Simmons-Smith reaction examples

The Simmons-Smith reaction is well suited for the synthesis of spirocyclic compounds. It has for example been applied for the construction of the fifth cyclopropane ring in the last step of a synthesis of the rotane 8 ... 

Two examples of substituted cyclopropane formation are shown below. This reactive zinc should dramatically increase the utility of the Simmons-Smith reaction. 

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. 

Preparation of spiro[2.3]hexanes is possible by the addition of methylene or a methylene equivalent to an exocyclic C —C double bond. Generally, the Simmons Smith reaction is used (see Section l.A.1.2.1.), but formation of carbenes from nitroso compounds can also be used.73-75,333 The 1,1-dihalo derivative can be prepared by phase-transfer-catalyzed reactions.48 For example, reaction of a mixture of cis- and trans-1,2-dimethyl-3-methylenecyclobutane with dibromo-carbene gave a mixture of cis- and lrans-1,1-dibromo-4,5-dimcthylspiro[2.3]hexanc (2).48... 

It is clear that free CH2 is not involved in the Simmons-Smith reaction, but there is substantial evidence to indicate that carbenes are formed as intermediates in certain other reactions that convert alkenes to cyclopropanes. The most studied examples of these reactions involve dichlorocarbene and dibromocarbene. 

The intermediates in the Simmons-Smith reaction show much more controlled reactivity than, for example, diazoalkanes. Competing side reactions are greatly reduced, and insertion reactions are generally not seen. For example, the free hydroxy group is tolerated as indicated by the above discussion of directing effects. The reaction is also compatible with many other functional groups. 

Examples of the Simmons-Smith reaction are presented in Table 5, with emphasis on more recent work. For additional examples, the reader is referred to extensive tabulations in earlier, comprehensive reviews. 1 e>57... 

The mechanism for the formation of this carbenoid and for its reaction with alkenes need not concern us here. Just remember that it reacts as though it is methylene. The Simmons-Smith reaction is an excellent way to prepare cyclopropane derivatives from alkenes, as shown in the following examples. Note the stereochemistry in the second equation. 

The reaction is known as the Simmons-Smith reaction, after the two chemists at the DuPont chemical factory who discovered it in 1958. Even after several decades, it is the most important way of making cyclopropane compounds, though nowadays a variant that uses more easily handled starting materials is often used. Diethyl zinc replaces the Zn/Cu couple of the traditional Simmons-Smitji reaction. In this example, a double cyclopropanation on a C2 symmetric diene derived from tartaric acid gives very good stereoselectivity for reasons we will soon discuss. 

The presence of ether functions in olefins frequently facilitates the Simmons-Smith reaction 457). For example, l-(o-methoxyphenyl)-propene gives a higher yield of a cyclopropane than the meta and para isomers, and coordination of (I) with ether oxygen was suggested 42, 457). 

Improved reaction. Conia et al. have reported two modifications of the Simmons-Smith reaction which ave improved yields. One is the use of a zinc-silver couple in place of the zinc copper couple. This couple is prepared by adding granular zinc to a stirred hot solution of silver acetate in acetic acid. The mixture is stirred for 30 sec. and the zinc-silver couple formed is isolated by decantation and washed with acetic acid and ether. It is then stabilized by addition of a small amount of silver wool. The second improvement is that the reaction mixture is not subjected to acid hydrolysis. Instead an amine, for example pyridine, is added. This forms the insoluble complexes Znlj-C HsN and ICH jZnl -(C, 115N)j the cyclopropane products are then isolated from the filtrate. 

There are many ways of generating what appear to be carbenes. But in some cases at least, it seems clear that no free carbene is actually an intermediate instead, a carbenoid (carbene-like) reagent transfers a carbene unit directly to a double bond. For example, in the extremely useful Simmons-Smith reaction... 

Table 7. Examples of improved Simmons-Smith reactions using zinc-silver couple and pyridine work-up... 

