Ring opening of some 1,1,2-trihalocyclopropanes with a polar substituent attached to C-2; evidence for regioselective attack directed by hydrogen bonding

Selected members of the title family of compounds, prepared from 1,1-dibromo-2-chloro-2-diethoxymethylcyclopropane by standard chemical transformations, were dissolved in mixtures of dichloromethane and a protic, nucleophilic reagent and treated with 50% aqueous sodium hydroxide in the presence of a phase-transfer catalyst, triethylbenzylammonium chloride (TEBA), at room temperature. In all cases except two, regiospecific ring opening of the cyclopropane took place, giving one product formed by nucleophilic attack of the carbon atom to which the polar substituent was attached. This clearly lends support to the notion that hydrogen bonding contributes significantly to direct the attack of protic nucleophiles.


Introduction
2][3][4][5] Mechanistic studies have shown that the reaction under these phase-transfer conditions (PTC) is a multistep process encompassing several dehydrohalogenations and involving a cyclopropene intermediate, the corresponding 1-R-3,3-dihalocyclopropene (Figure 1), which is consumed by nucleophilic attack of ethoxide and ethanol at C-1 and C-2, respectively, affording both ketal and acetal. 4 It has been established that the nucleophilic attack of the cyclopropene intermediate is sensitive to the steric bulk of R in such a way that the amount of acetylenic ketal decreases when R becomes sterically more demanding. 6However, one compound that appeared to deviate from this rule, was 1,1-dibromo-2-chloro-2-diethoxymethylcyclopropane (1a) which afforded 3,3,4,4tetraethoxybut-1-yne (2a) as the only product when treated with sodium hydroxide under standard conditions (Scheme 1). 7Exclusive formation of this ketal requires regiospecific attack of the cyclopropene intermediate at the carbon atom bearing the polar substituent, and this suggests that the steric repulsion between ethanol molecules and R, the diethoxymethyl moiety, is more then offset by attractive forces due to hydrogen bonding between the same entities.It is quite conceivable that this seemingly exceptional case is not really extraordinary, but reflects a general reactivity pattern which remains to be uncovered.We therefore decided to extend the scope of our studies by reacting selected 1,1,2-trihalocyclopropanes with a different polar substituent at C-2 under the reaction conditions employed to convert 1a to 2a, 7 and by reacting 1a in the presence of protic reagents other than ethanol.The results of our investigations are reported here.Aldehyde 1b is also an excellent starting material for the preparation of primary and secondary alcohols.When treated with sodium borohydride in ethanol, 2,2-dibromo-1chlorocyclopropylmethanol (1e) was obtained in 83% yield, and exposure of the same aldehyde to methylmagnesium iodide furnished 1-(2,2-dibromo-1-chlorocyclopropyl)ethanol (1f) in excellent yield (88%).It is noteworthy that no product due to reduction of the gem-dibromo moiety was observed in the latter case, since it is well known that this Grignard reagent has the ability to convert similar cyclopropanes to the corresponding monobromides. 9,10With 1f at hand formation of the corresponding ketone, 2,2-dibromo-1-chlorocyclopropyl methyl ketone (1g), was envisaged to take place by a simple Jones oxidation, and this was indeed achieved under standard conditions.
Exploratory experiments with 1a revealed that this cyclopropane could be converted directly to other acetals under various conditions.This reactivity pattern was utilized to prepare a thioacetal, 2-(2,2-dibromo-1-chlorocyclopropyl)-1,3-dithiolane (1h), which was obtained in good yield (78%) by treating 1a with 1,2-ethanedithiol in the presence of slightly acidic silica gel at room temperature. 11The same dithiolane could also be synthesized, with a slightly better yield (85%), by reacting aldehyde 1b with 1,2-ethanedithiol in the presence of boron trifluoride diethyl etherate following a somewhat modified literature procedure. 12ng opening of cyclopropanes 1b-1h under PTC in the presence of ethanol Cyclopropanes 1b -1h were treated with sodium hydroxide under the same phase-transfer conditions that were applied when 1a was converted quantitatively to 3,3,4,4-tetraethoxybut-1yne (2a).All the compounds appeared to react under these conditions, and most of them gave one product only, viz. the alkyne analogous to 2a, although there were exceptions, aldehyde 1b and alcohols 1e and 1f.
The primary alcohol (1e) furnished a 1:1 mixture of terminal alkyne 2,2-diethoxybut-3-yn-1ol (2e), a ketal, and the corresponding internal alkyne, 4,4-diethoxybut-2-yn-1-ol (3e), an acetal (Scheme 3), in a combined yield of 82%, which is lower than that of 2a from 1a (98%), but better than what was obtained when most of the other cyclopropanes are reacted under the same conditions (Table 1).The other alcohol, 1f, which is secondary, reacted completely differently from the majority of the cyclopropanes and afforded the internal alkyne, 5,5-diethoxypent-3-yn-2-ol (3f) in 85% isolated yield.Surprisingly enough, not even traces of the terminal-alkyne analogue 2f could be detected.Aldehyde 1b reacted much more diversely than the other trihalocyclopropanes and gave a product mixture containing at least 12 compounds as borne out by TLC analyses.IR and NMR spectra of the product mixture indicated the presence of a range of functional groups including conjugated and / or unconjugated alkyne, allene, aldehyde, and ethoxy moieties.Attempts to isolate and purify some of the products by column chromatography were unsuccessful, not only because several of the products had almost the same R f value, but also due to the fact that some of the compounds appeared to be unstable and suffered secondary reactions.
If the regiospecificity of the ring opening of 1 were mainly determined by steric influence, the size of most of the R groups in 1 is such that formation of the internal alkynes (3) should be favoured.This is not the case; on the contrary, in most cases, viz.1c, 1d, 1g and 1h, acetal 3 is not formed at all.This clearly indicates that the R groups in these four substrates form hydrogen bonds with ethanol that are strong enough to cause the same redirection as the hydrogen bonding between the diethoxymethyl moiety during ring opening of 1a.As a result ethanol attacks the cyclopropene intermediates at C-1 instead of C-2 (see Scheme 1) and affords the corresponding terminal alkynes 2 only.
Although 1e and 1f also contain R groups that can engage in hydrogen bonding with ethanol, both substrates deviate from the pattern outlined above, 1e by giving a mixture of the corresponding alkynes 2e and 3e, and in the case of 1f, by furnishing the internal acetylene 3f only.The reason for this behaviour is not clear, but one explanation can be that both compounds are alcohols, whose OH group can engage in hydrogen bonding with ethanol not only as an electron donor (like 1c, 1d, 1g and 1h), but also as an electron acceptor.This additional hydrogen bond is capable of facilitating ethanol attack at both C-1 and C-2, depending on conformational changes, thus preventing regiospecific ring opening by attack of C-2 to take place (Figure 2).The fact that 1f gives no 2f at all whereas 1e affords a reasonable yield of 2e could then be explained by the larger steric crowding of the (hydroxyl)(methyl)methyl moiety as compared to the (hydroxyl)methyl group.

