Formation of Cyclopropanes

The cyclopropylmethyl Grignard reagent can only be trapped with electrophiles before rearrangement if the Grignard reagent is generated and treated with the electrophile at -75 °C [54]. 

---

In other cases, sulfenic acid elimination can involve y-hydrogen atoms with the formation of cyclopropane derivatives. y-Klimination is favored when DMSO is the reaction solvent. An example involving l-methylsulfinyl-2-ethyl-3-phenyl propane [14198-15-3] is shown in equation 13 (45) ... 

These early studies on zinc carbenoids provide an excellent foundation for the development of an asymmetric process. The subsequent appearance of chiral auxiliary and reagent-based methods for the selective formation of cyclopropanes was an outgrowth of a clear understanding of the achiral process. However, the next important stage in the development of catalytic enantioselective cyclopropanations was elucidation of the structure of the Simmons-Smith reagent. 

The 1,3-elimination of y-keto sulfones leads to the formation of cyclopropane rings as seen in equation 4538. 

The formation of alkyl shifted products H and 14 can be explained in terms of the formation of endo-intermediate 21 formed by endo attack of bromine to 2 (Scheme 4). The determined endo-configuration of the bromine atom at the bridge carbon is also in agreement with endo-attack. Endo-Intermediate 21 is probably also responsible for the formation of cyclopropane products 12 and 15. The existence of cyclopropane ring in 12 and 15 has been determined by and 13c NMR chemical shifts and especially by analysis of cyclopropane J cH coupling constants (168 and 181 Hz). On the basis of the symmetry in the molecule 12 we have distinguished easily between isomers 12 and 15. Aryl and alkyl shift products IQ, H, and 14 contain benzylic and allylic bromine atoms which can be hydrolized easily on column material. 

In addition to a-additions to isocyanides, copper oxide-cyclohexyl isocyanide mixtures are catalysts for other reactions including olefin dimerization and oligomerization 121, 125, 126). They also catalyze pyrroline and oxazoline formation from isocyanides with a protonic a-hydrogen (e.g., PhCH2NC or EtOCOCHjNC) and olefins or ketones 130), and the formation of cyclopropanes from olefins and substituted chloromethanes 131). The same catalyst systems also catalyze Michael addition reactions 119a). 

The yield of trans product (18) is decreased by the presence of a radical scavenger such as 1,1-diphenylethylene and increased by dilution of the reactants with methylene chloride or butane, indicating this product to result from the triplet carbene. A heavy-atom effect on the carbene intermediate was observed by photolysis of a-methylmercuridiazoacetonitrile. With c/s-2-butene as the trapping agent either direct photolysis or triplet benzophenone-sensitized decomposition results in formation of cyclopropanes (19) and (20) in a 1 1 ratio ... 

Second, several investigations have implied that the formation of cyclopropanes is related to olefin metathesis (5, 12, 13). Extrication of the metal from the metallocyclobutane intermediate has been suggested (5) as a route to the three-membered ring ... 

At low temperatures, under conditions where carbonyl exchange is su-pressed, the highly reactive (CO)5W=CHPh did not exhibit any carbene exchange of the type in Eq. (4). Rather, the reaction products indicated a direct electrophilic attack on the olefin by the carbene. (The exclusive formation of cyclopropanes will be detailed in Section III.)... 

At this early stage of comprehension of the interrelation between metathesis and cyclopropanation, many questions remain. Why is the formation of cyclopropanes such a rare occurrence with typical metathesis catalysts, yet favored with some zero-valent carbene complexes What is the role of prior complexation of the olefin with the metal in determining the reaction course for metal-carbene species How are typical metathesis carbenes polarized, and how does this polarization influence selectivity of metathesis reactions (e.g., regenerative metathesis of a-... 

It was demonstrated (83) that the reaction of dinitrostyrenes (28) with aryl diazo compounds RR CN2 afford nitronates (24 g) in good yields. These products contain the nitro group at the C-4 atom in the trans position with respect to the substituent at C-5 (if R =H). Since the reaction mechanism remains unknown, the direct formation of cyclic nitronates (24 g) from pyrazolines A without the intermediate formation of cyclopropanes also cannot be ruled out. 

Scheme 14.21. Formation of cyclopropanes by the oxidative cleavage of titanacyclobutanes. A Me xMe A Me qvie...

The ammonium catalyst can also influence the reaction path and higher yields of the desired product may result, as the side reactions are eliminated. In some cases, the structure of the quaternary ammonium cation may control the product ratio with potentially tautomeric systems as, for example, with the alkylation of 2-naph-thol under basic conditions. The use of tetramethylammonium bromide leads to predominant C-alkylation at the 1-position, as a result of the strong ion-pair binding of the hard quaternary ammonium cation with the hard oxy anion, whereas with the more bulky tetra-n-butylammonium bromide O-alkylation occurs, as the binding between the cation and the oxygen centre is weaker [11], Similar effects have been observed in the alkylation of methylene ketones [e.g. 12, 13]. The stereochemistry of the Darzen s reaction and of the base-initiated formation of cyclopropanes under two-phase conditions is influenced by the presence or absence of quaternary ammonium salts [e.g. 14], whereas chiral quaternary ammonium salts are capable of influencing the enantioselectivity of several nucleophilic reactions (Chapter 12). 

