Alkynes-nitrones cycloaddition reaction

Recent advances and applications of strain-promoted alkyne-nitrone cycloaddition reactions in bio-orthogonal labeling (14COCB81) and of natural isoxazoline derivatives in the field of anticancer research (14EJM121) were reviewed. 

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). 

The common methods for the S5mthesis of p-lactams are cycloaddition reactions such as the Staudinger s ketene-imine cycloadditions, ester enolate-imine cycloadditions, alkyne-nitrone cycloadditions (Kinugasa reaction), alkene-isocyanate cycloadditions, and Torii s cyclocarbonylation of allyl halides with imines. Several cyclizahon reactions of p-amino esters, p-amino acids, p-hydroxamate esters, and a-diazocarbonyls have been developed for the formation of p-lactam ring. N,N-Disubstituted a-haloamides cyclize by C3-C4 bond formation leading to the formation of P-lactam ring. 

The electrophile-induced cyclization of heteroatom nucleophiles onto an adjacent alkene function is a common strategy in heterocycle synthesis (319,320) and has been extended to electrophile-assisted nitrone generation (Scheme 1.62). The formation of a cyclic cationic species 296 from the reaction of an electrophile (E ), such as a halogen, with an alkene is well known and can be used to N-alkylate an oxime and so generate a nitrone (297). Thus, electrophile-promoted oxime-alkene reactions can occur at room temperature rather than under thermolysis as is common with 1,3-APT reactions. The induction of the addition of oximes to alkenes has been performed in an intramolecular sense with A-bromosuccinimide (NBS) (321-323), A-iodosuccinimide (NIS) (321), h (321,322), and ICl (321) for subsequent cycloaddition reactions of the cyclic nitrones with alkenes and alkynes. 

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. 

Alcaide and coworkers have reported in 2002 the synthesis of various types of racemic and homochiral 1,3,4-trisubstituted- or fused polycyclic (3-lactams (III and IV, respectively, Fig. 9) via intermolecular 1,3-dipolar cycloaddition reaction of 2-azetidinone-tethered nitrones with a variety of alkenes or alkynes [264]. 

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>. 

Some examples are known of 1,3-dipolar cycloaddition reactions of trifluoromethyl-substituted alkenes and alkynes with other dipoles (see Table 12), such as diazomethane.nitrile imines, " " nitronates," and munchones." Depending on reaction conditions, cycloadditions may occur via a two-step process. 

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... 

Schreiber s early efforts in this area were focused on libraries of compounds having structural features reminiscent of rigid, complex, stereochemically rich natural products. In a key early example, solid-phase split-pool synthesis was used to generate a combinatorial library of over two million complex, polycyclic compounds derived from shikimic acid [17]. A stereoselective tandem acylation-nitrone cycloaddition was used to generate 18 tetracyclic scaffolds, to which 30 alkynes were coupled using a Sonogashira reaction, 62 amines were coupled via y -lactone aminolysis, and 62 carboxylic acids were coupled by alcohol esterification (Fig. 9.1-3(c)). In addition, a portion of the solid supports were left unreacted at each of the last three steps to generate a skip codon that further increased the diversity of the library. 

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). 

Namitharan, K. and Pitchumani, K. 2011. Copper(l)-catalyzed three component reaction of sulfonyl azide, alkyne, and nitrone cycloaddition/rearrangement cascades A novel one-step synthesis of imidazolidin-4-ones. Org. Lett. 13(21) 5728-5731. 

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. ... 

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