Synthesis of 1,1-disubstituted 2-vinylcyclopropanes by alkylation of 1,3-

1,1-Disubstituted 2-vinylcyclopropanes are accessible via well-known double alkylation of CH-acids with 1,4-dihalobut-2-enes (Scheme 3). This approach is described in literature enough to choose an appropriate synthetic method for a preparation of the gem-EWG disubstituted vinylcyclopropanes currently ordered for polymerization experiments (Scheme 10).

Scheme 10 CO₂Me

R

O R = CH₃, 4-CNC₆H₄, 4-MeO₂CC₆H₄

Among the required starting 1,3-dicarbonyl compounds, methyl acetoacetate (16) was commercially available, whereas 2-aroyl acetic acid methyl esters had to be prepared in some different ways. Thus, according to a modified CLAISEN condensation protocol,^[24] refluxing of methyl acetate (17) with methyl 4-cyanobenzoate (18) in the presence of sodium hydride excess, gave methyl 3-(4-cyanophenyl)-3-oxyprop-2-enoate (19) in good yield (Scheme 11).

Scheme 11

Unfortunately, this method could not be applied for the condensation of methyl acetate (17) with dimethyl terephthalate, because its low solubility could not provide a sufficient excess of diester in respect to the slowly added into the reaction media methylene component 17. It resulted in various self-condensation products instead of the desired cross-condensation product. On the other hand, previously described two-step procedure for the synthesis of ethyl [4-(methoxycarbonyl)benzoyl]acetate^[25] starting from 4-methoxycarbonylbezoyl chloride (20) and ethyl acetoacetate, has no preparative value because of its low yield (25% after column chromatography).

Therefore, an original protocol for the synthesis of 21 was developed. Lithium enolate generated from methyl acetate (17) and LDA at –78 °C, had been found to be acylated by a slow addition of 0.5 equivalents of 4-methoxycarbonylbezoyl chloride (20) at –78 °C, to give the target product 21 in satisfactory yield (40% after recrystallization) (Scheme 12).

Scheme 12

Thus prepared methyl 2-aroylacetates 19 and 21 were alkylated with cis-1,4-dibromobut-2-ene^[26] (22) in the presence of potassium carbonate according to JACOBI et al. protocol,^[27]

which was successfully reproduced in the case of methyl acetoacetate (16) to give a sufficient amount of 23 in good yield (71%) (Scheme 13). This protocol was chosen because of mild reaction conditions that excluded, so far as possible, various side reactions. Thus, at relatively

used^[13]), was avoided. Protic solvent (MeOH) reduced the formation of O-alkylated products, because nucleophilic oxygen atom of the corresponding enolate had been solvated.

Scheme 13

OH

OMe O

Br Br

R CO₂Me

R +

solvent 20 °C, 78 h

23-25 42–71%

16,19,21 22

K₂CO₃

Table 1. Synthesis of vinylcyclopropanes 23-25. Yields and reaction conditions.

Entry Starting

material R Product Solvent Yield, % (E/Z-ratio)

1 16 CH₃ 23 Methanol 71(~2:1)

2 19 4-CNC₆H₄ 24 Methanol/THF 42^[a]

3 21 4-CO₂MeC₆H₄ 25 Methanol/THF 65 (~5:1)^[b]

[a] Pure E-24 was obtained; E/Z-ratio was not determined. – ^[b] Yield of crude product is given.

As can be seen from the Table 1, increasing of electron-withdrawing character of substituent attached to a carbonyl group decreases the yield of target product. Thus, in the case of 24 and 25, some amounts of the corresponding 4-substituted benzoic acids and their methyl esters were found among the by-products. Their formation could be attributed to retro-CLAISEN reaction of the starting 1,3-dicarbonyl compounds 19 and 21. Commonly, a formation of relatively high number of by-products drastically complicated the purification of target product. Thus, even in case of 16, characterized by the highest yield in this series, purification of the product 23 by column chromatography had not been avoided. Fortunately, diastereomerically pure 24 appeared to be easily isolated just by recrystallization of a crude product from the mixture of hexane and iso-propanol, whereas a column chromatography of the crude 25 could reach only 90% purity.

Stereochemical assignment of the synthesized products 23-25 was conducted taking in consideration its ¹H NMR spectra. On the first look, they showed clear difference between signals of olefin proton 1'-H for major and minor isomers. Thus, δmaj(1'-H) < δmin(1'-H) and (³J2-H−1'-H)maj < (³J2-H–1'-H)min; this trend was maintained for all substances 23-25 (Table 2).

Table 2. Selected chemical shifts and coupling constants for the compounds 23-25.

Then, the pure minor isomer of 25 was isolated and investigated by 1D NOE. Correlation obtained between 2-H – Ar-Hortho as well as 1'-H – OCH3 attached to a cyclopropane ring, clearly evidences that minor isomer of 25 adopts (Z)-configuration (Figure 1). Hence the presented double alkylation of β-ketoesters resulted in more sterically congested E-isomer as a major product. This outcome may be explained in terms of a concerted ring closure process. Enolic double bond was supposed to attack diastereotopic carbon atom (C-4) in tautomeric enolate 21' only suprafacially because the conformation required for energetically more advantageous antarafacial ring-closure, is sterically impeded. Thus, growing of electron density towards C-4 position to be attacked in the enolate 21'-maj, occured from the Si-face, whereas the C-4 position of enolate 21'-min, was attacked from the Re-face (the direction of electron density redistribution is shown on Scheme 14). Since the only one concerted bond redistribution order has been assumed to be possible for each isomer, a stereochemical outcome of ring closure should depend on the ratio of tautomeric enolates in the reaction mixture.

H

Scheme 14

This consideration is in a good accordance with experimental data. Thus, the cyclization of more thermodynamically stable enolate 21'-maj resulted in less thermodynamically stable vinylcyclopropane E-25 as a major isomer, whereas less thermodynamically stable enolate 21'-min yielded after cyclization more thermodynamically stable vinylcyclopropane Z-25 as the minor one. Moreover, in terms of this assumption, the increasing of electron-withdrawing character of substituent R (which obviously would increase the tautomeric excess of enolate mixture) should also increase diastereomeric excess of the reaction, what in fact has been observed (Table 1). However, it should be noted that these revelations, together with a spectroscopical trend (because of alkoxycarbonyl group influence on chemical shifts of cyclopropane protons) (Table 1) cannot be applied for the structure elucidation of monosubstituted vinyl cyclopropanes, which formation is featured by clear trans- diastereoselectivity.^[28] That direction of monosubstituted enolate ring closure could be referred to an antarafacial process. Its realization becomes possible by removing one of the EWG substituent from α-position of enolate (Scheme 15). As it is shown on Scheme 15, coplanarity (and, correspondingly, the best overlapping) of the frontier orbitals forming cyclopropane bond, could be achieved by antarafacial process. It requires strain conformation, therefore such process is preferential only for R² = H. Otherwise, more bulky substituent (R² = CO2Me) pushed the 4-bromobut-2-enylic fragment onto the plane

perpendicular to that of 1,3-dicarbonyl fragment. That resulted in the less sterically strained conformation 21', though with less frontier orbital overlapping opportunity. Therefore, suprafacial ring closure mechanism was realized in this case.

Scheme 15

CH₂Br R²

O

R¹ H^* H^*

R² R¹

O

CH₂Br R²

O R¹ H^*

R¹ O

OMe

O Br

H^* O

R² O

CH₂Br H^*

R¹ H H

"cis-"

H^* R²

R¹ O R² = H

R² = CO₂Me H H

"trans-"