Nitrone reactions with cyclopropanes

SCHEME 10.26 In situ formation of nitrone and reaction with cyclopropane. 

This topological rule readily explained the reaction product 211 (>90% stereoselectivity) of open-chain nitroolefins 209 with open-chain enamines 210. Seebach and Golinski have further pointed out that several condensation reactions can also be rationalized by using this approach (a) cyclopropane formation from olefin and carbene, (b) Wittig reaction with aldehydes yielding cis olefins, (c) trans-dialkyl oxirane from alkylidene triphenylarsane and aldehydes, (d) ketenes and cyclopentadiene 2+2-addition, le) (E)-silyl-nitronate and aldehydes, (f) syn and anti-Li and B-enolates of ketones, esters, amides and aldehydes, (g) Z-allylboranes and aldehydes, (h) E-alkyl-borane or E-allylchromium derivatives and aldehydes, (i) enamine from cyclohexanone and cinnamic aldehyde, (j) E-enamines and E-nitroolefins and finally, (k) enamines from cycloalkanones and styryl sulfone. 

Christie and Jones first demonstrated in 2004 that appropriately substituted cyclopropanes adjacent to cobalt-alkyne complexes react with Lewis acids to yield 1,3-dipoles that are poised to participate in dipolar cycloadditions. Reaction of cyclopropane 21 with benzaldehyde and boron trifluoride provides tetrahydrofuran 22 in 83% yield. Kerr subsequently applied this strategy to the synthesis of tetrahydro-l,2-oxazines upon combination of cyclopranes like 21 with a variety of nitrones. ... 

SCHEME 10.25 Mechanism of reaction of cyclopropanes with nitrones. 

TABLE 10.8 Ni-Catalyzed Reaction of Cyclopropanes with Nitrones... 

Through the progression of the cycloaddition reaction of cyclopropane diesters with nitrones, Sapeta and Kerr thought it wise to investigate the mechanism of this [3+3] dipolar cycloaddition. 

Extension of this to other 2,3-disubstituted 1,1 -dicarboxyl cyclopropanes has been sparse [29-31]. In an attempt to extend the scope of the reaction, we looked at a series of disubstituted cyclopropanes and their cycloaddition with nitrones. The diaryl cyclopropanes were prepared by hydrogenation of the corresponding cyclopropane (Scheme 10.32 and Table 10.10), and optimization conditions showed that cycloaddition was best achieved with ytterbium triflate as the Lewis acid. Moving on to differentially substimted species. 

In fight of the successful methodology used by Young and Kerr in the ability of activated cyclopropanes to undergo nucleophilic ring-opening/cycloaddition reactions with indoles and nitrones [21], Johnson and coworkers reported the synthesis of tetrahydrofurans via an adaptation of this... 

It was demonstrated (83) that the reaction of dinitrostyrenes (28) with aryl diazo compounds RR CN2 afford nitronates (24 g) in good yields. These products contain the nitro group at the C-4 atom in the trans position with respect to the substituent at C-5 (if R =H). Since the reaction mechanism remains unknown, the direct formation of cyclic nitronates (24 g) from pyrazolines A without the intermediate formation of cyclopropanes also cannot be ruled out. 

It should be pointed out that the alkylidenecyclopropanes are not stable due to the exo double bond and strained cyclopropane ring. The 1,3-Dipolar Cycloaddition of alkylidenecyclopropanes with nitrones was reported by Akmanova in 1982 (i.e., the reaction between A -(phenylaminooxoethylidene) aniline A -oxide and 2,2-dimethylmethylene-cyclopropane), although the 1,3-Dipolar Cycloaddition has been known since the 1960s. 

Fig. 1.2b) classes wherein an enolizable nucleophile (commonly an enamine, nitronate or 1,3-dicarbonyl) cyclizes onto an sp carbon. Enolexo-exo-tet cyclizations (Fig. 1.2c) are less common however, and tend to occur predominantly in cyclopropanation reactions. Indeed, alkylations using secondary amine catalysis are difficult under standard organocatalytic conditions owing to problems associated with the alkylation of the catalyst itself, although various methods have been adopted to address this. Finally, exo-trig cyclizations of heteroatoms onto sp centres (Fig. 1.2d) are a useful way of constructing enantiopnre heterocycles. 

Scheme 4.11 Domino ring opening/cyclisation reaction of nitrones with activated cyclopropanes.

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. ... 

A zinc-silver couple has been reported to be an improved reagent for the reductive addition of allylic bromides to nitriles. l-Trimethylsilyl-2-methyl-cyclopropane is a convenient regio- and stereospecific precursor of unsaturated ketones [equation (37)]. The reaction of allylsilanes with a-nitro-olefins has been found to proceed smoothly in the presence of aluminium trichloride [equation (38)]. The unstable nitronic acid product may be converted readily into the unsaturated ketone by the Nef reaction. 

Kerr and coworkers have also successfully reported the use of cobalt hexacarbonyl cyclopropanes in [3-1-2] cycloadditions with nitrones via a purported Nicholas-type reaction in the presence of scandium triflate (Sc(OTf)3) to afford a variety of oxazines in high yields (Scheme 10.9) [11]. 

During their investigations. Young and Kerr found that in some instances the nitrones were unstable under the present Lewis acid conditions, making the reaction substrate specific [21]. Kerr and coworkers addressed this in developing a one-pot synthesis, where nitrones were prepared in situ, and subsequently reacted with the cyclopropane in the presence of the Lewis acid to afford the tetrahydro-l,2-oxazines as the cis diastereoisomer exclusively, in yields ranging from 66 to 93%. An example of this is shown in Scheme 10.26 [22a,b]. 

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