Proximity effects in the palladium-catalyzed substitution of aryl fluorides

Article abstract of DOI:10.1021/ol047413f

(Chemical Equation Presented) The aryl fluoride bond has long been considered inert toward Pd-catalyzed insertion reactions. This paper reports for the first time that aryl fluorides bearing an o-carboxylate group can undergo Pd-catalyzed couplings. On th

Full text of DOI:10.1021/ol047413f

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1011-1014
Proximity Effects in the
Palladium-Catalyzed Substitution of Aryl
Fluorides
S. Bahmanyar,* Bennett C. Borer, Young Mi Kim, David M. Kurtz, and Shu Yu*
Chemical Research and DeVelopment, Pfizer Global R&D-La Jolla,
10578 Science Center DriVe, San Diego, California 92121
sami.bahmanyar@pfizer.com; shu.yu@pfizer.com
Received December 16, 2004
ABSTRACT
The aryl fluoride bond has long been considered inert toward Pd-catalyzed insertion reactions. This paper reports for the first time that aryl
fluorides bearing an o-carboxylate group can undergo Pd-catalyzed couplings. On the basis of this computational study and subsequent
experimental verifications of its predictions, we herein report that such reactions are facilitated by stabilization of the transition state by
proximal oxyanions.
Carbon-fluorine bond activation has drawn considerable
interest in recent years.1 The aryl fluoride bond has long been
considered inert toward Pd-catalyzed insertion reactions.
However, recently reported discoveries in our laboratory2
and others3 have demonstrated for the first time that o-nitro-
substituted fluorobenzenes can undergo the Pd(0)-catalyzed
amination,2 Stille coupling, and Suzuki coupling reactions.2,3
Herein we report for the first time that aryl fluorides bearing
a substituent other than an o-nitro group can undergo Pd-
catalyzed couplings.
To fully understand the role that the o-nitro group played
in the successful Pd-catalyzed coupling reactions of aryl
fluorides, a computational study using hybrid density func-
tional theory was conducted in our laboratory. On the basis
of this computational study and subsequent experimental
verifications of its predictions, we report that such reactions
are facilitated by stabilization of the transition state by
proximal oxyanions. This stabilization allowed the prediction
of a nonobvious substrate (the carboxylate anion) that could
successfully undergo Pd-catalyzed coupling reaction.
Assuming that the Pd(0)-catalyzed coupling reaction
proceeds via the oxidative addition/reductive elimination
pathway4 and further assuming that the oxidative addition
of Pd(0) onto the aryl fluoride is rate-determining,5 the
addition step of Pd(0) to various aryl halides was modeled
(1) (a) Clot, E.; Megret, Cl.; Kraft, B. M.; Eisenstein, O.; Jones, W. D.
J. Am. Chem. Soc. 2004, 126, 5647-5653. (b) Reinhold: M.; McGrady, J.
E.; Perutz, R. N. J. Am. Chem. Soc. 2004, 126, 5268-5276. (c) Hughes, R.
P.; Laritchev, R. B.; Zakharov, L. N.; Rheingold, A. L. J. Am. Chem. Soc.
2004, 126, 2308-2309. (d) Braun, T.; Noveski, D.; Neumann, B.; Stammler,
H.-G. Angew. Chem., Int. Ed. 2002, 41, 2745-2748. (e) Mazurek, U.;
Schroder, D.; Schwarz, H. Angew. Chem., Int. Ed. 2002, 41, 2538-2541.
(2) Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2003, 125, 1696-1697.
(3) (a) Widdowson, D. A.; Wilhelm, R. Chem. Commun. 2003, 578-
579. (b) Jakt, M.; Johannissen, L.; Rzepa, H. S.; Widdowson, D. A.;
Wilhelm, R. J. Chem. Soc., Perkin Trans. 2 2002, 576-581. (c) Widdowson,
D. A.; Wilhelm, R. Chem. Commun. 1999, 2211-2212. (d) Wilhelm, R.;
Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 2000, 3808-3814. (e)
Mikami, K.; Miyamoto, T.; Hatano M. Chem. Commun. 2004, 2082-2083.
