Mild Ti-mediated transformation of t-butyl thio-ethers into thio-acetates

Abstract

We report a straightforward method for the rapid conversion of thio-ethers to thio-acetates using TiCl₄, in good to excellent yields. The reaction conditions tolerate a variety of functional groups, including halide, nitro, ether, thiophene and acetylene functionalities. A catalytic variant of this reaction is also described.

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Introduction

Numerous nanoscale materials and devices¹ are based on self-assembled monolayers (SAMs) of thiols on gold substrates.² Thiols have proven to be versatile anchoring groups³ for immobilising functional units for photoswitching,⁴ molecular electronics,⁵ control of surface wettability,⁶ cell adhesion,⁷ to name but a few examples. Although thiol chemistry is often used in SAM formation,³ the introduction of a thiol group in a compound frequently presents synthetic challenges⁸ because the R–S–H group can be deprotonated, is nucleophilic, and is prone to oxidation.² Hence, protected thiols such as thio-acetates are frequently used. Indeed, acetyl and trityl protected thiols can be deprotected readily in situ during self-assembly on gold surfaces.² In particular acetyl protected thiol substituted arenes are convenient in their use as these can typically be cleaved in situ without requiring an exogenous base to form stable monolayers equivalent to those formed starting from free thiols.^9–11

However, the thio-acetate group is often unstable under aqueous reaction conditions, while the thio-trityl group is unstable under various other reaction conditions, such as those employed in Suzuki–Miyaura cross-coupling reactions.¹² These drawbacks can be overcome through a method developed by Stuhr–Hansen in which the thiol is initially protected by a t-butyl protecting group and later exchanged for the desired acetyl protecting group by treatment with BBr₃.¹³ The t-butyl thio-ether is beneficial as it is typically stable under both acidic¹⁴ and basic conditions.¹⁵ Furthermore, t-butyl thio-ethers can be synthesised with relative ease, either from the free thiol using t-butyl chloride or t-butanol, or from halides (R-X) using t-butyl thiol. Once the synthetic steps incompatible with the thio-acetate have been performed, exchange of the protecting groups can be achieved by deprotection of the t-butyl thio-ether by BBr₃ followed by quenching with acetyl chloride at room temperature.¹³

Although S-t-butyl to S-acetyl exchange procedures have been reported (using BBr₃,¹³ but also Br₂ ⁸ or AlCl₃ ¹⁶), several important functionalities do not tolerate these conditions, examples being vinyl, TBDMSO, acetylene, aldehyde, and nitro functionalities.^8,13 This prompted us to identify more versatile Lewis acids, with which the exchange reaction can be performed under mild conditions while tolerating a wider variety of functionalities. One such candidate is TiCl₄, as there have been several examples of TiCl₄/n-Bu₄NI-mediated deprotection of ethers (R–O–R).¹⁷ Furthermore, TiCl₄ has been used in the deprotection of silyl ether protected alcohols. The results of Tanabe and co-workers, who successfully deprotected aryl and aliphatic TBDMS-ethers in excellent yields (91–99%) using TiCl₄-Lewis base (AcOEt, CH₃NO₂) complexes, are particularly encouraging.¹⁸ Finally, TiCl₄ was used with great efficacy as a deprotection reagent in the hydrolysis of t-butyl esters in β-lactam chemistry, whereas the use of AlCl₃, BF₃, and FeCl₃ resulted in degradation of the starting material or poor yields.¹⁹

Herein, we present a robust method for the conversion of t-butyl thio-ethers to thio-acetates using TiCl₄ instead of BBr₃. We have found that TiCl₄ is tolerant towards a wider variety of functional groups and performs consistently better than BBr₃, providing the desired thio-acetates in high yields and in shorter reaction times (Scheme 1).

Scheme 1 Rapid and clean conversion of thiotertbutyl ethers to acetyl protected thiols with stoichiometric and catalytic TiCl₄.

Results and discussion

12 substrates were examined to explore the utility of TiCl₄ for the conversion of thio-ethers (a) to thio-acetates (b) (Table 1). t-Butyl thio-ethers 1–6a were converted to the corresponding thio-acetates 1–6b in good to excellent isolated yields using TiCl₄ or BBr₃. However, whereas the reactions using BBr₃ were complete after 2.5 to 7 h, the use of TiCl₄ allowed for substantially shorter reaction times, in several cases providing the thio-acetate within a few seconds (2a, 4a, and 6a as well as 8a and 10a). In addition, improved yields were observed for several substrates when TiCl₄ was used (1a, 3a, and 5a). Conversion of 7a–10a using BBr₃ was found to result in decomposition only. In sharp contrast, 7a and 8a were converted to their corresponding thio-acetates in high yield when TiCl₄ was used.

