Intramolecular C-H insertion reactions

McKervey and Ye have developed chiral sulfur-containing dirhodium car-boxylates that have been subsequently employed as catalysts for asymmetric intramolecular C-H insertion reactions of y-alkoxy-ot-diazo-p-keto esters. These reactions produced the corresponding ci -2,5-disubstituted-3(2H)-furanones with diastereoselectivities of up to 47% de. Moreover, when a chiral y-alkoxy-a-diazo-p-keto ester containing the menthyl group as a chiral auxiliary was combined with rhodium(II) benzenesulfoneprolinate catalyst, a considerable diastereoselectivity enhancement was achieved with the de value being more than 60% (Scheme 10.74). 

In the same area, good levels of enantioselectivity have been achieved in intramolecular C H insertion reactions of a-diazocarbonyl compounds... 

Rhodium carboxylates have been found to be effective catalysts for intramolecular C—H insertion reactions of a-diazo ketones and esters.215 In flexible systems, five-membered rings are formed in preference to six-membered ones. Insertion into methine hydrogen is preferred to a methylene hydrogen. Intramolecular insertion can be competitive with intramolecular addition. Product ratios can to some extent be controlled by the specific rhodium catalyst that is used.216 In the example shown, insertion is the exclusive reaction with Rh2(02CC4F9)4, whereas only addition occurs with Rh2(caprolactamate)4, which indicates that the more electrophilic carbenoids favor insertion. 

The use of rhodium(II) acetate in carbenoid chemistry has also been extended to promoting intramolecular C/H insertion reactions of ketocarbenoids 277,280,280 ,). From the a-diazo-P-ketoester 305, highly functionalized cyclopentane 306 could thus be constructed in acceptable yields by regiospecific insertion into an unactivated... 

The intramolecular C-H insertion reaction of carbene species has been used in a number of studies for the synthesis of strained molecules and cage com-... 

Intramolecular C-H insertion reactions of metal carbenoids have been widely used for the stereoselective construction of substituted lactams, lactones, cyclopentanones, benzofurans, and benzopyrans. Several excellent reviews have been published covering the general aspects of intramolecular C-H insertion by metal carbenoids.46,47 62 71 99-104 The following section highlights the major advances made since 1994, especially in asymmetric intramolecular C-H insertion. 

A very impressive application of this chemistry is the total synthesis of (—)-ephedradine A 102.222 The key intermediate /rcarboxylic acid ester 101 was synthesized by intramolecular C-H insertion reaction. Upon treatment with a catalytic amount of Rh2(Y-DOSP)4, aryl diazo ester 100 possessing a chiral auxiliary underwent a C-H insertion reaction to give 101 in 63% yield and 86% de (Equation (83)). 

Thermolysis of 219a and 219b produced the benzofulvenes 221 as expected. However, the formation of 222 from 219c can best be accounted for by regarding the biradical 220a as the carbene 220b to allow an intramolecular C-H insertion reaction. The presence of a carbonyl group in 219 also permits the use of samarium(II) iodide, samarium(III) chloride, boron trifluoride and trifluoroacetic acid to promote the Schmittel cyclization reaction. 

Table 3.7. Intramolecular C-H insertion reaction of cationic iron carbene complexes generated in situ by S-alkylation of 1-(phenylthio)alkyl complexes (see Experimental Procedure 3.2.3).

Carbenes and transition metal carbene complexes are among the few reagents available for the direct derivatization of simple, unactivated alkanes. Free carbenes, generated, e.g., by photolysis of diazoalkanes, are poorly selective in inter- or intramolecular C-H insertion reactions. Unlike free carbenes, acceptor-substituted carbene complexes often undergo highly regio- and stereoselective intramolecular C-H insertions into aliphatic and aromatic C-H bonds [995,1072-1074,1076,1085,1086],... 

Use of Rh2(OAc)4 suggested that there was no inherent selectivity attributable to the coordinated carbene or to rhodium(ll). However, modification of dirhodium(ll) ligands to imidazolidinones provided exceptional diastereocontrol, obtained by influencing the conformational energies of the intermediate metal carbene [19, 23], as well as high enantiocontrol. Representative examples of products from these highly selective intramolecular C-H insertion reactions with cyclic systems is given in Scheme 15.6. Additional examples of effective insertions in systems from which diastereomeric products can result are illustrated in processes of the synthesis of 2-deoxyxylolactone (Scheme 15.7) [64, 65]. Here the conformation of the reactant metal carbene that is responsible for product formation is 32 rather than 33. Other examples in non-heteroatom-bound systems (for example, as in Eq. 15) confirm this preference. 

Using this approach, we have successfully predicted the major product from the cyclization of more than 30 a-diazo esters and a-diazo yS-keto esters [15]. Not all rhodium-mediated intramolecular C-H insertion reactions will proceed to give a single dominant diastereomer. Our interest in this initial investigation was to develop a model for the transition state that will allow us to discern those cyclizations that will proceed with high diastereoselectivity. 