The formation of cyclopropanes from 7C-deficient alkenes via an initial Michael-type reaction followed by nucleophilic ring closure of the intermediate anion (Scheme 6.26, see also Section 7.3), is catalysed by the addition of quaternary ammonium phase-transfer catalysts [46,47] which affect the stereochemistry of the ring closure (see Chapter 12). For example, equal amounts of (4) and (5) (X1, X2 = CN) are produced in the presence of benzyltriethylammonium chloride, whereas compound (4) predominates in the absence of the catalyst. In contrast, a,p-unsatu-rated ketones or esters and a-chloroacetic esters [e.g. 48] produce the cyclopropanes (6) (Scheme 6.27) stereoselectively under phase-transfer catalysed conditions and in the absence of the catalyst. Phenyl vinyl sulphone reacts with a-chloroacetonitriles to give the non-cyclized Michael adducts (80%) to the almost complete exclusion of the cyclopropanes. 

Finally, Nikishin and coworkers have reported that the mediated oxidations of doubly activated methylene compounds can be used to synthesize cyclopropane derivatives (Scheme 17) [30]. Reactions using dimethyl malonate, ethyl cyanoacetate, and malononitrile were studied. Metal halides were used as mediators. When the activated methylene compound was oxidized in the absence of a carbonyl compound, three of the substrate molecules were coupled together to form the hexasubstituted product. Interestingly, when the ethyl cyanoacetate substrate was used the product was formed in a stereoselective fashion (18b). In an analogous reaction, oxidation of the activated methylene compounds in the presence of ketones and aldehydes led to the formation of cyclopropane products that had incorporated the ketone or aldehyde (20). In the case of 19a, the reactions typically led to a mixture of stereoisomers. 

Photolysis of diazoaJkanes in liquid phase yields carbenes in a vibrationally relaxed state, since deactivation in solution immediately removes all excess vibrational energy. The addition of carbenes to the olefins, which results in nonstereospecific formation of cyclopropanes, must therefore result from the different multiplicity of carbenes — singlet or triplet. Since most of these multiplicity... 

Calculations [28] on the formation of cyclopropanes from electrophilic Fischer-type carbene complexes and alkenes suggest that this reaction does not generally proceed via metallacyclobutane intermediates. The least-energy pathway for this process starts with electrophilic addition of the carbene carbon atom to the alkene (Figure 1.9). Ring closure occurs by electrophilic attack of the second carbon atom... 

Few examples of the formation of cyclopropanes by intramolecular C-H insertion of electrophilic carbene complexes have been reported. This methodology for cyclopropane preparation seems only to be suitable for polycyclic compounds with little conformational flexibility. Illustrative examples are listed in Table 4.3. 

The formation of cyclopropane by reduction of 1,3-dibromopropane was discovered in 1887. Dissolving metals, in particular zinc dust in ethanol, were employed as an electron source [88], Electrochemical reduction in dimethyl-formamide at a mercury cathode has been found to give good yields of cyclopropane [89, 90], 1,3-dibromo, 1,3-diiodo and l-chloro-3-iodopropane all give greater than 90 % yield of cyclopropane, the other product being propene. 

With sulfur and triethylamine in dimethylformamide, compounds (86) give (89) (Equation (21)) <89JPR243>. With thiols or KjS, sulfides are produced (e.g., (90) and (91)), which show spasmolytic activity in vitro <86MI 404-01 >. Smooth 5N2-displacements of chlorine occur with phenol, thiophenol, SCN, and thiourea in dimethylsulfoxide. However, with K2CO3 or sodium cyanide, (86) (Ar = Ph) affords the trimers (92) or (93) (Scheme 32). With electron-deficient trans alkenes, stereoselective formation of cyclopropanes (94) was observed (Scheme 32). No reactions occur with maleates <66HCA412>. 

Scheme 29 Formation of cyclopropane derivatives catalyzed by RCIg.

When pyrroles, triazoles and other nitrogen containing heterocyclic compounds react with dichlorocarbene, no addition to their carbon-carbon double bonds has been observed. In some cases the formation of cyclopropane adducts has been suspected however, alternate ways to explain the reaction products cannot be excluded [228]. 

The increased reactivity of cyclopropanes results from the presence of bent bonds which can interact with electrophiles, and can be more easily cleaved thermally than ordinary C C bonds. One indication of the consequences of the distortion is found in the strain energies (SE)37 that are calculated as the difference between the observed heat of formation and that estimated for a strain-free model. One might, for example, consider cyclohexane as strain-free, and then a model for cyclopropane would be half the heat of formation for cyclohexane. The available data for heats of formation of cyclopropane and cyclobutane derivatives are given in Table 2,38 The heat of formation of cyclohexane is — 29.4 kcal/mol, and the strain energy of cyclopropane is 12.7-0.5( — 29.4) or 27.5 kcal/mol. 

Lack of stereospecificity, extensive formation of olefinic products, and extensive tar formation limit the thermal decomposition of pyrazolines as a route to cyclopropanes.182 263 Light-induced decomposition of stereoisomeric pyrazolines establishes a method for the formation of cyclopropanes stereospecifically.222 Photolysis of 3-carbomethoxy-cis-3,4-dimethyl-l-pyrazoline (CCLI) produced cis-l,2-dimethylcycIopropane-l-carboxylate (CCLII) and without olefinic formation. Furthermore, irradiation of 3-carbomethoxy-trans-3,4-dimethyl-l-pyrazoline (CCLIII) gave [Pg.123]

---