Carboxylic acids synthons

The DoM reaction of amino substituted heterocycles leads to versatile ortho-amino aldehydes, ketones, and carboxylic acids synthons that may be available only by lengthy and tedious classical routes. 

Evans, D. A., Morrissey, M. M., Dorow, R. L. Asymmetric oxygenation of chiral imide enolates. A general approach to the synthesis of enantiomerically pure a-hydroxy carboxylic acid synthons. J. Am. Chem. Soc. 1985, 107, 4346-4348. 

Symmetrical U-shaped molecules shown to form homodimers in the solid state include 1,8-naphthalenedicarboxylic acid (1,8-nap)8 and 2,7-di-tert-butyl-9,9-dime -thyl-4,5-xanthenedicarboxylic acid.9 The structures of the dimers are sustained by two carboxylic acid synthons that converge at the center of each assembly (Fig. 2). 

Unsymmetrical U-shaped molecules with two different hydrogen-bonding groups that give homodimers have also been reported. Specifically, a molecular cleft known as Rebek s imide has been shown to self-assemble in the solid state via two N-H -O and two O-H -O hydrogen bonds of two imide-carboxylic acid synthons (Fig. 4).11... 

Whereas most homodimers have been shown to exhibit host-guest behavior, Feldman and Campbell have described a crystalline homodimer that exhibits chemical reactivity (Fig. 24).44 In particular, two J-shaped dicarboxylic acids based on 1,8-disubstituted naphthalene units directed the assembly of two olefinic groups via two carboxylic acid synthons in an arrangement suitable for a [2 + 2] photodimerization.45 The two double bonds of the homodimer were organized parallel and separated by 3.65 A. Ultraviolet (UV) irradiation of the solid induced the... 

Zr-catalyzed ethylmagnesation product through three subsequent catalytic procedures (Ti-catalyzed hydromagnesation, Ni-catalyzed cross-coupling, and Ru-catalyzed oxidation) delivers the requisite carboxylic acid synthon in >99% ee. This synthesis route underlines the utility of the Zr-catalyzed carbomagnesation protocol the reaction product carries an alkene and an alcohol function and can thus be readily functionalized to a variety of other non-racemic intermediates. 

The crystal structures of six 3,6-diaryl-l,2,4,5-tetrazines have been determined and their molecular packing has been compared to the supramolecular architecture observed in related carboxylic acid dimers. In the tetrazines, covalent N-N bonds are considered to replace the intermolecular O-H- - -O hydrogen bonds of the carboxylic acids. In the system investigated, the covalent six-membered ring of the tetrazine was an appropriate replacement for the carboxylic acid synthon. This apparent interplay between molecular and supramolecular units may have applications in the crystal engineering of new materials (Figure 1) <2003HCA1205>. 

The carboxylic acid is well known to form stronger hydrogen bonds than the -NH2 moiety on the amide, and the best donor clearly displays a strong preference for the pyridine moiety, the best acceptor site. Once these functionalities have found each other via an acid py synthon, it is left to the amide to interact with itself (typically across an inversion center) via a classic homomeric amide amide dimer. In order to determine whether these structures are representative of cocrystals of acids and nicotinamide, we performed an additional analysis of all relevant data found in the Cambridge Stmctural Database [47]. The search, which included all nicotinamide and iso-nicotinamide co-crystals with carboxylic acids, but excluded other potentially competing moieties such as -OH, yielded 32 hits. In every single case, the pyridine - carboxylic acid synthon was present, which emphasizes that these intermolecular interactimis are very selective, remarkably reliable, and robust, despite the fact that we are dealing with readily reversible non-covalent interactions. The consistency of the motifs can be explained in the context of best donor-best acceptor scenario underpinned by electrostatic considerations. 

Reactants functionalized with self-complementary hydrogen bonding groups have been used to steer molecules into necessary arrangements for reaction. Feldman and Campbell [95] demonstrated that a J -shaped naphthoic acid-derived cinnamic acid 59 could assemble to a dimer in the solid state through carboxylic acid synthons, where the HT alignments of two olefins conform to the topochemical criteria... 

