Mechanistic study of the palladium-catalyzed stereoselective cross-coupling reaction of 1,1-Dibromo-3,3,3-trifluoro-2-tosyloxypropene

Article abstract of DOI:10.1246/bcsj.20110240

We prepared a Pd complex by the oxidative addition of 1,1-dibromo-3,3,3- trifluoro-2-tosyloxypropene to [Pd- (PPh₃)₄]. The atomic distance between Pd and F in the complex was 2.95A, which was shorter than the sum of the van der Waals

Full text of DOI:10.1246/bcsj.20110240

Short Articles
Bull. Chem. Soc. Jpn. Vol. 84, No. 12, 1339-1341 (2011) 1339
F3C
TsO
Br
Br
F3C
TsO
Ar1
Ar1B(OH)2
Selected Papers
Pd cat.
Br
Mechanistic Study of the Palladium-
Catalyzed Stereoselective Cross-
Coupling Reaction of 1,1-Dibromo-
3,3,3-trifluoro-2-tosyloxypropene
Z selective
2
3
One-pot reaction
is also possible.
Ar2B(OH)2
Pd cat.
Ar3B(OH)2
Pd cat.
F3C
Ar3
Ar1
Ar2
F3C
TsO
Ar1
Ar2
Masaki Shimizu,* Youhei Takeda,
1
4
³
and Tamejiro Hiyama
Scheme 1. Palladium-catalyzed threefold cross-coupling
reaction of 2 with arylboronic acids.
Department of Material Chemistry, Graduate School of
Engineering, Kyoto University, Kyoto Daigaku-Katsura,
Nishikyo-ku, Kyoto 615-8510
PhB(OH)2 (1.1 equiv)
[Pd(PPh3)4] (5 mol%)
F3C
TsO
Ph
Br
F3C
TsO
Br
2
+
aq. Cs2CO3 (2.0 equiv)
toluene, 80 °C, 10 h
Ph
Received August 9, 2011
E-mail: m.shimizu@hs2.ecs.kyoto-u.ac.jp
(Z )-3a
89
(E )-3a
99% (GC yield)
:
11
We prepared a Pd complex by the oxidative addition
of 1,1-dibromo-3,3,3-trifluoro-2-tosyloxypropene to [Pd-
(PPh3)4]. The atomic distance between Pd and F in the
complex was 2.95 ¡, which was shorter than the sum of the
van der Waals radii, suggesting that Pd-F interaction played
an important role in determining the stereochemical outcome
of the Pd-catalyzed cross-coupling reaction of the propene.
Br
Ph3P
F
[Pd(PPh3)4] (1.0 equiv)
F
Pd
Br
PPh3
F
toluene, 80 °C, 12 h
68% yield
TsO
trans-(E )-5
Scheme 2. Pd-Catalyzed coupling reaction of
2
with
PhB(OH)2 and isolation of the oxidative adduct 5.
Incorporation of fluorine atom(s) into biologically active
substances and functional materials serves as a versatile
molecular modification strategy to attain superior and unique
biological activities and material properties.1 Hence, it is
crucial to develop synthetic reactions/methodologies for
organofluorine compounds, which proceed with high efficiency
and selectivity to give the target fluorinated molecules with the
desired stereochemistry. Moreover, the elucidation of factors
that govern the stereoselectivity of designed reactions is very
important to construct new principles for the stereocontrol
of synthetic reactions. We have recently established a highly
versatile synthetic route to CF3-substituted triarylethenes 1; the
route involves palladium-catalyzed threefold sequential cross-
coupling reaction of 1,1-dibromo-3,3,3-trifluoro-2-tosyloxy-
propene (2) with arylboronic acids (Scheme 1).2 Using this
approach, any stereoisomers of 1 can be arbitrarily synthesized
in a stereochemically pure form simply by changing the order
in which the arylboronic acids are used. The one-pot
preparation of 1 was also demonstrated. The success of the
sequential cross-coupling approach was attributed to the high
Z-selectivity of the first coupling. Since the presence of a CF3
group was essential for attaining Z selectivity,2 we surmised
that electronic interaction between fluorine and palladium
might be involved. To verify this hypothesis, we isolated the
oxidative adduct of 2 to [Pd(PPh3)4] and monitored the
oxidative addition process by 19F and 31P NMR. Reported
herein are the details of the mechanistic studies.
