Cross-coupling of 1,1-difluoro-1-en-3-yn-2-yl tosylates with arylboronic acids: A new approach to 2-aryl-1,1-difluoro-1,3-enynes

Article abstract of DOI:10.1016/j.jfluchem.2016.08.014

The palladium-catalyzed direct alkynylation of 2,2-difluoro-1-tributylstannylethenyl p-toluenesulfonate 1 with alkynyl bromides provided the corresponding 1,1-difluoro-1,3-enynyl tosylates 2 in good yields. The Suzuki-Miyaura arylation reaction of 2 with arylboronic acids afforded the cross-coupled products, 2-aryl-1,1-difluoro-1,3-enynes 3, in good yields.

Full text of DOI:10.1016/j.jfluchem.2016.08.014

Accepted Manuscript
Title: Cross-coupling of 1,1-difluoro-1-en-3-yn-2-yl tosylates
with arylboronic acids: A new approach to
2-aryl-1,1-difluoro-1,3-enynes
Author: Su Jin Kim Hyun Kyu Ryu Sung Lan Jeon In Howa
Jeong
PII:
S0022-1139(16)30276-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.08.014
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13-5-2016
26-8-2016
28-8-2016
Please cite this article as: Su Jin Kim, Hyun Kyu Ryu, Sung Lan Jeon, In Howa
Jeong, Cross-coupling of 1,1-difluoro-1-en-3-yn-2-yl tosylates with arylboronic acids:
A new approach to 2-aryl-1,1-difluoro-1,3-enynes, Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2016.08.014
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Cross-coupling of 1,1-difluoro-1-en-3-yn-2-yl tosylates with arylboronic acids: A new
approach to 2-aryl--difluoro-1,3-enynes
Su Jin Kim, Hyun Kyu Ryu, Sung Lan Jeon, and In Howa Jeong*
Department of Chemistry, Yonsei University, Wonju, 220-710, S. Korea
* Corresponding author. Tel.: +82 33 760 2240; fax: +82 33 763 4323.
E-mail address: jeongih@yonsei.ac.kr (I.H. Jeong)
Graphical abstract
Alkynylation reaction of 2,2-difluoro-1-tributylstannylethenyl p-toluenesulfonate 1 with alkynyl
bromides in the presence of 10 mol% Pd(PPh3)4 and 10 mol% CuI in THF at reflux temperature
for 3 h provided the corresponding 1,1-difluoro-1,3-enynyl tosylates 2 in 61-84% yields. The
further arylation reaction of 2 with arylboronic acids in the presence of 2 mol% Pd(OAc)2, 4
o
mol% PCy3, K3PO4 (1.7 equiv) in dioxane /H2O (20/1) at 100 C for 3 h afforded the coupled
products 3 in 55-83% yields.

