Functionalizations 1,2,5-oxadiazole

X0 4,6-dihydrofuro[3,4-(]furazans 120 (79S977). Opening of the lactone ring with amines led to functionalized 1,2,5-oxadiazoles 123. 

Functionalized oxadiazoles have received considerable attention in the pharmaceutical industry as heterocyclic amide and ester isosteres [95]. Oxadiazoles have been employed in the design of biologically active templates, e. g. core structures for muscarinic agonists, kinase inhibitors, anti-inflammatory agents, histamine H3 antagonists, monoaminic oxidase inhibitors, etc. 

Cosford and coworkers presented a simple microreador setup for enabling multi-step synthesis of bis-substituted 1,2,4-oxadiazoles that required differential and controlled thermal treatments (between 0 and 200 °C) (Scheme 5.24) [34]. A base-assisted reaction between arylnitrile and hydroxylamine hydrochloride at 150°C in the first reactor produced amidoxime, which was quickly cooled to 0 °C before it was mixed with the add chloride. This mixture was then warmed and maintained at room temperature for 2 min in the connected tube before it entered a superheated chip-microreador where the high temperature (200 °C) and pressure (7.5-9.0 bar) accelerated the reaction leading to 40-63% of differently functionalized oxadiazoles within 30 min of total process time. Relativdy inferior yields were obtained from over three-day-long reaction in a sealed tube for the same products. 

Sulfonamido-l,3,4-oxadiazoles 141 Sulfonyloximes 147 Supports, functional, ionic liquid 115 Suzuki couplings 21,122 Suzuki-Miyaura reaction 164... 

The initial retrosynthetic analysis of 1 resulted in the cleavage of the two amide bonds and a C-N bond leading to the four components oxadiazole carbonyl chloride 2, methyl iodide, 4-fluorobenzylamine (4-FBA) and the densely functionalized hydroxypyrimidinone 3 (Scheme 6.1). These synthetic disconnections were reasonable and should be applicable for long term route development. 

Various derivatives were synthesized from the corresponding nitriles 178 as depicted in Scheme 3. A number of functional groups were introduced, including substituted thiazoles 179, oxadiazoles 180, and pyrimidine 181 <2004JME1329>. 

The Siegirst reaction was deployed in the synthesis of highly functionalized triazole 212 2-(/>- /t-butylphenyl)-5-(/>-tolyl)-l, 3,4-oxadiazole 213 was reacted with SchifFs base 214 in the presence of potassium v/-butoxide to give 1,2,4-triazole 212 in a yield of 90% after recrystallization (Equation 67) <2004MI209>. 

A new approach to functionally substituted 4,5-dihydro-l,2,3-oxadiazole 2-oxides 134 has been described (Scheme 9) <2005RJ0120>. The method allows access to new derivatives and better access to the known derivatives that relied on difficult-to-prepare starting materials such as A -nitrosulfamides and A -nitro-2-cyanoethylalkylamines. 

Succinic anhydride 211 reacts in the same fashion to produce the l,2,4-oxadiazol-5-yl propanoic acids 212 (Equation 34), which function as excellent substrates for coupling to amino acid derivatives <2000FES719, 1999HC0521, 1999H(51)2961>. 

The intermediate acylamidine 244 functions as the three-atom component in reaction with hydroxylamine to give the [l,2,4-oxadiazol-5-yl]pyrazole 245, where the intermediate acylamidine 244 was obtained in good yield from reaction of the corresponding amide 243 with dimethylacetamide-dimethyl acetal (Scheme 37) <1999JME2218>. 

The tautomerism of furoxan (l,2,5-oxadiazole-2-oxide) has been investigated by different computational methods comprising modern density functions as well as single-reference and multi-reference ab initio methods. The ring-opening process to 1,2-dinitrosoethylene is the most critical step of the reaction and cannot be treated reliably by low-level computations (Scheme 2). The existence of cis-cis-trans- 1,2-dinitrosoethylene as a stable intermediate is advocated by perturbational methods, but high-level coupled-cluster calculations identify this as an artifact <2001JA7326>. 

Numerous transformations of functional groups attached to 1,2,3-oxadiazoles have been reported in the last 10 years. The reactivity of substituents attached to ring carbon atoms was thoroughly discussed in CHEC(1984) and CHEC-11(1996). 

Halogenalkyl-substituted furazanes were also used for functionalization of the compounds. Thus, 3,4-bis(chloro-methyl)-l,2,5-oxadiazole 92 and 2(R)- fS>[ 3,5-bis(trifluoromethyl)pheny I ethoxy -3f.V,)-pheny I morpholine 93 gave 2W-[lW-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-dimethylaminomethyl-l,2,5-oxadiazol-3-yl)methyl-3( 3 Tphenyl-morpholine 94 (Equation 21) <1996W09629328>. 

