Stereoselective synthesis of α,α-difluoro-β,γ-alkenyl ketones by free-radical reaction of iododifluoromethyl ketones with alkynes

Tetrahedron 73 (2017) 3478e3484

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Stereoselective synthesis of a,a-difluoro-b,g-alkenyl ketones by freeradical reaction of iododifluoromethyl ketones with alkynes Danfeng Wang a, Jingjing Wu a, b, *, Jinwen Huang a, Junqing Liang a, Peng Peng a, Heng Chen a, Fanhong Wu a, ** a b

School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 20 March 2017 Received in revised form 26 April 2017 Accepted 4 May 2017 Available online 5 May 2017

A method for stereoselective synthesis of a,a-difluoro-g-iodo-b,g-alkenyl ketones via radical difluoroacetylation of iododifluoromethyl ketones with terminal and internal alkynes was reported. This methodology provides a straightforward access to 3,3-disubstitued allylic difluorides. © 2017 Elsevier Ltd. All rights reserved.

Keywords: Difluoroacetylation a,a-Difluoro-b,g-alkenyl ketones Iododifluoromethyl ketones Radical reaction 3,3-Disubstituted allylic difluorides

1. Introduction Molecules containing difluoromethylene group (CF2) have been well developed and widely used in the synthesis of biologically active compounds owing to the unique properties of CF2 moiety.1 Among those compounds, allylic difluorides have attracted much attention due to their applications in the pharmaceutical industry and serving as intermediates in the organofluorine chemistry. For example, Tafluprost, which contains gem-difluorinated allylic group, is a prostaglandin analogue used for the treatment of glaucoma (Fig. 1).2 Accordingly, the development of an efficient and economic strategy for the construction of allylic difluorides arouses much interesting. Until now, several methods for the preparation of allylic difluorides have been developed, such as the reactions between difluoroalkylation agents and alkenyl halides,3 Cu or iron catalyzed decarboxylative difluoromethylations of alkenes using different difluoromethylation agents,4 Pd or Cu catalyzed cross-coupling

* Corresponding author. School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China. ** Corresponding author. E-mail address: [email protected] (J. Wu). http://dx.doi.org/10.1016/j.tet.2017.05.021 0040-4020/© 2017 Elsevier Ltd. All rights reserved.

reactions of ethyl bromodifluoroacetate and different alkene derivatives,5 and Cu-catalyzed hydrofluoroacetylation of alkyne with ethyl bromofluoroacetates.6 However, most of these methodologies mentioned above afforded 3-monosubstituted allylic difluorides as products (Scheme 1 A). The general synthesis of 3,3-disubstituted allylic difluorides has been rarely reported. Arimitsu disclosed a stereoselective synthesis of a,a-difluoro-g,g-disubstituted butenals, which could be used as useful intermediates for the preparation of 3,3-disubstituted allylic difluorides via the catalytic reactions of L-proline and salicylic acid with g,g-disubstituted a,bunsaturated aldehydes and NFSI (Scheme 1 B).7 However, the method is suffered the disadvantage of using g,g-disubstituted a,bunsaturated aldehydes as starting materials, which have narrow substrate scope and limited availibility. Generally, the radical addition of polyfluoroalkyl iodides to unsaturated CeC bonds is an attractive method to introduce the polyfluoroalkyl groups into organic molecules.8 The iodine atom in the addition products could be easily transformed into other functional groups to construct diverse structural organofluorine compounds. Thus, the radical addition of difluoroalkyl iodides to alkynes could afford 3-substituted 3-iodo allylic difluorides as products and the addition products would be further transformed into 3,3-disubstituted allylic difluorides. However, these reactions have not been well explored.9 In the last decade, our group has

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Table 1 Optimization of reaction conditions.a

Fig. 1. The structure of Tafluprost.

Entry

Initia./Cat. (mol%)

Temp. ( C)

Conv. (%)

Yield(%) (Z/E)b

1 2c 3 4 5 6 7 8 9d

AIBN(20) Na2S2O4/NaHCO3 (20) Pd(PPh3)4 (20) PdCl2(PPh3)2 (20) ZnCl2(20) Ni(acac)2(20) AIBN(20) AIBN(10) AIBN(10)

60 60 60 60 60 60 80 80 80

80 20 60 55 24 22 98 86 90

65(0/100) trace(-) 24(0/100) 0(-) Trace(-) trace(-) 93(0/100) 72(0/100) 77(0/100)

The reaction condition described in entry 7 is the optimized condition. a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol, 1.2 equiv), neat, N2, 12 h. b The yields and the ratios were determined by LC. c The reaction was conducted in solvent CH3CN/H2O (3:1). d The reaction was conducted in air.

