Well-Defined, Shelf-Stable (NHC)Ag(CF2 ... - ACS Publications

Jun 3, 2015 - Well-Defined, Shelf-Stable (NHC)Ag(CF2H) Complexes for. Difluoromethylation. Yang Gu,. †. Dalu Chang,. †. Xuebing Leng,. †. Yuchen...
2 downloads 0 Views 759KB Size
Download PDF
Article pubs.acs.org/Organometallics

Well-Defined, Shelf-Stable (NHC)Ag(CF2H) Complexes for Difluoromethylation Yang Gu,† Dalu Chang,† Xuebing Leng,† Yucheng Gu,‡ and Qilong Shen*,† †

Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China ‡ Syngenta, Jealott’s Hill International Research Centre Bracknell, Berkshire RG42 6EY, U.K. S Supporting Information *

ABSTRACT: The preparation of the thermally stable, welldefined NHC-ligated difluoromethylated silver complexes 1a,b is described. The complexes were fully characterized, and the structural assignments were ambiguously further confirmed by single-crystal X-ray diffraction. Reactions of [(SIPr)Ag(CF2H)] with a variety of activated electrophiles such as diaryliodonium salts, vinyl(aryl)iodonium salts, aryldiazonium salts, and acid chlorides in the presence or absence of CuI occurred smoothly at room temperature to generate difluoromethylated compounds in good to excellent yields.

■

INTRODUCTION In recent years, incorporation of fluoroalkyl groups into druglike molecules has become a powerful and widely employed tactic in the process of drug design because of the well-known beneficial effects of the fluoroalkyl moiety, such as improved lipophilicity and increased metabolic stability.1 Among many fluoroalkyl groups, the difluoromethyl group (CF2H) is an intriguing structural motif with great potential, since it is well-known that it is a bioisostere of a hydroxyl or thiol group and can act as lipophilic hydrogen bond donor to improve the binding selectivity.2 Hence, the development of methods for direct difluoromethylation of small molecules under mild conditions is highly desirable.3 In sharp contrast to the tremendous recent success of the transition-metal-catalyzed trifluoromethylation reactions of aryl substrates,4 far fewer methods for the direct formation of the difluoromethylated compounds have been reported.5 In 2012, Hartwig and co-workers described a copper-mediated method for direct difluoromethylation of aryl and vinyl iodides with TMSCF2H using CsF as the activator.6 In the presence of 1.0 equiv of CuI, electron-rich aryl iodides were difluoromethylated in high yields, while reactions of electron-poor aryl iodides only generated the protonated side products. Prakash and coworkers improved the scope of the reaction to cover both electron-rich and electron-poor aryl iodides by employing nBu3SnCF2H as the nucleophilic difluoromethylating reagent.7 More recently, Qing discovered that the copper-mediated difluoromethylation reaction could be conducted at room temperature when KOtBu was used as the activator.8 In 2015, Goossen and co-worker described a Sandmeyer-type difluoromethylation process for direct conversion of (hetero)arenediazonium salts into the corresponding difluoromethylated (hetero)arenes under mild conditions.9 © XXXX American Chemical Society

Mechanistically, an in situ generated [Cu(CF2H)] was proposed to form by mixing a copper salt with TMSCF2H or n-Bu3SnCF2H in the presence of an activator. [Cu(CF2H)] then reacts with the electrophiles to form the difluoromethylated products. However, the intermediate [Cu(CF2H)] was not stable enough to be isolated. It has been well documented that difluoromethylated coinage-metal species in low oxidation states are unstable at room temperature.10 For example, Eujen reported that [Ag(CF2H)2]− decomposed at −50 °C to give tetrafluoroethane and silver11a and [Cu(CF2H)2]− dispropotionated to tetrakis(difluoromethyl)cuprate(III) [Cu(CF2H)4]− and metallic copper above 0 °C.11b Burton reported that a solution of [Cu(CF2H)] in DMF formed by the reaction of (HCF2)CdX with CuBr or CuCl at −50 to −60 °C reacted quickly with allyl halides to form difluoromethylated products in good yields. However, in the absence of electrophiles, the in situ formed complex decomposed rapidly at −30 °C to generate tetrafluoroethane and cis-difluoroethylene.12 Thus, investigations of well-defined, stable difluoromethylated coinage-metal complexes and an understanding of the fundamental reactivities of these complexes are vital to our ability to design new catalytic difluoromethylation processes. In 2014, we discovered that the N-heterocyclic carbene (NHC) ligated difluoromethylated silver complex [(SIPr)Ag(CF2H)] (SIPr = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2ylidene) is not sensitive to air or moisture over a period of 1 week in the solid state. On the basis of this discovery, we developed a cooperative bimetallic Pd/Ag catalyst for direct difluoromethylation of aryl bromides and iodides.13 More recently, we have extended the method to the difluoromethyReceived: April 28, 2015

A

DOI: 10.1021/acs.organomet.5b00350 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics lation of vinyl bromides, triflates, tosylates, and nonaflates in the presence of a palladium catalyst by using [(SIPr)Ag(CF2H)] as the difluoromethyl source.14 In a continuation of our efforts on the development of efficient methods for late-stage introduction of the difluoromethyl group into small molecules, we report herein the details of the preparation of the N-heterocyclic carbene15 (NHC) ligated difluoromethylated silver complex [(SIPr)Ag(CF2H)] and its analogue [(IPr)Ag(CF2H)].16 More importantly, we discovered that reactions of [(SIPr)Ag(CF2H)] with activated electrophiles such as diaryliodonium salts, vinyl(aryl)iodonium salts, aryldiazonium salts, and acid chlorides in the presence or absence of CuI occurred smoothly at room temperature to give the corresponding difluoromethylated compounds in good to excellent yields.

