Cyclopropanation butyl diazoacetate

Copper(II) triflate is quite inefficient in promoting cyclopropanation of allyl alcohol, and the use of f-butyl diazoacetate [164/(165+166) = 97/3%] brought no improvement over ethyl diazoacetate (67/6 %)162). If, however, copper(I) triflate was the catalyst, cyclopropanation with ethyl diazoacetate increased to 30% at the expense of O/H insertion (55%). As has already been discussed in Sect. 2.2.1, competitive coordination-type and carbenoid mechanisms may be involved in cyclopropanation with copper catalysts, and the ability of Cu(I) to coordinate efficiently with olefins may enhance this reaction in the intramolecular competition with O/H insertion. 

Katsuki has recently constructed a series of chiral Co(III)-salen complexes 30 and used them as catalysts for cyclopropanation of styrene using tert-butyl diazoacetate [78], Not only is enantiocontrol for addition greater than 90% ee, but diastereoselectivity favors the trans-... 

Copper powder, copper bronze, copper(I) oxide, copper(II) oxide, copper(Il) sulfate, and cop-per(I) halides, typically applied as a suspension in refluxing solvent or alkene, are used extensively for intermolecular cyclopropanation with diazoacetic esters or diazomalonic esters, and for intramolecular cyclopropanation of unsaturated diazocarbonyl compounds. Bis(acetylacetonato)copper(Il) [Cu(acac)2], a more recently introduced catalyst, is only sparingly soluble in the typical solvents and alkenes which are used and is therefore applied under the same conditions. Catalysts such as trialkyl phosphite and triaryl phosphite complexes of copper(I) halides and salicylaldimatocopper(II) chelates [e.g. 1 (R = (R)-a-phenylethyl, R = /ert-butyl ) and 2 ] are soluble in many organic solvents and liquid alkenes. 

Aryl-5,5-bis(oxazolin-2-yl)-l,3-dioxanes 169 have been easily prepared in three steps from diethyl bis(hydroxymethyl)malonate, amino alcohols, and aromatic aldehydes. They have been used for the copper-catalyzed asymmetric cyclopropanation of styrene with ethyl diazoacetate in up to 99% ee for the trawx-cyclopropane (maximum transicis ratio = 77/23) <05TA1415>. The same reaction performed on 2,5-dimethyl-2,4-hexadiene with tert-butyl diazoacetate in the presence of copper catalysts bearing ligand 170, prepared from arylglycines, exhibited remarkable enhancement of the rrawx-selectivity (transicis ratio = 87/13), with 96% ee for the trans product <05JOC3292>. 

Ishitani and Achiwa [16] have recently prepared an axially disymmetric rhodium (11) biphenylcarboxylate catalyst, Rh2(S-BDME)4 of Fig. 2, and found that although the transxis diastereoselectivity in its catalysis of the styrene-EDA reaction was poor, the enantiocontrol was better than that observed with the pro-linate catalyst. The biphenyl based catalyst yielded an 87% ee for the cyclopro-panation of 2-naphthylethene and tert-butyl diazoacetate, though again the diastereoselectivity was very low. Use of an additional chiral auxiliary in the diazoester as in the d-menthyl derivative in Eq. (10) furnished a mixture of cyclopropanes, the cis-isomer of which was found to have an ee of 99%. 

The cyclopropanation of styrene with f-butyl diazoacetate in the presence of 5 mol % of (salen)Co(III) bromide 23 produced the corresponding trans-cyclo-propane-carboxylate, with high diastereomeric ratio and enantiomeric excess (Eq. (5)). The asymmetric cyclopropanations of other styrene derivatives also showed high enantioselectivities as well as high transxis selectivities. However, the reaction of disubstituted olefins, such as indene, was sluggish. The use of Co(III) instead of Co(II) seemed to be critical, since Nakamura reported that much lower enantioselectivities were observed with optically active (salen)co-balt(II) complexes. 