Scheme 1. The synthesis of 3-monosubstituted allylic difluorides and 3,3disubstituted allylic difluorides.

developed novel radical-based fluoroalkylation reactions.10 We have reported the synthesis of difluoromethylene vinyl iodides through AIBN-initiated radical addition of ethyl iododifluoroacetate or 3-phenyl-5-iodo-difluoro-1,2,4-oxadiazole to alkynes.10c However, the stereoselectivity of the addition reaction varies with the alkyne substrates and only three difluoroalkyl iodides led to difluoroalkylated alkenes. The synthetic methods of a,a-difluoroketones have been well developed owing to their applications in the pharmaceutical science and organic synthesis.11 The difluoroacetylation reaction is an efficient method for the synthesis of a,a-difluoroketones.12 Recently, we have used iododifluoromethyl ketones as difluoroacetylation agents in the free-radical reactions for the preparation of difluoroalkyl-g-butyrolactones.13 The difluoroacetylation reaction of alkynes using iododifluoromethyl ketones would generate a wide variety of 3,3-disubstitued allylic difluorides. Herein, we introduce an AIBN-initiated free-radical addition of iododifluoromethyl ketones to both terminal and internal alkynes to afford benzoyldifluoro vinyl iodides in good yields and high selectivity for the E-isomers (Scheme 1C). These compounds could be conveniently converted to g,g-disubstituted a,a-difluoro-b,galkenyl ketones via coupling reactions. 2. Result and discussion The initial investigation commenced with the screening of the radial initiators. Thus, we chose 2,2-difluoro-2-iodo-1phenylethanone 1a and ethynylbenzene 2a as substrates to optimize the reaction condition, and the results are summarized in Table 1. Among the reaction initiators and transition-metal catalysts examined (entries 1e6), AIBN was the best radical initiator for the reaction and only E-isomer of the desired product 3a was obtained (entry 1). While Pd(PPh3)4 could also catalyze the reaction

but in a lower yield (entry 3). Next, we performed the reaction at higher temperature using AIBN as an initiator. To our delight, the yield of the addition product was significantly improved (entry 7). Decreasing the amount of AIBN led to a lower yield of 3a (entry 8). Furthermore, the reaction proceeded more efficiently under a nitrogen atmosphere, in air the yield of 3a decreased to 77% (entry 9). With the optimized reaction conditions in hand, we next explored the scope of the radical addition reaction with various alkynes (Table 2). Not only aromatic alkynes, but also with an aliphatic alkyne can be efficiently transformed into the corresponding product 3h in high yield. The addition reaction is completely stereoselective, thus yielding only E-isomers of compounds 3. Except for the substrate ethynyltrimethylsilane, which reacted with 1a to generate addition product 3g with a 3:1 E/Z ratio, aromatic alkynes bearing electron-rich or electron-poor groups on the aromatic ring were well tolerated to result the corresponding products 3a-e in good yields. It is noteworthy that an internal alkyne could be used for a reaction to afford 3i in a high yield with an excellent stereoselectivity. The determination of the stereochemistry of the products was based on the alkenyl hydrogen of E-isomer appearing at lower field than that of Z-isomer.9d The d 7.57 (JHeF ¼ 14.8 Hz) and d 7.15 (JHeF ¼ 11.6 Hz) chemical shifts on 1H NMR spectra of 3g were assigned to Z and E isomers. Correspondingly, the stereochemistry of 3a-3f, 3h-3s were also assigned to E-isomers. Further expansion of the scope of difluoromethylation was conducted using phenylacetylene 2a, hept-1-yne 2b and prop-1yn-1-ylbenzene 2c as the substrates. The results are summarized in Table 3. Phenyl iododifluoromethyl ketones containing an electron-donating CH3 group (3j) or halogen Br atom (3k) gave the corresponding products in high yields and excellent selectivity. However, the addition reaction of an electron-withdraw CF3 groupsubstituted aryl iododifluoromethyl ketone was unsuccessful and only the starting material was recovered. The reaction was not limited to phenyl iododifluoromethyl ketones. A thiophene and a naphthalene substituted substrates could also be employed and gave the E-isomers of the addition products 3l and 3m with relatively lower yield than compounds 3j and 3k. Similarly, aliphatic alkynes can also be efficiently transformed to corresponding products in high yields. Phenyl iododifluoromethyl ketones containing electron-donating groups or halogen atoms furnished the E-

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Table 2 Scope of the AIBNeinitiated radical addition of 2,2-difluoro-2-iodo-1-phenylethan-1-one 1a to alkynes.a

a Reaction conditions: 1a (1 mmol), 2 (1.2-1.5 equiv), AIBN (0.2 mmol), 80°C, neat, N2, 12–16 h. Yields are those of the isolated products. b The E- and Z-isomers of 3g were isolated.

