Nitronates cyclic nitronate preparation

Diacetates of 1,4-butenediol derivatives are useful for double allylation to give cyclic compounds. l,4-Diacetoxy-2-butene (126) reacts with the cyclohexanone enamine 125 to give bicyclo[4.3.1]decenone (127) and vinylbicy-clo[3.2.1]octanone (128)[85,86]. The reaction of the 3-ketoglutarate 130 with cij-cyclopentene-3,5-diacetate (129) affords the furan derivative 131 [87]. The C- and 0-allylations of ambident lithium [(phenylsulfonyl)methylene]nitronate (132) with 129 give isoxazoline-2-oxide 133, which is converted into c -3-hydroxy-4-cyanocyclopentene (134)[S8]. Similarly, chiral m-3-amino-4-hyd-roxycyclopentene was prepared by the cyclization of yV-tosylcarbamate[89]. 

Alicyclic hydroxamic acids undergo several specific oxidative cleavage reactions which may be of diagnostic or preparative value. In the pyrrolidine series compounds of type 66 have been oxidized with sodium hypobromite or with periodates to give y-nitroso acids (113). Ozonolysis gives the corresponding y-nitro acids. The related cyclic aldonitrone.s are also oxidized by periodate to nitroso acids, presumably via the hydroxamic acids.This periodate fission was used in the complex degradation of J -nitrones derived from aconitine. 

We are the first group to succeed with the highly enantioselective 1,3-dipolar cycloadditions of nitronates [75]. Thus, the reaction of 5,6-dihydro-4H-l,2-oxazine N-oxide as a cyclic nitronate to 3-acryloyl-2-oxazilidinone, at -40 °C in dichloro-methane in the presence of MS 4 A and l ,J -DBFOX/Ph-Ni(II) complexes, gave a diastereomeric mixture of perhydroisoxazolo[2,3-fe][l,2]oxazines as the ring-fused isoxazolidines in high yields. The J ,J -DBFOX/Ph aqua complex prepared from... 

Nitrones have been generally prepared by the condensation of /V-hydroxylamines with carbonyl compounds (Eq. 8.40).63 There are a number of published procedures, including dehydrogenation of /V,/V-disubstituted hydroxylamines, / -alkylation of imines, and oxidation of secondary amines. Among them, the simplest method is the oxidation of secondary amines with H202 in the presence of catalytic amounts of Na2W04 this method is very useful for the preparation of cyclic nitrones (Eq. 8.41).64... 

Kibayashi and coworkers have used enantiometrically pure allylic silyl ethers obtained from amino acids in cycloaddition with nitrones (Eq. 8.49).71 Cyclic nitrone reacts with a chiral allyl ether to give selectively the exo and erythro isomer (de 90%). Optically active alkaloids containing a piperidine ring such as (+)-monomorine,71c (+)-coniine,71a and (-)-oncinotine71b have been prepared from the addition product. 

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

Recently, Denmark and coworkers have developed a new strategy for the construction of complex molecules using tandem [4+2]/[3+2]cycloaddition of nitroalkenes.149 In the review by Denmark, the definition of tandem reaction is described and tandem cascade cycloadditions, tandem consecutive cycloadditions, and tandem sequential cycloadditions are also defined. The use of nitroalkenes as heterodienes leads to the development of a general, high-yielding, and stereoselective method for the synthesis of cyclic nitronates (see Section 5.2). These dipoles undergo 1,3-dipolar cycloadditions. However, synthetic applications of this process are rare in contrast to the functionally equivalent cycloadditions of nitrile oxides. This is due to the lack of general methods for the preparation of nitronates and their instability. Thus, as illustrated in Scheme 8.29, the potential for a tandem process is formulated in the combination of [4+2] cycloaddition of a donor dienophile with [3+2]cycload-... 

