In situ ortho-lithiation/functionalization of pentafluorosulfanyl arenes

Abstract

A general method for ortho-functionalization of pentafluorosulfanyl arenes has been developed. ortho-Lithiation with lithium tetramethylpiperidide at −60 °C in the presence of silicon, germanium, and tin electrophiles affords trapped products in moderate to high yields. Precise temperature regimes and the presence of electrophiles during lithiation are important for successful reactions, since the pentafluorosulfanyl group acts as a competent leaving group at temperatures above −40 °C. Fluoro, bromo, iodo, enolizable keto, cyano, ester, amide, and unsubstituted amino functionalities are compatible with the reaction conditions. Conversion of 2-dimethylsilylpentafluorosulfanyl benzene to 2-halosubstituted derivatives, useful as starting materials in cross-coupling chemistry, was also demonstrated.

Pentafluorosulfanyl arenes have attracted substantial interest due to unusual properties imposed by the SF₅ moiety.¹ The pentafluorosulfanyl moiety is strongly electron-withdrawing, lipophilic and chemically stable, and its size is comparable to that of a t-butyl group.^1a,2 Consequently, SF₅-substituted compounds have shown promise in materials science, drug discovery, biology, and catalysis.³ The pentafluorosulfanyl group has been intensively studied as a bioisostere of the trifluoromethyl moiety, and in some cases the biological activity of SF₅-modified compounds has been enhanced.^3f–j In spite of these promising properties, pentafluorosulfanyl arenes are substantially less explored than trifluoromethyl arenes due to a very limited set of methods available for their synthesis. Preparation of SF₅-containing drug analogues may require multi-step sequences to access pentafluorosulfanyl arene building blocks, resulting in lengthening of synthetic schemes.³ⁱ

Since their first synthesis by Sheppard,^4a the most common method for the preparation of pentafluorosulfanyl arenes involves oxidative fluorination of diaryl disulfides or aryl thiols, either directly or via intermediacy of aryl tetrafluorosulfanyl chlorides.^4b–k The literature inspection reveals that these methods have limited scope for the preparation of ortho-substituted pentafluorosulfanyl arenes (Scheme 1A–C).^4g,h,i,k Only ortho-fluoro-substituted ArSF₅ can be reliably prepared in modest yields by fluorination of diaryl disulfides. Other methods include cycloadditions or addition of SF₅Cl to double bonds followed by aromatization to give the desired ArSF₅ derivatives, often in multi-step sequences (Scheme 1D and E).⁵

Scheme 1.

Preparation of ortho-substituted ArSF₅.

The most direct pathway for accessing 2-substituted pentafluorosulfanyl arenes involves ortho-functionalization of ArSF₅ C–H bonds.⁶ In all reported instances, the regioselectivity of functionalization is dictated by groups other than SF₅.^6a–c The only exception is an example of pentafluorosulfanyl benzene argentation followed by quenching with iodine affording a 14% yield of 2-iodopentafluorosulfanyl benzene reported by Hirano and Uchiyama.⁶ⁱ Consequently, preparation of ortho-substituted arylsulfur pentafluorides presents a considerable synthetic challenge.

We report here a general method for in situ ortho-lithiation/functionalization of arylsulfur pentafluorides. Reactions proceed in a THF/pentane mixed solvent and employ LiTMP base in combination with a silyl, germyl, or stannyl electrophile at −60 °C. Excellent regioselectivity and broad functional group tolerance is observed, allowing for the first general procedure for preparation of ortho-substituted arylsulfur pentafluorides.

The pentafluorosulfanyl group is considered to possess properties similar to those of a trifluoromethyl group.¹ Since ortho-lithiation of trifluoromethylarenes is well precedented,⁷ we attempted lithiation of pentafluorosulfanyl benzene and its derivatives under multiple conditions reported for trifluoromethylbenzene. Following the quenching with electrophiles, the desired products were not obtained. Next, metalation with lithium tetramethylpiperidide was explored. At 0 °C, reaction with 4-methylpentafluorosulfanylbenzene gave a 1/0.6 mixture of isomeric N-methylphenyl tetramethylpiperidines 3 and 4 (Scheme 2). Presumably, ortho-lithiation of 1 to give 5 is followed by benzyne formation and reaction with another equivalent of LiTMP 2 forming a mixture of 3 and 4 in a 45% isolated yield. This result shows that the SF₅ group acts as a competent leaving group, and that formation and trapping of ortho-lithiated intermediates such as 5 requires careful temperature regimes.

