Reaction with 1,1-cyclopropane diesters

Through the progression of the cycloaddition reaction of cyclopropane diesters with nitrones, Sapeta and Kerr thought it wise to investigate the mechanism of this [3+3] dipolar cycloaddition. 

In contrast to ethyl diazoacetate, diethyl diazomalonate reacts with allyl bromide in the presence of Rh2(OAc)4 to give the ylide-derived diester favored by far over the cyclopropane (at 60 °C 93 7 ratio). This finding bespeaks the greater electrophilic selectivity of the carbenoid derived from ethyl diazomalonate. For reasons unknown, this property is not expressed, however, in the reaction with allyl chloride, as the carbenoids from both ethyl diazoacetate and diethyl diazomalonate exhibit a similarly high preference for cyclopropanation. 

Substitution of the VCP is tolerated both on and adjacent to the cyclopropane ring. Diester-substituted and heteroatom (O, NTs) tethers are well tolerated. Reactions were conducted with 2-10 mol% catalyst at up to 0.20 M, as illustrated. Most importantly, reactions with the naphthalene catalyst were found to be more rapid than those with other catalysts. For example substrate 54 is readily converted in >99% yield to cycloadduct 55 in only 15 min at room temperature (entry 1). Complex 93 efficiently catalyzes the reactions of both alkynes and alkenes with VCPs, offering greater generahty than thus far observed with non-rhodium catalysts. This catalyst is particularly advantageous in the cases of substrates 100 and 102, for which the desired product is not formed cleanly with Wilkinson s catalyst due to product isomerization. 

In a preliminary study toward the total synthesis of the kopsane alkaloid 140, which may exhibit cholinergic activity, the formal [3 + 2] annulation reaction of 3-alkylindoles with 1,1-cyclopropane diesters was studied in the presence of Yb(OTf)3 either at elevated temperature or at high pressure. For example, N-methyltetrahydrocarbazole (141) with styryl-substituted cyclopropane 142 produced a mixture of diastereomeric adducts 143a and 143b (3 1) in 49% yield at 1.3 GPa for 7 days (Scheme 39) [89]. 

Spiroacylal 2 was designed under the rationale that the constraint of the carbonyl groups into a conformation in which overlap of their 7r-orbitals with the bent bonds of the cyclopropane is assured should dramatically increase the vulnerability of the cyclopropane toward nucleophilic attack.8 Experimental support for this notion is abundant.8 Spiroacylal 2 is considerably more reactive than 1,1-dicarbethoxycyclopropane in such reactions. For instance, reaction of 2 with piperidine occurs at room temperature. The corresponding reaction in the case of the diester is conducted at 110°C.5 Reactions with enolates also occur under mild conditions.8 Compound 2 reacts with the weak nucleophile pyridine at room temperature to give a betaine.8 An illustrative mechanism for the reaction of the acylal 2 with aniline to afford 2-oxo-l-phenyl-3-pyrrolidinecarboxylic acid (3) is... 

Initially applied to thermal cydoaddition of fumarates of chiral alcohols with anthracene [118] (Figure I.34.a), cooperativity was extended to other reactions of symmetrical diesters. While reactions of mixed diesters bearing a single chiral alcohol residue are poorly stereoselective, those of symmetrical diesters can be quite useful. Indeed, the formation of cyclopropane diesters 43 from succinic add diesters and BrCB Cl is poorly diastereoselective when using a mixed methyl and menthyl ester. But it becomes highly diastereoselective when performed with symmetrical dimenthyl esters (Figure I.34.b). 

Intermolecular cyclopropanation of a diazo carbonyl compounds is also reported. For example, ethyl glycolate undergoes reaction with compound (1) to give the diazo diester, which was subsequendy reacted with Ceo to form a methanofullerene (eq 7). ... 

A tandem ring opening-cyclization reaction of 2-substituted 1,1-cyclopropane-diesters with N-benzyl imines in the presence of 5 mol% of Sc(OTf)3 was developed [149]. The 2,3,5-substituted pyrrolidines were obtained in moderate to high yields (42-98%) with high diaster eoselectivities (cis/trans = 8/1-30/1). 

The Lewis-acid-promoted formal intramolecular 3 + 2-cycloaddition of cyclopropane 1,1-diesters with allenes (25) produced [4.3.0]nonanes (26) and [3.2.1]octanes (27) by parallel-cycloaddition and cross-cycloaddition, respectively (Scheme 8). Similarly, the Lewis-acid-catalysed formal intramolecular 3 + 2-cycloaddition reactions of cyclopropane 1,1-diesters with alkenes produced bridged[n.2.1]carbocyclic compounds with excellent stereo- and regio-selectivity under mild conditions. This reaction has been successfully applied to the total synthesis of tetracyclic diterpenoids phallocladanol and phallocladene. ... 

