Frans-Cyclopropane

Chan et al. [38] prepared optically active atropoisomeric 2,2 -bipyridine by nickel(0)-catalyzed homo-couphng of 2-bromopyridylphenol derivatives (structure 28 in Scheme 16). Tested in the model test reaction, the copper catalyst led to frans-cyclopropanes as major products with up to 86% ee. 

As Table 13 shows, the opposite enantiomers of both cis- and frans-cyclopropanes are accessible if 207b or 207c are used instead of 207a 88). An analogous result was found for cyclopropanation of 1,1 -diphenylethylene with ethyl diazoacetate (Table 14). 

Experimental results [1361] and theoretical treatment [28] indicate that the cyclo-propanation of alkenes by electrophilic carbene complexes is a concerted process. Z-Olefins normally lead to the formation of the corresponding c7. -cyclopropanes, and -olefins yield fran -cyclopropanes. The relative configuration of the carbene-bound substituent and the substituents of the alkene in the final cyclopropane seems to be mainly determined by the steric bulk of these groups. In cyclopropanations of terminal alkenes with ethyl diazoacetate low diastereoselectivities are often observed [1024,1351]. These can be improved by increasing the steric demand of the substituents at the carbene or at the alkene [1033,1362]. High diastereoselectivities can, e.g., often be achieved with terf-butyl, neopentyl or 2,6-di(rerr-butyl)phenyl diazoacetate [1362] as carbene complex precursors (Figure 4.19). 

Salt crystals were prepared between cyclopropane mesoacid 76 and ten different optically pure amines. Solid-state irradiation of these crystals caused photoisomerization affording the optically active frans-cyclopropane 77 in moderate enantiomeric excesses (Scheme 17) [84]. The best results were obtained using (S)-proline, which gave 79% ee at low conversion. When salt crystals of the diphen-ylbenzoyl acid 78 with several optically pure amines were irradiated, then the compounds 79 or 80 of near quantitative enantiomeric excesses were obtained, with a slight diminution in ee as the conversion was increased [85]. 

Dimethyl substituted homoallylic alcohols undergo smooth cy-clization to frans-cyclopropanes upon treatment with TfxO and a... 

Stereospecificity (or lack of it) in the addition of a carbene to an alkene can be a good test of whether the carbene reacts as a singlet or triplet lack of stereospecificity in a carbene addition almost certainly indicates that a triplet carbene is involved, but the fact that an addition is stereospecific doesn t mean that the carbene must be a singlet. In some casest bond rotation may be quite slow, and spin-flipping rapid, leading to stereospecific addition. Notice that in this example the less stable cis (2) alkene was used the reaction will give the less encumbered frans-cyclopropane if it can. 

SCHEME 13.89 frans-Cyclopropane spiro componnds 433 from the reaction of Meldrum s acid 112 with aromatic aldehydes 432 and a-thiocyanato ketones 431. 

Addition of dicarboethoxycarbene to cycloocta-1,3-diene yields a mixture of cis-and fran -cyclopropane adducts, probably by addition of the singlet carbene on the partially isomerized diene (due to the irradiation). Diastereoselective cyclopropan-ation of a ,/3-unsaturated acetals has been described using a camphor-derived chiral auxiliary. Intramolecular cyclopropenation of a diazo ester, tethered through a naphthalene, to an alkyne was catalysed by rhodium acetate and reported as a efficient method unfortunately, the use of chiral rhodium catalysts gave a less efficient reaction and did not provide high asymmetric induction. ... 

While generation of a Mn(V)oxo salen intermediate 8 as the active chiral oxidant is widely accepted, how the subsequent C-C bond forming events occur is the subject of some debate. The observation of frans-epoxide products from cw-olefins, as well as the observation that conjugated olefins work best support a stepwise intermediate in which a conjugated radical or cation intermediate is generated. The radical intermediate 9 is most favored based on better Hammett correlations obtained with o vs. o . " In addition, it was recently demonstrated that ring opening of vinyl cyclopropane substrates produced products that can only be derived from radical intermediates and not cationic intermediates. ... 

Data are extant in the literature for four tra s-cyclopropylene sets. Of these, two are disubstituted (sets 39-9 and 39-11). Positions trans-2 and tranS 3 are completely equivalent in cyclopropanes bearing the reaction site at position 1. These sets have been correlated with eq. (30). The other two sets have been correlated with eq. (2). Three of the four sets studied gave significant correlations. The fourth set had only four points. The results obtained clearly show a significant resonance effect. They clearly demonstrate that the frans-cyclopropylene system does involve a resonance interaction between the substituent and the cyclopropane group. The rra s-cyclopropylene system again... 

The same type of porphyrin-Ru complex was immobilized by coordina-tive adsorption on aminopropylsilicas (Fig. 26) as either amorphous or crystalline supports [79]. Mesoporous crystalline MCM-48 was the best support, as shown by the improved results obtained in the epoxidation of styrene with 2,6-dichloropyridine N-oxide (TON > 13 000 and 74% ee). The versatility of this catalyst was demonstrated in the intramolecular cyclopropanation of frans-cinnamyl diazoacetate. TON was ten times higher than that obtained in solution and 85% ee was observed. The solid was recycled and reused, although partial loss of selectivity occurred. 