■

RESULTS AND DISCUSSION Preparation of the NHC-Ligated Difluoromethylated Silver Complexes [(SIPr)Ag(CF2H)] and [(IPr)Ag(CF2H)]. The NHC-ligated difluoromethylsilver complex [(SIPr)Ag(CF 2 H)] (1a; SIPr = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) was prepared in 82% yield by the reaction of [(SIPr)AgCl] with 2.0 equiv of TMSCF2H in THF at room temperature in the presence of 2.0 equiv of NaOtBu (eq 1). [(IPr)Ag(CF2H)] (1b; IPr = 1,3-bis(2,6-

Figure 1. ORTEP diagram of 1a. Ellipsoids are shown at the 50% probability level. Selected bond distances (Å) and angles (deg) for 1a: Ag−C1, 2.090(3); Ag−C28, 2.076(4); C1−Ag−C28, 177.14(17); N1−C1−N2, 108.5(2); N1−C1−Ag, 126.1(4); N2−C1−Ag, 125.2(4).

diisopropylphenyl)imidazol-2-ylidene) was prepared in 35% yield by an analogous reaction using KOtBu as the activator (eq 1). Complexes 1a,b were isolated as white crystalline solids and were characterized by 1H, 13C, and 19F NMR spectroscopy and elemental analysis. The structural assignments were ambiguously further confirmed by single-crystal X-ray diffraction (Figures 1 and 2). Complexes 1a,b, to our knowledge, are the first examples of isolable difluoromethylated silver(I) complexes. The solid-state structures of 1a,b comprise a silver atom coordinated by a carbene and a difluoromethyl group in a linear geometry. The Ag−C(NHC) bonds in both complexes (2.090(3) and 2.092(4) Å, respectively) are of similar length. The Ag−C(CF2H) bond length in complex 1b (2.104 (5) Å) is slightly longer (by 0.028 Å) than those in complex 1a (2.076(4) Å), likely due to the weaker σ-donating ability of IPr in comparison to that of SIPr. The C−N−C and C−Ag−C bond angles in complex 1a are larger than those in complex 1b by roughly 4 and 1°, respectively. Complex 1a is much more stable than complex 1b in the solid state. Complex 1a is air-stable and light-insensitive in the solid state. No decomposition was observed after 24 h at room temperature when it was left in a vial on the bench. Furthermore, complex 1a is stable at room temperature under an argon atmosphere in the dark for over 1 month without decomposition. In contrast, complex 1b turned black after exposure to light for 1 h.

Figure 2. ORTEP diagram of 1b. Ellipsoids are shown at the 50% probability level. Selected bond distances (Å) and angles (deg) for 1b: Ag−C1, 2.092(4); Ag−C28, 2.104(5); C1−Ag−C28, 176.2(2); N1− C1−N2, 104.4(4); N1−C1−Ag, 128.7(7); N2−C1−Ag, 126.7(7).

Complexes 1a,b are soluble in aprotic solvents, such as THF, CH2Cl2, and CHCl3, and insoluble in less polar solvents, such as benzene and hexane. In solution, both complexes were stable for at least 24 h in the dark on dissolution in CH2Cl2 or THF but completely decomposed after 24 h when exposured to light. Room-temperature 19F NMR spectra of 1a,b (CD2Cl2) displayed doublets at −113.01 (dd, 2J109Ag−F = 64.0 Hz, 2 107 J Ag−F = 56.4 Hz, 2JH−F = 45.1 Hz) and −112.76 ppm (dd, 2 109 J Ag−F = 63.9 Hz, 2J107Ag−F = 56.2 Hz, 2JH−F = 41.4 Hz), respectively. These patterns were not dependent on the concentration of the complexes, indicating that the complexes were not in equilibrium with the ionic form [(NHC)2Ag]+[Ag(CF2H)2]−. Reaction of [(NHC)Ag(CF2H)] Complexes with Diaryliodonium Salts. With the NHC-ligated difluoromethylsilver complexes [(SIPr)Ag(CF2H)] (1a) and [(IPr)Ag(CF2H)] (1b) in hand, we then studied their reactions with 4-tertbutylphenyl iodide in the presence of copper salts such as CuX (X = Cl, Br, I), Cu(OAc)2, and copper(I) thiophene-2B

