Palladium-catalyzed one-pot synthesis of 2-alkyl-2-arylcyanoacetates

Article abstract of DOI:10.1021/jo7024338

(Chemical Equation Presented) A one-pot procedure for the synthesis of 2-alkyl-2-arylcyanoacetates based on a Pd(OAc)₂/DPPF (DPPF = 1,1′-diphenylphosphino ferreocene)-catalyzed enolate arylation followed by in situ alkylation has been developed. This procedure tolerates a diverse range of aryl and heteroaryl bromides, and provides a rapid entry to a variety of 2-alkyl-2-arylcyanoacetates in good to excellent yield.

Full text of DOI:10.1021/jo7024338

more readily available aryl bromide substrates.5 As for palladium
catalysis, P(t-Bu)3/Pd(dba)2 failed to tolerate heteroaryl halides,
an important category of substrates for pharmaceutical appli-
cations.4a,b The cage-phosphine P(i-BuNCH2CH2)3N/Pd2(bda)3
catalyst system, which has been reported to provide excellent
substrate scope to include heteroaryl halides, was found to be
less attractive for our specific needs.6 Most importantly, these
state-of-the-art systems failed to directly couple aryl halides with
simple 2-alkylcyanoacetate, such as ethyl 2-methylcyanoacetate
(1) (Scheme 1). Therefore, we set out to find a more general
solution to this problem and herein we report our development
of a one-pot, air-stable palladium-catalyzed procedure for the
efficient synthesis of 2-alkyl-2-arylcyanoacetates in 60-90%
yields.
Palladium-Catalyzed One-Pot Synthesis of
2-Alkyl-2-arylcyanoacetates
Xiang Wang,* Anil Guram, Emilio Bunel, Guo-Qiang Cao,†
Jennifer R. Allen,† and Margaret M. Faul
Chemical Process R&D, Amgen Inc., One Amgen Center DriVe,
Thousand Oaks, California 91320
xiangw@amgen.com
ReceiVed NoVember 13, 2007
SCHEME 1. Direct Arylation of 1
A one-pot procedure for the synthesis of 2-alkyl-2-arylcy-
anoacetates based on a Pd(OAc)2/DPPF (DPPF ) 1,1′-
diphenylphosphino ferreocene)-catalyzed enolate arylation
followed by in situ alkylation has been developed. This
procedure tolerates a diverse range of aryl and heteroaryl
bromides, and provides a rapid entry to a variety of 2-alkyl-
2-arylcyanoacetates in good to excellent yield.
We first carried out a systematic screening of palladium,
ligands, and base in an effort to directly couple 2-alkylcyanoac-
etate 1 with bromobenzene. Unfortunately, we were unsuccessful
in identifying conditions to yield a detectable amount of coupling
product 2. We then took a step back and found that a catalyst
system comprised of Pd(OAc)2, DPPF, and KOt-Bu (DPPF )
1,1′-diphenylphosphino ferreocene) efficiently catalyzed reaction
of unsubstituted ethyl cyanoacetate (3) with a wide range of
aryl halides including heteroaryl bromides.7 Since more than 2
equiv of KOt-Bu was present in the catalytic system,8 we
reasoned that the arylated cyanoacetate product would exist as
an anion, and therefore, could be trapped by suitable alkyl elec-
trophiles. Thus, if the palladium catalyst did not interfere with
alkyl electrophiles, such as methyl iodide or allyl bromide,9 the
desired 2-alkyl-2-arylcyanoacetate could be accessed in a one-
pot procedure by sequential addition of an alkylating reagent
(Scheme 2).10 We were glad to find out that this is indeed
possible. Heating a mixture of 3 and phenyl bromide in the
presence of Pd(OAc)2 (2%), DPPF (4%), and KOt-Bu (2.5
equiv) in 1,4-dioxane at 70 °C for 1 h, followed by MeI (1.2
equiv) quench at room temperature cleanly afforded the desired
coupling product 2-methyl-2-phenylcyanoacetate (2) in 88%
isolated yield (Table 1, entry 2).
