Copper-Catalyzed Enantioselective Oxysulfenylation of Alkenols: Synthesis of Arylthiomethyl-Substituted Cyclic Ethers

Abstract

Saturated heterocycles containing oxygen and sulfur are found in biologically significant molecules. The enantioselective oxysulfenylation of alkenols provides a straightforward synthesis route. To date, organocatalytic methods have dominated this approach. Herein, a complementary approach via copper catalysis is presented. This exoselective method provides enantioenriched arylthiomethyl-substituted tetrahydrofurans, phthalans, isochromans, and morpholines from acyclic alkenols. This method provides the largest scope to date for the exocyclization mode, and with generally high enantioselectivity. The enantioselectivity of this copper-catalyzed oxysulfenylation is rationalized by a proposed mechanism involving alkene oxycupration followed by C─S bond formation via radical-mediated atom transfer.

Graphical Abstract

Thioethers are present in many bioactive small molecules of both natural and unnatural origin.^1-3 Bioactive compounds that contain both saturated oxygen heterocycles and thioethers have displayed COX-2 inhibition⁴ as well as dopamine receptor antagonist,⁵ antiviral, and antibiotic activities (Figure 1).² Biology’s methylating agent, S-adenosylmethionine, is a thioether functionalized saturated oxygen heterocycle (Figure 1). A common, albeit indirect, approach to the synthesis of saturated oxygen heterocycles bearing thioethers involves nucleophilic displacement of halide or activated alcohols by thiol nucleophiles.^4,6,7 Alternatively, alkene oxysulfenylation is a direct approach to the de novo synthesis of such thioethers⁸ where, to date, enantioselective developments have been made exclusively in the area of asymmetric organocatalysis.⁹ For example, Denmark’s pioneering organocatalytic protocol, which employs a chiral selenophosphoramide catalyst to activate N-arylsulfenylphthalimides, predominantly enables enantioselective endocyclization of internal (E)-configured alkenols (Scheme 1A).^10,11 In addition, Shi disclosed an exoselective oxysulfenylation employing (Z)-configured alkenols and a chiral Brønsted acid catalyst (Scheme 1A).^12a Related enantioselective oxysulfenylation of alkene-tethered aldehydes, amides, phenols, and carboxylic acids has also been reported.^9,12b These methods are thought to involve enantioenriched thiiranium intermediates.⁹

Figure 1.

Bioactive compounds containing saturated oxygen heterocycles and thioethers.

Scheme 1.

Oxygen Heterocycles via Alkene Oxysulfenylation

Concurrently, racemic copper-catalyzed oxysulfenylations^13-16 and sulfenylaminations^17-19 of alkenols and alkenylamine derivatives have appeared. A copper-catalyzed oxysulfenylation^14a involving thiyl radical alkene addition^14b followed by C─O bond formation is illustrated in Scheme 1B. Enantioselective copper-catalyzed oxysulfonylations of 4-aryl-4-pentenoic acids and styrene-tethered oximes involving sulfonyl radical alkene addition have also been reported.²⁰ Herein, we disclose an enantioselective copper-catalyzed alkenol oxysulfenylation. Given the ready occurrence of racemic copper-catalyzed alkenol oxysulfenylations,^13-16 and the lack of enantioselective oxysulfonylations of alkenols,²⁰ it was unclear if enantioselectivity could be achieved.

To actualize this transformation, we envisioned a mechanism wherein C─O bond formation could be secured via enantioselective oxycupration.²¹ Subsequent carbon radical formation via C─[Cu] homolysis and C─S bond formation via atom transfer would then complete the oxysulfenylation (Scheme 1C).²¹ Our lab has developed a strategy for the synthesis of enantioenriched saturated oxygen heterocycles that involves alkene oxycupration with chiral copper(II) salts such as [Cu(S,S)-t-Bu-Box](OTf)₂.²¹ Using this approach, enantioselective hydroetherification²² and carboetherification^23-25 of alkenols have been developed. In the hydroetherification reaction, the hydrogen atom source is 1,4-cyclohexadiene, which can react with the proposed carbon radical intermediate in Scheme 1C via a hydrogen atom transfer (HAT) mechanism. In the carboetherification reaction, the carbon radical intermediate adds to styrenes. An extension of this approach to a sulfur-based homolytic substitution (S_H2) protocol was envisioned. This required identification of an appropriate sulfur atom source that would engage with the substrate as the second moiety to add to the alkene, after the chiral C─O bond had been secured. In this regard, disulfides presented as potential reagents based on their prior application in S_H2 reactions.^26,27

