Cyclic nitroso acetals

Main Aspects of Chemistry and Stereochemistry of Cyclic Nitroso Acetals Chemistry of cyclic nitroso acetals or nitrosals (the term was introduced by Prof. Seebach) has attracted interest only after the discovery of the 1,3-dipolar cycloaddition reaction of nitronates with olefins in 1962 by the research group of Prof. Tartakovsky. (Principal data on nitroso acetals up to 1990 were summarized in the review by Rudchenko (395).)... 

Cyclic nitroso acetals (219,220), and (221) (Scheme 3.153) belong to the most interesting group of nitroso acetals, such as derivatives containing the -O-N-O-... 

Besides, cyclic nitroso acetals have attracted considerable interest because [3+ 2]-cycloaddition of nitronates to olefins provides a simple and efficient procedure for the synthesis of five-membered cyclic nitrosals (see Scheme 3.153). Hence, knowledge of the configurations of these products allows conclusions about the mechanism of this very important process. However, it is impossible to distinguish kinetic and thermodynamic products of [3+ 2]-cycloaddition of nitronates to olefins without studying such a fundamental problem as the stereodynamics of five-membered cyclic nitroso acetals, that is, the ring and nitrogen inversions. 

A recently developed general procedure for the synthesis of cyclic nitroso acetals is based on the reaction of cyclic nitronates with C-nucleophiles under conditions of electrophilic catalysis (Scheme 3.153 for more details, see Section 3.5.2.3). 

Transformations of Five-membered Cyclic Nitroso Acetals Containing the N-siloxy Fragment Under the Action of Acids and Nucleophiles These products are characterized by the fact that both the N-0 Si and O-Si bonds can... 

A large group of reactions leading to modifications of substituents in cyclic nitroso acetals (66, 152, 159, 160, 190, 214, 215, 367, 404, 405) is not considered because, in our opinion, this aspect of chemistry of nitroso acetals, is beyond the scope of the present section. 

Determination of the Configurations and Study of Stereodynamics of Cyclic Nitroso Acetals This determination is of obvious fundamental importance by itself and, in addition, it is of importance in considering the mechanism of [3+ 2]-cycloaddition and in predicting the conhgurations of the resulting stereocenters. 

The most reliable data on the relative conhgurations of different types of cyclic nitroso acetals can be obtained by X-ray diffraction (Chart 3.15). 

These data demonstrate that the nitrogen atom in practically all cyclic nitroso acetals A or B, containing the isoxazolidine ring, deviates from the plane through the other four atoms (envelope). The nitrogen lone pair always pseudo-equatorial. 

Investigations of the stereodynamics of cyclic nitroso acetals and, particularly, different types of isoxazolidines are of great importance. 

It should be noted that the equatorial position of the nitrogen lone pair in six-membered cyclic nitroso acetals is not so favorable. Hence, both stereodynamic processes can be observed for these compounds (Scheme 3.167, see also Ref. (274)). 

Second, one should take into account the stability of nitroso acetals (343) associated with the possibility of their rearrangement to give oxazines (344). In addition, it should be taken into account that cyclic nitroso acetals (343) can be transformed into halo derivatives of dihydrooxazines (345). (These transformations of nitroso acetals (343) will be considered in more detail in Section 3.5.4.3.3.)... 

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. 

In many cases, the yields of these products are high. However, the use of /V-silylated triazoles as nucleophiles or the use of cyclic nitroso acetals (475) substituted at the C-3 atom leads to a noticeable decrease in the yield of the oximes. Therefore, steric hindrance in nitroso acetals and a decrease in nucleophilicity of A-centered nucleophiles result in an increase in the contribution of side reactions. It should be emphasized that C -nucleophiles, such as anions of nitro compounds, are not involved in coupling reactions with cyclic nitroso acetals (475). However, the products, which formally correspond to the C,C-coupling mechanism, can be prepared by the nucleophilic substitution of chlorine in compound (476 d) by a Sa/2 mechanism (Scheme 3.254, product (483c), the yield was 79%). 

It should be noted that one of the N,C-coupling reactions, involving cyclic nitroso acetals, cannot be explained by a traditional explanation involving intermediate conjugated nitrosoalkenes (Scheme 3.256). 

If a good leaving group is absent at C-6 in cyclic nitroso acetal (507), the reaction induced by certain nucleophiles (F- or Et3N) proceeds through another pathway (Scheme 3.265). 

The process shown in Scheme 3.265 substantially complicates the reaction of cyclic nitroso acetals with nucleophiles at the p-C atom of the enamine fragment. 

Synthesis of 5,6-Dihydro-4H-Oxazines Containing Functionalized Substituents at the C-3 Atom Unlike BENAs, six-membered cyclic nitroso acetals do not form quaternary ammonium salts in the reactions with StX/Nu. ... 

