Cyclopropane synthesis reaction

Cyclopentenones reactions of 835, 836 synthesis of 620 Cyclopropanation 648 Cyclopropanecarboxylates, synthesis of 318 Cyclopropanes, synthesis of 772, 773, 785-787... 

Miscellaneous Iminium Catalyzed Transformations The enantioselective construction of three-membered hetero- or carbocyclic ring systems is an important objective for practitioners of chemical synthesis in academic and industrial settings. To date, important advances have been made in the iminium activation realm, which enable asymmetric entry to a-formyl cyclopropanes and epoxides. In terms of cyclopropane synthesis, a new class of iminium catalyst has been introduced, providing the enantioselective stepwise [2 + 1] union of sulfonium ylides and ot,p-unsaturated aldehydes.As shown in Scheme 11.6a, the zwitterionic hydro-indoline-derived catalyst (19) enables both iminium geometry control and directed electrostatic activation of sulfonium ylides in proximity to the incipient iminium reaction partner. This combination of geometric and stereoelectronic effects has been proposed as being essential for enantio- and diastereocontrol in forming two of the three cyclopropyl bonds. 

An asymmetric cyclopropane synthesis has been achieved by the addition-cyclization reaction of a chiral a,/ -unsaturated sulfoxide with a Grignard reagent (equation 32)49. 

The synthetic potential of organozirconocenes is greatly expanded by their easy transformation into other organometallics. Therefore, transmetalation-based approaches to cyclopropane synthesis have been reported. The reaction of zirconacyclopentene with phthaloyl chloride in the presence of CuCl was used for the preparation of cyclopropylenolate derivatives in moderate yields (Scheme 29) [39]. 

However, the development of cyclopropane synthesis through zirconocene chemistry is still in its infancy. The reactions presented in this chapter have only recently been reported for the most part, and not systematically studied. Further investigations appear to be desirable. Practical procedures involving optimized reaction conditions and simpler reagents would be welcomed. Advances should focus on the development of catalytic and asymmetric cyclopropanation reactions. 

The chiral acetonide 27 has been stereoselec-tively transformed into 28 by cyclopropanation. This reaction serves as the key step in the synthesis of 29 (Scheme 6) [28]. Cyclopropanated nucleosides such as 29 are interesting drug candidates for HIV therapy. 

Treatment of diethyl malonate and related compounds with 1,2-dihaloethane in the presence of base constitutes a classical method of cyclopropane synthesis. The reaction can be conveniently carried out under PTC conditions. An improved method utilizing solid-liquid phase transfer catalysis has been reported The reaction of dimethyl or diethyl malonate with 1,2-dibromoalkanes except for 1,2-dibromethane tends to give only low yields of 2-alkylcyclopropane-l, 1-dicarboxylic esters. By the use of di-/ r/-butyl malonate, their preparations in satisfactory yields are realized (equation 134). The 2-alkylcyclopropane derivatives are also obtained from the reaction of dimethyl malonate and cyclic sulfates derived from alkane-1,2-diols (equation 135) Asynunetric synthesis... 

Intramolecular cyclopropanations of pendant alkenes are more favorable. Heteroatom-substituted 2-aza- and 2-oxabicyclo[3.1.0]hexanes, together with 2-oxabicyclo[4.1.0] heptanes, can be prepared from chromium and tungsten Fischer carbenes having a tethered alkene chain. An interesting carbene formation via a cationic alkylidene intermediate, nucleophilic addition (see Nucleophilic Addition Rules for Predicting Direction), and intramolecular cyclopropanation is shown in Scheme 59. An intramolecular cyclopropanation via reaction of alkenyl Fischer carbene complex (28) andpropyne was used in a formal synthesis of carabrone (Scheme 60). 

Asymmetric synthesis of cyclopropanes, The reaction of dimethyloxosnifonium methylide with (E)-(2R,3S)-6-alkylidene-3,4-dimethyl-2-phenylperhydro-l,4-oxazepine-5,7-diones (1) yields cyclopropane derivatives (2) and dihydrofuranes (3). The ratio of the products depends on the solvent and temperature. Use of THF at 25° favors formation of 2, whereas formation of 3 is favored by use of DMF at -61°. The products (2 and 3) can be converted into optically pure cyclopropane-1,1-dicarboxylic acids (4) and 3-substituted y-butyrolactones (5), respectively. 

Reactions of this type represent an important group of methods employed in cyclopropane synthesis. The course of these cycloadditions is described in the formal equation shown in Scheme 2.132. Independent of the method of generation or its actual nature, the Ci addend can be viewed as a synthetic equivalent to the carbene 395, at least in terms of its ability to form two new C-C bonds at a single carbon center. 

Although the reaction of dihalocarbenes with alkenes gives good yields of halogenated cyclopropanes, this is not usually the case with methylene, tCH2, the simplest carbene. Methylene is readily formed by heating diazomethane, CH2N2, which decomposes and loses N2, but the reaction of CH2 with alkenes often affords a complex mixture of products. Thus, this reaction cannot be reliably used for cyclopropane synthesis. 

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... 

Other complementary methodologies include the preparation of substituted cyclopropanes from glycals using rhodium acetate carbenoid additions [65,66]. Additionally, acid catalyzed cyclopropane opening reactions in alcoholic solutions afford the 2-C-branched-glycosides. These combined reactions were used to prepare a key intermediate in marine diterpene norrisolide synthesis from D-mannose [67]. 

This asymmetric carbene reaction has been extended successfully, but in an unexpected direction [37]. Thus, as illustrated in Scheme 10, the cyclopropane synthesis is now used for the industrial synthesis of Cilastatin (36), which acts as an excellent in vivo stabilizer of the antibiotic Imipenem (37) (Merck Co., USA, and Sumitomo Chemical Co. Ltd., Japan). Chiral bisoxazolidine-Cu complexes (Structures 38 and 39) also exhibit high efficiency in asymmetric cyclopropanation [38]. 

Another application of rhodium carbenoid chemistry relates to the synthesis of strained-ring nitro compounds as high energy-density materials. Nitrocyclo-propanes are the simplest members of this class of compounds and catalyzed additions of a nitrocarbene to an olefin have only been described recently [40], Detailed studies have shown that the success of the reaction is, as expected, dependent on both the alkene and the nitrodiazo precursor. Consistently with the electrophilic character of rhodium carbenoids, only electron-rich alkenes are cyclopropanated. The reaction has been extended to the synthesis of nitrocyclo-propenes but the yields are good for terminal acetylenes only [41]. 

Cyclopropanation. The reaction of sulfonium ylides 96 with acrylic esters or methyl vinyl ketone provides rrany-2-arylcyclopropanecarboxylic esters and methyl ketones. Generation of the ylides with EtNP(NMe)2-N=P(NMe)j as base is convenient because dichloromethane can be used as solvent. Another synthesis of cyclopropanecarboxylates proceeds by a conjugate addition and 1,3-elimination sequence. ... 

The results of a series of reactions of Fischer carbene complexes with enynes are summarized in Tables 1 and 2. Cyclopropane synthesis is accomplished in the alkoxy series (Y = OMe) by the generation of a mixture of geometric isomers of enol ethers, whereas in the dialkyl-amino series, ketones are directly obtained after hydrolysis of the enamines. Higher yields have been obtained using the amino analog pentacarbonyl(l-pyrrolidinoethylidene)chromium [Y = N(CH2)J. - ... 

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