Nitrones reactions with alkynes

Nitrone cycloaddition reactions with alkynes have been widely used for the synthesis of imidazolidine nitroxides (736) and (737), containing chelating enam-ino ketone groups (821). Different heterocyclic systems were obtained, such as 3-(2-oxygenated alkyl)piperazin-2-ones (738) (822), also compounds containing the isoxazolo[3,2-i]indole ring system (739) (823) and a new class of ene-hydroxylamino ketones- (l )-2-( 1-hydroxy-4,4,5,5-tetraalkylimidazolidin-2-ylidene)ethanones (740) (824) (Fig. 2.46). 

Another interesting cascade involving nitrones is the copper catalyzed reaction with alkynes to produce p-lactams that was originally reported by Kinugasa (72CC466). Stoichiometric amounts of copper(I) phenylacetylide (61) react with various aryl nitrones 62 in pyridine to give p-lactams 63 in 50-60% yield (equation (2)). In each case, only the czs-lactams were isolated. 

Thus the simplest aliphatic monomeric nitrone (369) has been studied in its reactions with alkynes and isocyanates. Problems were encountered since the nitrone was found to be in the form of an adduct (370) with excess pivaldehyde, although it is possible to remove the aldehyde in vacuo at the melting point. The simple products of cycloaddition (371) and (372) were isolated in good yield. 

In constrast with intermolecular nitrone cycloadditions to alkynes and allenes, very little work has been done on the corresponding intramolecular cycloadditions. The bicyclic isoxazolidines (65a-b) were reported as products from reaction of an alkynone with methylhydroxylamine in ethanol.26b Presumably the initial strained bridgehead C—C double bond of the AMsoxazoline added ethanol under the reaction conditions. Cyclization of an allenyl ketone with methylhydroxylamine in ethanol solution also led to isoxazolidines (65a-b) as the major products and isoxazolidine (66) as a minor product.266 Thus, preferential cyclization to the internal C—-C double bond of the allene occurred followed by addition of ethanol to the exocyclic C—C double bond of the methyleneisoxazolidine intermediate. 

The 1,3-dipolar cycloaddition reactions of racemic as well as enantiopure azetidin-2-one-tethered nitrones 364 with alkenes and alkynes 365 (Equation 136) yielded isoxazolidinyl- or isoxazolinylazetidin-2-ones 366, exhibiting good regio- and facial stereoselectivity (Equation 136) <2002JOC7004>. 

The attacks of heterocyclic A -oxides, e.g. of pyridine, quinoline, isoquinoline, phenanthridine, etc., on activated alkynes (RC CR R = R = COOMe R = Ph, R = COOEt R = Ph, R = CN) pose similar problems . An acyclic intermediate has been postulated but is rarely detected. Some of the possibilities are illustrated in equation (126) . If the open intermediate is formed, then the paths to the ylid and the 2-substituted quinoline in equation (126) seem simple enough, but several possible mechanisms can lead to the 3-substituted products . Other workers regard the reaction of the nitrone (or azomethine oxide) with alkyne as simple cycloadditions - which yield 2,3-dihydro-l,2-oxazoles since these are often unstable, only decomposition products may be found (equation 127). The construction of the indolizine skeleton initiated by a similar process has been reviewed (equation 128). ... 

Hetero-[2 + 2]-cycloaddition has been extensively investigated since this process provides a variety of /Mactones and /Mactams.178 There are two types of hetero-[2 + 2]-cycloaddition reaction, as illustrated in Scheme 114 one is the reaction of ketenes with aldehydes or imines to give lactones and lactams (Scheme 114, route a) and the other is the reaction of alkynes with nitrones to give lactams (Scheme 114, route b).179... 

The same patent and publication (07W0106818,15JFC121) mentioned the preparation of 4-SF5-2,3,5-trisubstituted-4-isoxazolines 171a—d in case when nitrones 170a—c were used as 1,3-dipoles in cycloaddition reactions with SFs-alkynes 129a,c,d (Scheme 53). 

When a nitrone reacts with a vinyl ether, an isoxazolidine is formed via a [3+21-cycloaddition reaction.58 Similar reaction with an alkyne gives an isoxazole.58... 

The copper-catalysed 3 + 2-cycloaddition reactions of nitrones with alkynes leading to / -lactams have been extensively reviewed. The 3+2-cycloaddition reactions of dialkyl-substituted 2-benzylidenecyclopropane-l,l-dicarboxylates (54) and C-carbamoyl nitrones (53) produced simple isomeric spiro[cyclopropane-l,4-isoxazolidine] cycloadducts (55), which are readily transformed into isoxazolidine-fused / -lactams (56) in high yields (Scheme 15). BINOL-derived chiral phosphorami-date Au(l) catalysts have been used to catalyse the 3+2-cycloaddition of A(-allenyl amides with nitrones to produce chiral 4-alkylidenyl isoxazolidines in high yields and excellent enantioselectivity (up to 99% cc). The 3+2-cycloaddition of a-phenylnitroethene and (Z)-CA -diphenylnitrone in polar media (nitromethane and water) yielded 3,4-fra 5 -2,3,5-triphenyl-4-nitroisoxazolidine via a zwitterionic, two-step mechanism. ... 

The asymmetric version of this reaction has been carried out using nitrone 46a and terminal alkynes 48 in the presence of HETPHOX 49 ligand as catalyst to afford the -lactams 50 in good diastereoselectivity but moderate enantioselectivity (Scheme 3.19) [52]. Diastereoselectivity of the products depends on the nature of the alkynes. Most alkynes afforded the ds-adducts, whereas trans-products were obtained with the 3,5-trifluoromethylacetylene. Very recently, Chen and coworkers [53] reported a novel efficient catalyst, TOX [chiral tris(oxazoHne)] 51/Cu(I) complex, for the asymmetric Kinugasa reaction of terminal alkynes 48a with C-aryl nitrones 46 to afford the isomeric fi-lactams 52 and 53 in highly enantio- and diastereoselective manners (Scheme 3.20). The highly enantioselective Kinugasa reaction of nitrones 46 with terminal alkynes 48a in the presence of IndaBox 54/Cu(OTf)2 and dibutylamine has been reported to yield the isomeric P-lactams 52 and 53 (Scheme 3.21) [54]. 

In the racemic version, the reaction of various terminal alkynes 105 with nitrones 106 was carried out using 10 mol % of Cul in pyridine-DMF at room temperature. As expected, the corresponding azetidinones 107 were formed as a mixture of trans and czs-isomers, along with the imines 108 (Scheme 30). 

The reaction of nitrones with terminal alkynes proceeds in excellent yields and high purity, in the presence of stoichiometric quantities of diethylzinc and zinc triflate (219, 661-663). To optimize the process of diastereoselective addition of terminal alkynes to chiral nitrones, ZnCl2 and NEt3 in toluene were used. This reaction protocol is facile to perform, cost-effective and environmental friendly (664). 

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