11+2 Cycloaddition, with nitriles

Ethyl 3-azido-l-methyl-177-indole-2-carboxylate 361 is prepared in 70% yield by diazotization of amine 360 followed by substitution of the created diazonium group with sodium azide. In cycloadditions with nitrile anions, azide 361 forms triazole intermediates 362. However, under the reaction conditions, cyclocondensation of the amino and ethoxycarbonyl groups in 362 results in formation of an additional ring. This domino process provides efficiently 4/7-indolo[2,3-i ]l,2,3-triazolo[l,5- ]pyrimidines 363 in 70-80% yield (Scheme 57) <2006TL2187>. 

The conversion of the polystyrene-supported selenyl bromide 289 into the corresponding acid 290 allowed dicyclohexylcarbodiimide (DCC)-mediated coupling with an amidoxime to give the 1,2,4-oxadiazolyl-substituted selenium resin 291 (Scheme 48). Reaction with lithium diisopropylamide (LDA) and allylation gave the a-sub-stituted selenium resin 292, which was then used as an alkene substrate for 1,3-dipolar cycloaddition with nitrile oxides. Cleavage of heterocycles 293 from the resin was executed in an elegant manner via selenoxide syn-elimination from the resin <2005JC0726>. 

Cycloaddition with nitrile oxides occur with compounds of practically any type with a C=C bond alkenes and cycloalkenes, their functional derivatives, dienes and trienes with isolated, conjugated or cumulated double bonds, some aromatic compounds, unsaturated and aromatic heterocycles, and fullerenes. The content of this subsection is classified according to the mentioned types of dipolarophiles. Problems of relative reactivities of dienophiles and dipoles, regio- and stereoselectivity of nitrile oxide cycloadditions were considered in detail by Jaeger and... 

A study of the regioselectivity of the 1,3-dipolar cycloaddition of aliphatic nitrile oxides with cinnamic acid esters has been published. AMI MO studies on the gas-phase 1,3-dipolar cycloaddition of 1,2,4-triazepine and formonitrile oxide show that the mechanism leading to the most stable adduct is concerted. An ab initio study of the regiochemistry of 1,3-dipolar cycloadditions of diazomethane and formonitrile oxide with ethene, propene, and methyl vinyl ether has been presented. The 1,3-dipolar cycloaddition of mesitonitrile oxide with 4,7-phenanthroline yields both mono-and bis-adducts. Alkynyl(phenyl)iodonium triflates undergo 2 - - 3-cycloaddition with ethyl diazoacetate, Ai-f-butyl-a-phenyl nitrone and f-butyl nitrile oxide to produce substituted pyrroles, dihydroisoxazoles, and isoxazoles respectively." 2/3-Vinyl-franwoctahydro-l,3-benzoxazine (43) undergoes 1,3-dipolar cycloaddition with nitrile oxides with high diastereoselectivity (90% de) (Scheme IS)." " ... 

The thione group of dithiazolethiones is a very reactive heterodipolarophile. In Scheme 18 are given cycloadditions with nitrile oxides <67BSF2239>, diphenylnitrilimine, and ethyl azidoformate <85JCS(P1)1205>. The primary adducts are spiro derivatives, but only compound (131), which is obtained from nitrile oxides is isolable at low temperature. All are decomposed to give respectively compounds (132)-(134) and occasionally nitriles and sulfur. Compound (134) reacts further with nitrilimine affording compound (135) which is also isolated. 

The lactone 88 having an exo-cyclic double bond was applied in a 1,3-dipolar cycloaddition with nitrile oxides in recent work by Gallos et al. (Scheme 12.29) (133). The ip/ro-isoxazoline (89) was obtained as the sole diastereomer from the addition of the stable nitrile oxide 87. The resulting adduct 89 was further subjected to N—O bond cleavage by hydrogenolysis, followed by a spontaneous cyclization to give the carbocyclic product 90 in 64% yield. 

Fluoro-substituted chiral vinyl sulfoxides such as 103 have been used in 1,3-dipolar cycloadditions with various benzonitrile oxides (Scheme 12.34) (158). The reaction proceeded slowly at room temperature, however, after 5-10 days the isoxazoline (104) was obtained with excellent de in good yield. In some cases, the product tends to eliminate the 5-methoxy substituent of the isoxazoline, thus, after loss of two chiral centers, an isoxazole is obtained (158,159). Other chiral suMnyl derivatives have also been used in 1,3-dipolar cycloadditions with nitrile oxides (160,161), and in one case a racemic vinyl phosphine was used in reactions with various nitrile oxides, but with moderate selectivities (151). 

The auxihary acrylates 161 and 162 have been used in 1,3-dipolar cycloadditions with nitrile oxides. The camphor-derived acrylate 161 underwent a 1,3-dipolar cycloaddition with benzonitrile oxide with up to 56% de (Scheme 12.51) (263). The auxiliary in acrylate 162 is derived from naturally occurring L-quebrachitol, and provided an effective shielding of the re-face of the alkene in the reaction with benzonitrile oxide, as 90% de was obtained (273). Compound 163 was used in a reaction with the nitrone 1-pyrrole-1-oxide, and the reaction proceeded to give a complex mixture of products (274). 

The a,p-unsaturated amides 180-188a have all been used in 1,3-dipolar cycloadditions with nitrile oxides, and some of them represent the most diastereoselective reactions of nitrile oxides. The camphor derivative 180 of Chen and co-workers (294), the sultam 181 of Oppolzer et al. (295), and the two Kemp s acid derived compounds 186 (296) and 187 (297) described by Curran et al. (296) are excellent partners for diastereoselective reactions with nitrile oxides, as very high diastereos-electivities have been observed for all of them. In particular, compound 186 gave, with few exceptions, complete diastereoselection in reactions with a wide range of different nitrile oxides. Good selectivities were also observed when using compounds 183 (298) and 184 (299-301) in nitrile oxide cycloadditions, and they have the advantage that they are more readily available. Curran and co-workers also studied the 1,3-dipolar cycloaddition of 187 with silyl nitronates. However, compared to the reactions of nitrile oxides, lower selectivities of up to 86% de were obtained (302). 

