Synthesis of gem-difluoroalkenes via β-fluoride elimination of organorhodium(I)

Article abstract of DOI:10.1246/cl.2008.1006

Treatment of α-(trifluoromethyl)styrenes with arylboronic esters and MeMgCl in the presence of a rhodium(I) catalyst affords gem-difluoroalkenes. The reaction proceeds through the addition of arylrhodium(I) species across the electron-deficient carbon-carbon double bond and the subsequent β-fluoride elimination. Copyright

Full text of DOI:10.1246/cl.2008.1006

1006
Chemistry Letters Vol.37, No.9 (2008)
Synthesis of gem-Difluoroalkenes via ꢀ-Fluoride Elimination of Organorhodium(I)
Tomoya Miura, Yoshiteru Ito, and Masahiro Murakamiꢀ
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University,
Katsura, Kyoto 615-8510
(Received June 10, 2008; CL-080580; E-mail: murakami@sbchem.kyoto-u.ac.jp)
Treatment of ꢀ-(trifluoromethyl)styrenes with arylboronic
Table 1. Optimization of reaction conditionsa
esters and MeMgCl in the presence of a rhodium(I) catalyst
affords gem-difluoroalkenes. The reaction proceeds through the
addition of arylrhodium(I) species across the electron-deficient
carbon–carbon double bond and the subsequent ꢁ-fluoride
elimination.
PhB(OR)2
CF3
F
F
CF3
CF3
[RhX(cod)]2
Ph
5aa
Ph
Ph
Ph
Ph
Dioxane
100 °C, 12 h
Ph
Ph
1a
4aa
6aa
GC yield/%b
4aa 5aa 6aa
2a or 3a Additive
PhB(OR)2 (equiv) (3 equiv)
Entry
X
The rhodium-catalyzed addition reactions of organoboron
reagents to unsaturated functionalities have grown dramatically
in organic synthesis.1 The reaction generally proceeds via a
transmetalation step generating an organorhodium(I) species
from RhI–OR (OR = hydroxy or alkoxy) and organoboron
followed by a carborhodation step onto various unsaturated
functional groups. For regeneration of the RhI–OR species,
there are two major elementary steps available. One is protode-
metalation by a proton source, i.e., water or an alcohol that is
present as a co-solvent or an additive,2 and the other is ꢁ-oxygen
elimination from a ꢁ-oxy-substituted organorhodium(I) inter-
mediate.3 We have described a variety of catalytic reactions
which proceed through a sequential carborhodation/ꢁ-oxygen
elimination pathway.4 As a continuation of our studies on
rhodium-catalyzed addition reactions, we report herein a new
rhodium-catalyzed addition reaction of arylboronic esters to
ꢀ-(trifluoromethyl)styrenes,5 in which an organorhodium(I)
intermediate undergoes ꢁ-fluoride elimination6 to afford gem-
difluoroalkenes.7
1
2
3
4
5
6
7
8
OH PhB(OH)2 (3.0)
OH PhBneo (3.0)
OH PhBneo (3.0)
Cl PhBneo (3.0)
Cl PhBneo (3.0)
Cl PhBneo (3.0)
Cl PhBneo (3.0)
Cl PhBneo (1.5)
none
none
CsF
CsF
NaOEt
MeLi
39
60
55
51
37
60
2
5
1
4
3
5
2
1
22
8
4
4
0
0
0
0
MeMgCl 72
MeMgCl 73
aReaction conditions: la (0.2 mmol), 2a or 3a, additive (0.6
mmol), [RhX(cod)]2 (5.0 mmol, 5 mol % Rh) in dioxane (4 mL)
at 100 ꢁC for 12 h. GC analysis (J&W DB-1).
b
β
β
-Fluoride elimination
-Hydride elimination
4aa
5aa
6aa
RhI
Ph–RhI
CF3
Ph
1a
Ph
Protodemetalation
A
A mixture of ꢀ-(trifluoromethyl)styrene (1a) and phenyl-
boronic acid (2a, 3 equiv) in 1,4-dioxane was heated at 100 ꢁC
in the presence of [Rh(OH)(cod)]2 (5 mol % Rh, cod = cyclo-
octa-1,5-diene). An aqueous workup afforded a mixture of prod-
ucts 4aa (39%), 5aa (2%), and 6aa (22%) (Table 1, Entry 1).
Scheme 1 depicts the pathways conceivable for the formation
of the products. Initially, an alkylrhodium(I) intermediate A aris-
es from regioselective 1,2-addition of phenylrhodium(I) species
across the electron-deficient carbon–carbon double bond of 1a.
