov et a/.143,144 report the ring opening of the monoxide (116) to several 2-oxaadamantane derivatives, where 116 is readily obtained by perbenzoic acid oxidation of 35. Treatment of 116 under various conditions yields different products. Thus, with aqueous acid it yields l-hydroxy-3-hydroxymethyl-2-oxaadamantane (117), with alcohols (R = CH3, C2H5) in acidic or basic media 1-alkoxy-substituted (118), and with hydrochloric acid l-chloro-3-hydroxymethyl-2-oxaadamantane(119). l-Methyl-2-oxaadaman-tane (120) is prepared by LAH reduction of the carbonyl group in 35 to alcohol 121 and subsequent cyclization with acid.140,142... 

The addition of a carbonylation step extended a pyrrole synthesis to pyrrole-2-acetic acid derivatives <06ASC2212>. Treatment of enyne amine 1 with palladium diiodide in the presence of CO and methanol produced pyrrole-2-acetic ester 2 via a 5-exo-dig cyclization, oxidative carbonylation, and isomerization. 

Because the organosilane reduction of ketones passes through a positively charged intermediate via the complexation or protonation of the carbonyl oxygen, the presence of suitably placed C=C functions can lead to cyclizations with the hydride of the silane adding to the C=C group. This strategy applies to... 

Recently, four-component coupling reactions of aldehydes, alkynes, dienes, and dimethylzinc catalyzed by a nickel complex have been reported (Equation (78)).435 Similarly, l,c< -dienynes react with carbonyl compounds and dimethylzinc in the presence of an Ni catalyst to afford the corresponding cyclized products. 

In contrast to the rich chemistry of alkoxy- and aryloxyallenes, synthetic applications of nitrogen-substituted allenes are much less developed. Lithiation at the C-l position followed by addition of electrophiles can also be applied to nitrogen-containing allenes [10]. Some representative examples with dimethyl sulfide and carbonyl compounds are depicted in Scheme 8.73 [147, 157]. a-Hydroxy-substituted (benzotriazo-le) allenes 272 are accessible in a one-pot procedure described by Katritzky and Verin, who generated allenyl anion 271 and trapped it with carbonyl compounds to furnish products 272 [147]. The subsequent cyclization of 272 leading to dihydro-furan derivative 273 was achieved under similar conditions to those already mentioned for oxygen-substituted allenes. 

An a-allenic sulfonamide undergoes Pd-catalyzed carbonylative cyclization with iodobenzene, affording a mixture of isomeric heterocycles (Scheme 16.12) [17]. The coupling reaction of an allene with a PhCOPdl species takes place at the allenyl central catrbon to form a 2-acyl-Jt-allylpalladium complex, which is attacked by an internal sulfonamide group in an endo mode, affording a mixture of isomeric heterocycles (Scheme 16.13). 

On the other hand, when the oxidative carbonylation of a ,a -disubstituted propynylamines was carried out in the presence of an excess of CO2, the intermediate carbamate species could undergo cyclization with incorporation of CO2 into the five-membered cycle, either by direct nucleophilic attack of the carbamate oxygen to the triple bond coordinated to Pd(II) (Scheme 33, path a) or through the intermediate formation of a palladium carbamate complex followed by triple bond insertion (Scheme 33, path b). Carbon monoxide insertion into the Pd - C bond of the resulting stereoisomeric vinylpalladium intermediates then led to the final oxazolidi-none derivatives. 

MetaUation of 4-hetero-substituted dibenzothiins (427) with lithium, catalyzed by 4,4 -di-f-butylbiphenyl (equation 122), breaks one of the C—S bonds. Quenching with carbonyl compounds leads to the corresponding thiophenols (428) that may be cyclized to the homologous seven-membered heterocycles (429). The products can be characterized by IR, H and NMR spectroscopies and MS . ... 

Tetrahydrofuran itself can be opened using either the stoichiometric or the catalytic version of arene-promoted lithiation, but both cases need the activation by boron trifluoride. The catalytic reaction was performed by treating the solvent THF 324 with the complex boron trifluoride-etherate and a catalytic amount (4%) of naphthalene. The intermediate 325 was formed. Further reaction with carbonyl compounds and flnal hydrolysis yielded the expected 1,5-diols 326 (Scheme 95), which could be easily cyclized to the corresponding substituted tetrahydropyrans under acidic conditions (concentrated FlCl). 

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