Carbene cyclopropanation with

These carbene (or alkylidene) complexes are used for various transformations. Known reactions of these complexes are (a) alkene metathesis, (b) alkene cyclopropanation, (c) carbonyl alkenation, (d) insertion into C-H, N-H and O-H bonds, (e) ylide formation and (f) dimerization. The reactivity of these complexes can be tuned by varying the metal, oxidation state or ligands. Nowadays carbene complexes with cumulated double bonds have also been synthesized and investigated [45-49] as well as carbene cluster compounds, which will not be discussed here [50]. 

Addition reactions with alkenes to form cyclopropanes are the most studied reactions of carbenes, both from the point of view of understanding mechanisms and for synthetic applications. A concerted mechanism is possible for singlet carbenes. As a result, the stereochemistry present in the alkene is retained in the cyclopropane. With triplet carbenes, an intermediate 1,3-diradical is involved. Closure to cyclopropane requires spin inversion. The rate of spin inversion is slow relative to rotation about single bonds, so mixtures of the two possible stereoisomers are obtained from either alkene stereoisomer. 

Palladium(II) acetate was found to be a good catalyst for such cyclopropanations with ethyl diazoacetate (Scheme 19) by analogy with the same transformation using diazomethane (see Sect. 2.1). The best yields were obtained with monosubstituted alkenes such as acrylic esters and methyl vinyl ketone (64-85 %), whereas they dropped to 10-30% for a,p-unsaturated carbonyl compounds bearing alkyl groups in a- or p-position such as ethyl crotonate, isophorone and methyl methacrylate 141). In none of these reactions was formation of carbene dimers observed. 7>ms-benzalaceto-phenone was cyclopropanated stereospecifically in about 50% yield PdCl2 and palladium(II) acetylacetonate were less efficient catalysts 34 >. Diazoketones may be used instead of diazoesters, as the cyclopropanation of acrylonitrile by diazoacenaph-thenone/Pd(OAc)2 (75 % yield) shows142). 

When the cis/trans stereoselectivity of cyclopropanation with ethyl diazoacetate in the presence of CuCl P(0-z-Pr)3, Rh6(CO)16 or PdCl2 2 PhCN was plotted against that obtained with Rh2(OAc)4, a linear correlation was observed in every case, with slopes of 1.74,1.04 and 0.59, respectively (based on 22 olefins, T = 298 K) S9). These relationships as well as the results of regioselectivity studies carried out with 1,3-dienes point to the similar nature of the intermediates involved in Cu-, Rh-and Pd-catalyzed cyclopropanation. Furthermore, obvious parallels in reactivity in the transformations of Scheme 45 for a variety of catalysts based on Cu, Rh, Fe, Ru, Re and Mo suggest the conclusion that electrophilic metal carbenes are not only involved in cyclopropanation but also in ylide-forming reactions66. ... 

In 1986, Pfaltz et al. introduced a new type of pseudo C2-symmetrical copper-semicorrin complex (68) as the catalyst (Scheme 60).227 228 The complexes (68) are reduced in situ by the diazo compound or by pretreatment with phenylhydrazine to give monomeric Cu1 species (69), which catalyze cyclopropanation. Of the semicorrin complexes, complex (68a) (R = CMe2OH) showed the best enantioselectivity in the cyclopropanation of terminal and 1,2-disubstituted olefins.227,228,17 It is noteworthy that complex (68a) catalyzes cyclopropanation, using diazomethane as a carbene source, with good enantioselectivity (70-75% ee).17... 

It has been widely accepted that the carbene-transfer reaction using a diazo compound and a transition metal complex proceeds via the corresponding metal carbenoid species. Nishiyama et al. characterized spectroscopically the structure of the carbenoid intermediate that underwent the desired cyclopropanation with high enantio- and diastereoselectivity, derived from (91).254,255 They also isolated a stable dicarbonylcarbene complex and demonstrated by X-ray analysis that the carbene moiety of the complex was almost parallel in the Cl—Ru—Cl plane and perpendicular to the pybox plane (vide infra).255 These results suggest that the rate-determining step of metal-catalyzed cyclopropanation is not carbenoid formation, but the carbene-transfer reaction.254... 

Irradiation of DAAN in benzene gives 3AN. This carbene reacts with oxygen very rapidly to give an intermediate believed to be the carbonyl oxide. The triplet carbene reacts with labeled a-methylstyrene to give the cyclopropane with total loss of stereochemistry (Table 6). Direct irradiation in neat isopropyl alcohol gives the ether in low yield (relative to the yields from XA, DMFL, FL, and BFL). The other products are those expected to result from hydrogen-atom abstraction. Triplet-sensitized irradiation of DAAN in the alcohol does not give a detectable amount of the ether. 

