Intramolecular cyclopropanation reactions

These reactions serve as a link in understanding selectivity differences between inter- and intramolecular cyclopropanation reactions, and they have been useful in defining the mechanism of addition as a function of catalyst [50,69,70]. 

Dauben et al. (15) applied the Aratani catalyst to intramolecular cyclopropanation reactions. Diazoketoesters were poor substrates for this catalyst, conferring little asymmetric induction to the product, Eq. 10. Better results were found using diazo ketones (34). The product cyclopropane was formed in selectivities as high as 77% ee (35a, n = 1). A reversal in the absolute sense of induction was noted upon cyclopropanation of the homologous substrate 34b (n = 2) using this catalyst, Eq. 11. Dauben notes that the reaction does not proceed at low temperature, as expected for a Cu(II) precatalyst, but that thermal activation of the catalyst results in lower selectivities (44% ee, 80°C, PhH, 35a, n = 1). Complex ent-11 may be activated at ambient temperature by reduction with 0.25 equiv (to catalyst) DIBAL-H, affording the optimized selectivities in this reaction. The active species in these reactions is presumably the aluminum alkoxide (33). Dauben cautions that this catalyst slowly decomposes under these conditions. 

Pfaltz and co-workers (28) also showed that the semicorrin-derived catalyst is remarkably effective in intramolecular cyclopropanation reactions (28). Cycliza-tion of co-alkenyl diazoketones to form six-membered rings proceeds in high selectivity, while the analogous five-membered rings are somewhat more sensitive to substitution on the pendant alkene, Eqs. 16 and 17. 

Non-heteroatom-substituted vinylcarbene complexes are readily available from alkynes and Fischer-type carbene complexes. These intermediates can undergo the inter- or intramolecular cyclopropanation reactions of non-activated alkenes. Cyclopropanation of 1,3-butadienes with these intermediates also leads to the formation of cycloheptadienes (Entry 4, Table 2.24). 

The intramolecular addition of acylcarbene complexes to alkynes is a general method for the generation of electrophilic vinylcarbene complexes. These reactive intermediates can undergo inter- or intramolecular cyclopropanation reactions [1066 -1068], C-H bond insertions [1061,1068-1070], sulfonium and oxonium ylide formation [1071], carbonyl ylide formation [1067,1069,1071], carbene dimerization [1066], and other reactions characteristic of electrophilic carbene complexes. 

Intramolecular cyclopropanation reactions are not limited to the formation of five- to seven-membered rings, as once believed. They occur with high stereocon-... 

Beyond these systems, challenges in stereocontrol remain for both inter- and intramolecular cyclopropanation reactions with diazoketones, diazoketoesters (18), diazomalonates, and diazomethane. Although some progress has been made in intramolecular reactions of diazoketones, with selected examples having high % ee values,enantiocontrol is generally low to moderate for these systems. 

Intramolecular cyclopropanation reactions of alkenyl diazo carbonyl compounds are among the most useful catalytic metal carbene transformations, and the diversity of their applications for organic syntheses is substantial [7,10,24,84]. Their catalytic asymmetric reactions, however, have only recently been reported. An early application of the Aratani catalyst 2 (A = PhCH2) to... 

Pfaltz has also examined enantiocontrol in the intramolecular cyclopropanation of diazo ketones (Eq. 5.15), and found relatively high enantioselectivity with the use of his semicorrin Cu(I) catalyst [38]. This catalyst is obviously superior to the salicylaldimine catalysts for intramolecular cyclopropanation reactions and, furthermore, enantiocontrol increases with an increase in the ring size from five to six. 

Once again, cis-disubstituted olefins lead to higher enantioselectivities than do trans-disubstituted olefins, but here the differences are not as great as they were with allyl diazoacetates. Both allylic and homoallylic diazoacetamides also undergo highly enantioselective intramolecular cyclopropanation (40-43) [93,94], However, with allylic a-diazopropionates enantiocontrol i s lower by 10-30% ee [95], The composite data suggest that chi ral dirhodium(II) carboxamide catalysts are superior to chiral Cu or Ru catalysts for intramolecular cyclopropanation reactions of allylic and homoallylic diazoacetates. 