The stereoselectivity of 3 was almost constant (Z/E = ca.
9:1), regardless of the electronic or steric nature of the
substituents on the organoboronic acids.2 For example, 2 reacted
with PhB(OH)2 in the presence of [Pd(PPh3)4] (5 mol %) and aq.
Cs2CO3 (two molar equivalents) in toluene at 80 °C to give 3a
with a Z/E ratio of 89:11 (Scheme 2). Then, when a toluene
solution of 2 and a stoichiometric amount of [Pd(PPh3)4] were
heated at 80 °C, the oxidative adduct trans-(E)-5 (trans implies
the relative configuration of two PPh3 with regard to a Pd; (E)
expresses the configuration of the ethenyl moiety) was isolated
in 68% yield as colorless prisms by recrystallization from
EtOH/CH2Cl2. The complex trans-(E)-5 was fully character-
ized by 1H, 13C, 19F, and 31P NMR, IR, mass spectrometry, and
elemental analysis. Moreover, the structure of trans-(E)-5 was
unambiguously confirmed by single-crystal X-ray analysis
(Figure 1).3 The palladium atom adopted a square-planar
geometry; the bond angles are 91.47(2)° for Br(1)-Pd-P(1),
88.46(2)° for Br(1)-Pd-P(2), 91.43(16)° for P(1)-Pd-C(1), and
88.53(16)° for P(2)-Pd-C(1). The bond lengths of Br(1)-Pd
(2.4805(4) ¡), P(1)-Pd (2.3600(0) ¡), P(2)-Pd (2.3369(7) ¡),
and C(1)-Pd (1.978(7) ¡) are nearly the same as those reported
for the oxidative adduct of Br2C=CH(ferrocenyl) to Pd(0).4
Note that the atomic distance between F(1) and Pd is 2.959 ¡,
which is shorter than the sum (3.10 ¡) of the van der Waals
radii (1.47 ¡ for F and 1.63 ¡ for Pd),5 indicating that F-Pd
interaction might be operating to some extent in the complex-
³ Present address: Research and Development Initiative, Chuo
University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551
Published on the web November 29, 2011; doi:10.1246/bcsj.20110240

1340 Bull. Chem. Soc. Jpn. Vol. 84, No. 12 (2011)
© 2011 The Chemical Society of Japan
F3C
TsO
Br
PPh3
Br
2
Ph3P
F
PPh3
PPh3
PPh3
F
F
Pd
Br
[Pd(PPh3)4]
+
:
Pd
Br
PPh3
25 °C
oxidative
addition
TsO
major-6
minor-6
89
11
(–2 PPh3)
cis-trans
50 °C
isomerization
Br
F3C
TsO
Br
Ph3P
F
+
F
Pd
Br
PPh3
Pd
Figure 1. Molecular structure of trans-(E)-5.
F
3
Ph3P
TsO
Br
[Pd(PPh3)4]
(10 mol%)
major-6 89
major-7 90
major-7
minor-7
2 PPh3
90
:
10
2
:
:
+
+
[trans-(E)-5]
C6D6, 25 °C
50 °C
minor-6
minor-7
11
10
"transmetalation"
80 °C
Scheme 3. NMR monitoring of
a
mixture of 2 and
[Pd(PPh3)4].
