Palladium-catalyzed arylation of ethyl cyanoacetate. Fluorescence resonance energy transfer as a tool for reaction discovery [21]

Full text of DOI:10.1021/ja0157402

J. Am. Chem. Soc. 2001, 123, 4641-4642
Palladium-Catalyzed Arylation of Ethyl
4641
Cyanoacetate. Fluorescence Resonance Energy
Transfer as a Tool for Reaction Discovery
Shaun R. Stauffer, Neil A. Beare, James P. Stambuli, and
John F. Hartwig*
Department of Chemistry, Yale UniVersity
P.O. Box 208107, New HaVen, Connecticut 06520-8107
Figure 1. Yields by FRET for 113 reactions using different ligands.
ReceiVed March 1, 2001
ReVised Manuscript ReceiVed April 2, 2001
Scheme 1
Rapid, parallel methods to evaluate catalyst activity provide
the potential to accelerate the discovery of new reactions.1
Recently, we developed an efficient screen based on fluorescence
resonance energy transfer (FRET), and we demonstrated the utility
of this assay by identifying catalysts for room temperature Heck
reactions of aryl bromides.2,3 The FRET assay provides product
yields in roughly 1 s per sample. Although it requires an initial
synthetic investment, our assay can be more general and less
instrument-intensive than methods based on serial chromatogra-
phy,4,5 substrateswithspecialelectronicproperties,6IRthermography,7-9
or mass spectrometry.10-12 We describe our experiments using
the FRET-based method to uncover catalysts and reaction
conditions for the arylation of cyanoacetates. This work constitutes
an unusual example of high-throughput screening used during
the discovery of a new method of bond-construction.13,14
R-Aryl cyanoacetates are useful intermediates in the preparation
of amino alcohols,15 â-amino acids,16,17 and arylacetic acids,18 all
of which are common synthetic building blocks. Previous methods
for the direct coupling of cyanoacetates with aryl halides used
stoichiometric amounts or high catalyst loadings of copper and
required iodide substrates and high temperatures.13,19,20 The mild
arylation of cyanoesters reported here displays broad reaction
scope and the ability to construct materials with highly hindered
quaternary carbons.
FRET occurs when the fluorescence emission band of one
molecule (donor) overlaps with an excitation band of a second
(acceptor) that is proximal to the donor (20-80 Å).21,22 At an
appropriate constant total concentration of free and associated
FRET pairs, the emission of the FRET donor is inversely related
to the mole fraction of associated molecules, or reaction yield in
our case. A commercial, inexpensive fluorescence plate reader
provides the fluorescence measurements.
Scheme 1 shows the two reagents we used to evaluate catalysts
for cyanoester arylation. A dansyl fluorophore was tethered to a
cyanoester (1), and an azodye quencher was tethered to an aryl
bromide (2). Compounds 1 and 2 were synthesized by conven-
tional methods (see Supporting Information). The emission of
dansyl 1 overlaps with an absorption band of diazo dye 2. Upon
coupling of 1 with 2, the emission of the dansyl group was
quenched by the diazo compound. The emission intensity was
converted to reaction yield using a linear plot that correlated
emission intensity with mole fraction of coupled product.
With substrates 1 and 2 in hand, we conducted reactions in a
96-well format, delivering reagents from stock solutions using a
multichannel pipet. For the first experiment, each well contained
a different ligand from a 113-membered library, 39 of which were
commercially available and 38 of which are new materials. The
structures of the library components and synthetic procedures for
new ligands are provided as Supporting Information.
All reactions were conducted using a 1:1 ratio of 1 and 2, 5.0
mol % CpPd(allyl), 10.0 mol % ligand (5.0 mol % for bidentate
ligands), and 2.0 equiv of K3PO4. The final solutions contained
a 0.15 M concentration of substrate (7.5 µmoles) in a 10% H2O/
m-xylene solvent system. The plate was sealed and heated while
agitating at 80 °C for 8 h. After this time, an aliquot was removed
from each well, diluted with m-xylene to 10-5 M, and analyzed
with a fluorescent plate reader. This assay was run in duplicate.
The results of this screen are presented in Figure 1 as average
yields. Of the 23 ligands that showed measurable activity (>10%
yield) in at least one of the two experiments, only eight ligands
showed a coefficient of variation greater than 0.30. Reactions
using these eight ligands were conducted a third time. Using these
data, the overall 12 most effective ligands (Figure 2) were selected
for further optimization. The yields from this screen were low in
part due to the inherent hydrolysis of 1; however, the relative
amounts of hydrolysis product were similar enough to have no
bearing on the relative activities of the different catalysts.
