Nucleophilic and Electrophilic Double Aroylation of Chalcones with Benzils Promoted by the Dimsyl Anion as a Route to All Carbon Tetrasubstituted Olefins

Note pubs.acs.org/joc Nucleophilic and Electrophilic Double Aroylation of Chalcones with Benzils Promoted by the Dimsyl Anion as a Route to All Carbon Tetrasubstituted Olefins Daniele Ragno, Olga Bortolini,* Giancarlo Fantin, Marco Fogagnolo, Pier Paolo Giovannini, and Alessandro Massi* Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-27, I-44121 Ferrara, Italy S Supporting Information * ABSTRACT: Dimsyl anion promoted the polarity reversal of benzils in a Stetter-like reaction with chalcones to give 2-benzoyl-1,4-diones (double aroylation products), which, in turn, were converted into the corresponding tetrasubstituted olefins via aerobic oxidative dehydrogenation catalyzed by Cu(OAc)2. A tom-economical reactions represent a powerful tool in synthetic organic chemistry and a means to mitigate its negative effects on the environment.1 In this context, the formation of multiple bonds in a single organocatalytic transformation is of great significance to readily access diverse structural motifs displaying all portions of the starting materials.2 Bifunctional molecules constitute valuable substrates for the design of organocatalytic domino sequences; nevertheless, the use of highly reactive α-diketones has been rarely investigated in this type of approach,3 in which the double carbonyl functionality of 1,2-diones exhibits electrophilic behavior at the carbonyl carbon and nucleophilic character at the α position. A complementary mode of carbonyl reactivity is, however, possible for this class of substrates; as demonstrated by our group, α-diketones can be rendered nucleophilic at carbonyl carbon (umpolung reactivity) through the catalysis of thiamine diphosphate (ThDP)-dependent enzymes4 and Nheterocyclic carbenes (NHCs)5 in nucleophilic acylations. Recently, we also discovered the capability of methylsulfinyl (dimsyl) carbanion A to induce the polarity reversal of diaryl αdiketones (benzils) in chemoselective cross-benzoin condensations with aldehydes.6 Dimsyl anion, generated by deprotonation of the DMSO solvent, served as surrogate of hazardous cyanide ion, promoting the formation of benzoylated benzoins in an atom-economic fashion through sequential nucleophilic C-aroylations and electrophilic O-aroylations (Scheme 1). As a logical extension of the study on the benzoin reaction, we reasoned that utility of dimsyl anion catalysis could be further enhanced by conducting a double C-aroylation process on activated alkenes, thus providing a novel variant of the parent Stetter reaction (hydroacylation process).7 We also envisaged that the resulting activated 1,4-dicarbonyls could be further elaborated going back to the alkene stage via a catalytic oxidative dehydrogenation step to produce all carbon © 2014 American Chemical Society Scheme 1. Double Aroylation of Aldehydes and Activated Alkenes with Benzils Promoted by the Dimsyl Anion A tetrasubstituted olefins from chalcones through a simple and effective one-pot process (Scheme 1). On the other hand, tetrasubstituted alkenes with conjugated systems are challenging synthetic targets8 with unique structural and electronic features in material science9 as well as useful building blocks for synthetic chemistry.10 The reaction of benzil 1a with chalcone 2a was initially investigated to verify the feasibility of the project (Table 1). Reaction selectivity was a major issue to be addressed since formation of the desired double C-aroylation product 3aa could be accompanied by generation of byproducts 4aa and 5aa via competitive double C,O-aroylation and hydroacylation pathways, respectively (vide inf ra). Gratifyingly, under the Received: November 12, 2014 Published: December 26, 2014 1937 DOI: 10.1021/jo502582e J. Org. Chem. 2015, 80, 1937−1945 The Journal of Organic Chemistry Note in 75% yield (entry 8) were finally established using an excess of benzil 1a (2 equiv). For the sake of comparison, the catalytic activity of cyanide anion was also tested, detecting the same reaction selectivity and a comparable, but appreciably higher, yield of 3aa (83−82%, entries 10−11). In addition, commercially available NHC salts B−G were screened under suitable conditions evaluating the effects of altering the solvent, temperature, and base. After some experimentation, it was found that the sole triazolium salt BDBU couple catalyzed the reaction in CH2Cl2, affording 3aa in modest yield (15%, entry 12). Indeed, the more hindered triazolium salts C−D (entries 13−14) and thiazolium,12 imidazolium, and imidazolium precatalysts E−G (entries 15− 17) proved to be totally inactive, the observed formation of 3aa in DMSO being the result of a background activity of the dimsyl anion. The substrate scope of the disclosed double C-aroylation reaction was initially examined with benzils 1a−h and chalcones 2a−g displaying various substitution patterns under two sets of conditions (Table 2). In general, the process promoted by the dimsyl anion (100 mol % t-BuOK, DMSO; conditions 1) provided a safe and environmentally benign access to 2-benzoyl-1,4-diones 3 and 3′, albeit with slightly diminished yields (2−18%) compared to the same process catalyzed by the toxic KCN (25 mol %, DMSO; conditions 2). Relative efficiencies of reactions between benzil 1a and chalcones 2a−g bearing electron-withdrawing, -neutral, and -donating groups indicated a more pronounced effect of substituents on the benzoyl ring of chalcone, obtaining higher yields of 3 with electron-poor aromatic rings (entries 1−7). Investigation on the electronic requirements for the α-diketone 1 showed the 2,2′-pyridyl 1b with an electron-withdrawing moiety as a highly reactive substrate (entries 8−9); unexpectedly, the use of electron-deficient 4,4′-ditrifluoromethylbenzil 1c and 4,4′-difluorobenzil 1d led to a significant reduction of reaction efficiency (entries 10−11) mainly because of the diketone self-condensation side-reaction.13 The combination of the electron-rich 4,4′-dimethylbenzil 1e and activated chalcone 2b rendered the corresponding product 3eb with good conversion (entry 12). The employment of unsymmetrical benzils 1f−h produced the two regioisomers 3 and 3′ in variable isomeric ratios. The monosubstituted 2-chloro benzil 1f exhibited the highest capability in controlling the chemoselectivity (3:3′ cr) of the double C-aroylation process as it reacted with