Oxidative cross-coupling of ββ-difluoroenol silyl ethers with nucleophiles: A dipole-inversion method to difluoroketones

Article abstract of DOI:10.1021/ol049055m

Oxidative cross-coupling of α-aryl-β,β-difluoroenol silyl ethers with heteroaromatics in the presence of Cu(OTf)₂ in wet acetonitrile proceeds smoothly, affording heteroaryldifluoromethyl aryl ketones in 61-88% yields. Alcohols also react as nu

Full text of DOI:10.1021/ol049055m

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2733-2736
Oxidative Cross-Coupling of
â,â-Difluoroenol Silyl Ethers with
Nucleophiles: A Dipole-Inversion
Method to Difluoroketones
Kenji Uneyama,* Hiroaki Tanaka, Satoru Kobayashi, Manabu Shioyama, and
Hideki Amii
Department of Applied Chemistry, Faculty of Engineering, Okayama UniVersity,
3-1-1 Tsushimanaka, Okayama 700-8530, Japan
uneyamak@cc.okayama-u.ac.jp
Received May 21, 2004
ABSTRACT
Oxidative cross-coupling of r-aryl-â,â-difluoroenol silyl ethers with heteroaromatics in the presence of Cu(OTf)2 in wet acetonitrile proceeds
smoothly, affording heteroaryldifluoromethyl aryl ketones in 61−88% yields. Alcohols also react as nucleophiles under the same conditions
to provide alkoxydifluoromethyl aryl ketones in 73−80% yields.
Dipole inversion (umpolung) has been recognized as being
highly useful in synthetic organic chemistry and has been
employed as a basic concept for organic synthesis since
Seebach’s proposal.1,2 The synthetic utility of a substrate
could be greatly extended if a building block which, for
instance, is reactive as a nucleophile, is easily converted in
situ to an electrophile by a chemically induced dipole
inversion. Electrochemical oxidative generation of radicals
from carbanions and their subsequent reaction with vinyl
ethers3 (conversion of a nucleophile to an electrophile) and
lithium-halogen exchange of acyl halides with butyllithium
(conversion of an electrophile to a nucleophile)4 are some
of the typical examples.
elimination leading to R-substituted monofluoroalkenes (1
to 2)5 and by SN2′-type addition or Claisen rearrangement
to deliver formal products of SN2′-type addition (3 to 4)6 in
aprotic solvents due to the activation of the difluoromethylene
carbon atom by the strong electron-withdrawing nature of
fluorine atom7,8 (Scheme 1).
Scheme 1
gem-Difluoroalkenes mostly react electrophilically with
nucleophiles at the difluoromethylene carbon by addition-
(1) Seebach, D. Angew. Chem., Int. Ed. 1976, 18, 239.
(2) (a) Hase, T. A. Umpolung Synthons; Wiley: Nerw York, 1987. (b)
Schmittel, M. Top. Curr. Chem. 1994, 169, 183. (c) Enders, D.; Shilvock,
J. P. Chem. Soc. ReV. 2000, 29, 359.
(3) (a) Schafer, H.; Alazrak, A. Angew. Chem., Int. Ed. Engl. 1968, 7,
474. (b) Torii, S.; Uneyama, K.; Onishi, T.; Fujita, Y.; Ishiguro, M.; Nishida,
T. Chem. Lett. 1980, 1603.
In contrast, the introduction of an alkoxy or siloxy group
at the 2-carbon of 1,1-difluoro-1-alkenes alters the reactivity
(4) Braun, M. Angew. Chem., Int. Ed. 1998, 37, 430.
10.1021/ol049055m CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/07/2004

of the difluoroalkenes from electrophilic to the nucleophilic.
