Herein, we report a series of Pd-catalyzed reactions that
provide foundations for benzylic CꢀF substitution. The
reactivity of fluorides vs other benzylic leaving groups is
discussed, as well as the stereochemical course of substitu-
tion in one case. By analogy with our previous work on
allylic CꢀF substitution8 and allylic fluorination,9 this
study will facilitate development of the reverse reaction,
catalytic benzylic fluorination. The ability of benzylic
carbonates and carboxylates to undergo nucleophilic sub-
stitution or cross-coupling is very well documented, fol-
lowing the early work of Legros and Fiaud,10 and is
thought to proceed via an η3-benzyl metal complex.11
Nucleophilic addition typically occurs regioselectively at
the benzylic carbon, but substitution in the ring by a
tethered group has been observed.12 An instructive exam-
ple of noncatalytic Ir-mediated carbon fluorine activation
at a benzylic carbon is available.13 This process does not
occur via direct oxidative addition of the CꢀF bond to
iridium but is initiated instead by reversible CꢀH bond
cleavage. Our studies began withefforts to identify suitable
conditions for Pd-catalyzed substitution via CꢀF activa-
tion using 2-(fluoromethyl)naphthalene 1a (Table 1).
This model substrate does not allow for competitive
elimination and is more reactive than the benzyl ana-
logue.10,15 Dimethyl malonate (pKa = 15.9 in DMSO)
and Meldrum’s acid (pKa = 7.3 in DMSO)16 were exam-
ined under basic conditions. For both nucleophiles, Pd(η3-
Table 1. Effect of Pd Source and Ligand on the Reactivity of 1a
with Dimethyl Malonate I or Meldrum’s Acid II14
catalyst
liganda
solvent
base
time,
temp
entry
NuHb
convc
1
2
3
4
5
6
7
A
B
C
B
B
ꢀ
D
I
THF, NaH
48 h, 60 °C 38%
I
EtOH, K2CO3 16 h, 75 °C >95%d
II
II
II
II
II
DMSO, Et3N
DMSO, NaH
EtOH, Et3N
DMSO, Et3N
DMSO, Et3N
48 h, 60 °C 66%e,f
8 h, 60 °C
81%e,f
16 h, 50 °C 57%e,f
24 h, 60 °C 0%g
24 h, 60 °C 0%g
a A: 5 mol % Pd2(dba)3ꢀdppe (Pd/L = 1:1.5). B: 5 mol % Pd(η3-
C3H5)(COD) BF4ꢀDPEPhos (Pd/L = 1:2). C: 5 mol % Pd(η3-C3H5)-
3
(COD) BF4ꢀdppf (Pd/L = 1:2). D: No Pd, 10 mol % dppf. b I: Dimethyl
3
malonate. II: Meldrum’s acid. c Conversion determined by 1H NMR.
d Mixture of methyl and ethyl malonate. e Isolated yield. f Dialkylated
product. g Recovery of starting material. DPEPhos = bis(2-diphenyl-
phosphinophenyl)ether; dppf = 1,10-bis(diphenylphosphino)ferrocene.
ligand DPEPhos (10 mol %) (entries 2 and 4). EtOH and
DMSO are suitable solvents, but for subsequent studies
involving less reactive starting materials, EtOH was found
to be superior, as polar protic solvents are better able to
sequester the fluoride leaving group through hydrogen
bonding.17 Control reactions in the absence of a Pd catalyst
failed to produce more than traces of product (entries 6ꢀ7).
These results encouraged a study with a wide range of
substrates and nucleophiles (Figure 2). The favored condi-
tions used with Meldrum’s acid coupling proved effective for
1a. For this substrate, the reactions were conducted using
C3H5)(COD) BF4 (5 mol %) was the catalyst of choice
3
when used in combination with the bidentate phosphine
ꢀ
(7) Zhao, S.-B.; Becker, J. J.; Gagne, M. R. Organometallics 2011, 30,
3926.
(8) Hazari, A.; Gouverneur, V.; Brown, J. M. Angew. Chem., Int. Ed.
2009, 48, 1296.
(9) Hollingworth, C.; Hazari, A.; Hopkinson, M. N.; Tredwell, M.;
Benedetto, E.; Huiban, M.; Gee, A. D.; Brown, J. M.; Gouverneur, V.
Angew. Chem., Int. Ed. 2011, 50, 2613.
(10) (a) Legros, J.-Y.; Fiaud, J.-C. Tetrahedron Lett. 1992, 33, 2509.