chalcone 2b, yielding almost exclusively the isomer 3fb′ (5:95 cr; entry 13). This result implied that dimsyl/cyanide anion favorably added to the less hindered carbonyl carbon of 1f. Similarly, a comparison of the reactivity of monosubstituted 4-Cl and 4OMe benzils 1g and 1h toward chalcone 2a indicated the preferential attack of the catalyst to the diketone carbonyl carbon with lower electron density (entries 14−15). A limitation of the dimsyl anion-based methodology appeared evident from the representative couplings of enone 2h (R = H) with benzil 1a and activated 2,2′-pyridyl 1b (entries 16−17). The expected products 3ah and 3bh were, in fact, detected in only trace amounts by MS analysis of the crude reaction mixtures;14 by contrast, the cyanide-catalyzed couplings proceeded smoothly, affording 3ah and 3bh in moderate and good yield, respectively. All of these findings are in agreement with the following mechanistic proposal. Similarly to what is reported for the cyanide catalysis,15 addition of dimsyl anion A to the more Table 1. Optimization of the Model Double C-Aroylation of Chalcone 2a with Benzil 1aa entry solvent 1b 2b,c 3b 4 5 6d 7 8 9e 10 11 12 13 14 15 16 17 DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO CH2Cl2 CH2Cl2 CH2Cl2 DMSO DMSO DMSO (pre)catalyst (mol %) KCN (25) TBACN (25) B (20) C (20) D (20) E (20) F (20) G (20) base (mol %) yield (%) t-BuOK (30) t-BuOK (30) t-BuOK (100) DBU (100) Cs2CO3 (100) CsOH (100) Et3N (100) t-BuOK (100) t-BuOK (100) 34 28 46 24 32 35 DBU (50) DBU (50) DBU (50) NEt3 (50) DBU(50) DBU (50) 75 32 83 82 15 28 25 a Reaction conditions: benzil 1a (0.50 mmol), chalcone 2a (0.25 mmol), and anhydrous solvent (1.0 mL). b 2a: 0.50 mmol. c Temperature: 50 °C. dReaction performed in the presence of 4 Å MS. e2a: 1.00 mmol. conditions previously described for the generation of dimsyl anion A (anhydrous DMSO, 30 mol % t-BuOK, r.t.), the reaction of equimolar 1a and 2a gave the expected compound 3aa (34%, entry 1) with only trace amounts of the Stetter product 5aa and no evidence of 4aa. While a mild heating (50 °C) of the reaction mixture had a negative effect on the reaction output (entry 2), an increase of t-BuOK amount (100 mol %) improved the yield of 3aa (46%, entry 3), thus highlighting the importance of the excess of base to produce the necessary quantity of dimsyl anion (pKa [DMSO] = 35.0; pKa [t-BuOK] = 32.2).11 In line with our previous findings, the reaction output was strictly correlated to the strength of the base in DMSO; that is, t-BuOK > Cs2CO3 ≈ CsOH > DBU ≫ Et3N (entries 4−7). Optimal reaction conditions delivering 3aa 1938 DOI: 10.1021/jo502582e J. Org. Chem. 2015, 80, 1937−1945 The Journal of Organic Chemistry Note Table 2. Scope of the Double C-Aroylation Reactiona entry 1 2 3 4 5 6 7 8f 9f 10 11 12f 13 14 15 16 17f Ar1 Ph Ph Ph Ph Ph Ph Ph 2-pyridyl 2-pyridyl 4-CF3C6H4 4-FC6H4 4-MeC6H4 Ph Ph Ph Ph 2-pyridyl Ar2 Ph Ph Ph Ph Ph Ph Ph 2-pyridyl 2-pyridyl 4-CF3C6H4 4-FC6H4 4-MeC6H4 2-ClC6H4 4-ClC6H4 4-OMeC6H4 Ph 2-pyridyl 1 1a 1a 1a 1a 1a 1a 1a 1b 1b 1c 1d 1e 1f 1g 1h 1a 1b R Ph 4-ClC6H4 4-BrPh 4-MePh Ph Ph 4-ClC6H4 Ph 4-ClC6H4 Ph Ph 4-ClC6H4 4-ClC6H4 Ph Ph H H R′ 2 Ph Ph Ph Ph 4-ClC6H4 4-OMePh 4-OMePh Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 2a 2b 2c 2d 2e 2f 2g 2a 2b 2a 2a 2b 2b 2a 2a 2h 2h 3 (dr)b 3aa 3ab 3ac 3ad 3ae (1:1) 3af (1:1) 3ag (1:1) 3ba (1.5:1) 3bb (1.5:1) 3ca (19:1) 3da (1:1) 3eb (1:1) 3fb 3ga 3ha 3ah 3bh 3′ (dr)b e e e e e e e e e e e e 3fb′ (1.5:1) 3ga′g (1:1) 3ha′h (1:1) e e 3 + 3′ (%, %)c 75, 83 77, 89 70, 88 63,75 70, 86 40, 44 55, 70 79, 81 77, 84 30, 32 22, 29 67, 82 44, 51 52, 64 47, 58 <5, 28 <5, 75 3:3′ (cr)d 5:95 70:30 16:84 Conditions 1: t-BuOK (100 mol %), DMSO, r.t, 16 h. Conditions 2: KCN (25 mol %), DMSO, r.t., 16 h. bDiastereomeric ratio determined by 1H NMR analysis of crude reaction mixtures. cYields (conditions 1/conditions 2). dChemoselectivity ratio determined by 1H NMR analysis of crude reaction mixtures. e3′ = 3. fConditions 1 with Cs2CO3 (100 mol %) as the base. g3ga′ = 3ae. h3ha′ = 3af. a originates from partial hydrolysis of the species IV with benzoyl group elimination. It is important to emphasize that involvement in the catalytic cycle of the acyl anion equivalent III and dimsyl anion A has been previously supported by ESIMS/MS experiments and trapping of A with benzophenone.6 Next, to demonstrate the utility of the double C-aroylation process, we showed that the 2-benzoyl-1,4-diones 3/3′ could be converted into the corresponding all carbon substituted olefins 6/6′ in a straightforward manner. Accordingly, the copper-catalyzed oxidative dehydrogenation of isolated 3/3′ was briefly investigated in DMSO; full conversions in 6/6′ were achieved using 10 mol % of Cu(OAc)2·H2O, t-BuOK (1 equiv), and air as the terminal oxidant (80 °C, 2 h).18 This result paved the way for the development of a convenient one-pot two-step process for the direct elaboration of chalcones 2 into the doubly aroylated olefins 6/6′. Hence, to the solution of benzil 1 and chalcone 2 in DMSO was initially added t-BuOK (100 mol %) or KCN (25 mol %); then, after having established the completion of the reaction by TLC analysis, the reaction mixture containing the 2-benzoyl-1,4-dione 3/3′ was treated at 80 °C with Cu(OAc)2·H2O (10 mol %), giving the desired tetrasubstituted olefins 6/6′ in satisfactory overall yields (Table 3). To provide an insight into the mechanism of aerobic oxidative dehydrogenation,19 3aa oxidation was initially performed in the presence of the radical scavenger TEMPO; 6aa was obtained as the major product, thus suggesting that radicals were not involved in this reaction. Also, it was verified that 3aa dehydrogenation could proceed in the absence of tBuOK (or KCN) with lower kinetics but still high conversion efficiency. A parallel ESI-MS investigation on 3aa oxidation without the base was then carried out to identify key intermediates of the catalytic cycle. When an acetonitrile solution of 3aa was treated with Cu(OAc)2·H2O, formation of the ionic cluster V corresponding to [3aa + CuII(AcO)]+ was electrophilic carbon (blue colored) of α-diketone 1 forms the intermediate I, which, in turn, evolves to the carbanion III via the epoxide II (Scheme 2). Then, conjugate addition of III to Scheme 2. Proposed Mechanism of the Double C-Aroylation Reaction Promoted by the Dimsyl Anion A chalcone 2 (R = Ar) affords the anion IV, which finally liberates the double C-aroylation product 3/3′ and the promoter