Palladium/tris(tert-butyl)phosphine-catalyzed Suzuki cross-couplings in the presence of water

Article abstract of DOI:10.1002/adsc.201000267

Dipalladiumtris(dibenzylideneacetone)/tris(tert-butyl)phosphonium tetrafluoroborate/potassium fluoride dihydrate [Pd₂(dba) ₃/[HP(t-Bu)₃]BF₄/KF·2H₂O] serves as a mild, robust, and user-friendly method for the efficient Suzuki cross-coupling of a diverse array of aryl and heteroaryl halides with aryl- and heteroarylboronic acids.

Full text of DOI:10.1002/adsc.201000267

UPDATES
DOI: 10.1002/adsc.201000267
Palladium/Tris(tert-butyl)phosphine-Catalyzed Suzuki Cross-
Couplings in the Presence of Water
Sha Loua and Gregory C. Fua,*
a
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Fax : (+1)-617-324-3611; e-mail: gcf@mit.edu
Received: April 5, 2010; Published online: July 21, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000267.
Abstract: Dipalladiumtris(dibenzylideneacetone)/
tris(tert-butyl)phosphonium tetrafluoroborate/potas-
sium fluoride dihydrate [Pd2ACHTNUGTRENN(UG dba)3/[HPHCAUTNTGREN(NUGN t-Bu)3]BF4/
bly lower yield than an arylboronic acid that had
been freshly recrystallized from water [Eq. (1)].
In view of these observations, we decided to pursue
KF·2H2O] serves as a mild, robust, and user-friend-
ly method for the efficient Suzuki cross-coupling of
a diverse array of aryl and heteroaryl halides with
aryl- and heteroarylboronic acids.
the development of a new procedure for Pd/PACHTUNGTRENNUNG(t-Bu)3-
catalyzed Suzuki reactions that would be less depen-
dent on the origin of the arylboronic acid. In this
Update, we describe a method that we believe ad-
dresses this issue [Eq. (2)].
Keywords: boron; cross-coupling; halides; palladi-
um; water
Introduction
We and others have demonstrated that trialkylphos-
phines, including PACHTNUTRGNEUNG(t-Bu)3 and PCy3, are unusually ef-
fective ligands for a range of coupling processes.[1] Results and Discussion
This generalization includes the Suzuki reaction,
which is perhaps the most widely used cross-coupling In early experiments, we determined that the addition
method for carbon-carbon bond formation.[2–4]
of a small amount of water to the “dried” arylboronic
We have observed that the efficiency of Pd/PACHTUNGTERNN(UNG t- acid led to a more efficient Suzuki reaction (Table 1,
Bu)3-catalyzed Suzuki reactions can vary significantly, entries 2–5).[7,8] This suggested that, rather than em-
depending on the batch of arylboronic acid that is ploying anhydrous KF, it would be preferable to use
used. We hypothesized that this might be due to dif- the commercially available dihydrate (KF·2H2O;
ferences in the amounts of arylboronic acid vs. anhy- entry 2 vs. entry 6). In addition to restoring the effi-
dride (or water) that are present.[5,6] Indeed, we deter- ciency of the Pd/P
ACTHNUTRGNEU(GN t-Bu)3-catalyzed Suzuki cross-cou-
mined that, under the standard conditions that we pling, this modification has the added advantage of a
had described earlier,[3c] an arylboronic acid that had very substantial cost saving [price per mole: anhy-
been dried under vacuum cross-couples in considera- drous KF ($450/mol); KF·2H2O ($19/mol)].[9] The
Adv. Synth. Catal. 2010, 352, 2081 – 2084
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Sha Lou and Gregory C. Fu
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Table 1. Effect of reaction conditions on Pd/P
lyzed Suzuki cross-couplings.
(tBu)3-cata-
Table 2. Suzuki cross-couplings of aryl and heteroaryl bro-
mides with aryl-, heteroaryl-, and alkenylboronic acids [for
the reaction conditions, see Eq. (2)].
[a]
1
The yield was determined by H NMR spectroscopy vs.
an internal standard.
Anhydrous (Aldrich).
[b]
[c]
Heated at 1208C at 300 mtorr for 1.0 h.
procedure using KF·2H2O appears to be robust, pro-
viding good yields of the biaryl with a variety of bor-
onic acid sources (entries 6–8), as well as in the pres-
ence of additional water (entry 9).
