RESEARCH ARTICLE
25. V. V. Grushin, W. J. Marshall, J. Am. Chem. Soc. 126,
3068 (2004).
F
Fig. 9. Solvent screen and
fluorination of triflates that
gave regioisomers. Unless
otherwise noted, yields and
ratios determined by GC and
19F NMR.
OTf
F
5 mol% [(cinnamyl)PdCl]2
26. W. J. Marshall, V. V. Grushin, Organometallics 23, 3343
15 mol% 3
+
(2004).
2 equiv CsF, Solvent
27. S. A. Macgregor et al., J. Am. Chem. Soc. 127, 15304 (2005).
28. D. V. Yandulov, N. T. Tran, J. Am. Chem. Soc. 129, 1342
(2007).
29. A. H. Roy, J. F. Hartwig, J. Am. Chem. Soc. 123, 1232 (2001).
30. V. V. Grushin, W. J. Marshall, Organometallics 26, 4997
(2007).
CO2nBu
110 °C, 12 h
CO2nBu
CO2nBu
14
32
33
combined yield
ArH
Solvent
conversion
ratio 33/14
Toluene
Benzene
100
100
95
100
100
100
71%
69%
18%
60%
39%
80%
78:22
90:10
78:22
>98:2
85:15
99:1
2%
*
*
1%
*
1%
31. B. P. Fors, D. A. Watson, M. R. Biscoe, S. L. Buchwald,
J. Am. Chem. Soc. 130, 13552 (2008).
THF
Cyclohexane
n-Heptane
Cyclohexane†
32. Materials and methods are available as supporting
material on Science Online.
* Yield not determined. † Optimized condition 100 °C, isolated yield.
33. The lower yield in the absence of added aryl bromide
suggests that the 2·Pd(0) complex that results from
reductive elimination further reacts with remaining
[2·PdAr(F)] complex. Increased product yields have
previously been observed in the reductive elimination
of C-S bonds from Pd(II) centers when Pd0 scavengers
(exogenous ligand) have been added to the reaction.
See (34).
2.5 mol% [(cinnamyl)PdCl]2,
7.5 mol% 3, 2 equiv CsF,
Fig. 10. Use of cyclo-
hexane as solvent to
suppress formation of
regioisomers. Desired
isomer is shown. Prod-
uct ratios are for regio-
isomeric aryl fluorides as
indicated. Isolated yields
are for the major isomer,
with values in parentheses
denoting the amount of
reduced starting materi-
al based on the isolated
product yield.
F
OTf
solvent, 12 h, temp
R
R
34. G. Mann, D. Baranano, J. F. Hartwig, A. L. Rheingold,
I. A. Guzei, J. Am. Chem. Soc. 120, 9205 (1998).
35. Y. Pan, G. B. Young, J. Organomet. Chem. 577, 257 (1999).
36. After this paper was submitted, we found that the closely
related hetero-biaryl ligand 5-(di-tert-butylphosphino)-1-
(1,3,5-triphenyl-1H-pyrazol-4-yl)-1H-pyrazole
(Bippyphos) reported by Singer and co-workers [see (37)
and citations therein] can also provide catalysts with
moderate levels of activity for fluorination. For example,
with use of 10 mol% of this ligand and 5 mol%
[(cinnamyl)ClPd]2, a 52% yield of 10 along with 11%
reduction product was observed after heating for 12
hours at 150°C in toluene.
Boc
N
m
m
F
F
F
p
PhO
Me
m
p
o
F
m
Ph
p
OMe
34
35
36
37
m/p = 87:13
o/m = 77:23
tol*
cy†
p/m = 93:7
m/p = 93:7
m/p = 96:4
90% (<1%)
110 °C
o/m = 98:2
61% (~8%)
130 °C
p/m = >98:2
80% (3%)
100 °C
m/p = >98:2
77% (2%)
110 °C
* 2.5–5 mol% [(cinnamyl)PdCl]2, 7.5-15 mol% 3, solvent = toluene.
†solvent = cyclohexane.
37. G. J. Withbroe, R. A. Singer, J. E. Sieser, Org. Process Res. Dev.
can be strongly affected by solvent polarity; the we expect this method to be applicable to the
desired pathway is favored in highly apolar media. preparation of biologically active and radio-
Examination of a number of solvents for the labeled aryl fluorides.
conversion of 32 to 33 revealed that the formation
12, 480 (2008).
38. We followed the reaction of 9 to 10 by gas chromatography
(GC) and found that, after a brief initial period in which
about 20% of 9 was consumed, 10 began to form. By
adding 20 mol% water, we observed that the initial loss
of material increased to 60%. This result indicates that
one molecule of water consumes two molecules of 9
under the reaction conditions. Nevertheless, the reaction
proceeded to give 40% 10. We believe that the initial
loss of mass balance is due to formation of biaryl ether:
Presumably, adventitious water results in the formation
of phenol, which further reacts with a second molecule of
ArOTf in a Pd-catalyzed process.
of the undesired isomer 14 is almost completely
References and Notes
suppressed with use of cyclohexane (Fig. 9). This
trend appears to be general; in most instances in
which the undesired regioisomer was observed
with use of toluene, switching to cyclohexane
afforded almost exclusively the desired product.
For example, fluorinated aryls 33 to 37 could be
prepared with greater than 95:5 selectivity favor-
ing the desired isomer (Fig. 10). This modification
provides a highly practical means to minimize
formation of regioisomeric by-products.
Outlook. Starting from the observation of the
reductive elimination of ArF from a [2·PdAr(F)]
complex, we have developed a metal-catalyzed
direct conversion of aryl bromides and aryl tri-
flates into the corresponding aryl fluorides using
simple fluoride sources such as AgF and CsF. In
particular, the transformation of aryl triflates ex-
hibits a wide substrate scope and tolerates a
number of functional groups, allowing for the
introduction of fluorine atoms into highly func-
tionalized organic molecules. Key to these find-
ings was the use of the sterically demanding,
electron-rich biaryl monophosphine tBuBrettPhos
3 as the supporting ligand. We believe that this
ligand not only promotes reductive elimination of
the Ar-F bond because of its large size but also
prevents the formation of dimeric [LPdAr(F)]2
complexes. At present, both of these factors
appear to be critical in the successful catalytic
reaction. Although some limitations remain with
regard to substrate scope and reaction conditions,
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40. We thank the NIH for financial support of this project
(grant GM46059) and Merck, Nippon Chemical,
Boehringer Ingelheim, and BASF for gifts of chemicals
and additional funds. M.S. thanks the Singapore-MIT
Alliance for a graduate fellowship. J.G.-F. thanks the
Spanish Ministerio de Educación y Ciencia for a
postdoctoral fellowship. T.K. thanks the Alexander von
Humboldt Foundation for a Feodor Lynen postdoctoral
fellowship. The Varian NMR instrument used was
supported by the NSF (grants CHE 9808061 and DBI
9729592). We also thank P. Müller for obtaining the
crystal structure of 4. Cambridge Crystallographic Data
Centre (CCDC) 741377 contains the supplementary
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been filed by MIT covering portions of this work with
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Supporting Online Material
Materials and Methods
Figs. S1 to S60
Table S1 to S5
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25 June 2009; accepted 30 July 2009
Published online 13 August 2009;
10.1126/science.1178239
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Include this information when citing this paper.
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