DOI: 10.1002/chem.201402679

Communication

& Synthetic Methods

Direct Trifluoromethylthiolation of Alcohols under Mild Reaction Conditions: Conversion of R OH into R SCF3 Pavlo Nikolaienko, Roman Pluta, and Magnus Rueping*[a] The direct conversion of Csp3 X (X = halogen) by nucleophilic displacement has been reported.[9h, 12] The analogous direct transformation of alcohols into the corresponding SCF3 has not yet been accomplished. Two protocols have been described in the literature that either require the conversion of the hydroxyl group into an O-(N,N-diethylamido)phosphite followed by a subsequent reaction with an SCF3-based reagent, or conversion into the appropriate thiol followed by a subsequent trifluoromethylation (Scheme 1).[13]

Abstract: A direct process for the trifluoromethylthiolation of allylic and benzylic alcohols under mild conditions has been developed. A wide range of free alcohols underwent nucleophilic substitution in the presence of stable CuSCF3 and BF3·Et2O to give the corresponding products in good to excellent yields.

Functional-group exchange is remarkably relevant in modern synthetic chemistry. Among the wide array of established transformations, the introduction of fluorine and fluorine-containing groups is prominent owing to the wide utilization of the resulting products in the pharmaceutical and agrochemical industries.[1] Particularly, perfluoroalkylthio groups are of interest because they exhibit improved properties, including enhanced lipophilicity, substantial electron-withdrawing effects, and better metabolic stability.[2] The first member of the perfluoroalkylthio groups, the trifluoromethylthio group, is a stable pseudohalogenic group with special biological properties.[3] Furthermore, use of this group as a key intermediate in the synthesis of trifluoromethylsulfoxides and triflates has been demonstrated.[4] Based on these important features, the incorporation of a SCF3 group into biologically active molecules is desirable. Although the trifluoromethylthio group is known,[5] trifluoromethylthiolation has only recently attracted increased interest. In particular, new methods for a fast, efficient, and straightforward insertion have attracted attention. Initial work employed metal–SCF3 compounds or the use of Me4NSCF3 as stable salts.[5] The direct introduction of the SCF3 moiety by utilizing F3CSCl or F3CSSCF3 has also been described. However, owing to their high toxicity and gaseous conditions,[6] more-convenient and shelf-stable analogues were developed.[7] Subsequently, electrophilic,[8] nucleophilic,[9] and radical[10] approaches for the direct trifluoromethylthiolation with SCF3-containing reagents were reported.[11] However, most of these methods deal with Csp S and Csp2 S bond formation, whereas the creation of Csp3 S bonds remains less explored.

[a] P. Nikolaienko, R. Pluta, Prof. Dr. M. Rueping Institute of Organic Chemistry Institution RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402679. Chem. Eur. J. 2014, 20, 9867 – 9870

Scheme 1. Csp3 SCF3 bond formation approaches starting from alcohols.

Owing to their wide availability, alcohols are favorable substrates and a direct exchange[14] with a SCF3 group under mild reaction conditions would be desirable. Therefore, we decided to examine a direct trifluoromethylthiolation of alcohols, in which no prefunctionalization would be necessary. Herein, we report a straightforward trifluoromethylthiolation of hydroxyl groups employing CuSCF3 as readily available SCF3 source. CuSCF3 is a light-stable and a nontoxic nucleophilic trifluoromethylthiolating reagent, which can be easily synthesized in multigram scale.[5b] We chose diphenyl methanol (1 a) as a model substrate to search for the optimal reaction conditions. When CuSCF3 and AgSCF3 were used without any additive, no conversion was observed even at elevated temperatures (Table 1, entries 1 and 2). Acetate- and carbonate-protected alcohols 2 a and 3 a were also not active, and only very low conversions were observed (Table 1, entries 3 and 4). Thus, we concluded that the use of Brønsted or Lewis acids may be required. However, the main challenge was to uncover reaction conditions that would allow activation of the starting material, but would not cause decomposition of CuSCF3. Brønsted acids, such as methane sul-

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 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication Table 1. Optimization of reaction conditions for trifluoromethylthiolation of benzylic alcohols.[a]

Table 2. Trifluoromethylthiolation of benzylic alcohols under the optimized reaction conditions.[a]

Entry

R

CuSCF3 [equiv]

Additive [(equiv)]

Reaction time [h]

Yield[b] [%]

Entry

4

Ar

R1

R2

Yield[b] [%]

