Palladium-catalyzed decarboxylative arylation of potassium cyanoacetate: Synthesis of α-diaryl nitriles from aryl halides

Article abstract of DOI:10.1021/ol2009522

A palladium-catalyzed decarboxylative coupling of potassium cyanoacetate with aryl bromides and chlorides is described. The reaction conditions feature the absence of additional strong inorganic bases and provide ester functional group tolerance. With Pd(

Full text of DOI:10.1021/ol2009522

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2912–2915
Palladium-Catalyzed Decarboxylative
Arylation of Potassium Cyanoacetate:
Synthesis of r-Diaryl Nitriles from
Aryl Halides
Pui Yee Yeung, Kin Ho Chung, and Fuk Yee Kwong*
State Key Laboratory of Chirosciences and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong
bcfyk@inet.polyu.edu.hk
Received April 11, 2011
ABSTRACT
A palladium-catalyzed decarboxylative coupling of potassium cyanoacetate with aryl bromides and chlorides is described. The reaction
conditions feature the absence of additional strong inorganic bases and provide ester functional group tolerance. With Pd(dba)2 and XPhos ligand
as the catalyst system, R-diaryl nitriles can be obtained in good yields.
R-Arylated nitriles are important substructures in natu-
rally occurring molecules and pharmaceutically useful
compounds (Figure 1).1 The nitrile moiety is a versatile
functional group that allows further organic transforma-
tions to give the corresponding substituted carboxylic
acids, aldehydes, amides, and amines, as well as nitrogen
heterocycles.2 The FriedelÀCrafts reactions,3 dehydration
of R-substituted amides,4 and cyanation of benzyl halides5
are the traditional methods for synthesizing R-aryl nitriles.
Figure 1. Selected examples of pharmaceutically useful R-dia-
rylated nitriles.
(1) (a) Onuki, M.; Nishiyama, A. JP Patent, JP2010095453
A20100430. (b) Baker, D.; Burce, M.; Cahn, A.; Thomas, M. PCT Int.
Appl. WO2010097114, A1 20100902, 2010. (c) Kuwata, K.; Kimura, T.;
Recently, a palladium-catalyzed R-arylation of nitriles
Muto, J. PCT Int. Appl. WO2010131717, A1 20101118, 2010. (d) Tyagi,
O. D.; Ray, P. C.; Chauhan, Y. K.; Rao, K. Babu.; Reddy, N. M.; Reddy,
D. S. P., PCT Int. Appl. WO2009125430, A2 20091015, 2009. (e) Alnabari,
M.; Freger, B.; Arad, O.; Zelikovitch, L.; Seryi, Y.; Danon, E.; Davidi, G.;
Kaspi, J. U.S. Patent 2006/0035950 A1, 2006. For a review describing the use
of coupling technology for preparing pharmaceutically useful compounds,
see: (f) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442.
with aryl halides was independently established by
Hartwig6 and Verkade7 groups. This protocol applied a
strong base, NaN(TMS3)2, and limited the base-sensitive
functional group compatibility. A significantly improved
method was later reported by Hartwig and co-workers
(2) Friedrich, K.; Wallenfels, K. The Chemistry of the Cyano Group;
Wiley-Interscience: New York, 1970.
(3) For selected example, see: Kurz, M. E.; Lapin, S. C.; Mariam, A.;
Hagen, T. J.; Qian, X. Q. J. Org. Chem. 1984, 49, 2728.
(4) For selected example, see: Narsaiah, A. V.; Nagaiah, K. Adv.
Synth. Catal. 2004, 346, 1271.
(6) For an account, see: (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem.
Res. 2003, 36, 234. For their initial developments, see: (b) Culkin, D. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330. (c) Stauffer, S. R.;
Beare, N. A.; Stambuli, J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
4641.
(7) (a) You, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42, 5051.
(b) You, J.; Verkade, J. G. J. Org. Chem. 2003, 68, 8003.