A through an intramolecular Claisen-type reaction. Carbonyl group formation is supposed to be the driving force for the elimination of dimsyl anion in the final step of the proposed mechanism;16 on the other hand, regeneration of the promoter A requires the presence of stoichiometric t-BuOK because of the higher acidity of the product 3/3′ compared to that of DMSO.17 It can also be speculated that formation of the hydroacylation product of type 5aa (Table 1), occasionally detected in trace amounts in some substrate combinations, 1939 DOI: 10.1021/jo502582e J. Org. Chem. 2015, 80, 1937−1945 The Journal of Organic Chemistry Note elimination should then complete the formation of the double bond in 6aa with generation of a copper species,21 which is converted to the active catalyst by molecular oxygen. In conclusion, we have developed a novel umpolung reaction consisting in the double aroylation of chalcones with benzils promoted by dimsyl or cyanide anion. The utility of the resulting 2-benzoyl-1,4-diones has been also demonstrated by their facile conversion into the corresponding tetrasubstituted olefins. Table 3. One-Pot Two-Step Synthesis of Tetrasubstituted Olefins 6/6′a,b,c ■ EXPERIMENTAL SECTION Potassium tert-butoxide was purified by sublimation (200−220 °C at 1 mmHg) before utilization. Reactions were monitored by TLC on silica gel 60 F254 with detection by charring with phosphomolybdic acid. Flash column chromatography was performed on silica gel 60 (230− 400 mesh). 1H (300 MHz), 13C (75 MHz), and 19F (282 MHz) NMR spectra were recorded in CDCl3 solutions at room temperature. Peaks assignments were aided by 1H−1H COSY and gradient-HMQC experiments. ESI-MS routine analyses were performed in positive ion mode with samples dissolved in 10 mM solution of ammonium formate in 1:1 MeCN/H2O. For accurate mass measurements, the compounds were detected in positive ion mode by HPLC-Chip Q/ TOF-MS (nanospray) analysis using a quadrupole, a hexapole, and a time-of-flight unit to produce spectra. Residual water of commercially available anhydrous DMSO (0.016% w/w) was determined by Karl Fisher analysis. Diketones 1a, 1b, 1d, 1e, 1h and chalcones 2a−d are commercially available compounds. Diketones 1c,22 1f,6 1g,6 chalcones 2e−g,23 and enone 2h24 were synthesized as described. The 2-benzoyl1,4-dione 3ah is a known compound.7a Optimization of the Model Double C-Aroylation of Chalcone 2a with Benzil 1a. Entries 1−9. To a vigorously stirred mixture of benzil 1a (105 mg, 0.50 mmol), the stated amount of chalcone 2a, and anhydrous DMSO (1 mL), the stated amount of base (mol % based on 1a) was added in one portion. Then, the mixture was degassed under vacuum and saturated with argon (by an argon-filled balloon) three times. The mixture was stirred at the stated temperature for 16 h, then diluted with H2O (5 mL), and extracted with CH2Cl2 (2 × 25 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), concentrated, and eluted from a column of silica gel with 10:1 cyclohexane−AcOEt to give 3aa. Entries 10−11. To a vigorously stirred mixture of benzil 1a (105 mg, 0.50 mmol), 2a (54 mg, 0.25 mmol), and anhydrous DMSO (1 mL), potassium cyanide (8.1 mg, 0.13 mmol) or tetrabutylammonium cyanide (34 mg, 0.13 mmol) was added in one portion. Then, the mixture was degassed under vacuum and saturated with argon (by an argon-filled balloon) three times. The mixture was stirred at the stated temperature for 16 h, then diluted with H2O (5 mL), and extracted with CH2Cl2 (2 × 25 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), concentrated, and eluted from a column of silica gel with 10:1 cyclohexane−AcOEt to give 3aa. Entries 12−17. To a vigorously stirred mixture of benzil 1a (105 mg, 0.50 mmol), 2a (54 mg, 0.25 mmol), the stated amount of azolium salt (20 mol % based on 1a) and anhydrous DMSO (1 mL), the stated base (0.25 mmol) was added in one portion. Then, the mixture was degassed under vacuum and saturated with argon (by an argon-filled balloon) three times. Then, the mixture was degassed under vacuum and saturated with argon (by an argon-filled balloon) three times. The mixture was stirred at the stated temperature for 16 h, then diluted with H2O (5 mL), and extracted with CH2Cl2 (2 × 25 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), concentrated, and eluted from a column of silica gel with 10:1 cyclohexane−AcOEt to give 3aa (no product formation in entries 13−15). General Procedure for the Double C-Aroylation of Activated Alkenes 2 with Benzils 1 Promoted by the Dimsyl Anion (Conditions 1, Table 2). To a vigorously stirred mixture of benzil 1 (1.00 mmol), alkene 2 (0.50 mmol), and anhydrous DMSO (2 mL), potassium tert-butoxide (112 mg, 1.00 mmol) was added in one portion. Then, the mixture was degassed under vacuum and saturated a Yields (dimsyl catalysis/cyanide catalysis). bDiastereomeric ratio determined by 1H and 13C NMR analyses of crude reaction mixtures. c First step performed using Cs2CO3 (100 mol %) as the base. observed at m/z 540 (63Cu) (Scheme 3).20 Relevant is the fact that V released AcOH during the MS/MS fragmentation with Scheme 3. Proposed Mechanism for the Copper-Catalyzed Aerobic Dehydrogenation of 3/3′ Based on an ESI-MS/MS Study formation of the species VI (m/z 480), in which copper(II) replaces the lost proton.20 Elimination of AcOH in the presence of deuterated acetonitrile unequivocally confirmed the proton abstraction from the substrate. It can be hypothesized that a similar mechanism of copper-mediated C−H activation may also occur in solution;19a β-hydride 1940 DOI: 10.1021/jo502582e J. Org. Chem. 2015, 80, 1937−1945 The Journal of Organic Chemistry Note (432.5): 455.5 (M + Na+). HRMS (ESI/Q-TOF) calcd for C30H24NaO3 ([M + Na]+) 455.1623, found: 455.1614. 