Development of this enantioselective oxysulfenylation reaction is summarized in Table 1. Heating alkenol 1a with diphenyl disulfide in the presence of catalytic copper(II) triflate and achiral bis(oxazoline) L1 in PhCF₃ at 120 °C provided isochroman 2a in 68% yield (Table 1, entry 1). In these reactions, commercially available, activated MnO₂ (2.6 equiv, 85% by weight, <5 μ) serves as the stoichiometric oxidant.

Table 1.

Optimization of the Oxysulfenylation^a

entry	change from standard conditions	yield (%)	ee (%)
1	L1	68
2	none (first optimal)	86	90
3	L3	73	−90
4	DCE, 105 °C	70	91
5b	15 mol % [Cu] (second optimal)	87	90
6c	10 mol % [Cu]	59	ND
7	75 mol % Ph2S2	60d	ND
8	dry air, no K2CO3	42 (47)e	91
9	100% O2, no K2CO3	14 (49)e	ND
10	no oxidant	21 (70)e	ND
11	1 mmol scale	62	85

^aReaction run on 0.1 mmol of 1a, in PhCF₃ (0.1 M w/r 1a) in a sealed tube in a 120 °C oil bath under argon unless otherwise noted. The isolated yield is reported following flash chromatography on silica gel. Enantiomeric excess was measured by chiral HPLC.

^b18 mol % L2 was used.

^c13 mol % L2 was used.

^dConversion determined by analysis of crude ¹H NMR. Remainder is substrate 1a.

^eIsolated recovered substrate 1a in parentheses. ND = not determined.

Gratifyingly, application of the chiral (S,S)-t-Bu-Box ligand L2 resulted in the formation of isochroman 2a in 86% yield and 90% ee (entry 2, first optimal conditions). Interestingly, application of the (R,R)-Ph-Box ligand L3 under these conditions provided 73% yield of the enantiomer of 2a in 90% ee (entry 3). Running the [Cu·L2](OTf)₂-catalyzed reaction in the lower-boiling 1,2-dichloroethane (DCE) also gave 2a in excellent enantioselectivity (91% ee), albeit in somewhat diminished yield (70%, entry 4). Reducing the copper loading from 20 to 15 mol % under rigorously anhydrous conditions led to the formation of 2a in 87% yield in 90% ee (entry 5, second optimal conditions). Lowering the copper loading to 10 mol %, however, diminished the yield (entry 6). Lowering the disulfide loading from 1 to 0.75 equiv also resulted in lower conversion (entry 7). Changing the oxidant from MnO₂ to dry air, 2a was obtained in 42% yield and 91% ee, with 47% of starting 1a recovered (entry 8).²⁸ The use of 100% O₂ (1 atm) as an oxidant gave even lower yield of 2a (entry 9), and side products were observed. Without external oxidant (MnO₂ or O₂), only 21% isolated yield of 2a was obtained (entry 10). Using the first optimal conditions (entry 2), the oxysulfenylation was scaled to 1 mmol of 1a, providing isochroman 2a in 62% yield and 85% ee (entry 11).

The scope of sulfides amenable to the coupling with alkenol 1a was next explored (Table 2).

Table 2.

