2- Alkoxy substituted cyclopropanes

Functionalized zinc carbenoids have been prepared from carbonyl compounds by an indirect strategy. The deoxygenation of a carbonyl compound to an organozinc carbenoid can be induced by a reaction with zinc and TMSCl. Therefore, the aldehyde or ketone, when treated with TMSCl or l,2-bis(chlorodimethylsilyl)ethane in the presence of an alkene, generates the cyclopropanation product. This method is quite effective for the production of alkoxy-substituted cyclopropane derivatives. A 55% yield of the... 

In attempts to prepare alkoxy-substituted cyclopropane carbaldehydes like 29 only ring expanded compounds 30 have been isolated. The two-step route via carbinol 2820) and the selective reduction21) with DIBAI both afford the 2-alkoxy-dihydro-furan 30. 

Most prominent and well investigated is the group of donor-substituted cyclopropanes that readily react with electron-deficient dienophiles. Rate increase in polar solvents, the negative value of the partial molar volume and trapping reactions with methanol indicate a stepwise reaction via dipolar intermediates 2 for singly alkoxy-substituted cyclopropanes 1. 

Scheme 10.12 gives some examples of enantioselective cyclopropanations. Entry 1 uses the W.s-/-butyloxazoline (BOX) catalyst. The catalytic cyclopropanation in Entry 2 achieves both stereo- and enantioselectivity. The electronic effect of the catalysts (see p. 926) directs the alkoxy-substituted ring trans to the ester substituent (87 13 ratio), and very high enantioselectivity was observed. Entry 3 also used the /-butyl -BOX catalyst. The product was used in an enantioselective synthesis of the alkaloid quebrachamine. Entry 4 is an example of enantioselective methylene transfer using the tartrate-derived dioxaborolane catalyst (see p. 920). Entry 5 used the Rh2[5(X)-MePY]4... 

In addition to siloxy- and alkoxy-substituted VCPs, alkyl- and H-substituted VCPs are also effective in the intermolecular [5 + 2]-cycloaddition reaction (Scheme 11). In general, an increase in the steric bulk of the cyclopropane substituent (H vs. Me vs. Pr1) leads to increased reaction rates, putatively through preferential population of the more reactive as-oid arrangement of the vinyl and cyclopropane moieties.43... 

Scheme 5 summarizes the regiochemistry of ring opening of methyl- (6) and phenyl-substituted alkoxy-siloxy-cyclopropane (7) by LiOMe, ZnCl2, HgCl2) and TiCl4, as well as the 13C NMR chemical shifts of the respective metal methyls [27]. The NMR data correlate with the nature of the metal-carbon bond The more polarized it is, the less positive the chemical shift of the methyl group. 

Although it has been known since 1938 that alkoxy-substituted alkyl cyclopropanecar-boxylates can be opened to 1,4-dicarbonyl compounds it was not until 1970 that the synthetic merit of this route to a valuable class of intermediates was recognized. In this year Wenkert and coworkers described the preparation of cyclopentenones from this type of cyclopropane via 1,4-diketones as outlined in equation 83 " . Shortly later McMurry and Glass have published a ds-jasmone synthesis following the same principle ... 

Chiral catalysts with structures related to rhodium(II) acetate should principally afford optically pure enantiomeric > -lactones from diazoacetates of type 21. As a matter of fact, Doyle et al. have obtained alkoxy-substituted y-lactones 22 in 85-90% ee (eq. (10)) upon using a Rh2X4-catalyst derived from chiral 2-pyrroli-dinones [18], Related results suggest that the catalyst has a rigid stereochemistry throughout the catalytic cycle [19], which conclusion had already been drawn for enantioselective cyclopropanation [20] (cf. Section 3.1.7). 

The transient zirconocene butene complex, 105, has proved to be useful in a number of organic transformations. For example, butene substitution of zirconocene alkene complexes with alkoxy-substituted olefins results in /3-alkoxide elimination to furnish the zirconocene alkoxy compounds (R = Me, 123 R = Bnz, 124) (Scheme 16).50,51 Addition of propargyl alcohols to the zirconocene butene complex, 105, affords homoallylic alcohols. These reactions are of limited utility owing to the lack of stereoselectivity or formation of multiple products. Positioning the alkoxide functional group further down the hydrocarbyl chain allows synthesis of cyclopropanes, though mixtures of the carbocycle and alkene products are obtained in some cases (Scheme 16).52... 

Similarly, 4-halobutanoate (see Table 2) and 5-halo-l-(trimethylsilyl)alkynyl derivatives (Scheme 2) can undergo the base-catalyzed cyclopropane ring-forming reaction. With alkoxy substituents in the starting materials, synthetically versatile donor-acceptor substituted cyclopropanes (see Section l.B.2.1.4.) are thus formed. 

Palladium-catalyzed arylative and acylative ring openings (vide supra) can be successfully applied to 1-alkoxy-l-siloxycyclopropanes. Thus, ) -arylated esters and 4-oxo esters, respectively, are synthesized. Yields are generally higher and the reaction conditions milder for doubly oxygen-substituted cyclopropanes than for siloxycyclopropanes. For acylation, the procedure can be extended from aroyl chlorides to aliphatic acyl chlorides and carbon monoxide is no longer necessary for successful acylation. 

In the absence of water, the ester function was retained and a oxo carbonyl group was formed at the original alkoxy-substituted tertiary cyclopropane carbon atom, as demonstrated by the ring opening of bicyclic cyclopropane, e.g. 11 ° and 13, and spirocyclopropane, e.g. 