Aryl cyanoacetates are versatile synthons to synthesize a
variety of nitrogen-containing compounds such as amino
alcohols,1 isoquinolines,2 and â-amino acids.3 Recent develop-
ments in the field of transition metal-catalyzed cross-coupling
of enolates and aryl halides has greatly expanded the acces-
sibility of aryl cyanoacetates.4,5 We were interested in synthesiz-
ing a series of 2-alkyl-2-arylcyanoacetates as intermediates to
support our research in medicinal chemistry. However, our initial
efforts indicated that the current state-of-the-art catalyst systems
were poorly applicable to our desired substrates. Specifically,
copper-catalyzed systems, which are typically suitable for aryl
iodide substrates, were found to be generally unsuitable for the
* To whom correspondence should be addressed.
† Current address: Department of Medicinal Chemistry, Amgen Inc., One
Amgen Center Drive, Thousand Oaks, CA, 91320.
The general utility of one-pot sequential Pd(OAc)2/DPPF-
catalyzed arylation and traditional alkylation procedure for the
synthesis of a range of 2-alkyl-2-arylcyanoacetates was explored.
(1) (a) Joule, J. A. Sci. Synth. 2001, 10, 361-652. (b) Dornow, A.; Fust,
K. J. Chem. Ber. 1954, 87, 985-90.
(2) For a recent example see: Frohn, M.; Burli, R. W.; Riahi, B.;
Hungate, R. W. Tetrahedron Lett. 2007, 48, 487-489.
(3) (a) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1-15. (b) Liu,
T.-Y.; Long, J.; Li, B.-J.; Jiang, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen,
Y.-C. Org. Biomol. Chem. 2006, 4, 2097-2099.
(6) The P(i-BuNCH2CH2)3N ligand is a viscous and air-sensitive liquid.
The bench-top handling of this ligand in air for screening and scale-up was
found to be somewhat unattractive for our needs. See refs 4d,e.
(7) DPPF has been previously examined in related cross-coupling
reactions, see: (a) Gao, C.; Tao, X.; Qian, Y.; Huang, J. Synlett 2003, 1716-
1718. (b) Mitin, A. V.; Kashin, A. N.; Beletskaya, I. P. Russ. J. Org. Chem.
2004, 40, 802-812.
(8) When 1.2 equiv of KOtBu was used, incomplete conversion of 3
was observed.
(9) Allyl groups are susceptible to palladium-catalyzed olefin isomer-
izations under certain conditions, see: Negishi, E.-I. Handb. Organopal-
ladium Chem. Org. Synth. 2002, 2, 2783-2788.
(4) For Pd-catalyzed reactions, see: (a) Stauffer, S. R.; Beare, N. A.;
Stambuli, J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4641-4642.
(b) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541-555. (c)
Tao, X.; Huang, J.; Yao, H.; Qian, Y. J. Mol. Catal. A 2002, 186, 53-56.
(d) You, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42, 5051-5053.
(e) You, J.; Verkade, J. G. J. Org. Chem. 2003, 68, 8003-8007. (f) Uno,
M.; Seto, K.; Ueda, W.; Masuda, M.; Takahashi, S. Synthesis 1985, 506-
508.
(5) For Cu-catalyzed reactions, see: (a) Okuro, K.; Furuune, M.; Miura,
M.; Nomura, M. J. Org. Chem. 1993, 58, 7606-7607. (b) Pivsa-Art, S.;
Fukui, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1996, 69, 2039-
2042. (c) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.
Eur. J. 2004, 10, 5607-5622. (d) Widenhoefer, R. A.; Buchwald, S. L.
Organometallics 1996, 15, 3534-3542.
(10) Use of MeI as an in situ trapping reagent has been demonstrated
by Hartwig et al. in the palladium-catalyzed arylation of malonates but not
cyanoacetates, see ref 4b. No other alkylating reagents have been demon-
strated as in situ traps.
