Carbenoid C-H insertion

In contrast to the intramolecular carbenoid C-H insertion, the inter-molecular version has not been greatly developed and has been for a long time regarded as a rather inefficient and unselective process. In this context, Davies and Hansen have developed asymmetric intermolecular carbenoid C H insertions catalysed by rhodium(II) (5 )-A-(p-dodecylphenyl)sulfonylprolinate. " Therefore, these catalysts were found to induce asymmetric induction in the decomposition of aryldiazoacetates performed in the presence of cycloalkanes,... 

Recently, Yu and co-workers developed an operationally simple catalytic system based on [RuCl2(/>-cymene)]2 for stereoselective cyclization of a-diazoacetamides by intramolecular carbenoid C-H insertion.192 /3-Lactams were produced in excellent yields and >99% m-stereoselectivity (Equation (53)). The Ru-catalyzed reactions can be performed without the need for slow addition of diazo compounds and inert atmosphere. With a-diazoanilide as a substrate, the carbenoid insertion was directed selectively to an aromatic C-H bond leading to y-lactam formation (Equation (54)). 

In 2005, the group of Choi has reported a catalytic system based on [RuC12 (p-cymene)2] that produced the stereoselective cyclization of a-diazoacetamides by intramolecular carbenoid C-H insertion and afforded [I-lactams in excellent yield (>97%) with m-stereoselectivity (>99%), (Scheme 110), [239]. 

Hoffmann, R. W. Knopffi O. Kusche, A. Formation of rearranged Grignard reagents by carbenoid-C-H insertion. Angew. Chem. Int. 

Ruthenium porphyrins are effective catalysts for the cyclization of A-tosylhydrazones via intramolecular carbenoid C-H insertion to afford azetidin-2-ones <2003OL2535, 2003TL1445>. A non-porphyrin-based ruthenium catalyst, [RuCl2(/>-cymene)]2, has been developed recently for catalytic carbenoid transformation <20050L1081>. A [RuCl2(/>-cymene)]2-catalyzed stereoselective cyclization of a-diazoacetamides 418 by intramolecular C-H insertion produced azetidin-2-ones 419 in excellent yields and excellent (>99%) air-stereoselectivity (Equation 168). 

Reaction of diazolactones 362 with Rh2(OAc>4 as a catalyst proceeds through diastereoselective 1,5-carbenoid C-H insertion to afford the thienofuranones 363 <2004CC1772>. 

Rhodium(II) carboxylate-catalyzed decomposition of diazoacetoace-tamides (versus diazoacetamides) is a more efficient method for generating a jQ-lactam ring by carbenoid C—H insertion. Treatment of ring-substituted A-benzyl-A-ferf-butyl diazoacetamides 25 ( = 0) with Rh2(AcO)4 results in the exclusive production of /Q-lactams 26 (n = 0) in 90-98% yield... 

Stereo- and regiocontrol in the formation of lactams by rhodium-carbenoid C-H insertion of a-diazoacetamides 04EJO3773. 

Some examples of catalytic cyclopropanation reactions with diazoacetamides are given in Table 14. In reactions with a-diazo-A,7V-dimethylacetamide catalyzed by tetraacetatodi-rhodium, cyclopropane yields decrease with decreasing alkene reactivity (ethoxyethene, 82% styrene, 47% cyclohexene, 21%). - Furthermore, with A-alkyl substituents larger than methyl, intramolecular carbenoid C-H insertion is in competition with alkene addition, e.g. formation of 4.i -259... 

Keywords Asymmetric catalysis Carbenoids C-H insertion Diazo compounds Rhodium... 

Carbenoid C-H Insertion in the Synthesis of Pharmaceuticals and Natural Products.. 334... 

The earliest examples of transition metal carbenoid C-H insertion reactions were carried out with ethyl diazoacetate 13 (EDA) and simple alkanes acting as the reaction solvent. In 1974, Scott and DeCicco reported that CuS04 and CuCl were capable of decomposing EDA in the presence of cyclohexane (14) to generate C-H insertion product 15 [13]. Although these results, along with control experiments, provided proof that the copper catalyst was necessary for the transformation to take place, the maximum yield of the product was only 24%, and dimeric byproducts of the diazo compound dominated, even at high dilution (Scheme 3). 