(b) Legros, J.-Y.; Toffano, M.; Fiaud, J.-C. Tetrahedron: Asymmetry
1995, 6, 1899. (c) Legros, J.-Y.; Primault, G.; Toffano, M.; Riviere,
M.-A.; Fiaud, J.-C. Org. Lett. 2000, 2, 433. (d) Kuwano, R.; Kondo, Y.;
Matsuyama, Y. J. Am. Chem. Soc. 2003, 125, 12104. (e) Kuwano, R.;
Kondo, Y. Org. Lett. 2004, 6, 3545. (f) Kuwano, R.; Kondo, Y.;
Shirahama, T. Org. Lett. 2005, 7, 2973. (g) Yokogi, M.; Kuwano, R.
Tetrahedron Lett. 2007, 48, 6109. (h) Kuwano, R.; Kusano, H. Chem.
Lett. 2007, 36, 528. (i) Kuwano, R.; Kusano, H. Org. Lett. 2008, 10,
5 mol % Pd(η3-C3H5)(COD) BF4 and 10 mol % of DPE-
3
Phos in DMSO at 60 °C for 24 h. For all other substrates,
EtOH was a superior solvent. Morpholine, aniline, phenol,
and sodium benzenesulfinate all displace fluoride under Pd
catalysis; for 2cꢀe, the best yields were obtained using
20 mol % of tBuXPhos; the products were isolated with
yields ranging from 41% to 95%. The fluoromethylated
quinoline 3a, indole 4a, benzofuran 5a, and benzothiophene
6a also underwent successful substitution with yields above
75%; control experiments ruled out the possibility of an
uncatalyzed pathway for 1a and 2a; some background
reactivity was however observed for the heteroaromatic
systems 3a, 4a, 5a, and 6a (maximum 9% yield for 6a).
Pd-catalyzed substitution of monocyclic benzylic
fluorides is more challenging (attenuation of aromaticity
on π-allyl formation) and typically required extended
times at 70 or 75 °C to proceed efficiently using the same
catalyst and reagents. The data summarized in Scheme 1
indicate that the reaction tolerates benzylic fluorides with
p-phenyl, p-nitro, p-chloro, and p-bromo substituents and
ꢀ
1979. (j) Liegault, B.; Renaud, J.-L.; Bruneau, C. Chem. Soc. Rev. 2008,
37, 290. (k) Kuwano, R. Synthesis 2009, 7, 1049. (l) Assie, M.; Meddour,
A.; Fiaud, J.-C.; Legros, J.-Y. Tetrahedron: Asymmetry 2010, 21, 1701.
(m) Fields, W. H.; Chruma, J. J. Org. Lett. 2010, 12, 316. (n) Torregrosa,
R. R. P.; Ariyarathna, Y.; Chattopadhyay, K.; Tunge, J. A. J. Am.
Chem. Soc. 2010, 132, 9280. (o) Mukai, T.; Hirano, K.; Satoh, T.; Miura,
M. Org. Lett. 2010, 12, 1360. (q) Trost, B. M.; Czabaniuk, L. C. J. Am.
Chem. Soc. 2010, 132, 15534.
(11) The η3 hapticity of benzyl and naphthylmethyl Pd complexes
has been demonstrated in many crystal structures. Johns, A. M.;
Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 1828.
(12) Ueno, S.; Komiya, S.; Tanaka, T.; Kuwano, R. Org. Lett. 2012,
14, 338–341.
(13) Choi, J.; Wang, D. Y.; Kundu, S.; Choliy, Y.; Emge, T. J.;
Krogh-Jespersen, K.; Goldman, A. S. Science 2011, 332, 1545.
(14) For details, see the Supporting Information.
(15) η3-R-Arylalkyl complexes derived from (R)-Binap react faster
than η3-allyl complexes. The relative order of reactivity towards aniline
was naphthylmethyl > naphthylethyl > benzyl >1,1- dimethylallyl >
allyl; see: Johns, A. M.; Tye, J. W.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 16010.
(16) For pKa’s in DMSO, see: Arnett, E. M.; Maroldo, S. G.;
Schilling, S. L.; Harrelson, J. A. J. Am. Chem. Soc. 1984, 106, 6759.
(17) Enthalpy of solvation of fluoride ion in methanol at 25 °C is
488 kJ molꢀl; Ahrland, S. Pure Appl. Chem. 1990, 62, 2077.
B
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