Carbene insertions intramolecular

There are numerous examples of metal carbene insertion reactions, usually requiring a catalyst. " The C—H insertion reactions of metal carbenes can be highly selective. Intramolecular insertion reactions are very versatile and tolerate a... 

Furans. Reaction of a,a-dimethoxy ketones with 1 affords a dihydrofuran (2) presumably via a carbene (a) that inserts intramolecularly into a C—H of an adjacent methoxy group. The reaction often results directly in a furan, since the elimination of methanol from 2 is facile. 

The precursors were obtained from a mixture of several isomeric cycloheptatrienes formed from 2-phenoxy- or 2-phenylthiophenyl car-benes by intramolecular carbene insertion. 

The most spectacular application of the donor/acceptor-substituted carbenoids has been intermolecular C-H activation by means of carbenoid-induced C-H insertion [17]. Prior to the development of the donor/acceptor carbenoids, the intermolecular C-H insertion was not considered synthetically useful [5]. Since these carbenoid intermediates were not sufficiently selective and they were very prone to carbene dimerization, intramolecular reactions were required in order to control the chemistry effectively [17]. The enhanced chemoselectivity of the donor/acceptor-substituted carbenoids has enabled intermolecular C-H insertion to become a very practical enantioselective method for C-H activation. Since the initial report in 1997 [121], the field of intermolecular enantioselective C-H insertion has undergone explosive growth [14, 15]. Excellent levels of asymmetric induction are obtained when these carbenoids are derived... 

Intramolecular carbon-hydrogen insertion reactions have well known to be elTectively promoted by dirhodium(ll) catalysts [19-23]. Insertion into the y-position to form five-membered ring compounds is virtually exclusive, and in competitive experiments the expected reactivity for electrophilic carbene insertion (3°>2° 1°) is observed [49], as is heteroatom activation [50]. A recent theoretical treatment [51] confirmed the mechanistic proposal (Scheme 15.4) that C-C and C-H bond formation with the carbene carbon proceeds in a concerted fashion as the ligated metal dissociates [52]. Chemoselectivity is dependent on the catalyst ligands [53]. 

Many of the limitations of C—C bond formation by C —H insertion outlined for intermolecular reactions (Section 1.2.1.) can be overcome by making the reaction intramolecular. Thus, hydrogen atom abstraction followed by intramolecular radical-radical coupling or radical addition to an alkene are increasingly popular processes. Two-electron carbene insertions, either thermal or transition metal catalyzed, have also been used extensively. In either case, ring construction involves net C—C bond formation at a previously unactivated C-H site. 

Alkylidenes (alkylidene carbenes) are valence isomers of alkynes. They have been prepared by alkyne pyrolysis, by homologation of ketones, and by generation of alkenyl anions bearing oc-leaving groups. Generated by any of these means, an alkylidene will insert intramolecularly into a remote C- H bond to form a new C—C bond and thus a cyclopentene. A concerted two-electron process, this reaction proceeds with retention of absolute configuration at the C - H site. 

This reaction apparently proceeds by way of the normal phosphonate condensation product, the diazoalkylidene, which then spontaneously loses nitrogen to form the transient alkylidene car-bene. Careful work showed that, after statistical corrections were applied, the reactivity of a C-H bond toward insertion was approximately 0.003 for primary C-H bonds (methyl), 1.0 for secondary C-H bonds (methylene), 7.5 for benzylic (methylene) C-H bonds and 18.6 for tertiary C-H bonds. These relative reactivities are very similar to those previously observed for intramolecular C-H insertion by an alkylidene carbenoid generated from a vinyl bromide27. It was shown subsequently that the alkylidene carbene insertion reaction proceeds with retention of absolute configuration28. Using this approach, (l )-3-dimethyl-3-phenyl-l-cyclopentene and (i )-4-methyl-4-phenyl-2-cyclohexcnonc were prepared in high enantiomeric purity. 

Like carbene insertions into carbon-hydrogen bonds, metal nitrene insertions occur in both intermolecular and intramolecular reactions.For intermole-cular reactions, a manganese(III) meio-tetrakis(pentafluorophenyl)porphyrm complex gives high product yields and turnovers up to 2600 amidations could be effected directly with amides using PhI(OAc)2 (Eq. 51). The most exciting development in intramolecular C—H reactions thus far has been the oxidative cychzation of sulfamate esters (e.g., Eq. 52), as well as carbamates (to oxazolidin-2-ones), ° and one can expect further developments that are of synthetic... 

