Expedient synthesis of novel β-ketoesters from the Mizoroki-Heck coupling of ethyl 3-ethoxyacrylate with aryl and pyridyl halides

Article abstract of DOI:10.1016/j.tetlet.2013.10.076

It is well known that β-ketoesters are useful intermediates for the synthesis of a range of heterocyclic templates. While there are many useful synthetic methods available to access these intermediates, there are still opportunities for the discovery of useful methodologies for their construction from novel starting materials. In this regard, we report on the discovery of a facile Pd-catalyzed Mizoroki-Heck coupling of ethyl 3-ethoxyacrylate with aryl and heteroaryl halides to form substituted alkoxyacrylates which can be hydrolyzed to form novel aryl and heteroaryl β-ketoesters.

Full text of DOI:10.1016/j.tetlet.2013.10.076

Tetrahedron Letters 54 (2013) 7065–7068
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Tetrahedron Letters
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Expedient synthesis of novel b-ketoesters from the Mizoroki–Heck
coupling of ethyl 3-ethoxyacrylate with aryl and pyridyl halides
b
a
b
c
Jeffrey T. Kohrt a, , Ed Conn , Robert Maguire , Stephen W. Wright , Robert Singer
⇑
a CVMED Reaction Optimization Center, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, United States
b CVMED World Wide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, United States
c Chemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
It is well known that b-ketoesters are useful intermediates for the synthesis of a range of heterocyclic
templates. While there are many useful synthetic methods available to access these intermediates, there
are still opportunities for the discovery of useful methodologies for their construction from novel starting
materials. In this regard, we report on the discovery of a facile Pd-catalyzed Mizoroki–Heck coupling of
ethyl 3-ethoxyacrylate with aryl and heteroaryl halides to form substituted alkoxyacrylates which can be
hydrolyzed to form novel aryl and heteroaryl b-ketoesters.
Received 30 September 2013
Revised 11 October 2013
Accepted 16 October 2013
Available online 26 October 2013
Keywords:
Mizoroki–Heck
Coupling
Ó 2013 Elsevier Ltd. All rights reserved.
b-Ketoesters
Palladium
Catalysis
O
O
Alkyl, aryl, and heteroaryl b-ketoesters are key intermediates in
organic syntheses and often serve as intermediates for the forma-
tion of a wide range of heterocycles including substituted thioura-
cils, uracils, pyrroles, indoles, pyrazoles, pyridines, coumarins, and
fused ring systems.1 Many general routes have been developed for
the synthesis of b-ketoesters including the classical Claisen, Dieck-
mann, and Blaise syntheses.2,3 Also, diverse aryl and heteroaryl b-
ketoesters can be made readily from aryl or heteroaryl carboxylic
acids,4 aldehydes,5 acid chlorides,6 and methyl ketones7 or via car-
bonylation of aryl halides with palladium catalysis.8 While these
methods are of great utility, we sought to increase the diversity
of the aryl and heteroaryl b-ketoesters for use in our medicinal
chemistry programs by exploring their formation from the cou-
pling of aryl/heteroaryl halides and alkoxyacrylates via Heck–
Mizoroki coupling chemistry followed by an acid catalyzed hydro-
lysis (Fig. 1).
O
O
Het/Ar-X
Pd(0)
acid
OEt
OEt
OEt
OEt
Hydrolysis
EtO
Ar/Het
Ar/Het
1
2
3
Figure 1. General Mizoroki–Heck scheme for the preparation of b-ketoesters.
1
O
I
5% Pd-C, K2CO3
OEt
OEt
CH3CN, 120 o
C
Ph
(sealed tube), 72h
60%
4
Scheme 1. Yamanaka synthesis of 3,3-disubstituted ethoxyacrylates.
