Nitrene insertions

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]. 

Fig. 6. Coupling of polymer chains via (a) photoinduced hydrogen abstraction free-radical reactions and (b) nitrene insertion/addition reactions.

Intermediate arylamidine, 6S, is prepared by the aluminum chloride-catalyzed addition of aniline to the nitrile function of 4-cyanothiazole (67), Amidine, 65, is then converted to its N-chloro analog (69) by means of sodium hypochlorite. On base treatment, this apparently undergoes a nitrene insertion reaction to produce thiabendazole (70), ... 

In contrast, flash-vacuum pyrolysis (FVP)155 or spray-vacuum pyrolysis (SVP)154 of the homologous phenethyl azidoformates yield, in every instance except for the 4-cyano and 4-nitro-derivatives, the thermally stable [1,3]oxazino[3,4-a]azepines 9 accompanied by lesser amounts of the oxazolidinones 10, formed by nitrene insertion at the benzylic carbon center. 

Biphen-2-yl azidoformate (11) on SVP yields a mixture of 12 and 13, the products of nitrene insertion at the 1,2-position of the adjacent phenyl ring, and at the vacant ort/to-position, respectively.156... 

Modification of [Fe(TTP)Cl] due to intramolecular nitrene insertion to iron-nitrogen bond... 

N-benzylaniline with phosgene, and then with sodium azide to produce carbonyl azide 52. On heating, nitrogen is evolved and a separable mixture of nitrene insertion product 53 and the desired ketoindazole 54 results. The latter reaction appears to be a Curtius-type rearrangement to produce an N-isocyanate (54a), which then cyclizes. Alkylation of the enol of 54... 

Examples of such reactions are well known. Sloan, Breslow, and Renfrow found that both alkane and arenesulphonyl azides insert into the carbon-hydrogen bonds of saturated hydrocarbons 12>. Thus, 1-pentane,- 2-propane- and -toluene-sulphonyl nitrene inserted into cyclohexane to give 54, 60, and 58% yields of the corresponding IV-cyclohexylamide derivatives 8>. Similarly, 2-phenoxybenzene-, diphenyl sulphide-2-, and... 

The pyranofurooxazoline 109 can be prepared by a nitrene insertion reaction of the corresponding furan 110 upon treatment with ethyl azidoformate at — 50 °C under photolysis conditions. Compound 109 is moisture sensitive, and upon treatment with wet acidic THF was converted quantitatively to the more polar furanopyran 111. The structure and stereochemistry of 109 were proved unambiguously by X-ray diffraction, showing that the nitrene inserted anti to the bridgehead methyl group <1999JOC736> (Scheme 30). 

Aryl and heteroaryl nitrene insertion processes have also been employed in the synthesis of heterocycles. The azide 459, for example, is converted on irradiation into the imidazole 460,383 and dihydro-10-thiaisoalloxazines are obtained in good yield on photoelimination of nitrogen from 6-(2-azido-phenylthio)uracils.384... 

Pandurangi, R.S. et al. (1997b) Chemistry of bifunctional photoprobes Part 1. Perfluoro azido functionalized phosphorus hydrazides as novel photoreactive heterobifunctional chelating agents High efficiency nitrene insertion on model solvents and proteins./. Org. Chem. 62(9), 2798-2807. 

As shown in the manganese- and ruthenium-catalyzed intermolecular nitrene insertions, most of these results supposed the transfer of a nitrene group from iminoiodanes of formula PhI=NR to substrates that contain a somewhat activated carbon-hydrogen bond (Scheme 14). Allylic or benzylic C-H bonds, C-H bonds a to oxygen, and very recently, Q spz)-Y bonds of heterocycles have been the preferred reaction sites for the above catalytic systems, whereas very few examples of the tosylamidation of unactivated C-H bonds have been reported to date. 

Perez and co-workers reported the electron-deficient copper homoscorpionate catalyst TpBr3Cu(NCMe)-catalyzed nitrene insertion into C-H bonds of toluene, mesitylene, and cyclohexane, which are very unreactive substrates (Equations (100)—(102)). In contrast to the former reports, they obtained very high yields for these products. 