Although the reaction of a titanium carbene complex with an olefin generally affords the olefin metathesis product, in certain cases the intermediate titanacyclobutane may decompose through reductive elimination to give a cyclopropane. A small amount of the cyclopropane derivative is produced by the reaction of titanocene-methylidene with isobutene or ethene in the presence of triethylamine or THF [8], In order to accelerate the reductive elimination from titanacyclobutane to form the cyclopropane, oxidation with iodine is required (Scheme 14.21) [36], The stereochemistry obtained indicates that this reaction proceeds through the formation of y-iodoalkyltitanium species 46 and 47. A subsequent intramolecular SN2 reaction produces the cyclopropane. 

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. 

Bicyclic cyclopropanes.1 Reaction of the Fisher carbene 1 with the 1,6-enyne 2 results in the bicyclic cyclopropane 3 (a bicyclo[3.1.0]hexane) in 69% yield. The 1,7-enyne homolog of 2 reacts with 1 in the same way to form a bicyclo[4.1.0]-... 

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... 

Two of the most characteristic reactions of carbene complexes are olefin metathesis and olefin cyclopropanation. Olefin metathesis is a reaction in which the C-C double bond of an alkene is cleaved, and one of the resulting alkylidene fragments combines with the metal-bound carbene to form a new alkene. The second alkylidene fragment forms a new carbene eomplex with the metal. Olefin cyclopropanation is a reaction in which a a bond is formed between the metal-bound alkylidene and each of the two carbon atoms of the alkene, to yield a cyclopropane. 

Several reaction sequences have been reported in which Fischer-type carbene complexes are converted in situ into non-heteroatom-substituted carbene complexes, which then cyclopropanate simple olefins [306,307] (Figure 2.22). This can, for instance, be achieved by treating the carbene complexes with dihydropyridines, forming (isolable) pyridinium ylides. These decompose thermally to yield pyridine and highly electrophilic, non-heteroatom-substituted carbene complexes (Figure 2.22) [46]. 

Table 2.16. Cyclopropanations with stoichiometric amounts of heteroatom-substituted carbene complexes.

Experimental Procedure 2.2.2. Cyclopropanation with a Chromium Carbene Complex Diethyl n-a/i5-3-Methoxy-3-phenylcyclopropane-l,2-dicart>oxylate [325]. 

Low-valent, 18-electron (Fischer-type) carbene complexes with strong n-acceptors usually are electrophilic at the carbene carbon atom (C ). These complexes can undergo reactions similar to those of free carbenes, e.g. cyclopropanation or C-H insertion reactions. The carbene-like character of these complexes becomes more pronounced when electron-accepting groups are directly bound to C (Chapter 4), whereas electron-donating groups strongly attenuate the reactivity (Chapter 2). 

Experimental Procedure 3.2.1. Cyclopropanation with an Iron Carbene Conqjlex 1,1-Diphenylcyclopropane [468]... 

Fig. 3.33. Stoichiometric, intramolecular cyclopropanations with iron(IV) carbene complexes [477,624],...

Table 3.1. Cyclopropanation with stoichiometric amounts of chromium, molybdenum and tungsten carbene complexes.

Cyclopropanations with carbene complexes, such as those listed in Tables 3.1 and 3.2, are usually stereospecific (i.e. Z-alkenes yield cA-cyclopropanes) [29]. This suggests, in agreement with theoretical investigations [28], that this reaction is a concerted process. One remarkable feature of these cyclopropanation reactions is the high cii -diastereoselectivity frequently observed [619,629]. 

Fig. 3.34. Cyclopropanation with titanium carbene complexes generated in situ [33].

Experimental Procedure 3.2.2. Cyclopropanation with a Titanium Carbene Complex (E)-l-Hexyl-2-(2-phenylethenyl)cyclopropane [33]... 

Fig. 3.35. Mechanism for the catalyzed cyclopropanation with ylides as carbene complex precursors.

In cyclopropanations with electrophilic carbene complexes, yields of cyclopropanes tend to improve with increasing electron density of the alkene. As illustrated by the examples in Table 3.5, cyclopropanations of enol ethers with aryldiazomethanes often proceed in high yields. Simple alkyl-substituted olefins are, however, more difficult to cyclopropanate with diazoalkanes. A few examples of the cyclopropanation of enamines with diazoalkanes have been reported [650]. 

