Rapid Conversion of Hindered Arylsulfonates to Alkyl Chlorides with Retention of Configuration

Abstract

Arylsulfonates of hindered secondary alcohols are converted to the corresponding alkyl chlorides very rapidly and in good yields in the presence of titanium tetrachloride at low temperatures. These reactions proceed with exclusive retention of configuration.We are interested in the development of highly efficient leaving groups containing chelating units capable of attracting incoming nucleophiles. We envision that electrophiles containing sulfonate leaving groups could be rendered more reactive by modifying them to contain a metal chelating moiety. 1 In this chelated form, the nucleophilic portion of a salt or Lewis acid is localized near the electrophilic center thus decreasing the entropic barrier relative to intermolecular reactions. The chelated metal would also be expected to stabilize the developing negative charge on the oxygens of the sulfonate leaving group in the transition state. 2 We have recently demonstrated that metal halides react at greatly accelerated rates with arylsulfonatebased nucleophile assisting leaving groups (NALGs) that contain a polyether unit (including macrocyclic) attached to the aryl ring ortho to the sulphonate. 3 In an attempt to further explore the generality of the NALG technology, we discovered a highly efficient method to convert NALG sulfonates of hindered alcohols to the corresponding chlorides using TiCl 4 at low temperatures.While a related chlorination procedure with alkyl tosylates has been reported, 4 in this note, we demonstrate, for the first time, the stereospecificity and utility of the sulfonate/TiCl 4 technique in the synthesis of a variety of alkyl chlorides. 5 A series of alcohols were reacted with aryl sulfonyl chlorides containing a diethylene glycol moiety to give sulfonate esters 1 (Table 1). In general, the treatment of sulfonate esters 1 with TiCl 4 in methylene chloride at −78 °C led to high yields of the corresponding alkyl chlorides. In each case, the reaction was complete in less than 2 minutes. With 1,3-diphenyl-2-propanol, we have observed that its NALG and tosyl esters primarily give the elimination product in the With sulfonates of chiral secondary alcohols (Table 1, entries 2-4), the chloride products were obtained as single diastereomers with complete retention of configuration. 8 Thus, the NALG sulfonates of highly hindered menthol and isomenthol were both converted to the corresponding chlorides of the same configuration in excellent yields by exposure to TiCl 4 for two minutes. Similarly, the NALG sulfonate of cholesterol (entry 4) was converted to the corresponding chloride almost instantaneously at −78 °C. Proton NMR confirms the formation of one stereoisomer with retention of configurationIn the 2-adamantyl system, we observed a 90% conversion to the chloride with no side product arising from rearrangement of the adamantine nucleus (entry 5). 9 Backside nucleophilic displacement of 2-adamantyl sulfonate is essentially precluded due to steric crowding, 10 thus the chlorination reaction likely proceeds via a front-side S N i-type ...

A Direct and Stereoretentive Synthesis of Amides from Cyclic Alcohols

“…The initial inclination to use titanium(IV) fluoride in reactions with chelating leaving groups was based on our desire to develop a stereoretentive fluorination reaction as a follow-up to our success with chlorinations [14] and brominations [9] using the corresponding Ti(IV) halogen reagents. Although currently under study by various groups for use in dental varnishes, [15] titanium(IV) fluoride has received only modest attention from the organic synthesis community [16] probably due to its moderate complexing ability, [17] propensity for oligomer complex formation, and sparing solubility in typical reaction solvents.…”

“…[9],[14] However, the recent work of Braddock (Imperial College London) and Burton (Oxford) provide convincing evidence that an S N 1-type mechanism may also be operative in NALG/Ti(IV) reactions. [22] Specifically, the British researchers argue that these Ti(IV)-mediated reactions proceed via carbocation intermediates whose nucleophilic capture is under diastereomeric control.…”

Stereoretentive Halogenations and Azidations with Titanium(IV) Enabled by Chelating Leaving Groups

“…We have recently validated this strategy using TiCl 4 to bring about stereoretentive chlorination of secondary alkyl sulfonates. [6] Our continued study of this reaction with other titanium(IV) species reveals that this transformation is of significantly broader scope. Herein we describe several new titanium-mediated stereoretentive reactions including bromination, [7] iodination, and azidation that are enabled by new chelating leaving groups.…”

“…As we previously disclosed, the tosylate of menthol (a challenging substrate for nucleophilic displacement [8] ) was rapidly converted into the chloride with retention of configuration using TiCl 4 . [6] However, the analogous reaction with TiBr 4 was far more sluggish (Table 1). Also, tosylates performed unacceptably with other titanium(IV) reagents, such as Ti(N 3 ) 4 and TiI 4 , as discussed below.…”

Iron(III)‐Catalyzed Halogenations by Substitution of Sulfonate Esters

“…The authors proposed that the polyether chain or the quinolin‐8‐yl group coordinates the metal cation, simultaneously stabilizing the negative charge on the living sulfonate and attracting the nucleophile to effect the overall substitution. Additionally, the authors claim that the stereochemical outcome for the substitution is retention of configuration by an S N i mechanism 6b,c,7. This method has since been utilized by Kim et al.…”