2-Oxazolines nitriles

Dihydrofuran (376) and 2,5-dihydrofuran (377) react with nitrile oxides to give furo[2,3-6 ]isoxazoles (378) and furo[3,4-rf]isoxazoles (379), respectively, as cycloadducts. The double bonds of furan, pyrrole and thiophene also react when the nitrile oxide is generated in situ. Thus furan and benzonitrile oxide gave (380), and with 2-methyl-2-oxazoline the cycloadduct (381) was obtained (71AG(E)810). These and related cycloadditions are discussed in Chapter 4.36. 

Photolysis of 2,3-diphenyl-A -azirine (442) generates benzonitrile ylide (443). Irradiation in the presence of ethyl cyanoformate resulted in a mixture of the oxazoline (444) and the imidazole (445) by 1,3-dlpolar cycloaddition to the carbonyl and nitrile group, respectively (72HCA919). 

When the reaction is run with potassium fert-butoxide in THF at -5°C, one obtains (after hydrolysis) the normal Knoevenagel product (32), except that the isocyano group has been hydrated (16-65). With the same base but with DME as solvent the product is the nitrile (33). When the ketone is treated with 31 and thallium(I) ethoxide in a 4 1 mixture of absolute ethanol and DME at room temperature, the product is a 4-ethoxy-2-oxazoline (34). Since 33 can be hydrolyzed to a carboxylic acid and 34 to an a-hydroxy aldehyde, this versatile reaction provides a means for achieving the conversion of RCOR to RCHR COOH, RCHR CN, or RCR (OH)CHO. The conversions to RCHR COOH and to RCHR CN have also been carried out with certain aldehydes (R = H). 

The product of the reaction in Entry 8 was used in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxy group is determined by the structure of the oxazoline ring formed in the cycloaddition. Entry 9 portrays the early stages of synthesis of the biologically important molecule biotin. The reaction in Entry 10 was used to establish the carbocyclic skeleton and stereochemistry of a group of toxic indolizidine alkaloids found in dart poisons from frogs. Entry 11 involves generation of a nitrile oxide. Three other stereoisomers are possible. The observed isomer corresponds to approach from the less hindered convex face of the molecule. 

Numerous examples of nucleophilic attack on coordinated nitrile ligands are found in the literature, particularly when the transition metal is platinum(II).224 The nucleophilic attack of two equivalents of CIO I2CII20 on the electrophilic nitrile carbon atoms of both nitrile ligands in cis-or /r<7H.v-[PtC12(RCN)2] (R = Et, Prn, Pr1, Bu p-CF3C6H4, p- and o-MeC6H4) affords the corresponding A2-l,3-oxazoline complexes ((76) and (77), respectively), in which the heterocycle acts as a... 

Nitrile ylids generated in this way can be trapped with methanol108 Thus, on irradiation in methanol, the azirine 137 was converted to the methoxy-imine (138). The intramolecular equivalent reaction leading to the oxazoline 139 has also been observed on irradiation of the 2//-azirine (140 R = OH),... 

Photoelimination of carbon dioxide from the 2-oxazolin-5-one 474 in the presence of methyl acrylate affords the cis- and frans-l-pyrrolines 475 and 476.394 A nitrile ylid is believed to be involved in this and other analogous transformations.395... 

Bromoamidation of cyclic olefins allowed the synthesis of bicyclic oxazolines. For instance, treatment of cyclohexene with A-bromoacctamidc as the halogen source and different nitriles at 0 °C, in the presence of SnCU or BF3 Et20 and water, led to oxazolines 128 through intermediate traw.v-bromoamides 127. The scope of the bromoamidation appears quite broad with regard to olefinic and nitrile components <06JA9644>. 

A characteristic feature of contemporary investigations in the held under consideration, is the interest in cycloaddition reactions of nitrile oxides with acetylenes in which properties of the C=C bond are modified by complex formation or by an adjacent metal or metalloid atom. The use of such compounds offers promising synthetic results. In particular, unlike the frequently unselec-tive reactions of 1,3-enynes with 1,3-dipoles, nitrile oxides add chemo-, regio-and stereoselectively to the free double bond of (l,3-enyne)Co2(CO)6 complexes to provide 5-alkynyl-2-oxazoline derivatives in moderate to excellent yield. For example, enyne 215 reacts with in situ generated PhCNO to give 80% yield of isoxazoline 216 (372). 

The synthesis is similar to that of the PHOX catalysts (Scheme 29.6), starting with oxazoline formation from the pyrrole nitrile and an amino alcohol, followed by introduction of the phosphine group. 

The reactivity of oxiranes with lithium enoiates and related compounds has been widely explored and reviewed . Dianions derived from carboxylic acids react readily with oxiranes, but the reaction can be slowed by steric hindrance . The reaction of oxiranes with dianions of acetoacetates is greatly accelerated by the addition of BF3 Et20 " . Oxiranes react readily with lithium salts derived from nitriles , malonates and analogues , lithiated oxazolines and lithio enamines . 

The imidates (62) also serve as nitrile yhde synthons via cycloaddition and subsequent spontaneous elimination of ethanol (34,35). Cycloadditions were carried out to aldehydes, leading to 2-oxazolines (e.g., 64) and to isocyanates and isothiocyanates. In the preparation of the 2-oxazolines, a solvent-less mixture of the imidate and the required aldehyde were heated at 70 °C and the cycloadducts 64 (R=Ph, 2-furyl, Mc2CH, 2-HO C6H4, 2-pyridyl, cinnamyl) were isolated in yields of 64—91%. 