The use of substituted vinyl ethers or esters in the Mizoroki–
Heck reaction with aromatic halides has proven to be a useful
method for the synthesis of aromatic ketones and esters respec-
tively and has attracted much synthetic attention.9 Interestingly,
we were surprised to find that the use of this methodology was
typically not employed for the formation of b-ketoesters. We are
aware of only two reported studies of the coupling of aryl halides
with alkoxyacrylates to form vinyl alkoxide intermediates 2 that
could lead to b-ketoesters 3. First, Yamanaka et al. reported that
ethyl 3-ethyoxyacrylate 1 participated in Mizoroki–Heck cross-
coupling reactions with aryl and pyridyl iodides under relatively
harsh, ligandless conditions (Scheme 1).10 Secondly, Doucet re-
ported an improved Mizoroki–Heck coupling with three aryl bro-
mides and methyl 3-methoxyacrylate
6 mediated by the
tetraphosphine ligand Tedicyp 7 to provide b-alkoxyacrylates
which were subsequently converted into b-ketoesters via acid cat-
alyzed hydrolysis (Scheme 2).11a While the use of Tedicyp as a li-
gand was of interest, it is not commercially available and
requires a seven-step synthesis for its preparation.11b Here-in, we
⇑
Corresponding author.
E-mail address: Jeffrey.kohrt@pfizer.com (J.T. Kohrt).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.076

7066
J. T. Kohrt et al. / Tetrahedron Letters 54 (2013) 7065–7068
O
O
O
6, [Pd(C3H5)Cl)]2
NaHCO3, DMF, 150 o
C
H2SO4
Br
OMe
OMe
OMe
Ph2
P
PPh2
THF, water
56% 2-step
PPh2
Ph2
P
5
8
9
(Tedicyp 7)
Scheme 2. Doucet synthesis of aryl b-ketoesters.
Table 1
Mizoroki–Heck coupling with trialkylphosphine ligands
Br
O
O
N
OMe
10
MeO
N
OEt
OEt
OEt
11
Pd, ligand
EtO
MeO
N
DCMA, dioxane
1
12
MeO
N
Catalyst/ligand
Temp °C/time
% 11
% 12
Pd2(dba)3, HP(tBu)3BF4 13
PdP(tBu)3-Br dimer 14
Pd(P(tBu)3)2 15
80, 6 h
80, 16 h
80, 2.5 h
36
64
82
10
OMe
OMe
report the improvement of this chemistry to afford a variety of aryl
and pyridyl b-ketoesters using a commercially available, catalytic
system under mild conditions for the Mizoroki–Heck coupling of
ethyl 3-ethoxyacrylate 1 with aryl and pyridyl halides followed
by subsequent hydrolysis.
I
O
OMe
18
O
OMe
OEt
OMe
OMe
OEt
OEt
6% Pd(PtBu3)2
DCMA, Dioxane
80 oC
OMe
EtO
In our initial studies of Mizoroki–Heck coupling reactions, 2-
methoxy-5-bromopyridine 10 and ethyl 3-ethoxyacrylate 1 were
utilized as starting materials. A screen of commercially available
palladium catalysts, ligands, bases, and solvents revealed that a
combination of Fu-type trialkylphosphines 13–15 and the base dic-
yclohexylmethylamine (DCMA) in dioxane were the key to effect-
ing this coupling to provide acrylate 11 (Table 1).12 While three
different trialkylphosine ligands were successful, the bis-(tri-t-
butyl)phosphine palladium(0) complex 15 provided the best over-
all yield and fastest reaction. This catalyst system is also operation-
ally convenient due to its air stability, as opposed to the
significantly less stable Pd(I) dimer 14 which also gave high yields
in the Mizoroki–Heck coupling.13 One drawback to using the bis-
(tri-t-butylphoshine) palladium(0) 15 was the formation of the
homocoupled, pyridine-dimer 12. This byproduct was not detected
with the other tri-(t-butyl)phosphine ligand systems. Finally,
hydrolysis of the enol ether 11 with aqueous HCl in dichlorometh-
ane provided the ketoester 16 in high yield as a mixture with its
enol tautomer 17 (Scheme 3).14
Having identified high yielding, mild conditions utilizing cata-
lyst 15, we examined the scope of this system with additional het-
eroaryl and aryl halides. Aryl iodide 18 was selected as a more
difficult case and indeed proved to be problematic. Utilizing condi-
tions developed for 10, only 14% of 19 was isolated while the major
reaction product was the homo-coupled biaryl 20 (Scheme 4).
