Insertion reactions intramolecular, heterocycles

By analogy with the intramolecular insertion of phenylthiocarbenes, the reaction of (oo-oxido)diazoalkanes 93 resulted in the formation of cycloalkenes 94.38 However, the reaction was proven to proceed not via a carbene route b but a nitrene route a as shown in Scheme 26. The nitrene route is supported by the formation of heterocyclic products 98 and 99.39 This insertion reaction was used in the cydization step to the cyclopentene ring formation of isocarbacycline 97.40... 

The usefulness of this reaction for the preparation of heterocycles under mild conditions became apparent in 1978, when chemists from Merck, Sharp Dohme reported the synthesis of bicyclic 3-lactams by intramolecular carbene N-H insertion [1179]. Intramolecular N-alkylation of P-lactams by carbene complexes is one of the best methods for preparation of this important class of antibiotic and many P-lactam derivatives have been prepared using this methodology [1180 -1186] (Table 4.11). Intramolecular N-H insertion can also be used to alkylate amines [1187-1189], y-lactams [1190], and carbamates [1191-1193] (Table 4.11). 

Transition metal catalyzed insertion reactions offer a convenient route for the preparation of five membered heterocyclic rings. Besides intramolecular Heck-couplings and CO insertion, examples of the intramolecular insertion of an acetylene derivative constitute the majority of this chapter. Although some of these processes involve the formation of a carbon-heteroatom bond, they are discussed here. 

The alkyne insertion reaction is terminated by anion capture. As examples of the termination by the anion capture, the alkenylpalladium intermediate 189, formed by the intramolecular insertion of 188, is terminated by hydrogenolysis with formic acid to give the terminal alkene 192. Palladium formate 190 is formed, and decarboxylated to give the hydridopalladium 191, reductive elimination of which gives the alkene 192 [81]. Similarly the intramolecular insertion of 193 is terminated by transmetallation of 194 with the tin acetylide 195 (or alkynyl anion capture) to give the dienyne 196 [82], Various heterocyclic compounds are prepared by heteroannulation using aryl iodides 68 and 69, and internal alkynes. Although the mechanism is not clear, alkenylpalladiums, formed by insertion of alkynes, are trapped by nucleophiles... 

The nitrene 28 is not produced from the azide precursor, but from heterocycles via photolysis and thermolysis as shown in Sch. 11 [20]. Iminoacyl nitrenes react intramolecularly giving benzimidazoles with good yields (Sch. 11), and, dependending on the precursor used and the reaction conditions, varying amounts of carbodiimides are obtained. The reactivity of the acyl nitrenes is influenced by the substituent connected to the acyl group (see Sch. 10), however all acyl nitrenes are quite reactive and therefore rather unselective. Apart from cycloaddition reactions with Tt-bonds, insertion reactions into a-bonds, additions to lone pair electrons of... 

Metal complexes of heterocyclic compounds display reactivities changed greatly from those of the uncomplexed parent systems. All of the -electron system(s) of the parent heterocycle can be tied up in the complex formation, or part can be left to take part in alkenic reactions. The system may be greatly stabilized in the complex, so that reactions, on a heteroatom, for example, can be performed which the parent compound itself would not survive. Orbital energy levels may be split and symmetries changed, allowing hitherto forbidden reactions to occur. In short, a multitude of new reaction modes can be made possible by using complexes dimerization of azirines with a palladium catalyst serves as a typical example (Scheme 81). A variety of other insertion reactions, dimerizations, intramolecular cyclizations, and intermolecular addition reactions of azirines are promoted by transition metals. 

The intramolecular O—H insertion reaction of a carbene has been successful in the synthesis of the oxygen-containing heterocycle 216 in quantitative yield (85JOC5223). Carbene generated by photolysis of diazo precursor 217 in protic solvents gives 2-phenyl-2,5-dihydroisobenzofuran competitively with insertion into the O —H bonds of the solvent (90JOC2325). 

