Cyclopropyl substrates substitution

We have previously seen (p. 437) that this is the reason nucleophilic substitutions are not feasible at a cyclopropyl substrate. The reaction is often used to convert... 

Cyclic substrates. Cyclopropyl substrates are extremely resistant to nucleophilic attack.285 For example, cyclopropyl tosylate solvolyzes about 106 times more slowly than cyclobutyl tosylate in acetic acid at (WC.286 When such attack does take place, the result is generally not normal substitution (though exceptions are known,287 especially when an a stabilizing group such as aryl or alkoxy is present) but ring opening 288... 

The aminoquinolinamide auxiliary was also shown to mediate the construction of 1,1,2-trisubstimted arylcyclopropanes [43]. Substrate 78, bearing a cis-substituted cyclopropyl moiety, reacted smoothly with a variety of (hetero)aryl iodides in a Pd-catalyzed, Ag-mediated transformation (Scheme 21). Notably, substituents such as an aldehyde, a hydroxyl, or an unprotected indole were tolerated under the reaction conditions. Additionally, the reactivity of trans-cyclopropyl substrate 79 was investigated (Scheme 21). The challenge here was... 

Further evidence to exclude the triplet radical pathway includes the use of cyclopropyl substrates, which serve as a radical clock. In all cases, the reaction proceeds with no indication of ring fragmentation. The nature of the transition state of the C—H insertion step has been analyzed, via a Hammett study of the intermo-lecular C—H amination with p-substituted benzenes. A negative q value of 0.73 is obtained for the intermolecular reaction with trichloroethylsulfamate [71]. Such data indicate that there is a small, but significant, preference for electron-rich substrates, thus the resonance does contribute to the stabilization of a partial positive charge at the insertion carbon in the transition state. A kinetic isotope value of 1.9 is observed for competitive intramolecular C—H amination with a deuterated substrate (Eq. (5.21)). 

Trifluoromethanesulfonate (triflate) ion is an exceptionally good leaving grov. It can be used for nucleophilic substitution reactions on unreactive substrates. Acetolysis of cyclopropyl triflate, for example, occurs 10 times faster than acetolysis of cyclopropyl tosylate. Table 5.11 gives a conqiarison of the triftate group with some other common leaving groups. 

In the 1970s, Fuller examined the effects of jS,/f-difluoro substitution on the biological properties of a series of arylethylamines. Among the compounds prepared were p,p-difluoroamphetamine (19), )S,)S-difluoro phenethylamine (20), and A/-cyclopropyl-4-chloro-jS,jS-difluorophenylethylamine (21). A drop in amine pKg of about 2.5 pH units resulted from the fluorine substitution. Included in biological studies were effects on activities toward MAO. In vitro )S,)S-difluoroamphetamine was a less active inhibitor of MAO than amphetamine and )S,)S-difluorophenylethylamine was a poorer substrate for deamination than phenylethylamine. A/-Cyclopropyl-4-chlorophenylethylamine is an irreversible inhibitor of MAO. There was little difference in vivo in MAO inhibition in various tissues of the rat [72]. 

A variety of geminally substituted cyclopropyl ethers are synthesized employing Fischer carbene complexes [(CO)5M=CR (OR2) M = Cr, Mo, W R1 = alkyl, alkenyl and aryl] as alkoxycarbene sources. Electron-deficient alkenes and conjugated dienes are suitable substrates for the reaction (equation 108)237-245. Electron-rich enol ethers and enamines are also... 

Bridgehead bicyclic cyclopropanols or cyclopropyl silyl ethers 103 (R=H) cleaved to ring-expanded mixtures of cyclic (1-hydroxy ketones 105 and (1-diketones 106 in good overall yields catalyzed by 10 mol% of VO(acac)2 in the presence of oxygen (Fig. 32) [191, 192]. With 3-substituted substrates 103 (R=Me), mixtures of bicyclic endoperoxide hemiketals 104B and (1-hydroxy ketones 105 arose. In separate experiments it was shown that 105 is not oxidized to 106 under the reaction conditions, and thus the products most likely form from... 

