Oxazoles pyridines

Ring expansion of five- to six-membered rings such as oxazole —> pyridine derivatives via a Diels-Alder reaction is a well-established procedure. However, the conversion of a six-membered heterocycle into a five-membered ring system has not been exploited to any great extent, and those systems that have been studied usually involve a cationic species. 

For electron transport/hole blocking purposes, a wide variety of electron-deficient moieties are well known, e.g., 1,3,4-oxadiazoles [12], 1,2,4-triazoles [13], 1,3-oxazoles, pyridines and quinoxalines [14] (see Scheme 3). Materials with conjugated 7i-electron system (e.g., styrylarylenes, arylenes, stilbenes, oligo- and poly(thiophene)s — see Scheme 3) are widely used as combined charge transport and luminescence layers as well [12,15]. 

The presence of a cyano group seems to be important[649]. The reaction has been successfully applied to halides of pyridine, quinoline, isoquinoline, and oxazoles[650]. An interesting application is the synthesis of tetracyanoquino-dimethane (789) by the reaction of / -diiodobenzene with malononitrile[65l]. 

The current paradigm for B syntheses came from the first report in 1957 of a synthesis of pyridines by cycloaddition reactions of oxazoles (36) (Fig. 5). This was adapted for production of pyridoxine shordy thereafter. Intensive research by Ajinomoto, BASF, Daiichi, Merck, Roche, Takeda, and other companies has resulted in numerous pubHcations and patents describing variations. These routes are convergent, shorter, and of reasonably high throughput. 

In general, the solubility of heterocyclic compounds in water (Table 33) is enhanced by the possibility of hydrogen bonding. Pyridine-like nitrogen atoms facilitate this (compare benzene and pyridine). In the same way, oxazole is miscible with water, and isoxazole is very soluble, more so than furan. 

Nitration of monocyclic compounds is summarized in Table 4. Substitution occurs in the expected positions. The reaction conditions required are more vigorous than those needed for benzene, but less than those for pyridine. Ring nitration of oxazoles is rare, but (114) has been obtained in this way (74AHC(17)99). 

The 2-position in imidazoles, thiazoles and oxazoles is electron deficient, and substituents in the 2-position (332) generally show the same reactivity as a- or y-substituents on pyridines. 2-Substituents in azoliums of this type, including 1,3-dithiolyliums, are highly... 

Nicolaou and co-workers established the severely strained A-ring oxazole (21) in their total synthesis of antitumor agent diazonamide A through initial oxidation of the hindered alcohol of intermediate 20 with TPAP and subsequent Robinson-Gabriel cyclodehydration of the resultant ketoamide with a mixture of POCI3 and pyridine (1 2) at 70°C. ... 

In at least one case, the standard Bucherer-Bergs conditions gave rise to oxazole rather hydantoin. Specifically, when 5-benzyloxy-pyridine-2-carbaldehyde (11) was treated with potassium cyanide, ammonium chloride, and ammonium carbonate in boiling ethanol/water, 5-amino-oxazol-2-ol 12 was obtained. Subsequent heating of oxazole 12 with acetic acid at reflux overnight then produced the Bucherer-Bergs product, hydantoin 13. ... 

Independently, Kondrat eva reported that oxazoles 7 would undergo reactions with alkenes to afford pyridine derivatives 8. 

An example of this methodology was its use in the synthesis of vitamin Be, pyridoxine 12. Cycloaddition of oxazole 9, prepared from ethyl A-acetylalanate and P2O5, with maleic anhydride initially gave 10. Upon exposure to acidic ethanol, the oxabicyclooctane system fragments to afford pyridine 11. Reduction of the ester substituents with LiAlIU generated the desired product 12. 

Modification of the oxazole, as in 13 allowed for the formation of vitamin Ba analogs, such as 15 via intermediate pyridine 14. 

Kondrat eva pyridine synthesis. This methodology to pyridine rings continues to be applied in total synthesis. An approach to the antitumor compound ellipticine 34 ° makes use of a Diels-Alder reaction of acrylonitrile and oxazole 32 to form pyridiyl derivative 33. Addition of methyllithium and hydrolysis transforms 33 into 34. 

A final example of this synthetic methodology is the chiral synthesis of the cyclopenta[c]pyridine ring system of (-)-plectrodorine 43. Oxazole 41 was heated in o-... 

Treatment of a 3-aminotriazolopyridine with acid gave the imidazopyridine 242 (81T1787), also obtained from the 3-nitro derivative by catalytic reduction (83AHC79). Quaternary salts derived from compound 2, when treated with tri-ethylamine and subsequently heated give 2-pyridylcyanamides 243 or 2-(oxazol-l-yl)pyridines 244 depending on the alkyl group (86H(24)2563) the ylides are presumably intermediates (see also Section IV.I). 

Fig. 13 Synthesis of oxazoles on JandaJel. Reagents and conditions a toluene, alkyl acetoacetate (R0(C0)CH2C0R R =t-Bu), reflux, 6h or alkyl acetoacetate (R = Me, Et), toluene, LiC104, reflux, 6h fc dodecylbenzenesulfonyl azide, EtsN, toluene, rt, 16 h c benzamide, Rh2(oct)4, toluene, 65 °C, Ih rf Burgess reagent, pyridine, chlorobenzene, MW 100 °C, 15 min (or 80 °C, 4 h with conventional heating) e AICI3, piperidine, CH2CI2, rt, 16 h...

The N-silylated enol acetate 1523 is cyclized by TMSOTf 20 in CHCI3, in 95% yield, giving the oxazole 1524 [57]. The dimeric derivative 1525 affords the 2,2 -bis-oxazole 1526 in 46% yield [57]. 2-Benzoylamino-3-chloropyridine 1527 is cyclized by polyphosphoric acid trimethylsilyl ester (PPSE) 195 on heating for 15 h in boiling 1,2-dichlorobenzene to give 40-60% 2-phenyloxazolo[5,4-f)]pyridine 1528 [58] (Scheme 9.34). 

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

Furthermore, oxazoles of type 9-82 bearing a secondary amino functionality can be converted into pyrrolo[3,4-b]pyridines 9-86 by reaction with appropriate acid chlorides 9-83 in a triple domino process consisting of amide formation/hetero Diels-Alder reaction and retro-Michael cycloreversion via 9-84 and 9-85 (Scheme 9.17). The pyrrolo[3,4-fc]pyridines can be obtained in even higher yields when the whole sequence is carried out as a four-component synthesis in toluene. Here, 1.5 equiv. NH4C1 must be added for the formation of the now intermediate oxazoles [56b]. 

This section is divided into eight subsections, covering imidazoles, pyrazoles, isoxazoles, oxazoles, triazoles, tetrazoles, pyridines, and pyrimidines, purines, and nucleic acid bases respectively. 

---