(5) Chen, G.; Wang, Z.; Wu, J.; Ding, K. Org. Lett. 2008, 10, 4573.
r
10.1021/ol2009522
Published on Web 05/05/2011
2011 American Chemical Society

using relatively expensive R-silyl nitriles and zinc cyano-
alkyl reagents for coupling of aryl bromides.8
We embarked on this investigation from our initial
failure in the arylation of benzylic nitrile using weak
bases under palladium catalysis (Scheme 1). This reac-
tion did not proceed, possibly because of the inefficient
basicity of the weak base for assisting R-deprotonation
of nitriles. Thus, if the acidity of the R-proton is in-
creased by an additional neighboring activating group,
this process would likely be viable.19 Hence, we chose
cyanoacetate as the substrate for the attempted diaryla-
tion process (Scheme 1). Having the additional car-
boxylic group, this type of substrate offers both the
feasibility of R-deprotonation/arylation and a subse-
quent decarboxylative arylation step.
Decarboxylative couplings have been successful as an
alternative CÀC bond construction process to tradi-
tional cross-coupling reactions. Recently, Forgione,9
Glorius,10 Goossen,11 Liu,12 Myers,13 Tunge,14 and others15
made significant advancements of decarboxylative cou-
pling using various electrophiles and nucleophiles. Yet,
to the best of our knowledge, there have been very
limited literature reports16 describing the decarboxyla-
tive method for accessing 2-arylacetonitrile-related ske-
letons. Inspired by the advantages of using decarbox-
ylative coupling (in the absence of transmetallating
agent, e.g., B, Zn, Mg, Si, etc.)17 and our continuing
progress in nitrile synthesis,18 we were attracted to
developing a decarboxylative protocol for preparing
R-substituted nitriles. Herein, we report our exploration
on decarboxylative coupling of potassium cyanoacetates
with aryl halides for synthesizing the R-diarylated ni-
triles. This protocol features both coupling partners that
are readily available.
Scheme 1. Investigations on the Protocol for R-Diaryl Nitrile
Synthesis
(8) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824.
(9) Forgione, P.; Brochu, M. C.; St-Onge, M.; Thesen, K. H.; Bailey,
M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350.
(10) (a) Wang, C.; Rakshit, S.; Glorius, F. J. Am. Chem. Soc. 2010,
132, 14006. (b) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009,
131, 4194.
(11) (a) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662. (b)
Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng, G.; Levy, L. M.
J. Am. Chem. Soc. 2007, 129, 4824. (c) Goossen, L. J.; Zimmermann, B.;
Knauber, T. Angew. Chem., Int. Ed. 2008, 47, 7103. (d) Goossen, L. J.;
Rodriguez, N.; Linder, C. J. Am. Chem. Soc. 2008, 130, 15248. (e) Goossen,
L. J.; Rudolphi, F.; Oppel, C.; Rodriguez, N. Angew. Chem., Int. Ed. 2008,
47, 3043. (f) Goossen, L. J.; Rodriguez, N.; Lange, P.; Linder, C. Angew.
Chem., Int. Ed. 2010, 49, 1111.
(12) (a) Shang, R.; Yang, Z. W.; Wang, Y.; Zhang, S. L.; Liu, L.
J. Am. Chem. Soc. 2010, 132, 14391. (b) Zhang, S.-L.; Fu, Y.; Shang, R.;
Guo, Q.-X.; Liu, L. J. Am. Chem. Soc. 2010, 132, 638. (c) Shang, R.; Fu,
Y.; Li, J. B.; Zhang, S. L.; Guo, Q.-X.; Liu, L. J. Am. Chem. Soc. 2009,
131, 5738. (d) Shang, R.; Fu, Y.; Wang, Y.; Xu, Q.; Yu, H.-Z.; Liu, L.
Angew. Chem., Int. Ed. 2009, 48, 9350.
(13) (a) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc.
2005, 127, 10323. (b) Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433.
(c) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002,
124, 11250.
(14) (a) Weaver, J. D.; Ka, B. J.; Morris, D. K.; Thompson, W.;
Tunge, J. A. J. Am. Chem. Soc. 2010, 13, 12179. (b) Recio, A., III; Tunge,
J. A. Org. Lett. 2009, 11, 5630. (c) Waetzig, S. R.; Tunge, J. A. J. Am.
Chem. Soc. 2007, 129, 4138. (d) Burger, E. C.; Tunge, J. A. J. Am. Chem.
Soc. 2006, 128, 10002.