Occasionally, gew-dichlorocyclopropanes with phenyl or alkoxy substituents are transformed by strong base in aprotic or (rarely) protic solvents to allylic substitution products that do not obey at all the rules for cyclopropyl to allyl rearrangements with regard to their constitution and configuration. "These reactions are mechanistically distinct. They are usually initiated by base-induced elimination of hydrogen chloride to form phenyl- or alkoxy-substituted cyclopropenes, which are then intercepted by nucleophiles. ° These reactions are discussed in Section 2.B.2.I. Small structural differences can divert the reaction into one or the other reaction channel. Cyclopropane 25 on treatment at — 50°C with 2 equivalents of potassium /er/-butoxide in tetrahydrofuran in the presence of catalytic dicyclohexano-18-crown-6... 

The carbenoid reaction between alkyl diazoacetates and enol ethers, enol acetates and silyl enol ethers furnishes P-oxycyclopropane carboxylates (see Tables 2, 4, 5, 6, 7 and Scheme 5). The recently recognized synthetic versatility of these donor/acceptor-substituted cyclopropanes i 2,io3) (precursors of 1,4-dicarbonyl and P, 7-unsaturated carbonyl compounds, 4-oxocarboxylic acids and esters, among others) gave rise to the synthesis of a large number of such systems with a broad variation of substituents p-acetoxycyclopropanecarboxylates , p-alkoxy- or p-aryloxysubstituted cyclopropanecarboxylates 2-alkoxy-1-methyl-1-cy-... 

Scheme 2.6 Rearrangement of alkoxy- and hydroxy-substituted cyclopropanes 4.

Asymmetric versions of the cyclopropanation reaction of electron-deficient olefins using chirally modified Fischer carbene complexes, prepared by exchange of CO ligands with chiral bisphosphites [21a] or phosphines [21b], have been tested. However, the asymmetric inductions are rather modest [21a] or not quantified (only the observation that the cyclopropane is optically active is reported) [21b]. Much better facial selectivities are reached in the cyclopropanation of enantiopure alkenyl oxazolines with aryl- or alkyl-substituted alkoxy-carbene complexes of chromium [22] (Scheme 5). 

Some remarks concerning the scope of the cobalt chelate catalysts 207 seem appropriate. Terminal double bonds in conjugation with vinyl, aryl and alkoxy-carbonyl groups are cyclopropanated selectively. No such reaction occurs with alkyl-substituted and cyclic olefins, cyclic and sterically hindered acyclic 1,3-dienes, vinyl ethers, allenes and phenylacetylene95). The cyclopropanation of electron-poor alkenes such as acrylonitrile and ethyl acrylate (optical yield in the presence of 207a r 33%) with ethyl diazoacetate deserve notice, as these components usually... 

Lithium tributylmagnesate induced iodine-magnesium exchange reaction of 5-alkoxy-3-iodomethyl-l-oxacyclopentanes (Scheme 16). A following intramolecular nucleophilic substitution led to construction of a cyclopropane with concomitant opening of the oxa-cyclopentane ring. 

The carbenoid from Et2Zn/CH2I2 [17], particularly when generated in the presence of oxygen [18], is more reactive than the conventional Simmons-Smith reagents. The milder conditions required are suitable for the preparation of 1-[16, 19] or 2-alkoxy-l-siloxycyclopropanes [20], which are generally more sensitive than the parent alkyl substituted siloxycyclopropanes (Table 2). Cyclopropanation of silyl ketene acetals is not completely stereospecific, since isomerization of the double bond in the starting material competes with the cyclopropanation [19]. 

From the correspondingly substituted A -pyrazolines (18), 1-alkoxy- and l-acetoxy-l,2,2,3,3-pentasubstituted cyclopropanes were obtained in good yields by thermolysis in cyclohexane solution under nitrogen using a high-pressure vessel (91JHC1773). 

Heterosubstituted cyclopropanes can be synthesized from appropriate olefins and car-benes. Since cyclopropane resembles olefins in its reactivity and is thus an electron-rich car bo-cycle (p. 76ft). it forms complexes with Lewis acids, e.g. TiCL, and is thereby destabilized This effect is even more pronounced in cydopropanone ketals. If one of the alcohols forming the ketal is a silanol, the ketal is stable and distillable. The O—Si-bond is cleaved by TiCl4 and a d3-reagent is formed. This reacts with a -reagents, e.g. aldehydes or ketals. Various 4-substituted carboxylic esters are available from 1-alkoxy-l-siloxycyclopropanes in this way (E. Nakamura, 1977). If one starts with l-bromo-2-methoxycyclopropanes, the bromine can be selectively substituted by lithium. Subsequent treatment of this reagent with carbonyl compounds yields (2-methoxycyclopropyl)methanols, which can be transformed to /7,y-unsaturated aldehydes (E.J. Corey, 1975B). 

Diastereoselective and enantioselective (see Enantio-selectivity) cyclopropanations of chiral alkenes can be achieved (Scheme 57). Unactivated alkenes usually do not participate in cyclopropanation reactions of Fischer carbenes. However, alkenyl- and heteroaryl-substituted group 6 alkoxy carbene complexes cyclopropanate unactivated alkenes in good yield (Scheme 58). ... 

Alkoxy-1,3-dienes and 2-alkoxy-l,3-dienes undergo addition of dichlorocarbene to the more remote double bond or to the oxygen-substituted double bond, respectively. For example, 1 -alkoxy-1,3-diene 5 gives cyclopropane 6, and 2-alkoxy-l, 3-diene 7 gives cyclopropane 8. ... 

---