Increasing the reaction temperature from 80 °C to 110 °C and
increasing the amount of 1 from 1 to 3 equiv improved the yield
of 19 to 50%. Addition of lithium chloride further increased the
1
20
19
OMe
14%
Major by product
<10%
3 eq. LiCl, 110 o
C
75%
Scheme 4. Enhancement of the Mizoroki–Heck coupling via lithium chloride
addition.
yield of 19 to 75%. Lithium chloride is known to improve some
problematic Mizoroki–Heck reactions in which it is speculated that
the chloride ion may displace the iodide in the oxidative addition
complex (Ar–Pd–I) resulting in a highly active Ar–Pd–Cl intermedi-
ate which may accelerate subsequent steps in the catalytic cycle.15
With the addition of lithium chloride, several arrays were run to
test the scope of the modified Mizoroki–Heck coupling conditions
with aryl and heteroaryl halides (Table 2). Since each reaction was
run as part of an array, nothing was done to optimize the individ-
ual reactions except to monitor the consumption of starting halide.
The results from these arrays showed that the catalyst system tol-
erates a range of aromatic and pyridyl halides (Table 2). Similarly
to iodide 18, bromide 21a coupled under these conditions to give
22a in high yields. Other electron rich aryl halides also performed
well to give the desired aryl–alkyoxy acrylates 22b–22d, but the
sterically hindered 2,6-dimethoxylbenzene 22e was formed in a
moderate 57% yield. Electron deficient aryl-halides were also dem-
onstrated to couple under these conditions, but generally with
lower yields. While 3-ester 21g and 3-methylsulfone 21f formed
the desired product in good yields, the 3-cyano 21h afforded the
O
O
O
3 N HCl
OEt
OEt
OEt
OEt
CH2Cl2 RT
,
O
OH
82%
MeO
N
11
16
17
MeO
N
MeO
N
Scheme 3. Hydrolysis of 3,3-disubstituted acrylate to form a b-ketoester.

J. T. Kohrt et al. / Tetrahedron Letters 54 (2013) 7065–7068
7067
Table 2
Mizoroki-Heck coupling and hydrolysis reactions
Ar/Het-X 21
6% Pd (PtBu3)2
O
O
O
HCl or TFA
OEt
OEt
OEt
3 eq. LiCl, DCMA
110 oC, dioxane
CH2Cl2, 20oC
EtO
Het/Ar
% Yielda 23
ND
OEt
Ar
O
23
1
22
21
% Yield 22
21
% Yield 22
16
% Yielda 23
OMe
OMe
Br
NC
Br
a
b
c
80
h
i
ND
88b
86b
OMe
OMe
I
93
92
84
76
30
NC
NC
Br
OMe
OMe
OTf
Br
Br
91c
j
F
OMe
Br
d
e
77
57
91b
71
k
l
93
46
97, 98b
MeO
OMe
N
OMe
OMe
Br
36
I
OMe
N
Cl
CF3
O
S
O
f
52
71
82
m
n
27d, 56
56, 54b
Br
MeO
Br
N
O
MeO
OEt
g
85b
35
81e
Br
O
N
ND—not determined.
a
All yields are for 3 N HCl, CH2Cl2 except where listed.
10% TFA, CH2Cl2.
6 N HCl, DCE.
No LiCl added to the reaction.
100% TFA.
b
c
d
e
product in 16% yield. The coupling of aryl iodides containing an
ortho-electron withdrawing group only returned recovered start-
ing material with no observable formation of product. Not all cya-
no-aryl halides performed poorly in this reaction as 21i produced
the product in high yield. Interestingly, the triflate analog 21j also
delivered the desired product, but in a much lower yield.
