Formyl carboxylates, decarboxylation

We have previously seen (10-70) that dianions of carboxylic acids can be alkylated in the a position. These ions can also be acylated on treatment with a carboxylic ester ° to give salts of p-keto acids. As in 10-70, the carboxylic acid can be of the form RCH2COOH or RR CHCOOH. Since p-keto acids are so easily converted to ketones (12-40), this is also a method for the preparation of ketones R C0CH2R and R COCHRR, where R can be primary, secondary, or tertiary alkyl, or aryl. If the ester is ethyl formate, an a-formyl carboxylate salt (R = H) is formed, which on acidification spontaneously decarboxylates into an alde-hyde. ° This method accomplishes the conversion RCH2COOH RCH2CHO, and is an alternative to the reduction methods discussed in 19-39. When the carboxylic acid is of the form RR"CHCOOH, better yields are obtained by acylating with acyl halides rather than esters. 

Besides isomerization of the olefinic substrates, some other side reactions may complicate the hydroformylation of fatty acids. Such reactions are decarboxylation and decarbonylation (see also Chapter 8) under formation of saturated or unsaturated compounds reduced by one carbon atom (Scheme 6.88) [37]. For example, at high temperatures and long reaction times, the formed aldehydes can undergo dehydrocarbonylation (a). Subsequent hydrogenation produces saturated fatty acids [25, 38]. This reaction sequence may lead to the false conclusion that hydrogenation of the starting olefin has taken place. The same products can suffer decarbonylation (b). On the other hand, decarboxylation of formyl carboxyl acids produces aldehydes (c). 

Triazole has been prepared by the oxidation of substituted 1,2,4-triazoles, by the treatment of urazole with phosphorus pentasulfide, by heating equimolar quantities of formyl-hydrazine and formamide, by removal of the amino function of 4-amino-l,2,4-triazole, by oxidation of l,2,4-triazole-3(5)-thiol with hydrogen peroxide, by decarboxylation of 1,2,4-triazole-3(5)-carboxylic acid, by heating hydrazine salts with form-amide,by rapidly distilling hydrazine hydrate mixed with two molar equivalents of formamide, i by heating N,N -diformyl-hydrazine with excess ammonia in an autoclave at 200° for 24 hours, and by the reaction of 1,3,5-triazine and hydrazine monohydrochloride. ... 

A vigorous Claisen condensation ensues when a homophthalic ester and methyl formate are treated with sodium ethoxide and the active methylene group is formylated. Cyclization takes place with ease in acidic media to produce a methyl isocoumarin-4-carboxylate (50JCS3375). Hydrolysis under acid conditions is sometimes accompanied by polymerization, but the use of boron trifluoride in acetic acid overcomes this problem. Decarboxylation may be effected in the conventional manner with copper bronze, though it sometimes accompanies the hydrolysis. 

In ergosterol biosynthesis, side chain alkylation of lanosterol normally takes place to build 24-methylenedihydrolanosterol, which itself is then the substrate for demethylation reactions at and C. The C -demethylation has been studied in detail. It is an oxidative demethylation catalyzed by a cytochrome P -system. The first step involved in this reaction is the hydroxylation of the Cj -methy1-group to form the C -hydroxymethyl derivative. A second hydroxylation and loss of water lead to the C -formyl intermediate, which is hydroxylized a third time to form the corresponding carboxylic acid. Decarboxylation does not directly take place, but proceeds instead by abstraction of a proton from C, followed by elimination and formation of a A 4-double bond. The NADPH-dependent reduction of the A14 -double bond finishes the demethylation reaction. Subsequently, demethylation at has to take place twice, followed by a dehydrogenation reaction in A" -position and isomerization from A8 to A7 and A24(28) to A22. respectively. 

Figure 2 illustrates the formation of 5-acetyl-7-methyl-[iv], 5-acetyl-6-methyl-[v], 7-formyl-5-methyl-[vi] and [vii] 7-acetyl-5-methyl-2,3-dihydro-(lH)-pyrrolizines after Tressl et al. (5). The 2,3-dihydro-(lH)-pyrrolizines require both carbohydrate fragmentation products and proline for their formation. Both the 5-acetyl- pyrrolizines [iv] and [v] increased in quantity as the reaction temperature increased while [vi] and [vii] were found at maximum quantity at 152.5°C. The first pair are formed through an iminium carboxylate intermediate which is decarboxylated into an exocyclic iminium ion which then undergoes an aldol... 

