Alkyl nitronates

This chapter is divided into four major sections. The first (Section 2.1) will deal with the structure of both alkoxy and silyl nitronates. Specifically, this section will include physical, structural, and spectroscopic properties of nitronates. The next section (Section 2.2) describes the mechanistic aspects of the dipolar cycloaddition including both experimental and theoretical investigations. Also discussed in this section are the regio- and stereochemical features of the process. Finally, the remaining sections will cover the preparation, reaction, and subsequent functionalization of silyl nitronates (Section 2.3) and alkyl nitronates (Section 2.4), respectively. This will include discussion of facial selectivity in the case of chiral nitronates and the application of this process to combinatorial and natural product synthesis. 

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On the basis of this successful application of 23d, this catalyst was applied in a series of reactions (Scheme 6.22). For all eight reactions of nitrones 1 and alkenes 19 in which 23d was applied as the catalyst, diastereoselectivities >90% de were observed, and most remarkably >90% ee is obtained for all reactions involving a nitrone with an aromatic substituent whereas reactions with N-benzyl and N-alkyl nitrones led to lower enantioselectivities [65]. 

An experimentally simple ptocedure for stereoselecdvely preparing fi-nitro alcohols has been developed. The alkyl nitronates, formed by the acdon of u-butyUithiumonnitroalkanes in THF soludon, react v/ith aldehydes in the presence of isopropoxydtanium trichloride at room temperanire to give the fi-nitro alcohols enriched in the ruiri-thastereoisomers fEq. 3.711. 

Nitro compounds have been converted into various cyclic compounds via cycloaddidon reactions. In particular, nitroalkenes have proved to be nsefid in Diels-Alder reactions. Under thermal conditions, they behave as electron-deficient alkenes ind react v/ith dienes to yield 3-nitrocy-clohexenes. Nitroalkenes c in also act as heterodienes ind react v/ith olefins in the presence of Lewis acids to yield cyclic alkyl nkronates, which undergo [3- 2 cycloaddidon. Nitro compounds are precursors for nitnie oxides, alkyl nitronates, and trialkylsilyl nitronates, which undergo [3- 2 cycloaddldon reacdons. Thus, nitro compounds play important roles in the chemistry of cycloaddidon reacdons. In this chapter, recent developments of cycloaddinon chemistry of nitro compotmds and their derivadves are summarized. 

The addition of alkyl nitronate anions to imines in the presence of a Lewis acid proceeds in high yield with up to 10 1 diastereoselection favoring the anti isomer. This reaction is used for the stereoselective synthesis of 1,2-diamines (Eq. 4.121).167 Scandium triflate catalyzes the addition of 1-trimethylsilyl nitropropanoate to imines with a similar selectivity.35... 

X,P-Dehydro-a-amino acids are prepared by elimination of HN02 from P-nitro-a-amino acids, which are prepared by reaction of a-bromoglycine derivatives with alkyl nitronates (see Eq. 7.135).181 This process is a new type of the Michael addition of nitro compounds followed by elimination of HNOz. Such unusual amino acids are interesting as enzyme inhibitors.182... 

A number of a-aryl-A-alkyl nitrones and contrast enhancement compositions, which can be used to make contrast enhancement layer photoresist composites (230, 231), and inhibitors of free radical polymerization of monomers in nonexposed regions of the photoresist layer at selective actinic radiation (232). Histidine was used as a catalyst in the synthesis of a, A-diaryl nitrones in situ (233). To study diphenylborate chelates with mono- and bidentate ligands, a series of hydroxyl-containing nitrones have been synthesized (Fig. 2.7) (234-237). 

In the presence of Lewis acids (Znl2 and BF3 OEt2), aldoximes react with u,l )-unsaturated carbonyl compounds (129) at room temperature affording good yields of /V-alkyl nitrones (130) (Scheme 2.47) (299). 

Generation of the enhydroxyamine form takes place upon treatment with both bases and acids the reaction with a-alkyl nitrones in D2O shows a quick deutero exchange (537). 

Reactions with Carboxylic Acid Esters Alkyl nitrones can be metallized upon treatment with phenyl lithium in ether solution. The Li-derivatives react with carboxylic acid esters to give 3-oxo nitrones (305)- the analogs of 3-diketones and j3-keto esters (545). With the help of the 13C NMR method it has been found that 3-oxo nitrones (305) exist as an equilibrium mixture... 

It was shown (801) that the diastereoselectivity of a-fluoroalkyl nitrones is reversed to that of the corresponding a-alkyl nitrones. This fact supports the conclusion that the conformation, due to the relief of the dipole repulsion between the fluorine atom and the oxygen atom of the nitrone is preferred in a-fluoroalkyl nitrones. 

West PR, Davis GC, Regh KA. Contrast Enhancement Layer Compositions, Alkyl-nitrones, and Use, US Patent No. 5106723, April 21, 1992. 

Nowadays the main method for the synthesis of alkyl nitronates is based on alkylation of the corresponding AN. 

Diazo compounds and oxonium salts are the most efficient alkylating agents in the synthesis of alkyl nitronates. It is assumed that diazo compounds are inserted into the O-H bond in the aci forms of the corresponding AN, whereas oxonium salts generally react with AN anions. 

Conventional alkylating agents (alkyl halides, sulfates, etc.) are rather rarely used in the synthesis of alkyl nitronates. This is associated with relatively low reactivity of these compounds which, combined with low thermal stability of nitronates (for more details, see Section 3.3.1.1), does not allow one to isolate target products in the individual state. 