Thus, difluoroenol ethers and silyl ethers react with elec-
trophiles leading to R-substituted R,R-difluoroketones due
to the electron-donating nature of the ethereal oxygen atom
of 5 (5 to 6) in Scheme 2. Lewis acid-catalyzed carbon-
silyl ethers 9,11 but has never been reported. In this context,
the dipole-inversion approach would be promising to realize
the addition of a nucleophile to 5. The above hypothesis
suggests the oxidized form 7 should in principle react with
nucleophiles via simultaneous Si-O bond cleavage to
provide R-substituted R,R-difluoroketones 9; otherwise, the
transformation of 5 to 9 is difficult (Scheme 3).
The current demand in medicinal science for a variety of
difluoromethylene compounds,12 which have been less ex-
plored as compared with trifluoromethylated and mono-
fluorinated compounds, have prompted us to develop a new
synthetic method for difluoromethylene compounds. This is
the first example of the oxidative cross-coupling of difluo-
roenol silyl ethers with nucleophiles such as heteroaromatics
and alcohols.13
An extensive survey of oxidants [Cu(OTf)2, CuO, CuCl2,
Ag2O, CAN (cerium ammonium nitrate)], solvents [THF,
DMF, CH2Cl2, HFIP (hexafluoro-2-propanol), n-BuCN,
i-PrCN, n-PrCN, EtCN, MeCN] and reaction temperatures
revealed that a combination of copper(II) triflate and wet
acetonitrile at 0 °C was a choice for the optimized reaction
conditions and that the use of less polar solvents induced
the formation of triflate 17c. Although difluoroenol silyl
ethers are less oxidizable than nonfluorinated ones,14 the
Cu(II) reagent cleanly oxidized 10 at -30 °C to room
temperature within 15 min in acetonitrile to provide the dimer
2,2,3,3-tetrafluoro-1,4-diketones 11 in good to excellent
yields [11, Ar; C6H5 (71%), 4-ClC6H4 (72%), 4-MeC6H4
(70%), 4-MeOC6H4 (86%), 2-furyl (58%)] as shown in
Scheme 4.
Scheme 2
carbon bond formations of 5 with carbonyl compounds9 and
reactions with various electrophiles10 have been well dem-
onstrated and frequently employed as reliable methods for
introducing difluoroacyl moiety into organic molecules.
An important question is whether difluoroenol silyl ethers
5, typical nucleophiles react with other nucleophiles, afford-
ing R-substituted R,R-difluoroketones 9 or not? The trans-
formation of 5 to 9 as shown in Scheme 3, if possible, is
Scheme 3
Scheme 4
categorized as an addition reaction and would expand a scope
of the synthetic utility of the readily available difluoroenol
(5) For intermolecular reactions, see: (a) Tellier, F.; Sauvetre, R. J.
Fluorine Chem. 1996, 76, 181. (b) Shi, G.-Q.; Cao, Z.-Y. J. Chem. Soc.,
Chem. Commun. 1995, 1969. (c) De Tollenaere, C.; Ghosez, L. Tetrahedron
1997, 53, 17127. (d) Huang, X.-H.; He, P.-Y.; Shi, G.-Q. J. Org. Chem.
2000, 65, 627. For intramolecular reactions, see: (e) Ichikawa, J.; Wada,
Y.; Okauchi, T.; Minami, T. Chem. Commun. 1997, 1537. (f) Wada, Y.;
Ichikawa, J.; Katsume, T.; Nohiro, T.; Okauchi, T.; Minami, T. Bull. Chem.
Soc. Jpn. 2001, 74, 971. (g) Ichikawa, J.; Sakoda, K.; Wada, Y. Chem.
Lett. 2002, 282. (h) Sato, A.; Okada, M.; Nakamura, Y.; Kitagawa, O.;
Hirokawa, H.; Taguchi, T. J. Fluorine Chem. 2003, 123, 75.
(6) (a) Patel, S. T.; Percy, J. M.; Wilkes, R. D. J. Org. Chem. 1996, 61,
166. (b) Percy, J. M.; Prime, M. E.; Broadhurst, M. J. J. Org. Chem. 1998,
63, 8049. (c) Broadhurst, M. J.; Brown, S. J.; Percy, J. M.; Prime, M. E. J.
