Nitrenes generation methods

On the other hand, poly(ethoxycarbonylimino-4-vi-nylpyridinium ylide) (Scheme 13) was prepared essentially by the same method from 1-ethoxycarbonylimino-pyridinium ylide, as described by Hafner [15] from the reaction of poly (4-vinylpyridine) with nitrene, generated from the pyrolysis of ethyl azidoformate. 

When optically active hydrocarbons have been used as substrates, a similar pattern of insertion reactivity emerges. Phenylnitrene inserts with a maximum of 30% retention into the tertiary C—bond of optically active 2-phenylbutane implying a high degree of triplet involvement, whereas ethoxycarbonylnitrene inserts stereoselectively with 98-100% retention into the tertiary C—H of (S)-(+)-3-methyl-hexane. The result is independent of the method of nitrene generation, and of concentration, and lends support to the view that only singlet ethoxycarbonylnitrene inserts into unactivated C—bonds. 

The reaction of ethoxycarbonyl nitrene, generated by decomposition of the azide or by the a-elimination method, with enamines gave mixtures of aminimides and a-amino ketone derivatives30.. V-Methoxycarbonyl. A -cyano and N-sulfonyl azides reacted with 1,2-31 and 1,4-dihy-dropyridines32 to afford directly the corresponding aziridines 9 and 10. The configuration of the aziridine 10, relative to the R substituent, was not determined. 

Ethoxycarbonylamino)cyclohcxanoncs were obtained in low yield by hydrolysis of the aziridines formed by the addition of ethoxycarbonyl nitrene, generated in situ from 4-nitro-phenylsulfonyl carbamates, to enamines prepared from substituted cyclohexanones61,62. By the same method, optically active 2-(ethoxycarbonylamino)cyclohexanone 3 was prepared in low yield from the enamine 1 derived from an optically active 2-substituted pyrrolidine63. 

The classical methods utilized for the addition of nitrene to olefins generally suffer from several drawbacks including harsh conditions required to generate the nitrene and the lack of stereoselectivity in bond formation. Issues associated with triplet versus singlet nitrene generation have plagued this process and rendered it less useful than most epoxidation methods. 

The preparation of an indole (nitrene generated from an azide - the Hemetsberger-Knittel synthesis) and of carbazole ° (nitrene generated by deoxygenation of a nitro group) illustrate the power of the method. 

The most general preparations are based on the reaction of the heteroaromatic bases with O-substituted hydroxylamines. An alternative but less efficient method is the reaction of heteroaromatic bases with nitrenes generated from acyl and sulfonyl azides. 

In the presence of a chiral catalyst such as rhodium(II) (5)-/V l,8-naphthanoyl-tert-leucinate dimer, Troc-amino indane was produced with 56% yield and 2.57 1 enantiomeric ratio. In contrast to other methods, no hypervalent iodine reagent (typically used stoichiometrically or in excess and forming iodobenzene as by-product) is required for oxidation of the amine component. However, a slight excess of the aromatic alkane component (5 equiv) must be used to achieve good conversions. The reactivity of rhodium nitrenes generated from 2,2,2-trichloroethyl-/V-tosyloxycarbamate with aliphatic alkanes is similar to the one observed with metal nitrenes obtained from the oxidation of sulfamate with hypervalent iodine reagent. Troc-protected amino cyclohexane and cyclooctane were obtained, respectively, in 73 and 62% yields when 2 equiv of alkanes was used, whereas yields up to 85% were observed with 5 equiv (eq 3). 

Whether the nitrene generated reacts as a singlet or triplet depends upon the nature of the substituents on the aryl nucleus, the nature of the solvent, and the method of generation. These intermolecular reactions will be discussed according to the multiplicity of the nitrene thought to be involved. 

Nitrenes have enjoyed appreciable application in the synthesis of a wide variety of heterocyclic systems, and the majority of the methods used for generating nitrenes have been utilized in these syntheses. 

The nitrene can be generated by a variety of methods, the most popular being the thermal or photolytic decomposition of azidoformates. Other methods, particularly the base-catalyzed a-elimination of arylsulfonate ion from 7V-[(arylsulfonyl)oxy]urethanes, are useful as they avoid the use of the potentially explosive azido esters. 

Aziridines are important compounds due to their versatility as synthetic intermediates. In addition, aziridine rings are present in innumerable natural products and biologically active compounds. Nitrene addition to alkenes is one of the most well established methods for the synthesis of aziridines. Photolysis or thermolysis of azides are good ways to generate nitrenes. Nitrenes can also be prepared in situ from iodosobenzene diacetate and sulfonamides or the ethoxycarbonylnitrene from the A-sulfonyloxy precursor. 

The triplet state is usually the ground state for non-conjugated structures, but either species can be involved in reactions. The most common method for generating nitrene intermediates, analogous to formation of carbenes from diazo compounds, is by thermolysis or photolysis of azides.246... 

In recent years, the related C-H insertion chemistry of nitrenes has gained considerable momentum.36 Effective chiral catalysts have been developed as well as new methods for generation of the nitrene precursors. Even more impressive has been the application of this chemistry to the synthesis of complex natural products. The scope of this chemistry is described in Section 10.04.4. 

Nitrenes can be generated from many precursors such as azides, isocyanates, ylides, heterocycles, and nitro compounds.236,237 Amongst these, azides are the most convenient precursors since they are easily prepared and can be decomposed by heat, light or a suitable catalyst. Despite considerable endeavors, no one has yet provided a synthetically viable method to use azides as sources of nitrenes.237 The breakthrough of nitrene chemistry was the recognization of the value of A-arenesulfonyl iminoiodinanes (ArS02N=IPh) as nitrene precursors by Breslow and Mansuy. - They reported inter- and intramolecular C-H insertions by tosylimino phenyl-iodinane (TsN=IPh) in the presence of Mn(m) or Fe(m) porphyrins or [Rh2(OAc)4]. Subsequently, Muller... 

The established activity of ethereal a-C-H bonds toward carbene and nitrene insertion has evoked new applications for sulfamate oxidation [76-78] In principle, a C-H center to which an alkoxy group is attached should be a preferred site for amination irrespec-hve of the addihonal functionality on the sulfamate ester backbone (Scheme 17.20). Such a group can thus be used to control the regiochemistry of product formation. The N,0-acetal products generated are iminium ion surrogates, which may be coupled to nucleophiles under Lewis acid-promoted conditions [79]. This strategy makes available substituted oxathiazinanes that are otherwise difficult to prepare in acceptable yields through direct C-H amination methods [80]. 

Nitrenium ions have also been generated through the decomposition of azides under acidic conditions (e.g., trifluoroacetic acid-arene solvent mixtures). There are two potential pathways for the formation of the nitrenium ion from the precursors (Fig. 13.24). The first involves initial dissociation of the azide 41 to give a singlet nitrene 42, followed by proton transfer to the latter to yield the primary nitrenium ion 43. The second involves acid-induced decompostion of the azide, whereby preprotonation of the azide (44) forms the primary nitrenium ion in a direct manner. As with the hydroxylamine route, this method is limited to acidic or protic media. 

The singlet state, Si, is the first state reached when a nitrene is generated by most methods, including photolysis of the corresponding azide, R—N3. The reactions of... 

The most reliable method for generating nitrenes is the thermal or photochemical elimination of nitrogen from azides. An alternative method which is useful for indole and carbazole synthesis is the deoxygenation of aromatic nitro compounds with trivalent phosphorus compounds. Triethyl phosphite is the most commonly used reagent, though more reactive compounds may be useful in special cases (B-79MI30600). 

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