Accelerating palladium-catalyzed C-F bond formation: Use of a microflow packed-bed reactor

Article abstract of DOI:10.1002/anie.201104652

A flow process for Pd-catalyzed C-F bond formation is described. A microreactor with a packed-bed design allows for easy handling of large quantities of insoluble CsF with precise control over reaction times, efficient mixing, and the ability to safely handle elevated temperatures and pressures. A variety of aryl triflates, including heteroaryl ones, were converted into aryl fluorides in short reaction times (see scheme).

Full text of DOI:10.1002/anie.201104652

Communications
DOI: 10.1002/anie.201104652
Fluorination in Flow
À
Accelerating Palladium-Catalyzed C F Bond Formation: Use of a
Microflow Packed-Bed Reactor**
Timothy Noꢀl, Thomas J. Maimone, and Stephen L. Buchwald*
The aryl fluoride motif is a mainstay in a variety of disciplines,
most notably pharmaceuticals, agrochemicals, and in positron
emission tomography (PET). A large number of clinically
approved pharmaceuticals contain this substituent due to its
importance in tailoring the properties of organic molecules.[1]
While numerous methods have been developed to construct
À
aromatic C F bonds, most, if not all, suffer from at least one
drawback with regard to safety, practicality, and/or substrate
scope.[2] Recently, there has been an increase in the number of
new methods, particularly in the use of metal-catalyzed or
-mediated processes. In particular, work by the groups of
Grushin,[3] Sanford,[4] Ritter,[5] Yu,[6] and others[7] have both
À
increased the number of synthetically useful aryl C F bond-
forming reactions as well as deepened our understanding of
the underlying challenges inherent in such processes. The
state of the art of these methodologies, however, are far from
ideal especially when compared to other aryl carbon–
heteroatom bond forming reactions.[8]
Figure 1. Conversion dependence on CsF loading in batch.
We recently described the catalytic conversion of aryl
triflates to aryl fluorides using CsFas the fluoride source and a
Pd-catalyst based on tBuBrettPhos (1).[9]
This fluorination reaction utilized readily
available “FÀ” sources as the fluorine atom
donor. Owing to the exceedingly low
solubility of anhydrous CsF in the non-
polar solvents typically employed for this
transformation (e.g., toluene, cyclohex-
ane) the reaction is visibly saturated with
fluoride, yet increasing the amount of CsF
waste makes this strategy unattractive. Moreover, efficient
mixing becomes increasingly difficult when dealing with large
quantities of insoluble fluoride. These drawbacks in the batch
process make this heterogeneous fluorination reaction an
ideal candidate for microflow technology. Compared to batch
processes, microfluidics offer the advantage of enhanced
heat- and mass-transfer characteristics, high surface-to-
volume ratio, safety of operation at elevated temperatures
and pressures, precise control over residence (reaction) times
and isolation of sensitive reactions from air and moisture.[11]
Herein, we describe the development of a CsF packed-bed
reactor for the Pd-catalyzed conversion of aryl triflates to aryl
fluorides in flow.
À
increases the rate of C F bond formation
(Figure 1).[10] While short reaction times
can be attained using large excesses of CsF, the amount of
We chose to initiate our investigation by modifying our
stainless steel packed-bed reactor design, which has proven
[*] Dr. T. Noꢀl,[+] Dr. T. J. Maimone,[+] Prof. Dr. S. L. Buchwald
Department of Chemistry, Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
Homepage: http://mit.edu/chemistry/buchwald/
[+] These authors contributed equally to this work.
À
À
effective for both C N and C C bond-forming processes in
flow.[12] We anticipated that by replacing the stainless steel
packing with CsF, we could utilize large amounts of fluoride,
as well as capitalize on the excellent mixing that this design
provides. In such a packed-bed reactor, the interfacial area is
governed by the porosity of the packing, and the mean
particle size. To achieve a more uniform flow distribution in
the packed bed, the microreactor was filled with finely ground
CsF that had been filtered to obtain a uniform particle size
distribution of approximately 45–106 mm (see Supporting
Information for details). The typical amount of CsF in one
reactor corresponds to approximately 35 equivalents of
fluoride (based on a 1 mmol scale reaction).
[**] T.N., T.J.M., and S.L.B. thank the Novartis International AG and the
National Institutes of Health (Grant GM46059) for financial support
of this work. T.N. is a Fulbright Postdoctoral Fellow. T.J.M. thanks
the NIH for a postdoctoral fellowship (1F32GM088931). The Varian
300 mhz NMR spectrometer used for portions of this work was
purchased with funds from the National Science Foundation
(Grants CHE 9808061 and DBI 9729592). The authors would like to
acknowledge Dr. Simon Kuhn for helpful and stimulating discus-
sions as well as assistance in particle size distribution measure-
ments.
Due to the hygroscopic nature of CsF, the reactor was
packed in a nitrogen-filled glovebox, and then transferred and
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104652.
8900
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8900 –8903

