Heck reaction of Baylis-Hillman adducts with iodobenzenes using a catalytic amount of Pd/C under solvent-free conditions

Article abstract of DOI:10.1055/s-0032-1316992

The reaction of Baylis-Hillman adducts with iodobenzenes using commercially available palladium-on-carbon as a catalyst under solvent-free conditions afforded the corresponding coupling products, α-benzyl-β-keto esters, in high to excellent yields. The reactions are very efficient.

Full text of DOI:10.1055/s-0032-1316992

PAPER
▌3161
pHapeerck Reaction of Baylis–Hillman Adducts with Iodobenzenes Using a
Catalytic Amount of Pd/C under Solvent-Free Conditions
Heck Reaction of Baylis–Hillman Adducts with Iodobenzenes
Hyun-Soo Kim, Sang-Jin Lee, Boram Choi, Cheol Min Yoon*
Department of Advanced Material Chemistry, Korea University, Jochiwon, Choongnam 339-770, South Korea
Fax +82(42)8675396; E-mail: cmyoon@korea.ac.kr
Received: 23.05.2012; Accepted after revision: 10.07.2012
These reactions are less efficient. Recently, two Heck
methods were developed, the first using arenediazonium
salts as the substrate10a and the second an oxime-derived
palladacycle as the catalyst,10b that gave the coupling
products in high yields. However, both methods needed
extra steps for the preparation of the diazonium salt and
pallacycles, and showed limited scope.
Abstract: The reaction of Baylis–Hillman adducts with iodoben-
zenes using commercially available palladium-on-carbon as a cata-
lyst under solvent-free conditions afforded the corresponding
coupling products, α-benzyl-β-keto esters, in high to excellent
yields. The reactions are very efficient.
Key words: Baylis–Hillman adduct, Heck reaction, palladium-on-
carbon, iodobenzenes, α-benzyl-β-keto esters
One approach, with the appeal of green chemistry,11 is to
conduct palladium-catalyzed cross-coupling reactions un-
der heterogeneous conditions.12 Palladium-on-carbon is a
well-established reagent13 that has found increasing popu-
larity in several C–C bond-forming reactions (e.g.,
Suzuki–Miyaura,14 Heck,15 and Sonogashira16–18) because
the use of palladium-on-carbon avoids contamination of
the product with palladium and expedites recovery of the
metal, and, therefore, the reactions are practical and cost-
effective for large-scale reactions.
The Baylis–Hillman reaction1 is a useful pathway for C–
C bond formation, and Baylis–Hillman adducts1 have
been used as versatile building blocks to generate hetero-
cyclic compounds, synthetic intermediates, and natural
products.1,2 α-Benzyl-β-keto esters are important sub-
strates for synthetic transformations, such as multicompo-
nent reactions for the synthesis of heterocycles,3
asymmetric transformations,4 and the selective synthesis
of allenyl esters.5
As a result of our continued studies of the Baylis–Hillman
reaction,19 we report herein a simple and very efficient
synthetic method for the preparation of α-benzyl-β-keto
esters via Heck reaction of iodobenzenes with Baylis–
Hillman adducts using palladium-on-carbon as a catalyst
under solvent-free conditions (Scheme 1).
Two general syntheses of β-keto esters are (i) acylation of
carboxylic esters by acyl halides or esters, and (ii) acyla-
tion of ethyl acetoacetate and its substituted derivatives by
acyl halides or esters followed by base-promoted deacet-
ylation. However, these methods require the use of a spe-
cial base, anhydrous conditions, and low temperatures.6
O
OH
Heck reactions are one of the most important and attrac-
tive reactions among transition-metal-catalyzed C–C
bond formation methods; the mild reaction conditions
mean a variety of unprotected functional groups can be
present in the substrate.7 Therefore, Heck reactions of the
Baylis–Hillman adduct might be a very attractive alterna-
tive for syntheses of α-benzyl-β-keto esters via ben-
zylation of β-keto esters.8 Heck reactions of Baylis–
Hillman adducts were independently developed in 1998
by three research groups.9 Basavaiah et al.9c and Vankar et
al.9b reported that aryl bromides or iodides reacted with
Baylis–Hillman adducts using palladium(II) acetate as the
catalyst in the presence of tetrabutylammonium bromide
and a mineral base at 66–70 °C to afford the correspond-
ing β-keto esters in 60–81% isolated yields. Bhat et al9d
used bromobenzene with the palladium(II) acetate/triphe-
nylphosphine catalytic system in triethylamine at 100 °C
to give a mixture of the β-keto ester and the decarboxyl-
ation product; the ratio dependent on the reaction time.
Pd/C, 100 °C
Et3N, 4 h
EWG
Ar
EWG
ArI
+
R
R
2
1
3
Scheme 1
The optimization studies used ethyl acrylate 1a as a model
substrate, commercially available palladium-on-carbon as
the catalyst, and triethylamine as the base. The optimum
conditions were iodobenzene (2a, 2 equiv), triethylamine
(5 equiv), and palladium-on-carbon (0.5 mol%) at 100 °C.
The reaction of ethyl 2-[hydroxy(phenyl)methyl]acrylate
(1a, 0.97 mmol), iodobenzene (2 equiv), triethylamine (5
equiv), and 10% palladium-on-carbon (0.5 mol%) at 100
°C for four hours gave the arylated product 3a in 94% iso-
lated yield (Table 1, entry 1). Side products resulting from
a competitive retro-Baylis–Hillman reaction, further ary-
lation of the coupling product,20 and decarboxylation9
were not detected, and essentially quantitative yields of
crude product were observed. To examine the scope and
limitations, the reaction of iodobenzene (2a) with other
various Baylis–Hillman adducts 1 with electron-with-
drawing 1b,c or electron-donating groups 1d–1f on the ar-
SYNTHESIS 2012, 44, 3161–3164
Advanced online publication: 12.09.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316992; Art ID: SS-2012-F0442-OP
© Georg Thieme Verlag Stuttgart · New York