The effect of substrate structure on enantioselectivity has been explored for the catalytic intramolecular cyclopropanation reaction of a-diazo-/3-keto arylsulfones.56 It has especially been shown that substitution of the phenyl ring by a methyl at the ortho position of the sulfonyl group dramatically increased the ees, with values up to 93%. 

Dirhodium(II) tetrakis(carboxamides), constructed with chiral 2-pyrroli-done-5-carboxylate esters so that the two nitrogen donor atoms on each rhodium are in a cis arrangement, represent a new class of chiral catalysts with broad applicability to enantioselective metal carbene transformations. Enantiomeric excesses greater than 90% have been achieved in intramolecular cyclopropanation reactions of allyl diazoacetates. In intermolecular cyclopropanation reactions with monosubsti-tuted olefins, the cis-disubstituted cyclopropane is formed with a higher enantiomeric excess than the trans isomer, and for cyclopropenation of 1-alkynes extraordinary selectivity has been achieved. Carbon-hydro-gen insertion reactions of diazoacetate esters that result in substituted y-butyrolactones occur in high yield and with enantiomeric excess as high as 90% with the use of these catalysts. Their design affords stabilization of the intermediate metal carbene and orientation of the carbene substituents for selectivity enhancement. 

A-Cu,N-Co, and P-Cu to carbenoid transformations have been limited to intermolecular reactions, for which they remain superior to chiral dirhodium(II) catalysts for intermolecular cyclopropanation reactions. Few examples other than those recently reported by Dauben and coworkers (eq 1) (35) portray the effectiveness of these chiral catalysts for enantioseleetive intramolecular cyclopropanation reactions, and these examples demonstrate their limitations. However, with Rh2(5S-MEPY)4 intramolecular cyclopropanation of 3-methyl-2-buten-1 -yl diazoacetate (eq 2) occurs in high yield and with 92% enantiomeric excess (36). 

Several iodonium ylides, thermally or photochemically, transferred their carbene moiety to alkenes which were converted into cyclopropane derivatives. The thermal decomposition of ylides was usually catalysed by copper or rhodium salts and was most efficient in intramolecular cyclopropanation. Reactions of PhI=C(C02Me)2 with styrenes, allylbenzene and phenylacetylene have established the intermediacy of carbenes in the presence of a chiral catalyst, intramolecular cyclopropanation resulted in the preparation of a product in 67% enantiomeric excess [12]. 

The allylsilyl-substituted diazoester 1, while stable thermally up to 140 C and towards Rh2(pfb)4, undergoes a photochemically induced intramolecular cyclopropanation reaction leading to the rather strained 2-silabicyclo[2.1.0]butane 17 in surprisingly good yield [9]. 

More recently, Hodgson et al. have found that aziridinyl anions can also undergo a diastereoselective intramolecular cyclopropanation reaction to give 2-aminohicyclo[3.1.0]hexenes in good yield <20060L995>. Reversing the addition order so that the aziridine was added dropwise to the hase led to increased yields of the hicyclic amine. When the dienyl-substituted aziridine 386 was used, an 85% yield of the 2-amino hicyclo[3.1.0]hexane 387 was obtained, which contains the potentially useful vinyl cyclopropane moiety (Scheme 98). 

The fascinating carbenoid character of the epoxide anion is also manifested in an intramolecular cyclopropanation reaction, in which the anion adds across a tethered olefin to provide bicyclo[3.1.0]hexanols (Equation 52). The reaction is remarkably chemo- and diastereoselective. No C-H insertion is observed, and yields are generally very good. The stereochemical outcome is rationalized on the basis of a /ra r-lithiation, as well as the geometric constraints imposed by the [3.1.0] bicyclic system <2004JA8664>. 

