bromodifluoroacetate to imines and the reaction of difluo-
roenol ethers with N-acyliminiums or imines under Lewis
acid activation.5a,d-h Although these are effective methods,
they require the use of imines or N-acyliminiums prepared
from aldehydes and amines. Recently, transition-metal-
catalyzed C-H bond functionalization of tertiary amine has
attracted great attention in both academia and industry
because of its atom- and step-economy, high efficiency, low
cost, and minimal environmental impact.6-10 Generally,
direct oxidative transformation of tertiary amine developed
by Murahashi et al.,7 Doyle et al.,8 Li et al.,9a-m and
others9n-p is performed in two steps:10 R-H activation of
amine to produce iminium ion intermediates and subsequent
reaction with nucleophiles. To date, various nucleophiles6,8
have been used to capture the iminium ions generated in
situ by several transition metals.6-8 We envisioned that the
use of difluorinated reagents for catalytic C-H bond func-
tionalization of tertiary amine might be an alternative method
to synthesize ꢀ-amine-R,R-difluoro ketones without pre-
functionalization of substrates. To the best of our knowledge,
the direct oxidative difluoromethylation of amines has not
been reported. Herein, we disclosed the first effective atom-
and step-economical synthesis of ꢀ-amino-R,R-difluoro
ketones through addition of difluoroenol silyl ethers to
iminium ions generated in situ catalyzed by CuBr under mild
conditions.
Table 1. CuBr-Catalyzed Difluoromethylation of 1,2,3,4-
Tetrahydroisoquinoline with Difluoroenol Silyl Ether 2aa
entry
2a
temp (°C)
solvent
yield (%)b
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.5
2.0
2.5
3
60
rt
rt
rt
rt
rt
rt
rt
neat
neat
8c
17
61
64
75
78
98
83
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4
a Reaction scale: tertiary amine (0.2 mmol, 1 M). b Yield was determined
by 19F NMR using benzotrifluoride as an internal standard. c Reaction was
conducted in sealed tube.
(Table 1, entry 3). Increasing the amount of substrate 2a
increased the yield of the product (Table 1, entries 4-7).
When the ratio of 1a/2a was 1:3, an excellent yield (98%)
was afforded (Table 1, entry 7), and further increasing the
ratio of 1a/2a proved to be deleterious to the reaction yield
(Table 1, entry 8).
Inspired by Li’s work on CuBr-catalyzed sp3 C-H bond
activation for C-C bond formation,9a,d initially we started
the synthesis of ꢀ-amino-R,R-difluoro ketone by coupling
of difluoroenol silyl ether 2a11 with 1,2,3,4-tetrahydroiso-
quinoline 1a in the presence of catalytic amount of CuBr
and stoichiometric amount of oxidant tert-butyl hydroper-
oxide (TBHP) under neat conditions at 60 °C. Unfortunately,
only trace amount of desired product 3a was detected by
19F NMR (Table 1, entry 1). Considering the instability of
the difluoroenol silyl ether 2a,11 the reaction temperature was
decreased to room temperature; however, the yield of the
product slightly increased to 17% (Table 1, entry 2). To our
delight, the efficiency of the reaction was dramatically
improved when the reaction was conducted in CH2Cl2 and
61% yield of 3a was obtained (determined by 19F NMR)
With the optimized reaction conditions in hand (3 equiv
of difluoroenol silyl ether, 10 mol % of CuBr, TBHP (1.6
equiv) in CH2Cl2), we next examined the scope of the
reaction with a variety of substituted 1,2,3,4-tetrahydroiso-
quinoline derivatives. The results are summarized in Table
2. Substrates with various substitution patterns all provided
the expected results in moderate to good yields. Both N-aryl-
and N-alkyl-substituted tetrahydroisoquinolines were effec-
tive for the reaction (Table 2, entries 1-6). Electron-poor
aryl substitutents afforded better yields than electron-rich
substrates. Interestingly, a regioselectivity at the C1 position
for difluoromethylation of N-benzyl- and N-allyl-substituted
tetrahydroisoquinolines 1g and 1h was observed (regioiso-
meric couplings of 2a with benzyl R-methylene or methyl
were not observed) (Table 2, entries 7 and 8). The regiose-
lectivity might be due to the stability of the iminium ions
intermediate. Importantly, N,N-dimethylaniline and N-ben-
zyldimethylamine were also viable participants in the oxida-
tive difluoromethylation reaction, but the yields of products
were low (Tabel 2, entries 9 and 10).
(6) For reviews on C-H bond activation, see: (a) Bergman, R.-G. Nature
(London) 2007, 446, 391. (b) Godula, K.; Sames, D. Science 2006, 312,
67. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731
.
(7) (a) Murahashi, S.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem.
Soc. 2003, 125, 15312. (b) Murahashi, S.; Komiya, N.; Terai, H. Angew.
Chem., Int. Ed. 2005, 44, 6931. (c) Murahashi, S.; Nakae, T.; Terai, H.;
Komiya, N. J. Am. Chem. Soc. 2008, 130, 11005
.
(8) Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am.
Chem. Soc. 2006, 128, 5648.
(9) Copper-catalyzed oxiadative transformation of tertiary amines: (a)
Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810. (b) Li, Z.; Li, C.-J.
Org. Lett. 2004, 6, 4997. (c) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 15,
3173. (d) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (e) Li, Z.;
Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (f) Li, Z.; Bohle, D. S.; Li,
C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928. (g) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2006, 128, 56. (h) Li, Z.; Li, C.-J. J. Am. Chem. Soc.
2006, 128, 11810. (i) Zhang, Y.; Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2006,
128, 4242. (j) Basle, O.; Li, C.-J. Green Chem. 2007, 9, 1047. (k) Basle,
O.; Li, C.-J. Org. Lett. 2008, 10, 3661. (l) Zhao, L.; Li, C.-J. Angew. Chem.,
Int. Ed. 2008, 47, 7075. (m) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (n)
Xu, X.-L.; Li, X.-N. Org. Lett. 2009, 11, 1027. (o) Shen, Y.-M.; Li, M.;
Wang, S.-Z.; Zhan, T.-G.; Tan, Z.; Guo, C.-C. Chem. Commun. 2009, 8,
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3813.
Next, we turned our attention to the use of difluoroenol
silyl ethers 4,5h which are synthetic equivalents of R,R-
difluoroacylsilanes and can be easily transformed to R,R-
difluorocarbonyl compounds such as aldehydes, carboxylic
acids, amides, and other derivatives.12 To our disappointment,
(10) (a) Murahashi, S.-I. Angew. Chem., Int. Ed. 1995, 34, 2443. (b)
Murahashi, S.-I.; Naota, T.; Yonemura, K. J. Am. Chem. Soc. 1988, 110,
8256. (c) Murahashi, S.-I.; Naota, T.; Kuwabara, T.; Saito, T.; Kumoba-
yashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1990, 112, 7820. (d) Murahashi,
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Org. Lett., Vol. 11, No. 10, 2009