Three main synthetic routes have been used to prepare variously substituted carbapenems. Two involve an intramolecular Wittig reaction to form either the C(2)—C(3) bond (equation 1) or the C(l)—C(2) bond (equation 2). The third approach uses a carbene insertion step to form the C(3)—N(4) bond (equation 3). 

Intramolecular carbene insertion (e.g. 1 —> 3) has long been a useful method for ring construction. Masahisa Nakada of Waseda University in Tokyo now reports (J. Am. Chem. Soc. 125 2860, 2003) that with the addition of the ligand 2 this process can be made highly enantioselective. As the starting diazo ketone 1 is easily prepared by diazo transfer to the sulfonyl ketone, this should allow facile entry to enantioenriched cyclopentanones and cyclohexanones. 

Usually, carbon-carbon bonds are formed by coupling two carbons each of which are already functionalized in some way, as with the displacement of a C-Br with NaCN to form C-CN. It would be more efficient, and potentially less expensive and less polluting, if one of the partners could be an ordinary C-H bond. Intramolecular processes for carbene insertion into unactivated C-H bonds have been known for years. Practical intermolecular processes for C-C bond formation to a C-H bond are just starting to appear. 

Intramolecular carbene insertion has been utilized as a route to thiepins and benzothiepins but is seriously complicated by C—H insertion side reactions leading to alkylidene thiopyrans (Scheme 17) (78TL3567, 78CL723), while the generation of the 9-carbene from thioxanthene (via the diazo species) results in dimerization to the bisthioxanthylene compound. 

The known synthetic approaches to [1.1.1 ]propellanes can be divided into three general categories (Scheme 1) (i) intramolecular carbene insertion in a 3-methylenecyclobut-l-ylidene, (ii) intramolecular anionic ring closure in a bridgehead-substituted bicyclo-[1.1.0]butane, and (iii) 1,3-elimination in a bicyclo[l.l.l]pentane. 

Intramolecular carbene insertion into the O-H bond (Equation 11), which proceeds after the treatment of diethyl 6-hydroxy-2-oxo-l-diazoalkylphosphonates with rhodium(ll) diacetate, leads to the respective oxepanes <1994J(P1)501>. 

In addition to the preparations of ethanoadamantane via Lewis acid catalyzed rearrangement of various polycyclic hydrocarbons described above (Section II. A.1), a ring closure reaction of a substituted adamantane has also been developed. Treatment of 2-adamantyl diazoketone with copper results in the intramolecular carbene insertion illustrated in Eq. (48) 14°1. 

Reactions of alkynyliodonium salts 119 with nucleophiles proceed via an addition-elimination mechanism involving alkylidenecarbenes 120 as key intermediates. Depending on the structure of the alkynyliodonium salt, specific reaction conditions, and the nucleophile employed, this process can lead to a substituted alkyne 121 due to the carbene rearrangement, or to a cyclic product 122 via intramolecular 1,5-carbene insertion (Scheme 50). Both of these reaction pathways have been widely utilized as a synthetic tool for the formation of new C-C bonds. In addition, the transition metal mediated cross-coupling reactions of alkynyliodonium salts are increasingly used in organic synthesis. 

Preparation of Five-Membered Carbocydes and Heterocydes via Intramolecular Carbene Insertion... 

Various 2-substituted benzofurans 165 are obtained by the interaction of iodo-nium salts 164 with sodium phenoxide in methanol (Scheme 63) [126, 127]. This reaction proceeds via the intramolecular alkylidene carbene insertion into the ortho-CH bond of the phenoxy ring. Furopyridine derivatives 167 can be prepared similarly by the intramolecular aromatic C-H insertion of the alkylidenecarbenes generated by the reaction of alkynyliodonium tosylates 166 with potassium salts of 4- or 3-hydroxypyridines [128]. 

That carbenoid insertion products can be formed from cationic precursors is underlined by investigations of the base-induced decomposition of 21. Bicyclobutane (22), which could be rationalized as a product of intramolecular carbene insertion (Frey and Stevens, 1964),... 

Activation by silicon of a P-C-H bond to an intramolecular carbene insertion reaction is exemplified by the silicon-directed Bamford-Stevens reaction.68 For example, thermal decomposition of P-trimethylsilyl /V-aziridinyl imines 72 in toluene (Scheme 8) [with or without Rh2(OAc)4 catalyst] results in the formation of allylic silanes 73 as major or exclusive products by the preferential insertion of the carbene intermediate into the C-H bond P to the silicon substituent. 

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