Sulfide Scope^a

entry	sulfide	product	yield (%)	ee (%)
1	(4-MeC6H4)S2	2b, R = 4-MeC6H4	71	>95
2	(4-NO2C6H4)2S2	2c, R = 4-NO2C6H4	78	94
3	(4-FC6H4)S2	2d, R = 4-FC6H4	66	90
4	(3-FC6H4)S2	2e, R = 3-FC6H4	90	93
5	(2-FC6H4)S2	2f, R = 2-FC6H4	73	94
6b	PhSH	2a, R = Ph	67	90
7b	4-MeC6H4SH	2b, R = 4-MeC6H4	62	63
8	4-FC6H4SH	2d, R = 4-FC6H4	72	90
9b	PhC(O)SH	2g, R = C(O)Ph	—	—
10b	PMBSH	2h, R = PMB	—	—
11	Chx2S2	2i, R = Chx	—	—
12	t-Bu2S2	2j, R = t-Bu	—	—
13c	Ph2Se2		83	47

^aConditions from Table 1, entry 2, were applied with R₂S₂ (100 mol %) unless otherwise noted.

^b150 mol % RSH was used.

^cPh₂Se₂ (100 mol %) was used. PMB = p-methoxybenzyl.

A copper loading of 20 mol % was applied as the viability of the 15 mol % copper loading conditions was identified late in our studies. Diaryl disulfides bearing both electron-donating and electron-withdrawing substituents coupled well, providing isochromans 2b–2f in good yields and excellent enantioselectivities (Table 2, entries 1–5). Extension of the coupling to phenylthiol and 4-fluorophenyl thiol was also possible, and isochromans 2a and 2d were obtained with similar yields and enantioselectivities (Table 2, entries 6 and 8). Extension to 4-methylphenylthiol resulted in isochroman 2b being formed with lower selectivity (63% ee, vide infra). Formation of Ph₂S₂ was observed when PhSH was used (entry 6). Since MnO₂ is known to oxidize thiols to disulfides,²⁹ it is probable the arylthiols are oxidized to Ar₂S₂ prior to oxysulfenylation. Extension to thiobenzoic acid and an alkylthiol (entries 9 and 10, respectively, no reaction observed) and alkyldisulfides (entries 11 and 12, other alkenol cyclizations occurred) was not possible. No reaction was observed when N-phenylsulfenyl phthalimide was used (not shown). It is likely that some sulfides can poison the metal catalyst while, in other cases, they could be less reactive to atom transfer^30a with the carbon radical intermediates generated in this reaction. Diphenyl diselenide did undergo successful coupling with alkenol 1a under the copper-catalyzed conditions, providing selenide 3 in 83% yield and 47% ee (entry 13). The lower enantioselectivity in this reaction is likely the result of a competing racemic electrophilic pathway.^31,32

The alkenol scope was explored using either 15 or 20 mol % [Cu] loading (Table 3). In general, reactions of tertiary alcohol substrates were more enantioselective than those of primary alcohol substrates.^22,24 2-Allylbenzyl alcohol underwent oxysulfenylation, giving isochroman 2k in 54% yield and 65% ee. The most effective oxidant for this reaction was Ag₂CO₃, as the primary benzylic alcohol underwent competitive oxidation in the presence of MnO₂.^22,24 Both the electron-donating methoxy and the electron-withdrawing trifluoromethyl substituents were tolerated on the substrate’s arene, providing 21 and 2m, respectively. Morpholines 4a and 4b were synthesized in good yields and enantioselectivity from the coupling of N-allyl-N-(1-hydroxy-2-methylpropan-2-yl)benzenesulfonamide with diphenyl disulfide and 4-methoxyphenyl disulfide, respectively. Oxysulfenylation of variously substituted 4-pentenols provided tetrahydrofurans 5a–5d in moderate to very good yield. Production of the known tetrahydrofuran 5a¹⁰ under these copper catalysis conditions occurred more efficiently in DCE than in PhCF₃. Phthalans 6a and 6b were readily provided via the respective 2-vinylbenzyl alcohols. Phthalan 6a was obtained in >95% ee when Ph₂S₂ was used as the sulfide source while 6a was formed in 81% ee when PhSH was the sulfide source. We hypothesize that a competing racemic or less selective route to 6a is occurring in the latter reaction where PhS•, formed under the oxidizing reaction conditions, adds to the styrene substrate, giving a benzyl radical intermediate that can undergo coupling with the pendant alcohol in the presence of [Cu(II)] (analogous to the reaction in Scheme 1B).^14,15,20 We surmise that this did not noticeably occur in reactions with 1a with PhSH (Table 2, entry 6) because 1a’s alkyl-substituted alkene is not as good a radical acceptor as a styrene. The lower enantioselectivity observed in the formation of 2b, however (Table 2, entry 7), could indicate that the moderately less stable^30b 4-MeC₆H₄S•, generated from 4-MeC₆H₄SH, may appreciably add to the less reactive alkene, thereby eroding 2b’s enantioselectivity. Efficient formation of tetrasubstituted phthalan 6b indicates that 1,1-disubstituted alkenes are viable substrates for this enantioselective oxysulfenylation reaction. Conversely, trace phthalan 6c was formed (primarily unreacted substrate recovered).