Ar
F3C
TsO
Br
Ph3P
F
+
F
F
Pd
Br
Table 1. NMR Data of Oxidative Adducts 6 and 7
Chemical shift/ppm
PPh3
Pd
Ph3P
TsO
Ar
Major-6
Minor-6
major-8
minor-8
19F
31P
¹59.4 (d, J = 5.5 Hz)
20.2 (d, J = 29.6 Hz)
28.1 (dq, J = 29.6, 5.5 Hz)
¹59.2 (s)
19.6 (d, J = 26.0 Hz)
29.6 (d, J = 26.0 Hz)
Scheme 4. Proposed catalytic cycle.
definitely assigned as trans-(E)-5. Each 31P NMR spectrum of
major- and minor-7 showed only one signal, respectively. This
observation indicates that the two PPh3 groups in 7 are
magnetically equivalent; in other words, the configuration of
the two PPh3 groups with regard to the Pd center is trans, which
is consistent with the structure of trans-(E)-5 disclosed by the
X-ray analysis. Spin-spin coupling between fluorine and
phosphine was observed with major-7 (trans-(E)-5) but not
with minor-7, suggesting that the distances between the CF3
group and two PPh3 groups of minor-7 were long enough not to
interact with each other. Hence, the stereochemistry of minor-7
could be assigned as trans-(Z) (the structure is shown in
Scheme 4). The initially observed 6 can be assigned similarly.
Thus, the appearance of two signals of 31P NMR in major- and
minor-6, and their respective coupling constants of 29.6 and
26.0 Hz, indicate that the two PPh3 groups in each 6 are
magnetically nonequivalent and coordinated to Pd in a cis
fashion. The presence of P-F coupling in major-6 and its
absence in minor-6 are evidence that the configurations of the
ethenyl moieties are E and Z, respectively.
Based on the experimental results, we proposed a catalytic
cycle of the cross-coupling reaction of 2, shown in Scheme 4.
The oxidative addition of 2 to [Pd(PPh3)4] proceeds smoothly at
room temperature, giving rise to oxidative adduct 6 with high
E-selectivity. The subsequent cis-trans isomerization at a Pd
center should give 7. Considering the observed short contact of
F and Pd atoms of major-7 (trans-(E)-5), the thermodynamic
preference of major-7 to minor-7 is rationalized by the F-Pd
coordination, which allows Pd to fulfill the 18-electron rule.
As the E/Z ratios of 6 and 7 are almost constant, the cis
configuration of the CF3 and Pd moieties of major-6 may also
Major-7
Minor-7
19F
31P
¹61.5 (t, J = 5.6 Hz)
22.6 (q, J = 5.6 Hz)
¹59.9 (s)
23.3 (s)
ation.6a Such a short F-Pd contact has previously been observed
with [{Pd(®2-SC6F5)(®2-(Ph2P)2CH2)Pd}(®2-SC6F5)]4(Et2O)2
(2.945 ¡)6b and [Pd{2,4,6-(CF3)3C6H2}2] (2.897 ¡).6c
The isolated complex trans-(E)-5 was confirmed to catalyze
the cross-coupling of 2 with PhB(OH)2, giving rise to 3a
in 50% yield with the same stereochemical outcome as that
obtained with the aid of [Pd(PPh3)4]. This result clearly
indicates that trans-(E)-5 is involved in the catalytic cycle of
the coupling reaction.
To gain further insight into the oxidative addition step,
the reaction was monitored by 19F and 31P NMR (Scheme 3).