2-Benzoyl-1-(4-chlorophenyl)-3,4-diphenylbutane-1,4-dione (3ae). Column chromatography with 10:1 cyclohexane−AcOEt afforded 3ae (158 mg, 70%; conditions 1) as a 1:1 mixture of diastereoisomers. Conditions 2: 3ae (194 mg, 86%; dr = 1:1). Separation of the two diastereoisomers was carried by a second column chromatography using toluene as the elution system. The first eluted diastereoisomer was slightly contaminated by uncharacterized byproducts: 1H NMR: δ = 8.05−7.96 (m, 2 H, Ar), 7.89−7.82 (m, 2 H, Ar), 7.66−7.58 (m, 2 H, Ar), 7.53−7.22 (m, 10 H, Ar), 7.14−7.08 (m, 2 H, Ar), 7.07−7.00 (m, 1 H, Ar), 6.31 (d, J = 10.7 Hz, 1 H, H-2), 5.78 (d, J = 10.7 Hz, 1 H, H-3); 13C{1H} NMR: δ = 198.0, 195.6, 193.0, 139.9, 136.5, 135.8, 134.7, 134.5, 133.5, 133.2, 130.0, 129.1, 129.0, 129.0, 128.8, 128.6, 128.5, 128.4, 128.0, 127.8, 60.4, 55.3; IR (CDCl3) ν: 3067, 2924, 1697, 1667, 1665, 1589 cm−1. ESI MS (452.9): 475.8 (M + Na+). HRMS (ESI/Q-TOF) calcd for C29H21ClNaO3 ([M + Na]+) 475.1077, found: 475.1083. Second eluted diastereoisomer: 1H NMR: δ = 8.05−7.96 (m, 2 H, Ar), 7.92− 7.85 (m, 2 H, Ar), 7.66−7.58 (m, 2 H, Ar), 7.52−7.43 (m, 2 H, Ar), 7.41−7.32 (m, 4 H, Ar), 7.29−7.22 (m, 4 H, Ar), 7.18−7.08 (m, 2 H, Ar), 7.07−7.00 (m, 1 H, Ar), 6.31 (d, J = 10.7 Hz, 1 H, H-2), 5.77 (d, J = 10.7 Hz, 1 H, H-3); 13C{1H} NMR: δ = 197.9, 194.8, 193.8, 139.9, 136.1, 135.8, 134.9, 134.7, 133.5, 133.2, 130.0, 129.2, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 127.9, 60.4, 55.1; IR (CDCl3) ν: 3063, 2923, 1692, 1661, 1587 cm−1. ESI MS (452.9): 475.7 (M + Na+). HRMS (ESI/Q-TOF) calcd for C29H21ClNaO3 ([M + Na]+) 475.1077, found: 475.1092. 2-Benzoyl-1-(4-methoxyphenyl)-3,4-diphenylbutane-1,4-dione (3af). Column chromatography with 6:1 cyclohexane−AcOEt afforded 3af (89 mg, 40%; conditions 1) as an inseparable 1:1 mixture of diastereoisomers. Conditions 2: 3af (98 mg, 44%; dr = 1:1). 1H NMR: δ = 8.05−7.98 (m, 2 H, Ar), 7.95−7.88 (m, 2 H, Ar), 7.73−7.64 (m, 2 H, Ar), 7.52−7.41 (m, 2 H, Ar), 7.41−7.32 (m, 4 H, Ar), 7.31−7.26 (m, 2 H, Ar), 7.15−7.06 (m, 2 H, Ar), 7.06−6.98 (m, 1 H, Ar), 6.85− 6.69 (m, 2 H, Ar), 6.32 (d, J = 10.8 Hz, 0.5 H, H-2′), 6.31 (d, J = 10.8 Hz, 0.5 H, H-2″), 5.79 (d, J = 10.8 Hz, 0.5 H, H-3′), 5.78 (d, J = 10.8 Hz, 0.5H, H-3″), 3.80 (s, 1.5 H, CH3′), 3.78 (s, 1.5 H, CH3″); 13 C{1H} NMR: δ = 198.3 (0.5 C), 198.1 (0.5 C), 196.0 (0.5 C), 194.4 (0.5 C), 194.0 (0.5 C), 192.4 (0.5 C), 163.7 (0.5 C), 163.4 (0.5 C), 136.7, 136.2, 136.0, 134.9, 133.3, 133.2, 133.0, 131.1, 130.3, 129.7, 129.6, 129.0, 128.7, 128.6, 128.5, 128.4, 127.7, 113.8 (0.5 C), 113.6 (0.5 C), 60.4 (0.5 C), 60.2 (0.5 C), 55.4, 55.1 (0.5 C), 55.0 (0.5 C); IR (CDCl3) ν: 3062, 2936, 1672, 1669, 1667, 1596 cm−1. ESI MS (448.5): 471.7 (M + Na+). HRMS (ESI/Q-TOF) calcd for C30H24NaO4 ([M + Na]+) 471.1572, found: 471.1559. 2-Benzoyl-3-(4-chlorophenyl)-1-(4-methoxyphenyl)-4-phenylbutane-1,4-dione (3ag). Column chromatography with 7:1 cyclohexane−AcOEt afforded 3ag (134 mg, 55%; conditions 1) as an inseparable 1:1 mixture of diastereoisomers. Conditions 2: 3ag (169 mg, 70%; dr = 1:1). 1H NMR: δ = 8.03−7.95 (m, 2 H, Ar), 7.94−7.85 (m, 2 H, Ar), 7.76−7.68 (m, 2 H, Ar), 7.53−7.36 (m, 4 H, Ar), 7.35− 7.17 (m, 4 H, Ar), 7.11−7.04 (m, 2 H, Ar), 6.84−6.73 (m, 2 H, Ar), 6.29 (d, J = 10.7 Hz, 0.5 H, H-2′), 6.28 (d, J = 10.7 Hz, 0.5 H, H-2″), 5.78 (d, J = 10.7 Hz, 0.5 H, H-3′), 5.76 (d, J = 10.7 Hz, 0.5 H, H-3″), 3.81 (s, 1.5 H, CH3′), 3.78 (s, 1.5 H, CH3″); 13C{1H} NMR: δ = 198.0 (0.5 C), 197.9 (0.5 C), 195.7 (0.5 C), 194.3 (0.5 C), 193.6 (0.5 C), 192.2 (0.5 C), 163.8 (0.5 C), 136.6, 136.2, 135.8, 133.8, 133.5, 133.4, 133.3, 131.1, 130.4, 130.3, 129.4, 129.2, 129.0, 128.6, 113.9 (0.5 C), 113.8 (0.5 C), 60.3 (0.5 C), 60.1 (0.5 C), 55.5 (0.5 C), 55.4 (0.5 C), 54.3 (0.5 C), 54.1 (0.5 C); IR (CDCl3) ν: 3061, 2924, 1671, 1669, 1667, 1596 cm−1. ESI MS (482.9): 506.3 (M + Na+). HRMS (ESI/QTOF) calcd for C30H23ClNaO4 ([M + Na]+) 505.1183, found: 505.1175. 2-Benzoyl-3-phenyl-1,4-di(pyridin-2-yl)butane-1,4-dione (3ba). Column chromatography with 4:1 cyclohexane−AcOEt afforded 3ba (166 mg, 79%; conditions 1) as an inseparable 1.5:1 mixture of diastereoisomers. Conditions 2: 3ba (170 mg, 81%; dr = 1.5:1). 1H NMR: δ = 8.71−8.66 (m, 1 H, Ar), 8.66−8.60 (m, 0.4 H, Ar”), 8.41− 8.34 (m, 0.6 H, Ar′), 8.23−8.12 (m, 1 H, Ar), 8.06−7.94 (m, 1 H, Ar), with argon (by an argon-filled balloon) three times. The mixture was stirred at room temperature until complete disappearance or best conversion of the starting alkene (TLC analysis, ca. 2−16 h). The mixture was then diluted with H2O (5 mL), and extracted with CH2Cl2 (2 × 35 mL). The combined organic phases were washed with brine (8 mL), dried (Na2SO4), concentrated, and eluted from a column of silica gel with the suitable elution system to give 3/3′. General Procedure for the Double C-Aroylation of Activated Alkenes 2 with Benzils 1 Catalyzed by Potassium Cyanide (Conditions 2, Table 2). To a vigorously stirred mixture of benzil 1 (1.00 mmol), alkene 2 (0.50 mmol), and anhydrous DMSO (2 mL), potassium cyanide (16 mg, 0.25 mmol) was added in one portion. Then, the mixture was degassed under vacuum and saturated with argon (by an argon-filled balloon) three times. The mixture was stirred at room temperature until complete disappearance or best conversion of the starting alkene (TLC analysis, ca. 2−16 h). The mixture was then diluted with H2O (5 mL), and extracted with CH2Cl2 (2 × 35 mL). The combined organic phases were washed with brine (8 mL), dried (Na2SO4), concentrated, and eluted from a column of silica gel with the suitable elution system to give 3/3′. 2-Benzoyl-1,3,4-triphenylbutane-1,4-dione (3aa). Column chromatography with 10:1 cyclohexane−AcOEt afforded 3aa (155 mg, 75%; conditions 1) as a white amorphous solid. Conditions 2: 3aa (174 mg, 83%). 1H NMR: δ = 8.08−7.98 (m, 2 H, Ar), 7.95−7.89 (m, 2 H, Ar), 7.70−7.65 (m, 2 H, Ar), 7.54−7.44 (m, 2 H, Ar), 7.43−7.32 (m, 4 H, Ar), 7.31−7.21 (m, 5 H, Ar), 7.14−7.06 (m, 2 H, Ar), 7.05− 6.95 (m, 1 H, Ar), 6.38 (d, J = 10.7 Hz, 1 H, H-2), 5.80 (d, J = 10.7 Hz, 1 H, H-3); 13C{1H} NMR: δ = 198.1, 195.9, 194.2, 136.6, 136.2, 135.9, 134.8, 133.4, 133.3, 133.1, 129.1, 129.0, 128.6, 128.5, 128.4, 127.8, 60.5, 55.2; IR (CDCl3) ν: 3031, 2937, 1704, 1634, 1630, 1532 cm−1. ESI MS (418.4): 441.6 (M + Na+). HRMS (ESI/Q-TOF) calcd for C29H22NaO3 ([M + Na]+) 441.1467, found: 441.1474. 2-Benzoyl-3-(4-chlorophenyl)-1,4-diphenylbutane-1,4-dione (3ab). Column chromatography with 13:1 cyclohexane−AcOEt afforded 3ab (174 mg, 77%; conditions 1) as a white amorphous solid. Conditions 2: 3ab (202 mg, 89%). 1H NMR: δ = 8.04−7.96 (m, 2 H, Ar), 7.94−7.87 (m, 2 H, Ar), 7.74−7.67 (m, 2 H, Ar), 7.54−7.44 (m, 3 H, Ar), 7.44−7.35 (m, 3 H, Ar), 7.35−7.27 (m, 3 H, Ar), 7.24− 7.19 (m, 2 H, Ar), 7.12−7.03 (m, 2 H, Ar), 6.36 (d, J = 10.7 Hz, 1 H, H-2), 5.79 (d, J = 10.7 Hz, 1 H, H-3); 13C{1H} NMR: δ = 197.8, 195.5, 194.0, 136.5, 136.1, 135.7, 133.8, 133.6, 133.5, 133.3, 130.3, 129.2, 129.0, 128.7, 128.7, 128.6, 60.4, 54.3; IR (CDCl3) ν: 3061, 2960, 1689, 1660, 1659, 1596 cm−1. ESI MS (452.9): 475.7 (M + Na+). HRMS (ESI/Q-TOF) calcd for C29H21ClNaO3 ([M + Na]+) 475.1077, found: 475.1084. 