Highlights
1. Cross-coupling of 2,2-difluoro-1-tributylstannylethenyl p-toluenesulfonate with alkynyl
bromides
2. Arylation of 1,1-difluoro-1,3-enynyl tosylates with arylboronic acids
3. Use of less toxic arylboronic acids for the cross-coupling of 1,1-difluoro-1-en-3-yn-2-yl
tosylates
4. Efficient and straightforward preparation of 2-aryl-1,1-difluoro-1,3-enynes
Abstract
The palladium-catalyzed direct alkynylation of 2,2-difluoro-1-tributylstannylethenyl p-toluenesulfonate 1 with alkynyl
bromides provided the corresponding 1,1-difluoro-1,3-enynyl tosylates 2 in good yields. The Suzuki-Miyaura arylation reaction
of 2 with arylboronic acids afforded the cross-coupled products , 2-aryl-1,1-difluoro-1,3-enynes 3, in good yields.
Keywords : 2,2-difluoro-1-tributylstannylethenyl p-toluenesulfonate, alkynyl bromides, 1,1-difluoro-1,3-enynyl tosylates,
arylboronic acids
1. Introduction
1,3-Enyne functional group is an important structural frame in many natural products1-3 and
pharmaceuticals,4-6 and also was transformed to useful functional group in the multifunctional molecules and
material sciences.7-10 Of particular interests in 1,3-enynes are fluorine-containing conjugated enynes which
would be important building blocks for the synthesis of fluorinated compounds having unique biological and
physical properties.11-13 Especially, pharmaceutical application of fluorine-containing compounds have been
well reviewed in recent years.14,15 Although various methods for the preparation of nonfluorinated 1,3-
enynes have been well established in the previous literatures,16 there are only limited reports on the synthesis
of fluorinated 1,3-enynes and most of them described the synthesis of 1,2-difluorinated17,18 or
monofluorinated 1,3-enynes.19-22 Especially, the synthesis of 1,1-difluoro-1,3-enyne derivatives which have
high reactivity at gem-difluorinated vinyl carbon was scarcely reported. Burton et al. reported that 1,1-
difluoro-2-phenyl-1,3-enynes were synthesized in low yield via the hydrolysis of the trifluoromethylated
allenic phosphonium salt.23
Transition-metal catalyzed cross-coupling reactions between 2,2-
difluoroethenyl building blocks and alkynyl coupling partners are straightforward process to give 1,1-
difluoro-1,3-enynes. For example, 1,1-difluoro-1,3-enynes were prepared from the cross-coupling of 1,1-
difluorovinyl iodides with alkynylzinc chloride24 or terminal alkynes25,26 in the presence of Pd catalyst.
Ichikawa et al. synthesized 2-alkylated 1,1-difluoro-1,3-enynes via the cross-coupling of 1-alkyl-2,2-
difluorovinylboranes with 1-halo-1-alkynes in the presence of cuprous iodides.27 Hammond et al. reported
that the Pd-catalyzed reaction of gem-difluorohomoallenyl bromide with terminal alkynes provided the

corresponding 1,1-difluoro-1,3-enynes.28 We also prepared 1,1-difluoro-2-phenyl-1,3-enynes from the cross-
coupling of 2,2-difluoro-1-phenylethenylstannane with alkynyl iodides in the presence of catalytic amount of
Pd(PPh3)4 and CuI.29 We reported that 2-arylated 1,1-difluoro-1,3-enynes were prepared from the
palladium-catalyzed cross-coupling of 1,1-difluoro-1-en-3-yn-2-yl tosylates with arylstannane reagents.30
Wang et al. carried out the Cu(I)-catalyzed cross-coupling of terminal alkynes with trifluoromethyl ketone N-
tosylhydrazones to afford 1,1-difluoro-1,3-enynes.31 However, the previous methods still have several
limitations such as low yield preparation of the products, use of unstable vinylmetal reagents, lack of
generality, use of toxic stannyl group and tedius procedure for the synthesis of starting material. Herein, we
wish to report the preparation of 2-aryl-1,1-difluoro-1,3-enynes via the cross-coupling of 1,1-difluoro-1-en-
3-yn-2-yl tosylates 2 with relatively less toxic arylboronic acids in the presence of Pd catalyst and base.
2. Results and discussion
Although 1,1-difluoro-1-en-3-yn-2-yl tosylates can be prepared from the Pd-catalyzed cross-coupling of
2,2-difluoro-1-iodoethenyl tosylate with alkynylstannanes,30 we performed the Pd-catalyzed cross-coupling
of 2,2-difluoro-1-tributylstannylethenyl tosylate 132 with alkynyl bromides because the latter method would
be efficient and high yield preparation of 2. Thus, the reaction of 1 with phenylethynyl bromide in the
presence of 10 mol% Pd(PPh3)4 and 10 mol% CuI in THF provided the corresponding 1,1-difluoro-1,3-
enynes 2 in 61-84% yields. The results for the preparation of 2 were summarized in Table 1. The use of
alkynyl iodides in this cross-coupling reaction resulted in the formation of homocoupled diynes as a major
product. This result is speculated that transmetallation process in catalytic cycle is relatively slower than
self-dimerization after oxidative insertion of alkynyl iodides with Pd catalyst.
Although a couple of cross-coupling reactions of fluorinated alkenyl tosylate with arylboronic acids in
the presence of Pd catalyst have been previously reported,33,34 we recently developed the cross-coupling of
2,2-difluoro-1-iodoethenyl tosylate with arylboronic acids in the presence of Pd catalyst to give 2,2-difluoro-
1-arylethenyl tosylates or 2,2-difluoro-1,1-diarylethenes.35 In the course of our studies on the cross-coupling
of gem-difluorinated alkene, we extended to examine the reactivity of cross-coupling of 1,1-difluoro-1,3-
enynyl tosylates 2 with arylboronic acids. When 2a was treated with phenylboronic acid (1.2 equiv) in the
presence of Pd(PPh3)2Cl2 (5 mol%) and Cs2CO3 (1.7 equiv) in MeOH at room temperature for 12 hours, the
desired product 3a was not observed at all. A couple of catalysts was examined to promote the cross-
coupling of 2a with phenylboronic acid. The use of Pd catalysts such as Pd(OAc)2 or Pd2(dba)3 in the same
reaction also did not provide the coupled product, either. We also screened the effect of bases such as
Na2CO3 or K3PO4, but no coupled product was formed. However, when 2a was reacted with phenylboronic
acid (1.2 equiv) in the presence of Pd(OAc)2 (2 mol%), PCy3 (4 mol%) and K3PO4(1.7 equiv) in dioxane at
o
100 C for 14 hours, the coupled product 3a, along with homocoupled product of phenylboronic acid, was
obtained in only 28% yield based on the conversion of starting material. According to this result, it is