(1) Jandeleit, B.; Schaefer, D. J.; Powers, T. S.; Turner, H. W.; Weinberg,
W. H. Angew. Chem., Int. Ed. 1999, 38, 2495.
(2) Stambuli, J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F. J.
Am. Chem. Soc. 2001, 123, 2677.
(3) For a different fluorescent assay see: Harris, R. F.; Nation, A. J.;
Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2000, 122, 11270.
(4) Burgess, K.; Lim, H.-J.; Porte, A. M.; Sulikowski, G. A. Angew. Chem.,
Int. Ed. 1996, 35, 220.
(5) Porte, A. M.; Reibenspies, J.; Burgess, K. J. Am. Chem. Soc. 1998,
120, 9180.
(6) Lavastre, O.; Morken, J. P. Angew. Chem., Int. Ed. 1999, 38, 3163.
(7) Reetz, M. T.; Becker, M. H.; Liebl, M.; Furstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 1236.
(8) Taylor, S. J.; Morken, J. P. Science 1998, 280, 267.
(9) Holzwarth, A.; Schmidt, H.-W.; Maier, W. F. Angew. Chem., Int. Ed.
1998, 37, 2644.
(10) Guo, J.; Wu, J.; Siuzdak, G.; Finn, M. G. Angew. Chem., Int. Ed.
1999, 38, 1755.
(11) Reetz, M. T.; Becker, m. H.; Klein, H.-W.; Stockigt, D. Angew. Chem.,
Int. Ed. 1999, 38, 1758.
(12) Hinderling, C.; Chen, P. Angew. Chem., Int. Ed. 1999, 38, 2253.
(13) Three examples of palladium-catalyzed malonate arylation have been
reported: Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473.
Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. J. Am. Chem. Soc. 2000,
122, 1360.
(14) The palladium-catalyzed reaction of aryl iodides with ethyl cyano-
acetate and malononitrile has been reported, but we have not observed product
formation with the catalyst described. Uno, M.; Seto, K.; Ueda, W.; Masuda,
M.; Takahashi, S. Synthesis 1985, 506. Uno, M.; Seto, K.; Takahashi, S. Chem.
Commun. 1984, 932.
(15) Knabe, J.; Buchheit, W. Arch. Pharm. (Weinheim, Ger.) 1985, 318,
593.
(16) Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A. J. Org. Chem.
1994, 59, 2497.
(17) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1.
(18) Brunner, H.; Schmidt, P. Eur. J. Org. Chem. 2000, 2119.
(19) Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993,
58, 7606.
(21) Wu, P.; Brand, L. Anal. Biochem. 1994, 218, 1.
(22) Stryer, L.; Haugland, R. P. Proc. Natl. Acad. Sci. U.S.A. 1967, 58,
719.
(20) Osuka, A.; Kobayashi, T.; Suzuki, H. Synthesis 1983, 67.
10.1021/ja0157402 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/24/2001

4642 J. Am. Chem. Soc., Vol. 123, No. 19, 2001
Communications to the Editor
Table 1. Preparative Scale Arylation of Ethyl Cyanoacetatea
Figure 2. Ligands that gave >20% arylcyanoester (ligand #, yield).
a Reactions conducted on a 1 mmol scale in toluene using 1.1 equiv
of cyanoacetate, 1.0 equiv of aryl halide, and 3 equiv of Na3PO4. Yields
are for isolated material and are an average of two runs. b 1.0%
[(allyl)PdCl]2 used. c Room temperature, 96 h. d 0.050% [(allyl)PdCl]2
used, 7 h at 100 °C. e 1.0% [(allyl)PdCl]2 used, 8 h at 100 °C. f 1.0%
[(allyl)PdCl]2 used, 12 h at 100 °C.
Scheme 2
Using the reaction conditions that were optimal for rate, we
evaluated the scope of the process. Pd(dba)2 was not soluble
Figure 3. Evaluation of different bases using the FRET assay.
