2-Diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one: Another Utility for Electrophilic Trifluoromethylthiolation Reactions.

2-Diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one (diazo-triflone) (2) is not only a building block but also a reagent. In this study, diazo-triflone, which was originally used for the synthesis of β-lactam triflones as a trifluoromethanesulfonyl (SO2CF3) building block under catalyst-free thermal conditions, is redisclosed as an effective electrophilic trifluoromethylthiolation reagent under copper catalysis. A broad set of enamines, indoles, β-keto esters, pyrroles, and anilines were nicely transformed into corresponding trifluoromethylthio (SCF3) compounds in good to high yields by diazo-triflone under copper catalysis via an electrophilic-type reaction. A coupling-type trifluoromethylthiolation reaction of aryl iodides was also realized by diazo-triflone in acceptable yields.

Considerable attention in the past decade has been devoted to the trifluoromethylthio (SCF3) group more than ever before because of its high potential value as a structural unit of agrochemicals and pharmaceuticals, although SCF3 compounds have been known for three quarters of a century.1, 2 The highest lipophilicity of the SCF3 group allows molecules to dramatically improve their cell membrane permeability without altering their original structures/components too much when it is introduced into a suitable position in parent molecules.

Replacement of the trifluoromethyl (CF3) group in drug candidates by SCF3 is an attractive strategy for fine‐tuning a candidate's properties, due to their similar electron‐withdrawing properties [σm: 0.44 (CF3); 0.40 (SCF3)], albeit different lipophilicities [π: 0.88 (CF3); 1.44 (SCF3)].3 Thus, the development of effective methods for the synthesis of SCF3 compounds is of great importance in medicinal chemistry.2 SCF3 compounds are prepared by a halogen‐fluorine exchange reaction, trifluoromethylation of thiols or their derivatives, and direct trifluoromethylthiolation.2i, 4 The direct introduction of a SCF3 group into target compounds by trifluoromethylthiolation reagents is certainly the most straightforward method possible. However, reagents initially used for this purpose such as Hg(SCF3)2, HSCF3, ClSCF3, or CF3SSCF3 are toxic and/or gaseous in character, which make them difficult to handle.5 In this context, shelf‐stable electrophilic trifluoromethylthiolation reagents have been drawing attention (Figure 1).2, 6

Figure 1

Shelf‐stable reagents for electrophilic trifluoromethylthiolation.

Since the initial report of N‐trifluoromethylthiophthalimide by Munavalli,6a several shelf‐stable reagents have been reported, including trifluoromethanesulfenamide reagents (Billard, 2008),6b a trifluoromethylthio‐ether reagent (Shen, 2013),6d and trifluoromethylthio saccharine (Shen, 2014).6f In 2013, we disclosed trifluoromethanesulfonyl hypervalent iodonium ylide 1 as a novel, shelf‐stable reagent for the electrophilic trifluoromethylthiolation of enamines, indoles, and β‐keto ester,7a and the utility of 1 was greatly expanded to the functionalization of pyrroles,7b allylsilanes and silyl enol ethers,7c arylamines,7d boronic acids, and allylic alcohols (Figure 1).7e Even though 1 is a trifluoromethanesulfonyl (SO2CF3) compound, it effectively releases electrophilic SCF3 species via carbene generation. As part of an ongoing research program committed to trifluoromethylthiolation reactions, we were interested in the potential utility of 2‐diazo‐1‐phenyl‐2‐((trifluoromethyl)sulfonyl)ethan‐1‐one (2)8a,8b as a shelf‐stable reagent for electrophilic trifluoromethylthiolation reactions.

Diazo‐triflone 2 was originally developed as an effective SO2CF3 building block for the synthesis of triflones.8 Under thermal conditions, 2 reacts with imines to provide multiple substituted β‐lactam triflones in essentially quantitative yields via successive carbene‐generation, Wolf rearrangement (ketene), and Staudinger [2+2] cycloaddition (Scheme 1a).8b The similarity of carbene generation from 2 and that from 1 led us to investigate a new utility of 2 for electrophilic trifluoromethylthiolation, via successive carbene‐generation/oxathiirene‐2‐oxide/sulfoxide/thioperoxoate rearrangement (Scheme 1b).7b, 8b

Scheme 1

Double‐sided utility of 2 as an SO2CF3 building block and a reagent for electrophilic trifluoromethylthiolation reaction (SCF3‐reaction).