3162
H.-S. Kim et al.
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Table 1 Heck Reactiona of a Variety of Baylis–Hillman Adducts 1
with Iodobenzene (2a) (continued)
omatic ring were conducted under our conditions to give
the corresponding α-benzylated β-keto esters 3b–f in high
to excellent isolated yields (Table 1). Baylis–Hillman ad-
ducts with other heterocyclic ring systems, such as furan
1g and thiophene 1h, and with an alkyl group 1i reacted
with iodobenzene (2a) nicely under the reaction condi-
tions to give the corresponding coupling products 3g–i in
excellent isolated yields.
O
O
O
OH
I
Pd/C, 100 °C
Et3N, 4 h
R
OEt
+
R
OEt
2a
1
3
Entry
8
Substrate
Productb
Yieldc (%)
Table 1 Heck Reactiona of a Variety of Baylis–Hillman Adducts 1
with Iodobenzene (2a)
OH
O
O
O
S
OEt
O
OH
I
3h
86
Pd/C, 100 °C
Et3N, 4 h
R
OEt
+
R
OEt
1h
2a
1
OH
O
3
OEt
9
3i
84
Entry
1
Substrate
Productb
Yieldc (%)
1i
OH
O
a Reaction conditions: ethyl acrylate 1 (0.97 mmol), iodobenzene (2a,
2 equiv), Et3N (5 equiv), 10% Pd/C (0.5 mol%), 100 °C, 4 h.
b All products are known21 and their spectral data are consistent with
literature data.
OEt
3a
3b
94
92
c Isolated yields.
1a
OH
O
OEt
To expand the scope, Baylis–Hillman adduct 1a was re-
acted with a variety of electron-sufficient 2b–d and elec-
tron-deficient iodobenzenes 2e,f under the optimized
conditions to give the corresponding keto esters in high to
excellent isolated yields (Table 2).
2
O2N
1b
OH
O
OEt
Table 2 Heck Reactiona of Baylis–Hillman Adduct 1a with Various
3
4
5
3c
3d
3e
87
84
93
Iodobenzenes
Cl
O
OH
1c
OH
O
OEt
O
O
OEt
1a
Pd/C, 100 °C
Et3N, 4 h
OEt
+
1d
I
R
OH
O
3
OEt
R
2
MeO
Entry
1
Iodobenzene
Productb
Yieldc (%)
97
1e
OH
O
I
O
OEt
3j
6
7
3f
87
88
MeO
O
2b
1f
I
OH
O
O
OEt
2
3k
99
3g
MeO
1g
2c
Synthesis 2012, 44, 3161–3164
© Georg Thieme Verlag Stuttgart · New York

