Intramolecular decarboxylative cyclization

The third and fourth steps in the synthesis of Hagemann s ester from ethyl acetoacetate and formaldehyde (Problem 23.50) are an intramolecular aklol cyclization to yield a substituted cyclohexenone, and a decarboxylation reaction. Write both reactions, and show the products of each step. 

Several examples of transition metal catalysis for the synthesis of piperidines appeared this year. Palladium catalyzed intramolecular urethane cyclization onto an unactivated allylic alcohol was described as the key step in the stereoselective synthesis of the azasugar 1-deoxymannojirimycin . A new synthetic entry into the 2-azabicyclo[3.3.1]nonane framework was accomplished through a palladium mediated intramolecular coupling of amine tethered vinyl halides and ketone enolates in moderate yields . A palladium catalyzed decarboxylative carbonylation of 5-vinyl... 

Doll, M. K. H. A Short Synthesis of the 8-Azaergoline Ring System by Intramolecular Tandem Decarboxylation-Cyclization of the Minisci-... 

The decarboxylative cyclization could be prevented by using two equivalents of the corresponding aldehyde component 395, which led to spirodihydropyridines 396 as shown by Li et al. (Scheme 13.82) [139], or by exchanging the amino group by a hydroxyl substituent and adding ammonium acetate as the amine source [ 159]. In this 4CR, the Meldrum s acid moiety is hydrolyzed to give the carboxyhc acid 399 that is stabilized by an intramolecular hydrogen bond. 

The cyclic 8-keto ester produced in an intramolecular Claisen cychzation can be further alkylated and decarboxylated by a series of reactions analogous to those used in the acetoacetic ester synthesis (Section 17.5). Alkylation and subsequent decarboxylation of ethyl 2-oxocyclohexanecarboxylate, for instance, yields a 2-alkylcyclohexanone. The overall sequence of (1) intramolecular Claisen cyclization, (2) 8-keto ester alkylation, and (3) decarboxylation is a powerful method for preparing 2-substituted cyclohexanones and cyclopentanones. 

Although the oxidation potentials of carboxylates are relatively high compared to other electron donor groups (e.g., acetate Eqx. = 1-54 V in MeCN, 2.65 V in HjO vs. SCE), the decarboxylative cyclization proceeds very efficiently and many functional groups are tolerated. As the key step in the reaction, rapid intramolecular photoinduced electron transfer proceeds via the jt,7t state or the higher excited n,Jt triplet state in the nanosecond time regime. ... 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

The radical produced from the oxidative decarboxylation may also be trapped intramolecularly to form five- and six-membered rings (Scheme 17). The Kolbe protocol avoids the use of the toxic organ-otin reagents that are commonly used in the formation of radicals. Moreover, when alkyltin hydride reagents are used, a C—H bond is formed. The Kolbe reaction protocol, on the other hand, allows the radical formed after cyclization to be captured by a different radical in a coelectrolysis experiment, rather than being reduced. This tandem sequence of events has been exploited in the construction of prostaglandin precursor (70) [37-41]. Here, the cyclized... 

Enamine 106 (derived from Meldrum s acid), in a process of mono-decarboxylating transesterification and subsequent intramolecular alkylation, is cyclized to form enamino ester 107 (90H(31)1251). The direct route by flash vacuum thermolysis does not work in the case of 6/7 bicyclic 107. Methylene compound 109 originates (analogously to bicyclic 40b) from... 

In an extensive study into the application of the decarboxylative approach to azomethine ylides, Giigg reported the construction of numerous, complex polycyclic systems via an intramolecular protocol. Thiazolidine-4-carboxylic acid (263) was shown to react with 264 in refluxing toluene to furnish a 2 1 mixture of 265 and 266 in 63% yield (81). The reaction is assumed to occur via condensation of the aldehyde and amino acid to generate the imine 267, followed by cyclization to 268. Subsequent thermal decarboxylation of the ester generates either a syn dipole leading to 265 from an exo transition state, or an anti dipole and endo transition state generating adduct 266 (Scheme 3.90). 

The application of the Friedlander reaction to 3-aminopyridine-2-carbaldehyde (135) gives good yields of the 2,3-disubstituted 1,5-naphthyridines (136) (75CR(C)(280)38l). The intramolecular cyclization of /3- (3-aminopyridinyl)acrylic acid (137) results in the formation of l,5-naphthyridin-2-one (138) (66JHC357), whilst the condensation of 3-aminopyridine-2-carboxylic acid or its esters (139) with active methylene compounds yields 4-oxo (132) and 4-hydroxy-2-oxo compounds (134 R = H) after hydrolysis and decarboxylation of the intermediates (140) and (134 R = C02Et). Reductive cyclization of the 3-nitropyridine derivative (141) gives the 1,5-naphthyridine (142) (71JOC450). 

Thiepane (35) has been synthesized by an intramolecular radical addition of the thiyl radical (equation 59) which was generated by photolysis of a thiol (71TL2025). Similarly, C—S bond formation has been achieved (equation 60) by an intramolecular condensation of 6-mercaptohexanoic acid to give the thiolactone, thiepan-2-one (135) (64MI51700). A Dieckmann-type base-catalyzed cyclization of a diester precursor followed by acid-catalyzed hydrolysis and decarboxylation has been used in the synthesis of thiepan-3-one (41) as indicated in equation (61) (52JA917). 

In this synthetic sequence, displacement of the benzylic chloride from o-chlorobenzylchloride 100, with ethyl cyanoacetate anion afforded 3-(2-chlorophenyl)-2-carboethoxypropionitrile 101 in 68% yield after distillation. Saponification of the ethyl ester followed by thermal decarboxylation and fractional vacuum distillation, provided 3-(2-chlorophenyl)propionitrile 102 in 92% yield. Intramolecular cyclization was accomplished with sodium amide in liquid ammonia to afford 1-cyanobenzocyclobutene 103 as a colorless liquid in a... 

The reaction of iV-(2,4-dinitrophenyl)amino acids with base in aqueous dioxane has been shown to give benzimidazole iV-oxides (7). The rate-determining step is likely to be formation of an iV-alkylidene-2-nitrosoaniline intermediate (6), which is followed by rapid cyclization and decarboxylation.19 The loss of carbon dioxide from perbenzoate anions has been investigated by mass spectrometry and electronic structure calculations. The results, including isotopic labelling experiments, support a mechanism involving initial intramolecular nucleophilic attack at either the ortho- or ipso-ring positions. They also indicate that epoxides may be intermediates en route to the phenoxide products.20 There has also been a theoretical study of the formation of trichlorinated dibenzo-/ -dioxins by reaction of 2,4,5-trichlorophenolate ions with 2,4-dichlorophenol.21... 

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