Although the addition of carbene to a double bond to make a cyclopropane is well known, it is not particularly useful synthetically because of the tendency for extensive side reactions and lack of selectivity for thermally or photochemically generated carbenes. Similar processes involving carbenoids (species that are not free carbenes) are much more useful from the preparative standpoint [91,92]. For example, metal catalyzed decomposition of diazoalkanes usually results in addition to double bonds without the interference of side reactions such as C-H insertions. Consider the possible retrosynthetic approaches to a 1,2-disubstituted cyclopropane shown in Figure 6.8. Disconnection a entails the addition of a methylene across a double bond, a conversion that is often stereospecific e.g., the Simmons-Smith reaction [93]). Disconnections b and c are more problematic, since the issue of cis/trans product isomers (simple diastereoselection) arises. 

The rhodium chemistry just presented actually involves C=Rh species rather than a free carbene. In this section, we will look at a general class of compounds called carbenoids. A carbenoid is a reactive intermediate that reacts similarly to a carbene but does not actually involve formation of a carbene. The most commonly used carbenoid is generated by reaction of diiodomethane and a Zn/Cu couple this reaction, when it adds to alkenes, is called the Simmons-Smith reaction.316 A simple example is the conversion of cyclohexene to bicyclo[4.1.0]heptane (norcarane, 336). Initial reaction of diiodomethane with zinc gave an iodozinc compound (399-see sec. 9.8.B for a brief discussion of organozinc compounds), which added to the alkene to give 400. Loss of zinc iodide (Znl2) gave the cyclopropane derivative (343 in this case).3ll A one-step... 

Cyclopropanes are efficiently obtained from alkenes by Simmons-Smith reaction applying CH2l2/Zn-Cu couple or CH2l2/Et2Zn as reagents. A variety of compounds bearing a chiral moiety have been studied, as for example a,P-unsaturated acetals and oxazolidines, enolethers, allylic alcohols, alkenylboronic esters as well as a,p-unsaturated carbonyl compounds. 

Cyclopropanation of alkenes, in both inter- and intramolecular modes, constitutes an attractive route to polycycloalkanes. These cyclopropanations of alkenes are carried out through car bene or carbenoid intermediates . For the direct cyclopropanation of alkenes, the methylene iodide zinc-copper couple (Simmons-Smith reaction)reagent is commonly used. Several modifications of this procedure, including acceleration with ultrasound, are known °°. A somewhat less frequently used procedure for cyclopropanation is through methylene addition from diazomethane, which can be carried out either thermally or photochemically or in the presence of metal salts, e.g. Pd(OAc)2 or Rh2(OAc)4. In Table some examples of the preparation of cyclopropane bearing... 

This Section will cover these new developments as well as the older, more traditional, ones. As was the case with magnesium and lithium in the previous Sections, it should be mentioned that also not all the examples of zinc-activation presented here have been applied in Zn-Barbier reactions. Several of them come from other organic synthetic procedures such as the Reformatsky or the Simmons-Smith reaction. 

In the absence of a directing group, the cyclopropanation of cyclic olefins is generally under steric control. The stereochemical preference can be predicted from the ground state conformation of the molecule and often high levels of stereocontrol are observed. For example, Paquette and coworkers used a Simmons-Smith reaction in their total synthesis of the secondary marine metabolite (+)-acetoxycrenulide (30), whereby high P-face selectivity was observed. ... 

Cycloaddition Reaction. Cyclopropanes can be prepared from a variety of olefins and dihalo compounds using a copper catalyst and moderate temperatures (70 °C). The reaction is a convenient extension of the conventional Simmons-Smith reaction.Lithium 2,2,6,6-tetramethylpiperidide gives superior yields to methyl lithium in the synthesis of alkoxycyclopropanes and cyclopropenes. In the latter examples no base-induced isomerization of the double bond to the exo-position is observed (Scheme 42)T >9... 

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. 

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