isomers of the corresponding products (3n-p) in good yields. Unfortunately, the reaction of CF3-substituted phenyl iododifluoromethyl ketone failed to react to yield the product. Finally, the generality of the addition reaction was demonstrated by extending the scope of iododifluoromethyl ketones to prop-1-yn-1-ylbenzene 2c. To our delight, reactions of phenyl iododifluoromethyl ketones underwent smoothly. Even election-withdraw CF3 group substituted phenyl iododifluoromethyl ketone was also suitable substrate, thus providing the corresponding product 3s in moderate yield (51%). The addition products a,a-difluoro-g-iodo-b,g-alkenyl ketones 3 are versatile synthetic precursors for further functionalization. It was demonstrated by the Suzuki coupling and the Sonogashira coupling reactions using 3a as a substrate (Scheme 2). Both coupling reactions proceeded smoothly and afforded the products 4a and 4b in good yields. A plausible reaction mechanism is shown in Scheme 3. Firstly, a difluoromethyl radical B was initiated by AIBN (step 1). This radical B then adds to the unsaturated alkynes 2, forming the more stable radical C (step 2) which reacts with iododifluoromethyl ketones 1 to afford the products 3 and the difluoromethyl radical B enabling the cycle process to occur (step 3). The radical process was further conformed by a control experiment. When 2,2,6,6-tetramethyl-1piperidinyloxy (TEMPO) was added under optical conditions, no product 3a was detected (Scheme 4). 3. Conclusion In summary, we have developed an efficient and practical difluoroacetylation approach for the synthesis of a,a-difluoro-g-

iodo-b,g-alkenyl ketones via radical addition of iododifluoromethyl ketones to both terminal and internal alkynes. This methodology offers several remarkable advantages including using normal initiator AIBN, high alkyne tolerance, good yields of products and excellent stereoselectivity. The addition product 3a has been demonstrated to be a useful synthetic intermediate for preparing various g,g-disubstituted a,a-difluoro-b,g-alkenyl ketones via coupling reactions. The synthesis of more specific gem-difluoromethylenating agents derived from iododifluoromethyl ketones and the application of these novel gem-difluoromethylenated agents in the organofluorine synthesis filed are under way. 4. Experimental section 4.1. General information All reagents were of analytical grade, and obtained from commercial suppliers and used without further purification. All NMR spectra were recorded on a Bruker Avance 500 (resonance frequencies 500 MHz for 1H and 126 MHz for 13C) equipped with a 5 mm inverse broadband probe head with z-gradients at 295.8 K with standard Bruker pulse programs. The samples were dissolved in 0.6 mL CDCl3 (99.8% D.TMS). Chemical shifts were given in values of dH and dC referenced to residual solvent signals (dH 7.26 for 1H, dC 77.0 for 13C in CDCl3). The 19F NMR spectra were obtained using a 500 spectrometer (471 MHz) using trifluorotoluene as external standard. High resolution mass spectra (HRMS) were recorded on a Bruker solan X 70 FT-MS (samples was dissolved in CH3OH and the ion source was ESI), and the energy was 22.5 eV at MS/MS. Melting points are uncorrected.

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Table 3 Scope of the AIBN-initiated radical addition of iododifluoromethyl ketones 1 to phenylacetylene 2a or hept-1-yne 2b or prop-1-yn-1-ylbenzene 2c.

Reaction conditions: 1 (1 mmol), 2a or 2b or 2c (1.2-1.5 equiv), AIBN (0.2 mmol), 80°C, 12–16h. Yields are those of the isolated products.

a

Scheme 2. Further functionalization of the addition product 3a by the Suzuki coupling and the Sonogashira coupling reactions.

Scheme 3. A propose mechanism of the reaction.

4.2. General procedure for addition of iododifluoromethyl ketones 1 to alkynes 2 To a 10 mL sealed glass vial was added iododifluoromethyl ketones 1 (1 mmol), alkynes 2 (1.2e1.5 mmol, 1.2e1.5 equiv.), and AIBN (0.032 g, 0.2 mmol, 0.2 equiv). The reaction mixture was stirred at 80  C in the dark under N2 protection for 12e16 h. The reaction was quenched by H2O (2 mL) and extracted with CH2Cl2 (3  20 mL), The combined organic layer was dried over anhydrous sodium sulfate and the solvent evaporated in vacuo to give the crude product, which was purified by column chromatography (0e1% EtOAc/hexane) to yield alkenyl iodides 3a-s.

Scheme 4. Control experiment.

4.3. 2,2-Difluoro-4-iodo-1,4-diphenylbut-3-en-1-one 3a Light yellow liquid, 87% (E only); 1H NMR (500 MHz, CDCl3):

d 7.85e7.42 (m, 5H), 7.45e7.16 (m, 5H), 6.98 (t, J ¼ 11.4 Hz, 1H); 13C 0

NMR (125 MHz, CDCl3): 186.7 (t, 2 JC-F ¼ 29.9 Hz), 134.2, 133.7 (t, 2JC-

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F ¼ 27.2 Hz), 131.5, 129.8 (t, JC-F ¼ 2.5 Hz), 129.3, 128.5, 127.9, 127.8, 114.0 (t, 1JC-F ¼ 252.7 Hz), 108.7 (t, 3JC-F ¼ 9.7 Hz); 19F NMR (470 MHz, CDCl3): d 89.46 (m, 2F); HRMS calculated [MþNa]þ for C16H11F2IO: 406.9720, found: 406.9753.

