Nitrenes nitrene esters

The results with carboethoxynitrene are quite different from those obtained with pivaloyl azide 7 and the aroylnitrenes. Furthermore, photolysis of azidoesters 13 and 14 in contrast to pivalolyl and aroylazides at cryogenic temperatures produces persistent nitrene EPR signals. Thus, it is clear that the nitrene esters have triplet ground states. 

Why does the nitrene ester have a triplet ground state in contrast to the acetyl and benzoyl analogues This author speculates that the N—O bonding interaction in the singlet nitrene ester is weaker than that in the singlet acetylnitrene because such an interaction destroys resonance within the ester group. 

Nitrene esters have not yet been detected by matrix IR spectroscopy. IR spectroscopy is less sensitive than EPR spectroscopy and IR observes all the photoproducts, not just the paramagnetic triplet species of interest. 

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

The procedure described is essentially that of Shioiri and Yamada. Diphenyl phosphorazidate is a useful and versatile reagent in organic synthesis. It has been used for racemlzatlon-free peptide syntheses, thiol ester synthesis, a modified Curtius reaction, an esterification of a-substituted carboxylic acld, formation of diketoplperazines, alkyl azide synthesis, phosphorylation of alcohols and amines,and polymerization of amino acids and peptides. - Furthermore, diphenyl phosphorazidate acts as a nitrene source and as a 1,3-dipole.An example in the ring contraction of cyclic ketones to form cycloalkanecarboxylic acids is presented in the next procedure, this volume. 

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. 

In contrast to 6-azidobenzo[/)]thiophene, which yields only benzo[i]thiophen-6-amine (9 %) and JVh,Ar(1-diethylbenzo[/)]thiopheiie-6,7-diamine (25 % bp 175-177 C/0.7 Torr), 6-azido-2,3-dibromobcnzojhjthiophene (1 a, R = R2 = Br) on irradiation in diethylamine in the presence of pyrene, a triplet nitrene quenching agent, yields a mixture of 2,3-dibromo-./V6,./V6-diethyl-benzo[5]thiophene-6,7-diamine (2a, R1 = R2 = Br 13%) and the 8W-thieno[2,3-r]azepine 3a.14<1 Likewise, methyl 6-azidobenzo[6]thiophene-2-carboxylate (lb, R1 = C02Me R2 = H) yields the thienoazepine ester 3b.147... 

Asymmetric aziridination of a,P-unsaturated esters by use of N-nitrenes was studied in great detail by Atkinson and co-workers [34, 35]. Here, lead tetraacetate-mediated oxidative addition of N-aminoquinazolone 30 (Scheme 3.10) to a-methy-lene-y-butyrolactone 32 was reported to proceed with complete asymmetric indue-... 

A more practical, atom-economic and environmentally benign aziridination protocol is the use of chloramine-T or bromamine-T as nitrene source, which leads to NaCl or NaBr as the sole reaction by-product. In 2001, Gross reported an iron corrole catalyzed aziridination of styrenes with chloramine-T [83]. With iron corrole as catalyst, the aziridination can be performed rmder air atmosphere conditions, affording aziridines in moderate product yields (48-60%). In 2004, Zhang described an aziridination with bromamine-T as nitrene source and [Fe(TTP)Cl] as catalyst [84]. This catalytic system is effective for a variety of alkenes, including aromatic, aliphatic, cyclic, and acyclic alkenes, as well as cx,p-unsaturated esters (Scheme 28). Moderate to low stereoselectivities for 1,2-disubstituted alkenes were observed indicating the involvement of radical intermediate. 

Irradiation of 1-azidophosphetan-l-oxide (112) in methanol leads to the phosphonamide esters (113) and (114), although the stereochemistry of these products is not yet fully settled. Their formation is reasonably consistent with the intervention of a nitrene intermediate which inserts into the P—C and C—H bonds. 

Nitrene addition to alkenes can be aided by the nse of a transition metal, such as copper, rhodium, ruthenium, iron, cobalt, etc. NHC-Cu catalysts have been used in nitrene addition. For example [Cu(DBM)(IPr)] 147 (DBM = dibenzoyl-methane) was successfully employed in the aziridination of aliphatic alkenes 144 in presence of trichloroethylsulfamate ester 145 and iodosobenzene 146 (Scheme 5.38) [43]. 

Aryldioxophosphoranes such as aryl- and alkyl-iminooxophosphoranes number among the short-lived metaphosphonates. The former are best obtained by fragmentation of cyclic phosphinic esters, and the latter by rearrangement of aryl- and alkyl-substituted phosphoryl azides and nitrenes, respectively. This reaction is reminiscent of the phosphorylcarbene/methyleneoxophosphorane rearrangement discussed in Section 2. 