2-Benzoyl-3-(4-bromophenyl)-1,4-diphenylbutane-1,4-dione (3ac). Column chromatography with 13:1 cyclohexane−AcOEt afforded 3ac (173 mg, 70%; conditions 1) as a white amorphous solid. Conditions 2: 3ac (218 mg, 88%). 1H NMR: δ = 8.04−7.96 (m, 2 H, Ar), 7.95−7.88 (m, 2 H, Ar), 7.73−7.67 (m, 2 H, Ar), 7.53−7.43 (m, 3 H, Ar), 7.42−7.36 (m, 3 H, Ar), 7.35−7.27 (m, 3 H, Ar), 7.26− 7.20 (m, 2 H, Ar), 7.18−7.12 (m, 2 H, Ar), 6.35 (d, J = 10.7 Hz, 1 H, H-2), 5.78 (d, J = 10.7 Hz, 1 H, H-3); 13C{1H} NMR: δ = 197.8, 195.5, 194.0, 136.5, 136.1, 135.7, 134.0, 133.6, 133.5, 133.3, 132.2, 130.7, 129.0, 128.7, 128.7, 128.6, 122.0, 60.4, 54.4; IR (CDCl3) ν: 3062, 2924, 1690, 1663, 1661, 1595 cm−1. ESI MS (497.4): 520.6 (M + Na+). HRMS (ESI/Q-TOF) calcd for C29H21BrNaO3 ([M + Na]+) 519.0572, found: 519.0585. 2-Benzoyl-1,4-diphenyl-3-(p-tolyl)butane-1,4-dione (3ad). Column chromatography with 14:1 cyclohexane−AcOEt afforded 3ad (136 mg, 63%; conditions 1) as a white amorphous solid. Conditions 2: 3ad (163 mg, 75%). 1H NMR: δ = 8.05−7.98 (m, 2 H, Ar), 7.95− 7.88 (m, 2 H, Ar), 7.73−7.64 (m, 2 H, Ar), 7.52−7.39 (m, 4 H, Ar), 7.38−7.33 (m, 3 H, Ar), 7.32−7.27 (m, 2 H, Ar), 7.18−7.09 (m, 2 H, Ar), 6.93−6.88 (m, 2 H, Ar), 6.36 (d, J = 10.7 Hz, 1 H, H-2), 5.77 (d, J = 10.7 Hz, 1 H, H-3), 2.11 (s, 3 H, CH3); 13C{1H} NMR: δ = 198.2, 195.9, 194.3, 137.5, 136.8, 136.3, 136.0, 133.3, 133.1, 133.0, 131.7, 129.7, 129.0, 128.9, 128.7, 128.7, 128.6, 128.5, 128.4, 60.7, 54.8, 20.9; IR (CDCl3) ν: 3063, 2919, 1691, 1688, 1687, 1595 cm−1. ESI MS 1941 DOI: 10.1021/jo502582e J. Org. Chem. 2015, 80, 1937−1945 The Journal of Organic Chemistry Note 477.9 (M + Na+). HRMS (ESI/Q-TOF) calcd for C29H20F2NaO3 ([M + Na]+) 477.1278, found: 477.1296. 2-Benzoyl-3-(4-chlorophenyl)-1,4-di-p-tolylbutane-1,4-dione (3eb). Column chromatography with 12:1 cyclohexane−AcOEt afforded 3eb (161 mg, 67%; conditions 1) as an inseparable 1:1 mixture of diastereoisomers. Conditions 2: 3eb (197 mg, 82%; dr = 1:1). 1H NMR: δ = 7.95−7.86 (m, 2 H, Ar), 7.85−7.78 (m, 1 H, Ar), 7.74−7.66 (m, 1 H, Ar), 7.65−7.57 (m, 1 H, Ar), 7.50−7.40 (m, 1 H, Ar), 7.39−7.27 (m, 2 H, Ar), 7.23−7.15 (m, 5 H, Ar), 7.14−7.04 (m, 4 H, Ar), 6.32 (d, J = 10.7, 0.5 H, H-2′), 6.31 (d, J = 10.7, 0.5 H, H-2″), 5.77 (d, 1 H, J = 10.7 Hz, H-3′ and H-3″), 2.34 (s, 3 H, CH3), 2.32 (s, 3 H, CH3); 13C{1H} NMR: δ = 197.5 (0.5 C), 197.4 (0.5 C), 195.7 (0.5 C), 195.0 (0.5 C), 194.1 (0.5 C), 193.4 (0.5C), 144.7, 144.4, 144.2, 136.6, 136.2, 134.0, 133.8, 133.7, 133.6, 133.5, 133.4, 133.2, 130.3, 129.3, 129.1, 128.9, 128.8, 128.7, 128.6, 60.3 (0.5 C), 60.2 (0.5 C), 54.2 (0.5 C), 54.1 (0.5 C), 21.6; IR (CDCl3) ν: 3032, 2920, 1690, 1667, 1604, 1572 cm−1. ESI MS (481.0): 504.2 (M + Na+). HRMS (ESI/Q-TOF) calcd for C31H25ClNaO3 ([M + Na]+) 503.1390, found: 503.1388. 2-Benzoyl-4-(2-chlorophenyl)-3-(4-chlorophenyl)-1-phenylbutane-1,4-dione (3fb) and 2-Benzoyl-1-(2-chlorophenyl)-3-(4chlorophenyl)-4-phenylbutane-1,4-dione (3fb′). Column chromatography with 13:1 cyclohexane−AcOEt afforded 3fb and 3fb′ (107 mg, 44%; conditions 1) as a 1:19 mixture of isomers. Conditions 2: 3fb and 3fb′ (124 mg, 51%; cr = 1:19). 3fb: 1H NMR (selected data): δ = 6.38 (d, J = 10.7 Hz, 1 H, H-2), 5.98 (d, J = 10.7 Hz, 1 H. H-3). 3fb′: 1 H NMR (1.5:1 mixture of diastereoisomers): δ = 7.98−7.92 (m, 2 H, Ar), 7.75−7.65 (m, 1 H, Ar), 7.62−7.53 (m, 1 H, Ar), 7.52−7.42 (m, 2 H, Ar), 7.41−7.28 (m, 6 H, Ar), 7.26−7.13 (m, 4 H, Ar), 7.12−7.02 (m, 2 H, Ar), 6.42−6.27 (m, 1 H, H-2′ and H-2″), 5.79 (d, J = 10.7 Hz, 0.4 H, H-3′), 5.64 (d, J = 10.7 Hz, 0.6 H. H-3″). 13C{1H} NMR (1.5:1 mixture of diastereoisomers): δ = 198.6 (0.6 C), 198.0 (0.4 C), 194.9 (0.6 C), 194.4 (0.4 C), 194.1 (0.6 C), 193.2 (0.4 C), 137.2, 136.4, 136.2, 134.2, 134.1, 133.8, 133.6, 133.6, 133.4, 132.9, 132.2, 131.9, 131.4, 130.90, 130.8, 130.5, 130.3, 130.0, 129.6, 129.2, 129.0, 128.7, 128.6, 128.5, 126.7, 64.3 (0.4 C), 59.9 (0.6 C), 57.6 (0.6 C), 53.4 (0.4 C); IR (CDCl3) ν: 3063, 2920, 1688, 1686, 1665, 1594 cm−1. ESI MS (487.4): 510.9 (M + Na+). HRMS (ESI/Q-TOF) calcd for C29H20Cl2NaO3 ([M + Na]+) 509.0687, found: 509.0677. 2-Benzoyl-4-(4-chlorophenyl)-1,3-diphenylbutane-1,4-dione (3ga). Column chromatography with 10:1 cyclohexane−AcOEt afforded 3ga and 3ga′ (117 mg, 52%; conditions 1) as a 2.3:1 mixture of isomers. Conditions 2: 3ga and 3ga′ (144 mg, 64%; cr = 2.3:1). First eluted was 3ga′ (= 3ae). Second eluted was 3ga as a white amorphous solid. 1H NMR: δ = 7.98−7.92 (m, 2 H, Ar), 7.91−7.85 (m, 2 H, Ar), 7.70−7.64 (m, 2 H, Ar), 7.50−7.39 (m, 3 H, Ar), 7.38− 7.32 (m, 3 H, Ar), 7.28−7.21 (m, 4 H, Ar), 7.14−7.07 (m, 2 H, Ar), 7.06−6.98 (m, 1 H, Ar), 6.35 (d, J = 10.7 Hz, 1 H, H-2), 5.72 (d, J = 10.7 Hz, 1 H, H-3); 13C{1H} NMR: δ = 196.9, 195.7, 194.1, 139.6, 136.5, 136.0, 134.5, 134.2, 133.5, 133.4, 130.4, 129.2, 128.9, 128.9, 128.7, 128.6, 128.5, 128.2, 127.9, 60.3, 55.2; IR (CDCl3) ν: 3065, 2928, 1692, 1666, 1664, 1588 cm−1. ESI MS (452.9): 475.6 (M + Na+); HRMS (ESI/Q-TOF) calcd for C29H21ClNaO3 ([M + Na]+) 475.1077, found: 475.1098. 2-Benzoyl-4-(4-methoxyphenyl)-1,3-diphenylbutane-1,4-dione (3ha). Column chromatography with 6:1 cyclohexane−AcOEt afforded 3ha and 3ha′ (105 mg, 47%; conditions 1) as a 1:5.3 mixture of isomers slightly contaminated by uncharacterized byproducts. Conditions 2: 3ha and 3ha′ (130 mg, 58%; cr = 1:5.3). 3ha: 1 H NMR (selected data): δ = 6.39 (d, J = 10.7 Hz, 1 H, H-2), 5.80 (d, J = 10.7 Hz, 1 H, H-3), 3.86 (s, 3 H, OCH3); 13C{1H} NMR (selected data): δ = 55.0; IR (CDCl3) ν: 3063, 2927, 1673, 1671, 1597, 1575 cm−1. ESI MS (448.5): 471.6 (M + Na+); HRMS (ESI/Q-TOF) calcd for C30H24NaO4 ([M + Na]+) 471.1572, found: 471.1573. 3ha′ = 3af. 2-Benzoyl-1,4-diphenylbutane-1,4-dione (3ah). Conditions 1: trace amounts of 3ah as determined by MS analysis of the crude reaction mixture; ESI MS (342.4): 365.6 (M + Na+). Conditions 2: column chromatography with 5:1 cyclohexane−AcOEt afforded 3ah7a (48 mg, 28%) as a yellow solid: mp 154−155 °C. 1H NMR: δ = 8.06− 7.94 (m, 6 H, Ar), 7.62−7.54 (m, 3 H, Ar), 7.51−7.40 (m, 6 H, Ar), 7.88−7.80 (m, 1 H, Ar), 7.78−7.65 (m, 2 H, Ar), 7.62−7.52 (m, 0.6 H, Ar′), 7.48−7.41 (m, 0.4 H, Ar”), 7.41−7.12 (m, 8 H, Ar), 7.01−6.84 (m, 3 H, Ar), 6.90 (d, J = 11.5 Hz, 0.4 H, H-2″), 6.66 (d, J = 11.5 Hz, 0.6 H, H-2′), 6.42 (d, J = 11.5 Hz, 0.4 H, H-3″), 6.30 (d, J = 11.5 Hz, 0.6 H, H-3′); 13C{1H} NMR: δ = 199.1 (0.6 C), 198.6 (0.4 C), 198.2 (0.6 C), 197.9 (0.4 C), 196.3 (0.6 C), 195.1 (0.5 C), 152.3, 151.4, 149.1, 149.1, 148.5, 148.4, 138.0, 136.9, 136.6, 134.3, 133.1, 132.0, 130.2, 129.8, 129.1, 129.0, 128.4, 128.2, 127.9, 127.6, 127.3, 127.1, 127.0, 126.9, 126.9, 122.8, 122.7, 122.5, 59.7 (0.6 C), 58.1 (0.4 C), 52. Six (0.4 C), 52.1 (0.6 C); IR (CDCl3) ν: 3057, 2916, 1691, 1690, 1685, 1581 cm−1. ESI MS (420.5): 421.9 (M + H+). HRMS (ESI/QTOF) calcd for C27H21N2O3 ([M + H]+) 421.1552, found: 421.1541. 