Oxadiazoline Derivatives

Giezendanner, M. Marky, B. Jackson, H.-J. Hansen, and H. Schmid, Helv. Chim. Acta, 1972, 55, 745. 

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Warkentin and co-workers continued studies on gas-phase pyrolysis of oxadiazoline derivatives. DFT calculations and ab initio simulations of PE spectra were used in the interpretation of the experimental results <2006CJC546>. 

Eschenmoser, together with groups from Firmenich, Geneva, and CIBA, Basle, gave an extended scope to the synthesis of various alkynones. Some preparative variations and improvements have been introduced by the use of oximes, A-aminoaziridines, 2,4-dinitrobenzenesulfonohydrazides and 1,3,4-oxadiazolin derivatives. ... 

MacAlpine, G. A., Warkentin, J. Thermolysis of D3-1,3,4-oxadiazolin-2-ones and 2-phenylimino-D3-1,3,4-oxadiazolines derived from a,P-epoxyketones. An alternative method for the conversion of a,P-epoxyketones to alkynones and alkynals. Can. J. Chem. 1978, 56, 308-315. 

The oxazolinone (378) reacts with nitrosobenzene to yield the 1,2,4-oxadiazoline-derivative (380) by way of the 1,3-dipolar tautomer (379). —On the other hand, the formation of the dihydropyridone (382) from compound (378) and cinnamylideneaniline represents a Diels-Alder addition of the tautomeric hydro-... 

Oxadiazoline Derivatives. The thermal decomposition of A -l,3,4-oxadia-zolin-2-ones has been shown to occur by two parallel first-order pathways (Scheme 38). One gives the appropriate diazomethane and carbon dioxide, the other a ketone, nitrogen, and carbon monoxide. 

Ring enlargement of A-acyl compounds, generally observed with oxaziridines, is observed only occasionally with diaziridines. Under more forced conditions of acylation with acetic anhydride, oxadiazolines like (139) were obtained (76MIP50800). A 4-nitrobenzoyl derivative rearranged at room temperature (76JOC3229). 

The reaction of ADC compounds with carbenes and their precursors has already been discussed in Section IV,A- In general, the heterocyclic products are not the result of 1,2-addition but of 1,4-addition of the carbene to the —N=N—C=0 system.1 Thus the ADC compound reacts as a 4n unit in a cheletropic reaction leading to the formation of 1,3,4-oxadiazolines. Recent applications include the preparation of spiro-1,3,4-oxadiazolines from cyclic diazoketones and DEAZD as shown in Eq. (14),133 and the synthesis of the acyl derivatives 85 from the pyridinium salts 86.134 The acyl derivatives 85 are readily converted into a-hydroxyketones by a sequence of hydrolysis and reduction reactions. 

There are three nonconjugated reduced systems derived from 1,3,4-oxadiazole 1, namely 2,3-dihydro-l,3,4-oxadia-zole (A2-l,3,4-oxadiazoline) 5, 2,5-dihydro-l,3,4-oxadiazole (A3-l,3,4-oxadiazoline) 6, and 2,3,4,5-tetrahydro-l,3,4-oxadiazole (1,3,4-oxadiazolidine) 7. 

The synthesis of cephem derivative 99 involved S-alkylation of 5-methyl oxadiazoline-2-thione with the appropriate tosylate <2000BMC2317>. 

Microwaves were used to support S-arylation of 5-substituted oxadiazoline-2-thiones <2000BMC69> and <2000M1207>. 5-(4-Pyridyl)oxadiazoline-2-thiones treated with 2-haloesters also afforded A-alkyl derivatives <2000CHE851>. A similar reaction occurred in the case of 5-pyrazolyloxadiazoline-2-thiones <2000JFA5312>. Organophosphorus derivatives of 1,3,4-oxadiazole were obtained by the reaction of bis(oxadiazolinethiones) with 0,0-diethylchlorophosphate (Scheme 21) <1998JFA1609>. 

Aldimines, Ketimines, and Related Compounds as Dipolarophiles Reactions of aldimines with nitrile oxides proceed readily to give 1,2,4-oxadiazolines independently of the nature of substituents both in dipole and dipolarophile molecules. 1,2,4-Oxadiazolines were prepared by the regiospe-cihc 1,3-dipolar cycloaddition of nitrile oxides with fluoro-substituted aldimines (295). Phosphorylnitrile oxides gave with azomethines, PhCH NR, phosphory-lated 1,2,4-oxadiazolines 129 (296). Expected 1,2,4-oxadiazolines were also obtained from azomethines, derived from 4-formylcoumarine (179) and 1,3-diphenylpyrazole-4-carbaldehyde (297). 

CF3CN and CCI3CN leads to the corresponding substituted oxadiazolines (74, 829). Thus, reactions of (746) and (747), derived from 1-deoxynojirimycin with trichloroacetonitrile in toluene at room temperature leads to bicyclic compounds (748) and (749) (Scheme 2.308). 

