Diazoalkanes cyclopropane synthesis

PFAU - PLATTNER Cyclopropane synthesis DIazoalkane insertion Into olelins wtth lormation of cyclopropanes or ring enlargement ol aromatics to cydoheptatnenes see also lormation ol pyrazoHnes (von Pechman). 

Optically active complexes have been used for enantioselective cyclopropane synthesis. Decomposition of diazoalkanes in the presence of chiral rhodium copper, or ruthenium complexes leads to optically active cyclopropanes. 

The nitrogen extrusion from 1-pyrazolines and 3H-pyrazoles giving cyclopropanes and cyclopropenes, respectively, has been extensively reviewed The cyclopropane synthesis from 1-pyrazolines can be executed thermally as well as photochemically, but the latter method generally gives substantially better results than the former. The major side reaction observed in the thermal process is the production of olefins, which arise in the migration of a substituent from the C(4) to C(3) position. A retro-1,3-dipolar addition producing a diazoalkane and an olefin has been observed in certain cases. The decomposition of 3-acyl- or 3-alkoxycarbonyl-1-pyrazolines is catalyzed by acids, such as perchloric acid and boron trifluoride and by Ce The stereochemical course... 

PFAU PLATTNER Cyclopropane synthesis Diazoalkane insertion into olefins with formation of cyclopropanes or ring enlargement of aromatics to cydoheptatrienes see also formation of pyrazoDnes (von Pechman). 

Transition metal salts or complexes are known to catalyze effectively the cyclopropanation of olefins with diazoalkanes. Asymmetric synthesis with chiral copper catalysts (Nozaki et ai, 1966, 1968 Noyori et al., 1969 Moser, 1969), as well as a detailed kinetic study (Salomon and Kochi, 1973), has suggested the intervention of copper-carbene complexes as reactive intermediates. Recently synthesis of crysanthemic acid (CCXXXIV) (R = H) with high optical yield (60-70 %) has been achieved by applying this asymmetric catalysis (Aratani et al., 1975). The camphorglyoxime-cobalt(I) complex is also effective for the enantioselective reaction (Tatsuno et al., 1974). 

The diastereoselective and enantioselective preparation of cyclopropanes has attracted attention since chiral cyclopropanes were found to occur in many natural products [11]. Moreover, cyclopropanes are useful intermediates in organic synthesis. There are many methods of cyclopropane ring opening that transfer stereochemical information from the substrate to acyclic products in a stereocontrolled manner [12]. Among the methods used for the preparation of cyclopropanes from olehns, the Simmons-Smith and related reactions as well as reactions of diazoalkanes catalyzed by rhodium, copper and cobalt salts have frequently been applied [13]. The preparatively simple Makosza reaction [14] has scarcely been used. 

Rhodium(II)-mediated reactions have found many applications. The literature up to 1985 in intramolecular and intermolecular cyclopropanations, including choice of catalysts and mechanistic aspects, has been thoroughly reviewed by Maas [9]. More recent reviews are available that focus on the ligand effects and mechanism [10], and on their utilization in fine organic synthesis as well as in natural product synthesis [11]. All of these reviews, and in particular McKervey s comprehensive review [11a] on organic synthesis with a-diazocarbonyl compounds, deal with the utilization of functionalized diazo compounds as carbenoid precursors. Herrmann et al. surveyed the organometallic chemistry of diazoalkanes [11c, lid]. 

In contrast to the wealth of chemistry reported for catalyzed reactions of diazocarbonyl compounds, there are fewer applications of diazomethane as a carbenoid precursor. Catalytic decomposition of diazomethane, CH2N2, has been reported as a general method for the methylenation of chemical compounds [12]. The efficacy of rhodium catalysts for mediating carbene transfer from diazoalkanes is poor. The preparative use of diazomethane in the synthesis of cyclopropane derivatives from olefins is mostly associated with the employment of palladium cat-... 

Diazoalkanes 1 form a versatile class of functionalized organic compounds [1]. Their undisputed significance in organic synthesis is manifested in a number of organometallic and other metal-induced reactions [2], some of which have entered catalytic applications. Cyclopropanation is one of them (cf. Section 3.1.7) but intramolecular carbon-hydrogen insertion appears of much potential in synthesis, too. This type of reaction relates to the easily available, normally nonexplosive a-diazocarbonyl compounds (a-diazoketones. Structure 2). 

In some of these reactions, control of stereochemistry is critical and it is fortunate that for protected amino acid precursors, photochemical deazetization of the 4,5-dihydro-3//-pyrazole proceeds with high retention of stereochemistry. Hence, in the synthesis of the amino acid 12, the initial diazoalkane addition gave only one isomer (probably with the stereochemistry shown) and, although thermolysis gave a mixture of stereoisomers, photolysis gave the cyclopropane with the required trans configuration. 

For the synthesis of formyl-substituted cyclopropanes, acetal-substituted compounds, the functional equivalent of the formyl-substituted compounds, are employed. Either an acetal substituent is incorporated into the diazoalkane (e.g. 2,2-dimethoxy-l-diazoethane can be used ) or on the double bond. Here it provides sufficient activation for the addition step, as is seen in the synthesis of formylcyclopropane (31) and /ra .v-l,2-diformylcyclopropane (32). ... 

There are few syntheses where imino-substituted cyclopropanes have been made by the diazoalkane addition route. One example is, however, provided by the synthesis of 7-(4-chloro-phenyl)-4-morpholino-5-oxa-6-azaspiro[2.4]hept-6-ene (33). ... 

