Stereospecificity nitrene-insertion reactions

The stereochemistry of nitrene insertion into unactivated C—bonds has been studied using substituted cyclohexanes as substrates. For arylnitrenes which usually exhibit triplet reactivity, the reaction is nonspecific, but most other nitrenes undergo stereospecific C—insertion. For example, benzqylni-trene inserts selectively into the tertiary C—bond of toth cis and tra/u-1,4-dimethylcyclohexane with retention of configuration. Similarly with cis- and rra/is-l,2-dimethylcyclohexane as substrate, ethoxycarbonyl-, methatiesulfonyl- and cyano-nitrenes all insert with retention of configuration at the tertiary C—bond. 

This nitrene is somewhat more selective than simple carbenes, showing selectivities of roughly 1 10 40 for the primary, secondary, and tertiary positions in 2-methyl-butane in insertion reactions. The relationship between nitrene multiplicity and stereospecificity in addition to alkenes is analogous to that described for carbenes. The singlet gives stereospecific addition, while the triplet gives nonstereospecific addition products. 

The signature application for the G-H insertion in synthesis is probably the total synthesis of (—)-tetrodotoxin 126 by Du Bois and Hinman.233 Two stereospecific G-H activation steps, rhodium-catalyzed carbene G-H insertion and carbamate-based nitrene C-H insertion, have been used to install the two tetrasubstituted centers C6 and C8a (Scheme 12). Diazoketone 122 was treated with 1.5mol% Rh2(HNCOCPh3)4, and cyclic ketone 123 was selectively formed in high yield without purification. The reaction of carbamate 124 with 10mol% Rh2(HNCOCF3)4, PhI(OAc)4, and MgO in C6H6 solvent furnished the insertion product 125 in 77% yield. 

The intramolecular C(sp )—H amination of carbamates developed by Du Bois and coworkers can be performed from substrates derived from primary, secondary, and tertiary alcohols. The reaction allows the efficient functionahzation of benzyhc, aUyHc," and tertiary C(sp )—H bonds, as well as that of secondary unactivated positions, but, to a lesser extent. Its efficiency, in specific cases, can be improved by replacing Rh2(OAc)4 with Rh2(tpa)4." An important feature is the stereospecificity of the nitrene C—H insertion that was unambiguously demonstrated to proceed with retention of configuration using a stereochemical probe prepared from (S)-2-methyl-l-butanol (Scheme 6A). 

In their seminal paper on the rhodium(ll)-catalyzed C—H insertion with PhI=NNs, the group of Muller reached the conclusion that the reaction proceeds through the concerted asynchronous insertion of a rhodium-bound nitrene species.This hypothesis was supported by a Hammett analysis (/9= —0.90 vs. tr+), the absence of ring-opened products in reactions involving cyclopropyl radical clocks, and the stereospecific C(sp )—H ami-nation of (Ji)-2-phenylbutane that occurs with complete retention of configuration. However, the very low yields obtained for these test reactions as well as the kinetic isotope effect measured for the reaction from (1,3-D2)-adamantane (KIE = 3.5 0.2) put this conclusion into question as these did not rule out the possible involvement of radicals that could undergo fast recombination. Nevertheless, this initial study already highlighted the discrepancies that could be observed between the carbene and nitrene chemistries in terms of mechanism. The electronic structure of nitrenes, contrary... 

The results uncovered by Muller have been corroborated by the subsequent studies from the Du Bois group, particularly with respect to the intramolecular reaction. The stereospecific C(sp )—H insertion of the carbamate-derived nitrene depicted in Scheme 6A was the first relevant reaction in favor of the asynchronous concerted addition.More significantly, the extensive analysis of the rhodium-catalyzed intramolecular C(sp )-H amination of sulfamates has led to the same conclusion. The Hammett analysis (/0= —0.55 vs. and the kinetic isotope effect observed from the monodeuterated phenylpropyl sulfamate 9 (KIE = 2.6 0.2) clearly argue in favor of this mechanistic scenario (Scheme 17). Additionally, the reaction from the cyclopropyl radical clock 12 supports this hypothesis by furnishing a single product isolated with an excellent yield of 91%. 

---