Finally, the fourth approach (path d) involves the generation of conjugated nitro olefins C from the starting AN by known methods. The latter are involved in the conjugated [1,4]-addition to give target nitronates. This process is of most importance for the synthesis of six-membered cyclic nitronates (see Section 3.2.1.2.2). This method was also used to prepare a small series of boryl-, silyl-and acyl nitronates (see Sections 3.2.3 and 3.2.4). It is beyond reason to believe that all possibilities of the approach (d) are exhausted by these examples. 

In some cases, five-membered cyclic nitronates can be prepared by the chemos-elective replacement of one of two different halogen atoms in 1,3-dihalopropanes... 

In the synthesis of five-membered cyclic nitronates (5), the problem of stereoselectivity is in preparing these products with desired relative configurations of the stereocenters at the C-4 and C-5 atoms (see Scheme 3.12). Generally, the trans configuration of these substituents is most preferable. Several procedures giving exclusively this configuration were documented (see,e.g. (50, 55, 58, 63, 68)). 

Analogous intramolecular cyclization can be carried out by performing the reaction of CAN with nitro olefin (20) (73) (Scheme 3.23). However, this reaction is unlikely to be useful in the synthesis of a broad range of cyclic nitronates because the starting nitro compounds (similar to (20)) are difficult to prepare. 

Synthesis of Five-membered Cyclic Nitronates from a-Halogen-substituted AN. The key step of this approach is presented in Scheme 3.1, path (b). Until recently, this synthetic route to nitronates (24) has been of no preparative interest, because only two examples, such as elimination of trimethylsilyl nitrite (75) and 1,2-dinitrophenylethane (85) from the corresponding nitroso acetals were documented. 

The above described approaches were used in the several studies (96, 137, 138, 140, 150, 159-163) to prepare a representative series of enantiometrically pure six-membered cyclic nitronates (35). 

Nitronate(47a) is not the only oxazete derivative. For example, sterically hindered nitroalkenes (42b-d) can be prepared by nitration and halogenation of readily available allenes (48). Compounds (42b-d) are rather smoothly isomerized into the corresponding four-membered cyclic nitronates (47b-d) by the first-order reaction equation (168). Storage of nitronate (47c) is accompanied by its slow transformation into acid chloride (47e) from which amide (47f) can be easily synthesized. 

However, intramolecular O-alkylation can be performed under particular conditions leading to of annelation of a seven-membered heterocycle. Japanese researchers (170) prepared the corresponding seven-membered cyclic nitronates (50a-c) in good yields by the reaction of triethylamine with brominated aryl ketones (49a-c) containing the nitromethyl group in the ortho position. 

The yields of the target products are as yet moderate. However, the preparative significance of both [3 + 2]-addition of six-membered cyclic nitronates and the tandem [4 + 2] [3 + 2] processes with the involvement of these intermediates can be enhanced provided that this methodology will be improved. 

In addition, chiral five-membered cyclic nitronates can be prepared from optically inactive starting nitronates with the use of ligated palladium (catalyst) as a chiral inductor (71) (ee 97%). 

Taking into account all the aforesaid, simple procedures were developed for preparation of most six-membered cyclic nitronates. These procedures allow one to stereo- and regioselectively synthesize the corresponding cyclic nitroso acetals (343), which retain the configurations of the stereocenters of the starting nitronates (342) (see Table 3.19) (264, 472—474). It should be emphasized that, in the presence of the substituent R1, the internal C,C double bond in the resulting nitroso acetals (343) always is of lruns configuration. 

Table 3.19 The silylation of six-membered cyclic nitronates. The preparation of ene-nitroso acetals...

These enoximes can be prepared through available annelated six-membered cyclic nitronates (391) by their silylation giving rise to the iminium cations A, whose deprotonation affords annelated 2H-5,6-dihydrooxazines (392). After the known retro-fragmentation (490), the latter compounds are transformed into the target conjugated en oximes (395). 

Oxazines (517) can be prepared in somewhat lower yields directly from six-membered cyclic nitronates (518) without isolation of the corresponding nitroso acetals (516) (see Table 3.36). 

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

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