(4) Note: at this stage, we still could not completely exclude the
possibility of the operation of other mechanisms in those coupling reactions;
for direct observation of oxidative addition of Pd(0) to an aryl-fluorine bond,
see: Jasim, N. A.; Perutz, R. N.; Whitwood, A. C.; Braun, T.; Izundu, J.;
Neumann, B.; Rothfeld, S.; Stammler, H.-G. Organometallics 2004, 23,
6140-6149.
10.1021/ol047413f CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/24/2005

to understand further the role of the nitro substituent in
facilitating Pd(0)-catalyzed reactions. Pd(PH3)2 was used as
a smaller surrogate of the Pd(PPh3)2 catalyst (Scheme 1).
Table 1. Computed Activation Energy Barriers (Eact) in Gas
Phase (ꢀ ) 1) and (Eact(DMF)) in DMF (ꢀ ) 37.2)
Scheme 1
Gas phase ground state and transition structure geometry
optimizations6 were computed using hybrid density functional
theory B3LYP.7 The 6-31G(d)8 basis set was used for P, N,
O, C, and H and the LANL2DZ9 effective core potential
and its associated basis set was used for the halogens (I, Br,
Cl, F) and Pd as implemented in Gaussian 98.10 The
computed activation energies (Table 1) for the addition of
Pd(PH3)2 to unsubstituted aryl halides (1a-4a) agree with
the known experimental reactivity of these substrates toward
Pd-catalyzed oxidative addition.11 With the introduction of
the o-nitro substituent (1b-4b), the activation energy barriers
of the aryl halides decrease as shown in Table 1.12
The most dramatic change is observed for 1-fluoro-2-
nitrobenzene (4b). The activation energy barrier decreases
(5) It has been proposed that Pd(PPh3)4 dissociates and has two ligands
catalyzing the oxidative addition step as discussed by: (a) Fauvarque, J.
F.; Pfluger, F.; Troupel, M. J. Organomet. Chem. 1979, 208, 419-427. (b)
Amatore, C.; Pfluger, F. Organometallics 1990, 9, 2276-2282.
(6) All stationary points were characterized using frequency calculations
(reported energies include zero point energy corrections and were scaled
by 0.9806. Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502-
16513). Single point solvation energy calculations for reactants and transition
structures were computed using the polarizable continuum solvation model
PCM [(a) Miertus, S.; Tomasi, J. Chem. Phys. 1982, 65, 239-245. (b)
Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55, 117-129], as
implemented in Gaussian 98, with a permittivity of 37.2, the value for DMF.
Gas-phase energies in Table 1 are reported as zero point energy corrected
electronic energies. The energies computed for structures in solvent include
electronic energy plus the solvation energy as reported from PCM.
(7) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 1372-1377. (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789.
to 23.3 kcal/mol when compared to the activation energy
for fluorobenzene (4a), which is calculated to be 37.7 kcal/
mol.13 However, the computed activation energy barrier for
the addition of Pd(0) to 1-fluoro-4-nitrobenzene (4c) is only
slightly lower (32.5 kcal/mol) than that for fluorobenzene.
Similarly, 2-fluorobenzonitrile (5) is predicted to have an
activation energy barrier close to that of 1-fluoro-4-nitroben-
zene. A close examination of the transition structure geom-
etry of TS-4b reveals the presence of a very short Pd-O
(NO2) distance as shown in Figure 1.
(8) (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971,
54, 724-728. (b) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys.
1972, 56, 2257-2261. (c) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta
1973, 28, 213-222.
(9) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270-283.
(10) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.11; Gaussian,
Inc.: Pittsburgh, PA, 1998.
(11) (a) Hegedus, L. S. In Organometallics in Synthesis: A Manual;
2nd ed.; Schlosser, M., Ed.; Wiley: New York, 2002; pp 1123-1217. (b)
Tsuji, J. In Palladium Reagents and Catalysts; Wiley: New York, 1995.