Suitable a, tw-enynes can be cyclized when allowed to react with catalytic quantities of [RhCl(PPh3)3]. Alken-2-ynes do not react and the yield is greatly diminished in the case of alk-2-enyne substrates. However, substitution of the alkene bond does not appear to inhibit the dicyclization of dienynes or the cyclization of alkynenones. The dienyne s reaction, shown in equation (21), is catalyzed more effectively by rhodium(I) complexes containing tertiary phosphite ligands. Under similar conditions, trienes can also be cyclized. The cyclopropyl ring can serve as an alkene bond precursor in cyclizations (equation 22). ... 

Cyclopropyl-substituted ketones are suitable substrates for generating distonic radical anions from ketyl radical anions. A series of cycloalkanone substrates with unsaturated side-chains, to trap the primary radical formed after cyclopropylcar-binyl ring opening, has been investigated (Scheme 31) [118, 119]. For the first electron-transfer step triethylamine is used as electron donor. The reaction sequence is terminated by proton or hydrogen transfer from the solvent or the a-amino radical formed after deprotonation of the amine radical cation. 

Jullien and coworkers studied the cyclic voltammograms of variously substituted bicyclo[3.1.0]hexen-3-ones (Table 9) and found that the half-life times (ti/2 )are generally very short ( < lO"" s) except when the substrates were phenyl-substituted at C(4). In such cases the radical anions are very stable( 6 s) owing to the greater charge delocalization. A similar trend was found in some non-fused cyclopropyl ketones systems studied by House and coworkers. ... 

Many cyclopropyl chlorides and bromides have been converted to alkoxycyclopropanes by treatment with a strong base, in most cases potassium rerf-butoxide, in an appropriate organic solvent (Table 13). Under such conditions, hydrogen halide elimination takes place, yielding strained cyclopropene intermediates, which are trapped by nucleophilic attack of the alkoxide. Overall, a simple substitution occurs when a bond is formed between the alkoxide group and the carbon atom to which the halide was attached. This is the case when l-chloro-5-methyl-exo-6-phenyl-3-oxabicyclo[3.1.0]hexan-2-one (1) was reacted with potassium /ert-butoxide l-/er/-butoxy-5-methyl-ent/o-6-phenyl-3-oxabicyclo[3.1.0]hexan-2-one (2) was isolated in 94% yield.If a C-O bond is established at the other olefinic carbon atom, a C H bond is concomitantly formed at the carbon atom, to which the halide was attached. The result is a double substitution which is discussed elsewhere (see Section 5.2.1.3 ). When the substrate contains more than one halogen atom, several elimination reactions usually take place. Thus, treatment of 1 -bromo-2-chloro-2-methylcyclopropane (3) with an excess of potassium /er/-butoxide gave l-ter/-butoxy-2-methylenecyclopropane (4) in 30% yield. 

Cyclopropyl esters can be aflforded by substitution from a variety of different substrates. Almost all esters prepared are acetates. Even a hydrogen atom can be directly replaced by an acetate group. Thus, when tetracyclo[3.3.1.0. 0 - ]nonane (triaxane) was treated with lead(IV) acetate, 2-acetoxytetracyclo[3.3.1.0 . 0 ]nonane (1) was obtained in 72% yield together with exo-4-acetoxy-ant(-8-acetoxytricyclo[4.2.1.0 ]nonane (2, 17%). ... 

Three cyclopropyl-substituted vinyl triflates have yielded mixtures of cyclopropylpropa-1,2-diene, 1-cyclopropylpropyne and other products when subjected to solvolysis conditions in aqueous 2,2,2-trifluoroethanol buffered with pyridine. Table 14 shows the product distributions obtained from the three substrates after three days at 80 "C for different concentrations of 2,2,2-trifluoroethanol. 

A similar stereoselectivity has been described for the Lewis acid catalyzed pinacol rearrangement of vinyl-24 and cyclopropyl-substituLed25 hydroxysulfonates 16 (via mesylation) and 17. Of note is a dramatic rate enhancement observed for the [1,2] rearrangement of silyl-substituted substrates 16, an observation consistent with the well-documented ability of silicon substituents to stabilize / -carbocations. 

---