Carboxyl derivatives reacting with

The second fundamental reaction of carbonyl compounds, nucleophilic acyl substitution, is related to the nucleophilic addition reaction just discussed but occurs only with carboxylic acid derivatives rather than with aldehydes and ketones. When the carbonyl group of a carboxylic acid derivative reacts with a nucleophile, addition occurs in the usual way, but the initially formed tetra-... 

Reactions with Carboxylic Acid Esters Alkyl nitrones can be metallized upon treatment with phenyl lithium in ether solution. The Li-derivatives react with carboxylic acid esters to give 3-oxo nitrones (305)- the analogs of 3-diketones and j3-keto esters (545). With the help of the 13C NMR method it has been found that 3-oxo nitrones (305) exist as an equilibrium mixture... 

Sodium 3-aminothiophene-2-carboxylates were reacted with EMME in boiling toluene in the presence of acetic acid for 4-6 hr to give 3-thienylaminomethylenemalonates (58) in moderate yields (87T3295 88EUP269295). The 5-bromo derivative of compound 58 (R = Br) was prepared in the reaction of 3-amino-5-bromothiophene and EMME, but 2-amino-5-nitrothiophene failed to react (87T3295). 

Pyrazine 168 underwent cross-coupling with propyne in the tri-o-tolylphosphine, and copper(l) iodide to provide 170. The isocyanate or methyl chloroformate and sodium hydride to give An isolated example of the synthesis of chiral pteridines from a (Scheme 33). 2-Isothiocyanatopyrazine-3-carboxylates have been isothiocyanatopyrazine-2-carboxylate 172 reacted with R)- —) provided the pteridine derivative 173 and uncyclized pyrazine with pyridine precursors afforded pyrido[2,3 Pytitnidines. 

Use of a /3-ketocarboxylic acid derivative may circumvent this problem (8-ketocarboxylic acid derivatives react with esters of a-amino carboxylic acids to give (Y) a-aminonitriles afford (Z) in a condensation step. 

Amides are the least reactive carboxylic acid derivatives, and are easily obtained from any of the other carboxylic acid derivatives. Carboxylic acids react with ammonia and 1° and 2° amines to give 1°, 2° and 3° amides. 

Carboxylic acids and some of their derivatives react with diiodosilane SiH lj to give good yields of acyl iodides Keinan Sahai J. Org. Chem. 1990, 55, 3922. 

Dioxo-l,2,3,4-tetrahydropyrimidinc-5-carboxylic acid145 146 and 3,5-dioxo-2,3,4,5-tet-rahydro-l,2,4-triazine-6-carboxylic acid147 react with sulfur tetrafluoride in excess hydrogen fluoride to give the trifluoromethyl derivatives 4a and b, respectively. 

Ames and Ribeira (75JCS(Pl)1390) described a method for the preparation of thieno[2,3-c]pyridin-7-ones (Scheme 68). The sodium salt of 3-bromothiophene-2-carboxylic acid reacts with carbanions in the presence of copper or copper(II) acetate to give condensation products (274) by displacement of bromide ion, often with simultaneous deacetylation. Cyclization of (274) provides a convenient route to thieno[2,3-c]pyridin-7-ones. Thieno[2,3-c]pyridin-4-ones and thieno[3,2-c]pyridin-7-ones have been prepared by Friedel-Crafts cyclization of AT-(2-thenyl)- and A-(3-thenyl)-glycine derivatives (81H(l6)127l). 

Another interesting derivative of benzo[c]thiophene which may be useful for preparative purposes has been described by Castro and coworkers. Strictly analogous to a synthetic sequence outlined in Section 3.17.2.1.1, 3-iodothiophene-4-carboxylic acid reacts with a copper(I) acetylide in DMF at 125 °C to give a l//-thieno[3,4-c]pyran-2-one (equation 53) (68JHC227). 

There is, of course, no paucity of examples using heteroatom-based nucleophiles. For example, aziridine-2-/-butyl carboxylate 102 reacts with primary amines to give the dialkylated diamino-propionic acid derivatives 103, which are interesting precursors for the synthesis of cyclosporin analogs. Again, attack occurs overwhelmingly at the B-carbon [95TL4955]. 

In contrast, C=0-containing carboxylic acid and carbonic acid derivatives react with nucleophiles in substitution reactions. The one group or one of the two groups bound through a heteroatom to the carboxyl carbon of these substrates is substituted so that compounds A or B, respectively, are obtained. 

Carboxylic amides, carboxylic esters, and carboxylic acids react with acid-stable heteroatom nucleophiles in a neutral solution much more slowly via the mechanism of Figure 6.2 than in an acidic solution via the mechanism of Figure 6.5. In an acidic solution, their car-boxonium ion derivatives, which result from the reversible protonation of the carboxyl oxygen, act as precursors of the tetrahedral intermediate. According to the discussion earlier in... 

Ruthenium and platinum carbenoids, derived from tertiary propargyl carboxylates, also reacted with furans in a similar manner, leading to triene systems (as represented in Scheme 9) <20060L1741>. The initially formed mixture of (2Z,4E) and (2Z,47) isomers 20 and 21, respectively, could be isomerized completely to a single (2E,4E) isomer. 

To form a ketone fiom a carboxylic acid derivative, a less reactive organometallic reagent— namely an organocuprate—is needed. Acid chlorides, which have the hest leavii group (CO of the carboxylic acid derivatives, react with R 2CuLi, to give a ketone as product. 

Similar to he case of reaction with 1-chloroalkyl carbonates studied in section 3-2-2-3, carboxylates anions react with 1-chloroalkyl carbamates to give alkylation derivatives... 

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