speculated that the use of bulky ligand such as PCy3 has an effect on the reaction process. However, the use
of other ligands such as X-Phos, S-Phos or dppp did not provide the coupled product 3a. The increase of
amount of catalyst and ligand resulted in the decrease of yield of the coupled product 3a. Addition of small
amount of water into dioxane (dioxane : water = 20 :1) to resolve K3PO4 and phenylboronic acid in the same
reaction dramatically caused not only to increase the yield of 3a up to 70%, but also decrease the reaction
time to 3 hours. However, the use of quite excess of water (dioxane : water = 3:1) in this reaction, the desired
product 3a was not formed at all, but homocoupled product of phenylboronic acid was formed as a major
product. Reaction temperature was also important to the yield of 3a. Therefore, when the reaction was
performed at 50 oC under the same reaction conditions, 3a was obtained in only 24% yield. The results of the
optimization for the formation of the coupled product 3a were summarized in Table 2.
Optimized reaction condition was applied to prepare a variety of the coupled products 3. Therefore, the
reactions of 2a with a variety of arylboronic acids having electron-withdrawing group such as fluoro, chloro
or trifluoromethyl as well as electron-donating group such as methyl or methoxy on the meta- or para-
position of benzene ring under the same reaction conditions gave the corresponding 2-arylated 1,1-difluoro-
1,3-enynes 3b-3k in 55-83% yields. However, the reaction of 2a with ortho-substituted arylboronic acids
such as ortho-methylphenylboronic acid afforded the trace amount of product 3l. The results of the coupling
reaction between 2a and arylboronic acids were summarized in Table 3.
3. Conclusion
In summary, we have developed a general and efficient method for the preparation of 1,1-difluoro-1-
en-3-yn-2-yl tosylates 2 which were prepared in high yields from the palladium-catalyzed cross-coupling of
2,2-difluoro-1-tributylstannylethenyl tosylate with alkynyl bromides. The use of alkynyl iodides in this
reaction resulted in the formation of dimerized product of alkynyl iodides. Further Suzuki-Miyaura cross-
coupling of 2 with less toxic arylboronic acids in the presence of Pd(OAc)2 catalyst, PCy3 ligand, and
K3PO4 salt afforded the corresponding 2-aryl-1,1-difluoro-1,3-enynes in good yields. This latter reaction
is the first example of Suzuki-Miyaura cross-coupling in the 1,1-difluoro-1,3-enynyl tosylate system.
4. Experimental
1H and 13C NMR spectra were recorded on a 400 MHz Bruker AVANCEII++ NMR spectrometer with
tetramethylsilane (TMS) as an internal standard and 19F NMR spectra were also recorded on a 400 MHz
Bruker AVANCEII++ NMR spectrometer with C6H5CF3 (-63.72 ppm from CFCl3) as an internal standard and
the upfield as negative. All chemical shifts () are expressed in parts per million and coupling constants (J)
are given in Hertz. Mass spectra were obtained by using Agilent Technologies 6890N GC/5973 Network

