Cyclopropanation using diazoketones

Rhodium(II) carboxylate dimers and their carboxamide counterparts have been demonstrated to be exceptionally useful catalysts for carbene transfer processes involving diazocarbonyl substrates [1]. Doyle s seminal work identified Rh2(OAc)4 as the catalyst of choice for a variety of cyclopropanation, C-H insertion, and ylide rearrangement transformations using diazoketones or diazoesters [2]. Important contributions by Taber [3], Padwa [4], and Davies [5] further established the superior catalytic activity of dirho-dium catalysts and the excellent selectivity of rhodium-[Pg.417]

Metal catalysed decomposition of diazocarbonyl compounds in the presence of alkenes provides a facile and powerful means of constructing electrophilic cyclopropanes. The cyclopropanation process can proceed intermolecularly or intramolecularly. Early work on the topic of intramolecular cyclopropanation (mainly using diazoketones as precursors) has been surveyed31. With the discovery of powerful group VIII metal catalysts, in particular the rhodium(II) derivatives, metal catalysed cyclopropanation of diazocarbonyls is currently the most fertile area in cyclopropyl chemistry. In this section, we will review the efficiency and versatility of the various catalysts employed in the cyclopropanation of diazocarbonyls. Cyclopropanations have been organized according to the types of diazocarbonyl precursors. Emphasis is placed on recent examples. 

Intermolecular cyclopropanation of diazoketones is an effective method in organic synthesis. Wenkert and coworkers have applied this methodology to the synthesis of a substantial number of cyclopropane adducts 2868, 2969 and 307° which are synthetic intermediates in the preparation of natural products (equations 41—43). Copper catalysts were chosen for these transformations. Another interesting application of intermolecular cyclopropanation is to be found in Daniewski s total synthesis of an aromatic steroid. Palladium(II) acetate catalysed decomposition of 4-bromo-l-diazo-2-butanone in the presence of m-methoxystyrene was used to give the cyclopropyl ketone 31 which was a key intermediate in the total synthesis (equation 44)71. 

Intramolecular cyclopropanation of diazoketones to furnish [3.1.0] and [4.1.0] bicyclic systems are the most common and effective reactions in this category. Two recent examples are shown in equations 48 and 49. The bicyclic ketone 34 has been used in the synthesis of polycyclic cyclobutane derivatives77, whereas ketone 35 is the key intermediate in the total synthesis of ( )-cyclolaurene78. When the olefinic double bond is attached to, or is part of, a ring system, the cyclopropanation process also works well. Copper oxide catalysed decomposition of diazoketone 36 produces the strained tricyclic ketone 37 in 86% yield (equation 50)79. In another case, in which the cyclopropanation of diazoketone 38 gave stereospecifically the cyclopropyl ketone 39, copper sulphate catalysis was used. The cyclopropyl ketone 39 is the key intermediate in the total synthesis of ( )-albene 40 (equation 51). ... 

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). 

The dominant role of the traditional copper catalysts, generally used under heterogeneous conditions, has not been challenged as yet. Only a few reports shed light on the efficiency of alternative catalysts. Copper(II) triflate allows high-yield intramolecular cyclopropanation of y,8-unsaturated diazoketone 182160) it is superior to CuS04 (53 % yield 192 ) or Rh2(OAc)4160). The solvent is crucial for an efficient conversion If the reaction is carried out in ether, the solvent competes with the double bond for the electrophilic metal carbene to give 184, presumably via an oxonium ylide intermediate. 

Products of a so-called vinylogous Wolff rearrangement (see Sect. 9) rather than products of intramolecular cyclopropanation are generally obtained from P,y-unsaturated diazoketones I93), the formation of tricyclo[2,1.0.02 5]pentan-3-ones from 2-diazo-l-(cyclopropene-3-yl)-l-ethanones being a notable exception (see Table 10 and reference 12)). The use of Cu(OTf), does not change this situation for diazoketone 185 in the presence of an alcoholl93). With Cu(OTf)2 in nitromethane, on the other hand, A3-hydrinden-2-one 186 is formed 160). As 186 also results from the BF3 Et20-catalyzed reaction in similar yield, proton catalysis in the Cu(OTf)2-catalyzed reaction cannot be excluded, but electrophilic attack of the metal carbene on the double bond (Scheme 26) is also possible. That Rh2(OAc)4 is less efficient for the production of 186, would support the latter explanation, as the rhodium carbenes rank as less electrophilic than copper carbenes. 

Furans and some of its derivatives have been cyclopropanated with the ketocarbenoids derived from ethyl diazoacetate and copper catalysts. The 2-oxabicyclo[3.1.0]hex-3-enes thus formed are easily ring-opened to 1,4-diacylbutadienes thermally, thermo-catalytically or by proton catalysis 14,136). The method has been put to good use by Rh2(OAc)4-catalyzed cyclopropanation of furan with diazoketones 275 to bicyclic products 276. Even at room temperature, they undergo electrocyclic ring-opening and cis, trans-dienes 277a are obtained with fair selectivity 257,258). These compounds served as starting materials in the total syntheses 257 259) of some HETE s (mono-... 