Herein, we disclose that 2 is effective for the electrophilic trifluoromethylthiolation of a variety of nucleophiles including enamines, indoles, β‐keto esters, pyrroles, and anilines under copper catalysis to provide corresponding SCF3‐products in good to high yields. Trifluoromethylthiolation via a coupling‐type reaction of aryl iodides was also realized by 2 under copper catalysis, providing aryl‐SCF3 compounds in acceptable yields. This is a unique example of the two‐sided utility of the fluorinated compound 2 as a fluoro‐functionalized reagent (SCF3 reagent) and a fluorinated building block (SO2CF3 building block).

We first examined the reaction of enamine 3 a with 2 under standard conditions described in a previous report for the trifluoromethylthiolation of 3 a by 1.7a However, trifluoromethylthiolated product 4 a was detected in 41 % at room temperature for 48 h. The yield of 4 a was improved to 82 % at 50 °C for 12 h, and decreased slightly to 79 % at 100 °C for 12 h (Scheme 2).

Scheme 2

Copper‐catalyzed trifluoromethylthiolation of enamine 3 a with 2 (yield was detected by 19F NMR). Reagents and conditions: all conditions with CuCl (0.04 mmol), 1,4‐dioxane (1.5 mL); a) rt, 48 h, 41 %; b) 50 °C, 12 h, 82 %; c) 100 °C, 12 h, 79 %.

Under the optimized reaction conditions, enamine substrates 3 a–h were smoothly trifluoromethylthiolated by 2 to provide corresponding SCF3 products 4 a–h in moderate to good yields (Scheme 3). Enamino esters 3 a–d were nicely trifluoromethylthiolated by 2 with over 80 % yield almost independent of the size of esters and the substitution of the terminal aryl group. Enamino esters 3 e–g having an enolizable proton were also tolerated under the reaction conditions to furnish 4 e–g in 52–74 % yield. Enamino ketone 3 h was converted into the corresponding SCF3‐product 4 h in 46 % yield.

Scheme 3

Copper‐catalyzed trifluoromethylthiolation of enamines 3 a–h with 2. Reagents and conditions: a) enamine 3 (0.2 mmol), reagent 2 (0.4 mmol), CuCl (0.04 mmol, 20 mol %), 1,4‐dioxane (1.5 mL), 50 °C, 12 h, isolated yields shown (%). * Reagent 2 (0.3 mmol), 24 h.

Other nucleophilic substrates, such as indoles, β‐keto ester, pyrrole, and anilines, were next investigated for trifluoromethylthiolation by 2 (Scheme 4). Indole substrates 3 i and 3 j were transformed into corresponding SCF3 products in the presence of 20 mol % dimethylaniline as an additive to provide 4 i and 4 j in 61 % and 55 % yield, respectively. β‐Keto ester 3 k reacted with 2 in the presence of 20 mol % 2,4,6‐collidine affording 4 k in 58 % yield. Trifluoromethylthiolation of pyrrole 3 l and anilines 3 m–n with 2 was also achieved to give 4 l–n in good yields (61–86 %). Dimethylaniline and 2,4,6‐collidine presumably act as bases for deprotonation of substrates and/or activate a thioperoxoate intermediate (Scheme 1) to generate quaternary ammonium salts with SCF3.7a

Scheme 4

Copper‐catalyzed trifluoromethylthiolation of indoles, β‐keto ester, pyrrole, and anilines with 2. Reagents and conditions: a) indoles or β‐keto ester 3 (0.2 mmol), 2 (0.4 mmol), CuCl (0.04 mmol), 1,4‐dioxane (1.5 mL), 50 °C, 12 h; b) pyrrole or aniline 3 (0.2 mmol), 2 (0.4 mmol), CuF2 (0.04 mmol), NMP (1.5 mL), 50 °C, 24 h, isolated yields shown (%). * PhNMe2 (0.04 mmol) was added. ** 2,4,6‐Collidine (0.04 mmol) was added.

We further examined the trifluoromethylthiolation of aromatic compounds under a cross‐coupling type of trifluoromethylthiolation reaction. First, 4‐iodotoluene 3 o was selected as the model substrate for trifluoromethylthiolation by 2 (Table 1). A catalytic amount of copper salt afforded the reaction in low yields of 18–32 % (entries 1–4), and dimethylformamide (DMF) showed better results than N‐methyl‐2‐pyrrolidone (NMP) as a solvent (entries 3 and 4). Further optimization of the molar ratio of 3 o with reagent 2 and copper led to suitable conditions, 3 o/2: 1:2.5 and 5.0 equivalents of Cu in DMF, providing 4 o in 56 % (entries 5–10). A palladium catalyst in toluene was not effective (entry 11). A two‐step heating protocol i.e., 50 °C for 12 h, followed by 120 °C for 12 h, was preferred, as greater yield was obtained than single heating at 120 °C for 12 h (entry 12).