The equilibrium interconversion between an ethylene phosphite and a bicyclic spirophosphorane is shown to proceed by the insertion of the phosphite into the labile O-H bond of the hydroxyethyl ester. The mechanism is similar to the insertion of carbenes or nitrenes. Energy relationships of reaction intermediates were studied by MO RHF, MP2(full), MP4SDTQ, and DFT calculations. In most cases, they predicted that hydroxyethyl ethylene phosphates were more stable than the strained spirophosphoranes, which is not supported by the experimental evidence. The best correspondence to experimental data was obtained by DFT calculations with Perdew-Wang correlation functions <2003JST35>. 

Recently, Scott et al. have reported that a Cu complex bearing an axially chiral ligand (49) is an excellent catalyst for aziridination of 2,2-dimethylchromene and cinnamate esters (Scheme 36), though it is also less efficient for the reactions of simple olefins.157,158 On the basis of DFT investigation of the nitrenoid intermediate (50), one of the oxygen atoms of the A -sulfonyl group has been proposed to be interacting with the nitrene N-atom.158... 

Several reviews on the synthesis of aziridines have been published in the previous year. These publications include a review on the silver catalyzed addition of nitrenes (among other intermediates such as carbene) across a double bond <06EJOC4313> a review on sulfur ylide addition to imines to form aziridines <06SL181> a review on nitrogen addition across double bonds <06ACR194> a general review on functionalization of a,p-unsaturated esters with some discussion of aziridination <06TA1465>... 

FIGURE 7.10 Formation of the succinimido ester of IV-succinimidoxycarbonyl-P-alanine by reaction of three molecules of IV-hydroxysuccinimide (HONSu) with one molecule of dicy-clohexylcarbodiimide.25 The first molecule (N1) reacts to form the O-succinimido-isourea. The second molecule (N2) ruptures the ring by attack at the carbonyl, generating a nitrene that rearranges to the esterified carboxyalkyl isocyanate. The third molecule (N3) attacks the carbonyl of the latter. R3 = R4 = cyclohexyl SuN- = succinimido. 

FeCl2 has been used to catalyse nitrene transfer from l-butyloxycarbonyl azide to sulfoxides (to form sulfoximides), sulfides (to give sulfimides), and a ketene acetal (to form an a-amino ester). ... 

Esters of 2-(2-azidophenyl)ethyl alcohol are photolyzed under a high-pressure mercury lamp to a reactive nitrene intermediate which, following insertion into the alkyl side-chain, undergoes elimination to give the free carboxylic acid (up to 32%) and producing indole. The photochemical release was somewhat improved (65-80%) when 5-azido-4-(hydroxy-methyl)-l-methoxy naphthalene was used (see Scheme 27). 

Direct extrusion of methyl nitrene has been discounted as an explanation of these deamination reactions, which are apparently induced by attack of the acetylenic ester and thus more likely take place via an intermediate analogous to 176. On the other hand, the products from pyrolysis of 107 at 325° include 1,2,3,4-tetrafiuoronaphthalene (132) and hydrogen cyanide, and it was suggested that methyl nitrene was the precursor of the latter compound (see Section III,D). The adduct (180) of tetrafiuorobenzyne and thiophen extrudes sulfur so readily... 

Preliminary efforts to examine the mechanism of C-H amination proved inconclusive with respect to the intermediacy of carbamoyl iminoiodinane 12. Control experiments in which carbamate 11 and PhI(OAc)2 were heated in CD2CI2 at 40°C with and without MgO gave no indication of a reaction between substrate and oxidant by NMR. In Hne with these observations, synthesis of a carbamate-derived iodinane has remained elusive. The inability to prepare iminoiodinane reagents from carbamate esters precluded their evaluation in catalytic nitrene transfer chemistry. By employing the PhI(OAc)2/MgO conditions, however, 1° carbamates can now serve as effective N-atom sources. The synthetic scope of metal-catalyzed C-H amination processes is thus expanded considerably as a result of this invention. Details of the reaction mechanism for this rhodium-mediated intramolecular oxidation are presented in Section 17.8. 

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]. 

The addition of nitrenes leads predominantly to the closed [6,6] bridged isomers. The corresponding [5,6] bridged isomer is - if at all - formed only in small amounts, probably via a direct addition to the [5,6] bond [394]. Nitrenes have been generated by thermolysis of azido-formic esters [172,395 00], photolysis of aroyl azides [401] or aryl azide [402], elimination of O-4-nitrophenylsulfonylalkylhydroxamic acid [403] or reaction of amines with Pb(OAc)4 [404]. 

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