MSD (EI, 70 eV). Elemental analysis data were obtained by using EA1110 elemental analyzer. Melting
points were determined in open capillary tubes and are uncorrected.
Commercially available reagents were purchased from Aldrich, Lancaster, Tokyo Kasei and
Fluorochem. All solvents were dried by general purification method. Flash chromatography was
performed on 40-60 m silica gel (230-400 mesh).
4.1. General procedure for the preparation of 1,1-difluoro-1,3-enyn-2-yl p-toluenesulfonates 2
A 25 mL two-neck round bottom flask equipped with a magnetic stirrer bar, a septum and nitrogen tee
connected to an argon source was charged with Pd(PPh3)4 (10 mol%), CuI (10 mol%) and 3 mL of THF.
The solution of 2,2-difluoro-1-tributylstannylethenyl p-toluenesulfonate (0.200 g, 0.382 mmol) and alkynyl
bromide (0.450 mmol) dissolved in 3 mL of THF was added into the reaction mixture. After the reaction
mixture was refluxed for 3 hours and then cooled to room temperature, the mixture was quenched with water.
The reaction mixture was extracted with ether twice, dried over anhydrous MgSO4 and chromatographed on
SiO2 column. Elution with n-hexane and ethyl acetate (4:1) provided 1,1-difluoro-1,3-enyn-2-yl p-
toluenesulfonates 2.
The characterization data (1H and 13C NMR, Mass) for compounds 2a-e and 2h-k have been previously
reported.30
4.1.1. 1,1-Difluoro-4-phenylbut-1-en-3-yn-2-yl p-toluenesulfonate (2a)
2a was prepared in 78% yield (0.100 g) according to the general procedure. Anal. Calcd for
C17H12F2O3S: C, 61.07; H, 3.62. Found: C, 60.81; H, 3.57.
4.1.2. 1,1-Difluoro-4-p-tolylbut-1-en-3-yn-2-yl p-toluenesulfonate (2b)
2b was prepared in 68% yield (0.090 g) according to the general procedure. Anal. Calcd for
C18H14F2O3S: C, 62.06; H, 4.05. Found: C, 61.83; H, 3.98.
4.1.3. 4-(3,5-Bis(trifluoromethyl)phenyl)-1,1-difluorobut-1-en-3-yn-2-yl p-toluenesulfonate (2c)
2c was prepared in 84% yield (0.151 g) according to the general procedure. Anal. Calcd for
C19H10F8O3S: C, 48.52; H, 2.14. Found: C, 48.43; H, 2.09.
4.1.4. 1,1-Difluoro-4-(4-methoxyphenyl)but-1-en-3-yn-2-yl p-toluenesulfonate (2d)

