Nitrile oxides INOC reaction

Intramolecular 1,3-cycloadditions of nitrile oxides (INOC) provide a useful tool for the construction of fused cyclic ring systems. The stereochemical outcome of this reaction is presumed to be a consequence of reaction through the transition state that minimizes allylic 1,3 strain (Scheme 8.19).103... 

Aldoximes can be oxidatively dehydrogenated to nitrile oxides using a variety of oxidants such as lead tetraacetate [16a], alkali hypohalites [lla],NBS in DMF followed by base treatment [16b], chloramine-T [11b], 1-chlorobenzotriazole [16c], mercuric acetate [ 16 d], etc. However, we employed either NaOCl or chloramine-T for most of our INOC reactions. For instance, a piperidine ring fused to an isoxazoline as in 14 was constructed using the INOC methodology (Scheme 3) [17]. Monoalkylation of N-tosylallylamine 10 with the bromoacetal... 

The versatility of the INOC reaction is evident from the synthesis of tetrahy-drofurans fused to an isoxazoline 22a-f (Eq. 3) [181. a-Allyloxyaldoximes 21, formed by the reduction of jS-nitrostyrenes 19 with SnCl2 2H2O in the presence of an unsaturated alcohol 20, are transformed to isoxazolines 22 in high yield on treatment with NaOCl via stereoselective ring closure of a nitrile oxide intermediate (Table 2). 

A nitrile oxide generated from a sugar derived aldoxime 30 underwent INOC reaction to the chiral pyranoisoxazoline 31 (Eq. 4) [20]. Reductive cleavage of isoxazoline 31 followed by acetylation provided the tetrasubstituted pyran 32. 

Table 10. Molecular mechanics calculations on the INOC reactions of nitrile oxides 98 (energies in kcal/mol)...

A regio- and stereospecific INOC reaction of unsymmetrical silaketals 114, synthesized in one pot from unsaturated alcohols, nitro ethanol, and dichloro-silanes, via the nitrile oxide 115 to isoxazolines 116 has been described (Scheme 14) [37a]. The intermolecular version of the cycloaddition, under similar conditions, proceeds with poor regio and stereoselectivity. 

Although the unsaturated nitrile oxides 124 can be prepared via the aldoxime route (see Scheme 8), the older procedure suffers from the disadvantage that a tenfold excess of allyl alcohol and two additional steps are required when compared to Scheme 15. Therefore, unsaturated nitro ether 123 that can be prepared by condensation of an aldehyde 120 and a nitro alkane followed by Michael addition of alcohol 122, was a useful precursor to nitrile oxide 124 [381. The nitrile oxide 124 spontaneously cyclized to ether 125. This procedure is particularly suitable for the synthesis of tetrahydrofurans (125a-h) and tetrahydropyrans (125i-k) possessing Ar substituents in 72-95% yield (Table 12). The seven-membered ether 1251 was obtained only in 30% yield on high dilution. The acetylenic nitro ether 126 underwent INOC reaction to provide the isoxazole 127. 

As we found that furan and thiophene substituted oximes can be used as substrates for the INOC reactions (Eq. 5) [29b] similarly, furan substituted nitro alkane 134 is also a good substrate for INOC reactions (Eq. 13) [40]. The furfuryl derivative 134, prepared via Michael addition of furfuryl alcohol to 4-methoxy- -nitrostyrene, was subsequently transformed without isolation of the intermediate nitrile oxide 135 to the triheterocyclic isoxazoline 136 as a 5 1 mixture of isomers in high yield. 

Although nitrile oxide cycloadditions have been extensively investigated, cycloadditions of silyl nitronates, synthetic equivalent of nitrile oxides in their reactions with olefins, have not received similar attention. Since we found that the initial cycloadducts, hl-silyloxyisoxazolidines, are formed with high degree of stereoselectivity and can be easily transformed into isoxazolines upon treatment with acid or TBAF, intramolecular silylnitronate-olefin cycloadditions (ISOC) have emerged as a superior alternative to their corresponding INOC reactions [43]. Furthermore, adaptability of ISOC reactions to one-pot tandem sequences involving 1,4-addition and ISOC as the key steps has recently been demonstrated [44]. 

A potentially useful approach to the marine alkaloid papuamine based on INOC strategy is proposed as shown in Scheme 8.21. In fact, a tnms-hydrindane intermediate has been synthesized in racemic form using a model sequence of reactions involving a nitrile oxide cycloaddition as a key step (Eq. 8.69).106... 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

Recently, silicon-tethered diastereoselective ISOC reactions have been reported, in which effective control of remote acyclic asymmetry can be achieved (Eq. 8.91).144 Whereas ISOC occur stereoselectively, INOC proceeds with significantly lower levels of diastereoselection. The reaction pathways presented in Scheme 8.28 suggest a plausible hypo thesis for the observed difference of stereocontrol. The enhanced selectivity in reactions of silyl nitronates may he due to 1,3-allylie strain. The near-linear geometry of nitrile oxides precludes such differentiating elements (Scheme 8.28). 