25
enough to prepare stock solutions for the above screens, but it
was an equally effective precatalyst as [(allyl)PdCl]2 for prepara-
tive reactions. Table 1 shows results of synthetic studies using
ligands 66 and 72 and demonstrates the broad scope of the
process. Reactions of aryl bromides that are activated or deacti-
vated all occurred in high yields, as did reactions of ortho-
substituted aryl bromides. Even reactions of deactivated and ortho-
substituted aryl chlorides occurred in good yields.23,24 Generally,
2 mol % of catalyst was used, but the coupling of ethyl
cyanoacetate with bromobenzene occurred in 88% yield when
using 0.1 mol % catalyst at 100 °C. Furthermore, reactions could
be conducted at low temperatures when using adamantyl ligand
72. Ethyl cyanoacetate reacted with bromobenzene using 2.0 mol
% catalyst in 87% yield after 96 h at room temperature.
The process can be used to produce diarylcyanoacetates
(Scheme 2), as well as monoarylcyanoacetates. Using the standard
procedure, the addition of 2 equiv of bromobenzene generated
ethyl diphenylcyanoacetate in good yield. Alternatively, reaction
of a phenylcyanoacetate with a substituted aryl bromide gave the
unsymmetrical diaryl cyanoacetate efficiently. Thus, this meth-
odology is suitable for the formation of highly hindered quaternary
carbons. Alkyl-substituted ethyl cyanoacetates have not yet served
as suitable substrates.
The 12 ligands were examined in a second screen to determine
if the optimal precatalyst varied with ligand structure. Precatalysts
for this screen included CpPd(allyl), Pd(OAc)2, and [(allyl)PdCl]2.
We also included Ni(COD)2 in this assay. The most effective
precatalyst did not vary with ligand; catalysts formed from
[(allyl)PdCl]2 or CpPd(allyl) gave similar activity, while those
formed from Pd(OAc)2 showed lower activity. Those formed from
Ni(COD)2 showed no activity. A third screen conducted at 70
°C evaluated four tertiary amines in addition to K3PO4 and Na3PO4
as base (Figure 3). For 10 out of the 12 ligands screened, the use
of Na3PO4 greatly improved reaction yields, while Et3N was
shown to be effective when the bulky alkyl phosphines 66, 70,
and 72 were used. Use of this base would allow for reactions of
solid-supported substrates.
Nine of the ligands that generated the most active catalysts
from this screen, 4, 5, 17, 26, 31, 66, 70, 72, and 73, were chosen
to compare activity for anhydrous reactions on a 1 mmol scale
using phenyl bromide and ethyl cyanoacetate. Di(1-adamantyl)-
ferrocenyl phosphine was also included because of the somewhat
higher activity observed when using ligand 5 relative to 4 (see
Figure 3). At 70 °C in toluene solvent, using 3 equiv of Na3PO4
as base and 1 mol % [(allyl)PdCl]2 as catalyst precursor, reactions
containing the trialkyl phosphines 66, 70, 72, and 73 and the
pentaphenyl ferrocenyl 17 gave quantitative conversion of product
after 2 h, while reactions employing 4, 5, or di(1-adamantyl)-
ferrocenyl phosphine required 3-5 h for full conversion. Reac-
tions employing 26 and 31 were complete after 10 h.
As a final step, we fine-tuned the reaction conditions using
these most active ligands 66, 70, 72, and 73. Catalysts containing
the 1-adamantyl ligands 70 and 72 were similar in activity and
slightly more reactive than those containing P(t-Bu)3 66, which
were more active than those with the 2-adamantyl ligand 73.
Reactions in toluene solvent were the fastest, followed closely
by those in dioxane. Acetonitrile and 1,2-dichloroethane were also
suitable solvents, but reaction times were a factor of 2 to 3 longer.
In contrast to other coupling processes with ligand 66, no
difference in reaction rate was observed when using a 0.8:1.0;
1.0:1.0, or 2.0:1.0 ratio of ligand to metal.23,24
In summary, we have demonstrated a rare example of the
discovery and optimization of a new method for bond construction
using high-throughput screening. The coupling process is general
and should serve as a useful method for forming â-arylamines,
alcohols, and diarylacetic acids. Formation and reaction of these
products in an enantioselective fashion and an understanding of
the reaction mechanism will be the subject of future studies.
Acknowledgment. We thank the NIH (R01-GM58108) for support
of this work. S.R.S. thanks the NIH (GM-20191-01) for postdoctoral
fellowship support.
Supporting Information Available: Structures and synthetic methods
for preparation of ligands used in the screening assay and experimental
procedures for catalyst screening (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
JA0157402
(23) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575.
(24) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(25) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. J.
Organomet. Chem. 1974, 65, 253.