Chem. Soc., Perkin Trans. 1 2000, 3217. (d) Park, H. M.; Uegaki, T.; Konno,
T. Ishihara, T.; Yamanaka, H. Tetrahedron Lett. 1999, 40, 2985. (e)
Yamazaki, T.; Ueki, H.; Kitazume, T. Chem. Commun. 2002, 2670.
(7) As exceptional examples, 1,1-difluoroethene with sec-butyllithium
and 1,1-difluorovinyl phenyl ether with n-butyllithium undergo deproto-
nation-lithiation rather than addition of alkyllithiums. (a) Tellier, F.;
Sauvetre, R. J. Fluorine Chem. 1993, 62, 183. (b) Tellier, F.; Sauvetre, R.
J. Fluorine Chem. 1995, 70, 265. (c) Purrington, S. T.; Thomas, H. N. J.
Fluorine Chem. 1998, 90, 47.
Under the optimized conditions for homocoupling, cross-
coupling of 10d with furan 12 (X ) O) was studied (Scheme
(9) (a) Yamanaka, M.; Ishihara, T.; Ando, T. Tetrahedron Lett. 1983,
24, 507. (b) Xu, Y.-Y. J. Chem. Soc., Perkin Trans. 1 1993, 795. (c) Iseki,
K.; Kuroki, Y.; Asada, D.; Kobayashi, Y. Tetrahedron Lett. 1997, 38, 1447.
(10) For reaction with carbocations, see: (a) Whitten, J. P.; Barney, C.
L.; Huber, E. W.; Bey, P.; McCarthy, J. R. Tetrahedron Lett. 1989, 30,
3649. (b) Tellier, F.; Baudry, M.; Sauvetre, R. Tetrahedron Lett. 1997, 38,
5989. (c) Chorki, F.; Crousse, B.; Bonnet-Delpon, D.; Be´gue´, J.-P.; Brigaud,
T.; Portella, C. Tetrahedron Lett. 2001, 42, 1487. (d) Kodama, Y.; Okumura,
M.; Yanabu, N.; Taguchi, T. Tetrahedron Lett. 1996, 37, 1061. (e) Lefebvre,
O.; Brigaud, T.; Portella, C. Tetrahedron 1999, 55, 7233. (f) For the
reactions with other electrophiles, see: Prakash, G. K. S.; Hu, J. B.; Olah,
G. A. J. Fluorine Chem. 2001, 112, 357.
(11) (a) Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem.
Commun. 1999, 1323. (b) Mae, M.; Amii, H.; Uneyama, K. Tetrahedron
Lett. 2000, 41, 7893. (c) Amii, H.; Kobayashi, T.; Uneyama, K. Synthesis
2000, 2001. (d) Amii, H.; Kobayashi, T.; Terasawa, H.; Uneyama, K. Org.
Lett. 2001, 3, 3103. (e) Amii, H.; Hatamoto, Y.; Seo, M.; Uneyama, K. J.
Org. Chem. 2001, 66, 7216. (f) Kobayashi, T.; Nakagawa, T.; Amii, H.;
Uneyama, K. Org. Lett. 2003, 5, 4297.
(8) Hydroalkoxylation and hydrothioalkoxylation of some 1,1-difluoro-
alkenes in protic solvents are known. (a) De Tollenaere, C.; Ghosez, L.
Tetrahedron 1997, 53, 17127. (b) Mae, M.; Amii, H.; Uneyama, K.
Tetrahedron Lett. 2000, 41, 7893.
2734
Org. Lett., Vol. 6, No. 16, 2004

in hexafluoro-2-propanol.15 These heteroaryl-substituted di-
fluoroketones and acetates are useful synthetic building
blocks but have been less available so far.16 The present
cross-coupling approach provides us a straightforward access
to these important difluorinated compounds.