4.4. 2,2-Difluoro-4-iodo-1-phenyl-4-(p-tolyl)but-3-en-1-one 3b Light yellow liquid, yield: 88% (E only); 1H NMR (500 MHz, CDCl3): d 7.84e7.57 (m, 3H), 7.43e7.01 (m, 6H), 6.94 (t, J ¼ 11.4 Hz, 0 1H), 2.31 (s, 3H); 13C NMR (125 MHz, CDCl3): d 186.7 (t, 2 JC2 F ¼ 30.0 Hz), 139.5, 138.0, 134.1, 133.4 (t, JC-F ¼ 27.3 Hz), 131.5, 129.7 0 (t, 3 JC-F ¼ 2.4 Hz), 128.5, 128.4, 127.8, 113.9 (t, 1JC-F ¼ 252.3 Hz), 109.3 3 (t, JC-F ¼ 10.0 Hz), 21.3; 19F NMR (470 MHz, CDCl3): d 89.31 (m, 2F); HRMS calculated [MþNa]þ for C17H13F2IO: 420.9871, found: 420.9871. 4.5. 2,2-Difluoro-4-(4-fluorophenyl)-4-iodo-1-phenylbut-3-en-1one 3c

4.9. 2,2-Difluoro-4-iodo-1-phenyl-4-(trimethylsilyl)but-3-en-1one 3g Light yellow liquid, yield: 88% (Z and E combined yield). Z-isomer: Light yellow liquid; 1H NMR (500 MHz, CDCl3): d 8.09e7.64 (m, 3H), 7.57 (t, J ¼ 14.8 Hz, 1H), 7.53e7.50 (m, 2H), 0.31 (s, 9H); 13C 0 NMR (125 MHz, CDCl3): d 187.4 (t, 2 JC-F ¼ 32.1 Hz), 144.4 (t, 2JC3 F ¼ 25.4 Hz), 134.5, 131.6, 130.2, 130.1, 128.8, 123.9 (t, JC-F ¼ 7.3 Hz), 1 19 115.0 (t, JC-F ¼ 254.7 Hz), 1.1; F NMR (470 MHz, CDCl3): d 90.26 (m, 2F); HRMS calculated [MþH]þ for C13H15F2IOSi: 380.9983, found: 380.9975. E-isomer: Light yellow liquid; 1H NMR (500 MHz, CDCl3): d 8.07e7.62 (m, 3H), 7.51e7.48 (m, 2H), 7.15 (t, J ¼ 11.6 Hz, 0 1H), 0.22 (s, 9H); 13C NMR (125 MHz, CDCl3): d 187.1 (t, 2 JC2 F ¼ 30.6 Hz), 138.5 (t, JC-F ¼ 27.6 Hz), 134.2, 132.4, 130, 128.6, 119.8 (t, 3JC-F ¼ 8.3 Hz), 114.9 (t, 1JC-F ¼ 253.7 Hz), 1.8; 19F NMR (470 MHz, CDCl3): d 94.64 (m, 2F); HRMS calculated [MþNa]þ for C13H15F2IOSi: 402.9797, found: 402.9800. 4.10. 2,2-Difluoro-4-iodo-1-phenylnon-3-en-1-one 3h

Light yellow liquid, yield: 85% (E only); 1H NMR (500 MHz, CDCl3): d 7.87e7.59 (m, 3H), 7.45e7.12 (m, 4H), 6.96 (t, J ¼ 11.4 Hz, 0 1H), 6.92e6.88 (m, 2H); 13C NMR (125 MHz, CDCl3): d 186.7 (t, 2 JC2 F ¼ 29.9 Hz), 163.8, 161.9, 137.0, 137.0, 134.4, 134.2 (t, JC-F ¼ 27.1 Hz), 0 131.4, 130.0, 129.9, 129.8 (t, 3 JC-F ¼ 2.5 Hz), 128.6, 115.1, 115.0, 114.0 1 (t, JC-F ¼ 252.9 Hz), 107.2 (t, 3JC-F ¼ 9.3 Hz); 19F NMR (470 MHz, CDCl3): d 89.53 (s, 2F), 110.54 (s, 1F); HRMS calculated [MþNa]þ for C16H10F3IO: 424.9620, found: 424.9623.

