Catalytic interaction of 1,3-diheteracycloalkanes with diazo compounds

The results are presented of research on the catalytic interactions of 1,3-diheteracycloalkanes with diazocompounds (N 2 CH 2 , N 2 CHCO 2 Me), the influence of the nature of the catalyst and structure of the starting heterocycles on the yield and structure of products formed.

In the reactions of 3-ethyl-2-phenyl-and 2,3-diphenyl-oxazolidines with methoxycarbonylcarbene, which is generated by thermocatalytic decomposition of methyl diazoacetate in the presence of copper bronze, 16 insertion occurred predominantly into the C-N bond of the oxazolidine ring to give morpholine-3-carboxylic acid esters.It was also noted 16 that in the presence of Rh 2 (OAc) 4 neither insertion products of carbene into the C-N bond nor into the C-O bond are formed.
ARKAT USA, Inc.The morpholine derivatives 4a,b are generated apparently through the attack of methoxycarbonylcarbene on the oxygen atom of oxazolidines 3a,b to form O-ylides, which undergo the Stevens rearrangement leading to ring enlargement. 20It should be noted that thermocatalytic decomposition of N 2 CHCO 2 Me (120 °С, copper bronze) 16 with oxazolidine 1a affords a complex mixture of compounds, in which the percentage of morpholine 4a is lower than 13%.
The stereochemical compositions of compounds 4a,b were determined by analyzing the chemical shifts and spin-spin coupling constants in the 1 H NMR spectra.The 1 H NMR spectrum of compound 4a shows doublets at δ 3.36 and 3.95 ( 3 J 2,3 = 8.9 Hz) corresponding to the methine protons at the C(3) and C(2) atoms, respectively, of the morpholine ring.The spin-spin coupling constant is indicative of the trans arrangement of the substituents at the adjacent carbon atoms.The COLOC 2D NMR spectrum of ester 4a shows a cross-peak between the signal for the carbonyl carbon atom (δ 169.6) and a low-field signal for the methine proton at the C(2) atom (δ 3.95), which confirms that methoxycarbonylcarbene is inserted into the C(2)-O bond of oxazolidine 3a.

Scheme 3
To reveal the relationships between the structure of 1,3-diheteracyclopentanes and the rate of insertion of methoxycarbonylcarbene into the carbon-heteroatom bond, the reactions of compounds 1b, 3a, 3c with N 2 CHCO 2 Me in the presence of Rh 2 (OAc) 4 were studied by the competitive reaction method (Scheme 4).The relative reactivity was determined at 40 °С by adding a solution of N 2 CHCO 2 Me in dichloromethane to a mixture containing dioxolane 1b and its heteroanalog 3a or 3c in a molar ratio 1b: 3a (or 3c): N 2 CHCO 2 Me: Rh 2 (OAc) 4 = 250: 250: 100: 1.

Scheme 4
As expected, 2-phenyl-1,3-oxathiolane 3c showed the highest reactivity (k rel (3c/1b) = 9.8), whereas oxazolidine 1а appeared to be only just slightly more reactive than 1,3-dioxolane 1b (k rel 3a/1b) = 1.7) although it is characterized by the insertion of the carbene fragment into the C-O bond rather than into the C-N bond.This fact is apparently attributed to the additional replacement at the nitrogen atom, which hinders the intermediate formation of N-ylide.