Examples of enantioselective intramolecular C-H insertion reactions of diazoacetamides are known and though less extensive than those with diazoester substrates, there already are indications that excellent levels of stereocontrol are attainable. It is very likely that catalyst development will extend further the scope of this approach to the enantioselective synthesis of iY-heterocycles. 

The transition-metal-catalyzed reaction of diazo compounds 702, which have a N—H or O—H bond at an appropriate position, gives nitrogen- and oxygen-containing heterocycles 703 (Scheme 2 1 8).293 Wang and Zhu demonstrated a convenient synthesis of the polyfunctionalized /Tfluoropyrroles by the rhodium-catalyzed intramolecular N—H insertion reaction.2933 The reaction of d-amino-y,y-difluoro-a-diazo-/Tketo esters 704 in the presence of Rh2(OAc)4 gave the... 

More recent approaches include a rhodium(II)-catalyzed intramolecular insertion reaction to form the hve-membered heterocycle. Reformatsky-imine addition of 4-bromo-4,4-difluoroacetoacetate with aldimines gave b-amino-y.y-difluoroacetoa-cetates 67 that were readily converted to the key diazo intermediates 68 through the action of tosyl azide and molecular sieve. Rhodium(II)-catalyzed intramolecular insertion followed by aromatization through loss of HF gave the functionalized pyrroles 69 (Fig. 3.29). 

Isochromans result from the intramolecular C-H insertion reactions of contributing singlet and triplet states of 2-(alkoxymethyl)phenylcarbenes (94TL1699). The cyclisation of both the 2-ally 1 and the 2-prop-T-enyl substituted 3-(l-hydroxyethyl)naphthalene derivatives (9), (10) leads stereoselectively to the trans-n htho[2,3-c]pyrans (11), the heterocyclic moiety of some aphid pigments (94JCS(P1)859). The alkylation of 2-acetylnaphtho-... 

In particular, the rhodium acetate catalyzed carbenoid intramolecular insertion reactions has been demonstrated to be an efficient and regiospecific method for the construction of various heterocycles [2,77] such as azetidine, pyrrolidine, piperidine, tetrahydrofuran and... 

Rapoport and co-workers have reported a general synthesis of nitrogen, oxygen, and sulphur heterocycles (218) by rhodium-catalysed intramolecular N-H, 0-H, or S-H insertion reactions.of keto-ester precursors (217)- This reaction is well documented as an efficient route to B-lactams but this group has now shown that the reaction works well for the synthesis of five-and six-membered nitrogen heterocycles (Scheme 22). The reaction fails for seven-membered nitrogen heterocycles in this case C-H insertion to give a eyelopentanone is the preferred reaction mode. 

Quinazolinones are an important class of fused heterocycles that have been reported with remarkable activities in biology and pharmacology such as anticancer, antiinflammatory, anticonvulsant, antibacterial, antidiabetic, hypolipidemic, and protein tyrosine kinase inhibitors. Alper and Zheng reported a palladium-catalyzed cyclocarbonylation of o-iodoanilines with imidoyl chlorides to produce quinazolin-4(3H)-ones in 2008. A wide variety of substituted quinazolin-4(3H)-ones were prepared in 63-91% yields (Scheme 3.27a). The reaction is believed to proceed via in situ formation of an amidine, followed by oxidative addition, CO insertion, and intramolecular cyclization to give the substituted quinazolin-4(3H)-ones. Later on, a procedure was established based on generating the amidine in situ by a copper-catalyzed reaction of terminal allq nes, sulfonyl azide and o-iodo-anilines. The desired quinazolinones can be produced by carbonylation with Pd(OAc)2-DPPB-NEt3-THF as the reaction system. In the same year, Alper s group developed a procedure for 2,3-dihydro-4(lH)-quinazolinone preparation. The reaction started with the reaction of 2-iodoanilines and N-toluenesulfonyl aldimines followed by palladium-catalyzed intramolecular... 