Light yellow liquid, yield: 87% (E only); 1H NMR (500 MHz, CDCl3): d 8.07e7.49 (m, 5H), 6.69 (t, J ¼ 12.9 Hz, 1H), 2.60e0.88 (m, 0 11H); 13C NMR (125 MHz, CDCl3): d 187.2 (t, 2 JC-F ¼ 30.9 Hz), 134.4, 2 131.7 (t, JC-F ¼ 26.5 Hz), 131.4, 130.0, 128.7, 119.9 (t, 3JC-F ¼ 7.8 Hz), 114.7 (t, 1JC-F ¼ 254.1 Hz), 40.6, 30.4, 29.4, 22.3, 13.8; 19F NMR (470 MHz, CDCl3): d 91.94 (m, 2F); HRMS calculated [MþNa]þ for C15H17F2IO: 401.0189, found: 401.0183.

4.6. 4-(4-Chlorophenyl)-2,2-difluoro-4-iodo-1-phenylbut-3-en-1one 3d

White Solid, yield: 83% (E only), melting point: 73.6e74.0  C; 1H NMR (500 MHz, CDCl3): d 7.72e7.38 (m, 5H), 7.19e6.98 (m, 5H), 0 2.38 (s, 3H); 13C NMR (125 MHz, CDCl3): d 186.6 (t, 2 JC-F ¼ 30.2 Hz), 0 2 142.9, 136.3 (t, JC-F ¼ 23.4 Hz), 134.1, 131.8, 129.5 (t, 3 JC-F ¼ 2.3 Hz), 1 128.7, 128.6, 128.4, 127.8, 114.0 (t, JC-F ¼ 256.2 Hz), 109.4 (t, 3JC19 F NMR (470 MHz, CDCl3): d 89.99 (m, 2F); F ¼ 7.4 Hz), 25.8; HRMS calculated [MþNa]þ for C17H13F2IO: 420.9871, found: 420.9897.

Light yellow liquid, yield: 84% (E only); 1H NMR (500 MHz, CDCl3): d 7.86e7.42 (m, 5H), 7.21e7.10 (m, 4H), 6.96 (t, J ¼ 11.6 Hz, 0 1H); 13C NMR (125 MHz, CDCl3): d 186.7 (t, 2 JC-F ¼ 30.2 Hz), 139.4, 0 2 135.3, 134.4, 131.3, 134.1 (t, JC-F ¼ 26.8 Hz), 129.8 (t, 3 JC-F ¼ 2.5 Hz), 1 3 129.1, 128.6, 128.2, 114.0 (t, JC-F ¼ 253.5 Hz), 106.8 (t, JC-F ¼ 9.1 Hz); 19 F NMR (470 MHz, CDCl3): d 89.62 (m, 2F); HRMS calculated [MþNa]þ for C16H10ClF2IO: 440.9433, found: 440.9420. 4.7. 4-(3,3-Difluoro-1-iodo-4-oxo-4-phenylbut-1-en-1-yl) benzonitrile 3e Light yellow liquid, yield: 80% (E only); 1H NMR (500 MHz, CDCl3): d 7.89e7.54 (m, 5H), 7.47e7.29 (m, 4H), 6.99 (t, J ¼ 12.1 Hz, 0 1H); 13C NMR (125 MHz, CDCl3): d 186.8 (t, 2 JC-F ¼ 30.6 Hz), 145.5, 0 2 134.7, 134.7 (t, JC-F ¼ 26.1 Hz), 131.8, 131.2, 130.0 (t, 3 JC-F ¼ 2.5 Hz), 1 128.8, 128.3 (t, J ¼ 2.0 Hz), 118.1, 114.2 (t, JC-F ¼ 254.8 Hz), 112.9, 104.8 (t, 3JC-F ¼ 8.6 Hz); 19F NMR (470 MHz, CDCl3): d 90.01 (s, 2F); HRMS calculated [MþH]þ for C17H10F2INO: 409.9847, found: 409.9846. 4.8. 2,2-Difluoro-4-iodo-4-(6-methoxynaphthalen-2-yl)-1phenylbut-3-en-1-one 3f Light yellow liquid, yield: 72% (E only); 1H NMR (500 MHz, CDCl3): d 7.69e7.52 (m, 6H), 7.16e7.07 (m, 5H), 7.01 (t, J ¼ 11.0 Hz, 0 1H), 3.92 (s, 3H); 13C NMR (125 MHz, CDCl3): d 186.7 (t, 2 JC2 F ¼ 29.5 Hz), 158.8, 135.8, 134.7, 134.1, 133.8 (t, JC-F ¼ 27.7 Hz), 131.6, 0 130.0, 129.6 (t, 3 JC-F ¼ 2.4 Hz), 128.3, 127.4, 127.3, 126.6, 125.9, 119.6, 1 114.0 (t, JC-F ¼ 252.0 Hz), 109.6 (t, 3JC-F ¼ 10.6 Hz), 105.8, 55.3; 19F NMR (470 MHz, CDCl3): d 88.88 (s, 2F); HRMS calculated [MþNa]þ for C21H15F2IO2: 487.0085, found: 487.0091.