(15) For other recent selected references, see: (a) Fang, P.; Li, M.; Ge,
H. J. Am. Chem. Soc. 2010, 132, 11898. (b) Lindh, J.; Sjoberg, P. J. R.;
Larhed, M. Angew. Chem., Int. Ed. 2010, 49, 7733. (c) Voutchkova, A.;
Coplin, A.; Leadbeater, N. E.; Crabtree, R. H. Chem. Commun 2008,
6312. (d) Becht, J.-M.; Catala, C.; Le Drian, C.; Wagner, A. Org. Lett.
2007, 9, 1781.
(16) During the completion of the manuscript, a Pd-catalyzed mono-
R-arylation of nitriles appeared (April 7, 2011); see: Shang, R.; Ji, D.-S.;
Chu, L.; Liu, L. Angew. Chem., Int. Ed. 2011, Early View.
(17) For research books of traditional cross-couplings using trans-
metallating agents, see: (a) de Meijere, A.; Diederich, F., Ed. Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim,
2004; Vols. 1À2. (b) Beller, M.; Bolm, C. Transition Metals for Organic
Synthesis, Building Blocks and Fine Chemicals, 2nd ed.; Wiley-VCH:
Weinheim, 2004; Vols. 1À2. (c) Negishi, E., Ed. Handbook of Organo-
palladium for Organic Synthesis; Wiley-Interscience: New York, 2002;
Vols. 1À2. (d) Tsuji, J. Palladium Reagents and Catalysts, 2nd ed.; Wiley:
Chichester, 2004.
We began to examine the proposed study by using
potassium cyanoacetate and 4-chlorotoluene as the cou-
pling partners (Table 1). A scanning of commercially
available palladium precursors revealed that Pd(dba)2
and Pd(OAc)2 were the best choice (entries 1À6). Com-
monly used phosphine ligands for aryl chloride coupling
reactions were screened. XPhos20 gave the best results,
while SPhos21 and CM-phos22 provided slightly lower
product yield (entries 6À8). CataXium A,23 CataXium
PCy, and CataXium PInCy24 did not promote this
reaction well (entries 9À11). Xylene and mesitylene
solvents gave excellent yield, while DMF solvent af-
forded low substrate conversion (entries 12À14). This
decarboxylative coupling did not proceed at 100 °C
(entry 15).
(19) For a recent review on Pd-catalyzed R-arylation of the activated
methylene group, see: (a) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110,
1082. For our previous investigation on R-arylation of 1,3-dicarbonyl
compounds, see: Yip, S. F.; Cheung, H. Y.; Kwong, F. Y. Org. Lett.
2007, 9, 3469.
(20) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11818.
(21) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685.
(22) (a) So, C. M.; Zhou, Z.; Lau, C. P.; Kwong, F. Y. Angew. Chem.,
Int. Ed. 2008, 47, 6402. (b) So, C. M.; Lau, C. P.; Kwong, F. Y. Angew.
Chem., Int. Ed. 2008, 47, 8059. (c) So, C. M.; Lau, C. P.; Chan, A. S. C.;
Kwong, F. Y. J. Org. Chem. 2008, 73, 7731.
(23) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000,
39, 4153.
(24) Zapf, A.; Beller, M. Chem. Commun. 2005, 431.
(18) (a) Yeung, P. Y.; So, C. M.; Lau, C. P.; Kwong, F. Y. Angew.
Chem., Int. Ed. 2010, 49, 8918. (b) Yeung, P. Y.; So, C. M.; Lau, C. P.;
Kwong, F. Y. Org. Lett. 2011, 13, 648.