The 7-formyl- and 7-acetyl- pyrrolizines are formed by an iminium carboxylate intermediate followed by decarboxylation to the cyclic iminium ion which underwent nucleophilic addition followed by aldol ring closure. This pathway accounts for the 7-formyl-5-methyl [vi] and 7-acetyl-5-methyl [vii] depending if the iminium addition is by OHCCH2OH or CH3COCH2O. 

Bromine derivatives of thiophene are the most widely used for the preparation of isomeric thienothiophenes and related systems. A classical example is illustrated by the following transformation sequence formylation of 3,4-dibromothiophene (1) through lithium derivatives, repeated metallation and treatment with elemental sulfur and methyl bromoacetate. Ring closure of the second heterocycle occurs in the present of sodium alkoxide. Decarboxylation of the resulting 4-bromothieno[2,3-Z ]thiophene-2-carboxylic acid (2a) affords 3-bromothieno[2,3-Z)]thiophene (3a) (74IZV1570). The reaction with selenium instead of sulfur produced 4-bromosele-nolo[2,3-Z ]thiophene-2-carboxylic acid (2b) and 4-bromoselenolo[2,3-Z)]thiophene (3b). 

Dehydrative condensation of benzofurazan oxide with phenolic enolates affords phenazine di-N-oxides (Scheme 7). The condensation proceeds under mild conditions (NaOH/H20, H2O, MeOH/RNH2, Si02/CHs-CN at room temperature) and can be applied to a broad range of substituted nucleophiles of varying oxidation levels (phenolates, resorcinolates, hydro-quinones, and benzoquinones). A few limitations have been encountered for the phenol, and these include insufficient reactivity of dioxalane-protected p-formyl phenol and decarboxylation of free carboxylates at even mild reaction conditions (NaOH/H20, 60 Nucleophilic attack on the benzofurazan will occur from the para position in ortho- and meta-substituted phenolates, whereas para-substituted phenols will attack from the ortho position. Subsequently, elimination of H2O or ROH will take place if possible otherwise, elimination of H2 will give the phena-... 

The synthesis of thieno[3,2- >]thiophene [17, 18] is shown in Scheme 3.3. The commercially available 3-bromothiophene undergoes formylation via lithiation at the 2-position and the addition of Al-formy[piperidine. Subsequent treatment of 3 with ethyl 2-sulfanylacetate affords the ester 4, which is converted to thieno[3,2- >]thiophene by hydrolysis and decarboxylation steps. The product is thus obtained in a very satisfactory overall yield of 60%. A similar method can be used to prepare thieno[2,3- >]thiophene from thiophene-3-carboxaldehyde via the carboxylic acid [19], but an attractive alternative route was published in full by Otsubo et al. [20] following a brief communication from de Jong and Brandsma [21], In this strategy, trimethylsilyl-l,3-pentadiyne is treated with potassium rerr-butoxide, butyllithium and carbon disulfide and then with ferr-butanol in HMPA, to obtain thieno[2,3-fi]thiophene in 46 % yield. The reaction sequence can be used to obtain the product in multigram quantities and the diacetylene derivative can be easily prepared from (Z)-l-methoxybuten-3-yne in 65 % yield. 

Silver(I) carbonate functioned as an cooxidant with TEMPO. Tricyclohexylphosphine was employed to suppress homocoupling between heteroarenes. Substituted thiophenes, furans, and indoles could be selectively olefinated (C5-alkenylation for thiophenes and furans, C3-alkenylation for indoles, E/Z > 99 1). Unsubstituted thiophenes produced poor yields (24%) however, formyl, acetyl, and ketyl substituents were well tolerated. For electron-deficient substrates, tricyclohexylphosphine was reduced to 10 mol % to achieve good conversions. A variety of ketones could be employed using 2-methyl thiophene as a coupling partner. A related methodology employing saturated ketones and heterocyclic carboxylic acids via a Pd-catalyzed decarboxylative process was also reported (eq 44). ... 

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