Pyridine synthons

Figure 5.3 Acid- -pyridine heterosynthon and urea tape synthon in (a) co-crystal of m-pyridylmethylurea (3-PyMeU) and dicarboxylic acid methylurea (DiCOOHMeU) and (b) co-crystal of 4-PyMeU and DiCOOHMeU. Note the modular assembly via structurally insulated urea tape and acid-pyridine synthons in distinct domains of the crystal structure...

Similarly, nicotinamide was shown to form co-crystals with dodecanoic acid and indole acetic acid, and iso-nicotinamide with phloroglocinol and hydroquinone (Figure 7.7) [14b, c, e]. All these structures contain synthon I. The -COOH or -OH groups interact with the pyridine moiety and also with the second N-H group of amide which is not a part of synthon I. All these structures indicate that the acid-pyridine synthon is favoured over amide-acid according to the hierarchy of the interactions. 

Figure 2.5 Hydrogen-bonded units within the co-crystals (a) 4-cyanophe-nol 4,4 -bipyridine (2 1) and (b) 4,4 -biphenol 3-cyanopyridine (1 2), established by OH-pyridine synthons. ...

Figure 2.6 Chemical structures of (a) 3-hydroxypyridine and (b) 5-hydroxyiso-quinoline. Both molecules contain OH and pyridine groups and they form OH-pyridine synthons in their individual crystal structures.

To provide one practical example of the complexity of the situation, proton transfer in the carboxylic acid-pyridine synthon has been investigated systematically by Tocher and co-workers through co-crystallisation of pyridine or 4-dimethylaminopyridine (DMAP) with five different carboxylic acids (Table 2.1) Since the pATa value for the conjugate acid of DMAP (pATa = 9.70) is considerably larger than that of any of the carboxylic acids, salts should be expected for all crystals containing DMAP and this was indeed found to be the case. However, two different crystal forms were established for the fumarate salt, both of which also contained neutral fumaric add molecules. 

Trifluoroacetohydroximoyl bromide etherate is a synthon for thiadiazo-lines and oxadiazolines (87JHC1391). A fused isoxazolopyridine was obtained with excess malononitrile but, unexpectedly, dimeric malononitrile gave a highly substituted 2-(CF3)-pyridine, albeit in 9% yield (87BCJ4480). 

Reductive cleavage of 5-silyl-, 3-, 4-, and 5-silylmethylisoxazoles 1 gave silyl (3-enaminones 2, useful synthons in the regioselective synthesis of silyl- and silylmethylpyrazoles 3, as well as pyrrole-, pyrimidine-, and pyridine derivatives <06T611>. 

Mercaptoacetic acid could be used as a versatile synthon for the synthesis of 17/,3//-thiazolo[3,4-tf]benzimidazole-type compounds <1996FA279, 1997FA673>. For instance, 2,3-diaminopyridine and 2-mercaptoacetic acid were reacted in a three-component reaction with a suitable carbonyl compound and provided the 17/,3//-thiazolo[3,4- ]-imidazo[4,5- ]pyridines 451 (Equation 212) <1994FA345>. 

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]...

Despite the numerous studies devoted to the synthesis of five-membered ring heterocycles using enamines as synthons, most publications on the use of enamines in the synthesis of heterocycles deal with six-membered heterocyclic ring systems, especially pyridine, pyrimidine, and pyran derivatives. 

Ab initio and density functional theoretical studies of the 4 + 2-cycloaddition of 2-azabutadiene with formaldehyde predict a concerted reaction that agrees well with experimental evidence.184 The azadiene A-plienyl-l-aza-2-cyanobuta-l,3-diene reacts with electron-rich, electron-poor, and neutral dipolarophiles under mild thermal conditions.185 5,6-Diliydro-4//-1,2-oxazines have been shown to be usefiil as synthon equivalents of 2-cyano-l-azabuta-1,3-dienes.186 The intramolecular Diels-Alder reaction of 1-aza-l,3-butadienes (106) can be activated by a 2-cyano substituent (Scheme 37).187 Stereoselectivity in the hetero-Diels-Alder reactions of heterobutadienes, nitrosoalkenes, and heterodienophiles has been extensively reviewed.188 The azadiene l-(f-butyldimethylsilyloxy)-l-azabuta-1,3 -diene (107) reacts with halobenzo-quinones, naphthoquinones, and A-phcnylmalcimidc to yield low to good yields of various pyridine heterocycles (108) (Scheme 38).189 The 4 + 2-cycloaddition of homophthalic anhydride with A-(cinnamylidcnc)tritylaminc produces the 3,4-adduct whereas with A -(cinnamylidcnc)bcnzylidinc the 1,2-adduct is produced.190... 