10.1021/jo7024338 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/16/2008
J. Org. Chem. 2008, 73, 1643-1645
1643

TABLE 1. One-Pot Synthesis of 2-Alkyl-2-arylcyanoacetates via
Pd-Catalyzed Coupling of 3 with Aryl Halidesa
SCHEME 2. One-Pot Arylation-Alkylation of 3
The procedure was found to exhibit excellent scope (Table 1).
A variety of aryl and heteroaryl bromides participated effectively
in this arylation reaction. Similarly, a variety of alkyl electro-
philes participated effectively in the alkylation reaction. For
example, the reaction of 3 with phenyl bromide was efficiently
trapped by a range of alkyl electrophiles including alkyl iodides
(entry 2-3), benzyl bromide (entry 4), allyl bromide (entry 5),
and propargyl bromides (entry 6-8) to afford the desired
2-alkylarylcyanoacetates in good yields. Notably, use of allyl
bromide in the presence of the palladium catalyst did not result
in the formation of any undesired olefin isomerized products.
In addition, the Pd(OAc)2/DPPF-catalyzed reaction of 3 and
ortho-substituted (entries 9-11) and electron-poor aryl halides
(entries 12 and 13) proceeded efficiently. These reactions could
also be trapped with a range of alkyl halides to afford the desired
products in good yields. Specifically, reaction of 3 with
2-bromoanisole gave 79% yield of ethyl 2-methyl-2-(2-meth-
oxyphenyl)cyanoacetate after trapping with methyl iodide (entry
11) and reactionof 4-fluorobromobenzene gave 77% yield after
trapping with benzyl bromide (entry 12).
In contrast to the previously published reaction conditions
with P(t-Bu)3/Pd(dba)2,4b under which cyanoacetates failed to
couple with heteroaryl halides, this Pd(OAc)2/DPPF catalyst
system efficiently catalyzed the arylation of 3 with heteoaryl
halides. For example, under our standard conditions, 2-bro-
mopyridine reacted smoothly with 3 to give ethyl 2-(3-
pyridinyl)cyanoacetate in 84% isolated yield (entry 14) and ethyl
2-allyl-2-(2-pyridinyl)cyanoacetate in 79% isolated yield when
allyl bromide (1.2 equiv) was used as a trapping reagent (entry
15). Similarly, 3-bromopyridine and 5-bromopyrimidine both
reacted with 3 in high yield with or without a trapping reagent
(entry 16-19).11
In summary, we have developed an efficient one-pot proce-
dure for the synthesis of 2-alkyl-2-arylcyanoacetates based on
a Pd(OAc)2/DPPF catalytic system under basic conditions. This
procedure is compatible with a wide range of arylating and
alkylation reagents. Importantly, heteroaryl halides are well
tolerated by this protocol. While the mechanism of this Pd-
(OAc)2/DPPF-catalyzed arylation reaction is expected to go
through similar mechanism as that of P(t-Bu)3/Pd(dba)2,4b the
enhanced reactivity of the former toward heteroaryl halides may
be explained by the inability of nucleophilic nitrogens to replace
bidentate phosphine ligand from palladium and such a process
is facile for P(t-Bu)3-ligated Pd-aryl species.12 Overall, this
procedure provides a general and easy access to a variety of
2-alkyl-2-arylcyanoacetates in good yields.
Experimental Section
a Reaction conditions: ethyl cyanoacetate 3, Ar-X (1.2 equiv), Pd(OAc)2
(2%), DPPF (4%), KOt-Bu (2.5 equiv), 70 °C (1-4 h). RX (1.2 equiv),
rt/1-4 h. b Isolated yield. c EtI, 80 °C for 4 h. d NaH (1.1 equiv) added
with propargyl bromide. e 1-Bromo-3-trimethylsilyl propyne, 55 °C for 12 h.