Both C-alkylation products and the corresponding O-alkyl nitronates were detected in the reaction mixture prepared by the reactions of above mentioned salt with primary alkyl halides (Scheme 3.9, Eq. 1). However, isoxazolidines (1) are the main identified products of the reactions with secondary or tertiary alkyl halides. The possible pathway of their formation is shown in Scheme 3.9. Here, the key event is generation of the corresponding olefins from alkyl halides. These olefins can be trapped with O-nitronates that are simultaneously formed in [3 + 2]-cycloaddition reactions. Presumably, these olefins are generated through deprotonation of stabilized cationic intermediates (see Scheme 3.9). 

Stability of Acyclic Alkyl and Acyl Nitronates A weak point of acyclic alkyl nitronates is their thermal instability because these compounds can be involved in two electrocyclic reactions presented in Scheme 3.72. 

According to the first process, acyclic alkyl nitronates (73) afford corresponding oximes and carbonyl compounds (3) (Eq.l). This process is similar to the well-known Cope rearrangement (Eq.l ) (233). 

It should be noted that the mechanism of thermal decomposition of acyclic nitronates was not studied in detail. It is known that cis isomers of alkyl nitronates derived from primary AN are much less stable than the analogous trans isomers (49, 237a). 

Table 3.5 gives the most typical examples of acyclic nitronic esters, which have unusually high thermal stability. These data contradict the known data on fast thermal decomposition of alkyl nitronates derived from the simplest nitroalkanes (237) and relatively low thermal stability of nitronate (73a). On the basis of the available data, the following empirical mle can be derived an extension of the conjugation chain of the nitronate fragment increases stability of nitronates. 

I.2. Stability of Silyl- and Boryl Nitronates SENAs cannot decompose through pathways characteristic of alkyl nitronates (see Scheme 3.72). 

Table 3.5 Physical characteristics of acyclic alkyl nitronates...

Stability of Cyclic Nitronates For steric reasons, fragmentation of five-and six-membered cyclic nitronates cannot follow pathways presented in Scheme 3.72. Hence, stability of these compounds can be substantially higher than that of alkyl nitronates. These compounds generally exist in the crystalline state and can be purified by recrystallization or liquid chromatography. Selected melting points of nitronates are given in Table 3.8. 

French scientists (270) suggested that the configurations of stereoisomeric acyclic alkyl nitronates can be determined from the relative dipole moments which for trans- isomers of nitronates containing EWG at the a-C atom are substantially larger than those of the cis isomers (Chart 3.5). 

The energetically favorable conformations of model alkyl nitronate (88) and related compounds (89 to 91) (283) were determined by the B3LYP/6-31G(d) method (see Chart 3.9). It appeared that the marked conformations with the minimized dipole moments are energetically most favorable for compounds (88-91) (the use of the dipole-dipole interaction model in conformational analysis was also described in the publication (284)). Calculations including n-n interactions (see Fig. 3.1) did not change this situation because the contribution of this effect is equal in magnitude for both limiting conformations shown in Chart 3.9. 

I. Acyclic Alkyl Nitronates The reactions of this type of nitronates with nucleophiles and electrophiles have not been systematically studied. It is most likely that this is associated with the low thermal stability of acyclic alkyl nitronates (see Section 3.3.1.1). 

It was demonstrated that treatment of nitronate Me02CH=N(0)0Me with HCI (246), as well as heating (298) affords oxime (104a) as a result of standard thermal decomposition of alkyl nitronates, which occurs via a Cope rearrangement (233) (Scheme 3.87). 

As can be seen from Scheme 3.88, nitrile oxides can be generated in the reactions of acids or bases with other alkyl nitronates derived from a-functionalized nitro compounds (300, 301). 

Severin and coworkers (14c) performed the facile synthesis of alkyl nitronate (108) (304), which is an analog of the powerful antibiotic enteromycin (305) (Scheme 3.91). 

Unlike alkyl nitronates (302), their silyl analogs react with Grignard reagents at the silicon atom rather than at the a-C atom (306). All these processes may be represented as electrocyclic. 

Alkyl Nitronates In spite of the low stability of acyclic alkyl nitronates, these compounds were rather extensively studied in [3 + 2]-addition reactions with various alkenes (9, 18, 28, 49, 300, 301, 306, 307, 338b-354) (Chart 3.11). 

Silyl Nitronates The characteristic features of the behavior of SENAs in [3+ 2]-addition reactions (75, 133, 175-177, 185, 186, 189, 201a, 203, 205, 206, 216, 355-362c) are virtually identical to those of acyclic alkyl nitronates considered in the previous section. As mentioned above, minor but more reactive Z-tautomers of SENAs derived from primary AN can be detected by cycloaddition reactions (see Section 3.3.4.1 and Scheme 3.128). 

Here two facts can be mentioned. For example, cycloaddition of nitronate (Me02C)CH=N(0)0SiMe3 to ethylene was observed (203), whereas its O -methyl analog does not react with ethylene. It is hardly probable that this fact is due to the high reactivity of the silyl nitronate. More likely, the negative result for alkyl nitronate is attributed to low stability of this derivative. 

The reactions of alkyl nitronates (164) or (165) derived from a-functionalized primary AN with monosubstituted acetylenes produce mixtures of diastereomeric aziridines (166) in moderate to high yields. Most probably, the first step of this process involves normal concerted cycloaddition to give the corresponding intermediates A, which were not detected due to their fast rearrangement to give acyl-substituted aziridines (166). The reaction is regioselective and stereospecific. The latter fact was demonstrated by French researchers (95). 

As mentioned above (303) (Scheme 3.90, Eq. 1), bis-trifluoromethyl thioketene has the deoxygenating ability toward alkyl nitronates, which is also based on cycloaddition to the C=S bond. 

For acyclic alkyl nitronates, only one process of this type has been documented (17) (Scheme 3.176). 

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