We have already reported above the interest of Pd(0) and Ni(0) as catalysts for the synthesis of macrolides [39] and of various heterocycles through intramolecular reactions [40, 43]. Moreover, carbene chemistry also affords some interesting pathways to heterocyclic systems for example, the insertion reaction of carbalkoxy carbenes into an enol (acetylace-tone) yields furan derivatives [98] whereas the insertion reaction into diols affords lactones [99],... 

In the presence of a double bond at a suitable position, the CO insertion is followed by alkene insertion. In the intramolecular reaction of 552, different products, 553 and 554, are obtained by the use of diflerent catalytic spe-cies[408,409]. Pd(dba)2 in the absence of Ph,P affords 554. PdCl2(Ph3P)3 affords the spiro p-keto ester 553. The carbonylation of o-methallylbenzyl chloride (555) produced the benzoannulated enol lactone 556 by CO, alkene. and CO insertions. In addition, the cyclobutanone derivative 558 was obtained as a byproduct via the cycloaddition of the ketene intermediate 557[4I0]. Another type of intramolecular enone formation is used for the formation of the heterocyclic compounds 559[4l I]. The carbonylation of the I-iodo-1,4-diene 560 produces the cyclopentenone 561 by CO. alkene. and CO insertions[409,4l2]. 

The intramolecular G-H insertion of aryldiazoacetates is a very powerful strategy for synthesizing heterocyclic rings such as dihydrobenzofurans and dihydrobenzopyrans. The first effective asymmetric copper-catalyzed C-H activation reaction was reported by the group of Sulikowski in the synthesis of the anti-tumor antibiotic FR-66979 93 (Scheme 7)123 219 The G-H insertion of the aryldiazoacetate 90 formed four diastereomeric products 91a, 91b, 92a,... 

The reaction was further applied to the synthesis of spiro heterocycles (Scheme 16.4) [8], The oxidative addition of an iodide to a Pd(0) species generates an ArPdl species, into which an internal olefin inserts to form an alkylpalladium complex otherwise difficult to access. Allene participates in the reaction at this stage to provide a jt-allylpalladium complex, which is attacked by the amine intramolecularly to afford the procuct. 

The reaction of alkoxy(alkyl)carbene chromium complexes with alkynes has been reported to give modest yields of cyclopentenones [368] and a few examples of intramolecular carbene C-H insertions of Fischer-type carbene complexes, leading to five-membered heterocycles, have been reported [369,370] (Table 2.22). 

The halogenated derivatives of six membered heterocycles, like their carbacyclic analogues, usually participate readily in coupling reactions that involve the incorporation of an olefin or carbon monoxide. The insertion of carbon monoxide commonly leads to the formation of either a carboxylic acid derivative or a ketone, depending on the nature of the other reactants present. Intermolecular and intramolecular variants of the insertion route are equally popular, and are frequently utilized in the functionalization of heterocycles or the formation of annelated ring systems. 

A very large number of these systems with ring junction heteroatoms exists, and this number is constantly increasing. Only illustrative examples of the preparation of such systems can be given here. The synthetic methods for the formation of this type of heterocycle can be usefully classified as follows (i) various cyclocondensations between the corresponding heterocyclic derivatives and bifunctional units, (ii) intramolecular cyclizations of electrophilic, nucleophilic or (still rare) radical type, (iii) cycloadditions, (iv) intramolecular oxidative coupling, (v) intramolecular insertions, (vi) cyclization of open-chained predecessors, (vii) various reactions (quite often unusual) which are specific for each type of system. Examples given below illustrate all these cases. 

Palladium chemistry has been used in the synthesis of tetrahydroisoquinolines. Different combinations of iodoaryl-amine-alkene can be used in these multicomponent reactions. For example, the metal-mediated o-alkylated/alkenyl-ation and intramolecular aza-Michael reaction (Scheme 109) give moderate yields of heterocycle <2004TL6903>, whereas the palladium-catalyzed allene insertion-nucleophilic incorporation-Michael addition cascade (Equation 172) produces good yields of tetrahydroisoquinolines in 15 examples <2003TL7445> with further examples producing tetrahydroquinolines (Scheme 110) <2000TL7125>. 

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