Synthesis of substituted furoates from acrylates and aldehydes by Pd(OAc)2/HPMoV/CeCl3/O2 system

Article abstract of DOI:10.1021/jo701635f

(Chemical Equation Presented) A new synthetic method of substituted furoates from acrylates and aldehydes was developed by Pd-(OAc)₂ combined with molybdovanadophosphoric acid and Lewis acid under atmospheric dioxygen. The reaction was found to proceed through the palladium-catalyzed acetalization of acrylates with methanol followed by the reaction of the resulting acetals with aldehydes.

Full text of DOI:10.1021/jo701635f

Synthesis of Substituted Furoates from Acrylates and Aldehydes by
Pd(OAc)2/HPMoV/CeCl3/O2 System
Ken-ichi Tamaso, Yuji Hatamoto, Yasushi Obora, Satoshi Sakaguchi, and Yasutaka Ishii*
Department of Chemistry and Material Engineering, Faculty of Chemistry, Materials and Bioengineering
and High Technology Research Center, Kansai UniVersity, Suita, Osaka 564-8680, Japan
ishii@ipcku.kansai-u.ac.jp
ReceiVed July 26, 2007
A new synthetic method of substituted furoates from acrylates and aldehydes was developed by Pd-
(OAc)2 combined with molybdovanadophosphoric acid and Lewis acid under atmospheric dioxygen.
The reaction was found to proceed through the palladium-catalyzed acetalization of acrylates with methanol
followed by the reaction of the resulting acetals with aldehydes.
Introduction
furan carboxylate such as benzyl 5-methyl-3-furoate is known
to be an attractive synthetic intermediate of resmethrin and is
prepared through three steps from δ-phenyl levulic ester.5
Similar furoates are derived from unsaturated lactone6 and
methyl levulinate dimethyl acetal.7 However, most of these
methods suffer from several drawbacks such as the use of
uncommon chemicals, troublesome procedures, and/or the
necessity of several reaction steps.
Furan rings widely occur as key structural units in numerous
important products, which are utilized in pharmaceuticals,
essential oils and cosmetics, dyes and photosensitizers, fungi-
cides, etc.1 More specifically, furan carboxylates are important
precursors of pesticides such as pyrethroid. Frequently used
methods for the synthesis of furan derivatives are the intramo-
lecular cyclization of 1,4-diketones (Paal-Knorr method)1b and
the condensation between â-ketoesters and R-haloketones
(Feist-Be´nary reaction).1c Recently, a variety of transition-
metal-catalyzed reactions have been developed for the synthesis
of furan derivatives and heterocyclic compounds.2 For instance,
Pd(II)3- and Au4-catalyzed cycloisomerizations of 2-en-4-yn-
1-ols are reported to lead to substituted furan derivatives. A
We have now developed a novel, direct route to 5- and 2,5-
substituted 3-furoates (3), which are highly useful compounds
in the pharmaceutical industry and pesticide chemistry, from
acrylates (1) or acetyl acetones with aldehydes (2) under the
influence of catalytic amounts of Pd(II), H4PMo11VO40‚28H2O
(HPMo11V), and Lewis acid-like CeCl38 (eq 1). It is important
to note that the substituted furoates (3) can be directly
synthesized through a catalytic process from very cheap
chemicals such as acrylates and aldehydes. Therefore, this
method provides a proficient and convenient synthetic route to
substituted furoates.
(1) (a) Heaney, H.; Ahn, J. S. In ComprehensiVe Hetrocyclic Chemistry
II; Kartrizky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996; Vol. 2, pp 297-436. (b) Friedrichsen, W. In ComprehensiVe
Hetrocyclic Chemistry II; Kartrizky, A. R., Rees, C. W., Scriven, E. F. V.,
Eds.; Pergamon Press: Oxford, 1996, Vol. 2, p 352. (c) Friedrichsen, W.
In ComprehensiVe Hetrocyclic Chemistry II; Kartrizky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996; Vol. 2, p 359. (d)
The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and
Applications; Eicher, T., Hauptmann, S., Eds.; Wiley-VCH: Weinhein,
2003. (e) Lipshutz, B. H. Chem. ReV. 1986, 86, 795. (f) Hou, X. L.; Cheung,
H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C.
Tetrahedron 1998, 54, 1955.
(3) (a) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64,
7687. (b) Gabriele, B.; Salerno, G.; De Pascali, F.; Costa, M.; Chiusoli, G.
P. J. Org. Chem. 1999, 64, 7693.
(4) Liu. Y.; Song, F.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7,
5409.
(2) (a) Aurrecoechea, J. M.; Pe´rez, E. Tetrahedron 2004, 60, 4139. (b)
Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164. (c)
Ma, S.; Zhang, J.; Lu, L. Chem. Eur. J. 2003, 9, 2447. (d) Hoffmann-
Ro¨der, A.; Krause, N. Org. Lett. 2001, 3, 2537. (e) Ma, S.; Zhang, J. Chem.
Commun. 2000, 117. (f) Luo, F.-T.; Bajji, A. C.; Jeevanandam, A. J. Org.
Chem. 1999, 64, 1738. (g) Marshall, J. A.; Bartley, G. S. J. Org. Chem.
1994, 59, 7169. (h) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J.
Org. Chem. 1991, 56, 5816.
(5) Elliott, M.; Farnham, A. W.; Janes, N. F.; Needham, P. H.; Pearson,
B. C. Nature 1967, 213, 493.
(6) Asaoka, M.; Sugimura, N.; Takei, H. Chem. Lett. 1977, 171.
(7) Kotsuki, H.; Monden, M.; Ochi, M. Chem. Lett. 1983, 1007.
(8) Trisannelation, of acrylates to 1,3,5-benzenetricarboxylates using Pd-
(OAc)2/HPMoV/CeCl3/O2 catalyst system has been reported recently, see:
Tamaso, K.; Hatamoto, Y.; Sakaguchi, S.; Obora, Y.; Ishii, Y. J. Org. Chem.
2007, 72, 3603.
10.1021/jo701635f CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/18/2007
8820
J. Org. Chem. 2007, 72, 8820-8823

