Mode of alkylation of alcohols with O -cyclopropylmethyl trichloroacetimidate and O -cyclobutyl trichloroacetimidate

Acid promoted alkylation of hydroxy group containing acceptors 3 - 14 with O -cyclopropylmethyl and O -cyclobutyl trichloroacetimidates 1 and 2 , respectively, afforded ethers with cyclopropylmethyl, cyclobutyl, and homoallyl residues as a result of the rearrangement of the cation intermediates. The dependence of product formation on acceptor structure is discussed.


Introduction
2][3][4] A similar participation of C-C  bonds has been also discussed for the ion formed from the solvolysis of cyclobutyl substrates which often leads to the same products as they result from the corresponding cyclopropylmethyl substrates.The products from such solvolyses often include almost equal amounts of the cyclopropylmethyl (Cpm) and the respective cyclobutyl (Cb) derivatives in addition to minor amounts (5%) of the homoallyl (Ha) compound 1,5 (Scheme 1).7][8] Factors such as the nucleophilicity of the medium play a major role in this respect.With the above aspects in mind and in continuation of our work on glycoside bond formation utilizing O-glycosyl trichloroacetimidates as alkylating agents, 9 this paper describes the formation of O-cyclopropylmethyl trichloroacetimidate 1 and O-cyclobutyl trichloroacetimidate 2 and their behaviour as alkylating agents particularly of hydroxy groups of varying nucleophilicities under acid catalysis.[12]

Results and Discussion
The O-cyclopropylmethyl trichloroacetimidate (1) was readily obtained in 92% yield by reaction of cyclopropylmethanol with trichloroacetonitrile in the presence of DBU as a catalyst.1 can be stored at room temperature without decomposition; its structure was confirmed by the 1  Scheme 2. TMSOTf Promoted reaction of 1 and 2 with hydroxy groups.For structures 3-14, see Table 1.
Reaction of 1 with dibenzyl phosphoric acid (3) led exclusively to the cyclopropylmethyl derivative 3a (Table 1, entry 1) whereas reaction of 2 with 3 under the same conditions furnished a mixture of all three possible products (3a, 3b, 3c, ratio 4:3:2, entry 2).Also 1 and diphenyl phosphoric acid (4) gave a mixture of all three possible products (4a, 4b, 4c, ratio 4:2:1, entry 3) and p-toluenesulfonic acid (5) led to a 2:1 mixture of 5b and 5c (entry 4).Therefore, for the reaction of 1 with acceptor 3 transition state 3a  (Figure 1, SN2-type reaction) is proposed, thus avoiding rearrangement, whereas with more acidic acceptor 4 and particularly with 5 fast generation of cation intermediates 1 + (Cpm + ), 2 + (Cb + ) and Ha + (Scheme 2, SN1-type reaction) is favoured.Reaction of 3,5-dinitrobenzyl alcohol (6) with 1 and 2 in the presence of TMSOTf (0.6 equivalents) led to 1:1 mixtures of Cpm derivative 6a and Cb derivative 6b (entries 5, 6).However, the less acidic 7 and benzyl alcohol (8) gave only Cb products (7b, 8b, entries 7-9). 13holesterol (9) and the 6-O-and 4-O-unprotected glucose derivatives 10 and 11 gave similar results as 6 (entries 10-13), whereas due to steric hindrance low reactive alcohols 12 and 13 afforded only Cb derivatives (12b, 13b, entries 14, 15).The importance of the nucleophilicity of the acceptor was also demonstrated for the reaction with thiophenol ( 14) and 1 which gave exclusively the Cpm derivative 14a (entry 16). 14Therefore, in all these cases carbocation intermediates Cpm + and Cb + seem to be the decisive reaction partners which are trapped by typical alcohol acceptors in a close to 1:1 fashion whereas with increasing steric demand the Cb derivative is formed.The preference for the formation of Cb derivatives with 7 and 8 requires further studies.The equilibration between Cpm + , Cb + , and Ha + (Scheme 2) or formation of some kind of nonclassical carbocation intermediate 1 is very fast because lowering the reaction temperature to -40 °C (reaction of 1 + 10) or varying the reaction time before adding the acceptor had practically no effect on the result.
The Cpm and the Cb ethers can be readily identified by 1 H NMR spectroscopy where the former group appears as a multiplet at  0.26-1.10 and the latter as a multiplet at  1.4-2.4.These data are in accordance with those reported. 15The interest in the Cpm group and the 1-methyl CPM group as acid sensitive O-protecting groups 16,17 led us to investigate the hydrogenolysis of the Cpm and Cb group because this reaction is affected by the ring strain.In accordance with this effect, hydrogenolysis of 10a and then O-acetylation under standard conditions led to Cpm protected derivative 15 whereas hydrogenolysis of 10b led to removal of the Cb group and of the benzyl groups affording after O-acetylation 16 (Scheme 3).In conclusion, the Cpm and Cb trichloroacetimidates are excellent alkylating agents under acid catalysis.Equilibration between the generated carbocation intermediates is fast, 1 therefore product formation depends essentially on the nucleophilicity and the steric demand of the acceptors.In addition, the cyclobutyl group seems to be an interesting alternative to the benzyl group for hydroxy group protection.