Next, investigating heterocyclic halides in this protocol
demonstrated that 3-halo-pyridines provided the highest yields
of coupling products as exemplified by 21k and 21l. The coupling
of 3-chloropyridine 21m afforded the product 22m in moderate
yield. Initially, this reaction was run without lithium chloride
and resulted in a much lower yield of product. We note that under
these conditions 21m may be a special case due to activation by
the trifluoromethyl group, as other aryl chlorides and 2-chloropyri-
dines did not form the desired coupled products under these con-
ditions. Lastly, pyridine 21n coupled in a modest yield under these
conditions illustrating limitations on the efficiency of this method-
ology with this electron deficient substrate class.
was no attempt to isolate and specifically characterize each iso-
mer; instead, the isomer mixture was hydrolyzed to the b-ketoes-
ter 23. Initially, a mixture of 3.0 N aqueous hydrochloric acid and
dichloromethane was employed (Table 2);15 however, some alkene
products underwent hydrolysis slowly in the bi-phasic mixture. In
these cases, the rate of hydrolysis could be increased, and the reac-
tion pushed to completion via the use of 6 N HCl and dichloroeth-
ane (DCE) as in 23c or by switching to 10% trifluoroacetic acid in
dichloromethane as exemplified by examples 23d, 23g, 23j, and
23k or 100% trifluoroacetic acid for 21n.16
Typically, these Heck coupling reactions were run under anaer-
obic conditions in sealed reaction vials. While this was fine for
small scale array reactions, it could be quite cumbersome for larger
scale work. Further examination of the coupling conditions dem-
onstrated that the reaction could be scaled in good yields on a mul-
ti-gram scale in a standard round bottom flask and condenser as
exemplified in 22c (7.7 mmol, 92%).17,18
Finally, in one case we examined this protocol for the formation
of a b-ketonitrile. Accordingly, trans-3-ethoxyacrylonitrile 24 and
6-bromoquinoline 25 coupled to give the desired alkene products
Finally, depending on the halide starting material, the alkene
product 22 exhibited different ratios of E and Z-isomers. There

7068
J. T. Kohrt et al. / Tetrahedron Letters 54 (2013) 7065–7068
Br
Wang, M.; Wilkerson, C. R.; Hall, C. D.; Akhmedov, N. G. J. Org. Chem. 2004, 69,
1.
25
6% Pd(PtBu3)2
6617.
O
N
5. (a) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258; (b) Chand, D. K.;
Jeyakumar, K. Synthesis 2008, 11, 1685; (c) Iwamoto, M.; Murata, H.; Ishitani, H.
Tetrahedron Lett. 2008, 49, 4788.
CN
CN
3 eq. LiCl, DCMA
EtO
N
6. Wierenga, W.; Skulnick, H.I. Org. Synth, 1990, Coll. Vol. 7, 213.
7. Li, H.; He, Z.; Guo, X.; Li, W.; Zhao, X.; Li, Z. Org. Lett. 2009, 11, 4176.
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2011, 8, 172; (c) Felpin, F.-X.; Nassar-Hardy, L.; Le Callonnec, F.; Fouquet, E.
Tetrahedron 2011, 67, 2815; (d) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111,
1170; (e) Heravi, M. M.; Fazeli, A. Heterocycles 2010, 81, 1979; (f) Bellina, F.;
Chiappe, C. Molecules 2010, 15, 2211.
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Eur. J. Org. Chem. 2007, 3122–3132; (b) Laurenti, D.; Feuerstein, M.; Pepe, G.;
Doucet, H.; Santelli, M. J. Org. Chem. 2001, 66, 1633.
110 oC, dioxane, 74%
24
26
2. 6 N HCl, DCE,15 h, 85%
Scheme 5. Mizoroki–Heck coupling for the formation of a b-ketonitrile.
in moderate yield. Standard hydrolysis with hydrochloric acid in
dichloroethane led to the desired b-ketonitrile 26 (Scheme 5).