The photochemical reaction can also proceed via the triplet state and in this case no cyclization is observed. Especially when acetophenone is added as a triplet sensitizer, 41 is not formed. Remarkable is the observation that in the presence of anthracene or pyrene as triplet quencher, the yield of the cyclization product 41 was not enhanced and that nitrene insertion into CH bonds of anthracene or pyrene was observed. When the photochemical cyclization reaction was performed with the tosyl azide derivative 42a or the azido nitrile derivative 42b (Scheme 6), only low yields of the tricyclic amide 41 (32% from 42a, 9% from 42b, respectively) were obtained <2001JCS(PI)2476>. 

It is known that aromatic azides are photodecomposed to give active nitrenes as the transient species, which react with the environmental binder polymers to crosslink them. However, the mechanism of these photocrosslinking polymers has not been studied in detail. L.S.Efros et al. have proposed that the rubber polymer is crosslinkes in such a way that the aromatic nitrene inserts into an unsaturated bond of the polymer to give an aziridine ring. The experimental evidence for this, however, has not been given (8). 

Figure 16. Crosslinking reactions in bisarylazide-rubber resists. The primary photoevent is production of a nitrene which then undergoes a variety of reactions that result in covalent, polymer-polymer linkages. A schematic representation of crosslinking via nitrene insertion to form aziridine linkages is shown together with several other reaction modes available to the...

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]. 

Apart from the azirine pathway, a vinylnitrene 526 was postulated as a possible intermediate in the reaction (Scheme 14). The nitrene may be formed by a base-promoted elimination of the leaving group on the nitrogen and gives rise to the 277-azirine by electrocyclization (nitrene insertion) and, in view of current data, this pathway cannot be excluded. 

Raphael et al. reported the total synthesis of arcyriaflavin B (346) (759) and staurosporinone (293) (760) starting from 2-nitrocinnamaldehyde (1300). This synthetic route involves a double nitrene insertion as the key step. 

Moody and Rahimtoola reported a short synthesis of staurosporinone (293) without the use of protecting groups at the indole or the lactam nitrogen (761,762). This route involves an intramolecular Diels-Alder reaction of the pyrano[4,3- 7]indol-3-one 1325 and a subsequent cyclization by nitrene insertion. The pyrano[4,3-l7]indol-3-one 1325 was obtained in four steps from ethyl indol-2-yl... 

Trimethyl-2-azidobiphenyl thermolyzed in n-hexadecane gave only 4% 2,4,9-trimethylcarbazole, that is, the product of nitrene insertion into the ortho C-methyl bond the main products were 2 -amino-2,4,6-trimethyl-biphenyl and 250 (R = Me). An intramolecular dipolar cycloaddition com-... 

Another quinoxaline-yielding rearrangement, reported by Hanaineh-Abdelnour and coworkers, entailed treating imides 182 with sodium azide to produce quinoxalines 183 in moderate to good yields <99H2931, 99T11859>. The reaction presumably proceeds by a nitrene insertion to close the pyrazine ring. 

Baldwin has utilized an intramolecular nitrene insertion reaction in an approach to hydrolytically stable analogues of penicillin <2001T4999, 2003T8233>. Although the reaction proceeded in only moderate yields, the product is formed with excellent facial selectivity (Equation 43). 

Like carbene insertions into carbon-hydrogen bonds, metal nitrene insertions occur in both intermolecular and intramolecular reactions.For intermole-cular reactions, a manganese(III) meio-tetrakis(pentafluorophenyl)porphyrm complex gives high product yields and turnovers up to 2600 amidations could be effected directly with amides using PhI(OAc)2 (Eq. 51). The most exciting development in intramolecular C—H reactions thus far has been the oxidative cychzation of sulfamate esters (e.g., Eq. 52), as well as carbamates (to oxazolidin-2-ones), ° and one can expect further developments that are of synthetic... 

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