Cyclopropanation Diiodomethane-Diethylzinc

Camphor- 10-sulfonic acid, 62 (S)-2-(l-Hydroxy-1-methylethyl)-pyrrolidine, 146 a-Methylbenzylamine, 185 Quina alkaloids, 264 Cycloaddition reactions 2-Oxazolidones, chiral, 225 Cyclopropanation Diiodomethane-Diethylzinc, 276 Simmons-Smith reagent, 275 Deprotonation Lithium amides, chiral, 159... 

The cyclopropanation of 1-trimethylsilyloxycyclohexene in the present procedure is accomplished by reaction with diiodomethane and diethylzinc in ethyl ether." This modification of the usual Simmons-Smith reaction in which diiodomethane and activated zinc are used has the advantage of being homogeneous and is often more effective for the cyclopropanation of olefins such as enol ethers which polymerize readily. However, in the case of trimethylsilyl enol ethers, the heterogeneous procedures with either zinc-copper couple or zinc-silver couple are also successful. Attempts by the checkers to carry out Part B in benzene or toluene at reflux instead of ethyl ether afforded the trimethylsilyl ether of 2-methylenecyclohexanol, evidently owing to zinc iodide-catalyzed isomerization of the initially formed cyclopropyl ether. The preparation of l-trimethylsilyloxybicyclo[4.1.0]heptane by cyclopropanation with diethylzinc and chloroiodomethane in the presence of oxygen has been reported. "... 

Asymmetric cyclopropanation of olefins can also be achieved by the Simmons-Smith reaction (231). Reaction of ( )-cinnamyl alcohol and the diiodomethane-diethylzinc mixed reagent in the presence of a small amount of a chiral sulfonamide gives the cyclopropylcarbinol in up to 75% ee (Scheme 97) (232a). ( )-Cinnamyl alcohol can be cyclopro-... 

Asymmetric induction in the cyclopropanations of unsaturated substrates with methylene has been extensively investigated. A propensity of the Simmons-Simth and related reagents to make coordination to basic atoms is most frequently exploited. Treatment of a,/J-unsaturated aldehyde acetals derived from the aldehydes and chiral dialkyl tartrates or 2,4-pentanediol, with diiodomethane/diethylzinc in hexane, produces cyclopro-panecarboxaldehyde acetals with high diastereoselectivity (equation 69)109 110. Uniformly good diastereoselectivity has also been realized in the cyclopropanations of chiral acetals... 

In contrast to the reaction with diazomethane, the cyclopropanation of cyclopropylidene(di-spiro[2.0.2.1]heptylidene)methane (15) with diiodomethane/diethylzinc took place predominantly at the reactive central double bond. The product of double cyclopropanation was also obtained in good yield. 

The carbenoid generated from diiodomethane/diethylzinc is often found to be more reactive than the conventional Simmons-Smith reagent. Thus, in the case of 1-alkenylboronic acid esters, where diazomethane failed to cyclopropanate trisubstituted derivatives (Section 1.2.1.1.1.) diiodomethane/diethylzinc gave good yields of the required products 16. ... 

The last step in the synthesis of sesquiterpenoids africanol (44) and isoafricanol (45) employed the Simmons-Smith cyclopropanation with diethylzinc/diiodomethane. The addition occurred from the less hindered convex face bearing a hydroxy group to give the sesquiterpenes in good yield. ... 

With a view to the preparation of asymmetric tra i-a-(2-phenylcyclopropyl)glycines from L-serine, the latter was first converted to the chiral derivative, terf-butyl (ii,4/ )-2,2-dimethyl-4-(2-phenylvinyl)oxazolidine-3-carboxylate and this was then subjected to cyclopropanation with diethylzinc/diiodomethane in diethyl ether at reflux temperature. The resulting cyclopropane derivatives were obtained as a 25 75 mixture of diastereomers in 50% yield that could not be resolved, hence the sequence was not continued to the target compounds. 

As in the case of the / -series, the a-anomer with a free hydroxy group at C2 also showed good diastereoselectivity (13 1) in the Simmons-Smith cyclopropanation with diethylzinc/ diiodomethane in fert-butyl methyl ether at 0 C. Several substituted allylic ethers, e g. 70, were subjected to this reaction with success. While the auxiliary can be easily removed by a ring-contraction method to give cyclopropylmethanol derivatives, this methodology provides an efficient method to prepare both enantiomers. 

Acetals of a,j8-unsaturated aldehydes with 3-0-alkylated derivatives of 1,2-0-isopropylidene- -D-fructopyranose and l,2-0-isopropylidene-/l-D-psicopyranose, which are readily available from D-fructose, were cyclopropanated with diethylzinc/diiodomethane with good stereoselectivity. The acetals were hydrolyzed and the aldehydes reduced to give cyclopropyl-substituted alcohols e.g. cyclopropanation of 103 to give 104 and hydrolysis and reduction to R,2R)-2-phenylcyclopropylmethanol (105). Extensive studies were carried out, with both exo- and endo-acQta structures, to determine the effects of the structure of the acetals on the enantioselec-tivity. Among various isomeric compounds, the asymmetric cyclopropanation reaction provided good enantioselectivity (consistent attack on the same face) with high chemical yields especially with en sfo-acetals of l,2-0-isopropylidene-3-0-(4-phenylbenzyl)-iS-D-fructopyranose. 

The silyl enol ether prepared from (-)-menthone is transformed into a mixture of two diastereo-meric optically active cyclopropane derivatives by the diiodomethane/diethylzinc reagent28. 