DOI: 10.1021/acs.organomet.5b00350 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics carboxylate (CuTc). Nevertheless, less than 5% of the desired difluoromethylated arenes was observed even at 80 °C in several solvents such as THF, DMF, MeCN, and acetone. The main products observed were HCF2CF2H and an unidentified species with a chemical shift of −115 ppm in 19F NMR spectroscopy. Interestingly, when the more reactive Ar2IOTf (Ar = p-tert-butylphenyl)17 was reacted with [(SIPr)Ag(CF2H)] (1a) or [(IPr)Ag(CF2H)] (1b) in the presence of 1.0 equiv of CuI in CH3CN for 30 min at room temperature, the desired difluoromethylated 4-tert-butylbenzene was observed in 60% and 52% yield, respectively, as determined by 19F NMR spectroscopy with an internal standard. Since [(SIPr)Ag(CF2H)] (1a) is more stable than [(IPr)AgCF2H] (1b), we further optimized the reaction conditions by employing [(SIPr)Ag(CF2H)] (1a) as the nucleophilic difluoromethylating reagent. It was determined that the counterion of the diaryl hypervalent iodine was crucial for the conversion of the reaction. The reaction of diaryl hypervalent iodine with OTf as the counterion gave the highest yield, while compounds with other counterions such as BF4, NO3, and Br took place in much lower yields (Scheme 1, entries 1−4). Likewise, the addition of

Scheme 2. Scope for CuI-Promoted Difluoromethylation of Diaryliodonium Salts with [(SIPr)Ag(CF2H)]a

a

Reaction conditions: diaryliodonium salt (0.5 mmol), [(SIPr)Ag(CF2H)] (1.0 mmol), and copper salt (1.0 mmol) in CH3CN (2.5 mL) at room temperature for 30 min. Yields were determined by 19F NMR spectroscopy with trifluoromethoxybenzene as an internal standard. bIsolated yield.

Scheme 1. Optimization Conditions for Reaction of Diaryliodonium Salts with [(SIPr)Ag(CF2H)]a

substituted diaryliodonium salt also reacted with [(SIPr)Ag(CF2H)] to give the corresponding difluoromethylated arene in 69% yield (Scheme 2, 3m). The main side products of these reactions were aryl iodides that can be separated and reused for the preparation of diaryliodonium salts. To better understand the reactivity of the aryl group in the diaryliodonium salt with [(SIPr)Ag(CF2H)] (1a), (2,4,6trimethylphenyl)(phenyl)iodonium triflate (2n) was prepared and subjected to the standard reaction conditions. The reaction occurred smoothly after 30 min at room temperature to full conversion to give a mixture of 2-(difluoromethyl)-1,3,5trimethylbenzene and difluoromethylbenzene in overall 70% yield with a ratio of 1/2, as determined by 19F NMR spectroscopy and GC-MS (eq 2). The less hindered aryl group is slightly favored over the more hindered aryl group.

a

Reaction conditions: diaryliodonium salt (0.05 mmol), [(SIPr)Ag(CF2H)] (0.05 mmol), and copper salt (0.05 mmol) in CH3CN (0.5 mL) at room temperature for 30 min; bThe yields were determined by 19 F NMR spectroscopy with trifluoromethoxybenzene as an internal standard. c5.0 equiv of CuI was used. d2.0 equiv of (SIPr)Ag(CF2H) and 2.0 equiv of CuI were used.

CuI was important to the reaction and none of the desired difluoromethylated product was observed in the absence of CuI. Reactions in the presences of other copper salts such as CuCl, CuBr, CuTc, and Cu(OAc)2 occurred in lower yields (Scheme 1, entries 5−9). Finally, when 2.0 equiv of [(SIPr)Ag(CF2H)] was used, the yield of the reaction was improved to 85% (Scheme 1, entry 11). We next applied this room temperature difluoromethylation protocol to a variety of different diaryliodonium triflates. As shown in Scheme 2, diaryliodonium triflates bearing electrondonating and -withdrawing substituents underwent difluoromethylation in good to excellent yields under these conditions. This protocol is compatible with a variety of common functional groups such as chloride, bromide, and esters (Scheme 2, 3e,f,h). The presence of chloride or bromide in the products is very useful for further synthetic manipulations. Substrates containing ortho substituents also underwent efficient difluoromethylation under these optimized conditions (Scheme 2, 3k,l). A more hindered 2,6-dimethyl-

Reaction of [(SIPr)Ag(CF2H)] Complex with Vinyl(phenyl)iodonium Salts. Encouraged by the excellent results for the reaction of [(NHC)Ag(CF2H)] complexes with diaryliodonium salts, we next turned our attention to the copper-mediated difluoromethylation of vinyl(phenyl)iodonium salts. The selective formation of difluoromethylalkenes was expected, since it is well-known that the aryliodonio group is one of the best leaving groups and a vinyliodonium salt is generally considered as an equivalent of a vinylic cation.18 Indeed, the reaction of styrenyl(phenyl)iodonium triflates with 1.5 equiv of [(SIPr)Ag(CF2H)] (1a) in the presence of 1.5 equiv of CuI in CH3CN occurred smoothly after 30 min at room temperature to generate β-difluoromethylstyrene in 94% yield. C

DOI: 10.1021/acs.organomet.5b00350 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics Likewise, several substituted styenyl(phenyl)iodonium salts also reacted with [(SIPr)Ag(CF2H)] (1a) to give the corresponding difluoromethylated styrene derivatives in high yields (Scheme 3). Since the copper-mediated difluoromethy-