General Procedure for the Palladium-Catalyzed Arylation
of 3 with Aryl and Heteroaryl Bromides: Ethyl 2-Phenylcy-
anoacetate13 (Table 1, entry 1): To suspension of KOt-Bu (280
(11) In the absence of a Pd catalyst/ligand, the control experiment of
5-bromopyrimidine with 3 and KOt-Bu produced ∼30% conversion after
overnight heating, whereas 3-bromopyridine gave no detectable amount of
product, indicating efficiency of Pd catalysis.
mg, 2.5 mmol) in 1,4-dioxane (3 mL) was added 3 (113 mg, 1.0
mmol) and bromobenzene (188 mg, 1.2 mmol) sequentially,
resulting in a white suspension. A prepared solution of Pd(OAc)2
1644 J. Org. Chem., Vol. 73, No. 4, 2008

(4.5 mg, 0.02 mmol) and DPPF (23 mg, 0.04 mmol) in 1,4-dioxane
(1 mL) was then added. The resulting mixture was heated at 70 °C
for 1 h, when GC analysis of the reaction mixture indicated the
complete consumption of 3. The reaction was cooled to room
temperature, and AcOH (1 N, 2 mL) and EtOAc (8 mL) were added
sequentially. The organic layer was dried, concentrated, and
chromatographed (SiO2, hexanes f 15% EtOAc/hexanes) to give
mixture indicated the complete consumption of 3. The reaction was
cooled to room temperature, and methyl iodide (170 mg, 1.2 mmol)
was added. The resulting mixture was stirred at ambient temperature
for 1 h, and GC analysis indicated complete consumption of ethyl
2-phenylcyanoacetate. Hexanes (10 mL) was then added and the
resulting suspension was passed through a frit. The filtrate was
concentrated and column chromatographed (SiO2, hexanes f 10%
EtOAc/hexanes) to give ethyl 2-methyl-2-phenylcyanoacetate as a
colorless oil (179 mg, 88%). 1H NMR (400 MHz, CDCl3): δ 7.52-
7.54 (m, 2 H), 7.34-7.42 (m, 3 H), 4.18-4.27 (m, 2 H), 1.94 (s,
3 H), 1.23 (t, J ) 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ
167.9, 135.9, 129.2, 128.8, 125.7, 119.5, 63.2, 48.3, 24.9, 13.8.
1
ethyl 2-phenylcyanoacetate as a colorless oil (171 mg, 90%). H
NMR (400 MHz, CDCl3): δ 7.37-7.46 (m, 5H), 4.74 (s, 1H),
4.18-4.24 (m, 2H), 1.24 (t, J ) 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 165.1, 130.1, 129.3, 129.2, 127.9, 115.8, 63.2, 43.7,
13.9.
Ethyl 2-(2-Pyridinyl)cyanoacetate14 (Table 1, entry 14): 3 (113
mg, 1.0 mmol) and 2-bromopyridine (190 mg, 1.2 mmol) were
added sequentially to a suspension of KOt-Bu (280 mg, 2.5 mmol)
in 1,4-dioxane (3 mL), resulting in a white suspension. A prepared
solution of Pd(OAc)2 (4.5 mg, 0.02 mmol) and DPPF (23 mg, 0.04
mmol) in 1,4-dioxane (1 mL) was then added. The resulting mixture
was heated at 70 °C for 1 h, when GC analysis of the reaction
mixture indicated complete consumption of 3. The reaction was
cooled to room temperature and AcOH (1 N, 2 mL) and methylene
chloride (8 mL) were added sequentially. The organic layer was
dried, concentrated, and chromatographed (SiO2, CH2Cl2) to give
ethyl 2-(2-pyridinyl)cyanoacetate as a yellow solid (162 mg, 85%).