(12) (a) The activation energy barriers computed with B3LYP/6-
311+G** basis set for P, N, O, C, H and LANL2DZ effective core potential
and its associated basis set for Pd and the halogens (single point energy
calculations on fully optimized geometries of structures reported in Table
1) reflect the same general trend as those in Table 1. (b) The use of the
The coordination of the nitro group oxygen of 1-fluoro-
2-nitrobenzene to the Pd metal may be the source of
transition state stabilization.14 In the transition state, the nitro
LANL2DZ basis set for fluorine was successful in reproducing geometries
in crystal structures reported in Chu, Q.; Wang, Z.; Huang, Q.; Yan, C.;
Zhu, S. J. Am. Chem. Soc. 2001, 123, 11069-11070. The comparisons of
the calculated and experimental information are provided in Supporting
Information.
(13) IRC calculations on transition states 4a and 4b lead to intermediates
with distorted square planar geometries, supporting a concerted oxidative
addition mechanism in the gas phase at this level of theory. Geometries of
these intermediates are provided in Supporting Information.
(14) Widdowson et al. made a similar observation as discussed in ref
3a-d.
1012
Org. Lett., Vol. 7, No. 6, 2005

Figure 1. Transition structure geometries (labeled according to entries in Table 1) and activation energy barriers for the addition of Pd-
(PH3)2 to fluorobenzene (TS-4a), 2-fluoronitrobenzene (TS-4b), and 2-fluoro-5-nitrobenzoate (TS-8c). All energies are reported in kcal/
mol and distances are reported in angstroms.
and cyano substituents stabilize negative charge buildup in
the aryl ring,15 but the Pd-O coordination plays an equally
important (if not more important) role in transition state
stabilization and lowering of the activation energy barrier.
To explore further the extent of transition state stabilization
via Pd-O coordination, the activation energy barriers for
the addition of Pd(0) to 2-fluorobenzaldehyde, methyl
2-fluorobenzoate, and the 2-fluorobenzoate carboxylate anion
(6a-8a) were computed. These substrates were selected on
the basis of their varying amount of formal negative charge
density on the oxygen atom. The gas phase activation energy
barriers for addition to 6a, 7a, and 8a are predicted to be
27.5, 30.1, and 19.5 kcal/mol, respectively, as shown in Table
1. The transition state geometries illustrate that the carbonyl
oxygen of the formyl and methyl ester are only weakly
coordinated (Pd-O ∼2.5-2.7 Å) to the Pd metal.16
When the calculated activation energies for 6a-8a are
compared to their para-substituted counterparts 6b-8b, it
can be concluded that the transition state stabilization
originates mainly from Pd-O coordination and not just the
electron-withdrawing ability of the substituent. Thus, the
decrease in the activation energy barrier for Pd(0) addition
to substituted fluorobenzenes can be due to two main
factors: the electron-withdrawing ability of the substituents
on the ring, and the ability of the proximal oxygen atom of
the substituent at the ortho position to donate charge to the
Pd metal in the transition state. Both of these factors are
required to facilitate the oxidative addition of Pd(0) to the
aryl-fluorine bond. These computational data and the result-
ing conclusions were supported experimentally by study of
the reactivity of appropriately substituted aryl fluorides.
Stille coupling reactions have been demonstrated to be
useful model reactions due to the lack of non-Pd-catalyzed
background reactions.2 The experimental results of our
current studies are summarized in Table 2.
As previously reported, 2-fluoro-5-nitrobenzaldehyde and
2-fluoro-5-nitrobenzonitrile underwent Stille coupling with
ease (entries 1, 3, 7, and 9).2 When the positions of the
activating groups were switched, 4-fluoro-3-nitrobenzalde-
hyde and 4-fluoro-3-nitrobenzonitrile were not reactive under
the same reaction conditions or at higher temperatures
(entries 2, 4, 8, and 10). These results demonstrated the
importance of the proximity of the nitro group and were in
good agreement with the computational rationale. As the
computed activation energy barriers suggested, 2-fluoro-5-
nitrobenzoate indeed underwent Stille coupling in fair yields
(entries 5 and 11). The control experiments (entries 6 and
12) demonstrated that the coupling reaction required the
presence of palladium.
