Intramolecular carbenoid

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,... 

For 5-(2-diazo-l,3-dioxobutyl)-l-oxa-5-azaspiro[5,5]undecane (313), intramolecular carbenoid insertion into a (N)C—H bond represents quite an unusual way of constructing a P-laetam ring 285). 

Table 21. Rh2(OAc)4-catalyzed intramolecular carbenoid insertion into the N—H bond of JJ-lactams.

The Cu(acac)2-promoted transformation 368 - 369 represents an intramolecular carbenoid insertion into the penicillin C5—S bond 347). The original report did not mention the low-yield formation of a second product to which the tricyclic structure 370 was assigned 348,349 >. In both 369 and 370, the original stereochemistry at C-5 of 368 has been inverted this is seen as a consequence of intramolecular nucleophilic a-face attack in a presumed azetidinium enolate intermediate. Attempts to realize a more flexible intermediate which then would have a chance to undergo p-face attack centered on the chain-extended diazoketone 371. Its catalytic decomposition led to the tricycle 372 exclusively, however, C7/N rather than C5/S insertion having taken place 349). 

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)). 

Cyclic epoxides such as 124 can react in two ways with strong bases (a) via abstraction of a /3-proton to form allylic alcoholates 125 or (b) by deprotonation at the epoxide carbon atom forming the intermediate 126 and, after electrophilic substitution, the epoxides 128. If there is a suitable C—H bond in the vicinity of the C-Li moiety, intramolecular carbenoid insertion reactions to 127 may take place (equation 27) ° . ... 

As with any modern review of the chemical Hterature, the subject discussed in this chapter touches upon topics that are the focus of related books and articles. For example, there is a well recognized tome on the 1,3-dipolar cycloaddition reaction that is an excellent introduction to the many varieties of this transformation [1]. More specific reviews involving the use of rhodium(II) in carbonyl ylide cycloadditions [2] and intramolecular 1,3-dipolar cycloaddition reactions have also appeared [3, 4]. The use of rhodium for the creation and reaction of carbenes as electrophilic species [5, 6], their use in intramolecular carbenoid reactions [7], and the formation of ylides via the reaction with heteroatoms have also been described [8]. Reviews of rhodium(II) ligand-based chemoselectivity [9], rhodium(11)-mediated macrocyclizations [10], and asymmetric rho-dium(II)-carbene transformations [11, 12] detail the multiple aspects of control and applications that make this such a powerful chemical transformation. In addition to these reviews, several books have appeared since around 1998 describing the catalytic reactions of diazo compounds [13], cycloaddition reactions in organic synthesis [14], and synthetic applications of the 1,3-dipolar cycloaddition [15]. 

Reconversion of the ketonic carbonyl group into a diazo group sets the stage for intramolecular carbenoid addition to an alkene [276]. A recent paper described syntheses of 2-C-trifluoromethyl 3-deoxypentoses [277] from ethyl trifluoropyru-vate other approaches to heterocycles containing trifluoromethyl groups were reviewed recently and will therefore not be discussed further here [278]. 

Intramolecular carbenoid reactions of pyrrole derivatives have recently been applied in a total synthesis of ipalbidine (220 Scheme 46).167 The carbenoid generated from (221) was preferentially captured by the pyrrole ring, producing the indolizidinone (222) in 82% isolated yield, with only a trace of the in-danone side product (223) formed. In four steps (222) was readily converted to (220) in 13% overall yield. 

Efforts to trap the carbonyl ylide intermediate by intramolecular [3 + 2] cycloaddition to a C=C bond were unsuccessful. Rather, the decomposition of allyl (trimethylsilyl)diazoacetate (218) (equation 69) in the presence of aldehydes gave 1,3-dioxolan-4-oncs 219 their formation has been explained by 1,5-cyclization of the carbonyl ylide intermediate followed by a Claisen rearrangement122. With acetone as carbonyl component, the reaction proceeds analogously. Clean formation of 219 occurred only with Rh2(OOCC3F7)4 as catalyst, while the copper triflate catalyzed version led to a mixture of 219, an oxirane and the product of intramolecular carbenoid... 

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]. 

Beams, Halleday, and Mander (179) reported the preparation of the BCD ring system intermediates of the atisine- and veatchine-type alkaloids by intramolecular carbenoid addition reactions. 

In 1972, Indian chemists developed (188, 189) a method of introducing the C-20 functionality utilizing a regioselective intramolecular carbenoid... 

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). 

Intramolecular carbenoid and nitrenoid insertions are also quite effective for the preparation of peri-condensed heterocycles. Thus, photolysis of 1-naphthyl-1,2,3-triazoles 113 leads to bcnzo[d,e quinolines 115, possibly via carbene intermediate 114 (Scheme 55) <1987J(P1)413>. Similarly, on photolysis or thermolysis of 8-azido-l-arylazonaphtha-lenes 116 naphtho[l,8-<7, ]triazine derivatives 117 are formed along with A-aryhminobenzo[/y/]indazoles 118 (Scheme 56) <1978JOC2508, 1982JOC1996>. 