A variety of aryldiazonium salts were then treated with [(SIPr)Ag(CF2H)] (1a) in acetonitrile at room temperature, and the corresponding difluoromethylated azo compounds were obtained in high yields (Scheme 4). In general, reactions

Scheme 3. CuI-Promoted Difluoromethylation of Vinyl(phenyl)iodonium Triflate with [(SIPr)Ag(CF2H)]a,b

Scheme 4. Difluoromethylation of Aryldiazonium Salts with [(SIPr)Ag(CF2H)]a,b

a

Reaction conditions: vinyl(phenyl)iodonium salt (1.0 mmol), [(SIPr)Ag(CF2H)] (1.5 mmol), and CuI (1.5 mmol) in CH3CN (5.0 mL) at room temperature for 30 min. bIsolated yield.

lation of aryl iodides with TMSCF2H or nBu3SnCF2H typically requires high temperature, the current method represents an alternative and complementary method for the formation of difluoromethylated alkenes under relatively mild conditions. Reaction of [(SIPr)Ag(CF2H)] with Aryldiazonium Salts. The Sandmeyer reaction is one of the most fundamental functional group transformations routinely practiced in organic laboratories and applied industry.19 Under Sandmeyer reaction conditions, the amino group is efficiently tranformed into other functional groups such as halogen (F, Cl, Br, I), hydroxyl, cyano, and boryl groups.20 Very recently, Sandmeyer-type trifluoromethylations21 and trifluoromethylthiolations22 of aryldiazonium salts have also been successfully developed. Inspired by these recent advances, we envisaged that a similar Sandmeyer difluoromethylation reaction of aryldiazonium salts with [(SIPr)Ag(CF2H)] (1a) might be realized. With this in mind, we initially studied the reaction of (4-tertbutylphenyl)diazonium tetrafluoroborate with [(SIPr)Ag(CF2H)] (1a) in the presence of 1.0 equiv of a copper salt in acetonitrile (eq 3). Interestingly, less than a 40% yield of the expected 1-(difluoromethyl)-4-tert-butylbenzene was observed when different CuX (X = Cl, Br, I, CN) species were used as the catalysts. Instead, a compound with a new doublet having a chemical shift at −104.61 ppm in the 19F NMR spectrum was observed in more than 40% yield. The yield for the new product was even higher (89%) when the reaction was conducted in the absence of the copper salt (eq 3). After isolation and purification, the new compound was determined to be 1-(4-tert-butylphenyl)-2-(difluoromethyl)diazene (5a) by 1 H, 13C, and 19F NMR spectroscopy and mass spectroscopy. Obviously, the direct nucleophilic substitution reaction was faster than the denitrogenative Sandmeyer reactions under the reaction conditions.

a

Reaction conditions: aryldiazonium salt (1.0 mmol) and [(SIPr)Ag(CF2H)] (1.0 mmol) in CH3CN (10 mL) at room temperature for 30 min. bIsolated yield.

of aryldiazonium salts with electron-donating groups or electron-withdrawing groups also gave high yields. In addition, a variety of functional groups such as bromo, iodo, cyano, ester, and enolizable ketone were compatible with the reaction conditions. These azo compounds are not air- and moisturesensitive. No decomposition was observed after the compounds were left in a vial on the bench for 1 month. We further tried to convert the azo compounds to difluoromethylarenes by heating under reflux with CuI or photolysis in MeCN at 80 °C for 8 h. However, no formation of difluoromethylarenes was observed by 19F NMR spectroscopy. Reaction of [(SIPr)Ag(CF2H)] with Acid Chlorides. To further expand the reaction scope of [(SIPr)Ag(CF2H)] (1a), we studied the reaction of acid chlorides with [(SIPr)Ag(CF2H)] (1a). It was found that acid chlorides were more reactive than diaryliodonium triflates. One equivalent of [(SIPr)Ag(CF2H)] was required for the reaction of acid chlorides for full conversion to generated difluoromethylated ketones in excellent yields (Scheme 5). The reaction was compatible with a variety of functional groups such as bromide, cyano, and ester (Scheme 5, 6c−e). The reaction of benzo[b]thiophene-2-carboxylic acid with [(SIPr)Ag(CF2H)] in the presence of 5 mol % of CuI and 1,10-phenanthroline generated the heteroaryl difluoromethyl ketone in 92% yield (Scheme 5, 6g). Likewise, under the same conditions, cinnamoyl chloride was converted into the difluoromethylated ketone in 71% yield (Scheme 5, 6h). Aliphatic carboxylic acid chlorides were also reacted with [(SIPr)Ag(CF2H)] to give the corresponding difluoromethylated ketone, albeit in moderate yields (Scheme 5, 6i,j). Previous methods for the preparation of difluoromethyl ketone typically require multiple steps.23 D

