Nucleophilic cyclopropanation

An alternative synthetic approach, first developed by Bingel225 allowed the efficient nucleophilic cyclopropanation of fullerenes via their reaction with bromomalonate derivatives in the presence of base. This approach, the most reliable method for the synthesis of functionalized methanofullerenes, combined the advantages of mild... 

The two most commonly used derivatization methods for exohedral functionalization are the nucleophilic cyclopropanation with malonates (Bingel, 1993) and the formation of fulleropyrrolidines (Maggini et al., 1993). Both of these protocols have been used extensively to produce water-soluble fullerenes for biomedical applications. Other stable water-soluble fullerene adducts have also been reported (Hirsch and Brettreich, 2005). Sections 3.2.2-3.2.5 will give a short overview on the state-of-the-art of water-soluble fullerene derivatives and outline some general trends for designing such molecular structures. 

Cycloadditions to [6,6]-double bonds of Cjq are among the most important reactions in fullerene chemistry. For a second attack to a [6,6]-bond of a C q monoadduct nine different sites are available (Figure 10.1). For bisadducts with different but symmetrical addends nine regioisomeric bisadducts are, in principle, possible. If only one type of symmetrical addends is allowed, eight different regioisomers can be considered, since attack to both e - and e"-positions leads to the same product. Two successive cycloadditions mostly represent the fundamental case and form the basis for the regioselectivity of multiple additions. In a comprehensive study of bisadduct formations with two identical as well as with two different addends, nucleophilic cyclopropanations, Bamford-Stevens reactions with dimethoxybenzo-phenone-tosylhydrazone and nitrene additions have been analyzed in detail (Scheme 10.1) [3, 9, 10]. 

Scheme 10.10 Double nucleophilic cyclopropanation of all-e tetrakis-adduct 15 with second generation (G2) bromomalonates yields dendrimeric [4 2] hexakisadduct 54. (i) CHBr(COOG2)2, DBU, toluene-CH2Cl2, 3 d, room temp.

The first example of a tether remote functionalization was the synthesis of the tris-64 (Scheme 10.14) [75,78]. For this purpose the computer-aided chemically designed addend 63 was allowed to undergo a successive nucleophilic cyclopropanation/ [4-1-2] cycloaddition sequence yielding the tris-adduct 64 in 60% yield with complete regio selectivity. Subsequent cyclopropanation of the remaining octahedral sites with a large excess of diethyl bromomalonate and DBU afforded the hexakisadduct 65... 

Mono-functionalization of Cyg affords, preferrably, C(l)-C(2) adducts (type a) (Figure 13.3). In some cases, for example, upon nucleophilic cyclopropanations they even represent the exclusively formed monoadducts [1-3,17]. Typical examples of addition reactions that afford monoadducts are epoxidations [18,19], osmylation [9], transition metal complex formations [20, 21], hydrogenation [13, 22], many cycloadditions [1, 2] and additions of nucleophiles [23]. For the formation and the chemical transformation of azahomo[70]fullerenes see also Chapter 12 (Schemes 12.4 and 12.5). 

The synthetic utility of a-phosphorus- and a-thio-stabilized carbanions is the subject of numerous reviews.21 Notable are additions of phosphonium ylides (237),183 sulfonium ylides (238),l84 ° oxosulfo-nium ylides (239)184 " and sulfoximine ylides (240)184,1 to electron-deficient alkenes which afford nucleophilic cyclopropanation products. In contrast, with a-(phenylthio)-stabilized carbanions, which are not acyl anion equivalents, either nucleophilic cyclopropanation or retention of the hetero substituent occurs, depending on the acceptor and reaction conditions used. For example, carbanion (241) adds to 1,1-... 

The stereoselectivity of cyclopropane ester formation could also be effected by using reagents supported on linear or cross-linked polymers. The most important effects were noted with chloromethylated polymers cross-linked with divinylbenzene. The role of hyperconjugation in determining the stereochemistry of nucleophilic cyclopropanation of electrophilic alkenes has been studied and predicted In terms of equation 57 the... 

Cyclopropyl halides are versatile starting materials for the preparation of a wide range of cyelopropanes with an additional substituent, which is attached to the ring by a C-C bond. The majority of the reactions has been carried out with monohalocyclopropanes, but there is also a significant body of work dealing with conversions of 1,1-dihalocyclopropanes to 1-substituted 1-halocyclopropanes. Almost without exception the transformations involve ionic intermediates which in most cases include a nucleophilic cyclopropane species. 

Bisaddition reactions represent the simplest and most instructive model cases for regioselectivity investigations and form the basis for more complex situations. In a comprehensive study of bisadduct formations with two identical as well as with two different addends, nucleophilic cyclopropanations, Bamford-Stevens-reactions with dimethoxybenzophenone-tosylhydrazone and nitrene additions were used (Fig. 19, Scheme 9) [102]. 

Nucleophilic cyclopropanation of a 3 1 isomeric mixture of 62 - and D3-C78 with ca. 2 equivalents of diethyl 2-bromomalonate showed a high reactivity of these fullerene isomers since at least eight tris-adducts were formed as main products besides two Ci-symmetrical bis-adducts [15]. Most of the derivatives could be isolated in pure state by HPLC. 

Widi Nucleophiles.—Cyclopropanes and Cyclopropenes. The , Z-2-cyanoallylic anion (188) is produced by ring cleavage of the cyclopropyl anion (187). Subsequent topomerization to (189) does not proceed through the intermediacy of (187), but occurs by way of bond rotation (Scheme 23) and this experimental observation is supported by MO calculations. As a result of this observation it has been suggested that non-involvement of the cyclopropyl anion could well be a feature common to all such topomerization processes. 

Pyridine hydrochloride Nucleophilic cyclopropane ring opening... 

With Nucleophiles.—Cyclopropane Derivatives. Simple cyclopropanes are normally resistant to nucleophilic attack, though cyclopropane itself gives a complex mixture of products in a photolytic reaction with tetrafluorohydra-zine. The isotope exchange rates in methanolic sodium methoxide of 1-deuterio- and 1-tritio-cyclopropanes with I-CF3, 1-CN, and l-S02Ph... 

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