Simmons-Smith methylenation

Miscellaneous Additions.-The conversion of testosterone into 4-methyl-testosterone via a modified Simmons-Smith methylenation of the A3,5-dien-3-yl trimethylsilyl ether104 has now been varied by employing the A2,4-dien-3-yl trimethylsilyl derivative (86), produced by trapping the kinetically controlled A2,4-dienolate. The end product, via (87), was 2a-methyltestosterone (88).105... 

For reasons not yet understood, the Simmons-Smith methylenating agent [CH2Br2, Zn(Cu)] brings about cyclopropanation, instead, to provide cyclopropylaluminum derivatives in good yield (equation 60). ... 

Two reports of Simmons-Smith methylene addition (iodomethylzinc iodide) on to A -olefinic steroids contain several points of disagreement. The earlier paper states that cholest-5-en-3a-ol (epicholesterol) reacts readily to give the 5a,6a-methano-derivative (165). A stereospecific reaction in this sense would accord with earlier indications that a suitably placed hydroxy-group directs the approach of the reagent towards the same side of the olefinic bond. The 3/ -alcohol (cholesterol), as well as the methyl ethers and acetates of both alcohols, apparently failed to react. The later paper, by different authors, states that both unsaturated alcohols react, each giving a similar mixture of the 5a,6a- and 5) ,6/ -methano-adducts. with no evidence for control by the oxygen function. 

The equatorial hydroxyl function serves to direct the Simmons-Smith methylenation in the desired -stereochemical sense, H. E. Simmons and R. D. Smith, J. Amer. Chem. Soc.,80,5323 (1958) 81,4256 (1959). 

This reaction is called the Smmons-Smith reaction and is one of the few methods avail able for the synthesis of cyclopropanes Mechanistically the Simmons-Smith reaction seems to proceed by a single step cycloaddition of a methylene (CH2) unit from lodomethylzmc iodide to the alkene... 

The Simmons-Smith reaction has been used to great advantage in the conversion of 19-nor steroids to the naturally occurring 10)5-methyl steroids as well as the unnatural lOa-methyl steroids. Thus methylenation of androst-5(10)-ene-3a,17 -diol (9) proceeds in an autoclave at elevated temperatures with stereospecific a-face addition to give the 5a,10a-methylene compound (10) in 85% yield. 

The Simmons-Smith reaction (Section 14.12) Methylene transfer from iodo-methylzinc iodide converts alkenes to cyclopropanes. The reaction is a stereospecific syn addition of a CH2 group to the double bond. 

Without question, the most powerful method for cyclopropane formation by methylene transfer is the well-known Simmons-Smith reaction [6]. In 1958, Simmons and Smith reported that the action of a zinc-copper couple on diiodomethane generates a species that can transform a wide variety of alkenes into the corresponding cyclopropanes (Scheme 3.3) [7]. 

The landmark report by Winstein et al. (Scheme 3.6) on the powerful accelerating and directing effect of a proximal hydroxyl group would become one of the most critical in the development of the Simmons-Smith cyclopropanation reactions [11]. A clear syw directing effect is observed, implying coordination of the reagent to the alcohol before methylene transfer. This characteristic served as the basis of subsequent developments for stereocontrolled reactions with many classes of chiral allylic cycloalkenols and indirectly for chiral auxiliaries and catalysts. A full understanding of this phenomenon would not only be informative, but it would have practical applications in the rationalization of asymmetric catalytic reactions. 

These optimization studies are an important step in the study of Simmons-Smith cyciopropanations since they allowed for the development of a selective, catalytic method for introduction of a simple methylene unit. However, they also provide insights into the basic mechanism of this process. Together with earlier studies regarding carbenoid structure, the true nature of the reactive carbenoid, lCH2Znl, was confirmed. On the basis of these results, a revised transition structure was proposed. Although there is no direct evidence for such a transition... 

Cyclopropanation with Halomethylzinc Reagents. A very effective means for conversion of alkenes to cyclopropanes by transfer of a CH2 unit involves reaction with methylene iodide and a zinc-copper couple, referred to as the Simmons-Smith reagent.169 The reactive species is iodomethylzinc iodide.170 The transfer of methylene occurs stereospecifically. Free CH2 is not an intermediate. Entries 1 to 3 in Scheme 10.9 are typical examples. 

Taking 1,2-disubstituted cyclopropane as an example, retro synthesis analysis shows that there are three possible ways to disconnect the three-membered ring—a, b, and c as shown in Figure 5-11. Route a involves the addition of methylene across a double bond, and this is often a stereospecific conversion or Simmons-Smith reaction.92 One can clearly see that route b or c will encounter the issue of cis/trans-product formation. 

Finally, it should be mentioned that from a purely synthetic point of view the reactions involving "transfer" of methylene groups -like the Simmons-Smith reaction [27] or Seyferth s reagents [28]- may be considered formally as cheletropic additions of a [2 + 1] type. 

A simpler example of this kind of stereochemical control is the cyclopropanation of cyclopenten-2-ol (5) by the Simmons-Smith reagent in which the cij-biciclo[3.1.0]hexan-2-ol (7) is the diastereomer exclusively formed. As in the case of the hydrogen in strychnine, the methylene enters stereoselectively by intramolecular transference from an intermediate complex ( . 

The addition of different types of carbenes onto bicyclopropylidene (1) is a common method for the preparation of [3]triangulane derivatives as well as branched trianguianes and normally proceeds without complications (for a review see [77]). Thus, the cyclopropanation under Gaspar-Roth [60] or modified Simmons-Smith [111] conditions gave dispiro[2.0.2.1]heptane ([3]triangulane, 97) in 80 [105] and 15% yield [5], respectively (Scheme 23). The palladium(II) acetate-catalyzed cycloprop anation of 1 with diazomethane, however, gave a number of products resulting from insertion of one or more than one methylene units into an initially formed palladacyclobutane 115 [112,113] (Scheme 23). 

The Simmons-Smith reaction " and its variants are widely used for the stereospecific synthesis of cyclopropane compounds. The methodology involves the use of copper-treated zinc metal (the zinc-copper couple) with diiodomethane to add methylene to a carbon-carbon double bond. Alternative use of diazomethane in catalytic reactions does not offer the same synthetic advantages and is usually avoided because of safety considerations. As significant as is the Simmons-Smith reaction for cyclopropane formation, its employment for organic synthesis was markedly advanced by the discovery that allylic and homoallylic hydroxyl groups accelerate and exert stereochemical control over cyclopropanation of alkenes (e.g, Eq. 21), and this acceleration has been explained by a transition state model... 

Catalytic processes using diazo chemistry and stoichiometric methods with Fischer carbenes are complimentary for the introduction of a substituted carbene into a molecule. For methylene addition, however, there is no viable alternative to the modified Simmons-Smith reaction. Ring-closing metathesis, and its ROMP counterpart, have matured so fast that even now they rank among the most useful synthetic methodologies in organic chemistry. 

Methylene can be transferred directly from the reagent mixture, CHjIj + Zn-Cu alloy, to the alkene without being generated as an intermediate (Simmons-Smith reaction). 

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