Table 1 Thio-ether to thio-acetate exchange: comparison of BBr₃ and TiCl₄

	Substrate	Reaction time BBr3	Isolated yield	Reaction time TiCl4	Isolated yield
a Forms multiple products. b Full conversion to an unidentified product with an Rf = 0.19 on SiO2. c The Friedel–Crafts acylation product p-CH3(C=O)C6H4SCH3 was isolated in 94% yield.^22 Dec. = decomposition of the starting material.
1a		5 h	81%	<1 h	93%
2a		6 h	96%	5 s	94%
3a		5 h	76%	<1 h	88%
4a		7 h	>99%	5 s	>99%
5a		3 h	92%	1 h	>99%
6a		4 h	65%	5 s	89%
7a		—	Dec.	<1 h	88%
8a		—	—^a	5 s	83%
9a		—	Dec.	—	Dec.
10a		7 h	Dec.	5 s
11a		n/a	n/a	2 h	87%
12a		7 h	No conv.	3 h

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Aldehyde and pyrid-2-yl functionalized thioethers were examined to explore functional group limitations. Treatment of aldehyde 9a under these reaction conditions still resulted in decomposition. Analysis of the product revealed that with BBr₃ the t-butyl group was cleaved while with TiCl₄ the t-butyl group remained intact. In neither case, however, was thio-acetate 9b obtained. For thio-ether 10a, the TiCl₄-mediated reaction did not provide the desired product either with full conversion to an unidentified compound instead.^20,21 It was also attempted to use the above reaction conditions for the conversion of a methyl thio-ether group to the corresponding thio-acetate group. The methyl thio-ether group of 12a was found to be stable to both BBr₃ and TiCl₄. However, treatment of 12a with TiCl₄ for 3 h resulted in the aromatic Friedel–Crafts acylation product.

The stability of the OTBDMS protecting group, alkenes and THP ethers under reaction conditions was examined (Scheme 2). p-Br-phenyl TBDMS ether was found to be stable under reaction conditions (see ESI, Fig. S2†), however, both the THP and alkene of 2-(dec-9-en-1-yloxy)tetrahydro-2H-pyran were found to react. It should be noted, however, that more complex structures such as 11a are stable under reaction conditions (vide infra).

Scheme 2 Stability of (i) the OTBDMS protecting group and (ii) terminal alkenes and THP ethers under reaction conditions with 1.09 eq. of TiCl₄.

A possible mechanism by which the reaction may proceed is that addition of TiCl₄ to acetyl chloride results in the formation of the acylium ion (Scheme 3),²³ as is supported by the Friedel–Crafts acylation product obtained with compound 12a. The acylium ion undergoes nucleophilic attack from the sulphur of the thio-ether. Expulsion of the 2-methylpropan-2-ylium carbocation subsequently results in product formation. Conversion of the anionic Ti species is achieved by dissociation of a chloride and the subsequent capture of the chloride ion by the carbocation resulting in the formation of 2-chloro-2-methylpropane and TiCl₄, thus completing the catalytic cycle for the exchange of the t-Bu thio-ether to the thio-acetate. In d₂-dichloromethane, the formation of iso-2-chloro-2-methylpropane was observed, whereas the formation of isobutene was not, which supports the proposed pathway (see ESI†).

Scheme 3 Proposed cycle for the conversion of thio-ethers to thio-acetates using TiCl₄ as a catalyst.

The reaction mechanism proposed furthermore implies that TiCl₄ might be used catalytically. Indeed, it was found that treatment of 4a with a catalytic amount of TiCl₄ (10 mol%) resulted in full conversion to the thio-acetate in 3 h with isolated yields of ca. 86% (Scheme 4). These results therefore support the proposed mechanism and further establish the potential of TiCl₄ to mediate the S-t-Bu to S-acetyl exchange reaction. The conversion from 4a to 4b under stoichiometric conditions was completed within 5 s, whereas under catalytic conditions the reaction was finished within 3 h. It should be noted that under these catalytic conditions the catalytic reaction still proceeds faster with TiCl₄ then when a stoichiometric quantity of BBr₃ is used.

Scheme 4 Thio-ether to thio-acetate conversion as catalysed by TiCl₄.

In summary, the method reported herein provides a versatile, mild and selective method compared to existing thio-ether to thio-acetate exchange methods. The use of TiCl₄ is more atom economic then the use of BBr₃ given that the former can be employed catalytically. Furthermore, conditions using TiCl₄ for the exchange tolerate a wider range of functional groups than BBr₃-mediated methods, including acetylene groups, which is in contrast to conditions using Br₂ that provide only moderate conversion to the thio-acetate.⁸ The exchange of the t-butyl protecting group for a thio-acetate group in aliphatic thio-ether 11a provides 11b in high yield (Table 1), even though 11a contains a dithienyl ethene photochromic switching unit. The high reaction rate at room temperature implies that the exchange reaction is also able to proceed at low temperature. Indeed, the reaction was found to proceed with full conversion of 4a to 4b within 30 min at −78 °C. Performing the exchange at low temperature opens opportunities to avoid undesirable side-reactions of sensitive substituents.

Conclusions

In conclusion, the conversion from thio-ether to thio-acetate using TiCl₄ represents a highly versatile and fast method for a wide range of applications, not least those involving the synthesis of SAM forming thiols.

Acknowledgements

Funding from the Ministry of Education, Culture and Science (Gravity program 024.001.035, WRB, BLF), the European Research Council (Advanced Investigator grant no. 227897) and Netherlands organization for Fundamental Research on Materials (FOM, TCP) are acknowledged for financial support.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures, characterization and spectroscopic data. See DOI: 10.1039/c4ob02120g

‡ Both authors contributed equally.

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