Scheme 5
The possible mechanism of the reaction can include the generation of ylide followed by 1,2anionic rearrangement (the Stevens rearrangement). 1,20Apparently, the O(1) atom is involved in the formation of ylide; this is confirmed by the selective formation of products of formal insertion of methoxycarbonylcarbene into O(1)-C(2) bond.Successful reaction of methyl diazoacetate with benzaldehyde derivatives correlates well with the mechanism of 1,2-anionic rearrangement. 20According to this mechanism, the migrating group in its transition state is a free radical stabilized by conjugation in its substituents, and thus the process occurs more easily.
Catalytic interaction of N 2 CH 2 and N 2 CHCO 2 Me with unsaturated 1,3-diheteracycloalkanes.It has been demonstrated 24 that the introduction of the oxazolidine or boronate group into unsaturated compounds leads to an increase in both the yields of cyclopropanation products compared to those obtained in reactions with unfunctionalized molecules and the regioselectivity of cyclopropanation of dienes with N 2 CH 2 in the presence of Pd 2 (OAc) 2 .The influence of the characteristics of the acetal substituents in olefins on catalytic reactions of the latter with N 2 CH 2 has not been previously examined.In the present study, we examined the influence of the nature of the acetal group and the catalyst on the catalytic cyclopropanation with diazomethane of a series of unsaturated compounds, derived from trans-crotonaldehyde (8a,d), trans-cinnamaldehyde (8b,e) and hex-5-en-2-one (8c,f) (Scheme 6).
Cyclopropanation was carried out at 5-10 °C by adding a solution of N 2 CH 2 in Et 2 O or CH 2 Cl 2 to an unsaturated compound in the presence of a catalyst, in the molar ratio of 50: 150: 1 of olefin: N 2 CH 2 : catalyst, for 30 min.Investigation of cyclopropanation of dioxolane 8a with the use of Pd(OAc) 2 , PdCl 2 , Pd(acac) 2 , CuCl, [CuOTf] 2 •C 6 H 6 , Cu(acac) 2 , and Cu(OTf) 2 , as the catalysts demonstrated that Pd(acac) 2 and Cu(OTf) 2 are the most efficient palladium and copper catalysts, respectively, under the reaction conditions used.Cyclopropanation catalyzed by Pd(acac) 2 or Cu(OTf) 2 afforded products in 99 and 49% yields, respectively.Hence, all further reactions were carried out with the use of these two catalysts.The resulting cyclopropanes were isolated by preparative TLC and characterized by 1 H-and 13 C-NMR spectroscopy.
Compound 8a reacts with N 2 CH 2 in the presence of Pd(acac) 2 or Cu(OTf) 2 to give a complex mixture of products.By contrast, cyclic acetal 8d containing two electron-withdrawing butoxycarbonyl groups at positions 4 and 5 of the dioxolane fragment is readily subjected to cycloprotonation in the presence of Pd(acac) 2 to form dibutyl 2-(trans-2-methylcyclopropyl)-1,3dioxolane-trans-4,5-dicarboxylate (8d).Unlike simple crotonaldehyde derivatives 8a, cinnamaldehyde derivatives react with N 2 CH 2 in the presence of Pd(acac) 2 to give the corresponding cyclopropane derivatives 9b,e in high yields.Cyclopropanation of hexenone derivatives 8c,f occurs with a somewhat higher efficiency compared to hexenone and produces cyclopropanes 9c,f in 87-99% yields.
The Cu(OTf) 2 catalyst is less efficient than Pd(acac) 2 in cyclopropanation of cinnamaldehyde derivatives 8b,e or hexenone derivatives 8c,f, and these reactions give the corresponding cyclopropanes in low yields.In the reaction of unsaturated compound 8b, Cu(OTf) 2 catalyzes the acetal deprotection giving rise to the starting cinnamaldehyde, the reaction being typical only of cinnamaldehyde derivatives.
The higher efficiency of Pd compounds in the cyclopropanation of unsaturated acetals is apparently associated with intramolecular stabilization of π -olefin complexes by oxygen atoms.13b The study of catalytic cyclopropanation of 1,2-disubstituted double bonds in unsaturated carbonyl compounds and their acetal (ketal) derivatives with diazomethane provided evidence for higher selectivity of cyclopropanation of the latter compared to the starting unsaturated carbonyl compounds and for the activating effect of the acetal fragments on the reactivity of the C=C bond compared to the cyclopropanation of usual 1,2-disubstituted alkenes.13b The interaction of equimolar quantities of methyl diazoacetate with cyclic acetals 10a,b and 1,3-oxathiolanes 10c,d in the presence Rh 2 (OAc) 4 proceeds selectively and results in products of C-X insertion 11a-c and [2,3]-sigmatropic rearrangement 12a-d (Scheme 7).The absence of cycloaddition products of methoxycarbonylcarbene to the C=C bond in the reaction mixture and arrangement of substituents in the isolated products testifies that reaction proceeds through formation of one ylide.The formation of ylides takes place by the electrophilic addition of carbenoid species generated from methyl diazoacetate to the heteroatom under the action of the catalyst.The selectivity of formation of products of Stevens rearrangement 11a-c and [2,3]-ARKAT USA, Inc. sigmatropic rearrangement 12a-d is defined by the influence of both electronic and steric factors of the substituents. 25,26

Experimental Section
General Procedures.The 1 H-and 13 C-NMR spectra were recorded on a Bruker AM-300 spectrometer (300.13 and 75.47 MHz, respectively) in CDCl 3 with SiMe 4 as the internal standard.The IR spectra were measured on a Specord M82-63 instrument in a thin layer.The mass spectra were obtained on an MX-1320 instrument; the ionizing electron energy was 70 eV; the temperature of the ionization chamber was 50-70 °С.The GLC analysis was carried out on a Chrom-5 chromatograph equipped with a flame ionization detector (with a 1200×5 mm column with 5% SE30 on Inerton N-AW DMCS (0.125-0.160 mm) using helium as the carrier gas.The TLC analysis was performed on Silufol chromatographic plates (Merck).Preparative separation was performed by column chromatography on silica gel Chemapol (60 L, 100/160 µm).Starting 1,3-diheteracycloalkanes were synthesized according to known procedures, 19,27 distilled under a stream of argon, and stored under an inert atmosphere over metallic sodium.The solvents (CH 2 Cl 2 , diethyl ether, benzene, hexane, and petroleum b.p. 40-70 °С) were purified according to standard procedures.
Reactions of 1,3-dioxolanes 1a-f with methyl diazoacetate in the presence BF 3 .OEt 2 (general procedure).Methyl diazoacetate 2.5 g (25 mmol) was added with vigorous stirring at 20 °С over 1 h to a solution of l,3-dioxolane (50 mmol) and BF 3 .OEt 2 0.07 g (0.5 mmol).The reaction mixture was additionally stirred for 1 h.The residue was dissolved in 10 mL of diethyl ether and passed through a thin layer of Al 2 O 3 .All products 2a-f were purified by vacuum distillation.