Cyclopropanation with alkyl dlazoacetates. Rhodium(Il) acetate is an efficient catalyst for the insertion of carboethoxycarbene into activated C-H-bonds (5, 571-572), but it is less effective than rhodium(II) n-butanoate or pivalate for catalysis of cyclopropanation of alkenes with alkyl diazoacetates, possibly because the latter carboxylates are more soluble in organic solvents. However, rhodium(ll) trifluoroacetate is readily soluble, but it is a poor catalyst for cyclopropanation. The alkyl group of the diazoacetate strongly influences the yields, which are highest with n-butyl diazoacetate. 

Figure 7.26 When concave 1,10-phenanthrolines are used as ligands for copper(l) ions in the cyclopropanation of indene by diazoacetates, the exo/endo-selectivities can be controlled by the choice of the ligand. The concave 1,10-phenanthroline from Figure 7.10 [X = (Cff2hol in combination with ten-butyl diazoacetate is highly exo-selective (exo/endo = 140 1) while the 1,10-phenanthroline bridged calix[6Iarene from Figure 7.15 is endo-selective (best results for N2CHCOOMe, exo/endo = 14 86) °...

Apart from 37, other carboxamidate catalysts are also efficient intramolecular cyclopropanation catalysts. Rh2(4S-MPPIM)4 38, derived from chiral imidazole, is particularly effective in the cyclopropanation of diazoacetates, which contain rans-disubstituted or n-butyl allyl alkenes, with high enantioselectivities (Scheme 25) (117). In addition, this catalyst also proved to be efficient for the substrates of A -methyl substituted A-allyldiazoacetate, with high yields (88-93%) and high percentage of ee values (>92%) of the corresponding cyclopropanes (118). Catalyst Rh2(4S-MEOX)4, based on chiral oxazoline, is another efficient... 

Cyclopropanation Processes. (V-Methylimidazole also serves as a useful additive in Co-catalyzed asymmetric cyclo-propanations. In the reaction between st)frene and fert-butyl diazoacetate, an increased reaction rate and improved enantios-electivity (84% ee for the irons isomer compared to 75% ee without NMI) was observed when NMI was used as an axial ligand for (5)-MPAC, an aldiminato Co(II) complex (eq 34). Although other alkyl- and benzylic-substituted imidazoles gave similar selectivity, NMI gave the highest yield. ... 

The same cyclopropanation between styrene and terf-butyl diazoacetate was also investigated using fraws-selective Co(III)-salen and c/s-selective Ru(It)-salen catalysts. Although both gave excellent enantioselectivity, 1 gave better conversion compared to 2(eq 35). 

The common by-products obtained in the transition-metal catalyzed reactions are the formal carbene dimers, diethyl maleate and diethyl fumarate. In accordance with the assumption that they owe their formation to the competition of olefin and excess diazo ester for an intermediate metal carbene, they can be widely suppressed by keeping the actual concentration of diazo compound as low as possible. Usually, one attempts to verify this condition by slow addition of the diazo compound to an excess (usually five- to tenfold) of olefin. This means that the addition rate will be crucial for the yields of cyclopropanes and carbene dimers. For example, Rh6(CO)16-catalyzed cyclopropanation of -butyl vinyl ether with ethyl diazoacetate proceeds in 69% yield when EDA is added during 30 minutes, but it increases to 87 % for a 6 h period. For styrene, the same differences were observed 65). 

Ligand 55c is also efficient in the cyclopropanation of other alkenes. 1,1 -Disub-stituted alkenes afford cyclopropanes in high enantioselectivity with ethyl diazoacetate as carbenoid source, Eq. 25 (34). Internal dissymetric trans alkenes are also excellent substrates. trans-P-Methyl styrene afforded a 95 5 diastereomeric mixture with cyclopropane 56a predominating in 96% ee, when the butylated hydroxy toluene (BHT) diazoester was used, Eq. 26 (35). 

