Carbenes, coupling cyclopropane

Organic halides play a fundamental role in organic chemistry. These compounds are important precursors for carbocations, carbanions, radicals, and carbenes and thus serve as an important platform for organic functional group transformations. Many classical reactions involve the reactions of organic halides. Examples of these reactions include the nucleophilic substitution reactions, elimination reactions, Grignard-type reactions, various transition-metal catalyzed coupling reactions, carbene-related cyclopropanations reactions, and radical cyclization reactions. All these reactions can be carried out in aqueous media. 

More useful for synthetic purposes, however, is the combination of the zinc-copper couple with methylene iodide to generate carbene-zinc iodide complex, which undergoes addition to double bonds exclusively to form cyclopropanes (7). The base-catalyzed generation of halocarbenes from haloforms (2) also provides a general route to 1,1-dihalocyclopropanes via carbene addition, as does the nonbasic generation of dihalocarbenes from phenyl(trihalomethyl)mercury compounds. Details of these reactions are given below. 

In contrast to silylcarbenes, the analogous stannylcarbenes 2p are not stable, which explains why they have attracted little interest. Their instability is probably due to the long carbon-tin bond, which does not allow sufficient steric protection of the carbene center. Their reactivity seems to be quite similar to that of stable (phosphino)(silyl)carbenes Cyclopropanation reactions have been reported with methyl acrylate as well as coupling reactions with tert-butyl isonitrile.73... 

Addition of electrophilic carbenes to enamines usually does not proceed with good efficiency, very likely because of the disturbance by the Lewis basic nitrogen 15). If however the less basic enamide derivatives are used as olefins, high conversions to donor-acceptor cyclopropanes are possible. Thus cyclic carbamate 245, which itself originates from an oxycyclopropane, gives the bicyclic compound 246 almost quantitatively. Its cleavage with aqueous base provides lactone 247 that could be coupled with tryptophyl bromide to afford 248, a direct precursor of the alkaloid eburnamoni-ne 105>. 

In the previous chapters we discussed alkene-based homogeneous catalytic reactions such as hydrocarboxylation, hydroformylation, and polymerization. In this chapter we discuss a number of other homogeneous catalytic reactions where an alkene is one of the basic raw materials. The reactions that fall under this category are many. Some of the industrially important ones are isomerization, hydrogenation, di-, tri-, and oligomerization, metathesis, hydrocyana-tion, hydrosilylation, C-C coupling, and cyclopropanation. We have encountered most of the basic mechanistic steps involved in these reactions before. Insertions, carbenes, metallocycles, and p -allyl complexes are especially important for some of the reactions that we are about to discuss. 

Whereas Fischer-type chromium carbenes react with alkenes, dienes, and alkynes to afford cyclopropanes, vinylcyclopropanes, and aromatic compounds, the iron Fischer-type carbene (47, e.g. R = Ph) reacts with alkenes and dienes to afford primarily coupled products (58) and (59) (Scheme 21). The mechanism proposed involves a [2 -F 2] cycloaddition of the alkene the carbene to form a metallacyclobutane see Metallacycle) (60). This intermediate undergoes jS-hydride elimination followed by reductive elimination to generate the coupled products. Carbenes (47) also react with alkynes under CO pressure (ca. 3.7 atm) to afford 6-ethoxy-o -pyrone complexes (61). The unstable metallacyclobutene (62) is produced by the reaction of (47) with 2-butyne in the absence of CO. Complex (62) decomposes to the pyrone complex (61). It has been suggested that the intermediate (62) is transformed into the vinylketene complex... 

Many other 1,3-dipolar cycloadditions are known, amongst which is the addition of diazomethane (CH2N2). Expulsion of nitrogen from the adduct leads to the formation of a cyclopropane ring. Another way of achieving the same result involves the addition of a carbene such as the Simmons Smith reagent. This is generated from methylene iodide (CHjIj) and a zinc/copper couple. 

Coupling of a Fischer carbene complex with an alkene can generate a vinylcarbene intermediate 12 via an insertion-rearrangement reaction, which can then further react with a double bond. For intramolecular reactions of tethered enynes 10, the products formed are bicyclic cyclopropanes 14 intermolecular reactions lead to cycloalkenylcyclopropanes. 

The Simmons-Smith reaction seems to be of little value for transfer of an alkoxycarbonyl-carbene to alkenes. Thus, reaction of the reagent formed from ethyl diiodoacetate and zinc-copper couple with 2,5-dimethylhexa-2,4-diene (reflux, 14 days) furnished ethyl 2,2-dimethyl-3-(2-methylprop-l-enyl)cyclopropane-l-carboxylatein only 12% yield, and ethyl dichloroacetate was an even less suitable starting material. ... 

A side reaction encountered in most metal-catalyzed processes of diazo compounds is the coupling of two diazo compounds to give an alkene. In cyclopropanations with ethyl diazoacetate, e.g., mixtures of diethyl fumarate and maleate are always formed to some extent. Obviously, the diazo compound and the olefin compete in the reaction with the metal-carbene intermediate. In order to suppress this undesired side reaction, the concentration of the diazo compound has to be kept low by slow addition, preferably by means of a syringe pump. 

Cyclopropanation from alkenes and carbenes with alkyl gem dihalides and Zn-Cu couple (Simmons-Smith) or Et2Zn (Furukawa) EtgAI (Yamamoto) or Sm (Molander) with high diastereoselectivity (see 1st edition). 

All disconnections are the same on cyclopropane, requiring a carbene equivalent which will add to an unactivated double bond. Diazomethane will do this, but one of the best carbene sources is CH2I2 with a zinc-copper couple (the Simmons-Smith reaction ). This works particularly well on allylic alcohols (31), no doubt because of hydrogen bonding between the OH group and the reagent. The reaction is then totally stereoselective. 

This carbene insertion reaction has been used in a variety of syntheses, and is especially attractive when coupled with other synthetic techniques. Taber et al. used carbene cyclopropanation in several synthetic endeavors. In one example, the diazoketone was treated with bis-A-tert-butylsalicylaldiminato copper(II) [Cu(TBS)2, 388] to induce the carbene cyclopropanation reaction. The diazoketone was prepared by treating 386 with mesyl azide to give 387 in 82% yield, which was followed by treatment with the Cu(TBS)2 reagent to produce 389 in 80% yield in Taber and co-workers synthesis of (-i-)-isoneonepatelactone.308... 

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... 

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