The chemical shifts and coupling constants observed in the
monitoring are summarized in Table 1. When 2 and [Pd(PPh3)4]
(10 mol %) were mixed in C6D6 at 25 °C, the resonance at
16.9 ppm in the 31P NMR spectrum, which corresponded to
[Pd(PPh3)4], completely disappeared within 15 min. In turn, one
major pair of resonances appeared at 20.2 and 28.1 ppm, and
one minor pair at 19.6 and 29.6 ppm in the 31P NMR spectrum,
together with a resonance of free PPh3 (¹4.2 ppm). The
19F NMR spectrum also showed two new resonances at ¹59.4
and ¹59.2 ppm with a ratio of 89:11, which was the same as that
estimated from the 31P NMR spectrum. These results indicated
that two species (major-6 and minor-6) formed in a ratio of
89:11 by mixing of 2 and [Pd(PPh3)4]. Heating the mixture at
50 °C for 3 h resulted in complete disappearance of 6 and the
generation of two species (major-7 and minor-7) in a ratio of
90:10.7 On the basis of the 19F and 31P NMR data, major-7 was

M. Shimizu et al.
ArSnBu3 (1.05 equiv)
Bull. Chem. Soc. Jpn. Vol. 84, No. 12 (2011) 1341
495 cm¹1. MS (FAB): m/z (%) 976 (15, [M+ ¹ Br + H] + 2),
975 (20, [M+ ¹ Br] + 2), 974 (15, [M+ ¹ Br + H]), 973 (20,
[M+ ¹ Br]), 449 (100). Anal. Calcd for C46H37Br2F3O3P2PdS:
C, 52.37; H, 3.53%. Found: C, 52.21; H, 3.64%.
F3C
TsO
Ar
Br
F3C
TsO
Br
Ar
2
+
:
[Pd2(dba)3] (2.5 mol%)
P(2-furyl)3 (20 mol%)
toluene, 90 °C, 24 h
(Z)-3
(E)-3
General Procedure for Coupling Reaction of 2 with
Organotin Reagents. A Schlenk tube (20 mL) equipped with
a magnetic stirring bar was charged with [Pd2(dba)3] (11 mg,
13 ¯mol), P(2-furyl)3 (24 mg, 0.1 mmol), and 2 (0.21 g, 0.50
mmol). The tube was then capped with a rubber septum,
evacuated for 5 min, and purged with argon. The evacuation
and purge operations were repeated twice. Toluene (5 mL) was
added to the mixture at room temperature. The solution was
stirred at room temperature for 5 min and degassed by three
freeze-thaw operations before the addition of arylstannane
(0.53 mmol). The resulting mixture was heated at 90 °C for
24 h. After the mixture was allowed to cool to room temper-
ature, 1 M aq. KF (5 mL) was added. The resulting mixture
was stirred for 1 h at room temperature. The organic layer was
extracted with AcOEt (15 mL © 3). The combined organic
layer was washed with 1 M aq. KF (15 mL) and saturated aq.
NaCl (15 mL), dried over anhydrous MgSO4, and then
concentrated in vacuo. The residue was purified by column
chromatography on silica gel containing 5 wt % of finely
ground KF, followed by recrystallization.8
Ar
3
Yield/%
(Z)-3
(E)-3
4-Me2NC6H4
4-OHCC6H4
2-furyl
3b
3c
3d
3e
76
93
84
87
90
88
87
93
:
:
:
:
10
12
13
7
2-thienyl
Scheme 5. (Z)-Selective Pd-catalyzed coupling reaction of 2
with organotin reagents.
be attributed to F-Pd coordination. Transmetalation of 7 with
arylboronic acids would give alkenyl(aryl)palladium complexes
8, which then undergo cis-trans isomerization and subsequent
reductive elimination, producing monocoupled products 3 with
a Z/E ratio of approximately 9:1. Considering that heating at
80 °C, which was higher than the temperatures of the oxidative
addition (25 °C) and cis-trans isomerization (50 °C), was essen-
tial to perform the coupling reaction smoothly, the rate-deter-
mining step should be transmetalation or reductive elimination.
Supposing that this mechanism, in which the stereoselectiv-
ity is determined before transmetalation, is valid, it is expected
that the coupling reaction of 2 with organometallic reagents
other than boron would also proceed with similar stereo-
selectivity. This is the case with organotin reagents. The results
are shown in Scheme 5. A catalyst system consisting of
[Pd2(dba)3]/P(2-furyl)3 was effective in performing coupling
reaction of 2 with arylstannanes, giving rise to 3 in high yields
with high selectivity (ca. 9:1). These results clearly prove the
validity of the proposed mechanism.