On the other hand, in the transition state the negatively
charged carboxylate oxygen of 2-fluorobenzoate (8a) has a
much stronger coordination to the Pd metal, as observed in
the Pd-O distances (Pd-O 2.171 Å). With the presence of
additional electron-withdrawing substituents on the ring, the
computed activation energy barriers are 13.9 kcal/mol for
2-fluoro-5-nitrobenzoate (8c) and 16.2 kcal/mol for 2-fluoro-
5-trifluoromethylbenzoate (8d). The transition structure
geometries illustrate that the charged carboxylate oxygen has
a stronger Pd-O coordination when compared to the nitro
group (Pd-O distances for TS-4b, 2.397 Å and for TS-8c,
2.132 Å) as shown in Figure 1.17 These are approaching
Pd-O distances in Pd(II) complexes, which are considered
to be covalent,18 and this stabilizing interaction in the
transition state lowers the activation energy barrier and
should make these substrates susceptible to palladium-
catalyzed oxidative addition.
Considering that methyl 2-fluoro-5-nitrobenzoate was
unreactive (entry 13), the reactivity of the parent 2-fluoro-
5-nitrobenzoate must stem from the coordinating power of
the carboxylate anion to Pd. Since the computational studies
suggested the reactivity of 2-fluorobenzoate, extensive efforts
were made to verify the predictions. Unfortunately, all
attempts to date have failed (entry 14). From an experimental
standpoint, these results appear to suggest that the proximity
of an oxyanionic coordinating group is necessary but alone
not sufficient to activate the fluorobenzene; it requires the
(15) Experimentally it has also been shown that the reactivity of aryl
halides towards Pd(0) addition increases with electron-withdrawing sub-
stituents on the ring as discussed by Fitton, P.; Rick, E. A. J. Organomet.
Chem. 1971, 28, 287-291.
(16) Transition structure geometries (TS-6a, TS-7a, and TS-8a) are
provided in Supporting Information.
(17) Transition structure geometry (TS-8d) is provided in Supporting
Information.
(18) (a) Adam, S.; Bauer, A.; Timpe, O.; Wild, U.; Mestl, G.; Bensch,
W.; Schlo¨gl, R. Chem. Eur. J. 1998, 4, 1458-1469. (b) Quintal, S. M. O.;
Nogueira, H. I. S.; Fe`lix, V.; Drew, M. G. B. New J. Chem. 2000, 24,
511-517. (c) Shi, P.-Y.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Organometallics
2002, 21, 3203-3207.
Org. Lett., Vol. 7, No. 6, 2005
1013

Table 2. Stille Coupling of Aryl Fluorides
Table 3. Suzuki Coupling of Aryl Fluorides
catalyst
temp yield
catalyst
temp yield
entry
R
R1
NO2
CHO
NO2
CN
R2
base
Pd(PPh3)4 (°C)
(%)
entry
R
R1
NO2
R2
base
Pd(PPh3)4 (°C)
(%)
1
Ph
CHO
NO2
CN
10%
10%
10%
10%
65
65
65
65
80
80
65
65
65
65
80
80
80
80
65a
b
1
2
3
4
5
H
H
H
H
H
CHO Cs2CO3
NO2 Cs2CO3
10%
10%
10%
10%
80
80
80
80
80
86a
b
2
Ph
Ph
Ph
Ph
Ph
CHO
NO2
CN
3
56a
b
CN
Cs2CO3
64a
b
4
NO2
NO2 Cs2CO3
5
CO2H
CO2H
NO2 Triton B 10%
NO2 Triton B 40% PPh3
29
c
CO2H
NO2 Triton B, 10%
43
6
Cs2CO3
7
vinyl NO2
vinyl CHO
vinyl NO2
vinyl CN
vinyl CO2H
vinyl CO2H
CHO
NO2
CN
10%
10%
10%
10%
45a
b
6
H
CO2H
NO2 Triton B, 40% PPh3
Cs2CO3
80
c
8
33a
b
9
28a
b
7
CH3O NO2
CH3O CHO
CH3O NO2
CH3O CN
CHO Cs2CO3
NO2 Cs2CO3
10%
10%
10%
10%
65
65
65
65
80
10
11
12
13
14
NO2
8
NO2 Triton B 10%
NO2 Triton B 40% PPh3
36a
c
9
CN
Cs2CO3
49a
b
10
11
NO2 Cs2CO3
vinyl CO2CH3 NO2
vinyl CO2H
10%
Triton B 10%
b
b
CH3O CO2H
NO2 Triton B, 10%
30a
H
Cs2CO3
12
CH3O CO2H
NO2 Triton B, 40% PPh3
Cs2CO3
80
c
a The reactions were carried out using 2.7 mmol of organotin compound,
1.5 equiv of fluorobenzene derivative, and 1.5 equiv of Triton B for entries
5, 6, 11, 12, and 14 in 25 mL of DMF; the amount of the catalyst, ligand,
and temperature are indicated. The reaction mixtures were degassed three
times by alternately connecting to house vacuum and nitrogen prior to
heating. All reactions were carried out at the listed temperature for at least
24 h. b No product was detected at higher temperatures. c Control experiment
in the absence of Pd source. No product was detected.