Org. Lett., Vol. 13, No. 11, 2011
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Table 1. Screening of Reaction Conditionsa
Table 2. Palladium-Catalyzed Diarylation of Potassium/
Sodium Cyanoacetates with Aryl Chloridesa
entry
Pd precursor
ligand
XPhos
yieldb (%)
1
2
PdCl2
77
46
30
92
66
96 (92)c
81
87
31
0
Pd(MeCN)2Cl2
Pd(COD)Cl2
Pd(OAc)2
[Pd(allyl)Cl]2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
XPhos
3
XPhos
4
XPhos
5
XPhos
6
XPhos
7
SPhos
8
CM-phos
CataXium A
CataXium PCy
CataXium PInCy
XPhos
9
10
11
12d
13e
14f
15g
54
57
12
92
4
XPhos
XPhos
XPhos
a Reaction conditions: 4-chlorotoluene (0.5 mmol), palladium pre-
cursor (3.0 mol % or 1.5 mol % for Pd dimer), ligand (6.0 mol %),
potassium cyanoacetate (0.5 mmol), xylene (1.0 mL) were stirred at
140 °C for 4 h under nitrogen. b Calibrated GC yields were reported
using dodecane as the internal standard. c Isolated yield in parentheses.
d Reaction was conducted with Pd(dba)2 (1.0 mol %). e Reaction was
conducted in DMF instead of xylene. f Reaction was conducted
in mesitylene instead of xylene. g Reaction was conducted at 100 °C
for 24 h.
Having the optimized reaction conditions in hand, we next
tested a series of substituted aryl chlorides in this decarbox-
ylative coupling (Table 2). Ortho-, meta-, and para-substi-
tuted aryl chlorides coupled smoothly with cyanoacetates to
generate R-diaryl nitriles. Keto and ester functional groups
were found to be compatible under these reaction conditions
(entries 3, 4, 11, and 12). Sterically hindered aryl chlorides
showed applicability in this decarboxylative coupling (entries
11À14). Naphthyl chloride gave a moderate product yield,
associated with naphthalene side product (entries 15 and 16).
In general, potassium cyanoacetate performed better than
sodium cyanoacetate in this reaction, except for the naphthyl-
and keto-substituted coupling partners.
a Reaction conditions: ArCl (0.5 mmol), Pd2(dba)3 (1.5 mol %),
XPhos (6.0 mol %), potassium/sodium cyanoacetate (0.5 mmol), xylene
(1.0 mL) were stirred at 140 °C for 4 h under nitrogen (reaction times
were not optimized for each substrate). b Isolated yields. c [Pd(allyl)Cl]2
was used instead of Pd2(dba)3.
Scheme 2 illustrates the arylation of potassium cyanoa-
cetate using aryl bromides. No coupling products were
found when the reaction temperature was lowered to
110 °C. Substituted aryl bromides were coupled smoothly
to furnish desired products. Notably, a highly sterically
2914
Org. Lett., Vol. 13, No. 11, 2011

Scheme 2. Palladium-Catalyzed Diarylation of Potassium
Cyanoacetates with Aryl Bromidesa
Scheme 3. Palladium-Catalyzed Diarylation of Potassium
Cyanoacetates with Aryl Sulfonates
However, the arylation did not proceed when aryl tosylate
was used.
In summary, we have developed a simple decarboxyla-
tive arylation of cyanoacetates using aryl chlorides, bro-
mides, and sulfonates as the coupling partners. We believe
this Pd system will be useful for R-diaryl nitrile synthesis.
Further mechanistic studies are in progress.
a Reaction conditions: ArBr (0.5 mmol), Pd(dba)2 (3.0 mol %),
XPhos (6.0 mol %), potassium cyanoacetate (0.5 mmol), and xylene
(1.0 mL) were stirred at 140 °C for 4 h under nitrogen (reaction times
were not optimized for each substrate). Isolated yields were reported.
Acknowledgment. We thank the Research Grants
Council of Hong Kong (GRF: PolyU5008/08P) and
PolyU Internal Competitive Research Grant (A-PG13)
for financial support. A UGC special large equipment
grant (SEG PolyU01) is gratefully acknowledged.
hindered 2-bromobiphenyl was found to be a feasible
coupling partner in this reaction.
To expand the substrate scope further, we next investi-
gated the possibility of using phenol-derived electrophiles
asthe couplingpartners(Scheme3). Itshouldbe notedthat
previous R-arylations of nitriles applied strong bases and
were incompatible with base-sensitive aryl triflates.6,7 Un-
der our new reaction conditions, p-tolyl triflate was found
to couple well with potassium cyanoacetate (Scheme 3).
Supporting Information Available. Detailed experimen-
tal procedures, compound characterization data, and
copies of 1H NMR, 13C NMR, and HRMS spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 11, 2011
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