Ring opening of 1a under PTC in the presence of an alcohol or a thiol
A consequence of the results presented and discussed above is that ring opening of 1,1-dibromo-2-chloro-2-diethoxymethylcyclopropane (1a) with NaOH under phase-transfer conditions in the presence of alcohols other than ethanol should give terminal alkyne only.In order to test the validity of this line of reasoning 1a, dissolved in methylene chloride containing either an alcohol different from ethanol or a thiol, was reacted with sodium hydroxide under the same phasetransfer conditions that were applied when 1a was converted to 2a in quantitative yield.The results, which are summarized in Table 2, exhibit at least two noteworthy trends.Most importantly, when ring opening took place only one alkyne was obtained, viz.2, the formation of which is facilitated by hydrogen bonding.Secondly, the yield of 2 drops as the acidity of the alcohol or thiol drops; thus, whereas methanol gives the corresponding ketal (2i) in quantitative yield, 1a is recovered unchanged when tert-butyl alcohol is employed (Table 2).This very considerable difference in reactivity is closely connected to the hydroxide's ability to convert the alcohols into the corresponding alkoxides; the reaction appears to be unsuccessful with tert-butyl alcohol, but satisfactory with methanol (which furnishes methoxide that generates the reactive cyclopropene precursor to 2i, see Scheme 1) because methanol is far more acidic than tert-butyl alcohol. 13 The importance of a proper balance between the nucleophilicity and the acidity of the organic protic reactant and its corresponding anion(s) is illustrated by the outcome of the reactions involving 1,2-ethanedithiol and 2-mercaptoethanol instead of a simple alcohol.When exposed to an excess of sodium hydroxide, the dithiol is converted to the corresponding dithiolate, which is an excellent nucleophile, but such a weak base that 1a does not suffer elimination to give the reactive cyclopropene intermediate (Figure 1) involved in the ring-opening reaction.When 2mercaptoethanol is exposed to the same conditions, on the other hand, formation of the corresponding thiolate takes place (because RSH is much more acidic than ROH).This hydroxythiolate is subsequently in part converted to -SCH 2 CH 2 O -dianion, which is a strong base as well as a good nucleophile.Attack on 1a by the alkoxide moiety affords 3,3-dibromo-1diethoxymethylcyclopropene, which first reacts with the thiolate at C-1 followed by several transformations that ultimately lead to formation of 2-diethoxymethyl-2-ethynyl-1,3-oxathiolane (2n) (Scheme 4) in moderate yield (Table 2).The reaction involving 2-amionoethanol is a special case in the sense that the primary product, conceivably N,O-ketal 4 (a 1,3-oxazolidine), appears to be unstable under the reaction conditions and reacts further to furnish 1,1-diethoxy-3-butyn-2-one (2m).This secondary reaction is not surprising when the instability of N,O-ketals is taken into account. 14n conclusion, it has been substantiated that the regioselectivity of the ring opening of 1,1,2trihalocyclopropanes with a polar group R attached to C-2 by protic reagents is strongly influenced by hydrogen bonding between R and the reagents.As a result attack at C-2 predominates in most cases and leads to formation of terminal alkynes.