1 2[d] 3[d] 4[e] 5 6 7 8 9 10 11 12 13 14 15

H H Ac CO2Et H H H H H H H H H H H

1 1 1 1 1 1 1 1 1 1 1 1 2 1.5 3

– – – – MsOH (1.5) TsOH (1.5) TFA (1.5) Sc(OTf)3 (0.1) Bi(OTf)3 (0.1) In(OTf)3 (0.1) BF3·Et2O (0.25) BF3·Et2O (1) BF3·Et2O (1) BF3·Et2O (2) BF3·Et2O (2)

12 12 12 12 1 1 1 1 1 1 1 0.5 0.5 0.5 0.5

n.d. n.d. n.d. n.d. < 5[f] < 5[f] < 5[f] n.d. n.d. n.d. 12 21 61 96 (93)[c] 95

1 2 3 4 5 6 7 8 9 10 11 12 13 14

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n

C6H5 p-biphenyl o-FC6H4 p-FC6H4 p-CF3C6H4 p-MeOC6H4 2,4,6-Me3C6H2 3,4-MDOC6H3[d] 3,4,5-(MeO)3C6H2 3,4-(MeO)2C6H3 3,4-MDOC6H3[d] methyl ferrocene 5-methylthienyl C6H5

C6H5 C6H5 C6H5 C6H5 C6H5 p-MeO-C6H4 Me Me Me H H H H 2-furyl

H H H H H H H H H H H H H H

93 90 83 85 50[c] 96 98 99 97 93 90 91 88 51

15

4o

Ar, R1:

H

91

16

4p

Ar, R1:

H

98

17 18

4q 4r

C6H5 C6H5

Me

90 98

[a] All reactions were carried out under air atmosphere on a 0.1 mmol scale. Reactions were stopped by addition of three equivalents of Et3N. OTf = triflate. [b] Yield based on 1H or 19F NMR spectroscopy with internal standards mesitylene and C6H5CF3, respectively. n.d. = not determined. [c] Yield after purification. [d] CuSCF3 and AgSCF3 were tested at 80 8C. [e] DMF was used as solvent at 100 8C. [f] Formation of a substantial amount of F3CSH was detected.

fonic acid (MsOH), toluene sulfonic acid (TsOH), and trifluoroacetic acid (TFA) gave a substantial amount of highly volatile F3CSH (detected by NMR spectroscopy) without product formation (Table 1, entries 5–7). Metal triflates also did not act as efficient catalysts (Table 1, entries 8–10). To our delight, boron trifluoride etherate (BF3·Et2O) was effective. The first attempt with a catalytic amount of BF3·Et2O gave only 12 % yield. Further optimization (Table 1, entries 12–15) revealed that two equivalents of BF3·Et2O are optimal, and the desired trifluoromethylthiodiphenylmethane (4 a) was obtained in 93 % yield (Table 1, entry 14). With the optimized conditions in hand, we explored the substrate scope of this reaction. Benzylic trifluoromethylthiolation of a variety of alcohols, 1 a–r, proceeded smoothly to give the desired products 4 a–r with moderate to very high yields. Primary, secondary, and tertiary alcohols were tested and the corresponding trifluoromethylthioethers 4 a–r were obtained in all cases. Substrates bearing electron-donating groups, 1 a, 1 b, and 1 f–k, which stabilize the carbocation intermediate, gave higher conversion within short reaction times (Table 2, entries 1, 2 and 6–11). Pleasingly, substrates 1 c–e bearing electron-withdrawing substituents, were also tolerated, although with lower yields and longer reaction times (Table 2, entries 3– 5). Ferrocene derivative 1 l (Table 2, entry 12), as well as different heterocyclic derivatives, such as thiophene and furan derivatives 1 m and 1 n (Table 2, entries 13 and 14), were compatible with the new reaction conditions and gave the trifluoromethylthiolated products 4 l,n in good yields. Tertiary alcohols 1 q Chem. Eur. J. 2014, 20, 9867 – 9870

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iPr R1, R2 : cyclohexyl

[a] Reaction conditions: 1 (0.4 mmol), CuSCF3 (0.6 mmol), BF3·Et2O (0.8 mmol), CH3CN (2 mL), see the Supporting Information for details. [b] Yields after purification by column chromatography. [c] 48 h reaction time; [d] MDO = methylendioxy (-OCH2O-).