I. New Procedures for Reduction of Nitroso Acetals Containing the N- OSiMejRu1 Fragment Selective reduction of cyclic nitroso acetals was briefly considered in Section 3.4.3.4.3. The latest data on catalytic hydrogenation of cyclic and NOSiN Bu -containing acyclic nitroso acetals (including... 

A one-pot synthesis of the tetra cyclic nitroso acetal 58a and 58b was achieved using methoxycyclohexene (56) as enol ether and cyclohexenone (50) as dipolar-ophile (Scheme 9.20). Heating of the one-pot reaction mixture at 15 kbar for 96 h up to 50 °C produced nitroso acetal 58a and 58b as a mixture of two diastereomers (3 1) in 53 % yield together with a small amount of intermediate nitronate 57. 

The second method (path b) involves the initial transformation of AN into nitroso acetals A containing the good leaving group Y followed by 1,3-elimination of the Si Y fragment from the above mentioned intermediate to form the target nitronates. The use of this method in the synthesis of only five-membered cyclic nitronates has been documented (see Section 3.2.1.2.1.2). However, there are no obvious obstacles to the extension of the scope of this method. 

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. 

Selective Reduction of the O-N-O Fragment in Cyclic and Bicyclic Fused Nitroso Acetals From the point of development of methodology of organic synthesis, selective reduction of the nitroso acetal fragment and associated processes are the most important reactions of nitroso acetals (also see Scheme 3.154). 

Silylation of 3-alkyl-substituted five-membered cyclic nitronates remains virtually unknown, although one example of the successful synthesis of the corresponding nitroso acetal was documented (Scheme 3.203) 475. 

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

The C,C-coupling reactions of six-membered cyclic nitronates were studied in most detail (274, 478). Here silyl ketene acetal was also used as the test nucleophile. The configurations of most of the starting nitronates and the resulting nitroso acetals were determined by NMR spectroscopy and X-ray diffraction, and also a conformational analysis was performed (see Tables 3.24 and 3.25). 

Detailed configurational and conformational analyses of the starting six-membered cyclic nitronates (356) of cationic intermediates (357), and (decoupling products (357 + Nu), taking into account slow nitrogen inversion (Ijv) in nitroso acetals (see Section 3.4.3.4.4), made it possible to propose a mechanistic model based on the stereochemical outcome of the C,C-coupling process (Chart 3.23). 

Silylation of AN and cyclic nitronates affords SENA and BENA or cyclic N-siloxy-ene nitroso acetals as the major primary products (see Sections 3.2.1.3 and 3.5.1). All these relatively unstable derivatives can undergo various elimination reactions, which will be considered in separately. 

Chemistry of A7,A-Bis(sil xy)I namincs and Conjugated Cyclic Ene-Nitroso Acetals... 

To summarize, all data from physicochemical methods are indicative of a substantial weakening of the htt conjugation in ene nitroso acetals (430) and (431) compared to classical enamines and this should decrease the nucleophilicity of the Tt system of BENAs and cyclic ene nitroso acetals. 

Very interesting results were obtained in studies of the reactions of cyclic ene- nitroso acetals (430) with electrophiles E-X (Scheme 3.235, Table 3.30) (264, 515). 

Reactions of Cyclic Conjugated Ene Nitroso Acetals with Nucleophiles The reaction of six-membered cyclic ene nitroso acetals (475) with nucleophiles has a high potential and will probably provide the basis for a promising procedure for the synthesis of polyfunctional compounds from very simple precursors, the more so that the configurations of stereocenters in the starting nitronate (475) can be retained in particular transformations (Scheme 3.253). Unfortunately, the available data (264) are insufficient to elucidate the complete mechanism of this process. 

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). 

In some cases, silylation of AN and their derivatives produces nitroso acetals containing the N -siloxy fragment or cyclic ethers of oximes (predominantly substituted 5.6-dihydro-4f/-oxazines). To use these products in strategies for synthesis, it is worthwhile to develop convenient procedures for selective reductions of the above derivatives to the corresponding amines. 

Aside from the relatively trivial conversions of nitronates to the corresponding oxime and carbonyl compounds (10,11), the chemistry of nitronates remained relatively unexplored for much of the early 1900s. However, in 1964, Tartakovskii et al. (12) demonstrated that alkyl nitronate esters were competent partners in the newly discovered class of dipolar cycloadditions with alkenes (Scheme 2.1). Both cyclic and acyclic nitronates participated, thus providing a new functional group were the nitrogen atom existed at the center of an acetal (13). These compounds were subsequently referred to as nitroso acetals (14) or nitrosals (15). 

In the case of unactivated cyclic nitronates, elevated temperatures are necessary. Reaction of a variety of enones with the nitronate 49 proceeds smoothly at room temperature over several hours, whereas allyl alcohol requires 1.5 h at 80 °C (Table 2.48) (84). The resulting nitroso acetals are produced in good yields as mixtures of diastereomers. 

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