Experimental Section
General Procedures.IR spectra were recorded on a Nicolet Impact 410 infrared spectrophotometer.NMR spectra were run on a Bruker Spectrospin AC 200 F or a Bruker Spectrospin DMX 400.Chemical shifts are reported downfield from TMS and coupling constants are given in Hz.GC analyses were performed on a HP 5890 Gas Chromatograph with a flame ionization detector and a HP Ultra 1 column (100% dimethyl-polysiloxane, 25 m, 0.2 mm i.d., 0.33 µm).Flash chromatography was carried out with Silica gel (230-400 mesh) as the stationary phase and mixtures of hexane and ethyl acetate as the mobile phase.The eluent composition is given in each case.TLC analyses of the reaction mixtures were performed with Silica gel (60 F 254 ) on aluminium sheets with mixtures of hexane and ethyl acetate as the mobile phase.Mass spectra were obtained on a VG 7070 Micromass spectrometer, an Autospec Ultima mass spectrometer, a three-sector instrument with EBE geometry from Micromass Ltd Manchester, or JEOL AccuTOF T100GC, which were operated in the EI mode at 70 eV, the DART mode, or the CI mode as indicated for each spectrum.All boiling and melting points are uncorrected.

Scheme 2 .
Scheme 2. Structures and yields of cyclopropanes 1b-1h prepared from 1a as described in this paper.The synthesis of 1a from ethyl vinyl ether is described in refs.7 and 8.

a
Taken from ref. 7. b All of 1b was consumed, but neither 2b nor 3b could be isolated from the reaction mixture.

Figure 2 .
Figure 2. Two extreme conformations of 1e (R = H) and 1f (R = Me) engaged as electron acceptors in hydrogen bonding with ethanol.