The reaction of 3,4-diacyl-l,2,5-oxadiazole 2-oxides (furoxans) with activated nitriles in ionic liquids and in ethanol unexpectedly resulted in 3-acyl-4-acylamino-l,2,5-°xadiazoles (furazans) <2003MC230>. 3-Formyl-4-phenyl-l,2,5-oxadiazole Ar-oxide 105 is a good precursor for the synthesis of functional substituted furoxans (Scheme 28) <1999JME1941, 2000MOL520, 2000JFA2995>. 

The 1,3-dipolar cycloaddition of azidofurazans to acetylenes afforded 1,2,3-triazoles linked with furazan cycle <2000CHE91>. Treatment of 3-azido-2-amino-l,2,5-oxadiazole 194 with ethyl 4-chloroacetoacetate gives access to the functionalized [l,2,3]-triazoles 195, which are good precursors for GSK-3 inhibitors with favorable water solubility (Equation 38) <2003JME3333>. 

The preparation and the base-promoted Smiles rearrangement of phenylfuroxans bearing 2-hydroxyethylthio, 2-hydroxyethylsulfonyl, carbamoylmethylthio, and carbamoylmethylsulfonyl functions at the heterocyclic ring have been described. The rearrangement was also investigated in related furazans (1,2,5-oxadiazoles) for comparison <2001J(P1)1751>. 

An analysis of the principal methods for construction of compounds with 1,2,5-oxadiazole heterocyclic units was published in CHEC(1984) and CHEC-II(1996) < 1984CHEC(6)393, 1996CHEC-II(4)229>. In this chapter only reactions that lead to the formation of 1,2,5-oxadiazole cyclic fragments are considered. The functionalization or replacement of substituents of heterocyclic ring as well as oxidation or deoxidation of nitrogen atoms are described in Section 5.05.4. 

AMI semi-empirical and B3LYP/6-31G(d)/AMl density functional theory (DFT) computational studies were performed with the purpose of determining which variously substituted 1,3,4-oxadiazoles would participate in Diels-Alder reactions as dienes and under what conditions. Also, bond orders for 1,3,4-oxadiazole and its 2,5-diacetyl, 2,5-dimethyl, 2,5-di(trifluoromethyl), and 2,5-di(methoxycarbonyl) derivatives were calculated <1998JMT153>. The AMI method was also used to evaluate the electronic properties of 2,5-bis[5-(4,5,6,7-tetrahydrobenzo[A thien-2-yl)thien-2-yl]-l,3,4-oxadiazole 8. The experimentally determined redox potentials were compared with the calculated highest occupied molecular orbital/lowest unoccupied molecular orbital (HOMO/LUMO) energies. The performance of the available parameters from AMI was verified with other semi-empirical calculations (PM3, MNDO) as well as by ab initio methods <1998CEJ2211>. 

A synthesis and physicochemical characterization, including molecular second-order nonlinear optical properties, of new push-pull-based chromophores 170 properly functionalized for polymerization and containing oxadiazole rings were reported <2002J(P2)1791>. 

A series of 3,5-diarylisoxazole and 3,5-diaryl-l,2,4-oxadiazole derivatives, novel classes of small molecule interleukin-8 (IL-8) receptor antagonists, 456 (Ar = 4-FC6H4), have been identified as IL-8 inhibitors. These compounds exhibit activity in an IL-8 binding assay as well as in a functional assay of IL-8 induced... 

A series of inhibitors containing an electrophilic keto-l,3,4-oxadiazole moiety as the warhead has been reported in which the substituent at the 5-position was varied resulting in the identification of furan as the optimal prime side substituent. Exploration of P3 substituents led to the identification of 10 with a K, of 1 nM against Cat K with > 700-fold selectivity over off-target cathepsins (Cat B Ki = 730 nM Cat L Rj = 960 nM Cat S Rj = 700 nM) [54], The potency of this compound was shifted in a functional bone resorption assay (Cat K IC50= 132 nM). 

A theoretical study of degenerate Boulton-Katritzky rearrangements concerning the anions of 3-formylamino-l,2,4-oxadiazole and 3-hydroxy-iminomethyl-1,2,5-oxadiazole has been carried out7 The treatment has shown the participation of asymmetric transition states and non-concerted processes via symmetrical intermediates. A detailed ab initio and density functional study of the Boulton-Katritzky rearrangement of 4-nitrobenzofuroxan has indicated a one-step mechanism for the process. 

Oxadiazoles owe their importance mainly to their biological activities. A basic idea behind many developments is that the 1,2,4-oxadiazole ring is a hydrolysis resisting bioisosteric replacement for an ester functionality <90JMC1128,91JMC140,91QSAR109>. 

Until 1995 the only A-substituted 1,2,5-oxadiazoles for which the chemistry had been examined in any depth were the furoxans, and the first section is therefore devoted to the principal reaction of their A-oxide function, i.e. deoxygenation to the furazan other aspects of their chemistry... 

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