Whereas ꢁ-fluoride elimination takes place with A to afford
the product 4aa, ꢁ-hydride elimination of A gives the product
5aa.8 On the other hand, protodemetalation of A by H2O or 2a
forms 6aa.
Scheme 1. Plausible reaction pathways.
of methylboronic ester and phenylmagnesium chloride (eq 1).
The sequential arylation/ꢁ-fluoride elimination reaction pro-
ceeded under similar conditions to give 4aa in 67% yield. This
result indicated generation of magnesium methyl(phenyl)borate
from organoboronic esters and Grignard reagents.11
2.5 mol % [RhCl(cod)]2
3.0 equiv PhMgCl
O
1a
4aa
5aa
Me
B
ð1Þ
O
Dioxane, 100 °C, 12 h
67%
3%
(3.0 equiv)
When phenylboronic ester 3a (PhBneo = 5,5-dimethyl-2-
phenyl-1,3,2-dioxaborinane) was used in place of phenylboronic
acid (2a), the formation of 6aa was diminished and the yield
of 4aa increased to 60% (Table 1, Entry 2). Next, the effect of
several additives was examined (Entries 3–7). Among them,
the use of methylmagnesium chloride gave a better yield of
4aa.9 We assume that the Mg–F interaction activates the C–F
bond to promote the ꢁ-fluoride elimination step.10 The product
4aa was obtained in 73% yield even with 1.5 equiv of phenylbo-
ronate 3a (Entry 8).
Under the optimized reaction conditions using MeMgCl
as the activator, a wide range of arylboronic esters 3b–3i partici-
pated in the reaction with 1a to furnish gem-difluoroalkenes
4ab–4ai (Table 2).
The scope of the substrate 1 was also examined (Table 3).
The methoxy-substituted substrate 1b was more reactive than
the substrates having electron-withdrawing substituents 1c–1e
(Entries 1–4). No reaction took place with alkyl-substituted
substrate 1g (Entry 6).
When ꢀ-(difluoromethyl)styrenes 7a and 7b were subjected
to similar reaction conditions, ꢁ-fluoride elimination occurred
A control experiment was carried out using a combination
Copyright ꢀ 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.9 (2008)
1007
Table 2. Scope of arylboronate reagents 3a
Dedicated to Professor Ryoji Noyori on the occasion of his
70th birthday.
2.5 mol % [RhCl(cod)]2
3.0 equiv MeMgCl
F
F
CF3
O
O
Ar
B
References and Notes
Ar
Ph
Dioxane, 100 °C, 12 h
Ph
1
For reviews, see: a) K. Fagnou, M. Lautens, Chem. Rev.
2003, 103, 169. b) T. Hayashi, K. Yamasaki, Chem. Rev.
2003, 103, 2829. c) T. Miura, M. Murakami, Chem. Com-
mun. 2007, 217.
1a
3 (1.5 equiv)
4
Entry
Ar
Product
Yield/%b
1
2
3
4
5
6
7
8
3b
3c
3d
3e
3f
3g
3h
3i
4-Me–C6H4
4-F–C6H4
3-Cl–C6H4
3-MeO–C6H4
3-CN–C6H4
3-MeO2C–C6H4
2-Me–C6H4
2-Cl–C6H4
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
78
77
79
77
55c
74c
75
48
2
3
a) T. Hayashi, M. Takahashi, Y. Takaya, M. Ogasawara, J.
Am. Chem. Soc. 2002, 124, 5052. b) P. Zhao, C. D. Incarvito,
J. F. Hartwig, J. Am. Chem. Soc. 2007, 129, 1876.
a) M. Lautens, C. Dockendorff, K. Fagnou, A. Malicki, Org.
ˆ
Lett. 2002, 4, 1311. b) L. Navarre, S. Darses, J.-P. Genet,
Chem. Commun. 2004, 1108. c) L. Dong, Y.-J. Xu, L.-F.
Cun, X. Cui, A.-Q. Mi, Y.-Z. Jiang, L.-Z. Gong, Org.
Lett. 2005, 7, 4285. d) F. Menard, T. M. Chapman, C.
Dockendorff, M. Lautens, Org. Lett. 2006, 8, 4569.
aReaction conditions: 1a (0.5 mmol),
3
(0.75 mmol),
MeMgCl (1.5 mmol), [RhCl(cod)]2 (12.5 mmol, 5 mol %
4
5
6
a) T. Miura, M. Shimada, S.-Y. Ku, T. Tamai, M. Murakami,
Angew. Chem., Int. Ed. 2007, 46, 7101. b) M. Shimada,
T. Harumashi, T. Miura, M. Murakami, Chem. Asian J.
2008, 3, 1035, and references therein.