Scheme 2.

Reaction of 4-Me-PhSF₅ with LiTMP at 0 °C.

Instability of intermediate aryllithium species can be mitigated by in situ quenching with an electrophile that is stable in the presence of lithium tetramethylpiperidide.⁸ Relevant examples include Martin’s use of LiTMP base for in situ deprotonation/silylation of aromatic nitriles, esters, and pyridine derivatives.^8a,b Gilman and Schlosser have lithiated trifluorobenzene by t-BuLi in the presence of TMSCl.^8c,d Similar methodologies have been described with other electrophiles as well.^8e–j

The optimization reactions for ortho-silylation of PhSF₅ are summarized in Table 1. Initially, five equivalents of LiTMP base and ten equivalents of Me₂SiHCl electrophile were used. Silylation at −78 °C in THF gave a 20% yield of 9, while no reaction was observed in diethyl ether (entries 1 and 2). Increasing the temperature to −60 °C gave a 30% yield of 9 in THF (entry 3). Use of a THF/pentane mixed solvent resulted in the formation of 9 in 45 and 77% yields at −60 °C (entries 4 and 5, 1/1 and 1/3 THF/pentane, respectively). It is possible to decrease the amount of Me₂SiHCl to seven equivalents with almost no change in yield (entry 6, 75% NMR and 70% isolated yields). Employing three equivalents of LiTMP resulted in a lower yield of 9 (entry 7). Performing the reaction at −40 °C resulted in a 56% yield of the product (entry 8). Attempted silylations by using cheaper lithium dicyclohexylamide (entry 9) or a bulkier lithium di-1-adamanthylamide⁹ (entry 10) base did not result in the formation of 9. Regioisomers of 9 were not observed in the crude reaction mixtures showing that the metalation/quenching sequence is highly selective, in contrast with lithiation of trifluoromethylbenzene, which affords isomer mixtures.^7c,d

Table 1.

Optimization of the reaction conditions^a

Entry	7/2/8	Solvent	T (°C)	Yieldb (%)
1	1/5/10	THF	−78	20
2	1/5/10	Et2O	−78	ND
3	1/5/10	THF	−60	30
4	1/5/10	THF/pentane 1/1	−60	45
5	1/5/10	THF/pentane 1/3	−60	77
6	1/5/7	THF/pentane 1/3	−60	75(70)c
7	1/3/7	THF/pentane 1/3	−60	47
8	1/5/7	THF/pentane 1/3	−40	56
9d	1/5/7	THF/pentane 1/3	−60	ND
10e	1/5/7	THF/pentane 1/3	−60	ND

^aPhSF₅ (0.2 mmol), solvent (1.5 mL), LiTMP, Me₂SiHCl, and 24 h.

^bYields determined by ¹⁹F NMR analysis using hexafluorobenzene as an internal standard.

^cIsolated yield.

^dLithium dicyclohexylamide base.

^eLithium diadamantylamide base.

With the optimal reaction conditions in hand, the scope of ortho-silylation with respect to substitution on the aryl moiety was explored (Table 2). The simplest substrate, PhSF₅, was silylated in 70% yield (entry 1). Halogen-containing substrates undergo double silylation (entries 2–4). Interestingly, in all cases except for the fluoro-substituted derivative, the silyl groups are introduced at positions 2 and 4 of the aromatic ring, and not at presumably the most acidic position between the halogen and pentafluorosulfanyl group. Presumably, small size of the fluoro substituent explains regioselectivity differences observed for entry 2 vs. entries 3 and 4. High yields of products show that aryne formation from the lithiated intermediates does not occur under the in situ lithiation/quench conditions. Somewhat surprisingly, a free amino group is compatible with the reaction conditions, and after workup, mono-substitution products were isolated in excellent yields (entries 5 and 6). It is likely that N-silylation occurs before C-silylation, and silyl groups are removed from nitrogen upon workup. 3-Methoxypentafluorosulfanyl benzene is silylated at the 4-position in an acceptable yield (entry 7). This appears to be the only case where silylation does not occur ortho to the pentafluorosulfanyl group. Nitrile and enolizable keto functionalities are tolerated and the products were isolated in 90 and 66% yields, respectively (entries 8 and 10). An ester-containing substrate was disilylated in 95% yield (entry 11). Aryl pentafluorosulfides possessing an amide functionality were mono-silylated in 70 and 75% yields (entries 12 and 13). Reaction of 3-cyanopentafluorosulfanyl benzene with 1.1 equiv. LiTMP and 1.2 equiv. Me₂SiHCl resulted in silylation ortho to the cyano group. This result points to the pentafluorosulfanyl moiety being a relatively weak directing group for ortho-lithiation. In all cases, ¹⁹F NMR analysis of crude reaction mixtures showed formation of one isomer of product.