2d was prepared in 62% yield (0.086 g) according to the general procedure. Anal. Calcd for
C18H14F2O4S: C, 59.34; H, 3.87. Found: C, 59.11; H, 3.81.
4.1.5. 1,1-Difluoro-4-(2-methoxyphenyl)but-1-en-3-yn-2-yl p-toluenesulfonate (2e)
2e was prepared in 61% yield (0.085 g) according to the general procedure. Anal. Calcd for
C18H14F2O4S: C, 59.34; H, 3.87. Found: C, 59.11; H, 3.82.
4.1.6. 1,1-Difluoro-4-(4-chlorophenyl)but-1-en-3-yn-2-yl p-toluenesulfonate (2f)
1
2f was prepared in 72% yield (0.101 g) according to the general procedure. 2f: yellow oil; H NMR
(CDCl3)  7.90 (d, J = 7.6 Hz, 2H), 7.37-7.22 (m, 4H), 7.11-7.07 (m, 2H), 2.42 (s, 3H); 19F NMR (CDCl3,
internal standard C6H5CF3)  -80.57 (d, J = 7.5 Hz, 1F), -93.51 (d, J = 7.5 Hz, 1F); 13C NMR (CDCl3) 
160.7 (dd, J = 302, 301 Hz), 146.4, 134.4, 132.7, 131.4, 130.3, 129.9, 129.6, 129.1, 128.6, 122.8, 100.4, 98.8
(dd, J = 9, 7 Hz), 75.9 (dd, J = 9, 3 Hz), 21.9; MS, m/z (relative intensity) 368 (M+, 2), 163 (64), 139 (10), 91
(100), 75 (6), 65 (26). Anal. Calcd for C17H11ClF2O3S: C, 55.37; H, 3.01. Found: C, 55.15; H, 3.05.
4.1.7. 1,1-Difluoro-4-(4-trifluoromethylphenyl)but-1-en-3-yn-2-yl p-toluenesulfonate (2g)
1
2g was prepared in 79% yield (0.121 g) according to the general procedure. 2g: yellow oil; H NMR
(CDCl3)  7.90 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.36-7.31 (m, 4H), 2.40 (s, 3H); 19F NMR
(CDCl3, internal standard C6H5CF3)  -79.87 (d, J = 11.3 Hz, 1F), -79.87 (s, 3F), -92.77 (d, J = 11.3 Hz, 1F);
13C NMR (CDCl3)  160.7 (dd, J = 302, 296 Hz), 146.3, 132.5, 131.4, 130.2, 129.1, 128.6, 125.4, 122.4,
101.2 (dd, J = 59, 50 Hz), 99.4, 30.4, 21.8; MS, m/z (relative intensity) 402 (M+, 1), 383 (6), 197 (77), 155
(41), 139 (10), 91 (100), 65 (31). Anal. Calcd for C18H11F5O3S: C, 53.74; H, 2.76. Found: C, 53.61; H,
2.74.
4.1.8. 1,1-Difluorooct-1-en-3-yn-2-yl p-toluenesulfonate (2h)
2h was prepared in 75% yield (0.090 g) according to the general procedure. Anal. Calcd for C15H16F2O3S:
C, 57.31; H, 5.13. Found: C, 57.07; H, 5.06.
4.1.9. 1,1-Difluorodec-1-en-3-yn-2-yl p-toluenesulfonate (2i)
2i was prepared in 71% yield (0.093 g) according to the general procedure. Anal. Calcd for C17H20F2O3S:
C, 59.63; H, 5.89. Found: C, 59.47; H, 5.83.