Scheme 5
In entry 6, methyl 2-furancarboxylate was less reactive,
but gave 13f in 61% yield. In contrast to the higher reactivity
at the 2-position of furan, benzo[b]furan reacted at the
3-position, affording 16 in 50% yield. The reactions of 10
with other heteroaromatics such as N-tosylpyrrole and
thiophene were successful, suggesting the generality of the
oxidative cross-coupling of 10. Thus, both N-tosylpyrrole
and thiophene reacted at the 2-position to provide the desired
14 and 15 in 67% and 84% yields, respectively.
The key factor which decisively governs the feasibility
for the cross-coupling is the relative oxidizability between
10 and heteroaromatics 12. The successful cross-coupling
strictly requires the heteroaromatics12 must be less oxidizable
than 10. The more oxidizable heteroaromatics are oxidized
exclusively and the ether 10 remains intact. In fact, no cross-
coupled products were formed on reacting 10 with 2-meth-
oxyfuran and pyrrole. A simple calculation of HOMO levels
of 10 and heteroaromatics 12 by PM3 level geometry
optimization is useful for estimation of the feasibility for
the cross-coupling.17
As one of the applications for the cross-coupling reaction,
Cu(II)-promoted alkoxylation of 10 in the presence of
alcohols provided R-alkoxylated R,R-difluoroketones 17 in
good yields, demonstrating the further promisimg extension
of the present reaction.
5). However, the desired cross-coupled product 13d was
produced in unsatisfactory yields, while homocoupled prod-
uct 11d was mainly formed and triflate 17c was always
produced as a byproduct. The cation radical 7 reacted with
furan, the silyl ether 10d, and even triflate anion competi-
tively. Therefore, decreasing the rate of addition of 10d to
suppress the sharp increase of the concentration of 10d and
also increasing the concentration of heteroaromatics in the
reaction mixture resulted in the predominant formation of
13d in satisfactory yields. Interestingly, water is a good
additive for the selective formation of cross-coupling product
13d.
Both electron-withdrawing and electron-donating groups
attached to the phenyl ring of 10 affected the yield slightly
as shown in Table 1. Particularly noteworthy is the fact that
As for the mechanism for the present oxidative cross-
coupling, it is most plausible that the radical cations 7 initially
formed by the oxidation of 10 with Cu(OTf)2 would attack
heteroaromatics 12 to generate radicals 8 with the simulta-
neous release of trimethylsilyl group.18 Then, the radicals 8
of which radical center is located on the heteroaromatic ring-
Table 1. Oxidative Cross-coupling of 10 with Heteroaromatics
12a
12
10
(13) Schmittel first reported oxidative alkoxylation of phenylacetone and
its enolsilyl ethers: (a) Schmittel, M.; Levis, M. Chem. Lett. 1994, 1935.
(b) Schmittel, M.; Levis, M. Chem. Lett. 1994, 1939.
entry
R
X
Ar
product
yield,b %
1
2
3
4
5
6
7
8
H
H
H
H
H
O
O
O
O
O
O
C6H5
13a
13b
13c
13d
13e
13f
14
88
72
75
82
63
61
67
84
(14) Oxidative homocoupling of nonfluorinated enolsilyl ethers is well-
known. (a) Ito, Y.; Konoike, T.; Saegusa, T. J. Am. Chem. Soc. 1975, 97,
649. (b) Kobayashi, Y.; Taguchi, T.; Tokuno, E. Tetrahedron Lett. 1977,
18, 3741. (c) Moriarty, R. M.; Penmasta, R.; Prakash, I. Tetrahedron Lett.
1987, 28, 873. (d) Moriarty, R. M.; Prakash, O.; Duncan, M. P. J. Chem.
Soc., Chem. Commun. 1985, 420. (e) Inaba, S.; Ojima, I. Tetrahedron Lett.