4.11. 2,2-Difluoro-4-iodo-3-methyl-1,4-diphenylbut-3-en-1-one 3i

4.12. 2,2-Difluoro-4-iodo-4-phenyl-1-(p-tolyl)but-3-en-1-one 3j Light yellow liquid, yield: 83% (E only); 1H NMR (500 MHz, CDCl3): d 7.78e7.76 (m, 2H), 7.29e7.19 (m, 7H), 6.99 (t, J ¼ 11.6 Hz, 0 1H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3): d 186.3 (t, 2 JC2 30 F ¼ 29.7 Hz), 145.4, 140.9, 133.7 (t, JC-F ¼ 27.1 Hz), 129.9 (t, JC1 F ¼ 2.4 Hz), 129.2, 128.9, 127.8, 127.7, 114.0 (t, JC-F ¼ 252.9 Hz), 108.5 3 19 (t, JC-F ¼ 9.4 Hz), 21.7; F NMR (470 MHz, CDCl3): d 89.54 (m, 2F); HRMS calculated [MþNa]þ for C17H13F2IO: 420.9871, found: 420.9895. 4.13. 1-(4-Bromophenyl)-2,2-difluoro-4-iodo-4-phenylbut-3-en-1one 3k Light yellow liquid, yield: 85% (E only); 1H NMR (500 MHz, CDCl3): d 7.69e7.57 (m, 4H), 7.30e7.15 (m, 5H), 6.96 (t, J ¼ 11.4 Hz, 0 1H); 13C NMR (125 MHz, CDCl3): d 185.8 (t, 2 JC-F ¼ 30.4 Hz), 140.7, 2 30 133.3 (t, JC-F ¼ 27.3 Hz), 131.9, 131.1 (t, JC-F ¼ 2.5 Hz), 130.2, 129.8, 129.4, 127.9, 127.8, 113.8 (t, 1JC-F ¼ 252.7 Hz), 109.1 (t, 3JC-F ¼ 9.9 Hz); 19 F NMR (470 MHz, CDCl3): d 89.29 (s, 2F); HRMS calculated [MþH]þ for C16H10BrF2IO: 462.9006, found: 462.8992. 4.14. 2,2-Difluoro-4-iodo-4-phenyl-1-(thiophen-2-yl)but-3-en-1one 3l Light yellow liquid, yield: 80% (E only); 1H NMR (500 MHz,