The diverse chemistry of carbenes is beyond the scope of this account, but a few typical reactions are shown here to illustrate the usefulness of the photochemical generation of these reactive species. A carbene can insert into a C—H bond, and this finds application in the reaction of an a-diazoamide to produce a P-lactam (5.29). Carbenes derived from o-diazoketones can rearrange to ketenes, and thus a route is opened up to ring-contraction for making more highly strained systems <5.301. Carbenes also react with alkenes, often by cycloaddition to yield cyclopropanes in a process that can be very efficient (5.31) and highly stereoselective (5.321. 

Where the diene function is attached to or is part of a carbocyclic system, the vinyl cyclopropane formation and subsequent rearrangement affords a reliable approach to the formation of tricyclic carbocycles. Some of the most elegant demonstrations of the use of this methodology in total synthesis of fused cyclopentanoid terpenes come from the work of Hudlicky and coworkers (equations 63-66)90 95"100. In these cases the diazoketones bear a carboxylate-substituted double bond of diene and the intramolecular cyclopropanation requires the combination of CuS04/Cu(acac)2 as catalyst. 

The intramolecular cyclopropanation of appropriate y,(5-unsaturated a-diazoketones following a stereoselective catalytic reduction of the cyclopropyl ketone group provides a useful approach in diterpenoid synthesis. Some examples of the use of the cyclopropanation-reductive cleavage approach in synthesis are shown in equations 67 and 68l0f103. 

Thus changing the ligands on dirhodium(II) can provide a switch which, in some cases, can turn competitive transformations on or ofT146. Other examples include the use of dirhodium(II) carboxamides to promote cyclopropanation and suppress aromatic cycloaddition146. For example, catalytic decomposition of diazoketone 105 with dirhodium(II) caprolactamate [Rh2(cap)4] provides only cyclopropanation product 106. In contrast, dirhodium(II) perfluorobutyrate [Rh2(pfb)4] or dirhodium(II)triphenylacetate [Rh2(tpa)4] gave the aromatic cycloaddition product 107 exclusively (equation 100)l46 148. Although we have already seen that rhodium(II) acetate catalysed decomposition of diazoketone 59, which bears both aromatic and olefinic functionalities, afforded stable norcaradiene 60 (equation 70)105, the rhodium(II) acetate catalysed carbenoid transformation within an acyclic system (108) showed no chemoselectivity (equation 101). However, when dirhodi-um(II) carboxamides were employed as catalysts for this type of transformation, only cyclopropanation product 109 was obtained (equation 101). ... 

Certain diazoketones, for example diazopyruvate, alkyl 2-diazo-3-oxobutyrate or 3-diazo-2,4-pentanedione, react with vinyl ethers under metal catalysis to give dihydrofurans rather than cyclopropanes l Most work on this type of transformation has been that of Wenkert and Alonsoand their respective groups. A representative example is shown in equation 107. Finally, carbenoid dimerization is also a competitive reaction in metal catalysed intermolecular cyclopropanation. However, control of the chemoselectiv-ity to favour the cyclopropanation is possible. In general, the dimeric product can be avoided by using excess of alkene or by very slow addition of the diazo compound to a mixture of alkene and catalyst... 

Polymer-supported benzenesulfonyl azides have been developed as a safe diazotransfer reagent. ° These compounds, including CH2N2 and other diazoalkanes, react with metals or metal salts (copper, paUadium, and rhodium are most commonly used) to give the carbene complexes that add CRR to double bonds. Diazoketones and diazoesters with alkenes to give the cyclopropane derivative, usually with a transition-metal catalyst, such as a copper complex. The ruthenium catalyst reaction of diazoesters with an alkyne give a cyclopropene. An X-ray structure of an osmium catalyst intermediate has been determined. Electron-rich alkenes react faster than simple alkenes. ... 

An unprecedented cyclopropanation reaction was observed during the reaction of ketene alkylsilyl acetals (191) with bromoform-diethylzinc. When monosubstituted acetals were used, cyclopropanecarboxylic esters (195) were formed by a novel C-H insertion. When disubstituted ketene acetals were used, byproducts such as a,)5-ethylenic esters (197) were also formed presumably via 196 (equation 49). This reaction provides a convenient method for the preparation of the bicyclo[3.1.0] hexane system and can be advantageously compared to the copper-catalysed intramolecular cyclization of unsaturated a-diazoketones . 

Copper powder, copper bronze, Cu O, CuO, CuSO, CuCl and CuBr were the first catalysts which were used routinely for cyclopropanation of olefins as well as of aromatic and heteroaromatic compounds with diazoketones and diazoacetates. Competing insertion of a ketocarbene unit into a C—H bond of the substrate or solvent remained an excpetion in contrast to the much more frequent intramolecular C—H insertion reactions of appropriately substituted a-diazoketones or diazoacetates Reviews dealing with the cyclopropanation chemistry of diazo-acetic esters (including consideration of the efficiency of the copper catalysts mentioned above) and diazomalonic esters as well as with intramolecular cyclopropanation reactions of diazoketones have appeared. 

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