DOI: 10.1021/acs.organomet.5b00350 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics

diisopropylphenyl)imidazolidin-2-yl)(difluoromethyl)silver, [(SIPr)Ag(CF2H)] (1a), as a white solid (698 mg, 82%). Crystals suitable for X-ray analysis were obtained by laying a solution of complex 1a in THF (70 μL)/pentane (3.5 mL) at −30 °C. 1H NMR (400 MHz, THF-d8): δ 7.36 (t, 3JH−H = 8.0 Hz, 2 H), 7.26 (d, 3JH−H = 8.0 Hz, 4 H), 5.90 (td, 2JH−F = 43.6, 3JH−H =14.0 Hz, 1 H), 4.04 (s, 4 H), 3.15 (hept, 3JH−H = 6.8 Hz, 4 H), 1.34 (d, 3JH−H = 7.2 Hz, 12 H), 1.32 (d, 3 JH−H = 7.2 Hz, 12 H). 19F NMR (376 MHz, THF-d8): δ −113.66 (dd, 2 109 J Ag−F = 62.4 Hz, 2J107Ag−F = 54.5 Hz, 2JH−F = 43.6 Hz). 13C NMR (101 MHz, CDCl3): δ 24.11, 25.76, 28.96, 124.55, 129.78, 134.80, 146.76, 153.67 (dt, 1J109Ag−C = 260.6 Hz, 1J107Ag−C = 225.2 Hz, 1JC−F = 280.8 Hz), 211.41 (d, 1J109Ag−C = 151.5 Hz, 1J109Ag−C = 131.3 Hz) ppm. Anal. Calcd for C28H39AgF2N2: C, 61.20; H, 7.15; N, 5.10. Found: C, 60.91; H, 6.87; N, 4.78. Preparation of [(IPr)Ag(CF2H)] (1b). To a solution of [(IPr)AgCl] (552 mg, 1.00 mmol) and KOtBu (225 mg, 2.00 mmol) in THF (90 mL) was added TMSCF2H (250 μL 3.00 mmol) in THF (10 mL), and the resulting mixture was stirred for 4 h at ambient temperature. The mixture was filtered through a short plug of Celite, and the solvent was evaporated under vacuum to give an off-white solid. The solid was recrystallized from THF/pentane to give (1,3-bis(2,6diisopropylphenyl)-2,3-dihydro-1H-imidazol-2-yl)(difluoromethyl)silver [(IPr)Ag(CF2H)] (1b) as a white solid (189 mg, 35%). Crystals suitable for X-ray analysis were obtained by laying a solution of complex 1a in THF (70 μL)/pentane (3.5 mL) at −30 °C. 1H NMR (400 MHz, CDCl3): δ 7.48 (t, 3JH−H = 7.6 Hz, 2 H), 7.28 (d, 3JH−H = 7.6 Hz, 4 H), 7.14 (s, 2 H), 6.25 (td, 2JH−F = 43.2, 3JH−H = 16.0 Hz, 1 H), 2.53 (hept, 3JH−H = 7.2 Hz, 4 H), 1.26 (d, 3JH−H = 6.8 Hz, 12 H), 1.20 (d, 3JH−H = 6.8 Hz, 12 H). 19F NMR (376 MHz, CDCl3) δ −112.76 (dd, 2J109Ag−F = 63.5 Hz, 2J107Ag−F = 54.9 Hz, 2JH−F = 43.2 Hz). 13 C NMR (126 MHz, CDCl3): δ 23.94, 24.54, 28.68, 123.23, 124.10, 125.03, 130.39, 134.67, 145.61, 155.00 (dt, 1J109Ag−C = 262.6 Hz, 1 107 J Ag−C = 227.3 Hz, 1JC−F = 281.5 Hz), 188.66 (d, 1JAg−C = 142.6 Hz) ppm. Anal. Calcd for C28H37AgF2N2: C, 61.43; H, 6.81; N, 5.12. Found: C, 61.32; H, 6.88; N, 4.99. General Procedure for the Difluoromethylation of Ar2IOTf. Anhydrous MeCN (2.5 mL) was added to a mixture of Ar2IOTf (0.5 mmol, 1.0 equiv), CuI (0.19 g, 1.0 mmol, 2.0 equiv), and [(SIPr)Ag(CF2H)] (550 mg, 1.00 mmol, 2.0 equiv) in a 20 mL vial in a glovebox under an argon atmosphere. The vial was sealed and moved out of the glovebox. The mixture was stirred for 30 min. The dark solution was diluted with CH2Cl2 (15 mL). The mixture was filtered through a short plug of Celite and washed with CH2Cl2 (20 mL × 3). The organic layers were combined and washed with brine (20 mL × 3). The filtrate was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel with pentane or a pentane/Et2O mixture as the eluent to give the product. General Procedure for the Difluoromethylation of Vinyl(phenyl)iodonium. Anhydrous MeCN (5.0 mL) was added to a mixture of Ar2IOTf (1.0 mmol, 1.0 equiv), CuI (0.29 g, 1.5 mmol, 1.5 equiv), and [(SIPr)Ag(CF2H)] (825 mg, 1.5 mmol, 1.5 equiv) in a 20 mL vial in a glovebox under an argon atmosphere. The vial was sealed and moved out from the glovebox. The mixture was stirred for 30 min. The dark solution was diluted with CH2Cl2 (15 mL). The mixture was filtered through a short plug of Celite and washed with CH2Cl2 (20 mL × 3). The organic layers were combined and washed with brine (20 mL × 3). The filtrate was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel with pentane or a pentane/Et2O mixture as the eluent to give the product. General Procedure for the Difluoromethylation of Vinyl(phenyl)iodonium. Anhydrous MeCN (10 mL) was added to a mixture of ArN2BF4 (1.0 mmol, 1.0 equiv) and , [(SIPr)Ag(CF2H)] (550 mg, 1.0 mmol, 1.0 equiv) in a 20 mL vial in a glovebox under an argon atmosphere. The vial was sealed and moved out from the glovebox. The mixture was stirred for 30 min. The dark solution was diluted with CH2Cl2 (15 mL). The mixture was filtered through a short plug of Celite and washed with CH2Cl2 (20 mL × 3). The organic layers were combined and washed with brine (20 mL × 3).