Acetals from a,/3-unsaturated aldehydes and optically active 1-aryl-1,3-propanediols are cyclopropanated by the diiodomethane/diethylzinc reagent with moderate selectivity69. After oxidative cleavage of the auxiliary, cyclopropanecarboxylic acids are obtained with 21 -78% ee. Thus, the C2-symmetric auxiliaries seem to be superior for this kind of [2 + 1] cycloaddition. 

Treatment with triisobutylaluminum converts the saturated acetal 6 into the optically active enol ether 770. Cyclopropanation of 7 with the Simmons-Smith reagent then provides the cyclopropanol derivative 8 with a d.r. of 95 5. Even better side discrimination is observed when the more active diiodomethane/diethylzinc system is applied under optimized conditions70 the cyclopropanol derivative is obtained diastereomerically almost pure. 

Cyclopropanation of eA o-A-[(lf ,25,3/ ,4S)-2-hydroxy-1,7,7-trimethylbicyclo[2.2.1]hept-3-yl]-3-phenyl-2-propenamide with the diiodomethane/diethylzinc reagent proceeds with moderate diastereofacial selectivity only. However, the corresponding O-triisopropylsilyl-protected compound reacts with excellent but opposite diastereoselectivity the added diethyl tartrate has no influence on the stereoselectivity but only on the rate of the reaction. Similar effects are observed for the related cWo-derivatives of the amino alcohol auxiliary, which induces the opposite absolute configurations at the cyclopropane ring101. 

Preparative Methods for the synthesis of the parent and the 2-monoalkyl-substituted compounds, reduction of ethyl 3-chloropropionate with sodium-potassium alloy in the presence of chlorotrimethylsilane in ether. A recent modification using ultrasound irradiation is much more convenient and more widely applicable. Other substituted derivatives are prepared by cyclopropanation of alkyl silyl ketene acetals with the Furukawa reagent (diiodomethane/diethylzinc). ... 

The Simmons-Smith reaction has been used as the basis of a method for the indirect a methylation of a ketone. The ketone (illustrated for cyclohexanone) is first converted to an enol ether, an enamine (16-12) or silyl enol ether (12-22) and cyclopropanation via the Simmons-Smith reaction is followed by hydrolysis to give a methylated ketone. A related procedure using diethylzinc and diiodomethane allows ketones to be chain extended by one carbon. In another variation, phenols can be ortho methylated in one laboratory step, by treatment with Et2Zn and... 

During preparation of cyclopropane derivatives, it is important to add the diiodomethane slowly to a solution of diethylzinc in the alkene. Addition of diethylzinc to an alkene-diiodomethane mixture may be explosively violent. 

A homogeneous solution of the bis(iodomethyl)zinc DME complex in dichloromethane can be prepared by adding diethylzinc to 1 equivalent of 1,2-dimethoxyethane in dichloromethane followed by 2 equivalents of diiodomethane . The presence of DME makes the preparation of the reagent safer by ensuring that the mixture is constantly homogeneous. This reagent has been useful in enantioselective cyclopropanation reactions vide infra). 

The first reaction is deprotection of the alcohol. Benzoate 16 is hydrolyzed with NaOH. What follows is a modified Simmons-Smith cyclopropanation with diiodomethane (41) and diethylzinc i40)... 

Cyclopropanation of olefins (Simmons-Smith reaction) smoothly proceeds using diethylzinc in combination with diiodomethane. The reaction is much faster with allylic alcohols or its ether derivatives than that with simple olefins. 

The Simmons-Smith reaction is an efficient and powerful method for synthesizing cyclopropanes from alkenes [43]. Allylic alcohols are reactive and widely used as substrates, whereas a,j8-unsaturated carbonyl compounds are unreactive. In 1988, Ambler and Davies [44] reported the electrophilic addition of methylene to a,/3-unsaturated acyl ligands attached to the chiral-at-metal iron complex. The reaction of the racemic iron complex 60 with diethylzinc and diiodomethane in the presence of ZnCl2 afforded the c/s-cyclopropane derivatives 61a and 61b in 93 % yield in 24 1 ratio (Sch. 24). 

With regard to the preparation of the Zn/Cu couple, several methods have been developed Dibromomethane may be used instead of diiodomethane when a specifically prepared Zn/Cu couple is applied . The use of Zn/Ag couple often gives better results . Ultrasound irradiation of the reaction mixture has been shown to facilitate the reaction . The cyclopropanation of alkenes with diiodomethane and diethylzinc can be carried out in hydrocarbon solvents and is particularly suitable with easily polymerizable olefins such as vinyl ethers . It has been reported that molecular oxygen remarkably promotes the reaction of diiodomethane with diethylzinc and substantially increases the yield of the adducts . A convenient modification which avoids the handling of pyrophoric diethylzinc has been reported . In reaction of olefins which are sensitive to the unavoidably produced zinc iodide (the Lewis acid), the addition of one equivalent of dimethoxyethane (DME) to the solvent has been recommended . Zinc iodide is then precipitated as the 1 1 DME complex as it is formed. Zinc salts, which often complicate the workup of the reaction mixture, can also be removed as precipitates by the addition of pyridine prior to the workup . ... 

A number of modifications of the original Simmons-Smith cyclopropanation procedure have been reported. Furukawa s reagent, (iodomethyl)zinc derived from diethylzinc and diiodomethane, ° or its modification using chloroiodomethane instead of diiodomethane, ° allows more flexibility in the choice of solvent. The reagent is homogeneous and the cyclopropanation of olefins can be carried out in non-complexing solvents, such as dichloromethane or 1,2-dichloroethane, which greatly increase the reactivity of the zinc carbenoids. 

---