4.1.10. 1,1-Difluoro-4-(triisopropylsilyl)but-1-en-3-yn-2-yl p-toluenesulfonate (2j)
2j was prepared in 74% yield (0.117 g) according to the general procedure. Anal. Calcd for C20H28F2O3SSi:
C, 57.94; H, 6.81. Found: C, 57.59; H, 6.72.
4.1.11. 1,1-Difluoro-4-(trimethylsilyl)but-1-en-3-yn-2-yl p-toluenesulfonate (2k)
2k was prepared in 76% yield (0.096 g) according to the general procedure. Anal. Calcd for
C14H16F2O3SSi: C, 50.89; H, 4.88. Found: C, 50.68; H, 4.83.
4.2. General procedure for the preparation of 2-aryl-1,1-difluoro-4-phenylbut-1-en-3-ynes 3
A 10 mL two-neck round bottom flask equipped with a magnetic stirrer bar, a septum and nitrogen tee
connected to an argon source was charged with Pd(OAc)2 (2 mol%), PCy3 (4 mol%), K3PO4 (0.51 mmol)
and 1 mL of dioxane/H2O (20/1). The solution of 2a (0.100 g, 0.30 mmol) and arylboronic acid (0.36
mmol) dissolved in 2 mL of dioxane/H2O (20/1) was added into the reaction mixture. After the reaction
o
mixture was heated at 100 C for 3 hours and then cooled to room temperature, the mixture was quenched
with water. The reaction mixture was extracted with ether twice, dried over anhydrous MgSO4 and
chromatographed on SiO2 column. Elution with n-hexane and ethyl acetate (20:1) provided 2-aryl-1,1-
difluoro-4-phenylbut-1-en-3-ynes 3.
The characterization data (1H and 13C NMR, Mass) for compounds 3a-e and 3g-k have been previously
reported.30
4.2.1. 1,1-Difluoro-2,4-diphenylbut-1-en-3-yne (3a)
3a was prepared in 70% yield (0.050 g) according to the general procedure. Anal. Calcd for C16H10F2: C,
79.99; H, 4.20. Found: C, 79.71; H, 4.14.
4.2.2. 1,1-Difluoro-4-phenyl-2-p-tolylbut-1-en-3-yne (3b)
3b was prepared in 61% yield (0.046 g) according to the general procedure. Anal. Calcd for C17H12F2: C,
80.30; H, 4.76. Found: C, 80.01; H, 4.70.
4.2.3. 1,1-Difluoro-4-phenyl-2-m-tolylbut-1-en-3-yne (3c)

3c was prepared in 59% yield (0.045 g) according to the general procedure. Anal. Calcd for C17H12F2: C,
80.30; H, 4.76. Found: C, 80.05; H, 4.71.
4.2.4. 2-(p-Chlorophenyl)-1,1-difluoro-4-phenylbut-1-en-3-yne (3d)
3d was prepared in 83% yield (0.068 g) according to the general procedure. Anal. Calcd for C16H9ClF2: C,
69.96; H, 3.30. Found: C, 69.65; H, 3.25.
4.2.5. 2-(m-Chlorophenyl)-1,1-difluoro-4-phenylbut-1-en-3-yne (3e)
3e was prepared in 80% yield (0.066 g) according to the general procedure. Anal. Calcd for C16H9ClF2: C,
69.96; H, 3.30. Found: C, 69.57; H, 3.34.
4.2.6. 1,1-Difluoro-2-(p-methoxyphenyl)-4-phenylbut-1-en-3-yne (3f)
1
3f was prepared in 64% yield (0.052 g) according to the general procedure. 3f: yellow oil; H NMR
(CDCl3)  7.54-7.49 (m, 3H), 7.38-7.33 (m, 3H), 7.27-7.25 (m, 1H), 6.94-6.90 (m, 2H), 3.83 (s, 3H); 19F
NMR (CDCl3, internal standard C6H5CF3)  -77.56 (d, J = 7.5 Hz, 1F), -81.90 (d, J = 7.5 Hz, 1F); 13C NMR
(CDCl3)  159.5 (dd, J = 300, 296 Hz), 134.4, 131.7, 130.1, 129.3, 128.9, 128.7, 128.6, 123.1, 114.4, 114.3,
94.4 (dd, J = 8, 4 Hz), 82.5 (dd, J = 28, 20 Hz), 80.6 (dd, J = 8, 4 Hz), 55.6; MS, m/z (relative intensity) 270
(M+, 100), 255 (5), 225 (7), 207 (16), 176 (11), 151 (10), 135 (9), 110 (15). Anal. Calcd for C17H12F2O: C,
75.55; H, 4.48. Found: C, 75.21; H, 4.43.
4.2.6. 1,1-Difluoro-2-(m-methoxyphenyl)-4-phenylbut-1-en-3-yne (3g)
3g was prepared in 55% yield (0.045 g) according to the general procedure. Anal. Calcd for C17H12F2O: C,
75.55; H, 4.48. Found: C, 75.18; H, 4.42.
4.2.7. 1,1-Difluoro-2-(p-fluorophenyl)-4-phenylbut-1-en-3-yne (3h)
3h was prepared in 82% yield (0.063 g) according to the general procedure. Anal. Calcd for C16H9F3: C,
74.42; H, 3.51. Found: C, 74.15; H, 3.46.
4.2.8. 1,1-Difluoro-2-(m-fluorophenyl)-4-phenylbut-1-en-3-yne (3i)
3i was prepared in 77% yield (0.060 g) according to the general procedure. Anal. Calcd for C16H9F3: C,