PAPER
Heck Reaction of Baylis–Hillman Adducts with Iodobenzenes
3163
Table 2 Heck Reactiona of Baylis–Hillman Adduct 1a with Various
Iodobenzenes (continued)
palladium into the iodobenzene 2 followed by ligand ex-
change affords η2-complex 4, which provides an interme-
diate 5 via the insertion of Pd–Ar bond into the C=C bond
(Scheme 2). syn-β-Elimination from 5 gives η2-complex 6
followed by ligand exchange and tautomerism of 7 to give
the expected keto ester 3.
O
OH
OEt
O
O
1a
Pd/C, 100 °C
Et3N, 4 h
OEt
In conclusion, a synthetic protocol for the Heck reaction
of a variety of Baylis–Hillman adducts with iodobenzenes
was developed using commercially available palladium-
on-carbon [STREM, 46-1900] as the catalyst and triethyl-
amine as the base at 100 °C without an additive or solvent.
The protocol is very efficient due to high to excellent
yields and solvent-free conditions, and essentially quanti-
tative yields for crude products.
+
I
R
3
R
2
Entry
3
Iodobenzene
Productb
Yieldc (%)
91
I
All chemicals were purchased from specialized suppliers with ana-
lytical purity and used without further purification. 10% Pd/C [46-
1900] was dry powder and purchased from STREM. Baylis–
Hillman adducts used in Heck reactions were prepared by known
methods.22 IR spectra of samples were recorded on a Perkin-Elmer
3l
2d
I
1
FT-IR 240-c spectrophotometer using KBr disks. H NMR (300
4
5
3m
3n
94d
87
MHz) and 13C NMR (75 MHz) spectra were recorded on a Bruker
300 spectrometer in CDCl3. Column chromatography was per-
formed using Merck silica gel (230–400 mesh). All Heck coupling
products have physical, spectroscopic, and analytic data identical to
those given in the literature.21 The following procedure is represen-
tative for all α-benzyl-β-keto esters 3 prepared in this work.
O2N
2e
I
Cl
Ethyl 2-Benzyl-3-oxo-3-phenylpropanoate (3a); Typical Proce-
dure
2f
a Reaction conditions: ethyl acrylate 1a (0.97 mmol), iodobenzene 2
(2 equiv), Et2N (5 equiv), 10% Pd/C (0.5 mol%), 100 °C, 4 h.
b All products are known21 and their spectral data are consistent with
literature data.
The mixture of ethyl acrylate 1a (200 mg, 0.97 mmol), iodobenzene
(2a, 0.217 mL, 1.94 mmol, 2 equiv), Et3N (0.676 mL, 4.85 mmol, 5
equiv), and 10% Pd/C (5 mg, 0.5 mol%) was heated at 100 °C. After
4 h, the mixture was diluted with EtOAc and filtered through a bed
of Celite. The filtrate was concentrated under reduced pressure and
chromatographed on short pad of silica gel (EtOAc–hexane, 1:4) to
give coupling product 3a (257 mg, 94%) (Table 1, entry 1).
c Isolated yields.
d The reaction is relatively slow due to the low solubility of 1-iodo-4-
nitrobenzene in Et3N or relatively high melting point of 1-iodo-4-ni-
trobenzene. Reaction time: 8 h.
IR (film): 3369, 2959, 1734, 1687, 1598, 1582, 1496, 1449, 1368,
1270, 1231, 1152, 749 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.11 (t, J = 7.5 Hz, 3 H), 3.33 (d,
J = 6.6 Hz, 2 H), 4.09 (q, J = 7.5 Hz, 2 H), 4.63 (t, J = 7.8 Hz, 1 H),
The first step of the Heck reaction mechanism is the oxi-
dative addition of the iodobenzene. Oxidative addition of
O
OH
EWG
EWG
HI
R
R
Ar
H
Pd
Ar
I
I
Pd(0)
Ar
3
7
2
EWG
Ar
HO
Ar Pd
I
6
R
R
H
Pd
R
I
OH
EWG
1
H
R
OH
OH
EWG
EWG
Pd
Ar Pd
I
Ar
I
5
4
Scheme 2 Mechanism of the Heck reaction of Baylis–Hillman adducts
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3161–3164

3164
H.-S. Kim et al.
PAPER
7.18–7.29 (m, 5 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.56 (t, J = 7.5 Hz, 1
H), 7.96 (d, J = 7.8 Hz, 2 H).
13C NMR (75MHz, CDCl3): δ = 14.2, 34.9, 56.3, 61.9, 126.7, 128.6
(2 C), 128.8 (2 C), 128.9 (2 C), 129.2 (2 C), 133.6, 136.2, 138.5,
169.3, 194.5.
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This work was supported by Korea University.
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Synthesis 2012, 44, 3161–3164
© Georg Thieme Verlag Stuttgart · New York