Carboalkoxy

Many. groups such as carhoxamido, carboalkoxy, amidino, etc. are rather readily decomposed by nucleophiles. Some, such as nitrile and aldehyde groups, add nucleophiles reversibly (cf. 96). 

Carboxyl-related and acyl substituents. Included here are cyano, protonated amidinium ion, thionoacyl, acyl (Ar—CO, H—CO, Alkyl—CO), carboxamido, carboaryloxy, carboalkoxy, carboxy (unionized), amidino (unionized), and carboxylate anion, listed approximately in order of decreasing electron attraction or activation. The relative activation by some of these groups (e.g., ketone, aldehyde, nitrile) will change upon reversible interaction with the nucleophile, which will vary with the group and with the nucleophile (e.g., MeO , N3, NCS ). Irreversible interaction will be obvious when the reaction products in kinetic studies are characterized. 

Alteration of positional selectivity will result from built-in solvation of the transition state by an adjacent carboxyl-related function.Aminations will be so affected by carboxyl, carboxylate ion, carboalkoxy and less so by carboxamido groups (cf. Section I,D,2,b, structure 12.) Other substitutions such as alkoxylations can be so affected by carboxamido and amidino groups (cf. Section I,D, 2,b, structure 14). The effect of the cyclic hydrogen-bonded form (63) of 2-carboxamidopyridine on the reactivity of a leaving group is not known. 

The self-reactions of 2-carboalkoxy-2-propyl radicals (8-10) have been examined.89 Ia> 104 The results of these studies are reported in Table 5.3. Combination is slightly favored over disproportionation. The value of kjkw for 8 was found to be essentially independent of temperature. 

The secondary benzylic alcohol l-phenylethan-l,2-diol requires 20 hours of treatment at room temperature to produce a 64% yield of 2-phenylethanol (Eq. 43).137 Under the same conditions, methyl mandelate fails to undergo reduction, presumably because of the greater carbocation-destabilizing effect of a neighboring carboalkoxy compared to a hydroxymethyl group (Eq. 43).137... 

The same results obtain whether carboalkoxy compounds 12,13 or alkoxyacetyl complexes 6,7 are treated with excess acid. Alkyl acetate liberated in these experiments, of course, derives from two CO ligands on CpFe(CO)3+ (1). 

The trans-cis isomerization process observed in the eudesmane/germacrane ring system has been utilized for the synthesis of the c/s-fused sesquiterpene occidentalol, 48a, and its 7-epi isomer, 48b (Scheme ll)22. Photolysis of the traws-fused diene 45 at —78°C afforded triene 46, which upon warming underwent disrotatory electrocyclization to give 47a and 47b as a 1 2 mixture of diastereomers. Apparently, the carboalkoxy group imparts... 

Methyl isocyanoacetate is known to react with such electron deficient alkenes under basic conditions to give 2-carboalkoxy pyrroles (6) via... 

A different method of reduction involves the reaction with strong base, such as OH- and OR-. In this case, the primary reaction is nucleophilic attack on a carbon atom of a terminal carbonyl group as shown by the formation of a carboalkoxy group on reaction with alkoxide ... 

In the case of cobalt (R = /-Pr)61 the anion has a low stability and decomposes in a few hours, probably by demolition with carbon monoxide. With rhodium185) and iridium102) (R = OMe-), it has been possible to isolate the carbomethoxy anion in a pure form. The carboalkoxy group undergoes further reaction with sodium hydroxide to give the corresponding dianion18 s) ... 

In the other mechanism, the catalytic cycle initiates through the insertion of CO into a Pd-alkoxy bond, with formation of a Pd-carboalkoxy intermediate, which inserts the olefin with formation of an alkylcarboalkoxy /i-chelate, which undergoes protonolysis by the alkanol through the intermediacy of its enolate isomer (see Sect. 2.3.1), yielding the ester and the Pd-alkoxy species, which then initiates a new catalytic cycle [122-125]. 

Moreover, catalysis is enhanced when carried out in the presence of HC1, which does not favour the formation of the carboalkoxy complex because of Eq. 22. In addition, no catalysis is observed when carried out in the presence of a base such as NEt3, which favours the formation of the carboalkoxy complex in this case there is formation of inactive Pd(0) complexes [127]. 

The isolation of acyl and carboalkoxy complexes proves that the insertion of CO into both a Pd-alkyl and into a Pd - OR species occurs easily. Quite interestingly, it has been found that CO inserts only into the Pd - OCH3 bond of the complex [Pd(CH3)(OCH3)(P - P)] and that after insertion methyl acetate eliminates with the formation of [Pd(CO)2(P - P)] [131]. 

That the carbomethoxy is unlikely to be operative is suggested also by the fact that in an attempt to synthesize a carboalkoxy derivative, [PdCkIdtbpx)] was allowed to react with EtOH in the presence of NEt3, or with Na(OCH3), in... 

Figure 2.26 shows an alkoxide attack at co-ordinated CO giving a carboalkoxy complex, and a borohydride attack at co-ordinated CO in which the boron simultaneously acts as a Lewis acid. The BH3 complexation now stabilises the formyl complex that would otherwise be thermodynamically inaccessible. So far the latter reaction has only been of academic interest in homogeneous systems (it may be relevant to heterogeneous systems though proof is lacking). 