74.42; H, 3.51. Found: C, 74.18; H, 3.46.
4.2.9. 1,1-Difluoro-2-(p-trifluoromethyl)phenyl-4-phenylbut-1-en-3-yne (3j)
3j was prepared in 76% yield (0.070 g) according to the general procedure. Anal. Calcd for C17H9F5: C,
66.24; H, 2.94. Found: C, 65.92; H, 2.89.
4.2.10. 1,1-Difluoro-2-(m-trifluoromethyl)phenyl-4-phenylbut-1-en-3-yne (3k)
3k was prepared in 70% yield (0.065 g) according to the general procedure. Anal. Calcd for C17H9F5: C,
66.24; H, 2.94. Found: C, 65.98; H, 2.91.
Acknowledgment
This work was supported by a Basic Research Grant (2011-0022295) funded by the National Research
Foundation.
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Table 1. The preparation of 1,1-difluoro-1-en-3-yn-2-yl tosylates 2
OTs
F
F
OTs
F
F
Pd(PPh3)4(10 mol%) /CuI(10 mol%)
THF, reflux, 3 h
+
Br
R
C
SnBu3
C
1
2
R
Compound
Yield (%)a
R
2a
2b
C6H5
78
68
84
62
61
p-CH3C6H4
2c
2d
2e
3,5-(CF3)2C6H3
p-CH3OC6H4
o-CH3OC6H4
2f
p-ClC6H4
72
79
75
71
74
76
p-CF3OC6H4
2g
n-C4H9
n-C6H13
(i-Pr)3Si
Me3Si
2h
2i
2j
2k
aIsolated yield.

Table 2. Optimization for the formation of the coupled product 3a
F
F
OTs
F
F
Ph
C
Pd catalyst (X mol%) / ligand (Y mol%)
base (1.7 equiv), solvent, T oC, t h
+
PhB(OH)2
(1.2 equiv)
C
C
C
Ph
2a
3a
Ph
t (h) Yield (%)a
T (oC)
Entry
Pd Catalyst (X)
Solvent
ligand (Y)
base
_
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2 (5)
Cs2CO3 MeOH
Cs2CO3 MeOH
25
25
25
25
12
12
0
0
0
0
_
_
_
Pd2(dba)3 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Cs2CO3
Na2CO3 MeOH
12
12
MeOH
_
Pd(OAc)2 (5)
Pd(OAc)2 (2)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
K3PO4
K3PO4
K3PO4
K3PO4
MeOH
25
12
14
14
14
0
PCy3 (4)
PCy3 (10)
PCy3 (20)
100
100
100
28
21
18
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
X-Phosb (4)
9
Pd(OAc)2 (2)
Pd(OAc)2 (2)
K3PO4
K3PO4
100
100
14
14
0
0
S-Phosc (4)
dppp (4)
PCy3 (4)
PCy3 (4)
PCy3 (4)
PCy3 (4)
PCy3 (4)
10
11
12
13
14
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
K3PO4
K3PO4
Na2CO3
Cs2CO3
K3PO4
K3PO4
100
100
14
3
0
Dioxane/H2O (20/1)
Dioxane/H2O (20/1)
Dioxane/H2O (20/1)
Dioxane/H2O (3/1)
Dioxane/H2O (20/1)
70
45
56
0
100
100
100
50
3
3
15
16
3
14
24
aIsolated yield. bX-Phos =
cS-Phos =
i-Pr
OMe
PCy2
i-Pr
PCy2
MeO

Table 3. The coupling reaction of 2a with arylboronic acids