For addition of organolithium reagents to ꢀ-(trifluoro-
methyl)styrenes, see: a) R. Fontanelli, D. Sianesi, Ann. Chim.
(Roma) 1965, 55, 862. b) J.-P. Begue, D. Bonnet-Delpon,
M. H. Rock, J. Chem. Soc., Perkin Trans. 1 1996, 1409.
For ꢁ-fluoride elimination of transition-metal complexes,
see: [Rh]: a) A. A. Peterson, K. McNeill, Organometallics
2006, 25, 4938. [Pd]: b) W. Heitz, A. Knebelkamp,
Makromol. Chem. Rapid Commun. 1991, 12, 69. c) K.
Sakoda, J. Mihara, J. Ichikawa, Chem. Commun. 2005,
4684. d) J. Ichikawa, R. Nadano, N. Ito, Chem. Commun.
2006, 4425. e) M. Yokota, D. Fujita, J. Ichikawa, Org. Lett.
2007, 9, 4639.
Rh) in dioxane (10 mL) at 100 ꢁC for 12 h unless otherwise
noted. Isolated material of >95% purity. 3 (1.5 mmol).
b
c
Table 3. Scope of substrates 1a
2.5 mol % [RhCl(cod)]2
3.0 equiv MeMgCl
F
F
CF3
O
O
´
´
Ph
B
Ph
Ar
Dioxane, 100 °C, 12 h
Ar
1
3a (3.0 equiv)
4
Entry
Ar
4-MeO–C6H4
4-F–C6H4
4-Br–C6H4
4-CN–C6H4
2-Naphthyl
n-C10H21
Product
Yield/%b
1
2
3
4
5
6
1b
1c
1d
1e
1f
4ba
4ca
4da
4ea
4fa
80
60
61
54
88
0
1g
4ga
7
For other synthetic methods of gem-difluoroalkenes, see:
a) J. Ichikawa, J. Fluorine Chem. 2000, 105, 257. b) J.
Ichikawa, H. Fukui, Y. Ishibashi, J. Org. Chem. 2003, 68,
7800, and references therein.
aReaction conditions: 1a (0.2 mmol), 3a (0.6 mmol),
MeMgCl (0.6 mmol), [RhCl(cod)]2 (5.0 mmol, 5 mol % Rh)
in dioxane (4 mL) at 100 ꢁC for 12 h unless otherwise noted.
bIsolated material of >95% purity.
´
8
9
M. Lautens, A. Roy, K. Fukuoka, K. Fagnou, B. Martın-
Matute, J. Am. Chem. Soc. 2001, 123, 5358.
No reaction took place when the substrate 1a was heated
with phenylboronic ester and methylmagnesium chloride in
the absence of a rhodium catalyst. Other Grignard reagents
such as methylmagnesium bromide and iodide gave lower
yields.
selectively to produce fluoroalkenes 8aa and 8ba in good yield
as a single stereoisomer (E/Z = >95 : 5, eq 2).12
2.5 mol % [RhCl(cod)]2
3.0 equiv MeMgCl
F
CF2H
3a
Ph
R
ð2Þ
Dioxane, 100 °C, 12 h
R
(3.0 equiv)
10 a) J. Terao, H. Watabe, N. Kambe, J. Am. Chem. Soc. 2005,
127, 3656. b) N. Yoshikai, H. Mashima, E. Nakamura, J. Am.
Chem. Soc. 2005, 127, 17978.
7a (R = Ph)
7b (R = 2-Naphthyl)
8aa 80%
8ba 83%
11 For a reaction of lithium methyl(phenyl)borates generated
from phenylboronic esters and MeLi, see: Y. Kobayashi,
R. Mizojiri, E. Ikeda, J. Org. Chem. 1996, 61, 5391.
12 The geometrical configurations of fluoroalkenes were
assigned based upon a previous paper: R. Ocampo, W. R.
Dolbier, Jr., F. Zuluaga, Collect. Czech. Chem. Commun.
2002, 67, 1325.
13 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
In summary, we have demonstrated that the rhodium-
catalyzed addition of arylboronic esters to ꢀ-(trifluoromethyl)-
styrenes provides a new synthetic route to gem-difluoro-
alkenes.13 This catalytic process presents a rare example of ꢁ-
fluoride elimination of an organorhodium(I) complex.
This research was partly supported by Grant-in-Aids for
Young Scientists (B) No. 18750084 and Scientific Research on
Priority Areas No. 18032040 from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Published on the web (Advance View) September 5, 2008; doi:10.1246/cl.2008.1006