A convenient method to affect the oxidation p- to nitrogen in piperidines is based on the anodic oxidation of N-carboalkoxy piperidines (Scheme 35). The electrochemical oxidation of piperidine (152) in the presence of acetic acid and potassium acetate, for example, afforded a mixture of isomeric 2-hydroxy-3-acetoxypiperidines (153) in a combined yield of 93%, following an aqueous workup [61]. Reduction with sodium boro-hydride severed the C-OH bond. Treatment with acid and then base completed a synthesis of pseudoconhydrine (154). 

Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry has contributed remarkably to unravelling the termination and initiation steps of the styrene/CO copolymerisation catalysed by the highly active bis-chelated complex [Pd(bipy)2](Pp5)2 in TFE [40]. Chain-end group analysis of the material produced in the absence of BQ showed that the termination by P-H elimination is accompanied by three different initiators two palladium alkyls from Pd-H formed by reaction of the precursor with CO and water (a and b) and a palladium carboalkoxy species formed by reaction of the precursor with the fluorinated alcohol and CO (c) (Chart 7.4). The suppression of the chain-transfer by alcoholysis was proposed to be responsible for the enhanced stability of the palladium acyl intermediates and hence for the high molecular weight of the copolymers produced. 

Shtamburg and coworkers have reported that A,A -dialkoxy-A,A -dicarboalkoxyhydra-zines (219) have lower barriers to amide isomerization and weaker anomeric interactions . They measured a barrier to amide isomerization of only 9.8 kcalmoD. Furthermore, benzylic methylenes in A-benzyloxy systems were isochronous down to at least —90°C. These results are in line with observations for the A,A -diacyl-A,A -dialkoxyhydrazines since, in the carboalkoxy systems, the nitrogen lone pairs are lowered in energy by the additional electron demand, thereby reducing both amide conjugation and anomeric overlap. 

The presence of nitro, carboalkoxy, carboxyl, chloro, formyl, alkyl, and acyl groups does not interfere with the reaction. A single alkoxy group also does not interfere, but if two or more are present, the yields are markedly decreased. The reaction is inhibited by the presence of unhindered, basic nitrogen substituents, by the phenolic group, and probably by the thiol group. 

The Gould-Jacobs sequence (Scheme 4.1) commences with an addition-elimination reaction between aniline 30 and substituted ethylenemalonate derivative 31 to yield malonic ester 32. Subsequent intramolecular cychzation delivers the 4-hydroxy-3-carboalkoxy-quinolone 33. In the presence of an alkylating agent, 33 is converted to 34. Saponfication of the ester affords quinolone core 35. 

The most common approach to the synthesis of a fused pyrimidine ring involves condensation reactions between adjacent carboalkoxy and amino groups. Therefore, it is not surprising that the majority of pyrrolo[3,2-4]pyrimidines that involve a pyrrole precursor follow this pathway. 

In nearly all cases of syntheses from pyrimidines, the presence of a sulfur atom at position 6 is a prerequisite. Having either a cyano group or a carboalkoxy group at position 5 represents the majority of compounds used in the preparation of thieno[2,3-,7 pyrimidines. 

The examples above open up synthetic approaches that involve manipulating either the amino or carboalkoxy moieties. The following examples illustrate the variety of ways in which these transformations have been used to synthesize thieno[3,2-4 pyrimidines. Scheme 37 describes one such method in which an intermediate urea derivative 456 is formed from 455 by reaction with ethyl isothiocyanatoformate. Cyclization to 457 occurs upon heating in an ethanolic alkoxide medium <2003BML107>. 

If the amide moiety, in lieu of the carboalkoxy group, is used, then a monooxy derivative is obtained. Thus, the simple thiophene 465 is first acylated on the amine using chloroacetyl chloride. Subsequent treatment with piperidine affords intermediate 466. Cyclization in alkali produces the thienopyrimidine 467 (no yield given) (Scheme 38) <1998JME4021>. 

The use of aldehyde derivatives serves in lieu of the carboalkoxy group in cyclization reactions. The oxime 473, when allowed to react with triethyl orthoformate, gives the -oxide 474 (Equation 177) <1996H(43)389>. 

The lesser stereoselectivity observed for the acrylate dimers [2c] in THF is readily understood in terms of the lesser coordinative ability of the carboalkoxy group compared to that of pyridine ( 7) (Table 3). 

H-Aziridines. In the presence of BF3 etherate, this reagent adds to double bonds substituted with three cyano or carboalkoxy groups to give an adduct that is converted into a I //-aziridine by treatment with triethylamine. 

Buchner reaction (1, 368-369). The reaction of benzene with an alkyl diazoacetate is catalyzed efficiently by rhodium(Il) carboxylates, particularly Rh(OCOCF3)2. Cyclohcptatricnes are formed at room lemperlure. Of more importance, the l-carboalkoxy-2,4,6-cycloheptatriene is formed in almost quantita-... 

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