In three separate papers, the use of chiral boronic esters in 1,3-dipolar cycloadditions with nitrile oxides have been described (316-318). The reaction of 203 with nitrile oxides proceeded with low diastereoselectivities (Scheme 12.58). 

Enamines are known to undergo cycloaddition with nitrile oxides. However, 3-pyrrolidinothiophene with mesitonitrile oxide gave only the oxime (289) no isoxazoline could be detected (74RTC321). Whether an isoxazoline is an intermediate in the formation... 

The thione groups of dithiazolethiones are very reactive heterodipolarophiles. Several cycloadditions with nitrile oxides, diphenylnitrilimine, and ethyl azidoformate to give spiro derivatives have been reported <1996CHEC-II(4)517>. 

Reactions of 3,5-dichloro-2,4,6-trimethyl benzonitrile oxide 241 with fluoro-methyl substituted alkenes 242, bearing a chiral sulfinyl group at -position of the double bond, afford diastereoisomeric 4,5-dihydroisoxazoles 243 and 244 [180] with a stereoselectivity lower than 2 1 (Scheme 110). The authors conclude that the efficiency of allyl sulfoxides to control diastereoselectivity of 1,3-dipolar cycloadditions with nitrile oxides is lower than that of vinyl sulfoxides. 

Cycloadditions with nitrile oxides occur across the C=S bond both with 1,3,5-oxathiazole-2-thiones (66JOC2417) and l,3,4-dithiazole-2-thiones (Scheme 28) (67BSF2239), the reaction proceeding via an interesting spiro compound which has been isolated in some cases. 

An investigation concerning intramolecular aza Diels-Alder reactions of 3-(co-alkynyl)-l,2,4-triazines has been published by Taylor et al. [327] and trichloro-1,2,4-triazine has been introduced as novel triazine diene recently [328]. 1,2,4-Triazines are a useful alternative of 1,4-diaza-l,3-butadienes with regard to the aforementioned synthesis of pyrazines since Taylor s group has found them to undergo cycloadditions with nitriles followed by extrusion of nitrogen [329]. This reaction is noteworthy since it is a Diels-Alder reaction of both electron-deficient diene and dienophile. 

In two examples, type 2 reagents produce 4-nitroisoxazoles. Nitro-keteneaminals undergo cycloaddition with nitrile oxides to produce the 4-nitroisoxazoles 61 (10-25%) [(Eq. 19)].30 Substrates possessing a methylene group activated on one side by a nitro group and on the other by either a nitrile or a carbonyl, react with hydroxamoyl chlorides in presence of base to produce the 4-nitroisoxazoles (62) and (63) [Eqs. (20,21)].57... 

Cycloaddition with nitrile oxides is also efficient with trisubstituted enol ethers and enolates. With fluoro-substituted chiral vinyl sulfoxides 10. cycloadditions performed with aryl chloroaldoximes, at room temperature in carbon tetrachloride in the presence of triethylaminc, are slow but give the homochiral dihydroisoxazoles 11 with high regio- and diastereoselectivity. ... 

Alkynols complexed to cobalt can be oxidized to alkynals without decomplexation. Propargyl aldehydes are protected from polymerization upon complexation with Co2(CO)6. These aldehydes smoothly undergo Wittig-type reactions. Carbonyl-ene reactions have been demonstrated (Scheme 194). Complexation to cobalt protected the enyne in complex (132) from Michael-type reactions (Scheme 195). Alkenyl-substituted complexes undergo [3 + 2]cycloadditions with nitrile A-oxides (Scheme 196). 

Dipolar Cycloadditions with Nitrile Oxides (Alkene-+-Isoxazoline) 1,3-Dipolar cycloaddition reactions of N-acryloyl-a-t-butyltoluene-2,a-sultam (6) with various nitrile oxides give isoxazolines with extremely high C(a)-re rr-facial control (eq 3). The levels of selectivity exceed those obtainable with the 10,2-camphorsultam auxiliary and are comparable to the highest levels reported for such cycloadditions. The corresponding reactions of a-methyltoluene-2,a-sultams are less selective. 

The dianion of TOSMIC will react readily by a [An -(- 2n] cycloaddition with nitriles to give A -unsubstituted 4-substituted imidazoles (7) (Scheme 4.2.1). These reactions also occur with other C—N multiple bonds with much more facility than with the monoanion, while other isocyanides susceptible to a-metallation can also take part [8, 9]. As mentioned above, the dilithiated derivative of TOSMIC is much more reactive than the monolithio derivative. It is also considerably more stable, e.g. the half-life of the monoanion at 20°C under nitrogen in THF-hexane is about 3h under the same conditions the dianion is still 80% recoverable after 24 h. It is possible, therefore, to prepare 4-phcnyl-5-tosylimidazole quite rapidly in 33% yield from the dianion and benzonitrile. The same product is formed only reluctantly from the monoanion. The dianion will also react even with azaaromatics (e.g. isoquinoline) with weakly electrophilic C=N bonds [9]. 

Methyl 3-(/>-nitrobenzoyloxy)acrylate was exploited as a methyl propiolate equivalent with reverse regioselectivity in 1,3-dipolar cycloaddition with nitrile oxides, leading to 3-aryl-4-methoxycarbonylisoxazoles in moderate to good yields <2000JHC75>. 

---