A sequential highly stereoselective hydroboration and Suzuki-Miyaura cross-coupling reaction of fluoroalkylated internal acetylenes: A practical one-pot synthesis of fluoroalkylated trisubstituted alkenes

Article abstract of DOI:10.1039/b316065c

The one-pot synthesis of trisubstituted alkenes starting from fluoroalkylated internal alkynes was investigated. Hydroboration of the alkynes proceeded in a highly regio- and stereoselective manner to give the corresponding vinylboranes in excellent yields. Without isolation, treatment of the vinylboranes with various aryl halides under the Suzuki-Miyaura cross-coupling conditions gave the fluoroalkylated trisubstituted alkenes in high yields with complete retention of the olefinic geometry.

Full text of DOI:10.1039/b316065c

A sequential highly stereoselective hydroboration and Suzuki–Miyaura
cross-coupling reaction of fluoroalkylated internal acetylenes: a practical
one-pot synthesis of fluoroalkylated trisubstituted alkenes
Tsutomu Konno,* Jungha Chae, Tomoo Tanaka, Takashi Ishihara and Hiroki Yamanaka
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku,
Kyoto 606-8585, Japan. E-mail: konno@chem.kit.ac.jp; Fax: 81-75-724-7580; Tel: 81-75-724-7573
Received (in Cambridge, UK) 9th December 2003, Accepted 27th January 2004
First published as an Advance Article on the web 12th February 2004
The one-pot synthesis of trisubstituted alkenes starting from
fluoroalkylated internal alkynes was investigated. Hydro-
boration of the alkynes proceeded in a highly regio- and
stereoselective manner to give the corresponding vinylboranes
in excellent yields. Without isolation, treatment of the vinylbor-
anes with various aryl halides under the Suzuki–Miyaura cross-
coupling conditions gave the fluoroalkylated trisubstituted
alkenes in high yields with complete retention of the olefinic
geometry.
( < 10%). 19F NMR spectra of 2a showed a singlet peak, strongly
suggesting that a dicyclohexylboryl group is attached to a carbon
bearing a trifluoromethyl group.6 Without product isolation, the
reaction mixture was subjected to acid hydrolysis to afford the
disubstituted alkene 3a as a major product. The analysis of the 1H
NMR of 3a showed the coupling constant of Ha and Hb to be 12.6
Hz, indicating that 3a has the Z configuration.7 Accordingly, it was
revealed that the present hydroboration proceeded in a highly cis
addition manner.
Next, we attempted the Suzuki–Miyaura cross-coupling reac-
tion8 of vinylborane 2a with iodobenzene in the presence of
palladium catalyst. Thus, a benzene solution of the vinylborane 2a
was treated with 5 mol% of Pd(PPh3)4 and 3 equiv. of NaOEt, and
the whole was refluxed for 4 h. After quenching the reaction with
acetic acid, 19F NMR analysis indicated that the desired coupling
product 4a was formed in 23% yield, together with 76% of 3a
(Table 1, Entry 1). Prolonged reaction time led to the significant
decrease of the yield (Entry 2). Switching the palladium catalyst
from Pd(PPh3)4 to Pd(PPh3)2Cl2 brought about a slight increase of
the yield (Entry 3). It is interesting to note that the base used in this
reaction was crucial for the high yield. Thus, changing the base
from NaOEt to NaOH resulted in a dramatic increase of the yield as
described in Entry 4. In this case, 10% of 3a was recovered
unchanged. The use of 10 mol% of the palladium catalyst led to the
complete consumption of the vinylborane 2a, giving the desired
product in 89% yield (Entry 5). In Entries 4 and 5, high
regioselectivity (4a-cis + 4a-trans : 5a-cis = 94 : 6) and high