Aryldiazomethane can also be used for iron porphyrin-catalyzed alkene cyclopropanation [55]. For example, the treatment of p-tolyldiazomethane with styrene in the presence of [Fe(TTP)] afforded the corresponding arylcyclopropapane in 79% yield with a high transicis ratio of 14 1 (eq. 1 in Scheme 11). Interestingly, when bulkier mesityldiazomethane was used as carbene source, ds-selectivity was observed (cisitrans = 2.0 1). Additionally, mesityldiazomethane was found to react with frans-p-styrene, the latter was found not to react with EDA or trimethyl-silyldiazomethane under the similar reaction conditions, to give l-mesityl-2-methyl-3-phenylcyclopropane in 35% yield. Trimethylsilyldiazomethane is also an active carbene source for [Fe(TTP)]-catalyzed cyclopropanation of styrene, affording l-phenyl-2-trimethylsilylcyclopropane in 89% yield with transicis ratio of 10 1 (eq. 2 in Scheme 11). 

A striking example for the preferred formation of the thermodynamically less stable cyclopropane is furnished by the homoallylie halides 37, which are cyclopro-panated with high c/s-selectivity in the presence of copper chelate 3891 The cyclopropane can easily be converted into cw-permethric acid. In contrast, the direct synthesis of permethric esters by cyclopropanation of l,l-dichloro-4-methyl-l,3-pentadiene using the same catalyst produces the frans-permethric ester (trans-39) preferentially in a similar fashion, mainly trans-chrysanthemic ester (trans-40) was obtained when starting with 2,5-dimethyl-2,4-hexadiene 92). 

Easily available copper(II) tartrate has also been used for an enantioselective cyclopropanation. From 3-methoxystyrene and 4-bromo-l-diazo-2-butanone, the cyclopropanes cis/trans-204 were obtained the mainly formed frans-isomer displayed an enantiomeric excess of 46% i99>. This reaction constituted the opening step of asymmetric total syntheses of equilenin and estrone. 

Cyclopropanation of l,3-dienes. a,0-Unsaturated carbenes can undergo [4 + 2]cycloaddition with 1,3-dienes (12, 134), but they can also transfer the carbene ligand to an isolated double bond to form cyclopropanes. Exclusive cyclopropanation of a 1,3-diene is observed in the reaction of the a,(3-unsaturated chromium carbene 1 with the diene 2, which results in a frans-divinylcyclopropane (3) and a seven-membered silyl enol ether (4), which can be formed from 3 by a Cope rearrangement. However, the tungsten carbene corresponding to 1 undergoes exclusive [4 + 2]cycIoaddition with the diene 2. 

Scheme 7 Photoisomerization of salts of frans,frans-2,3-diphenyl-1-benzoyl-cyclopropane-p-carboxylic acid...

Conant and Lutz is a two-step process involving initial di-bromination of the diketone followed by ring closure with zinc and sodium iodide. The overall yield of traws-l,2-dibenzoyl-cyclopropane is approximately 15%. The submitters have extended the described method to the preparation of other frans-1,2-diaroylcyclopropanes, namely acidic hydrogens on both a-carbons. A probable mechanism for this transformation is as follows ... 

We have examined the above-described series of trans- and c/s-2-fluoro-2-phenylcyclopropylamine analogues (60a-d, 61a-d) as inhibitors of recombinant human liver MAO A and B [134]. The presence of fluorine attached to a cyclopropane ring, especially for frans-isomer 8a, was found to result in an increase in inhibitory activity toward both MAO A and B (Table 4). In addition, p-substitution of electron-withdrawing groups, such as Cl and F, in the aromatic ring of the frans-isomers (60b-d) increased the inhibition of both enzymes. On the other hand, the introduction of fluorine at 2-position of c/s-isomer 8b resulted in loss of inhibitory activity for both MAO A and B, and no further p-aromatic substitution for c/s-isomer greatly affected on the inhibitory activity with either enzymes. In addition, both MAO A and B were selectively inhibited by the (1S,2S)-enantiomer of 60a, while no inhibition was observed with the (1f ,2f )-enantiomer [134]. As already described in the former section, several questions on the mechanistic pathway for MAO inhibition by cyclopropylamines still remain. However,... 

H and 13C chemical shifts have been reported for many 1,2-disubstituted oxiranes432 436-439. Similar to cyclopropanes, oxirane ring carbon chemical shifts are smaller in the cis- than in the frans-isomers, and an increment rule using pairwise substituent interaction cross-terms has also been developed439. 

Table 2 Comparison of the Reactivity of l,l-Dimethyl-fran.s-bis-2,3-(2 2 -dimethylcyclopropyHdene)-l-sila-cyclopropane (2) and 1,1-Dimethyl-l-silacyclobutane Towards Ring Opening Reagents ...

More recently, an analogous combination of lithium, magnesium, zinc and copper reagents led to the stereocontrolled synthesis of cyclopropanes, illustrated for the synthesis of fran -divinylcyclopropane (equation 33)84. 

Purify the crude product by chromatography using pentane ether (4 1). Pure frans-1-(hydroxymethyl)-2-methyl-2-(4-methyl-3-pentenyl)cyclopropane is obtained as a colourless oil (940 mg, 80%). Characterize the product by 1H and 13C NMR. 

It seems obvious that the same mechanism could also apply to the cyclopropanation of the fran,s-crotonic ester (Figure 9.3, bottom). A Michael addition of the S ylide would then convert it directly into the ester enolate B. This species would cyclize exclusively to the fratw-disubstituted cyclopropane exactly as when it is produced from the cis-crotonic ester in two steps via the conformer A. 

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