stored on the benchtop. A microfluidic system was assembled
as shown in Figure 2. Notably, all reagent solutions were
prepared on the bench top and then loaded into a reagent
loop. The reagents were subsequently introduced in the
reactor through a single syringe pump.
Lowering the catalyst loading to 2.5 mol% allowed for full
conversion within 20 min, however unsatisfactory results were
obtained at 1.25 mol% Pd loading (Figure 3a). It is worth
noting that the infusion of stainless steel spheres into the
reactor matrix was also investigated, due to presumed
increases in heat transfer,[13] but gave no advantage over a
pure CsF packing in terms of residence times or product yield.
As stated, one of the major advantages of flow chemistry is
the ability to “superheat” solvents above their boiling point in
a safe and controlled manner by employing a backpressure
regulator (BPR).[14] Figure 3b depicts the temperature
dependence of the Pd-catalyzed fluorination of 1-naphthyl-
triflate in flow employing low catalyst loadings (1.25 mol%
Pd). Although low conversions and yields were obtained at
1108C, excellent conversions and yields were obtained at
temperatures between 120–1408C with 1308C being opti-
mum.
Figure 2. Schematic representation of the microreactor setup for the
The substrate scope of the process is shown in Table 1. For
simplicity of experimental set-up, we utilized a standard
temperature of 1208C and residence time of 20 min for all
fluorination of aryl triflates in flow.
We began by examining the conversion of 1-naphthyltri-
flate to 1-fluoronaphthalene in flow (Figure 3). Utilizing
conditions similar to that in Figure 1 (5 mol% Pd, 0.2m
ArOTf in toluene, 1108C), we were pleased to find that full
conversion was achieved with a residence time of only 10 min.
Table 1: Substrate scope of the Pd-catalyzed fluorination of aryl triflates
in flow.[a–c]
[a] Reaction conditions: ArOTf (1 mmol), [(cinnamyl)PdCl]2 (0.50–2.5
mol%), tBuBrettPhos (1) (Pd:L=1:1.5), toluene (5 mL), 1208C,
35 mLminÀ1 flow rate, 20 min residence time. [b] Yields of isolated
products, average of two runs. [c] mol% of palladium equivalents (“Pd”).
[d] Yield for 3 mmol experiment=80% (8 h experiment). [e] T=1308C.
substrates. A single reactor was used to process the substrates
in groups of two or three (1 mmol each) with an intermittent
wash step of the reactor (using anhydrous toluene) between
runs. Importantly, this demonstrated that the reactor could be
re-used multiple times. Excellent results were obtained for a
Figure 3. Pd-catalyzed fluorination of 1-naphthyltriflate in flow: a) Cata-
lyst loading and residence time comparison at 1108C. b) Temperature
dependence with low catalyst loading (1.25 mol% Pd, 20 min resi-
dence time).
Angew. Chem. Int. Ed. 2011, 50, 8900 –8903
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8901