1977, 18, 2009. (f) Baciocchi, E.; Casu, A.; Ruzziconi, R. Tetrahedron
Lett. 1989, 30, 3707. (h) Schmittel, M.; Burghart, A. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2550 and references therein. (i) Ryter, K.; Livinghouse,
T. J. Am. Chem. Soc. 1998, 120, 2658.
(15) Baeyer-Villiger oxidation of 13d, 14, and 15 with m-CPBA in
dichloromethane-HFIP (1:1 v/v) at rt for 10 min provided the corresponding
p-methoxyphenyl esters in 90%, 80%, and 87% yields, respectively. See
the following reference for the detailed Baeyer-Villiger oxidation condi-
tions: Kobayashi, S.; Tanaka, H.; Amii, H.; Uneyama, K. Tetrahedron 2003,
59, 1574.
(16) There have been no report on the syntheses of difluoro(heteroaryl)-
methyl aryl ketones 13 and 14. Difluoro(2-thienyl)methyl aryl ketone 15
(Ar ) 4-F-C6H4) was prepared in an overall yield of 52% in two steps. For
the arylation of ethyl difluoro(2-thienyl) acetate with 4-fluorophenyllithium,
which was derived from the Cu-catalyzed cross-coupling of 2-bro-
mothiophene with ethyl 2-bromo-2,2-difluoroacetate in DMSO, see: Eto,
H.; Kaneko, Y.; Sakamoto, T. Chem. Pharm. Bull. 2000, 48, 982.
(17) HOMO levels of 10, furan, N-tosylpyrrole, thiophene, 2-methoxy-
furan, and pyrrole estimated by MacSpartan Pro package program with PM3
level geometry optimization are -9.0, -9.4, -9.1, -9.5, -8.8, -8.9 eV,
respectively.
4-Cl-C6H4
4-Me-C6H4
4-MeO-C6H4
2-furyl
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
CO2Me
H
H
N-Ts
S
15
a Each reaction was carried out in MeCN-H2O (50:1 v/v) at 0 °C for 3
h. b Isolated yield.
p-methoxyphenyl compound 10d provided 13d in an excel-
lent yield, which is readily transformed to the corresponding
2-(2-furyl)-2,2-difluoroacetate by Baeyer-Villiger oxidation
(12) The difluoromethylene moiety has been recognized as a mimic of
ethereal oxygen in phosphates and sugars, and these difluorinated com-
pounds often behave as enzyme inhibitors: (a) Berkowitz, D. B.; Bose,
M.; Pfannenstiel, T. J.; Doukov, T. J. Org. Chem. 2000, 65, 4498. (b) Burke,
T. R.; Yao, Z. J.; Liu, D. G.; Voigt, J.; Gao, Y. Biopolymers 2001, 60, 32.
(c) Akahoshi, F.; Ashimori, A.; Sakashita, H. J. Med. Chem. 2001, 44, 1297.
(d) Skiles, J. W. Miao, C.; Sorcek, R. J. Med. Chem. 1992, 35, 4795.
Org. Lett., Vol. 6, No. 16, 2004
2735

(Nu of 8 in Scheme 3) would be further oxidized with Cu-
oxidant followed by deprotonation leading to the formation
of 13-15 as final products.
13555254, Grant-in-Aid for Young Scientists (B), No.
14750684, and Grant-in-Aid for Scientific Research on
Priority Areas (“Reaction Control of Dynamic Complexes”),
No. 16033621). We also thank the SC-NMR laboratory of
Okayama University for 19F NMR analysis.
Acknowledgment. This work has been supported by the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan (Grant-in-Aid for Scientific Research (B), No.
Supporting Information Available: Experimental pro-
cedures and details of compound characterization for com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) The ethers 17 would be formed by the cross-coupling of radical
cation 7 with alcohols. Therefore, the fact that three products 11, 13, and
17c were produced at the same time under the reaction conditions in
MeCN-H2O-Cu(OTf)2 system suggests the reactive intermediate would
be the radical cation 7 rather than difluoro(benzoyl)methyl radical.
OL049055M
2736
Org. Lett., Vol. 6, No. 16, 2004