The enantioselective 3 + 3-cycloaddition reaction of aromatic azomethine imines with donor-acceptor cyclopropane diesters produced 6,6,6-tricyclic dihydroquinolines in high yields (99%) and up to 98% ee. The side-arm-modified In-TOX/Ni(II) complex was shown to be an effective stereoselective catalyst for this reaction. The formal 3 + 3-cycloaddition reaction of allylic phosphonium ylides (127) to a, -unsaturated carbonyls (128) formed multi-substituted benzenes (129) in high yields (36-93%) (Scheme 38). °... 

One drawback of the vinylcyclopropane-cyclopentene rearrangement is the need to use elevated temperatures. However, such conditions are not necessary with cyclopropanes that are activated by two electron-withdrawing groups and when the reaction is carried out in the presence of a Pd catalyst, as shown for the diester (59). ... 

The cobalt complexed cyclopropane diester 4 was then reacted with a variety of aldehydes in the presence of boron trifluoride etherate in dichloromethane to afford the desired tetrahydrofurans 5 in high yields with poor diastereoselective control (Scheme 10.6). The cycloaddition reaction was limited to electron deflcient aromatic, aliphatic, and functionalized aldehydes, where no reaction was observed with electron rich aromatic aldehydes. The tetrahydrofurans were obtained as a 1 1 mixture of cis- and fran -isomers, where the best diastereomeric ratio obtained was 2 1 (5d) in favor of the fran -isomer. Modifying the temperature of the reaction had little effect on the diastereoselectivity. Confirmation of the stereochemistry was achieved by X-ray and NMR analysis of the separated diastereoisomers, including... 

In 2007, Kang et al. improved the method conducted by Sibi and coworkers by maintaining the diastereoselectivity of the reaction of which Kerr and coworkers had originally reported, as well as maintaining excellent enantioselectivity with monosubstituted cyclopropane diesters [26]. This was achieved with the trisoxazoline Ugand as shown in Scheme 10.29. 

The synthesis of isatisine A113 started with the formation of the tetrahydroftiran ring through a Lewis acid-catalyzed cycloaddition reaction of the chiral (5)-vinyl cyclopropane diester 23 and iV-tosyl-indole-2-carboxaldehyde 24 (Scheme 10.42) [40]. 

The discovery that imines undergo a cycloaddition reaction with activated cyclopropane diesters to afford 2,5-disubstimted pyrrolidines was a significant development on previous methods. However, the substrate scopes of the imines used were limited to aryl substituents, where no reaction was observed with aliphatic imines. Kerr and coworkers originally thought that the substrate scope could be improved by the use of oxime ethers, as they envisioned this would increase the nucleophilicity of the nitrogen toward... 

However, the diastereoselectivity of the reaction for the formation of the 2,5-cis cycloadducts were poor compared to the diastereoselectivity observed with the oxime ether cyclopropane diesters [43]. It was thought that this happened due to a decrease in selectivity for the formation of the Z-aza-iminium intermediate. To overcome this issue, the Boc-... 

Dehydrohalogenation sometimes leads to cyclization which gives cycloalkanes or heterocycles. The fluorinated diester 1 has proved to be a convenient source of polyfluoroalkylated cyclopropanes. Reaction of 1 with aqueous potassium hydroxide gives 2- HA //-hepta-fluorobutyl)cyclopropane-l, 1 -dicarboxylic acid (2) in quantitative yield.120 The diethyl ester 3 ot this acid is obtained in a yield of 87% by the reaction of 1 with sodium ethoxide in anhydrous ethanol.120... 

The intermediacy of >/2-cyclopropene complexes of nickel has been proposed in catalyzed 2+1 reactions of free cyclopropene with electron-poor olefins, to give vinylcyclo-propanes. For example, the reaction of fumarate esters with 3,3-disubstituted cyclopropenes in the presence of Ni(COD)2 catalyst gave vinyl-substituted trans-2,3-cyclopropane dicarboxylate esters (equation 235)72 302. However, when maleic esters were used instead, a mixture of both cis and trans vinylcyclopropane diesters is obtained. 

Reaction of the cyclopropane-1,1-dicarboxylate (410) with the enamine (552) followed by extraction with dilute hydrochloric acid gives rise to the ketodiester (564) presumably via the intermediacy of 563 (equation 197). This difference in reactivity of the diester... 

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