Communications
1886; c) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur,
Chem. Soc. Rev. 2008, 37, 320 – 330; d) S. M. Ametamey, M.
Honer, P. A. Schubiger, Chem. Rev. 2008, 108, 1501 – 1516;
e) K. L. Kirk, Org. Process Res. Dev. 2008, 12, 305 – 321.
[2] a) G. Balz, G. Schiemann, Ber. Dtsch. Chem. Ges. 1927, 60, 1186 –
1190; b) G. C. Finger, C. W. Kruse, J. Am. Chem. Soc. 1956, 78,
6034 – 6037; c) V. W. Pike, F. I. Aigbirhio, J. Chem. Soc. Chem.
Commun. 1995, 2215 – 2216; d) H. Sun, S. G. DiMagno, Angew.
Chem. 2006, 118, 2786; Angew. Chem. Int. Ed. 2006, 45, 2720;
e) G. Sandford, J. Fluorine Chem. 2007, 128, 90 – 104; f) V. V.
Grushin, J. W. Marshall, Organometallics 2008, 27, 4825 – 4828;
g) B. Wang, L. Qin, K. D. Neumann, S. Uppaluri, R. L. Cerny,
S. G. DiMagno, Org. Lett. 2010, 12, 3352 – 3355; h) J. W.
Graskemper, B. Wang, L. Qin, K. D. Neumann, S. G. DiMagno,
Org. Lett. 2011, 13, 3158 – 3161; i) P. Anbarasan, H. Neumann,
M. Beller, Angew. Chem. 2010, 122, 2265 – 2268; Angew. Chem.
Int. Ed. 2010, 49, 2219 – 2222; j) S. Yamada, A. Gavryushin, P.
Knochel, Angew. Chem. 2010, 122, 2261 – 2264; Angew. Chem.
Int. Ed. 2010, 49, 2215 – 2218.
[3] a) S. L. Fraser, M. Y. Antipin, V. N. Khroustalyov, V. V. Grushin,
J. Am. Chem. Soc. 1997, 119, 4769 – 4770; b) V. V. Grushin,
Chem. Eur. J. 2002, 8, 1006 – 1014; c) W. J. Marshall, V. V.
Grushin, Organometallics 2003, 22, 555 – 562; d) V. V. Grushin,
W. J. Marshall, Organometallics 2007, 26, 4997 – 5002; e) V. V.
Grushin, U.S. Patent 7,202,388, 2007; f) V. V. Grushin, Acc.
Chem. Res. 2010, 43, 160 – 171.
[4] a) K. L. Hull, W. Q. Anani, M. S. Sanford, J. Am. Chem. Soc.
2006, 128, 7134 – 7135; b) N. D. Ball, M. S. Sanford, J. Am. Chem.
Soc. 2009, 131, 3796 – 3797; c) N. D. Ball, J. W. Kampf, M. S.
Sanford, Dalton Trans. 2010, 39, 632 – 640.
[5] a) T. Furuya, H. M. Kaiser, T. Ritter, Angew. Chem. 2008, 120,
6082 – 6085; Angew. Chem. Int. Ed. 2008, 47, 5993 – 5996; b) T.
Furuya, T. Ritter, J. Am. Chem. Soc. 2008, 130, 10060 – 10061;
c) T. Furuya, A. E. Strom, T. Ritter, J. Am. Chem. Soc. 2009, 131,
1662 – 1663; d) T. Furuya, T. Ritter, Org. Lett. 2009, 11, 2860 –
2863; e) P. Tang, T. Furuya, T. Ritter, J. Am. Chem. Soc. 2010,
132, 12150 – 12154; f) T. Furuya, D. Benitez, E. Tkatchouk, A. E.
Strom, P. Tang, W. A. Goddard III, T. Ritter, J. Am. Chem. Soc.
2010, 132, 3793 – 3807.
[6] X. Wang, T.-S. Mei, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131, 7520 –
7521.
[7] a) A. W. Kaspi, A. Yahav-Levi, I. Goldberg, A. Vigalok, Inorg.
Chem. 2008, 47, 5 – 7; b) A. W. Kaspi, I. Goldberg, A. Vigalok, J.
Am. Chem. Soc. 2010, 132, 10626 – 10627.
wide variety of substrates. Aryl triflates bearing esters,
ketones, and cyano groups were well tolerated, as well as a
variety of heteroaryl triflates. A number of electron-deficient
substrates could be fluorinated using relatively low catalysts
loadings (1.5–2.0 mol% Pd) and by employing higher
temperatures (i.e. 1308C), 4-nonanoylphenyl triflate could
be converted to its corresponding fluoride in 86% yield using
only 1 mol% Pd. These results represent some of the lowest
À
catalyst loadings reported for any aryl C F bond forming
reaction. The reactors performance for continuous, longer
experiments was also examined. We were pleased to find that
3 mmol of 1-naphthyltriflate could be fluorinated without a
decrease in yield and without any noticeable microreactor
clogging during the 8 h experiment. Similar to the batch
process,[9] electron-rich aryl triflates, especially those lacking
ortho substituents, were problematic. The requirement of full
dissolution of the starting materials in toluene also represents
a known technical limitation of the described chemistry,
although conducting the reaction under dilute conditions can
partially circumvent this problem.
À
In summary, we have described the first aryl C F bond
forming reaction in flow.[15] A packed-bed reactor design
allowed for easy handling of large quantities of insoluble CsF
with excellent mixing, precise control over reaction times, and
the ability to safely handle elevated temperatures and
pressures. Moreover the reusability of the reactor design
was demonstrated as well as its capacity to handle longer
experiments. The apparent complexity of many microfluidic
systems can be overwhelming at times to users unfamiliar with
such equipment. The system described herein, however, is
operationally simple—only a single syringe pump is required.
Vital to the success of this technology is the exceedingly low
solubility of CsF in the reaction medium thus preventing
simple dissolution of the reactor.[16] While efforts to improve
the batch process with respect to substrate scope are ongoing,
we feel the results reported herein will allow for smooth
transfer of future enhancements to flow.
[8] a) A. R. Muci, S. L. Buchwald, Top. Curr. Chem. 2002, 219, 131 –
209; b) J. F. Hartwig, Nature 2008, 455, 314 – 322; c) J. F. Hartwig,
Acc. Chem. Res. 2008, 41, 1534 – 1544; d) D. Surry, S. L.
Buchwald, Chem. Sci. 2011, 2, 27 – 50.
[9] D. A. Watson, M. Su, G. Teverovskiy, Y. Zhang, J. Garcꢁa-
Fortanet, T. Kinzel, S. L. Buchwald, Science 2009, 325, 1661 –
1664.
[10] While mechanistic studies are ongoing, we have also observed
that the reaction rate is highly dependent on the CsF particle
size. A particle size measurement for the CsF employed in this
study can be found in the Supporting Information.
[11] For some selected reviews pertaining to flow chemistry, see:
a) S. V. Ley, I. R. Baxendale, Nat. Rev. Drug Discovery 2002, 1,
573 – 586; b) B. P. Mason, K. E. Price, J. L. Steinbacher, A. R.
Bogdan, D. T. McQuade, Chem. Rev. 2007, 107, 2300 – 2318;
c) K. Geyer, T. Gustafsson, P. H. Seeberger, Synlett 2009, 2382 –
2391; d) R. L. Hartman, K. F. Jensen, Lab Chip 2009, 9, 2495 –
2507; e) D. Webb, T. F. Jamison, Chem. Sci. 2010, 1, 675 – 680;
f) C. G. Frost, L. Mutton, Green Chem. 2010, 12, 1687 – 1703;
g) R. L. Hartman, J. P. McMullen, K. F. Jensen, Angew. Chem.
2011, DOI: 10.1002/ange.201004637; Angew. Chem. Int. Ed.
2011, DOI: 10.1002/anie.201004637; h) T. Noꢂl, S. L. Buchwald,
Chem. Soc. Rev. 2011, DOI: 10.1039/c1cs15075h.
Experimental Section
A toluene solution of the aryl triflate (0.2m), [(cinnamyl)PdCl]2 (1–
5 mm), and tBuBrettPhos (3–15 mm) was injected into a reagent loop
(5 mL). This solution was delivered to a packed-bed reactor (700 mL,
packed with anhydrous, ground CsF (particle size 45–106 mm) at
1208C using a single Harvard Apparatus syringe pump (35 mLminÀ1).
Next, the sample was collected, which corresponded to exactly
1 mmol. Further details on the equipment setup and workup
procedures can be found in the Supporting Information.
Sample analysis: GC analysis and 19F NMR spectroscopy were
used to determine the conversions. NMR and IR spectroscopies were
used to identify the products.
Received: July 5, 2011
Published online: August 11, 2011
Keywords: cross-coupling · flow chemistry · fluorination ·
.
microreactors · palladium
[1] a) M. E. Phelps, Proc. Natl. Acad. Sci. USA 2000, 97, 9226 – 9233;
b) K. Mꢀller, C. Faeh, F. Diederich, Science 2007, 317, 1881 –
8902 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8900 –8903