Experimental Section
General.Solvents were purified in the usual way.TLC was performed on plastic plates coated with silica gel 60 F254 (E.Merck, layer thickness = 0.2 mm).Detection was achieved by treatment with a solution of ammonium molybdate (20 g) and cerium(IV) sulfate (0.4 g) in 10% H2SO4 (400 mL) or with 15% H2SO4 and heating at 150 °C.Flash chromatography was carried out on silica gel (Baker, 30-60 µm).Medium-pressure liquid chromatography (MPLC): LiChroprep Si 60 (Merck; particle size 15-25 µm) and detection was carried out with a differential refractometer.Optical rotations were determined at 20 °C with a Perkin-Elmer 241/MC polarimeter (1-dm cell).NMR spectra were recorded with Bruker AC 250 and 600 DRX instruments using tetramethylsilane as the internal standard.The 1 H NMR spectral assignments were based on chemical shift correlation (DQF COSY) and rotating frame nuclear Overhauser effect spectroscopy (ROESY).The 13 C NMR spectral assignments were based on carbon-proton shift-correlation heteronuclear multiple quantum coherence (HMQC).MS spectra were recorded with a MALDI-Kompakt (Kratos) spectrometer; matrix: 2,5-dihydroxybenzoic acid (DHB).
Microanalyses were performed at the Microanalysis unit at the Fachbereich Chemie, Universität Konstanz.

B. General procedure for the reaction of (1) or (2) with acceptors (6-14).
A solution of 1 or 2 (0.3 g, 1.4 mmol) and acceptor (1.4 mmol) were dissolved in dry dichloromethane (10 mL) at room temperature.TMSOTf (0.15 mL, 0.83 mmol) was added and the reaction mixture stirred for 0.5-3.0h.The reaction mixture was quenched by addition of solid sodium bicarbonate, then diluted with dichloromethane, filtered and concentrated.The crude product was purified by column chromatography.For details, see Table 1.

Figure 1 .
Figure 1.Reaction of 1 and 3 and proposed transition state for the reaction.Reaction of 3,5-dinitrobenzyl alcohol(6) with 1 and 2 in the presence of TMSOTf (0.6 equivalents) led to 1:1 mixtures of Cpm derivative 6a and Cb derivative 6b (entries 5, 6).However, the less acidic 7 and benzyl alcohol(8) gave only Cb products (7b, 8b, entries 7-9).13Cholesterol (9) and the 6-O-and 4-O-unprotected glucose derivatives 10 and 11 gave similar results as 6 (entries 10-13), whereas due to steric hindrance low reactive alcohols 12 and 13 afforded only Cb derivatives (12b, 13b, entries 14, 15).The importance of the nucleophilicity of the acceptor was also demonstrated for the reaction with thiophenol (14) and 1 which gave exclusively the Cpm derivative 14a (entry 16).14Therefore, in all these cases carbocation intermediates Cpm + and Cb + seem to be the decisive reaction partners which are trapped by typical alcohol acceptors in a close to 1:1 fashion whereas with increasing steric demand the Cb derivative is formed.The preference for the formation of Cb derivatives with 7 and 8 requires further studies.The equilibration between Cpm + , Cb + , and Ha + (Scheme 2) or formation of some kind of nonclassical carbocation intermediate 1 is very fast because lowering the reaction temperature to -40 °C (reaction of 1 + 10) or varying the reaction time before adding the acceptor had practically no effect on the result.The Cpm and the Cb ethers can be readily identified by1  H NMR spectroscopy where the former group appears as a multiplet at  0.26-1.10 and the latter as a multiplet at  1.4-2.4.These data are in accordance with those reported.15The interest in the Cpm group and the 1-methyl CPM group as acid sensitive O-protecting groups16,17 led us to investigate the hydrogenolysis of the Cpm and Cb group because this reaction is affected by the ring strain.In accordance with this effect, hydrogenolysis of 10a and then O-acetylation under standard conditions led to Cpm protected derivative 15 whereas hydrogenolysis of 10b led to removal of the Cb group and of the benzyl groups affording after O-acetylation 16 (Scheme 3).

Table 1 .
Continued a For abbreviations and experimental procedures see text.