Tricarbonyliron complexes of conjugated trienes react with diazoalkanes at the free (uncom-plexed) double bond. In the synthesis of dimethyl 2-formylcyclopropane-l, 1-dicarboxylate (48), the ceric ion served the double function of catalyzing the deazetization and removing the tricarbonyl iron protecting group. When the optically active iron carbonyl complex was used, the addition of diazomethane gave selectively one diastereomer and this was used to make optically active dimethyl 2-formylcyclopropane-l,1-dicarboxylate (>90% ee). A similar route was employed to make the optically active formyl cyclopropanes 49, precursors to optically active cis- and tran.v-chrysanthemic acids. 

The copper-catalyzed cyclopropanation of alkenes with diazoalkanes is a particularly important synthetic reaction (277). The reaction of styrene and ethyl diazoacetate catalyzed by bis[/V-(7 )- or (5)-a-phenyl-ethylsalicylaldiminato]Cu(II), reported in 1966, gives the cyclopropane adducts in less than 10% ee and was the first example of transition metal-catalyzed enantioselective reaction of prochiral compounds in homogeneous phase (Scheme 90) (272). Later systematic screening of the chiral Schiff base-Cu catalysts resulted in the innovative synthesis of a series of important cyclopropane derivatives such as chrysanthemic acid, which was produced in greater than 90% ee (Scheme 90) (273). The catalyst precursor has a dimeric Cu(II) structure, but the actual catalyst is in the Cu(I) oxidation state (274). (S)-2,2-Dimethylcyclopropanecar-boxylic acid thus formed is now used for commercial synthesis of ci-lastatin, an excellent inhibitor of dehydropeptidase-I that increases the in vivo stability of the caibapenem antibiotic imipenem (Sumitomo Chemical Co. and Merck Sharp Dohme Co.). Attempted enantioselective cyclopropanation using 1,1-diphenylethylene and ethyl diazoacetate has met with limited success (211b). A related Schiff base ligand achieved the best result, 66% optical yield, in the reaction of 1,1-diphenylethylene and ethyl diazoacetate (275). 

As with other diazoalkanes, diazomethane reacts with alkenes to form cyclopropane derivatives (sec. 13.9.C.i).272 Reaction with aromatic derivatives leads to ring expansion to cycloheptatriene derivatives.223 Both of these reactions (addition to an alkene or arene insertion) involve generation of an intermediate carbene and addition to a jt bond they will be discussed below. Many of the reactions of diazomethane tend to be ionic in nature and are, therefore, set aside from the other diazoalkane chemistry in this section. One of the commonest uses of diazomethane itself is esterification of small quantities of acids, especially acids that are precious for one reason or another. The reaction is quantitative and gives good yields of a single product, as in Tadano s conversion of 338 to the methyl ester of 339224 in a synthesis of (-)-verrucarol. 

The synthesis of optically active cyclopropanes via formation of dihydro-pyrazoles by 1,3-cycloaddition and azo-extrusion has been studied since the late 1950 s. Modest success (10% ee) was achieved by cycloaddition of diazoalkanes to acrylic acid, esterified with ( —)-menthol, as studied by Walborsky s group (Impastato et al., 1959). Today, the use of chiral metal complexes as catalysts for the synthesis of chiral... 

The discussed reactions of carbene and carbyne complexes show that they have essential significance as catalysts or unstable transient intermediate compounds in such catalytic processes as metathesis of olefins and other unsaturated compounds, Fischer-Tropsch synthesis, syntheses of cyclopropanes from diazoalkanes and olefins, and polymerization of olefins and alkynes as well as in organic synthesis. Except for alkynes [reaction (5.132) ] some compounds containing double bonds react with carbon monoxide and carbene ligands to form bonds with those groups. Examples of such compounds are enamines, ynamines, and Schiff bases. The JV-vinylpyrrolidone (enamine), methoxyphenylcarbene, and excess of CO (higher pressure) react to furnish enaminoketone. 

The asymmetric synthesis of cyclopropanes has attracted continual efforts in organic synthesis, due to their relevance in natural products and biologically active compounds. The prevalent methods employed include halomethylmetal mediated processes in the presence of chiral auxiliaries/catalysts (Simmons-Smith-type reactions), transition-metal-catalyzed decomposition of diazoalkanes, Michael-induced ring closures, or asymmetric metalations [8-10,46], However, the asymmetric preparation of unfunctionahzed cyclopropanes remains relatively undisclosed. The enantioselective activation of unactivated C-H bonds via transition-metal catalysis is an area of active research in organic chemistry [47-49]. Recently, a few groups investigated the enantioselective synthesis of cyclopropanes by direct functionalization reactions. 

In contrast to the aforementioned diazoalkanes and aryldiazomethanes, whose instability and high explosiveness have diminished their general utility as a monomer for polymer synthesis, diazocarbonyl compounds have been known to be rather stable and frequently used as a reagent for organic synthesis [35, 36], In particular, transition metal catalyzed cyclopropanation of diazocarbonyl compounds with C=C double bonds has been extensively investigated and established as a very useful method for the formation of cyclopropane frameworks, where application for asymmetric synthesis using various optically active ligands has been successfully achieved. 

Cyclopropanation by diazoalkane in the presence or absence of transition metal catalysts is widely used in organic synthesis [107]. The recent explosion of research reports has enabled many types of formation of cyclopropanes in a diastereo- and enantioselective manner. The most commonly used transition metals are iliodium, copper, and mthenium however, oflier metals, such as palladium and cobalt, are also used. It may not be possible to report all of the results in this chapter, because numerous papers have been published so far. We selected recent representative examples. 

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