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CDCl3): d 7.77e7.57 (m, 2H), 7.29e7.13 (m, 6H), 6.92 (t, J ¼ 11.8 Hz, 0 1H); 13C NMR (125 MHz, CDCl3): d 180.5 (t, 2 JC-F ¼ 31.6 Hz), 141.1, 30 2 137.9, 136.4, 135.6 (t, JC-F ¼ 4.1 Hz), 133.2 (t, JC-F ¼ 26.9 Hz), 129.3, 128.6, 128.0, 127.7 (t, J ¼ 1.7 Hz), 113.9 (t, 1JC-F ¼ 253.5 Hz), 109.2 (t, 3 JC-F ¼ 9.7 Hz); 19F NMR (470 MHz, CDCl3): d 90.93 (m, 2F); HRMS calculated [MþNa]þ for C14H9F2IOS: 412.9279, found: 412.9281. 4.15. 2,2-Difluoro-4-iodo-1-(naphthalen-2-yl)-4-phenylbut-3-en1-one 3m Light yellow liquid, yield: 75% (E only); 1H NMR (500 MHz, CDCl3): d 8.42e7.84 (m, 5H), 7.68e7.59 (m, 2H), 7.30e7.18 (m, 5H), 0 7.06 (t, J ¼ 11.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 186.8 (t, 2 JC2 30 F ¼ 29.9 Hz), 141.0, 135.9, 133.8 (t, JC-F ¼ 27.1 Hz), 132.4 (t, JCF ¼ 3.1 Hz), 132.1, 130.0, 129.3, 128.8, 128.3, 127.9, 127.8, 127.7, 127.0, 124.6, 114.2 (t, 1JC-F ¼ 253.0 Hz), 108.7 (t, 3JC-F ¼ 10.3 Hz); 19F NMR (470 MHz, CDCl3): d 89.08 (m, 2F); HRMS calculated [MþNa]þ for C20H13F2IO: 456.9979, found: 456.9935. 4.16. 2,2-Difluoro-4-iodo-1-(p-tolyl)non-3-en-1-one 3n Light yellow liquid, yield: 87% (E only); 1H NMR (500 MHz, CDCl3): d 7.95e7.30 (m, 4H), 6.64 (t, J H-F ¼ 12.9 Hz, 1H), 2.56e2.53 (m, 2H), 2.44 (s, 3H), 1.53e1.47 (m, 2H), 1.34e0.86 (m, 7H); 13C NMR 0 (125 MHz, CDCl3): d 187.1 (t, 2 JC-F ¼ 30.5 Hz), 145.8, 129.5, 128.9, 0 2 132.0 (t, JC-F ¼ 26.6 Hz), 130.3 (t, 3 JC-F ¼ 2.5 Hz), 119.8 (t, 3JC1 F ¼ 8.3 Hz), 114.9 (t, JC-F ¼ 254.0 Hz), 40.7, 30.5, 29.5, 22.4, 21.8, 13.9; 19 F NMR (470 MHz, CDCl3): d 92.03 (s, 2F); HRMS calculated [MþNa]þ for C16H19OF2I: 415.0340, found: 415.0324. 4.17. 1-(4-Chlorophenyl)-2,2-difluoro-4-iodonon-3-en-1-one 3o Light yellow liquid, yield: 86% (E only); 1H NMR (500 MHz, CDCl3): d 8.01e7.46 (m, 4H), d 6.57 (t, J ¼ 11.9 Hz, 1H), 1.57e1.25 (m, 0 6H), 1.24e0.86 (m, 5H); 13C NMR (125 MHz, CDCl3): d 187.1 (t, 2 JC2 30 F ¼ 30.5 Hz), 145.8, 132.1 (t, JC-F ¼ 26.6 Hz), 130.3 (t, JC-F ¼ 2.5 Hz), 129.6, 129.0, 119.8 (t, 3JC-F ¼ 8.3 Hz), 114.9 (t, 1JC-F ¼ 254.0 Hz), 40.8, 30.5, 29.5, 22.4, 21.8, 13.9; 19F NMR (470 MHz, CDCl3): d 93.69 (s, 2F); HRMS calculated [MþNa]þ for C15H16OF2ICl: 434.9794, found 434.9798. 4.18. 2,2-Difluoro-4-iodo-1-(thiophen-2-yl)non-3-en-1-one 3p Light yellow liquid, yield: 80% (E only); 1H NMR (500 MHz, CDCl3): d 7.93e7.20 (m, 3H), 6.58 (t, J ¼ 13.2 Hz, 1H), 2.60e1.49 (m, 0 4H), 1.34e0.87 (m, 7H); 13C NMR (125 MHz, CDCl3): d 180.9 (t, 2 JC30 2 JC-F ¼ 4.3 Hz), 131.4 (t, JCF ¼ 32.4 Hz), 137.9, 136.6, 135.7 (t, 3 1 F ¼ 26.7 Hz), 128.8, 120.4 (t, JC-F ¼ 7.9 Hz), 114.5 (t, JC-F ¼ 254.2 Hz), 40.9, 30.5, 29.5, 22.4, 13.9; 19F NMR (470 MHz, CDCl3): d 93.14 (m, 2F); HRMS calculated [MþNa]þ for C13H15OF2IS: 406.9748, found: 406.9742. 4.19. 2,2-Difluoro-4-iodo-3-methyl-4-phenyl-1-(p-tolyl)but-3-en1-one 3q White solid, yield: 81% (E only), melting point: 112.1e112.3  C; H NMR (500 MHz, CDCl3): d 7.63e7.62 (m, 2H), 7.20e7.00 (m, 7H), 0 2.41 (s, 3H), 2.36 (s, 3H); 13C NMR (125 MHz, CDCl3): d 186.2 (t, 2 JC2 30 F ¼ 30.4 Hz), 145.2, 143.0, 136.2 (t, JC-F ¼ 23.2 Hz), 129.7 (t, JC1 F ¼ 2.2 Hz), 129.3, 129.1, 128.6, 128.5, 127.7, 114.1 (t, JC-F ¼ 256.2 Hz), 3 19 109.2 (t, JC-F ¼ 7.4 Hz), 25.8, 21.7; F NMR (470 MHz, CDCl3): d 90.10 (m, 2F); HRMS calculated [MþNa]þ for C18H15ClF2IO: 435.0027, found: 435.0034. 1

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4.20. 1-(4-Chlorophenyl)-2,2-difluoro-4-iodo-3-methyl-4phenylbut-3-en-1-one 3r White solid, yield: 84% (E only), melting point: 124.5e124.3  C; H NMR (500 MHz, CDCl3): d 7.64e7.35 (m, 4H), 7.19e6.98 (m, 5H), 0 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3): d 185.5 (t, 2 JC-F ¼ 30.6 Hz), 2 30 142.7, 140.7, 136.1 (t, JC-F ¼ 23.3 Hz), 130.8 (t, JC-F ¼ 2.3 Hz), 130.1, 128.8, 128.7, 127.8, 113.8 (t, 1JC-F ¼ 255.4 Hz), 109.5 (t, 3JC-F ¼ 7.6 Hz), 25.7; 19F NMR (470 MHz, CDCl3): d 89.93 (m, 2F); HRMS calculated [MþNa]þ for C17H12ClF2IO: 454.9481, found: 454.9484. 1