The application of intramolecular dipolar cycloaddition reactions to the synthesis of complex natural products has recently come to be recognized as a very powerful synthetic tool, one equally akin to the intramolecular Diels-Alder reaction in its potential scope of application.69 This is particularly the case with nitrile oxides and the 1NOC reaction has been extensively utilized in total synthesis.70 The intramolecular nitrile oxide cycloaddition (INOC) generally displays exceptional regio- and stereo-chemical control which undoubtedly accounts for the popularity of this reaction. Internal cycloadditions of nitrile oxides have been found to offer a powerful solution to many problems in complex natural product synthesis.48 For example, Confalone and coworkers have utilized the INOC reaction for the stereospecific synthesis of the key amino alcohol (60), which was converted in five subsequent steps to ( )-biotin (61 Scheme 14).71... 

Kozikowski s group has been particularly active in the application of the INOC reaction toward the construction of a variety of natural products. One of the many examples from his laboratory involves the synthesis of tetracyclic compounds possessing suitably functionalized C rings for elaboration to a diverse number of ergot alkaloids via the INOC reaction. A total synthesis of chanoclavine I (65) was accomplished by this chemistry (Scheme 15). The key step in the synthesis involved the conversion of the nitro group of indole (62) into the corresponding nitrile oxide using the phenyl isocyanate procedure developed by Mukaiyama.57 The major product corresponded to isoxazoline (64). The isoxazoline nucleus was converted into chanoclavine I (65) in a series of subsequent steps. The application of nitrile oxide cycloaddition chemistry to the construction of other natural products can be expected to be an active area in future years. 

Intermolecular nitrile oxide cycloadditions have been known for a very long time.27 However, it was not until the mid-1970s that intramolecular nitrile oxide cycloaddition (INOC) reactions were studied.28... 

Nitroalkenes have also been used as cycloadduct precursors in the INOC reaction (Scheme 86). The nitroalkene (647 R1 = Me, R2 = COEt) was prepared by the addition of an unsaturated alkoxide (645) to the /3-nitroenone (646). Formation of the required nitrile oxide was accomplished by dehydration of the primary nitromethyl group with phenyl isocyanate and triethylamine. The resulting nitrile oxide underwent cycloaddition and gave the adduct (648 R1 = Me, R2 = COEt). 

An allylic chiral center between the nitrile oxide and alkene groups can also affect the stereochemistry of INOC reactions. For example, the production of only the cycloadduct (191) in the reaction of the (Z)-nitroalkene (190) (Scheme 90), compared to the formation of a 3 1 mixture of the isoxazolines (193) and (194) from the ( )-isomer (192) (Scheme 91) (84ACR410) is a dramatic example of the influence of allylic 1,3-strain (89CRV1841) on these processes. 

A chiral center adjacent to the nitrile oxide is also known to affect INOC reactions, as illustrated in the formation of the isoxazoline (195a),... 

Pyranoisoxazoles 425 have been prepared by intramolecular 1,3-dipolar cycloaddition of nitrile oxides obtained by treatment of nitrooxaheptynes with -BuLi and AC2O (Scheme 102) <2003H(59)685>. The coupling of the Ugi multicomponent reaction with the intramolecular T-oxide cyclization (Ugi/INOC) provided access to novel fused isoxazoles 426 in two steps from easily available starting materials in moderate to good overall yields... 

An alternative to the Diels-Alder reaction for establishing the carbon skeleton is the intramolecular nitrile oxide cyclization (INOC) reaction. An (INOC) reaction was utilized by Kozikowski and MaloneyHuss [119] as the key... 

Zanze and co-workers recently reported an Ugi reaction followed by intramolecular nitrile oxide cycloaddition for the synthesis of novel isoxazo-hnes 130 (Scheme 34) [135]. The substrates required for INOC were synthesized by a multicomponent Ugi reaction utilizing aldehyde 125, aUyl amine 126, isocyanide 128 and -nitro carboxylic acids 127. 

While the diastereoselectivity was high when the INOC reaction of substrates possessing a chiral center at the allyhc position was conducted, the chiral center at the cr-position of the nitrile oxide moiety provided the isoxazoUnes 206 with moderate selectivity [153]. The ISOC provided better selectivity as compared to the INOC at the expense of the product yields. 

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