2-Benzoyl-3-(4-chlorophenyl)-1,4-di(pyridin-2-yl)butane-1,4dione (3bb). Column chromatography with 4:1 cyclohexane−AcOEt afforded 3bb (175 mg, 77%) as an inseparable 1.5:1 mixture of diastereoisomers. Conditions 2: 3bb (191 mg, 84%; dr = 1.5:1). 1H NMR: δ = 8.71−8.64 (m, 1.4 H, Ar), 8.44−8.37 (m, 0.6 H, Ar′), 8.18−8.11 (m, 1 H, Ar), 8.05−7.96 (m, 1.6 H, Ar), 7.89−7.82 (m, 1.4 H, Ar), 7.81−7.70 (m, 2 H, Ar), 7.66−7.59 (m, 1 H, Ar), 7.47−7.20 (m, 7 H, Ar), 6.98−6.87 (m, 2 H, Ar) 6.91 (d, J = 11.5 Hz, 0.4 H, H2″), 6.63 (d, J = 11.5 Hz, 0.6 H, H-2′), 6.40 (d, J = 11.5 Hz, 0.4 H, H3″), 6.28 (d, J = 11.5 Hz, 0.6 H, H-3′); 13C{1H} NMR: δ = 198.8 (0.6 C), 198.3 (0.4 C), 198.0 (0.6 C), 197.6 (0.4 C), 196.0 (0.6 C), 194.8 (0.4 C), 152.2, 152.1, 151.3, 149.1, 149.0, 148.6, 148.5, 137.9, 137.0, 136.8, 136.7, 136.4, 133.2, 133.1, 133.0, 132.2, 131.5, 131.1, 129.1, 129.0, 128.5, 128.4, 128.1, 127.8, 127.3, 127.2, 127.1, 127.0, 122.9, 122.8, 122.6, 122.6, 59.6 (0.6 C), 57.9 (0.4 C), 51.9 (0.4 C), 51.4 (0.6 C); IR (CDCl3) ν: 3057, 2920, 1692, 1670, 1669, 1581 cm−1. ESI MS (454.9): 456.3 (M + H + ). HRMS (ESI/Q-TOF) calcd for C27H20ClN2O3 ([M + H]+) 455.1162, found: 455.1150. 2-Benzoyl-3-phenyl-1,4-bis(4-(trifluoromethyl)phenyl)butane1,4-dione (3ca). Column chromatography with 16:1 cyclohexane− AcOEt afforded 3ca (83 mg, 30%; conditions 1) as a 19:1 mixture of diastereoisomers slightly contaminated by uncharacterized byproducts. Conditions 2: 3ca (88 mg, 32%; dr = 19:1). 1H NMR: δ = 8.12−8.06 (m, 2 H, Ar), 8.02−7.96 (m, 2 H, Ar), 7.78−7.70 (m, 2 H, Ar), 7.69− 7.58 (m, 4 H, Ar), 7.52−7.43 (m, 2 H, Ar), 7.32−7.27 (m, 2 H, Ar), 7.25−7.21 (m, 2 H, Ar), 7.16−7.10 (m, 2 H, Ar), 6.35 (d, J = 10.7 Hz, 1 H, H-2), 5.75 (d, J = 10.7 Hz, 1 H, H-3). 13C{1H} NMR: δ = 197.2, 195.2, 193.4, 138.7, 138.5, 136.2, 133.8, 130.5, 129.4, 129.3, 128.9, 128.6, 128.6, 128.3, 128.3, 126.5, 125.8, 125.7, 123.1 (q, J = 270 Hz, 2 CF3), 60.5, 55.6. 19F NMR: δ = −63.0, −63.2, −63.3, −63.4; IR (CDCl3) ν: 3071, 2918, 1700, 1681, 1679, 1582 cm−1. ESI MS (554.5): 577.1 (M + Na+). HRMS (ESI/Q-TOF) calcd for C31H20F6NaO3 ([M + Na]+) 577.1214, found: 577.1231. 2-Benzoyl-1,4-bis(4-fluorophenyl)-3-phenylbutane-1,4-dione (3da). Column chromatography with 18:1:1 cyclohexane−AcOEt− dichloromethane afforded 3da (50 mg, 22%; conditions 1) as an inseparable 1:1 mixture of diastereoisomers. Conditions 2: 3da (66 mg, 29%; dr = 1:1). Separation of the two diastereoisomers was carried by a second column chromatography using toluene as the elution system. First eluted diastereoisomer: 1H NMR: δ = 8.09−7.98 (m, 2 H, Ar), 7.97−7.89 (m, 2 H, Ar), 7.68−7.61 (m, 2 H, Ar), 7.47−7.40 (m, 1 H, Ar), 7.32−7.22 (m, 4 H, Ar), 7.16−6.96 (m, 7 H, Ar), 6.30 (d, J = 10.7 Hz, 1 H, H-2), 5.72 (d, J = 10.7 Hz, 1 H, H-3); 13C{1H} NMR: δ = 196.5, 195.6, 192.6, 165.7 (d, J = 255 Hz, 2 CF), 136.5, 134.6, 133.5, 131.8, 131.7, 131.4, 131.3, 129.2, 128.9, 128.6, 128.0, 115.7, 115.6, 60.4, 55.2; 19F NMR: δ = −103.8 to −104.0 (m), −104.7 to −104.9 (m); IR (CDCl3) ν: 3065, 2920, 1693, 1667, 1593 cm−1. ESI MS (454.5): 477.1 (M + Na+). HRMS (ESI/Q-TOF) calcd for C29H20F2NaO3 ([M + Na]+) 477.1278, found: 477.1293. Second eluted diastereoisomer: 1H NMR: δ = 8.09−7.98 (m, 2 H, Ar), 7.93− 7.84 (m, 2 H, Ar), 7.77−7.63 (m, 2 H, Ar), 7.53−7.45 (m, 1 H, Ar), 7.40−7.30 (m, 2 H, Ar), 7.27−7.20 (m, 2 H, Ar), 7.17−7.01 (m, 5 H, Ar), 7.01−6.88 (m, 2 H, Ar), 6.29 (d, J = 10.7 Hz, 1 H, H-2), 5.70 (d, J = 10.6 Hz, 1 H, H-3); 13C{1H} NMR: δ = 196.6, 194.5, 194.2, 165.9 (d, J = 255 Hz, CF), 136.3, 134.8, 133.8, 133.2, 132.5, 132.0, 131.9, 131.7, 131.5, 129.5, 129.1, 129.0, 128.8, 128.25, 116.1, 115.8, 60.5, 55.3; 19F NMR: δ = −104.2 to −104.3 (m), −104.7 to −104.9 (m); IR (CDCl3) ν: 3075, 2919, 1691, 1666, 1593 cm−1. ESI MS (454.5): 1942 DOI: 10.1021/jo502582e J. Org. Chem. 2015, 80, 1937−1945 The Journal of Organic Chemistry Note 6.12 (t, J = 7.0 Hz, 1 H, H-2), 3.78 (d, J = 7.0 Hz, 2 H, 2 H-3); IR (CDCl3) ν: 3062, 2924, 1731, 1678, 1663, 1596 cm−1. 2-Benzoyl-1,4-di(pyridin-2-yl)butane-1,4-dione (3bh). Conditions 1: trace amounts of 3bh as determined by MS analysis of the crude reaction mixture; ESI MS (344.4): 345.8 (M + H+). Conditions 2: column chromatography with 3:1 cyclohexane−AcOEt afforded 3bh (129 mg, 75%;) as a yellow foam. 1H NMR: δ = 8.68−8.64 (m, 1 H, Ar), 8.58−8.54 (m, 1 H, Ar), 8.14−8.00 (m, 4 H, Ar), 7.86−7.78 (m, 2 H, Ar), 7.60−7.52 (m, 1 H, Ar), 7.50−7.39 (m, 4 H, Ar), 6.47 (dd, 1 H, J = 5.0, 8.0 Hz, H-2), 4.17 (dd, 1 H, J = 8.0, 18.5 Hz, H-3a), 3.75 (dd, 1 H, J = 5.0, 18.5 Hz, H-3b); 13C{1H} NMR: δ = 198.5, 197.3, 197.0, 152.8, 151.7, 149.0, 148.9, 137.0, 136.9, 136.0, 133.2, 128.9, 128.7, 127.3, 122.6, 121.9, 50.6, 37.0; IR (CDCl3) ν: 3057, 2924, 1695, 1673, 1596, 1582 cm−1. HRMS (ESI/Q-TOF) calcd for C21H17N2O3 ([M + H]+) 345.1239, found: 345.1255. Model Aerobic Oxidative Dehydrogenation of 3aa. To a vigorously stirred mixture of 3aa (209 mg, 0.50 mmol), potassium tertbutoxide (56 mg, 0.50 mmol), and anhydrous DMSO (2 mL), Cu(OAc)2·H2O (10 mg, 0.05 mmol) was added in one portion. The mixture was stirred at 80 °C for 2 h under atmospheric air (balloon), then cooled to room temperature, diluted with H2O (5 mL), and extracted with CH2Cl2 (2 × 35 mL). The combined organic phases were washed with brine (8 mL), dried (Na2SO4), concentrated, and eluted from a column of silica gel with 10:1 cyclohexane−AcOEt to give 6aa (197 mg, 95%). General Procedure for the One-Pot Two-Step Synthesis of Tetrasubstituted Olefins 6/6′ (Conditions 1, Table 3). To a vigorously stirred mixture of benzil 1 (1.00 mmol), alkene 2 (0.50 mmol), and anhydrous DMSO (2 mL), potassium tert-butoxide (112 mg, 1.00 mmol) was added in one portion. Then, the mixture was degassed under vacuum and saturated with argon (by an argon-filled balloon) three times. The mixture was stirred at room temperature until complete disappearance or best conversion of the starting alkene (TLC analysis, ca. 2−16 h); then, Cu(OAc)2·H2O (20 mg, 0.10 mmol) was added in one portion. The mixture was stirred at 80 °C for 2 h under atmospheric air (balloon), then cooled to room temperature, diluted with H2O (5 mL), and