magnesiations at the 3 position of the quinoline proceed
without protection of the kinetically more favored C2
position. Thus, the quinoline 7b smoothly reacted with
TMPMgCl·LiCl (4a) at 0 °C within 1 h. The corresponding
magnesium reagent was then transmetalated with ZnCl2 and
subsequently acylated with pivaloyl chloride in the presence
of CuCN·2LiCl12 (10 mol %) giving the heteroaromatic
ketone 8b in 62% yield (entry 2). A cross-coupling reaction
of the Zn-reagent derived from 7b with ethyl 4-iodobenzoate
in the presence of a Pd-catalyst (Pd(dba)2 (5 mol %), P(2-
furyl)3 (10 mol %)14) furnished the 3-arylated quinoline 8c
in 83% yield (entry 3). Moreover, the regioselective func-
tionalization of the C7 position was possible using this
protocol. Thus, the 2-chloroquinoline 7c is readily magne-
siated with TMPMgCl·LiCl (4a) at 0 °C within 1 h. A
transmetalation with ZnCl2 followed by the addition of
methallyl bromide in the presence of CuCN·2LiCl12 (10 mol
%) led to the allylated quinoline 8d in 87% yield (entry 4).
The addition of 4-chlorobenzoyl chloride under the same
conditions furnished the ketone 8e in 74% yield (entry 5).
The 2-bromoquinoline 7d also underwent a smooth magne-
siation at 0 °C with TMPMgCl·LiCl (4a). After transmeta-
lation with ZnCl2, a cross-coupling reaction with (4-
iodophenoxy)(triisopropyl)silane in the presence of Pd(dba)2
(5 mol %) and P(2-furyl)3 (10 mol %)14 led to the arylated
bromoquinoline 8f in 81% yield (entry 6). The introduction
of an ethyl ester in position 7 was achieved by reacting the
7-magnesiated quinoline 7d with NC-CO2Et leading to the
ester 8g in 77% yield (entry 7). Magnesiations or lithiations
on quinoxalines are often difficult to achieve as these
systems are prone to undergo nucleophilic substitution
reactions.8a,15 However, quinoxaline 7e bearing a phospho-
rodiamidate group as DMG was smoothly magnesiated with
TMP2Mg·2LiCl (4b) at -50 °C in 1.5 h without any
dimerization side reaction. After a transmetalation with ZnCl2
it underwent a Negishi cross-coupling in the presence of a
Pd(dba)2 (5 mol %) and P(2-furyl)3 (10 mol %)14 with either
4-chloroiodobenzene or ethyl 4-iodobenzoate leading to the
2-arylated quinoxalines 8h and 8i in up to 79% yield (entries
8 and 9). Treatment of the quinoxalylzinc reagent with
methallyl bromide in the presence of CuCN·2LiCl12 (10
mol %) furnished the allylated quinoxaline 8j in 71% yield
(entry 10).
Scheme 1. Synthesis of Etoricoxib
(7) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem.,
Int. Ed. 2006, 45, 2958. (b) Lin, W.; Baron, O.; Knochel, P. Org. Lett.
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Org. Lett. 2007, 9, 5525. (e) Rohbogner, C. J.; Wunderlich, S. H.; Clososki,
G. C.; Knochel, P. Eur. J. Org. Chem. 2009, 1781. (f) Rohbogner, C. J.;
Wagner, A. J.; Clososki, G. C.; Knochel, P. Org. Synth. 2009, 86, 374. (g)
Piller, F. M.; Knochel, P. Org. Lett. 2009, 11, 445. (h) Despotopoulou, C.;
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As an application, we have prepared etoricoxib (2),
talnetant (1), and a P-selectin inhibitor16 (14) (Schemes 1
and 2). For the preparation of etoricoxib (2), a phospho-
rodiamidate DMG group was first attached at 2-pyridinol
leading to 5a in 90% yield.10 In a second step, 5a was
selectively metalated in the 3-position using TMPMgCl·LiCl
(4a; 1.5 equiv, 0 °C, 1 h).17 After Zn-transmetalation, a
subsequent cross-coupling reaction with 4-bromophenyl
methyl sulfone in the presence of Pd2(dba)3 (1 mol %) and
RuPHOS11 (2 mol %) gave the arylated pyridine 6g in 88%
yield. Cleavage of the directing group with an HCl/dioxane
mixture18 (25 °C, 24 h) led to the pyridone 9 in 95% yield.
Chlorination at the C5 position was achieved by reacting
9 with KClO3 in the presence of concd HCl19 furnishing
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P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442.
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(17) For experimental details, see the Supporting Information.
(18) Chao, H.-G.; Leitning, B.; Reiss, P. D.; Burkhardt, A. L.; Klimas,
C. E.; Bolen, J. B.; Matsueda, G. R. J. Org. Chem. 1995, 60, 7710.
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1986
Org. Lett., Vol. 12, No. 9, 2010