Scheme 5. Scope for CuI-Catalyzed Difluoromethylation of Acid Chlorides with [(SIPr)Ag(CF2H)]a,b

a Reaction conditions: acid chloride (0.5 mmol), [(SIPr)Ag(CF2H)] (1.0 mmol), CuI (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) in CH3CN (5.0 mL) at room temperature for 2 h. bIsolated yield.

■

CONCLUSION In summary, we have shown the preparation and characterization of the first thermally stable and well-defined (NHC)AgI(CF2H) complexes. It was discovered that [(SIPr)Ag(CF2H)] can efficiently difluoromethylate various activated electrophiles such as diaryliodonium salts, vinyl(phenyl)iodonium salts, aryldiazonium salts and acid chlorides in the presence or absence of CuI under mild conditions. Further explorations in ligand and reagent design and an understanding of the mechanism of the copper-mediated difluoromethylation with [(NHC)Ag(CF2H)] are ongoing in our laboratory.

■

EXPERIMENTAL SECTION

General Information. All manipulations were conducted under an inert atmosphere with an argon-filled glovebox unless otherwise noted. All reactions were conducted in oven-dried 4.0 or 20.0 mL vials fitted with a Teflon-lined screw cap under an atmosphere of argon unless otherwise noted (the preparation of diaryliodonium salts Ar2IOTf was conducted in air). The diaryliodonium salts Ar2IOTf were prepared following known procedures.24−26 The vinyl(phenyl)iodonium salts were prepared following known procedures.27 The aryldiazonium salts were prepared following known procedures.9 The carbonyl chlorides were obtained from commercial sources, except for 6g. m-CPBA was dried under high vacuum at 23 °C for 4 h.28 All solvents were purified by standard methods. 1 H, 13C, and 19F NMR spectra were acquired on 400, 100, and 376 MHz spectrometers (400 or 300 MHz for 1H; 100 or 125 MHz for 13 C; 282 or 376 MHz for 19F). Chemical shifts are reported in ppm and referenced to residual solvent peaks, and 19F spectra were referenced to CFCl3 set to 0. Coupling constants are reported in hertz. The following abbreviations are used to explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Preparation of [(SIPr)Ag(CF2H)] (1a). To a solution of [(SIPr)AgCl] (831 mg, 1.50 mmol) and NaOtBu (285 mg, 3.00 mmol) in THF (30 mL) was added TMSCF2H (375 uL, 3.00 mmol). The resulting mixture was stirred for 1.5 h at ambient temperature. The mixture was filtered through a short plug of Celite, and the solvent was evaporated under vacuum to give an off-white solid. The solid was recrystallized from THF/pentane to give (1,3-bis(2,6E

DOI: 10.1021/acs.organomet.5b00350 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics The filtrate was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel with pentane or a pentane/Et2O mixture as the eluent to give the product. General Procedure for the Difluoromethylation of vinyl(phenyl)iodonium. Anhydrous MeCN (5.0 mL) was added to a mixture of RCOCl (0.5 mmol, 1.0 equiv), CuI (4.8 mg, 0.025 mmol, 0.05 equiv), 1,10-phenanthroline (4.5 mg, 0.025 mmol, 0.05 equiv), and [(SIPr)Ag(CF2H)] (550 mg, 0.5 mmol, 1.0 equiv) in a 20 mL vial in a glovebox under an argon atmosphere. The vial was sealed and moved out from the glovebox. The mixture was stirred for 30 min. The dark solution was diluted with CH2Cl2 (15 mL). The mixture was filtered through a short plug of Celite and washed with CH2Cl2 (20 mL × 3). The organic layers were combined and washed with brine (20 mL × 3). The filtrate was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel with pentane or a pentane/Et2O mixture as the eluent to give the product.