extracted with CH2Cl2 (2 × 35 mL). The combined organic phases were washed with brine (8 mL), dried (Na2SO4), concentrated, and eluted from a column of silica gel with the suitable elution system to give 6/6′. General Procedure for the One-Pot Two-Step Synthesis of Tetrasubstituted Olefins 6/6′ (Conditions 2, Table 3). To a vigorously stirred mixture of benzil 1 (1.00 mmol), alkene 2 (0.50 mmol), and anhydrous DMSO (2 mL), potassium cyanide (16 mg, 0.25 mmol) was added in one portion. Then, the mixture was degassed under vacuum and saturated with argon (by an argon-filled balloon) three times. The mixture was stirred at room temperature until complete disappearance or best conversion of the starting alkene (TLC analysis, ca. 2−16 h); then, Cu(OAc)2·H2O (20 mg, 0.10 mmol) was added in one portion. The mixture was stirred at 80 °C for 2 h under atmospheric air (balloon), then cooled to room temperature, diluted with H2O (5 mL), and extracted with CH2Cl2 (2 × 35 mL). The combined organic phases were washed with brine (8 mL), dried (Na2SO4), concentrated, and eluted from a column of silica gel with the suitable elution system to give 6/6′. 2-Benzoyl-1,3,4-triphenylbut-2-ene-1,4-dione (6aa). Column chromatography with 10:1 cyclohexane−AcOEt afforded 6aa (135 mg, 65%; conditions 1) as a white amorphous solid. Conditions 2: 6aa (158 mg, 76%). 1H NMR: δ = 8.01−7.93 (m, 2 H, Ar), 7.89−7.84 (m, 2 H, Ar), 7.84−7.77 (m, 2 H, Ar), 7.50−7.38 (m, 3 H, Ar), 7.37−7.32 (m, 3 H, Ar), 7.31−7.24 (m, 5 H, Ar), 7.17−7.10 (m, 3 H, Ar); 13 C{1H} NMR: δ = 195.0, 194.3, 193.1, 151.7, 141.9, 136.6, 136.1, 135.7, 134.0, 133.7, 133.4, 133.3, 129.8, 129.7, 129.6, 129.4, 128.8, 128.6, 128.6, 128.5, 128.3; IR (CDCl3) ν: 3063, 2923, 1662, 1646, 1595, 1578 cm−1. ESI MS (416.5): 439.1 (M + Na+); HRMS (ESI/QTOF) calcd for C29H20NaO3 ([M + Na]+) 439.1310, found: 439.1318. 2-Benzoyl-3-(4-chlorophenyl)-1,4-diphenylbut-2-ene-1,4-dione (6ab). Column chromatography with 13:1 cyclohexane−AcOEt afforded 6ab (155 mg, 69%; conditions 1) as a white amorphous solid. Conditions 2: 6ab (184 mg, 82%). 1H NMR: δ = 8.01−7.94 (m, 2 H, Ar), 7.88−7.85 (m, 4 H, Ar), 7.54−7.44 (m, 2 H, Ar), 7.44−7.33 (m, 5 H, Ar), 7.33−7.20 (m, 4 H, Ar), 7.18−7.08 (m, 2 H, Ar); 13 C{1H} NMR: δ = 194.8, 193.9, 192.8, 150.2, 142.6, 136.4, 136.0, 135.9, 135.5, 134.1, 133.6, 133.5, 132.4, 129.9, 129.8, 129.7, 129.4, 129.16, 128.8, 128.6, 128.4; IR (CDCl3) ν: 3062, 2924, 1652, 1595, 1579 cm−1. ESI MS (450.9): 473.4 (M + Na+). HRMS (ESI/Q-TOF) calcd for C29H19ClNaO3 ([M + Na]+) 473.0920, found: 473.0917. 2-Benzoyl-1,4-diphenyl-3-(p-tolyl)but-2-ene-1,4-dione (6ad). Column chromatography with 14:1 cyclohexane−AcOEt afforded 6ad (112 mg, 52%; conditions 1) as a white amorphous solid. Conditions 2: 6ad (129 mg, 60%). 1H NMR: δ = 8.02−7.93 (m, 2 H, Ar), 7.89− 7.83 (m, 2 H, Ar), 7.82−7.76 (m, 2 H, Ar), 7.51−7.39 (m, 3 H, Ar), 7.39−7.30 (m, 4 H, Ar), 7.30−7.21 (m, 2 H, Ar), 7.21−7.11 (m, 2 H, Ar), 6.99−6.87 (m, 2 H, Ar), 2.17 (s, 3 H, CH3); 13C{1H} NMR: δ = 195.2, 194.5, 193.2, 152.2, 141.1, 140.0, 136.7, 136.2, 135.8, 133.6, 133.3, 133.2, 131.0, 129.8, 129.7, 129.6, 129.3, 128.6, 128.5, 128.5, 128.3, 21.2; IR (CDCl3) ν: 3063, 2921, 1663, 1643, 1595, 1578 cm−1. ESI MS (430.5): 453.1 (M + Na+). HRMS (ESI/Q-TOF) calcd for C30H22NaO3 ([M + Na]+) 453.1467, found: 453.1470. (E/Z)-2-Benzoyl-1-(4-chlorophenyl)-3,4-diphenylbut-2-ene-1,4dione (6ae). Column chromatography with 10:1 cyclohexane−AcOEt afforded 6ae (129 mg, 60%; conditions 1) as a 1:1 mixture of diastereoisomers. Conditions 2: 6ae (186 mg, 83%; E/Z = 1:1). 1H NMR: δ = 8.01−7.94 (m, 1 H, Ar′), 7.94−7.88 (m, 1 H, Ar”), 7.87− 7.73 (m, 4 H, Ar), 7.52−7.40 (m, 2 H, Ar), 7.40−7.32 (m, 3 H, Ar), 7.32−7.21 (m, 5 H, Ar), 7.21−7.08 (m, 3 H, Ar); 13C{1H} NMR: δ = 194.9 (0.5 C), 194.8 (0.5 C), 194.2 (0.5 C), 193.2 (0.5 C), 193.0 (0.5 C), 192.0 (0.5 C), 151.9 (0.5 C), 151.7 (0.5 C), 141.6 (0.5 C), 141.4 (0.5 C), 140.3 (0.5 C), 139.9 (0.5 C), 136.5, 135.9, 135.6, 134.9, 134.4, 133.9, 133.8, 133.6, 133.5, 133.4, 131.1, 130.8, 129.9, 129.8, 129.7, 129.3, 129.0, 128.9, 128.9, 128.8, 128.7, 128.4, 128.5, 128.4; IR (CDCl3) ν: 3061, 2928, 1653, 1652, 1586, 1582 cm−1. ESI MS (450.9): 473.6 (M + Na+). HRMS (ESI/Q-TOF) calcd for C29H19ClNaO3 ([M + Na]+) 473.0920, found: 473.0903. (E/Z)-2-Benzoyl-3-(4-chlorophenyl)-1-(4-methoxyphenyl)-4phenylbut-2-ene-1,4-dione (6ag). Column chromatography with 7:1 cyclohexane−AcOEt afforded 6ag (115 mg, 48%; conditions 1) as a 1:1 mixture of diastereoisomers. Conditions 2: 6ag (144 mg, 60%; E/Z = 1:1). 1H NMR: δ = 8.05−7.99 (m, 1 H, Ar′), 7.99−7.92 (m, 1 H, Ar”), 7.84−7.80 (m, 4 H, Ar), 7.53−7.43 (m, 2 H, Ar), 7.42−7.31 (m, 3 H, Ar), 7.29−7.19 (m, 3 H, Ar), 7.18−7.07 (m, 2 H, Ar), 6.89−6.81 (m, 1 H, Ar), 6.81−6.72 (m, 1 H, Ar), 3.83 (s, 1.5 H, CH3), 3.78 (s, 1.5 H, CH3); 13C{1H} NMR: δ = 194.9 (0.5 C), 194,9 (0.5 C), 194.0 (0.5 C), 192.9 (0.5 C), 192.1 (0.5C), 190.9 (0.5 C), 164.3 (0.5 C), 164.0 (0.5 C), 149.2 (0.5 C), 149.0 (0.5 C), 143.3 (0.5 C), 143.1 (0.5 C), 136.4, 136.0, 135.6, 134.1, 133.6, 133.4, 132.5, 132.4, 132.1, 129.8, 129.7, 129.4, 129.3, 129.1, 128.8, 128.6, 128.4,114.1 (0.5 C), 113.7 (0.5 C), 55.5 (0.5 C), 55.4 (0.5 C); IR (CDCl3) ν: 3060, 2920, 1652, 1650, 1581, 1579 cm−1. ESI MS (480.9): 503.6 (M + Na+). HRMS (ESI/Q-TOF) calcd for C30H21ClNaO4 ([M + Na]+) 503.1026, found: 503.1032. (E/Z)-2-Benzoyl-3-(4-chlorophenyl)-1,4-di-p-tolylbut-2-ene-1,4dione (6eb). Column chromatography with 12:1 cyclohexane−AcOEt afforded 6eb (148 mg, 62%; conditions 1) as a 1:1 mixture of diastereoisomers. Conditions 2: 6eb (191 mg, 80%; E/Z = 1:1). 1H NMR: δ = 8.01−7.94 (m, 1 H, Ar′), 7.92−7.85 (m, 1 H, Ar”), 7.85− 7.69 (m, 4 H, Ar), 7.59−7.43 (m, 1 H, Ar), 7.43−7.33 (m, 1 H, Ar), 7.33−7.25 (m, 1 H, Ar), 7.25−7.19 (m, 2 H, Ar), 7.18−7.05 (m, 6 H, Ar), 2.35 (s, 1.5 H, CH3), 2.34 (s, 3 H, CH3), 2.29 (s, 1.5 H, CH3); 13 C{1H} NMR: δ = 194.5 (0.5 C), 194.4 (0.5 C), 194.0 (0.5 C), 193.5 (0.5 C), 192.8 (0.5 C), 192.3 (0.5 C), 149.8, 145.2, 144.7, 144.5, 142.7, 136.5, 136.0, 135.7, 134.0, 133.6, 133.4, 133.2, 132.7, 130.1, 130.0, 129.9, 129.8, 129.7, 129.6, 129.5, 129.3, 129.1, 129.1, 128.8, 128.3, 127.0, 21.7, 21.6; IR (CDCl3) ν: 3039, 2920, 1651, 1650, 1602, 1580 cm−1. ESI MS (479.0): 502.3 (M + Na+). HRMS (ESI/Q-TOF) calcd for C31H23ClNaO3 ([M + Na]+) 501.1233, found: 501,1250. (E/Z)-2-Benzoyl-1-(2-chlorophenyl)-3-(4-chlorophenyl)-4-phenylbut-2-ene-1,4-dione (6fb′). Column chromatography with 13:1 cyclohexane−AcOEt afforded 6fb′ (92 mg, 38%) as a 1:1 mixture of diastereoisomers. Conditions 2: 6fb′ (111 mg, 46%; E/Z = 1:1). 