With quinoline [(100), X = H] the first retrosynthetic transform is reduction to 1,2-dihydroquinoline (cf. pyridines above) to facilitate recognition of the derived synthons obtained in the subsequent disconnection. 

A key compound for levoglucosan chemistry is 1,6-anhydro-2,4-di-<3-tosyl-/ -D-gl ucopyranose (36)176 which, after treatment with sodium ethoxide, affords a valuable starting compound, l,6 3,4-dianhydro-2-O-tosyl-jS-D-galactopyranose, as a single product (see Section IV. 1). Another example illustrating synthetic versatility of the ditosylate 36 is its oxidation to 3-keto derivative 37124.210.211 followed by reductive detosylation to afford the useful chiral synthon, l,6-anhydro-2,4-dideoxy-/i-D-g/ycero-hcxopyranos-3-ulose (38).210,212 Keto derivative 37 is readily isomerized by the action of pyridine into compounds of the D-arabino, D-xylo, and D-lyxo configurations.210... 

T.R. Shattock, K.K. Arora, P. Vishweshwar, M.J. Zaworotko, Hierarchy of supramolecular synthons persistent carboxylic acid pyridine hydrogen bonds in cocrystals that also contain a hydroxyl moiety, Cryst. Growth Des. 8 (2008) 4533M545. 

The Diels-Alder reaction of 5-acetyl-3-methylthio-l,2,4-triazine with cyclic enam-ines produces 3-acetyl-l-methylthiocycloalka[c]pyridines, which are synthons for the preparation of sempervirine and its analogues.126 Cycloadditions of aryl-substituted 1,2,4-triazines (117) with 2-cyclopropylidene-l,3-dimethylimidazolidine (118) yield Diels-Alder adducts (120) that eliminate N2 to form dispiropyridines (121), which rearrange to pyrrolo[3,2-c]pyridines (122). At low temperatures, zwitterions (119) formed by nucleophilic attack of (118) on the triazines could be detected spectroscopically and, in some reactions, isolated (Scheme 34).127... 

As mentioned above, amines of the thienopyridine series synthesized by the Thorpe reaction always contain an electron-withdrawing substituent (acyl, alkoxy-carbonyl, etc.) at position 2. The presence of the o-aminocarbonyl fragment in these compounds makes these compounds useful as synthons for pyridine ring construction in the Friedlaender synthesis. Generally, condensation occurs in the presence of a basic catalyst. The acid-promoted synthesis can be exemplified by the preparation of tetracyclic structure 59 from pyranothienopyridine 60 (1996RFP1417446). 

In addition to procedures for pyridine ring closure based on the use of 3-amino-thiophene derivatives, there are alternative methods for the construction of thieno [3,2-Z>]pyridines. One approach made use of cyclic (3-keto sulfones, which proved to be convenient synthons for the modified Hantzsch synthesis of fused pyridines (1986KGS1563, 1990JHC1453, 2000MI1, 2002USP6191140). For example, the reactions of benzothiophene 1,1-dioxide 168 with enamines 169 or methylene-active compounds 170 in the presence of NH4OAc produced fused dihydropyridines 171 (1990JHC1453). 

Another recently identified synthon involves the interaction between the C-H of a pyridinium ring and a carbonyl oxygen, which comes about due to the large positive charges on the pyridinium hydrogen atoms <2001EJ01519>. This is demonstrated in Figure 10 for the pyridine derivative 135. 

The primary synthesis of 1,5-naphthyridines may be accomplished by double cyclization of appropriate aliphatic substrates by cyclization of appropriately substituted pyridines by cyclocondensation of pyridine substrates with one or more aliphatic synthons or from other heterocyclic substrates by degradation, rearrangement, or the like. Partially or fully reduced 1,5-naphthyridines are often made by somewhat similar procedures such cases are usually illustrated toward the end of each subsection. Some reviews of naphthyridine chemistry contain material on the primary synthesis of 1,5-naphthyridines49 52 61 231 265 670 1260 1273 1430 1432... 

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