[12] a) J. R. Naber, S. L. Buchwald, Angew. Chem. 2010, 122, 9659 –
9664; Angew. Chem. Int. Ed. 2010, 49, 9469 – 9474; b) T. Noꢂl, S.
Kuhn, A. J. Musacchio, K. F. Jensen, S. L. Buchwald, Angew.
Chem. 2011, 123, 6065 – 6068; Angew. Chem. Int. Ed. 2011, 50,
5943 – 5946; c) P. Li, S. L. Buchwald, Angew. Chem. 2011, 123,
6520 – 6524; Angew. Chem. Int. Ed. 2011, 50, 6396 – 6400.
[15] For fluorination reactions of aliphatic alcohols using diethyla-
minosulfur trifluoride (DAST) in flow, see: a) T. Gustafsson, R.
Gilmour, P. H. Seeberger, Chem. Commun. 2008, 3022 – 3024;
b) M. Baumann, I. R. Baxendale, S. V. Ley, Synlett 2008, 2111 –
2114; c) M. Baumann, I. R. Baxendale, L. J. Martin, S. V. Ley,
Tetrahedron 2009, 65, 6611 – 6625.
[13] Thermal conductivities (l) at 298 K: stainless steel =
[16] We flowed ca. 20 mL of anhydrous toluene through the reactor
(T= 1208C) and then evaporated the resulting solution to
dryness; no solid CsF was detected.
16 WmÀ1 KÀ1; CsF = 3.37 WmÀ1 KÀ1
.
[14] T. Razzaq, C. O. Kappe, Chem. Asian J. 2010, 5, 1274 – 1289.
Angew. Chem. Int. Ed. 2011, 50, 8900 –8903
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8903