Semicorrinato)copper catalysts have also been used for intramolecular cyclopropanation reactions of alkenyl diazo ketones (eq 9 and eq 10). In this case the (semicorrinato)copper catalyst derived from complex (5) proved to be superior to related methylene-bis(oxazoline)copper complexes. Interestingly, analogous allyl diazoacetates react with markedly lower enantioselectivity under these conditions, in contrast to the results obtained with chiral Rh complexes which are excellent catalysts for intramolecular cyclopropanations of allyl diazoacetates but give poor enantioselectivities with alkenyl diazo ketones (see Dirhodium(II) Tetrakis(methyl 2-pyrrolidone-5(S -carboxylate ) Moderate enantioselectivities in the reactions... 

Enantioselective Intramolecular Cyclopropanation Reactions. The exceptional capabilities of the Rh2(55 -MEPY)4 and... 

Consequently, various Grignard reagents have been shown to be effective for the intramolecular cyclopropanation reactions with insignificant differences in yields. Whereas several titanium alkoxides and aryloxides can also be employed, chlorotitanium triisopropoxide and methyltitanium triisopropoxide have often been found to be the titanium reagent of choice. Ether, THE, toluene, or even dichloromethane are generally appropriate reaction solvents. 

The use of chiral additives with a rhodium complex also leads to cyclopropanes enantioselectively. An important chiral rhodium species is Rh2(5-DOSP)4, which leads to cyclopropanes with excellent enantioselectivity in carbene cyclopro-panation reactions. Asymmetric, intramolecular cyclopropanation reactions have been reported. The copper catalyzed diazoester cyclopropanation was reported in an ionic liquid. ° It is noted that the reaction of a diazoester with a chiral dirhodium catalyst leads to p-lactones with modest enantioselectivity Phosphonate esters have been incorporated into the diazo compound... 

Obtained from active methylene compounds, such as malonic esters, -0x0 esters and jS-oxo sulfones, iodonium ylides serve as precursors of the corresponding carbenes. Their decomposition by a catalytic amount of a copper salt in the presence of a C-C double bond has been used for inter- and intramolecular cyclopropanation reactions. Thus, reaction of cyclohexene with bis(methoxycarbonyl)methylene(phenyl)iodine(III) under the catalytic action of bis(acetylacetonato)copper(II) yielded dimethyl bicyclo[4.1.0]heptane-7,7-dicarboxylate (1) (38%, mp 91-93°C) in addition to tetrakis(methoxycarbonyl)ethene (41%). ... 

The same statement is true for intramolecular cyclopropanation reactions by purely thermal decomposition of a-diazocarbonyl compounds, which have been reported even less frequently. The following three examples allow a comparison of the efficiency of the thermal versus the transition metal catalyzed or photochemical procedure. 

Bis(acetylacetonato)nickel(II) has been recommended as a homogeneous catalyst for intramolecular cyclopropanation reactions of unsaturated diazo ketones(see Section 1.2.1.2.4.2.6.3.4.). As the experiments were carried out, without exception, by irradiating the diazo ketone at elevated temperature in the presence of the catalyst, the actual significance of the catalyst is, however, unclear. 

The great majority of intramolecular cyclopropanation reactions of unsaturated a-diazo-carbonyl compounds have been achieved with copper catalysts, especially with copper powder or copper bronze, copper(II) sulfate, and bis(acetylacetonato)copper(II). Homogeneous catalysis by bis(salicylaldimato)copper(II) or copper(I) halide/trialkyl phosphite complexes has repeatedly been reported to be superior to heterogeneous catalysis by other copper(I) and cop-per(II) salts, e.g. formation of and 2. ... 