The intramolecular C-H insertion reaction of phenyldiazoacetates on cyclohexadiene, utilizing the catalyst Rh2(S-DOSP)4, leads to the asymmetric synthesis of diarylacetates (Scheme 8). Utilizing the phenyl di azoacetate 38 and cyclohexadiene, the C-H insertion product 39 was produced in 59% yield and 99% ee. Oxidative aromatization of 39 with DDQ followed by catalytic hydrogenation gave the diarylester 40 in 96% ee. Ester hydrolysis followed by intramolecular Friedel-Crafts gave the tetralone 31 (96% ee) and represents a formal synthesis of sertraline (5). Later studies utilized the catalyst on a pyridine functionalized highly cross-linked polystyrene resin. ... 

Asymmetric induction in intramolecular C-H insertion reactions was first reported by McKervey and co-workers [53], who used chiral Rh(II) prolinate 17a (Eq. 5.24). Although enantiocontrol was low, this report established the feasibility of the methodology and left open advances that were subsequently made by Ikegami and Hashimoto, who were able to convert a-diazo-p-ketoester 47 into cyclopentanone 48 with 18a (Eq. 5.25) with 32-76% ee, dependent on the substituent Z and the size of the ester alkyl group [54,116],... 

Intramolecular C-H insertion reactions, N-H insertion reactions, and intermolecular C-H insertion reactions of aminocyanocarbenes (NCC NX2, X = H, CH3, CF3) have been studied using restricted and unrestricted CCD, CCSD, QCISD, B3LYP, and MP2 methods with the 6-31G(d), 6-311+G(d,p), cc-pVDZ, and cc-pVTZ basis sets. 66 HC NH2, NCC NH2, NCC N(CH3)2, and NCC N(CF3)2 have singlet ground states. 

The oxime nitrogen lone pair of electrons must be properly oriented so as to interact with the rhodium carbenoid.84 Thus, subjection of the -oximino isomer 182 to a catalytic quantity of Rh2(OAc)4 in CH2C12 (40 °C) with a slight excess of DMAD afforded the bimolecular cycloadduct 184 in 93% yield. In sharp contrast, when the isomeric Z-oximino diazo derivative 183 was exposed to the same reaction conditions, only indanone-oxime 185 (80%) was obtained. The formation of this product is most likely the result of an intramolecular C-H insertion reaction. 

Intramolecular C-H insertion reactions of ( -cyclo-pentadienyl)dicarbonyliron carbene complexes can be used to prepare complex polycyclic compounds. Carbon-hydrogen bond insertion using an iron carbene was used as a key step in the synthesis of sterpurene andpentalene (Scheme 81). ... 

Enantioselective Intramolecular Carbon-Hydrogen Insertion Reactions. The suitability of Rh2(55-MEPY)4 and Rh2(5R-MEPY)4 for enantioselective intramolecular C-H insertion reactions is evident in results with 2-alkoxyethyl diazoacetates (eq 4). Both lactone enantiomers are available from a single diazo ester. Other examples have also been reported, especially those with highly branched diazo substrate structures. ... 

The most common example of this type of migration is that in which the carbene is adjacent to a carbonyl group. The initial product of what is known as the Wolff rearrangement is a ketene, which cannot be isolated but is hydrolysed to the ester in the work-up. Wolff rearrangement is a typical reaction of diazoketones on heating, though these species do also undergo intramolecular C-H insertion reactions. 

Copper powder, copper bronze, Cu O, CuO, CuSO, CuCl and CuBr were the first catalysts which were used routinely for cyclopropanation of olefins as well as of aromatic and heteroaromatic compounds with diazoketones and diazoacetates. Competing insertion of a ketocarbene unit into a C—H bond of the substrate or solvent remained an excpetion in contrast to the much more frequent intramolecular C—H insertion reactions of appropriately substituted a-diazoketones or diazoacetates Reviews dealing with the cyclopropanation chemistry of diazo-acetic esters (including consideration of the efficiency of the copper catalysts mentioned above) and diazomalonic esters as well as with intramolecular cyclopropanation reactions of diazoketones have appeared. 

Our initial objective, in this investigation, had been to design a useful chiral auxiliary. We were pleased to find that naphthylbomeol 33 itself, on optimization of the catalyst and the reaction temperature, served effectively. Until effective chiral catalysts are developed, naphthylbomeol 33 wiU be of significant practical value for directing the absolute course of rhodium-mediated intramolecular C-H insertion reactions. 

In a useful extension of this methodology for enantioselection in intramolecular cyclopropanation, Doyle s group have used chiral rhodium (II) carbox-amidates to effect enantiomer differentiation in reactions of racemic secondary allylic diazoacetates [47]. The catalyst-enantiomer matching approach has also been applied very successfully to intramolecular C-H insertion reactions vide infra). The (R)- and (S)-enantiomers, (10) and (11), respectively, of cyclohex-2-en-1 -yl diazoacetate are displayed in Scheme 7. On exposure to Rh2(4i -MEOX)4 the (R)-enantiomer (10) undergoes cyclopropanation to form tricyclic ketone... 

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