Table 3.

Alkenol Scope^a

^aConditions from Table 1, entry 2, were applied with R₂S₂ (100 mol %) unless otherwise noted.

^bReaction run in DCE.

^cAg₂CO₃ (1.5 equiv) was used as oxidant instead of MnO₂.

^d15 mol % [Cu] and 18 mol % L2 were used.

^eReaction run for 24 h.

^f300 mol % Ph₂S₂ was used.

^g150 mol % RSH was used instead of Ph₂S₂. Absolute configuration of 5a was assigned by comparison to the literature.¹⁰ Other compounds are assigned by analogy.^22,23

Extension of this protocol to aminosulfenylation of unsaturated amine derivatives 7 was briefly explored using (4S,5R)-bis-Ph-Box, a ligand shown to be optimal in related copper-catalyzed aminooxygenation and carboamination reactions.²¹ While N-tosyl-2-allylaniline 7a provided only (self-cyclization) sultam 8,³³ the 3,5-di-t-butyl-4-methoxybenzenesulfonyl-2-allylaniline 7b, designed to minimize carbon radical cyclization onto the arylsulfonyl,³⁴ provided 2-((phenylthio)-methyl)indoline 9a in 54% yield and 92% ee (eq 1), indicating

(1)

that the method can be extended to this substrate class. Reaction of the N-mesyl substrate 7c gave 9b in 70% ee, indicating that the arylsulfonamide of 7 is important for achieving high enantioselectivity. Expansion to 4-fluorophenyl disulfide was feasible, giving 9c from 7c in 76% ee, indicating that the sulfide scope of this aminosulfenylation could be broader than the complementary organocatalytic approach, whose sulfide scope is more limited by the enantioselectivity-determining step.³⁵

Synthetic manipulation of thioether 2a was briefly examined. Thioether 2a was converted to its corresponding aldehyde 10 via Pummerer rearrangement (eq 2).³⁶ Crude aldehyde 10 was

(2)

(3)

reduced to its alcohol 11 prior to further analysis to avoid potential epimerization on silica gel chromatography. In a second demonstration, thioether 2a was converted to its sulfone 12 via mCPBA oxidation (eq 3). The X-ray structure of 12 confirmed the absolute configuration of 2a and related isochromans 2 by analogy.

The oxysulfenylation herein disclosed demonstrates that the enantioselective alkene oxysulfenylation of alkenols is amenable to transition metal catalysis. Based on the observed enantioselectivity in these copper-catalyzed reactions, we can conclude that the mechanistic path, thought to initiate with alkene oxycupration (Scheme 1C),^23,24 must be lower in energy than competing racemic pathways (e.g., Scheme 1B^13-15). This approach is complementary to existing highly enantioselective alkenol oxysulfenylations enabled by main group catalysts⁹ in that the exocyclization products predominate for a broad alkenol scope. A range of diaryldisulfides and arylthiols were compatible with this enantioselective oxysulfenylation protocol. Enantioselective aminosulfenylations were also briefly demonstrated under these conditions using alkenyl sulfonamides as substrates. It is anticipated that this protocol will find application in the synthesis of compounds with medicinal interest.

ABBREVIATIONS

HFIP

1,1,1,3,3,3-hexafluoroisopropanol

mCPBA

meta-chloroperbenzoic acid