and 1 r furnished the corresponding products 4 q and 4 r in excellent yields (Table 2, entries 17 and 18). Following the successful direct trifluoromethylthiolation of benzylic alcohols, we turned our attention to allylic alcohols as more flexible substrates with further functionalization potential.[15] Initially, the same reaction conditions were applied for 1,3-diphenylallylic alcohol 5 a and the corresponding trifluoromethylallyl thioether 6 a was obtained in 96 % yield within 30 min (Table 3, entry 1). Encouraged by this result we investigated the trifluoromethylthiolation of other 1,3-disubstituted allylic alcohols, 5. It was found that substrates 5 b–g proceed in the transformation to give the desired products in high to excellent yields and high regioselectivity (Table 3, entries 2–7). As expected, the same isomeric product was obtained in the case of allylic alcohols 5 b and 5 c (Table 3, entries 2 and 3). Tertiary allylic alcohol 5 h and primary alcohol 5 i were also tested and gave the corresponding trifluoromethylthioethers 6 h and 6 i in high yields (Table 3, entries 8 and 9). In most cases a 4:1 volume ratio of dichloromethane and acetonitrile was chosen owing to the solubility of CuSCF3 and the starting allylic alcohols. To confirm the mechanism of the reaction, optically pure allylic alcohol 5 b was submitted to the typical reaction conditions (Scheme 2, [Eq. (1)]). Only the racemic product, 6 b, was

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Communication no prefunctionalization of the alcohols is necessary. A wide variety of differently substituted substrates were applied in the reaction with CuSCF3 to give the corresponding products in good to high yields, within short reaction times. The developed reaction procedure shows broad scope, uses safe and nontoxic metals and reagents, and can be carried out under mild reaction conditions, making it a useful reaction for preparative organic synthesis.

Table 3. Trifluoromethylthiolation of allylic alcohols.[a]

Entry

5

1

6/6’

6a

Ratio [6/6’]



Yield[b] [%] 96[c]

Experimental Section 2

6b

100:0

3

6’c

11:89

87

4

6d

88:12

95

5

6e

6

6’f

3:97

95

7

6’g

3:97

91

8

6h

97:3

85

9

6i

97:3

81

96:4

General procedure for the direct trifluoromethylthiolation of benzylic and allylic alcohols

90

For benzylic alcohols: A vial equipped with a septum and a stirring bar was charged with CuSCF3 (98.7 mg, 0.6 mmol), the relevant benzylic alcohol (0.4 mmol), and CH3CN (4 mL), and the vial was closed. Borontrifluoride etherate (0.1 mL, 0.8 mmol) was added dropwise with vigorous stirring. For allylic alcohols: A vial equipped with a septum and a stirring bar was charged with CuSCF3 (131.4 mg, 0.8 mmol) and the relevant allylic alcohol (0.4 mmol). The reaction vessel was closed and CH3CN/CH2Cl2 (1:4, 4 mL) was added. Then, Borontrifluoride etherate (0.1 mL, 0.8 mmol) was added dropwise with vigorous stirring.

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The solution was stirred at room temperature for 0.5 h until a precipitate was formed and the starting material was consumed (in the case of incomplete transformation the reaction time was prolonged). The suspension was filtered through a short pad of silica, the filter cake was rinsed with additional Et2O (2  5 mL), and the solvent was concentrated in vacuum. The crude product was purified by column chromatography on silica gel with pentane/diethyl ether mixtures as eluent.

Keywords: alcohols · nucleophilic substitution · thioethers · trifluoromethyl sulfenylation

[a] Reaction conditions: Alcohol 5 (0.4 mmol), CuSCF3 (0.8 mmol), BF3·Et2O (0.8 mmol), CH3CN/CH2Cl2 (1:4, 4 mL), 0.5–2 h, see the Supporting Information for details. [b] Yields after column chromatography. [c] 1 mmol of CuSCF3 and 2 mL CH3CN as solvent were used.

Scheme 2. Mechanistic experiments.

obtained. Moreover, optically pure benzylic alcohol 1 i also gave trifluorormethylthiolated product 4 i in a racemic form (Scheme 2, [Eq. (2)]). From these observations an SN1-type mechanism, in which F3CS reacts with the carbocation intermediate formed, is plausible. In summary we have developed a new method for the synthesis of trifluoromethyl thioethers starting from readily available allylic and benzylic alcohols. In contrast to earlier reports, Chem. Eur. J. 2014, 20, 9867 – 9870

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Received: March 30, 2014 Published online on July 14, 2014

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Direct trifluoromethylthiolation of alcohols under mild reaction conditions: conversion of R-OH into R-SCF3.

A direct process for the trifluoromethylthiolation of allylic and benzylic alcohols under mild conditions has been developed. A wide range of free alc...
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