In conclusion, it has been shown that a two-step Mizoroki–Heck
coupling and hydrolysis procedure utilizing ethyl 3-ethoxyacrylate
1 and a readily available, conveniently handled catalyst with aryl
or pyridyl halides provides ready access to novel substituted b-
ketoesters in either library or batch platforms. Also, a similar meth-
od has been utilized in the formation of a b-ketonitrile. These sim-
ple processes offer a mild and generally applicable alternative for
the synthesis of the structural diverse b-ketoesters and nitriles
which may be employed in the subsequent construction of novel,
substituted heterocycles.
12. (a) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989; (b) Netherton, M. R.;
Fu, G. C. Org. Lett. 2001, 3, 4295; (c) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555.
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16. Bowman, R. E. Synth. Commun. 1983, 13, 151.
17. Typical procedure—preparation of 22c:
A flask containing LiCl (980 mg,
23.1 mmol), 2-bromo-4-fluoroanisole (1.0 mL, 7.7 mmol), DCMA (1.8 mL,
8.4 mmol) and ethyl 3-ethoxyacrylate (3.3 mL, 23 mmol) in 1,4-dioxane
(20 mL) was degassed by passing a stream of nitrogen through the mixture
for 10 min. Bis(tri-t-butylphosphine) palladium(0) (166 mg, 0.32 mmol) was
added, and reaction mixture was heated at reflux under nitrogen for 16 h. The
brown mixture was then cooled and partitioned between ethyl acetate and
water. The layers were separated, and the organic layer was washed
sequentially with aqueous NH4Cl and brine, followed by drying over Na2SO4.
The mixture was filtered, and the filtrate was concentrated under reduced
pressure to give an oil which was purified by flash chromatography on silica
(40 g, 10–50% ethyl acetate in heptane) to afford 22c as an orange oil (1.93 g,
92%) as an inseparable mixture of E- and Z-isomers: 1H NMR (CDCl3, 500 MHz)
alkene protons d: 5.21, 5.33 ppm (1:1 ratio); LCMS (ESÀ): 269.2 (MÀH). HRMS
Calcd for C14H17FO: 269.1184. Found: 269.1196.
Supplementary data
Supplementary data (for the NMR and mass spectra for the b-
ketoesters 16, 23a–23n, and 26) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.10.076.
References and notes
18. Typical procedure—preparation of 23c: To a solution of 22c (1.93 g, 7.18 mmol)
in DCE (20 mL) was added 6 M HCl (6.0 mL, 40 mmol), and the biphasic
mixture was stirred vigorously for 15 h at rt. The layers were then separated,
and the DCE layer dried over Na2SO4. The mixture was filtered, and the filtrate
concentrated to afford an orange oil which by NMR contains highly pure 22c
(1.58 g, 92%) as a 9:1 mixture of ketone and enol: Ketone 1H NMR (CDCl3,
500 MHz) d: 1.23 (t, 3H, J = 7.1 Hz), 3.88 (s, 3H), 3.96 (s, 2H), 4.18 (q, 2H,
J = 7.1 Hz), 6.93 (dd, 1H, J = 9.15, 4.0 Hz), 7.16–7.24 (m, 1H), 7.59 (dd, 1H,
J = 9.03, 3.17 Hz). Enol key peaks—6.10 (s, 1H, =CH), 12,69 (s, 1H, OH); LCMS
(ES+); 241.2 (M+H). HRMS Calcd for C12H13FO: 241.0871. Found: 241.0873. In
cases where substantial impurities were present in the hydrolysis step, the
products were purified by silica flash chromatography with ethyl acetate and
heptane to give product 23 as inseparable mixtures of the ketone and enol
ranging from 9:1 to 1:1, respectively. When the reactions contained pyridyl
derivatives, the aqueous layer containing the protonated product was made
basic with saturated aqueous NaHCO3 followed by extraction with ethyl
acetate or dichloromethane to isolate the products.
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