The above examples clearly illustrate that early carbenoid C-H insertion reactions were far from being synthetically useful. Even when conducted on simple substrates, selective transformations were not achieved. In addition, dimerization of the carbenoid was a competing reaction, rendering yields of the desired products low. Both the low selectivity of the insertion events and the facile dimerization reactions suggested that the carbenoids were simply too reactive. In order to... 

Although the dirhodium catalysts are the most commonly used today, other metals are still being explored for carbenoid C-H insertion [35], These include copper [36-45], silver [46, 47], iron [48-50], gold [40], and magnesium [51, 52], and most will be discussed in context, particularly in Sect. 3.1. 

Intramolecular carbenoid C-H insertion has been a useful method for the construction of small to medium rings since the early 1980s, and these transformations can occur with good regio-, diastereo-, and enantioselectivity with appropriate choice of catalyst [6], Taber, Doyle, and Hashimoto have been key players in this area and have also developed a number of chiral catalysts for increasing levels of enantioin-duction. Many studies have been conducted concerning the effects of substrate conformation, sterics, stereoelectronics, and catalyst on the regioselectivity, diastereoselectivity, and enantioselectivity of the C-H insertion events, but these are outside the scope of this chapter. For detailed discussion, refer to the reviews cited in Sect. 1.3. 

Scheme 5 General scheme of intramolecular carbenoid C-H insertion and representative examples...

Another quite fascinating use of intramolecular carbenoid C-H insertion was demonstrated in the synthesis of analogs of artemisinin, which exhibits antimalarial properties (Scheme 10) [63], Beginning from 10-dihydroartemisinin, diazo ester 48 was constructed. Intramolecular C-H insertion into the adjacent methyl group (Cl6) occurred in 90% yield with 5% Rh2(pfb)4 (25f) to provide lactone 49. Importantly, the labile endoperoxide moiety was left untouched throughout the sequence. 

The results above clearly demonstrate that donor/acceptor carbenoids (specifically those derived from aryldiazoacetates) are capable of better reactivity than their acceptor or acceptor/acceptor counterparts with certain catalysts. Cyclohexane, however, is not appropriate for examining the selectivity of intermolecular carbenoid C-H insertion reactions. In order to achieve selective transformations on more complex substrates, it would be crucial to determine what level of differentiation could be obtained between different types of C-H bonds. Thus Davies and coworkers studied the relative rate of insertion of methyl phenyldiazoacetate into a number of simple substrates through competition studies (Fig. 6) [81]. 

Despite the unexpected challenges associated with benzylic carbenoid C-H insertion, the Davies group successfully employed this methodology toward the concise total syntheses of (+)-imperanene and (-)-a-conidendrin [84], Although the imperanene synthesis will be discussed in a later context (Sect. 4.2), the route to conidendrin 84 is outlined below (Scheme 17). The key carbenoid insertion took place between vinyldiazoester 82 and substituted toluene 81 in moderate yield, but provided the precursor (83) to the tricyclic structure in 92% ee. 

One unique aspect of the carbenoid C-H insertion chemistry is its ability to form products that are typically obtained from more classical organic reactions. One example is the allylic insertion into silyl enol ethers 102 to form products equivalent to those from an asymmetric Michael reaction (Scheme 22) [92], Cyclic substrates provided the desired Michael adducts 103 in the highest ee values for the major isomer (89-96%), but with only moderate de, favoring the diastereomer shown about 1.5 1 to 3 1. The diastereoselectivity was markedly improved to >90% de with acyclic substrate 104 with sterically differentiated substituents, but the enantioselectivity dropped to below 85% ee. Notably, this transformation was limited to aryldiazoacetates. When EDA was utilized as the carbene precursor, cyclo-propanation of the olefin was the major reaction pathway, and only small amounts of the desired C-H insertion were observed. 

As shown in Fig. 6, THF is a very active substrate for carbenoid C-H insertion adjacent to the oxygen atom. A number of catalysts have been used for this transformation, with varying results (Scheme 25). Davies and coworkers have used Rh2(5 -DOSP)4 (26) as the catalyst, obtaining 114 in yields ranging from 48 to 74%, diastereoselectivities from 1.6 1 to 4.0 1, and up to 98% ee [79, 81]. It was noted that the highest enantioselectivity was obtained not in neat THF, but when the reactions were conducted in hexanes at -50 °C with two equivalents of THF. 

Scheme 30 Influence of a 3 oxygen substituent on carbenoid C-H insertion...

---