13
14
CH3O CO2CH3 NO2 Cs2CO3
CH3O CO2H
10%
Triton B, 10%
80
80
b
b
H
Cs2CO3
a The reactions were carried out using 2.7 mmol of the boronic acid, 1.5
equiv of fluorobenzene, 2.25 equiv of base (as well as 1.5 equiv of Triton
B for entries 5, 6, 11, 12, and 14) in 25 mL of DMF; the amount of the
catalyst, ligand and temperature are indicated. The reaction mixtures were
degassed three times by alternately connecting to house vacuum and nitrogen
prior to heating. All reactions were carried out at the listed temperature for
at least 24 h. b No product was detected at higher temperatures. c Control
experiment in the absence of Pd source. No product was detected.
combination of a properly positioned strong electron-
withdrawing group as well as the proximity of a coordinating
group to activate the system toward palladium-catalyzed
coupling.19
zenes is a general effect and will be observed for other
fluorobenzenes with a proximal anionic group and electron-
withdrawing substituents on the ring. The generality of this
effect and the extent in activating other aryl halides toward
Pd-catalyzed coupling reactions is currently under investiga-
tion in our laboratory and will be reported in due course.
The Suzuki coupling is another useful transformation to
study the reactivity of fluorobenzenes. The reactivity of
fluorobenzenes toward phenylboronic acid and 4-methoxy-
phenylboronic acid was studied, and the results are sum-
marized in Table 3. A very similar reactivity pattern (to Stille
coupling) was observed, i.e., fluorobenzenes need to be
doubly activated to undergo the Suzuki coupling reaction.
The substrates that afforded Suzuki coupling products (Table
3, entries 1, 3, 5, 7, 9, and 11) all contain at least one properly
positioned strong electron-withdrawing group, such as nitro,
formyl, or cyano, as well as a good coordinating group (nitro
or carboxylate) at the ortho position. These results provided
further evidence for the necessity of the combination of a
properly positioned strongly electron-withdrawing group and
a proximal oxyanionic coordinating group to activate fluo-
robenzenes.
Acknowledgment. The authors would like to thank
Professors Stephen L. Buchwald, E. J. Corey, Kendall N.
Houk, Tomas Hudlicky, Larry Overman, and Dean J. Tantillo
for helpful discussions and suggestions. Special thanks are
extended to Drs. Kim Albizati, Mark Guzman, and Robert
Scott for insightful discussions. D.M.K. and Y.M.K. thank
Drs. Melissa Rewolinski, Wolfgang Notz, Qingping Tian,
and the Pfizer summer internship program for financial
support.
Note Added after ASAP Publication. The calculated
activation energies for 6a-8a were incorrectly listed as
6a-6b in the text below Figure 1 in the version published
ASAP February 24, 2005; the corrected version was pub-
lished ASAP February 25, 2005.
In summary, our computational predictions and the
experimental verification confirm that fluorobenzenes with
an o-carboxyl and para electron-withdrawing substituents,
similar to 2-fluoronitrobenzene, are activated toward Stille
and Suzuki couplings. To the best of our knowledge, this is
the first report on Pd-catalyzed coupling reactions of fluo-
robenzenes that do not have an o-nitro group. We predict
that the enhanced reactivity observed for these fluoroben-
Supporting Information Available: Experimental pro-
cedures and spectral data for all of the new compounds and
Cartesian coordinates for all structures. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) To date, the reactivity of 2-fluorobenzoate has not been observed
experimentally. Further screening of experimental conditions is underway
in our laboratory, and results will be reported in due course.
OL047413F
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Org. Lett., Vol. 7, No. 6, 2005