Experimental results [1361] and theoretical treatment [28] indicate that the cyclo-propanation of alkenes by electrophilic carbene complexes is a concerted process. Z-Olefins normally lead to the formation of the corresponding c7. -cyclopropanes, and -olefins yield fran -cyclopropanes. The relative configuration of the carbene-bound substituent and the substituents of the alkene in the final cyclopropane seems to be mainly determined by the steric bulk of these groups. In cyclopropanations of terminal alkenes with ethyl diazoacetate low diastereoselectivities are often observed [1024,1351]. These can be improved by increasing the steric demand of the substituents at the carbene or at the alkene [1033,1362]. High diastereoselectivities can, e.g., often be achieved with terf-butyl, neopentyl or 2,6-di(rerr-butyl)phenyl diazoacetate [1362] as carbene complex precursors (Figure 4.19). 

Highly efficient catalytic asymmetric cyclopropanation can be effected with copper catalysts complexed with ligands of type 2.3 These bis(oxazolines) are prepared by reaction of dimethylmalonyl dichloride with an a-amino alcohol. As in the case of ligands of type 1, particularly high stereoselectivity obtains when R is /-butyl. Cyclopropanation of styrene with ethyl diazoacetate catalyzed by copper complexed with... 

Dirhodium(ll) tetrakis[methyl 2-pyrrolidone-5(R)-oarboxylate], Rh2(5R-MEPV)4, and its enantiomer, Rh2(5S-MEPY)4, which is prepared by the same procedure, are highly enantioselective catalysts for intramolecular cyclopropanation of allylic diazoacetates (65->94% ee) and homoallylic diazoacetates (71-90% ee),7 8 intermolecular carbon-hydrogen insertion reactions of 2-alkoxyethyl diazoacetates (57-91% ee)9 and N-alkyl-N-(tert-butyl)diazoacetamides (58-73% ee),10 Intermolecular cyclopropenation ot alkynes with ethyl diazoacetate (54-69% ee) or menthyl diazoacetates (77-98% diastereomeric excess, de),11 and intermolecular cyclopropanation of alkenes with menthyl diazoacetate (60-91% de for the cis isomer, 47-65% de for the trans isomer).12 Their use in <1.0 mol % in dichloromethane solvent effects complete reaction of the diazo ester and provides the carbenoid product in 43-88% yield. The same general method used for the preparation of Rh2(5R-MEPY)4 was employed for the synthesis of their isopropyl7 and neopentyl9 ester analogs. 

Enantioselective Cyclopropanation of Alkenes. Cationic Cu complexes of methylenebis(oxazolines) such as (1), which have been developed by Evans and co-workers, are remarkably efficient catalysts for the cyclopropanation of terminal alkenes with diazoacetates. The reaction of styrene with ethyl diazoacetate in the presence of 1 mol % of catalyst, generated in situ from Copper(I) Trifluoromethanesulfonate and ligand (1), affords the (rans -2-phenylcyclopropanecarboxylate in good yield and with 99% ee (eq 3). As with other catalysts, only moderate transicis selectivity is observed. Higher transicis selectivities can be obtained with more bulky esters such as 2,6-di-r-butyl-4-methylphenyl or dicyclohexylmethyl diazoacetate (94 6 and 95 5, respectively). The efficiency of this catalyst system is illustrated by the cyclopropanation of isobutene, which has been carried out on a 0.3 molar scale using 0.1 mol % of catalyst derived firom the (R,R)-enantiomer of ligand (1) (eq 4). The remarkable selectivity of >99% ee exceeds that of Aratani s catalyst which is used in this reaction on an industrial scale. 