For small-scale reactions and/or for parallel synthe-
sis, weighing small amounts of Pd
or [HP
(t-Bu)3]BF4 can be tedious and inaccurate.[10]
To circumvent these issues, we recommend the use of
pre-made mixture of Pd2A(dba)3/[HP(t-Bu)3]BF4
[Pd:P(t-Bu)3 =1:1.2] as a convenient one-component
2ACHTUNGTNERNUG(dba)3 and PACHTUNTGERN(NUGN t-Bu)3
ACHTUNGTRENNUNG
a
C
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
source of palladium and P
ACHTUNGTNER(NUGN t-Bu)3 (see the Supporting
Information).[11]
The Pd2ACHTUNGTRENNUNG(dba)3/[HPCAHTUNGTRNE(NUGN t-Bu)3]BF4/KF·2H2O procedure
can be applied to Suzuki cross-couplings of a wide
array of substrates (Table 2).[12] Thus, a variety of aryl
bromides are suitable reaction partners, including hin-
dered (entries 1–3) and deactivated (entry 4) com-
pounds. In addition, an aryl bromide can be cross-
coupled selectively in the presence of an aryl chloride
(entry 5). Furthermore, a range of nitrogen-containing
[a]
Yield of purified product (average of two experiments).
Not only aryl bromides, but also aryl iodides [Eq.
heteroaryl bromides and heteroarylboronic acids are (3)] and vinyl bromides [Eq. (4)], undergo Suzuki
useful reaction partners (entries 6–10). coupling under this standard set of conditions. In ad-
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Palladium/Tris(tert-butyl)phosphine-Catalyzed Suzuki Cross-Couplings
Table 3. Suzuki cross-couplings of activated aryl and hetero-
Experimental Section
aryl chlorides with aryl-, heteroaryl-, and alkenylboronic
acids [for the reaction conditions, see Eq. (2)].
General Procedure for Pd/P
Cross-Couplings
ACHTUNGTNER(NNUG t-Bu)3-Catalyzed Suzuki
Pd
(dba)3/[HP
E
[Pd:P
G
8.1 mg,
0.0050 mmol of Pd CTHUNGTRENNUNG
and KF·2H2O (310 mg, 3.30 mmol) were added to a 4-mL
vial that contained a stir bar. The vial was purged with
argon for 3 min, and then it was sealed with a septum cap.
THF (2.0 mL) and the aryl halide (1.00 mmol) were added,
and the reaction mixture was stirred at room temperature.
Next, the mixture was diluted with Et2O (2 mL) and filtered
through a plug of silica gel [washed with Et2O (10 mL)].
The filtrate was concentrated, and the residue was purified
by flash chromatography on silica gel.
Supporting Information
General information and compound characterization data
are available as Supporting Information.
Acknowledgements
Support has been provided by the National Institutes of
Health (National Institute of General Medical Sciences, grant
R01-GM62871), Merck Research Laboratories, and Novartis.
We thank Dr. Xing Dai for a preliminary study.
[a]
Yield of purified product (average of two experiments).
The isolated biaryl product is a 4:1 mixture of the alde-
[b]
hyde and its hydrate.
References
dition,
Pd
(dba)3/[HP
E
can
[1] For leading references, see: G. C. Fu, Acc. Chem. Res.
2008, 41, 1555–1564.
[2] For reviews, see: a) Metal-Catalyzed Cross-Coupling
Reactions, (Eds.: A. de Meijere, F. Diederich), Wiley-
VCH, New York, 2004; b) Handbook of Organopalla-
dium Chemistry for Organic Synthesis, (Ed.: E.-i. Ne-
gishi), Wiley-Interscience, New York, 2002.
achieve cross-couplings of a variety of activated aryl
chlorides with an array of arylboronic acids
(Table 3).[13] Both nitrogen and sulfur heterocycles are
tolerated (entries 4–7), as are a wide range of sub-
stituents. Alkenylboronic acids are also suitable cou-
pling partners (entry 7).
[3] For the development of methods for Pd/PACTHNURGTNEUNG(t-Bu)3- and
Pd/PCy3-catalyzed Suzuki reactions, see: a) A. F.
Littke, G. C. Fu, Angew. Chem. 1998, 110, 3586–3587;
Angew. Chem. Int. Ed. 1998, 37, 3387–3388; b) A. F.
Littke, C. Dai, G. C. Fu, J. Am. Chem. Soc. 2000, 122,
4020–4028; c) M. R. Netherton, G. C. Fu, Org. Lett.
