Table 1. Copper-Catalyzed Arylation of Tetrahydroisoquinolinea
entry
2a
cat.[Cu]
[O] (equiv)
solvent (concn)
DME (1 M)
DME (1 M)
DME (1 M)
DME (+ 5 µL of H2O)
H2O
DME (1 M)
DME (1 M)
DME (1 M)
DME (2 M)
neat
T (°C)
3ac (%)
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
1.5
1.5
1.6
1.5
CuBr
CuBr
CuBr
CuBr
CuBr
Cul
CuBr
CuBr
CuBr
CuBr
TBHP (1.2)
95
95
120
95
95
95
95
95
95
95
15
75
50
65
<5
10b
80
85
90
30
T-HYDRO (1.2)
T-HYDRO (1.2)
TBHP (1.2)
TBHP (1.2)
T-HYDRO (1.2)
T-HYDRO (1.5)
T-HYDRO (1.6)
T-HYDRO (1.6)
T-HYDRO (1.6)
9
10
a Reactions scale: tertiary amine (0.1 mmol). b Use of other copper(I) salts resulted in decreased yield. c NMR yields based on tetrahydroisoquinoline
using an internal standard.
type intermediate via oxidation of the tertiary amine in the
presence of a peroxide and a copper salt.5d The key challenge
was the absence of a neighboring heteroatom directing group
generally required in the Petasis reaction to form the more active
tetracoordinate borate species.9 We reasoned that copper would
compensate for this absence.10,11 Considering previous work
on transition-metal-catalyzed sp3 C-H bond activation for
C-C bond formation, we began our investigation using tert-
butyl hydroperoxide (TBHP) as a stoichiometric oxidant.12
While optimizing the reaction conditions, we discovered the
critical role of water in the oxidative arylation reaction. In
the absence of water, only 15% of the benzylic R-arylated
product was obtained when the CuBr/TBHP system was
tested in DME (dimethoxyethane) at 95 °C (Table 1, entry
1). Very interestingly, when the solvent of the oxidant was
switched from decane to water, the efficiency of the reaction
dramatically increased, providing the arylated product in 75%
yield (Table 1, entry 2). Increasing the reaction temperature
to 120 °C lowered the yield due to an increase of biphenyl
byproduct formation (Table 1, entry 3). Instead of using tert-
butyl hydroperoxide, 70 wt % in water (T-HYDRO), adding
a small amount of water with anhydrous TBHP in decane is
also effective (entry 4). However, a large amount of water
prevents the reaction from occurring (Table 1, entry 5).
It is also important to note that no product was obtained when
2a was replaced by its corresponding ester.13 The optimized
reaction conditions required 1.6 equiv of phenylboronic acid
in the presence of an equivalent amount of T-HYDRO in DME
(2 M) at 95 °C (Table 1, entry 9).
Next, we examined the scope of the oxidative arylation reaction
with a variety of substituted aryl boronic acids (Scheme 1). Both
electron-withdrawing and electron-donating substituted arylboronic
acids were successfully coupled to tetrahydroisoquinolines. Both
N-phenyl-protected and N-PMP-protected tetrahydroisoquinolines
were effective for this transformation. N-PMP can easily be
deprotected to give the R-arylated free N-H tetrahydroisoquino-
line.14 Interestingly, the very sterically hindered 2-naphthylboronic
was coupled in good yields under the optimized conditions.
Futhermore, we considered the use of molecular oxygen for
the oxidative arylation reaction.15 Unfortunately, no product
could be detected under the previously reported CuBr/O2/water
system (Table 2, entry 1).5e Nevertheless, when the reaction
was performed in DME as solvent, 20% of the desired arylated
product was obtained (entry 2). The role of water was also
critical under aerobic conditions. In fact, addition of a small
amount of water to the previous conditions increased the yield
to 60% (entry 3). The yield was further improved to generate
80% of the desired product when a catalytic amount of peroxide
was used (Table 2, entry 4).
(8) Renaud, J.; Bischoff, S. F.; Buhl, T.; Floersheim, P.; Fournier, B.;
Geiser, M.; Halleux, C.; Kallen, J.; Keller, H.; Ramage, P. J. Med. Chem.
2005, 48, 364.
(9) (a) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063. (b) Petasis,
N. A.; Zavialov, I. A. Tetrahedron Lett. 1996, 37, 567.
(10) (a) Chan, D. M. T.; Lam, P. Y. S. In Boronic Acids; Hall, D. G.,
Ed.; Wiley-VCH: Weinheim, 2005; pp 205-240. (b) Lam, P. Y. S.; Bonne,
D.; Vincent, G.; Clark, C. G.; Combs, A. P. Terahedron Lett. 2003, 44,
To have a better understanding of the reaction mechanism
and since the biological potency of 1-phenyl-1,2,3,4-tetrahy-
droisoquinoline is highly enantioselective,7 we briefly investi-
gated the asymmetric oxidative arylation reaction. Very inter-
estingly, lowering the temperature to 50 °C together with
1693
.
(11) (a) Prokopcova´, H.; Kappe, C. O. Angew. Chem., Int. Ed. 2008,
47, 3674. (b) Villalobos, J. M.; Srogl, J.; Liebeskind, L. S. J. Am. Chem.
Soc. 2007, 129, 15734
.
(12) (a) Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9, 3813.
(b) Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am. Chem.
Soc. 2006, 128, 5648. (c) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127,
3672. (d) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, n/a, 3173. (e) Li, Z.;
Li, C.-J. Org. Lett. 2004, 6, 4997. (f) Li, Z.; Li, C.-J. J. Am. Chem. Soc.
2004, 126, 11810. (g) Murahashi, S.; Naota, T.; Yonemura, K. J. Am. Chem.
Soc. 1988, 110, 8256.
(13) Phenylboronic acid pinacol ester and phenylboronic acid glycol ester
were ineffective under the optimized conditions.
(14) Taniyama, D.; Hasegawa, M.; Tomioka, K. Tetrahedron: Asymmetry
1999, 10, 221.
(15) Caution: peroxides are potentially explosive.
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