Asymmetric induction in intramolecular cyclopropanation reactions can be achieved by substrate and catalyst control. In the example of 24, a stereogenic center in the tether of the unsaturated diazocarbonyl compound controls the diastereofacial selectivity of the cyclopropanation reaction. In the examples of and 27, the diastereoselectivity of the cycli-zation process is controlled by the siloxy group at the stereogenic center obviously, this group prefers the exo position in the transition state. However, the catalyst is also important, since practically no diastereoselectivity for 26 resulted when bis(Al-tc/-t-butylsalicylaldimato)cop-per(II) was used. 

Chiral copper catalysts have been used less frequently for enantioselective intramolecular cyclopropanation reactions. Decomposition of allyl terr-butyl diazomalonate with a chiral bis(oxazo-line)methane-copper(I) complex gave tert-butyl 3-oxa-2-oxobicyclo[3.1.0]hexane-l-carb-oxylate in 50% yield and with 32% ee. ° ... 

Intramolecular cyclopropanation reactions with alkoxycarbonylnitrile ylides are also known and have been described in detail. ... 

Method A and C have been used for intramolecular cyclopropanation reactions. Thus, 2-silabicyclo[3.1.0]hexanes 5b,c and 2-silabicyclo[4.1.0]heptane 5d have been prepared in moderate yields by treatment of alkenyl(chloromethyl)dimethylsilanes 4b-d with sodium. In the case of 4d, C-H insertion of the intermediate carbene competes with cyclopropanation, and for 4e, it becomes the sole carbene reaction. The corresponding allylsilane 4a does not undergo intramolecular cyclopropanation, and in the case of vinylsilane 6, intramolecular cyclopropanation is probably involved in the formation of silylcyclopropane 7. 

Herein, intermolecular and intramolecular cyclopropanation reactions of diazo compounds will be discussed separately. Most of the diazo compounds presented here belong to two major classes, diazo(trialkylsilyl)methanes 1 or trialkylmetal-substituted diazoacetates 2 (metal = silicon, germanium, tin, lead). 

Copper powder, copper bronze, Cu O, CuO, CuSO, CuCl and CuBr were the first catalysts which were used routinely for cyclopropanation of olefins as well as of aromatic and heteroaromatic compounds with diazoketones and diazoacetates. Competing insertion of a ketocarbene unit into a C—H bond of the substrate or solvent remained an excpetion in contrast to the much more frequent intramolecular C—H insertion reactions of appropriately substituted a-diazoketones or diazoacetates Reviews dealing with the cyclopropanation chemistry of diazo-acetic esters (including consideration of the efficiency of the copper catalysts mentioned above) and diazomalonic esters as well as with intramolecular cyclopropanation reactions of diazoketones have appeared. 

The dimethyl 1-allyloxycarbonyl-l-diazomethylphosphonate and diallyl l-ZerZ-butoxycarbonyl-1-diazomethylphosphonate under Rh2(OAc)4 catalysis or in refluxing cyclohexane in the presence of copper powder undergo intramolecular cyclopropanation reaction in good yields and with moderate levels of diastereoselectivity. 

Recently, Shibasaki et al. [70] reported an example of a highly selective intramolecular cyclopropanation reaction of a silyl enol ether (Scheme 13). The most effective Hgand in this case was a bisoxazoUne with two sterically demanding (Me3SiO)Me2C groups at the stereogenic centers. 

Enantiocontrol in intramolecular cyclopropanation reactions of diazoacetamides has been developed to levels comparable with those now accessible with diazoesters. Several substituent variations in Eq. (20) are summarized in Table 3, which reveals examples where ee s exceed 90%. In general diazoamides have a conformational feature which differs from their diazoester counterparts, namely, the relatively slow syn-anti isomerization by rotation about the N-CO bond. If the interconversion of (18) and (19) or their respective metal carbenes is slow relative to the reaction timescale [50], only isomer (18) can lead to intramolecular cyclopropanation. However, an alternative process to which (18) is prone un-... 

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