■

6679−6687. (f) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem., Int. Ed. 2012, 51, 5048−5050. (5) (a) Dolbier, W. R., Jr.; Médebielle, M.; Ait-Mohand, S. Tetrahedron Lett. 2001, 4811−4814. (b) Fujikawa, K.; Fioka, Y.; Kobayashi, A.; Amii, H. Org. Lett. 2011, 13, 5560−5563. (c) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494−1497. (d) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon, D.; Rodriguez, R. A.; Baxter, R. D.; Herlé, B.; Sach, N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95−99. (e) Li, Z.-J.; Cui, Z.-L.; Liu, Z.-Q. Org. Lett. 2013, 15, 406−409. (f) Xia, J.-B.; Zhu, C.; Chen, C. J. Am. Chem. Soc. 2013, 135, 17494−17500. (g) Mizuta, S.; Stenhagen, I. S. R.; Duill, M. O.; Wolstenhulme, J.; Kirjavainen, A. K.; Forsback, S. J.; Tredwell, M.; Sandford, G.; Moore, P. R.; Huiban, M.; Luthra, S. K.; Passchier, J.; Solin, O.; Gouverneur, V. Org. Lett. 2013, 15, 2648−2651. (h) Xu, P.; Guo, S.; Wang, L.-Y.; Tang, P.-P. Angew. Chem., Int. Ed. 2014, 53, 5955−5958. (i) Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Synlett 2012, 3015−3018. (j) Sun, X.-Y.; Yu, S.-Y. Org. Lett. 2014, 16, 2938−2941. (k) Su, Y.-M.; Hou, Y.; Yin, F.; Xu, Y.-M.; Li, Y.; Zheng, X.-Q.; Wang, X.-S. Org. Lett. 2014, 16, 2958−2961. (6) (a) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524− 5527. (b) Ge, S.; Chaładaj, W.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 4149−4152. (7) Prakash, G. K. S.; Ganesh, S. K.; Jones, J. P.; Kulkarni, A.; Masood, K.; Swabeck, J. K.; Olah, G. A. Angew. Chem., Int. Ed. 2012, 51, 12090−12094. (8) Jiang, X.-L.; Chen, Z.-H.; Xu, X.-H.; Qing, F.-L. Org. Chem. Front. 2014, 1, 774−776. (9) Matheis, C.; Jouvin, K.; Goossen, L. J. Org. Lett. 2014, 16, 5984− 5987. (10) Difluoromethyl-ligated transition-metal complexes: (a) Blake, D. M.; Winkeman, A.; Chung, Y.-L. Inorg. Chem. 1975, 14, 1326−1332. (b) Schultz, A. J.; Khare, G. P.; McArdle, J. V.; Eisenberg, R. J. Am. Chem. Soc. 1973, 95, 3434−3436. (c) Schultz, A. J.; McArdle, J. V.; Khare, G. P.; Eisenberg, R. J. Organomet. Chem. 1974, 72, 415−423. (d) Brothers, P. J.; Burrell, A. K.; Clark, G. R.; Rickard; Clifton, E. F.; Roper, W. R. J. Organomet. Chem. 1990, 394, 615−642. (e) Burrell, A. K.; Clark, G. R.; Jeffrey, J. G.; Rickard, C. E. F.; Roper, W. R. J. Organomet. Chem. 1990, 388, 391−408. (f) Huang, D.-J.; Caulton, K. G. J. Am. Chem. Soc. 1997, 119, 3185−3186. (g) Huang, D.-J.; Koren, P. R.; Folting, K.; Davidson, E. R.; Caulton, K. G. J. Am. Chem. Soc. 2000, 122, 8916−8931. (11) (a) Eujen, R.; Hoge, B.; Brauer, D. J. Inorg. Chem. 1997, 36, 3160−3166. (b) Eujen, R.; Hoge, B.; Brauer, D. J. J. Organomet. Chem. 1996, 519, 7−20. (12) (a) Hartgraves, G. A.; Burton, D. J. J. Fluorine Chem. 1988, 39, 425−430. (b) Burton, D. J.; Hartgraves, G. A. J. Fluorine Chem. 2007, 128, 1198−1125. (13) Gu, Y.; Leng, X.-B.; Shen, Q. Nat. Commun. 2014, 5, 5405. (14) Chang, D.-L.; Gu, Y.; Shen, Q. Chem. - Eur. J. 2015, 21, 6074− 6078. (15) Reviews on N-heterocyclic carbene (NHC) ligated silver complexes: (a) Arnold, P. L. Heteroat. Chem. 2002, 13, 534−539. (b) Carrison, J. C.; Youngs, W. Chem. Rev. 2005, 105, 3978−4008. (c) Lin, J. C. Y.; Huang, R. T. W.; Lee, C. S.; Bhattacharyya, A.; Hwang, W. S.; Lin, I. J. B. Chem. Rev. 2009, 109, 3561−3598. (d) Dı ́ez-Gonzaĺ ez, S.; Marrion, N.; Nolan, S. P. Chem. Rev. 2009, 109, 3612−3676. (16) Pioneering works on N-heterocyclic carbene (NHC) stabilized coinage-metal fluorinated or fluoroalkylated complexes: (a) Dubinina, G. G.; Fururachi, H.; Vicic, D. A. J. Am. Chem. Soc. 2008, 130, 8600− 8601. (b) Dubinina, G. G.; Ogikubo, J.; Vicic, D. A. Organometallics 2008, 27, 6233−6235. (c) Zhang, C. P.; Vicic, D. A. Organometallics 2012, 31, 7812. (d) Akana, J. A.; Bhattacharyya, K. X.; Müller, P.; Sadigha, J. P. J. Am. Chem. Soc. 2007, 129, 7736−7737. (17) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299− 5358. (b) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052−9070.