Epoxides provide another useful a -synthon. Nucleophilic ring opening with dianions of carboxylic acids (P.L. Creger, 1972) leads to y-hydroxy carboxylic acids or y-lactones. Addition of imidoester anions to epoxides yields y-hydroxyaldehyde derivatives after reduction (H.W. Adickes, 1969). 

Allyl anion synthons A and C, bearing one or two electronegative hetero-substituents in the y-position are widely used for the combination of the homoenolate (or / -enolate) moiety B or D with carbonyl compounds by means of allylmetal reagents 1 or 4, since hydrolysis of the addition products 2 or 5 leads to 4-hydroxy-substituted aldehydes or ketones 3, or carboxylic acids, respectively. At present, 1-hetero-substituted allylmetal reagents of type 1, rather than 4, offer the widest opportunity for the variation of the substitution pattern and for the control of the different levels of stereoselectivity. The resulting aldehydes of type 3 (R1 = H) are easily oxidized to form carboxylic acids 6 (or their derivatives). 

Compounds 137 and 138 are thus synthons for carboxylic acids this is another indirect method for the a alkylation of a carboxylic acid, representing an alternative to the malonic ester synthesis (10-104) and to 10-106 and 10-109. The method can be adapted to the preparation of optically active carboxylic acids by the use of a chiral reagent. Note that, unlike 132, 137 can be alkylated even if R is alkyl. However, the C=N bond of 137 and 138 cannot be effectively reduced, so that aldehyde synthesis is not feasible here. ... 

It is well-known, that in most carboxylic acid crystal structures, the conformation of the carboxyl group is synplanar and that the most frequent and dominant interlink is the syn-syn centrosymmetric dimer synthon, II. This synthon is found in nearly a third of all crystalline carboxylic acids, with or without any other functionality being present in the molecule, signifying robustness.1211 Against such a background, the crystal structures of 1,4-cubane-... 

That the dimer synthon is found in as many as a third of all carboxylic acids is quite impressive, considering the very large variety of other functional groups that are present in the acids contained in the CSD. If, however, one were to consider only simple carboxylic adds - that is, with no other functionality present other than carboxyl and hydrocarbon residues - then the proportion of acids that contain dimer synthon II rises to around 85 %. Hence, the qualifier robust is justified in this case. 

Table 8. Cyclization of carboxylic acids onto alkenes acyl radical synthon...

A new stereocenter is formed when a synthon 143 with umpoled carbonyl reactivity (d reactivity) is introduced into aldehydes or imines. The enantioselective variant of this type of reaction was a longstanding problem in asymmetric synthesis. The very large majority of a-hetero-snbstitnted carbanions which serve as eqnivalents for synthons like 142 and 143 lead to racemic products with aldehydes or imines. However, enantiomerically pnre acylions and a-hydroxy carboxylic acids or aldehydes (144 and ent-144, respectively) as well as a-amino acids and aldehydes (145 and ent-145) are accessible either by nsing chiral d reagents or by reacting the components in the presence of chiral additives (Scheme 18). 

Scheme 9 Strategy for the 1,6-polymerization of triacetylene, a Polymerization principles for triacetylene, b Supramolecular synthon as the host to arrange triacetylene molecules as the guest with a stacking distance of 7.4 A. c Successful and unsuccessful examples for the combination of host and guest molecules with carboxylic acid or pyridine moieties [63]...

The C,-synthon is usually a carboxylic acid or a derivative of a carboxylic or carbonic acid and introduces substituent R . An example is the reaction of 4-oxo-6-methyl-HP (16) and formic acid in Scheme 9 (59JOC787). 

Hu et al. (91MI1) report the Dimroth rearrangement of 2-hydrazino- to 2,3-diamino quinazolin-4-ones under catalysis of carboxylic acid derivatives this reaction is followed by an in situ cyclization in which the same carboxylic acid derivatives serve as C,-synthons. l-Acylamino-2-alkylthiopyrimidines are hydrazinolyzed and cyclized to 3-amino-1,2,4-triazolofl, 5-a]pyrimidinium salts (89EGP270711). 

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