There is no published example of a cyclopropanation of the double bond in chlorocyclopropylideneacetate 1-Me with retention of the chlorine atom. Thus, attempted cyclopropanations under Simmons-Smith [37] or Corey [38] conditions failed [25]. The treatment of the highly reactive methylenecyclopropane derivative 1-Me with dimethoxycarbene generated by thermal decomposition of 2,2-dimethoxy-A -l,3,4-oxadiazoline 26 (1.5 equiv. of 26,PhH, 100 °C,24 h),gave a complex mixture of products (Scheme 7) [39], yet the normal cycloadduct 28 was not detected. The formation of compounds 29 - 33 was rationalized via the initially formed zwitterion 27, resulting from the Michael addition of the highly nucleophilic dimethoxycarbene to the C,C-double bond of 1-Me. The ring closure of 27 to the normal product 28 is probably reversible, and 27 can rearrange or add a second dimethoxycarbene moiety and a molecule of acetone to form 33. 

Nonoxidative cyclization of acylhydrazones in acetic anhydride yields 4-acetyloxadiazolines, as in the conversion of hydrazone (96f R = 2-benzthiazolyl) into oxadiazoline (90b) <89MI 406-03). Hydrazones derived from tetra-O-acetyl-D-arabinose cyclized (Ac20/ZnCl2) to oxadiazoles pos-... 

As another important mechanistic type, fragmentation into at least three products that are formed more or less simultaneously has to be mentioned. Such [5 - 2 + 2 + 1] reactions were encountered in 2-pyrrolidinones (65, 67), certain pyrazolidine derivatives (68, 72, 73), l,2,4-triazolidine-3-ones (69) and l,2,4-triazolidine-3,5-diones (70), 2//-pyrrol-2-ones (71), 1,3-dithiolane 1-oxides (78), 1,2,3,4-thiatriazoles (74), 1,2,4-oxadiazolines (75), and in several rings containing sulfur in an oxidized state (76-79,82). Most of these molecules have an exocyclic double bond. 

When ethyl iodide acts on the silver salt of the 5-hydroxy derivative (83), a 1 1 mixture of the O- and A-ethyl derivatives (84 and 85) are obtained. Evidently 85 is thermodynamically the more stable of the two isomers, since on standing for 3 days as much as 90% of 4-ethyl-3-methyl-l,2,4-oxadiazolin-5-one (85) is formed. Only 84 can be converted to the amino derivative 86. 

Only one example is known where it seems certain that both N-2 and N-4 derivatives of an oxadiazoline have been obtained85, 86 [Eq. (29)]. Compound 22 had a chemical shift for the N—CH3 group 1.03 ppm farther down field than for the same group in 21. (See also Scheme 7). 

Diphenyl-1,2,4-oxadiazolin-5-one undergoes a similar cleavage with evolution of carbon dioxide on photolysis in dioxane [Eq. (18)].66 The reactive intermediate formed on photolysis of 2,4-diphenyl-l,3,4-oxadiazolin-5-one forms dihydropyrazole, pyrazole, and 1,2,4-triazole derivatives by cycloaddition to conjugated alkenes, acetylenes, and nitriles [Eq. (19)], respectively.66... 

In recent years there has been a growing interest in the use of carbonyl ylides as 1,3-dipoles for total synthesis.127-130 Their dipolar cycloaddition to alkenic, alkynic and hetero multiple bonded dipolaro-philes has been well documented.6 Methods for the generation of carbonyl ylides include the thermal and photochemical opening of oxiranes,131 the thermal fragmentation of certain heterocyclic structures such as A3-l,3,4-oxadiazolines (141) or l,3-dioxolan-4-ones132-134 (142) and the reaction of carbenes or car-benoids with carbonyl derivatives.133-138 Formation of a carbonyl ylide by attack of a rhodium carbenoid... 

Heating bromide 30c in the absence of solvent gave oxadiazoline hydrobromide 158, which yielded, after basification, the free base 159. However, treatment of 30c with sodium hydroxide solution at room temperature or at reflux furnished a mixture of the triazolone derivative 162 (75% yield) and 5-bromothenoic acid 163, presumably via intramolecular displacement of the bromine atom to give 161, followed by alkaline cleavage of the thenoyl group (78JHC1393). 

Of the possible structures 1-16 shown, the known structures are represented by 1,2,3,4-oxatriazolium salts 2, mesoionic derivatives 3-6, and 1,2,3,5-oxatriazolidines 15 and 16. Derivatives of A -1,2,3,4-oxadiazoline 7 have now been synthesized and are the first representatives of this particular ring system. 

The structure of 1,2,4-oxadiazoles has not been in dispute since covalent structures can be drawn from the methods of synthesis. The geometry of the ring was estimated for theoretical calculations years before X-ray measurements were available. Microwave spectra and recently fluorescence spectra have been used to determine the dipole moments of oxadiazoles and oxadiazolines, the latter being high by comparison (Table 7). Electron densities were calculated for 5-methyl-3-phenyl-l,2,4-oxadiazole (88) and its 2,3-dihydro derivative (89) (77JOC1555). 

Enough 1,2,4-oxadiazoles and their reduced derivatives have been made that there is general agreement on where to expect the C=N absorption in the IR spectrum, i.e. 1560-1590 cm-1. In the partially reduced (oxadiazoline) ring the A2 double bond appears at 1550-1565 cm-1 and the NH bands at 3320 and 3220-3250 cm-1. In an amino derivative, 5-amino-3-phenyl-l,2,4-oxadiazole, the C=N bond absorbs at higher frequency (1660 cm"1) (63PMH(2)229>. 

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