Continuing with our research on palladium-catalyzed
arylation reactions of different nucleophiles,5 we envisaged
a straightforward approach to the Trileptal skeleton through
a sequence of palladium-mediated C- and N-arylation reac-
tions in intermolecular and intramolecular fashions, respec-
tively. Such an ambitious strategy, based on an entirely
catalytic reaction in the key steps of the sequence and
avoiding the use of any transmetallating agent, starts from
commercially available 2′-aminoacetophenone 3 and 1,2-
dibromobenzene 4. According to this plan, the synthesis of
intermediate deoxybenzoin 5 through an intermolecular
palladium-catalyzed R-arylation of ketone enolates and its
subsequent cyclization employing palladium-mediated N-
arylation protocols would provide the tricyclic framework
of oxcarbazepine 1 (Scheme 1).
Table 1. Selected R-Arylation Assays Performed on Substrates
6a,b
entry
1
reaction conditions
7a
6a, 1.7% Pd2dba3, 4.5% BINAP, 2.6 equiv
7a 0 (0)
NaOtBu, THF, 80 °C, 22 hb
2
6a, 2% Pd(dba)2, 4% P(tBu)3, 5 equiv K3PO4, 7a 0 (100)
Scheme 1
PhMe, 80 °C, 24 hb
3
6a, 4.7% Pd(OAc)2, 10% PPh3, 2.4 equiv
Cs2CO3, DMF, 80 °C, 22 hb
6a, 7.3% Pd(dba)2, 9% DPPF, 2.3 equiv
NaOtBu, THF, 80 °C, 8 hb
6a, 4.5% Pd(OAc)2, 6% IPr‚HCl, 1.5 equiv
NaOtBu, 1,4-dioxane, 80 °C, 8 hb
7a 0 (0)
7a 0 (0)
7a 0 (0)
4
5
6
6a, 3.7% Pd(OAc)2, 5.4% Xantphos, 1.4 equiv 7a 61 (76)
Cs2CO3, PhMe, 130 °C, 5 hb
7
6b, 4.7% Pd(OAc)2, 4.9% Xantphos, 2.8 equiv 7b 17 (20)
Cs2CO3, PhMe, 130 °C, 20 hc
8
6b, 1.4% Pd2dba3, 3.7% BINAP, 1.5 equiv
NaOtBu, THF, 80 °C, 24.5 hd
7b 0 (10)
9
6a, 3.6% Pd(OAc)2, 7.7% Xantphos, 1.4 equiv 7a 76 (73)
Cs2CO3, PhMe, 130 °C, 5 hb
To promote the initial selective C-arylation reaction, the
nucleophility of substrate 36 was diminished by transforming
it into sulfonamide 6a and carbamate 6b. A full range of
reaction conditions evaluated to promote such C-arylation
reaction revealed first that, in comparison with carbamate
6b, N-tosyl derivative 6a displayed a higher chemoselectiv-
ity.7
To our surprise, several of the previously reported
procedures for the R-arylation of acetophenone enolates and
related substrates8 clearly failed in our case, rendering
unreacted 6a (Table 1, entries 1-5). Paradoxically, a ligand
commonly employed in N-arylation reactions but barely used
in R-arylation of enolates, Xantphos,9 turned out to be the
10
11
12
6a, 3.6% Pd(OAc)2, 7.8% Xantphos, 1.5 equiv 7a 72 (96)
K3PO4, PhMe, 130 °C, 29 h.e
6a, 4.4% Pd(OAc)2, 8.5% Xantphos, 1.4 equiv 7a 86 (85)
Cs2CO3, PhMe/H2O, 120 °C, 48 h.f,g
6a, 4% Pd(OAc)2, 8% Xantphos, 1.4 equiv
Cs2CO3, PhMe/H2O, 120 °C, 48 h.f,h
7a 79 (66)
a Isolated yields calculated on the basis of the conversion rate. The value
in parentheses indicates conversio´n rates of substrates 7. b [6a]:[4] ) 1:1.1.
c [6b]:[4] ) 1.2:1. d [6b]:[4] ) 1:1.2. e 3.15 equiv of 4. f 2.4 equiv of 4.
g PhMe/H2O (v/v ) 5.2). h PhMe/H2O (v/v ) 0.2).
key for the best conditions leading to C-arylated product 7a
(Table 1, entries 6, 7, and 9-12). The use of K3PO4 as the
base provided the best conversion (Table 1, entry 10), and
despite the bidentate nature of Xantphos, the optimized L/Pd
ratio was set at 2 (Table 1, entries 9-12). The addition of
relatively small quantities of water resulted in an enhance-
ment of the selectivity so that the reaction proceeded more
cleanly, but the rate of the process was noticeably slower
(Table 1, entry 11). The use of water to mediate several
palladium-catalyzed reactions has already been described in
the literature, but it usually requires specifically designed
water-soluble ligands, in almost entirely aqueous media as
the one described in entry 12.10
(4) (a) Lohse, O.; Beutler, U.; Fu¨nfschilling, P.; Furet, P.; France, J.;
Kauffmann, D.; Penn, G.; Zaugg, W. Tetrahedron Lett. 2001, 42, 385. (b)
Kauffmann, D.; Fu¨nfschilling, P.; Beutler, U.; Hoehn, P.; Lohse, O.; Zaugg,
W. Tetrahedron Lett. 2004, 45, 5275.
(5) (a) Herna´ndez, S.; SanMartin, R.; Tellitu, I.; Dom´ınguez, E. Org.
Lett. 2002, 4, 1591. (b) Churruca, F.; SanMartin, R.; Carril, M.; Tellitu, I.;
Dom´ınguez, E. Tetrahedron 2004, 60, 2393.
(6) Initial attempts to perform R-arylation directly from aminoketone 3
gave negligible results.
(7) All R-arylation assays performed on substrate 6b provided, apart from
null or very low yields of target intermediate 7b, variable amounts of
N-arylated/deprotected product 9.
(9) For one of the few examples in which Xantphos is used for the
R-arylation of carbonyl compounds, see: Fox, J. M.; Huang, X.; Chieffi,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360.
(8) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382.
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