1H NMR (400 MHz, CDCl3): δ 14.01 (s, 1H), 7.65 (d, J ) 6.0
Hz, 1H), 7.59 (t, J ) 8.0 Hz, 1H), 7.30 (d, J ) 9.2 Hz, 1 H), 6.67
(t, J ) 6.4 Hz, 1H), 4.24 (q, J ) 7.2 Hz, 2 H), 1.33 (t, J ) 7.6 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 170.5, 155.6, 139.7, 134.0,
120.4, 119.3, 112.5, 62.6, 60.2, 14.6.
General Procedure for the One-Pot Synthesis of 2-Alkyl-2-
arylcyanoacetates with Aryl and Heteroaryl Bromides: Ethyl
2-Methyl-2-phenylcyanoacetate5b (Table 1, entry 2): To suspen-
sion of KOt-Bu (280 mg, 2.5 mmol) in 1,4-dioxane (3 mL) was
added 3 (113 mg, 1.0 mmol) and bromobenzene (188 mg, 1.2
mmol) sequentially, resulting in a white suspension. A prepared
solution of Pd(OAc)2 (4.5 mg, 0.02 mmol) and DPPF (23 mg, 0.04
mmol) in 1,4-dioxane (1 mL) was then added. The resulting mixture
was heated at 70 °C for 1 h, when GC analysis of the reaction
2-Allyl-2-(2-pyridinyl)cyanoacetate (Table 1, entry 15): 3 (113
mg, 1.0 mmol) and 2-bromopyridine (190 mg, 1.2 mmol) were
added sequentially to a suspension of KOt-Bu (280 mg, 2.5 mmol)
in 1,4-dioxane (3 mL), resulting in a white suspension. A prepared
solution of Pd(OAc)2 (4.5 mg, 0.02 mmol) and DPPF (23 mg, 0.04
mmol) in 1,4-dioxane (1 mL) was then added. The resulting mixture
was heated at 70 °C for 1 h, when GC analysis of the reaction
mixture indicated the complete consumption of 3. The reaction was
cooled to room temperature, and allyl bromide (145 mg, 1.2 mmol)
was added. The resulting mixture was stirred at ambient temperature
for 1 h, and HPLC analysis indicated complete consumption of
ethyl 2-(2-pyridinyl)cyanoacetate. Aqueous AcOH (1 N, 2 mL) and
methylene chloride (8 mL) were added sequentially. The filtrate
was concentrated and column chromatographed (SiO2, 10% f 50%
EtOAc/hexanes) to give ethyl 2-allyl-2-(2-pyridinyl)cyanoacetate
as a pale yellow oil (191 mg, 83%). 1H NMR (400 MHz, CDCl3):
8.62 (d, J ) 4.8 Hz, 1 H), 7.78 (t, J ) 7.6 Hz, 1 H), 7.62 (d, J )
8.4 Hz, 1 H), 7.30-7.33 (m, 1 H), 5.73-5.83 (m, 1 H), 5.19-5.26
(m, 2 H), 4.25-4.30 (m, 2 H), 3.17 (dd, J ) 7.2, 14.0 Hz, 1 H),
3.04 (dd, J ) 7.2, 14.0 Hz, 1 H), 1.25 (t, J ) 7.2 Hz, 3 H). 13C
NMR (100 MHz, CDCl3): δ 164.7, 152.2, 148.3, 136.0, 129.3,
122.1, 120.1, 119.6, 116.4, 61.8, 54.6, 39.3, 12.4.
Acknowledgment. X.W. thanks Drs. Jinkun Huang and
Robert R. Milburn for helpful discussions and suggestions and
Drs. Tiffany Correll and Kevin Turney for assistance on HRMS
analysis and IR measurement.
(12) (a) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew.
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S. L. Organometallics 1996, 15, 3534-3542. (c) Frederic, P.; Patt, J.;
Hartwig, J. F. Organometallics 1995, 14, 3030-3039.
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Supporting Information Available: Synthetic methods and
spectral assignments and copies of 1H NMR and 13C NMR for all
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO7024338
J. Org. Chem, Vol. 73, No. 4, 2008 1645