1H 1943 DOI: 10.1021/jo502582e J. Org. Chem. 2015, 80, 1937−1945 The Journal of Organic Chemistry Note NMR: δ 7.99−7.91 (m, 4 H, Ar), 7.59−7.53 (m, 1 H, Ar), 7.52−7.45 (m, 2 H, Ar), 7.41−7.33 (m, 4 H, Ar), 7.24−7.17 (m, 5 H, Ar), 7.13− 7.05 (m, 2 H, Ar); 13C{1H} NMR: δ = 194.1, 193.2, 192.7, 146.7 (0.5 C), 146.6 (0.5 C), 136.2, 135.9, 135.6 (0.5 C), 135.5 (0.5 C), 134.2, 133.8, 132.9, 132.7, 131.8, 131.6, 130.8, 130.5, 130.2, 130.0, 129.8, 129.6, 129.5, 128.9, 128.7, 128.6, 128.5, 126.7; IR (CDCl3) ν: 3067, 2923, 1655, 1651, 1594, 1590 cm−1. ESI MS (485.4): 508.0 (M + Na+). HRMS (ESI/Q-TOF) calcd for C29H18Cl2NaO3 ([M + Na]+) 507.0531, found: 507.0520. 2-Benzoyl-4-(4-chlorophenyl)-1,3-diphenylbut-2-ene-1,4-dione (6ga). Column chromatography with 10:1 cyclohexane−AcOEt afforded 6ga (85 mg, 38%; conditions 1) as a white amorphous solid. Conditions 2: 6ga (99 mg, 44%). 1H NMR: δ = 7.99−7.92 (m, 2 H, Ar), 7.82−7.74 (m, 4 H, Ar), 7.50−7.39 (m, 2 H, Ar), 7.38−7.30 (m, 5 H, Ar), 7.29−7.22 (m, 3 H, Ar), 7.19−7.12 (m, 3 H, Ar); 13 C{1H} NMR: δ = 194.2, 194.0, 193.1, 151.8, 142.0, 140.0, 136.5, 136.0, 134.1, 133.9, 133.6, 133.5, 131.1, 130.0, 129.9, 129.4, 129.0, 128.8, 128.7, 128.6, 128.5; IR (CDCl3) ν: 3063, 2920, 1653, 1651, 1588, 1585 cm−1. ESI MS (450.9): 473.8 (M + Na+). HRMS (ESI/QTOF) calcd for C29H19ClNaO3 ([M + Na]+) 473.0920, found: 473.0922. Aerobic Oxidative Dehydrogenation of 3aa in the Presence of TEMPO. To a vigorously stirred mixture of 3aa (209 mg, 0.50 mmol), potassium tert-butoxide (112 mg, 1.00 mmol), (2,2,6,6tetramethyl-piperidin-1-yl)oxyl (78 mg, 0.50 mmol), and anhydrous DMSO (2 mL), Cu(OAc)2·H2O (20 mg, 0.10 mmol) was added in one portion. The mixture was stirred at 80 °C for 2 h under atmospheric air (balloon), then cooled to room temperature, diluted with H2O (5 mL), and extracted with CH2Cl2 (2 × 35 mL). The combined organic phases were washed with brine (8 mL), dried (Na2SO4), concentrated, and eluted from a column of silica gel with 10:1 cyclohexane−AcOEt to give 6aa (135 mg, 65%). ■ (4) Giovannini, P. P.; Bortolini, O.; Cavazzini, A.; Greco, R.; Fantin, G.; Massi, M. Green Chem. 2014, 16, 3904−3915 and references therein. (5) (a) Bortolini, O.; Cavazzini, A.; Dambruoso, P.; Giovannini, P. P.; Caciolli, L.; Massi, A.; Pacifico, S.; Ragno, D. Green Chem. 2013, 15, 2981−2992. (b) Bortolini, O.; Fantin, G.; Fogagnolo, M.; Giovannini, P. P.; Massi, A.; Pacifico, S. Org. Biomol. Chem. 2011, 9, 8437−8444. (c) Bortolini, O.; Fantin, G.; Fogagnolo, M.; Giovannini, P. P.; Venturi, V.; Pacifico, S.; Massi, A. Tetrahedron 2011, 67, 8110−8115. (6) Bortolini, O.; Fantin, G.; Ferretti, V.; Fogagnolo, M.; Giovannini, P. P.; Massi, A.; Pacifico, S.; Ragno, D. Adv. Synth. Catal. 2013, 355, 3244−3252. (7) During the preparation of this manuscript, Takaki and co-workers reported the NHC-catalyzed double acylation of enones with benzils: (a) Takaki, K.; Ohno, A.; Hino, M.; Shitaoka, T.; Komeyama, K.; Yoshida, H. Chem. Commun. 2014, 50, 12285−12288. For the double aroylation of acrylates with O-aroylmandelonitriles, see: (b) Miyashita, A.; Matsuoka, Y.; Numata, A.; Higashino, T. Chem. Pharm. Bull. 1996, 44, 448−450. (8) (a) Liu, S.; Tang, L.; Chen, H.; Zhao, F.; Deng, G.-J. Org. Biomol. Chem. 2014, 12, 6076−6079 and references therein. (b) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698−4745. (9) (a) Itami, K.; Yoshida, J. Bull. Chem. Soc. Jpn. 2006, 79, 811−824. (b) Feringa, B. L.; van Delden, R. A.; Koumura, N.; Geertsema, E. M. Chem. Rev. 2000, 100, 1789−1816. (10) (a) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693−11712. (b) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 9570−9571. (11) Equilibrium acidities in DMSO: Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456−463. Residual water content of anhydrous DMSO higher than 0.016% (w/w) determined a marked reduction of the reaction efficiency. (12) For a different reactivity of the thiazolium salt E with benzils, see: Bertolasi, V.; Bortolini, B.; Donvito, A.; Fantin, G.; Fogagnolo, M.; Giovannini, P. P.; Massi, A.; Pacifico, S. Org. Biomol. Chem. 2012, 10, 6579−6586. (13) The homocoupling reaction of benzils produces the corresponding benzoylated benzoins through hydrolysis of one benzoyl group of α,α′-stilbenediol dibenzoate intermediates (see ref 6). (14) The rapid degradation of enone 2h under the coupling conditions was confirmed by a control experiment performed in the absence of benzil 1a (2h, 100 mol % t-BuOK, DMSO, 30 min). (15) (a) Kuebrich, J. P.; Schowen, R. L. J. Am. Chem. Soc. 1971, 93, 1220−1223. (b) Kwart, H.; Baevsky, M. M. J. Am. Chem. Soc. 1958, 80, 580−588. (16) The reversible (equilibrium) addition of dimsyl anion to carbonyl compounds has been reported: Walling, C.; Bollyky, L. J. Org. Chem. 1963, 28, 256−257. (17) The proton exchange between DMSO and t-BuOK is a very fast process: (a) Brauman, J. I.; Nelson, N. J.; Kahl, D. C. J. Am. Chem. Soc. 1968, 90, 490−491. (b) Brauman, J. I.; Nelson, N. J. J. Am. Chem. Soc. 1968, 90, 491−492. (18) Yang, Y.; Ni, F.; Shu, W.-M.; Yu, S.-B.; Gao, M.; Wu, A.-X. J. Org. Chem. 2013, 78, 5418−5426. (19) (a) Liang, L.; Yang, G.; Wang, W.; Xu, F.; Niu, Y.; Sun, Q.; Xu, P. Adv. Synth. Catal. 2013, 355, 1284−1290. (b) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062− 11087. (20) The positive charge of cations V and VI detected in the gas phase is balanced in the solution phase by the acetate counteranion. The formation of a dicarbonyl copper chelate complex through elimination of AcOH from V cannot be excluded by our MS study because this species would be isobaric with VI; this latter isomer has been suggested to justify the subsequent β-hydride elimination step already claimed in similar copper-catalyzed oxidative dehydrogenations (see ref 19a). (21) The mechanism by which Cu(OAc)2 is regenerated after the supposed β-hydride elimination step is not clear to us; recent studies ASSOCIATED CONTENT S Supporting Information * NMR spectra of 3/3′ and 6/6′ and ESI-MS spectra of V−VI. This material is available free of charge via the Internet at http://pubs.acs.org. ■ AUTHOR INFORMATION Corresponding Authors *E-mail: olga.bortolini@unife.it (O.B.). *E-mail: alessandro.massi@unife.it (A.M.). Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We thank the student Maurizio Mazzoni for his valuable contribution. 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