The authors thank Professor Atsushi Wakamiya of Kyoto
University for his assistance with the X-ray diffraction analysis.
This work was supported by a Grant-in-Aid for Creative
Research, No. 16GS0209, from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Supporting Information
Crystallographic data of trans-(E)-5 and characterization
data for coupling products 3b-3e. This material is available
free of charge on the web at http://www.csj.jp/journals/bcsj/.
In summary, we have demonstrated that high Z-selectivity of
the Pd-catalyzed coupling reaction of 2 originates from F-Pd
interaction in the oxidative adducts. The present study sheds
light on F-Pd interaction as a tool for stereocontrol in synthetic
reactions.
References
1
2000.
2
T. Hiyama, Organofluorine Chemistry, Springer, Berlin,
Experimental
Y. Takeda, M. Shimizu, T. Hiyama, Angew. Chem., Int. Ed.
2007, 46, 8659.
Preparation of trans-(E)-5. A vial tube (5 mL) equipped
with a magnetic stirring bar was charged with 2 (85 mg,
0.20 mmol) and [Pd(PPh3)4] (0.23 g, 0.20 mmol) under an argon
atmosphere. Toluene (2 mL) was added to the mixture at room
temperature. The resulting solution was heated on a hot plate at
80 °C for 12 h. The reaction mixture was allowed to cool down
to room temperature, diluted with hexane (3 mL), filtered, and
concentrated. Recrystallization of the crude product from
CH2Cl2/EtOH gave trans-(E)-5 as colorless prisms (0.14 g,
68%). Mp: 225.1-225.9 °C (dec.) 1H NMR (400 MHz, CDCl3):
¤ 2.40 (s, 3H), 7.19 (d, J = 8.4 Hz, 2H), 7.35-7.42 (m, 18H),
7.53 (d, J = 8.4 Hz, 2H), 7.64-7.69 (m, 12H); 13C NMR (100
MHz, CDCl3): ¤ 21.7, 119.6 (q, J = 272.2 Hz), 127.6, 128.0
(t, J = 5.3 Hz), 128.8, 130.2, 130.3 (t, J = 24.4 Hz), 131.2 (q,
J = 29.7 Hz), 134.3, 134.8 (t, J = 6.1 Hz), 144.2, 146.5 (q,
J = 6.8 Hz); 19F NMR (282 MHz, CDCl3): ¤ ¹61.5 (t, J =
5.6 Hz); 31P NMR (121 MHz, CDCl3): ¤ 22.6 (q, J = 5.6 Hz).
IR (KBr): ¯ 3055, 1596, 1573, 1481, 1434, 1363, 1280, 1195,
1170, 1128, 1095, 1041, 889, 744, 692, 655, 563, 520,
3
Crystallographic data for compound trans-(E)-5 have been
deposited with Cambridge Crystallographic Data Centre: Deposi-
tion number CCDC-837537. Copies of the data can be obtained
free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge, CB2 1EZ, U.K.; Fax: +44 1223 336033;
e-mail: deposit@ccdc.cam.ac.uk).
4
S. Clément, L. Guyard, M. Knorr, F. Villafañe, C.
Strohmann, M. M. Kubicki, Eur. J. Inorg. Chem. 2007, 5052.
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6
http://www.ccdc.cam.ac.uk/products/csd/radii/table.php4.
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L. R. Falvello, M. A. Usón, I. Usón, S. Herrero, Inorg. Chem.
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7
This conversion was very sluggish at room temperature, as
evidenced by the fact that almost no change was observed in the
19F and 31P NMR spectra after 4 h.
8
D. C. Harrowven, I. L. Guy, Chem. Commun. 2004, 1968.