Table 2.

Silylation scope with respect to ArSF₅^a

Entry	ArSF5	Product	Yield (%)
1	PhSF5		70
2b			86
3b			95
4			87
5			72
6			77
7			50
8			90
9c			60
10			66
11			95
12			70
13d			75

^aArSF₅ (0.5 mmol, 1 equiv.), 2 (5 equiv.), 8 (7 equiv.), a THF/pentane mixed solvent, −60 °C or −78 °C, and 9–48 h. Yields are isolated yields.

^bStructure confirmed by X-ray diffraction analysis of the silanol derivative.

^c2 (1.1 equiv.), 8 (1.2 equiv.), THF/pentane (1/3), and −60 °C.

^dStructure verified by X-ray crystallographic analysis. Please see ^ESI for details.

Next, the reaction scope with respect to electrophiles was explored (Scheme 3). The conditions used for the reactions in Table 2 were employed. Trimethylsilylation of PhSF₅ gave the ortho-substituted product 10 in a 60% yield. Use of chloro-methylphenylsilane electrophile afforded 11 in 50% yield. The yields decrease if bulkier silyl electrophiles are employed. This trend holds also for germanium electrophiles, where Me₃GeCl gave a 65% yield of 12, while use of bulkier Et₃GeCl resulted in a 57% yield of 13. Trialkyltin chloride reagents did not give acceptable yields of stannylation products. Instead, bis(tributyltin) electrophile could be used to give a 40% yield of 14. Analysis of crude reaction mixtures by ¹⁹F NMR showed formation of only one product in all cases except for 14, where a minor amount (o5%) of another isomer was detected.

Scheme 3.

Use of other electrophiles.

2-Dimethylsilylpentafluorosulfanyl benzene 9 was converted to the corresponding phenol 15 by reaction with KF/H₂O₂ (Scheme 4).¹⁰ Conversion to 2-halosubstituted derivatives, useful as starting materials in cross-coupling chemistry, was also explored.¹¹ 2-Bromopentafluorosulfanyl benzene 16 was obtained in a 90% isolated yield, while the iodo-derivative 17 was isolated in a 95% yield. Aryl silanols can be used for palladium-catalyzed cross-coupling reactions with aryl chlorides and bromides.¹² Silanol 18 was prepared by oxidation of 9 catalyzed by [RuCl₂(p-cymene)]₂ in an acetonitrile/water mixed solvent.

Scheme 4.

Transformations of 9.

In conclusion, we have developed the first general method for the preparation of ortho-substituted pentafluorosulfanyl arenes. ortho-Lithiation by lithium tetramethylpiperidide at −60 °C in the presence of silyl and germyl chlorides as well as bis(tributyltin) electrophiles affords trapped products in moderate to high yields and excellent regioselectivities. Temperature regimes are very important for high-yielding reactions since lithiated pentafluorosulfanyl arenes form arynes at temperatures as low as −40 °C. The lithiation/trapping sequence is compatible with fluoro, bromo, iodo, enolizable keto, cyano, ester, amide, and unsubstituted amino groups. Preparation of 2-halo- and 2-hydroxypentafluorosulfanyl benzenes from 2-dimethylsilylpentafluorosulfanyl benzene was also demonstrated.

We are grateful to the Welch Foundation (Chair E-0044) and NIGMS (Grant No. R01GM077635) for supporting this work. We thank Dr Xiqu Wang for collecting diffraction data and solving the X-ray structures of compounds S1 and S2, and the product of entry 13 in Table 2.