4.21. 2,2-Difluoro-4-iodo-3-methyl-4-phenyl-1-(4-(trifluoro methyl)phenyl)but-3-en-1-one 3s White solid, yield: 51% (E only), melting point: 54.9e55.9  C; 1H NMR (500 MHz, CDCl3): d 7.79e7.64 (m, 4H), 7.19e6.96 (m, 5H), 0 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3): d 185.9 (t, 2 JC-F ¼ 30.8 Hz), 2 200 142.6, 136.0 (t, JC-F ¼ 23.5 Hz), 135.2 (q, JC-F ¼ 32.9 Hz), 134.6, 0 129.8 (t, 3 JC-F ¼ 2.3 Hz), 129.0, 128.0, 127.9, 125.4 (q, 3'’JC-F ¼ 3.6 Hz), 100 123.4 (q, JC-F ¼ 272.9 Hz), 113.7 (t, 1JC-F ¼ 255.7 Hz), 109.7 (t, 3JC19 F NMR (470 MHz, CDCl3): d 89.92 (s, F ¼ 7.7 Hz), 25.7; 2F), 63.33(s, 3F); HRMS calculated [MþNa]þ for C18H12F5IO: 488.9745, found: 488.9758. 4.22. Procedures for coupling reactions To a 10 mL sealed glass vial was added compound 3a (0.192 g, 0.5 mmol), PdCl2(PPh3)2 (35 mg, 0.05 mmol, 0.1 equiv.), K2CO3 (0.138 g, 1 mmol, 2 equiv.), PhB(OH)2 (0.079 g, 1 mmol, 2 equiv.), Toluene (1 mL) and H2O (0.2 mL). The reaction mixture was stirred at 60  C under N2 protection for 6 h, and quenched with water (2 mL) and extracted with ethyl acetate (3  20 mL). The combined organic layer was dried over anhydrous sodium sulfate and the solvent evaporated in vacuo to give the residue purified by column chromatography (0e1% EtOAc/hexane) affording the product 4a (0.142 g, 85%). Light yellow liquid, yield: 85%; 1H NMR (500 MHz, CDCl3): d 7.90e7.57 (m, 3H), 7.44e7.03 (m, 8H), 6.58 (t, J ¼ 12.2 Hz, 0 1H); 13C NMR (125 MHz, CDCl3): d 187.3 (t, 2 JC-F ¼ 29.7 Hz), 151.1 (t, 0 3 JC-F ¼ 9.1 Hz), 140.5, 137.0, 133.8, 131.9, 129.8, 129.7 (t, 3 JC2 F ¼ 2.0 Hz), 129.0, 128.6, 128.3, 128.2, 127.8, 120.2 (t, JC-F ¼ 27.6 Hz), 115.2 (t, 1JC-F ¼ 247.3 Hz); 19F NMR (470 MHz, CDCl3): d 87.24 (s, 2F); HRMS calculated [MþNa]þ for C22H16F2O: 357.1067, found: 357.1097. To a 10 mL sealed glass vial was added compound 3a (0.192 mg, 0.5 mmol), Pd(PPh3)4 (0.057 g, 0.05 mmol, 0.1 equiv.), K2CO3 (0.138 g, 1 mmol, 2 equiv.), 4-ethynyltoluene (0.116 g, 1 mmol, 2equiv), CuI (0.019 g, 0.1 mmol, 0.2 equiv) and TEA (1 mL). The mixture was stirred at 50  C under N2 protection for 6 h. The reaction was quenched with water (2 mL) and extracted with ethyl acetate (3  20 mL), the combined organic layer was dried over anhydrous sodium sulfate and the solvent evaporated in vacuo to give the crude product, which was purified carefully by column chromatography (0e5% EtOAc/hexane) affording the product 4b (0.16 g, 87%). Light yellow liquid, yield: 87%; 1H NMR (500 MHz, CDCl3): d 7.83e7.35 (m, 8H), 7.29e7.15 (m, 6H), 6.59 (t, J ¼ 12.8 Hz, 0 1H), 2.38 (s, 3H); 13C NMR (125 MHz, CDCl3): d 187.2 (t, 2 JC30 F ¼ 29.2 Hz), 139.4, 135.7, 134.0, 131.7, 129.7 (t, JC-F ¼ 1.8 Hz), 129.1, 129.0, 128.7, 128.3, 128.0, 127.1 (t, 2JC-F ¼ 27.0 Hz), 126.6, 114.7 (t, 1JC19 F ¼ 248.3 Hz), 94.0, 88.8, 21.5; F NMR (470 MHz, CDCl3): d 88.23 (s, 2F); HRMS calculated [MþNa]þ for C25H18F2O: 395.1218, found: 395.1222. Acknowledgment We are grateful for financial supports from the National Natural

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