stereoselectivity (4a-cis : 4a-trans = 98 : 2) were observed.
With the optimized reaction conditions in hand, the scope of the
one-pot reaction was investigated with various alkynes in detail
(Table 2). As shown in Entries 1-4 and 6, various types of alkynes
carrying an electron-donating group (Me, MeO) or an electron-
withdrawing group (EtO2C) on the benzene ring could participate
well in the reaction to give the corresponding trisubstituted alkenes
in high yields. However, a significant decrease of the yield was
observed when an alkyne having a nitro group on the benzene ring
was used (Entry 5). The regioselectivity was also decreased
slightly. Additionally, a fluoroalkylated alkyne having an aliphatic
side chain (p-MeOC6H4CH2-) was not a good substrate, a low
regioselectivity (4 : 5 = 58 : 42) being obtained and 6 being
produced in 26% yield (Entry 7, Fig. 1). We also examined the
effect of the coupling reagents (R1I) on the reaction as shown in
Entries 8–14. The position of the substituent on the benzene ring
significantly influenced the coupling reaction. Thus, the dimer 7
Considerable attention has been paid to fluorine-containing materi-
als due to their unique properties arising from altered electron
density, acidity, and hydrogen-bonding patterns.1 Fluoroalkyl
groups increase lipophilicity allowing for easier drug transporta-
tion, cellular absorption, blood–brain barrier penetration, and
improved binding within hydrophobic pockets of receptors.1
Accordingly, the development of novel methods for the synthesis of
fluoroalkylated molecules has been becoming more and more
important in fluorine chemistry.
Among various types of fluoroalkylated molecules, alkenes
possessing a fluoroalkyl group are well known as one of the most
important synthetic targets because they are found in the framework
of biologically active compounds such as panomifene.2 Though
several synthetic methods for such molecules have been reported
thus far,3 the hydrometallation of fluoroalkylated alkynes is
potentially attractive because the hydrometallation reaction very
often proceeds in a stereoselective fashion and the resulting
vinylmetal intermediates can be transformed further to variously
substituted ethylenes under the influence of a transition metal
catalyst. Despite such great utility, little attention has been paid to
such reaction of fluorine-containing alkynes so far.4 Herein we
wish to describe a highly regio- and stereoselective hydroboration
reaction of fluorine-containing internal alkynes, followed by
Suzuki–Miyaura cross-coupling reaction, which realized the one-
pot synthesis of fluoroalkylated alkenes in high yields.
Initially, the reaction of trifluoromethylated internal alkyne 1a5
with dicyclohexylborane was examined (Scheme 1). On treating 1a
with 1.2 equiv. of dicyclohexylborane (prepared by stirring
cyclohexene (2.4 equiv.) with borane·THF complex (1.2 equiv.) in
benzene at room temperature for 2 h), the vinylborane 2a was
formed selectively, together with a small amount of other isomers
Table 1 Examination of the reaction conditions
Catalyst
Yielda of
Yielda of
Entry
(5 mol%)
Base
Time/h
4a + 5a (%) 3a (%)
1
2
3
4
5
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
NaOEt
NaOEt
NaOEt
NaOH
NaOH
4
20
4
4
4
23
7
76
35
63
10
0
37
80b
c
89 (64)b
a Determined by 19F NMR. Value in parentheses is of isolated yield. b 4a :
5a = 94 : 6; 4a-cis : 4a-trans = 98 : 2. c Ten mol% of Pd(PPh3)2Cl2 was
employed.
Scheme 1
690
C h e m . C o m m u n . , 2 0 0 4 , 6 9 0 – 6 9 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