A similar reaction of 70 leads to an amino nitrile ylide synthon (36,37), which reacts with a range of aromatic and heteoaromatic aldehydes to give the 2-oxazolines (71), but which fails to react with ahphatic aldehydes, simple ketones, or activated alkenes. 

A common and effective direct approach to unsubstituted or multiply substituted oxazolines is the Lewis acid catalyzed reaction of nitriles with amino alcohols in an alcoholic or aromatic solvent (chlorobenzene) at reflux. The most common Lewis acids employed include ZnCl2, ZnBr2, NiBr2, CuCl2, and kaolinitic clay. Microwave irradiation has also been reported to facilitate the transformation. Alternatively, the condensation can be carried out in the presence of catalytic amounts of potassium carbonate. The method works well for both aliphatic and aromatic nitriles, with retention of stereochemistry. Some representative examples from the recent literature are listed in Table 8.16 (Scheme 3 40),2 35.2oi-2i3... 

TABLE 8.16. OXAZOLINES EROM NITRILES AND AMINO ALCOHOLS... 

Aliphatic and aromatic nitriles are often converted to the corresponding imidates that then react with amino alcohols to provide oxazolines. This two-step process offers milder conditions. Generally, a mixture of the imidate (free base or hydrochloride) is allowed to react with the amino alcohol in a solvent (alcohols, CH2CI2, CHCI3) with or without a tertiary base. As expected, the cylization proceeds with retention of stereochemistry when chiral amino alcohols are used. Representative examples are shown in Table g 17 33,62,63,139,216-225 ready availability of benzimidates and trimethyl orthobenzoates make them ideal surrogates for benzonitrile. ... 

Allyl alcohols readily react with trichloroacetonitrile to give the corresponding trichloroacetimidates 145. Activation of the double bond with electrophilic reagents results in ring closure to yield oxazolines 146. The most commonly employed electrophiles include iodine, iodine monochloride, phenylselenyl chloride, and mercuric trifluoroacetate. Other nitriles including cyanogen bromide and N,N-dimethylcyanamide can also be used. Since oxazolines readily hydrolyze to amides, the net effect of this reaction sequence is to produce p-amino alcohols 147 from an allyl alcohol. This strategy has been employed in numerous total syntheses of natural products. Examples are listed in Table 8.18 (Fig. 8.7 Scheme 8.43). ° ... 

Ritter reaction of cw-indane-l,2-diol with other nitriles leads to C2-symmetric bis(oxazolines) 178-180 that are ligands in a number of transition metal catalyzed... 

Epoxides also participate in the Ritter reaction with nitriles. An investigation of the ring opening of several alkyl-substituted glycidic esters and amides 181 showed that this transformation occurs with inversion and is completely regiospecific. ° Esters appeared to be somewhat more reactive than amides. However, phenyl-substituted glycidic esters and amides 184 are almost totally nonstereoselective. In addition, the oxazolines 186 are isolated in low yield due to the propensity of intermediate 185 to generate an aldehyde byproduct 187 (Scheme 8.53). 

Epoxides also undergo the Ritter reaction in good yields with retention of configuration via a episulfonium intermediate 190a (double-inversion process). For monosubstituted epoxides, the yields of oxazolines are lower due to nondis-criminatory attack of the nitrile on both the primary and the secondary carbon atom of the episulfonium intermediate. Complete retention of configuration is still observed despite the lower yield (Scheme 8.54). 

Olefins also undergo the Ritter reaction with nitriles in the presence of diphenyl diselenide, ammonium persulfate, and trifluoromethanesulfonic acid to produce oxazolines.When cyanamide is used, 2-aminooxazolines are obtained. The active electrophilic agent is phenylselenyl sulfate formed by oxidation of diphenylselenide with ammonium persulfate. The reaction is trans-stereospecific. 

The carbanion generated by ot-proton abstraction of a 2-alkyloxazoline is capable of typical enolate chemistry. Thus, the carbanion was found to react with nitriles to give an enamine, with formate esters to give an aldehyde that can be trapped,with chiral sulfinate esters to give chiral sulfoxides,and with alkylating agents. A carbamate-protected aminomethyl chiral oxazoline was deprotonated and alkylated with diastereoselectivities up to 92% de. ... 

Williams group observed low enantioselectivities for the Michael addition of a prochiral nucleophile, ethyl 2-cyanopropionate 623, to methyl vinyl ketone 624 catalyzed by chiral platinum complexes (Scheme 8.196)." The NMR analysis indicated that these cationic Pt complexes act as Lewis acids toward nitriles. The X-ray crystal structure as well NMR analysis showed that the solvent ligand that is readily displaced by an organic substrate is situated cis to the nitrogen donor in the Pt complex and, therefore, is in a chiral pocket created by the oxazoline ring. 

OXAZOLINES FROM NITRILES AND AMINO ALCOHOLS, 385-386 OXAZOLINES FROM IMIDATES AND AMINO ALCOHOLS, 388-389 CONVERSION OF ALLYLIC ALCOHOLS TO P-AMINO ALCOHOLS VIA OXAZO-... 

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