Intramolecular 1,5-C-H Insertions

In acceptor-substituted carbene complexes with hydrogen at Cp fast hydride migration to the carbene will usually occur [1094,1095]. The resulting olefins are often formed with high stereoselectivity. 1,2-Hydride migration will also occur in P-hydroxy carbene complexes, ketones being formed in high yields (Table 4.2). Intramolecular 1,5-C-H insertion can sometimes compete efficiently with 1,2-insertion [1096]. 

Starting Material Reagents, Conditions Product Yield Ref. 

---

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... 

Scheme 10.74 Rh-catalysed intramolecular C-H insertions of y-alkoxy-a-diazo-P-keto esters with sulfonamide ligands.

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. 

Photolysis of alkoxysilyl-diazoacetic esters 1 generates l-oxa-2-sila-cyclopentanes 2 by carbenic intramolecular C/H insertion. Four- and six-membered rings are not observed. 

Intramolecular C/H insertion by copper-catalyzed decomposition of a-diazoketones provides a convenient cyclization procedure which is limited, however, to diazo compounds which allow energetically favorable realization of the transition state leading to the cyclized product. 

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... 

C—H bond 174-280,28i por comparison, only trace amounts of cyclopentane resulted from the CuS04-catalyzed decomposition of 1 -diazo-2-octanone or l-diazo-4,4-dimethyl-2-pentanone 277). It is obvious that the use of Rh2(OAc)4 considerably extends the scope of transition-metal catalyzed intramolecular C/H insertion, as it allows for the first time, efficient cyelization of ketocarbenoids derived from freely rotating, acyclic diazoketones. This cyelization reaction can also be highly diastereo-selective, as the exclusive formation of a m is-2,3-disubstituted cyclopentane carboxylate from 307 shows281 a). The stereoselection has been rationalized by... 

Using the results of an earlier study concerning enantioselective copper-catalyzed intramolecular C—H insertion of metal carbenoids,109 an interesting system for optimizing the proper combination of ligand, transition metal, and solvent for the reaction of the diazo compound (75) was devised (see Scheme 19).110 The reaction parameters were varied systematically on a standard 96-well microtiter/filtration plate. A total of five different ligands, seven metal precursors, and four solvents were tested in an iterative optimization mode. Standard HPLC was used to monitor stereoselectivity following DDQ-induced oxidation. This type of catalyst search led to the... 

Cyclometallation of thiophene imine 110 with platinum complex 111 proceeded to give metallacycle 112 via an intramolecular C-H insertion on the thiophene ring . 

F. Ring-Construction by Intramolecular C-H Insertion of (Phenylthio)carbenes... 

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. 

Effective double stereodifferentiation is possible in intramolecular C-H insertion.199 For example, catalytic decomposition of enantiopure (lY,2Y)-diazoacetate 74 by Rh2(4A-MEOX)4 directed the reaction toward the preferential formation of y-lactone (lY)-75, whereas the corresponding reaction catalyzed by Rh2(4i -MEOX)4 prefers initially forming y-lactone (lY)-76 (Equation (66)). Similarly, treatment of (lY,2i )-diazoacetate 77 with Rh2(5A-MEPY)4 or Rh2(4i -MPPIM)4 gave (lY)-78 or (lY)-79, respectively (Equation (67)).199... 

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)). 

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... 

Dioxo-derivatives 150 can be efficiently synthesized via Rh(ll)-catalyzed intramolecular C-H insertion from various a-diazoamides. For example, intramolecular C-H insertion occurred readily in 149 under refluxing benzene conditions and produced the corresponding 7-lactams 150 with improved yields and excellent stereoselectivity (Equation 21) <2004JOC9313>. 

The rhodium acetate complex catalyzed the intramolecular C-H insertion of (/ )-diazo-fR)-(phenylsulfonyl)acet-amides 359 derived from (f )-amino acids to afford in high yield the 6-benzenesulfonyl-3,3-dimethyl-7-phenyl-tetrahydro-pyrrolo[l,2-c]oxazol-5-one 360 (Equation 63) <2002JOC6582, 2005TL143>. 

Michael addition to the salt to form an alkylidenecarbene, which undergoes intramolecular C—H insertion to form a cyclopentene. 

Lim and Sulikowski (84) explored the intramolecular C-H insertion in 119 alpha to the nitrogen atom as a rapid entry to the mitomycin skeleton and the antitumor agent FR-900482. Rhodium(II) based catalysts provide nearly racemic products. Bis(oxazoline) (55b) affords highest selectivities in this system and chloroform was found to be the optimal solvent, Eq. 71. The authors note that the reaction is somewhat capricious. 

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. 

This unique C-C bond-forming reaction has been applied to the synthesis of natural products [480,481]. In the examples reported, intramolecular C-H insertion into R3C-H groups was used for the construction of more elaborate, polycyclic carbon frameworks. Representative examples are listed in Table 3.7. 

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).

The different synthetic applications of acceptor-substituted carbene complexes will be discussed in the following sections. The reactions have been ordered according to their mechanism. Because electrophilic carbene complexes can undergo several different types of reaction, elaborate substrates might be transformed with little chemoselectivity. For instance, the phenylalanine-derived diazoamide shown in Figure 4.5 undergoes simultaneous intramolecular C-H insertion into both benzylic positions, intramolecular cyclopropanation of one phenyl group, and hydride abstraction when treated with rhodium(II) acetate. 

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],... 

As early as in 1973 it was shown [1089] that the C-H insertion of acceptor-substituted carbene complexes can take place with retention of configuration (e.g. Table 4.5, Entry 3) [953,1090,1091]. In the case of intramolecular C-H insertions into methylene groups high diastereoselectivities are often observed when 4-6-membered rings are formed (see examples in Tables 4.4-4.S). 

Enantiomerically pure rhodium(II) complexes have been shown to catalyze enantioselective, intramolecular C-H insertions. Because high enantioselectivities (> 97% ee [1092]) can be achieved, it can be inferred that in the transition state of these C-H insertions the catalyst is in close proximity to the reacting groups. With the same type of catalyst highly enantioselective (up to 93% ee) intermolecular C-H insertions can also be realized [1093]. 

Few examples of the formation of cyclopropanes by intramolecular C-H insertion of electrophilic carbene complexes have been reported. This methodology for cyclopropane preparation seems only to be suitable for polycyclic compounds with little conformational flexibility. Illustrative examples are listed in Table 4.3. 

Examples of the formation of four-membered rings by intramolecular C-H insertion of electrophilic carbene complexes are listed in Table 4.4. 

---