Table 1

Optimization of reaction conditions of 4‐iodotoluene 3 o with reagent 2.[a]

Entry	Molar ratio [3 o:2]	Catalyst	Cu [equiv]	Solvent	Yield[b] [%]
1	1:1.5	CuF2	2.5	DMF	18
2[c]	1:2.5	CuF2	2.5	DMF	23
3	1:2.5	CuOAc	2.5	DMF	32
4	1:2.5	CuOAc	2.5	NMP	25
5	1:2.5	—	2.5	DMF	35
6	1:2.5	—	5.0	DMF	56
7	1:5	—	5.0	DMF	19
8	1:2.5	—	10.0	DMF	32
9[d]	1:2.5	—	5.0	DMF	10
10[e]	1:2.5	—	5.0	DMF	5
11	1:2.5	Pd(Ph3P)2Cl2	5.0	Toluene	0
12[f]	1:2.5	—	5.0	DMF	trace

[a] Reaction conditions: 4‐iodotoluene (3 o, 0.2 mmol), reagent 2, catalyst, Cu, solvent (2.5 mL), 50 °C for 12 h then 120 °C for another 12 h. [b] Yields were determined by 19F NMR spectroscopy with trifluoromethyl benzene as the internal standard. [c] 2, Cu, DMF (2.5 mL), 50 °C for 12 h, then 4‐iodotoluene (3 o, 0.2 mmol), and 120 °C for another 12 h. [d] Bipyridine (1.0 equiv) was added. [e] KF (1.0 equiv) was added. [f] The reaction was heated directly at 120 °C for 12 h.

With standard reaction conditions in hand, substrate scope was next investigated using aryl iodides 3 o–t bearing electron‐donating or electron‐withdrawing groups. Although yields were not attractive, the desired Ar−SCF3 products 4 o–t were obtained in 34–56 % isolated yields (Scheme 5).

Scheme 5

Copper‐mediated trifluoromethylthiolation of aryl iodides 3 o–t with 2. Reagents and conditions: a) aryl iodide 3 (0.2 mmol), 2 (0.5 mmol), Cu (1.0 mmol, 5.0 equiv), DMF (2.5 mL), 50 °C for 12 h then 120 °C for 12 h, isolated yields shown (%).

In summary, diazo‐triflone 2 was found to be effective for electrophilic trifluoromethylthiolation of a variety of substrates including enamino esters, enamino ketones, indoles, β‐keto esters, pyrroles, and anilines under copper catalysis in good to high yields. The copper‐mediated coupling‐type trifluoromethylthiolation of aryl iodides was also made possible by 2 in acceptable yields. Since diazo‐triflone 2 was originally examined as a fluorinated building block for the synthesis of β‐lactam triflones, the present result reveals a unique double‐sided property of 2, as an SO2CF3‐contaning building block and as an electrophilic SCF3‐transfer reagent. Further investigation of 2 is underway in our laboratory.

Experimental Section

Typical procedure for copper‐catalyzed trifluoromethylthiolation of enamines, indoles, pyrroles, and anilines

To nucleophiles 3 a–n (0.2 mmol) in 1,4‐dioxane (or NMP) solution (1.5 mL), diazo‐triflone 2 (0.4 mmol) and CuCl (or CuF2) (0.04 mmol) were added under N2 atmosphere in the presence or absence of additives described in Schemes 3 and 4. The mixture was then heated at 50 °C for 12 or 24 h. The mixture was diluted with Et2O (30 mL), washed once with H2O (20 mL) and brine (20 mL), and the organic phase was dried by dry Na2SO4. Solvent was removed in vacuo, and the sample purified by column chromatography to afford SCF3‐products 4 a–n.

Typical procedure for copper‐mediated trifluoromethylthiolation of aryl iodides

To aryl iodides 3 o–t (0.2 mmol) in DMF solution (2.5 mL) in a sealed tube, diazo‐triflone 2 (0.5 mmol) and Cu (1.0 mmol) were added under N2 atmosphere, the tube was sealed, and the mixture was heated at 50 °C for 12 h. The temperature was increased to 120 °C and heated for another 12 h. The mixture was diluted by Et2O (30 mL) and washed once with H2O (20 mL) and brine (20 mL), and the organic phase was dried by dry Na2SO4. Solvent was removed in vacuo, and the sample purified by column chromatography (or preparative thin‐layer plates) to afford SCF3‐products 4  o–t.

Complete synthetic protocols together with characterization data, including spectra for all compounds described herein, are provided in the Supporting Information.

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Supplementary

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