The intramolecular carbenoid-carbonyl cyclization reaction (Scheme 2) is a particularly effective method for generating carbonyl ylide dipoles undoubtedly as a consequence of... 

Since the observation that Rh(II) carboxylates are superior catalysts for the generation of transient electrophilic metal carbenoids from a-diazocar-bonyls compounds, intramolecular carbenoid insertion reactions have assumed strategic importance for C-C bond construction in organic synthesis [1]. Rhodium(ll) compounds catalyze the remote functionalization of carbon-hydrogen bonds to form carbon-carbon bonds with good yield and selectivity. These reactions have been particularly useful in the intramolecular sense to produce preferentially five-membered rings. 

An intramolecular carbenoid addition onto a carbon-carbon double bond provides a possible synthetic route to the pyrrolidine ring. The rho-dium(II) acetate-catalyzed reaction of diazo amide 106 leads to a mixture of diastereomers 107 and 108 (6 1) in 43% yield (88TL1181). The decomposition of AjA-diallyl-a-diazoacetamide catalyzed by Rh2(55-MEPY)4 forms product 109 from an enantioselective intramolecular cyclopropanation (50% yield, 72% e.e.) (94T1665). Spiro-fused ring systems were produced by this route from quinonediazides 110 and 111 under irradiation (83TL4773 86TL2687). 

The intramolecular carbenoid insertion into the N — H bond of j8-lactams is frequently used for constructing the l-azabicyclo[4.2.0]octane ring system. Thus, in the synthesis of (-)-homothienamycin, the crucial ring closure was effected by refluxing compound 160 in a benzene solution containing Rh2(OAc)4 (80TL1193). Such an approach was used to advantage in... 

Intramolecular cyclopropanation is used to advantage for the preparation of cyclopropa[h]/[c]pyridine derivatives. Decomposition of diazoacetamides 174 catalyzed by Rh2(55-MEPY)4 and Rh2(4S-MEOX)4 affords 175, the products of intramolecular carbenoid addition onto the C=C... 

Diazetidinones 487 were obtained in high yield (75-100%) by the decomposition of diazo compounds 488 in the presence of Rh2(OAc)4 in refluxing benzene. This result is rationalized in terms of an intramolecular carbenoid insertion into the y-NH bond [85TL3171 87JCS(P1)899],... 

The intramolecular carbenoid O — H insertion accompanying decomposition of diazo keto ester 592 leads, however, to the formation of the corresponding 1,4-oxazine derivative in 90% yield (94JOC2447). Similarly, the tetrahydroindeno[l,2-h]-l,4-oxazin-3(2//)-one system was stereoselectively synthesized via BF3-Et20- or Rh2(OAc)4-catalyzed ring closure of j8-hydro-xydiazoacetamides 593 (83JOC2675). 

In the laboratory of J.D. White, the asymmetric total synthesis of the non-natural (+)-codelne was accomplished via intramolecular carbenoid insertion In the late stages of the total synthesis It was necessary to Install a 6-membered piperidine moiety. This transformation was accomplished utilizing a Beckmann rearrangement of the cyclopentanone oxime portion of one of the intermediates. Later the 6-membered lactam was reduced to the corresponding amine with LAH. To this end, an oxime brosylate (Bs) was prepared, which underwent a smooth Beckmann rearrangement in acetic acid to provide a 69% yield of two isomeric lactams in an 11 1 ratio in favor of the desired isomer. 

The asymmetric total synthesis of (+)-codeine, the unnatural enantiomer, was accomplished by J.D. White and coworkers using an intramolecular carbenoid insertion as the key step. The first stereogenic center that directed all subsequent stereochemical events was installed by the asymmetric hydrogenation of an alkylidene succinate that was obtained using the Stobbe condensation. Dimethyl succinate and isovanillin were reacted in the presence of excess sodium methoxide at reflux and the resulting reaction mixture was acidified to obtain the monomethyl ester. 

White, J. D., Hrnciar, P., Stappenbeck, F. Asymmetric Total Synthesis of (+)-Codeine via Intramolecular Carbenoid Insertion. J. Org. Chem. 1999,64, 7871-7884. 

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... 

Bis(acetylacetonato)nickel(II) has also been recommended as an effective catalyst for intramolecular cyclopropanation, and more recently, rhodium(II) carboxylates have also emerged as valuable catalysts.The choice of the catalyst may become crucial when alternative intramolecular carbenoid reactions enter into competition with cyclopropanation (vide infra). 

Intramolecular carbenoid reactions of diazo compounds have been limited to the formation of only a few silicon-substituted cyclopropanes from unsaturated silicon-substituted diazo compounds. 

The Cu(acac)2-promoted transformation 368 - 369 represents an intramolecular carbenoid insertion into the penicillin C,—S bond The original report did not mention the low-yield formation of a second product to which the tricyclic structure 370 was assigned in both 3 and 370, the original stereochemistry at C-5... 

Jones, G.B. Huber, R.S. Mathews, J.E. Towards enediyne libraries cyclic enediynes via an intramolecular carbenoid coupling protocol. J. Chem. Soc., Chem. Commun. 1995, 1791-1792. 

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