2001, 3, 4295–4298; d) N. Kudo, M. Perseghini, G. C.
Fu, Angew. Chem. 2006, 118, 1304–1306; Angew.
Chem. Int. Ed. 2006, 45, 1282–1284.
Conclusions
In summary, we have developed a versatile, user-
friendly method for Suzuki reactions that employs a
commercially available one-component source of
Pd/P
ACHTUNGTRENNUNG
[4] For a few recent examples of applications of Pd/PACHTUNGTRENNUNG(t-
Pd2A(dba)3/[HPACHTUNGTRENNUNG
G
Bu)3-catalyzed Suzuki reactions, see: a) T. Amaya, T.
Nakata, T. Hirao, J. Am. Chem. Soc. 2009, 131, 10810–
10811; b) W. Huang, L. Su, Z. Bo, J. Am. Chem. Soc.
2009, 131, 10348–10349; c) H. Ihara, M. Suginome, J.
Am. Chem. Soc. 2009, 131, 7502–7503.
cross-couplings of a diverse set of aryl/heteroaryl hal-
ides with a range of aryl/heteroarylboronic acids at
room temperature in good yield. The reaction compo-
nents are air-stable, and the method is not moisture-
sensitive. We anticipate that this procedure may
prove useful to others.
[5] For an example of related, independent observations
by others, see: A. Antoft-Finch, T. Blackburn, V.
Snieckus, J. Am. Chem. Soc. 2009, 131, 17750–17752.
[6] For an overview of boronic acids, see: Boronic Acids,
(Ed.: D. G. Hall), Wiley-VCH, Weinheim, 2005.
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Sha Lou and Gregory C. Fu
UPDATES
[7] We have previously described the use of dioxane/water
as a solvent for Pd/PCy3-catalyzed Suzuki reactions
(ref.[3d]).
[11] Pd
able from Strem Chemicals (catalog number 46-3015).
We have observed that Pd2A(dba)3/[HP(t-Bu)3]BF4 can
2CAHTUNGTRNENU(GN dba)3/[HPAHCTUNRTEGG(NNUN t-Bu)3]BF4 [Pd:PACHTNUGTERN(NUGN t-Bu)3 =1:1.2] is avail-
C
ACHTUNGTRENNUNG
[8] For examples of reports of the beneficial effect of
be exposed to air for seven months without a change in
its activity as a Suzuki cross-coupling catalyst.
water on Pd/PACTHUNRGTNEUNG(t-Bu)3-catalyzed Suzuki reactions, see:
a) R. T. Lewis, W. P. Blackaby, T. Blackburn, A. S. R.
Jennings, A. Pike, R. A. Wilson, D. J. Hallett, S. M.
Cook, P. Ferris, G. R. Marshall, D. S. Reynolds, W. F. A.
Sheppard, A. J. Smith, B. Sohal, J. Stanley, S. J. Tye,
K. A. Wafford, J. R. Atack, J. Med. Chem. 2006, 49,
2600–2610; b) S. T. Handy, D. Mayi, Tetrahedron Lett.
2007, 48, 8108–8110; c) M. J. Fray, A. T. Gillmore,
M. S. Glossop, D. J. McManus, I. B. Moses, C. F. B. Pra-
quin, K. A. Reeves, L. R. Thompson, Org. Process Res.
Dev. 2010, 14, 263–271.
[12] a) Under our standard conditions: aryltrifluoroborates
and pinacolboronate esters are not suitable cross-cou-
pling partners; replacement of HPACTHNURGTNEUNG(t-Bu)3]BF4 with
[HPCy3]BF4 results in a slower reaction. b) A gram-
scale reaction (entry 1 of Table 2) proceeded in 97%
yield (1.14 g). c) According to 1H NMR spectroscopy,
the addition of water to the “dried” arylboronic acid in
THF at room temperature led to rapid formation of the
arylboronic acid.
[13] For unactivated aryl chlorides, the catalyst system de-
scribed in ref.[3d] is more effective than the method pro-
vided in Eq. (2).
[9] Aldrich (online prices on 31 March 2010): anhydrous
KF ($196/25 g); KF·2H2O ($100/500 g).
[10] The Pd:PACHTUNGTRENNUNG(t-Bu)3 ratio has an impact on the rate of
cross-coupling. For a discussion, see ref.[3b]
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Adv. Synth. Catal. 2010, 352, 2081 – 2084