Unexpected reactivity of 10-hydroxycamphor under triflic anhydride treatment : formation of a C 2-pseudosymmetric camphor-derived sulfite

Treatment of enantiopure 10-hydroxycamphor with triflic anhydride and triethylamine yields enantiopure bis(10-camphoryl) sulfite, a novel interesting camphor-based C2-pseudosymmetric chiral sulfite with a prochiral sulfonyl group. The process takes place by initial formation of 10camphoryl triflinate, which undergoes an unexpected nucleophilic substitution with displacement of trifluoromethyl anion (attack of a second equivalent of 10-hydroxycamphor on the sulfur atom). The mentioned pseudosymmetric sulfite has also been obtained by standard reaction of 10-hydroxycamphor with thionyl chloride.


Introduction
During the last years we have developed a methodology for the straightforward synthesis of enantiopure 10-substituted camphor derivatives starting from natural camphor. 1 This class of compounds has been used for many years as interesting intermediates for the preparation of a large variety of valuable chirality transfer agents, namely chiral resolving agents, auxiliaries, ligands, catalysts, etc. (some examples are depicted in Figure 1).However, those derivatives having an atom different from sulfur at position 10 of camphor were usually hard to obtain.In contrast, 10-S-derivatives were easily prepared from commercially available 10-camphorsulfonic acid.It was in this context that we developed the stereocontrolled synthetic route shown in Scheme 1 for the preparation of differently substituted 10-substituted camphors from camphor in just three steps.1a The introduction of a substituent at position 10 of camphor was achieved by reaction of intermediate 7 with an appropriate electrophile, capable of adding to the olefin and promoting a pinacol-type Wagner-Meerwein rearrangement.By this synthetic route, we have introduced different atoms at position 10 of camphor (halogens, oxygen, sulfur, selenium, carbon, etc.).1a However, certain heteroatoms could not be introduced at such position by this electrophile-based methodology.With the aim of finding alternative ways to obtain all kinds of 10-substituted camphor derivatives, we decided to prepare 10-triflyloxycamphor (8b) from 10-hydroxycamphor (8a). 2 The nucleofugacity of the triflyloxyl group would make this derivative a versatile intermediate from which a particular substituent could be introduced at such position by an SN reaction. 3hus, treatment of 10-hydroxycamphor (8a) with triflic anhydride (in the absence of base) gave place to 10-triflyloxycamphor (8b).This derivative proved to be a versatile intermediate for the preparation of other 10-substituted camphors, such as amino or amido derivatives (Scheme 2).

Results and Discussion
In the search for conditions for the preparation of 10-triflyloxycamphor (8b), we found an interesting and unexpected reactivity of 10-hydroxycamphor (8a) with triflic anhydride.Thus, when 10-hydroxycamphor (8a) was treated with triflic anhydride in standard conditions (triethylamine as base and dichloromethane as solvent), enantiopure C2-pseudosymmetric sulfite 10 and triflinate 9 (as a diastereomeric mixture, e.d.26%) were obtained instead of the expected triflate 8b (route a, Scheme 3).The same sulfite 10 was obtained in the reaction of 8a with thionyl chloride using pyridine as both catalyst and base (route b, Scheme 3). 4,5This new pseudosymmetric chiral sulfite is a potential interesting precursor for the enantioselective preparation of chiral sulfoxides 6 from asymmetric sulfites, according to Kagan´s methodology.Formation of triflinates is well-known in the reaction of sterically hindered alcohols with triflic anhydride and triethylamine.Under these conditions, a mixed anhydride, triflinyl triflate 11, is formed.This new anhydride can react with an alcohol to give rise to the corresponding triflinate 12. 8 These highly reactive electrophilic triflinates 12 usually undergo a subsequent in situ nucleophilic substitution reaction with a second molecule of the starting alcohol to yield the symmetric ethers 13 (Scheme 4).Unexpectedly, no ether was detected in our case, but C2-pseudosymmetric sulfite 10 was isolated instead.This fact must be due to the neopenthylic character of both, the starting alcohol 8a and the triflinate 9, which favors the nucleophilic attack of a second molecule of alcohol on the sulfur atom (b or c, Scheme 5) over the more hindered neopenthylic carbon atom (a, Scheme 5).
On the other hand, the mentioned nucleophilic attack can take place with O-S fission and alkoxide as leaving group (b, Scheme 5) or with C-S fission and trifluormethyl anion as leaving group (c, Scheme 5). 9 The first option would lead to the same mixture of products (8a and 9), whereas the second would yield sulfite 10 and trifluoromethane.The formation of volatile and less nucleophilic trifluoromethane must be the driving force for the equilibrium displacement towards the sulfite formation.

Conclusions
In summary, unexpected reactivity of 10-hydroxycamphor (8a) with triflic anhydride has been described.Treatment of 8a with triflic anhydride and base affords C2-symmetric sulfite 10, instead of the expected triflate 8b.The synthetic process involves the formation of a key intermediate triflinate 9 by reaction of the corresponding starting alcohol with Tf2O/Et3N.In mechanistic terms, the described sulfite formation implies an unexpected sterically-controlled electrophilic reactivity of the mentioned triflinate.

Experimental Section
General Procedures.Et2O and CH2Cl2 were distilled over sodium / benzophenone and calcium hydride, respectively, immediately prior to use.Triethylamine was dried with KOH and distilled over CaH2.Pyridine was dried and distilled over KOH.Thionyl chloride was purchased from Aldrich and used without further purification.Triflic anhydride was prepared from triflic acid according the previously described procedure 10 and distilled over P2O5 immediately prior to use.Flash chromatography was performed over silica gel (230-400 mesh). 1 H and 13 C NMR were recorded in a Bruker AC-200 spectrometer (200 MHz for 1 H and 50 MHz for 13 C) in CDCl3 at room temperature.Chemical shift values are reported in ppm, using chloroform as internal reference (7.27 ppm for 1 H and 77.0 ppm for 13 C) and coupling constants are in hertz.IR spectra were recorded on a Shimadzu FTIR-8300 spectrometer.Wave numbers are reported in cm -1 .
Mass spectra were recorded on a 60-eV mass spectrometer.HRMS were recorded on a mass VGspectrometer using the FAB technique.

Scheme 4 .
Scheme 4. Formation of triflinyl triflate 11 from triflic anhydride and base, and general reaction with alcohols.