Most electrophilic carbene complexes with hydrogen at Cjj will undergo fast 1,2-proton migration with subsequent elimination of the metal and formation of an alkene. For this reason, transition metal-catalyzed cyclopropanations with non-acceptor-substituted diazoalkanes have mainly been limited to the use of diazomethane, aryl-, and diaryldiazomethanes (Tables 3.4 and 3.5). 

The most common byproducts encountered in cyclopropanations with diazoalkanes as carbene precursors are azines and carbene dimers , i.e. symmetric olefins resulting from the reaction of the intermediate carbene complex with the diazoalkane. The formation of these byproducts can be supressed by keeping the concentration of diazoalkane in the reaction mixture as low as possible. For this purpose, the automated, slow addition of the diazoalkane to a mixture of catalyst and substrate (e.g. by means of a pump or a syringe motor) has proven to be a very valuable technique. 

Table 3.6. Transition-metal-catalyzed cyclopropanations with carbene precursors other than diazoalkanes.

Calculations performed for cyclopropanation with Fischer-type carbene complexes [28] indicate that the electrophilic attack of the carbene complex at the alkene and the final ring closure are concerted. Extrapolation from this result to the C-H insertion reaction (in which a a-bond instead of a 7i-bond is cleaved) suggests that C-H bond cleavage and the formation of the new C-C and C-H bonds might also be concerted (Figure 3.38). 

The reaction of acceptor-substituted carbene complexes with alcohols to yield ethers is a valuable alternative to other etherification reactions [1152,1209-1211], This reaction generally proceeds faster than cyclopropanation [1176], As in other transformations with electrophilic carbene complexes, the reaction conditions are mild and well-suited to base- or acid-sensitive substrates [1212], As an illustrative example, Experimental Procedure 4.2.4 describes the carbene-mediated etherification of a serine derivative. This type of substrate is very difficult to etherify under basic conditions (e.g. NaH, alkyl halide [1213]), because of an intramolecular hydrogen-bond between the nitrogen-bound hydrogen and the hydroxy group. Further, upon treatment with bases serine ethers readily eliminate alkoxide to give acrylates. With the aid of electrophilic carbene complexes, however, acceptable yields of 0-alkylated serine derivatives can be obtained. 

A wide range of olefins can be cyclopropanated with acceptor-substituted carbene complexes. These include acyclic or cyclic alkenes, styrenes [1015], 1,3-dienes [1002], vinyl iodides [1347,1348], arenes [1349], fullerenes [1350], heteroare-nes, enol ethers or esters [1351-1354], ketene acetals, and A-alkoxycarbonyl-[1355,1356] or A-silyl enamines [1357], Electron-rich alkenes are usually cyclopropanated faster than electron-poor alkenes [626,1015],... 

Alkynes can be converted into cyclopropenes by inter- [587,1022,1052,1060-1062] or intramolecular [1070] cyclopropanation with electrophilic carbene complexes, Because of the high reactivity of cyclopropenes, however, in some of these reactions unexpected products can result from rearrangement or other transformations of the cyclopropenes initially formed (cf. Section 4,1,3),... 

Since the first experiments with chiral copper complexes reported by Nozaki [650] and Aratani [1027] many different catalysts have been examined, both for intermolecular and intramolecular cyclopropanations (for a review, see [1369]). Syntheses of natural products [955,1370] and drugs [1371] using asymmetric cyclopropanation with chiral electrophilic carbene complexes have been reported. A selection of useful catalysts is given in Figure 4.20 (see also Experimental Procedure 4.1.1). 

Intramolecular cyclopropanation with acceptor-substituted carbene complexes is a powerful method for the synthesis of bicyclo[n.l.0]alkanes [1359,1375-... 

The preparation of cyclopropanes by intermolecular cyclopropanation with acceptor-substituted carbene complexes is one of the most important C-C-bond-forming reactions. Several reviews [995,1072-1074,1076,1077,1081] and monographs have appeared. In recent decades chemists have focused on stereoselective intermolecular cyclopropanations, and several useful catalyst have been developed for this purpose. Complexes which catalyze intermolecular cyclopropanations with high enantiose-lectivity include copper complexes [1025,1026,1028,1029,1031,1373,1398-1400], cobalt complexes [1033-1035], ruthenium porphyrin complexes [1041,1042,1230], C2-symmetric ruthenium complexes [948,1044,1045], and different types of rhodium complexes [955,998,999,1002-1004,1010,1062,1353,1401-1405], Particularly efficient catalysts for intermolecular cyclopropanation are C2-symmetric cop-per(I) complexes, as those shown in Figure 4.20. These complexes enable the formation of enantiomerically enriched cyclopropanes with enantiomeric excesses greater than 99%. Illustrative examples of intermolecular cyclopropanations are listed in Table 4.24. 

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