Table 2 The synthesis of a variety of trisubstituted alkenes
Entry
Rf
Ar
R1
Yielda,b of 4+5 (%)
4 (cis : trans) : 5a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CF3 (a)
CF3 (a)
CF3 (a)
CF3 (a)
CF3 (a)
CF3 (a)
CF3 (a)
CF3 (a)
CF3 (a)
CF3 (a)
CF3 (a)
CF3 (a)
CF3 (a)
CF3 (a)
CHF2 (b)
HCF2CF2CF2 (c)
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
o-ClC6H4
m-ClC6H4
p-ClC6H4
p-MeC6H4
p-MeOC6H4
p-O2NC6H4
p-EtO2CC6H4
C6H5
85 (73)
89 (64)
83 (66)
99 (88)
25
95 (100 : 0) : 5
94 (98 : 2) : 6
94 (100 : 0) : 6
96 (100 : 0) : 4
88 (100 : 0) :12
95 (100 : 0) : 5
58 (100 : 0) :42
92 (100 : 0) : 8
93 (100 : 0) : 7
96 (100 : 0) : 4
94 (99 : 1) : 6
98 (93 : 7) : 2
100 (91 : 9) : 0
91 (100 : 0) : 9
84 (100 : 0) :16
83 (100 : 0) :17
p-ClC6H4
p-MeC6H4
p-MeOC6H4
p-O2NC6H4
p-EtO2CC6H4
p-MeOC6H4CH2
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
99
62c
53d
74
83 (74)
86 (55)
68 (56)
54
99
67
C6H5
78
a Determined by 19F NMR. b Values in parentheses are of isolated yields. c The product 6 was obtained in 26% yield, together with 8% of 1. d The dimer
7 was obtained in 20% yield.
2 (a) T. Konno, T. Daitoh, A. Noiri, J. Chae, T. Ishihara and H. Yamanaka,
accepted for Org. Lett.; (b) G. Németh, R. Kapiller-Dezsøofi, G. Lax and
G. Simig, Tetrahedron, 1996, 52, 12821; (c) Drugs Fut., 1990, 15, 532;
(d) Drugs Fut., 1988, 13, 480; (e) G. Ábrahám, T. Horváth, L. Toldy, J.
Borvendég, E. Csányi, É. Kiss, I. Hermann-Szene and K. Tory,
Hungarian Patent 17853, 1979 (Gyógyszerkuntató Intézet).
3 (a) M. P. Jennings, E. A. Cork and P. V. Ramachandran, J. Org. Chem.,
Fig. 1 Byproducts.
2000, 65, 8763; (b) G. Prié, J. Thibonnet, M. Abarbri, A. Duchêne and J.-
L. Parrain, Synlett, 1998, 839; (c) Y. Shen and Q. Liao, J. Fluorine
Chem., 1995, 73, 251.
4 The hydroboration reaction of g-trifluoromethylated propargylic alcohol
is reported to proceed in a highly stereoselective manner. See Y.
was formed in 20% yield when o-chloroiodobenzene was used as
R1I (Entry 8, Fig. 1), while a satisfactory result was obtained in the
case of m-chloroiodobenzene. The reaction using coupling reagents
having various types of substituents such as chloro, methyl,
methoxy, and ethoxycarbonyl groups proceeded smoothly to afford
the trisubstituted alkenes in a highly regio- and stereoselective
manner (Entries 10–12 and 14). However the use of p-ni-
troiodobenzene resulted in a decrease of the yield (Entry 13). It
should also be noted that changing the fluoroalkyl group from a
trifluoromethyl group to a difluoromethyl or hexafluoropropyl
group did not have a significant influence on the reaction (Entries
15 and 16).
Hanzawa, K. Kawagoe, N. Tanahashi and Y. Kobayashi, Tetrahedron
Lett., 1984, 25, 4749.
5 Fluoroalkylated alkynes were prepared according to our recently reported
methods. See T. Konno, J. Chae, M. Kanda, G. Nagai, K. Tamura, T.
Ishihara and H. Yamanaka, Tetrahedron, 2003, 59, 7571.
6 A similar effect due to an electron-withdrawing trifluoromethyl group
was observed. See J. Chae, T. Konno, M. Kanda, T. Ishihara and H.
Yamanaka, J. Fluorine Chem., 2003, 120, 185.
7 In our previous study, the coupling constants of 3a-cis and 3a-trans were
observed to be 12.5 and 16.5 Hz, respectively. See ref. 6.
In summary, we have developed a practical one-pot method for
the preparation of fluoroalkylated trisubstituted alkenes, starting
from a variety of fluoroalkylated alkynes.9 Various types of alkynes
were demonstrated to be suitable for the present reaction, affording
the desired compounds in excellent yields. In almost all cases, over
95% regio- and stereoselectivity were observed.
8 (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457; (b) A. Suzuki,
Acc. Chem. Res., 1994, 66, 213.
9 A typical procedure is as follows: To a solution of cyclohexene (0.12 mL,
1.18 mmol) in benzene (2 mL) was added a THF solution of borane–THF
complex (0.59 mL, 1 M THF solution, 0.59 mmol) at 0 °C. After stirring
of the reaction mixture for 20 min followed by the addition of 1a (100 mg,
0.49 mmol), the reaction mixture was allowed to warm to room
temperature, then stirred for 2 h. To this reaction mixture was added
iodobenzene (119 mg, 0.59 mmol), Pd(PPh3)2Cl2 (34 mg, 0.049 mmol),
and 10% NaOH aq. (1.71 mL, 1.46 mmol) in this order. After refluxing
of the mixture for 4 h, the reaction was cooled to room temperature, and
the whole was extracted with ethyl acetate three times. The combined
organic layers were dried over anhydrous Na2SO4, then evaporated in
vacuo. The residue was purified by silica gel column chromatography to
give the corresponding alkenes 4a-cis, 4a-trans, and 5a-cis as an
inseparable mixture.
Notes and references
1 (a) J. T. Welch, Tetrahedron, 1987, 43, 3123; (b) B. E. Banks, B. E.
Smart and J. C. Tatlow, Eds., Organofluorine chemistry, Principles and
Chemical Applications; Plenum Press: New York, 1994; (c) R. Filler and
Y. Kobayashi, Eds., Biochemical Aspects of Fluorine Chemistry; Elsevier
Biomedical Press and Kodansya Ltd; Amsterdam, 1982.
C h e m . C o m m u n . , 2 0 0 4 , 6 9 0 – 6 9 1
691