ASSOCIATED CONTENT

S Supporting Information *

Text, figures, and CIF files giving details of all syntheses, NMR spectra of the isolated products, and X-ray crystallographic data for complexes 1a,b. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.5b00350.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail for Q.S.: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors gratefully acknowledge the financial support from the National Basic Research Program of China (2012CB821600), the National Natural Science Foundation of China (21172245/21172244/21372247/21421002), the Syngenta Ph.D. fellowship (Y.G.), and the SIOC. We also thank Dr. John Clough of Syngenta at Jealott’s Hill International Research Centre for proof-reading of the manuscript.

■

REFERENCES

(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications; Wiley-VCH: Weinheim, Germany, 2004. (b) Hiyama, T. Organofluorine Compounds: Chemistry and Properties; Springer-Verlag: Berlin, 2000. (c) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford, U.K., 2006. (d) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308−319. (e) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119−6146. (f) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1−PR43. (g) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111, 455−529. (h) Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105, 827−856. (2) (a) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619−8683. (b) Shimizu, M.; Hiyami, T. Angew. Chem., Int. Ed. 2005, 44, 214−231. (c) Hu, J.-B.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465−7478. (3) (a) Markovski, L. N.; Pahinnik, V. E.; Kirsanov, A. V. Synthesis 1973, 787−789. (b) Kuroboshi, M.; Hiyama, T. Synlett 1991, 909− 910. (4) Recent reviews on transition-metal-catalyzed trifluoromethylation of arene substrates: (a) Burton, D. J.; Yang, Z.-Y. Tetrahedron 1992, 48, 189−275. (b) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432−5446. (c) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470−477. (d) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475−4521. (e) Liu, T.; Shen, Q. Eur. J. Org. Chem. 2012, 34, F

DOI: 10.1021/acs.organomet.5b00350 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics (18) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 1996, 96, 1123− 1178. (b) Pirkuliev, N. S.; Brel, V. K.; Zeforov, N. S. Russ. Chem. Rev. 2000, 69, 105−120. (c) Stang, P. J. Angew. Chem., Int. Ed. 1992, 31, 274−285. (19) (a) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 1633−1635. (b) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 2650−2653. (20) For reviews on functionalization of aryldiazonium salts, see: (a) Hodgson, H. H. Chem. Rev. 1947, 40, 251−277. (b) Roglans, A.; Pla-Quintana, A.; Moreno-Maňas, M. Chem. Rev. 2006, 106, 4622− 4643. (c) Mo, F.-Y.; Dong, G.-B.; Zhang, Y.; Wang, J.-B. Org. Biomol. Chem. 2013, 11, 1582−1593. (d) Hari, D. P.; Konig, B. Angew. Chem., Int. Ed. 2013, 52, 4734−4743. (21) (a) Wang, X.; Xu, Y.; Mo, F.-Y.; Ji, G.; Qiu, D.; Feng, J.; Ye, Y.; Zhang, S.; Zhang, Y.; Wang, J.-B. J. Am. Chem. Soc. 2013, 135, 10330− 10333. (b) Dai, J.-J.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z.-J.; Lu, X.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 8436−8439. (c) Danoun, G.; Bayamagnai, B.; Grünberg, M. F.; Gooßen, L. J. Angew. Chem., Int. Ed. 2013, 52, 7972−7972. (d) Tlili, A.; Billard, T. Angew. Chem. Int. Ed. 2013, 52, 6818−6819. (22) (a) Adams, D. J.; Goddard, A.; Clark, J. H.; Macquarrie, D. J. Chem. Commun. 2000, 987−988. (b) Danoun, G.; Bayarmagnai, B.; Gruenberg, M. F.; Gooßen, L. J. Chem. Sci. 2014, 5, 1312−1315. (c) Bayarmagnai, B.; Matheis, C.; Risto, E.; Gooßen, L. J. Adv. Synth. Catal. 2014, 356, 2343−2348. (23) Previous methods for the formation of difluoromethyl ketone: (a) Wagner, P. J.; Thomas, M. J.; Puchalski, A. E. J. Am. Chem. Soc. 1986, 108, 7739−7744. (b) Zupan, M.; iskra, J.; Stavber, S. J. Org. Chem. 1995, 60, 259−260. (c) Peng, W.; Shreeve, J. J. Org. Chem. 2005, 70, 5760−5763. (d) Kirij, N. V.; Babadzhanova, L. A.; Movchun, V. N.; Yagupolskii, Y. L.; Tyrra, W.; Naumann, D.; Fischer, H.; Scherer, H. J. Fluorine Chem. 2008, 129, 14−21. (24) Zhu, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 10815−10818. (25) Bielawski, M.; Zhu, M.; Olofsson, B. Adv. Synth. Catal. 2007, 349, 2610−2618. (26) Zhu, M.; Jalalian, N.; Olofsson, B. Synlett. 2008, 4, 592−596. (27) Skucas, E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 134, 9090−9093. (28) Gademann, K.; Jana, C. K.; Neuburger, M.; Thommen, C. Org. Lett. 2013, 15, 1390−1393.

G

DOI: 10.1021/acs.organomet.5b00350 Organometallics XXXX, XXX, XXX−XXX