The catalytic activity of low-valent ruthenium species in carbene-transfer reactions is only beginning to emerge. The ruthenium(O) cluster RujCCO), catalyzed formation of ethyl 2-butyloxycyclopropane-l-carboxylate from ethyl diazoacetate and butyl vinyl ether (65 °C, excess of alkene, 0.5 mol% of catalyst yield 65%), but seems not to have been further utilized. The ruthenacarborane clusters 6 and 7 as well as the polymeric diacetatotetracarbonyl-diruthenium (8) have catalytic activity comparable to that of rhodium(II) carboxylates for the cyclopropanation of simple alkenes, cycloalkenes, 1,3-dienes, enol ethers, and styrene with diazoacetic esters. Catalyst 8 also proved exceptionally suitable for the cyclopropanation using a-diazo-a-trialkylsilylacetic esters. ... 

Allyl methyl ether (ethyl diazoacetate, rhodium catalysis) and allyl terf-butyl ether (dimethyl diazomalonate, copper catalysis) yield cyclopropanes exclusively. With y-substituted allyl methyl ethers, C-0 insertion is generally strongly favored over cyclopropanation, even with tetraacetatodirhodium as catalyst.In view of these findings, the cyclopropanation of ( )- ,4-dibenzyloxybut-2-ene in moderate yield, only, to give (la,2a,3j5)-31 is notable. 

Diazo ester/rhodium(II) carboxylate combinations other than EDA/Rh2(OAc)4 have been tested It turned out that the solubility of the rhodium(II) carboxylate greatly influenced the efficiency of cyclopropanation. For the reaction of monoolefins with ethyl diazoacetate, markedly higher yields than with Rh(II) acetate were obtained with the better soluble rhodium(II) butanoate and rhodium(II) pivalate, the latter one being soluble even in pentane. However, only poor yields resulted from the use of rhodium(Il) trifluoroacetate, even though this compound is readily soluble, Rh CCFjCOO), in contrast to the other rhodium(II) carboxylates, is able to form 1 1 complexes with olefins particularly with electron-rich ones thus, competition of olefin and diazo compound for the only available coordination site at the metal atom could be responsible for the reduced catalytic action of Rh2(CF3COO)4 (as will be seen in Section 4.1, this complex is an excellent catalyst for cyclopropanation of aromatic substrates). The diazoester substituent also has some influence on the yields. Increasing yields were obtained in the series methyl ester, ethyl ester, n-butyl... 

Although many different bisoxazolines and other semicorrin-type ligands have been prepared [53,54], the bis(ferf-butyl)oxazoline 11 is still the most versatile ligand for cyclopropanation. However, there are certain applications which give better results with other ligands. For the cyclopropanation of trisubstituted and 1,2-disubstituted (Z)-olefins, Lowenthal and Masamune found the bisoxa-zoline 12 to be superior to the bis(ferf-butyloxazoline) 11 [56]. This is illustrated by the reaction of 2,5-dimethyl-2,4-hexadiene leading to chrysanthemates (Scheme 9). Again, the best diastereo- and enantioselectivities were obtained with bulky diazoacetates. Both the trans/cis ratios and ees were similar to those reported for Aratani s catalyst (Scheme 5). 

Similarly, significant improvements with methallyl and ( -butyl)allyl diazoacetates can be achieved by switching catalysts from Rh2(MEPY)4 to Rh2(MP-PIM)4. Allyl diazo esters other than diazo acetates have not yet been examined in detail. Encouragingly, Doyle s group [41] have found that high levels of enantio-control in intramolecular cyclopropanation can be realized with allyl diazopropionates and the Rh2(4S-MEOX)4 catalyst, Eq. (25). 

The ruthenium(ll) complex 20175c,d and the cobalt complexes 21179a and 22197b are also able to produce remarkable enantioselectivities in intermolecular cyclopropanation reactions. For the cyclopropanation of styrene with alkyl diazoacetates, the following ee-values have been reported 20 /t/V-buty , 94% (trans), 85% (cis), /-menthyl, 95% (as), 76% (trans), /-menthyl, 86% (cis), 95% (trans) 21 ethyl, 75% (cis), 20% (trans) 22 tert-butyl, 73% (trans). It is interesting to note that a catalyst analogous to 20, but with copper(II) triflate instead of ruthenium, displayed only low enantiocontrol.220b... 

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