Direct Synthesis of Substituted Furoates
TABLE 1. Reaction of 1a with 2a by Pd(OAc)2 Combined with
HPMo11V and CeCl3 under Various Conditionsa
Pd(OAc)2/
mmol
HPMoV/
µmol
CeCl3/
mmol
conv/
%
yield/
%
b
entry
1
0.2
0.2
0
15
15
15
0
15
15
7.5
7.5
15
15
15
0.2
0.2
0.2
0.2
0
0.2
0.1
0.1
0.2
0.2
0.2
>99
>99
5
34
50
94
77
80
21
90
83
2c
3
ndd
3
Results and Discussion
4
0.2
0.2
0.2
0.1
0.1
0.2
0.2
0.2
5
ndd
38
74
The reaction of methyl acrylate (1a) with propanal (2a) was
chosen as a model reaction and carried out under various
reaction conditions (Table 1). To a mixture of Pd(OAc)2 (0.2
mmol), HPMo11V (15 µmol), and CeCl3‚7H2O (0.2 mmol) in
methanol/acetic acid solution, was added 1a (1 mmol) and 2a
(6 mmol) in acetic acid over a period of 3.5 h by using a syringe
pump under O2 (1 atm); the reaction mixture stirred at 70 °C
for an additional 4.5 h to give methyl 5-methyl-3-furoate (3a)
in 90% yield (entry 1). When a mixture of 1a and 2a in acetic
acid was added all at once to the catalytic solution, the yield of
3a somewhat decreased (entry 2). Removal of either HPMo11V
or Pd(OAc)2 from the catalytic system resulted in sluggish
reaction and recovery of the starting materials (entries 3 and
4). The reaction in the absence of CeCl3 produced polymeric
products (entry 5). Furoate 3a was not obtained by the reaction
in methanol or acetic acid alone, but the addition of water to
acetic acid produced 3a in 38% yield (entry 6). These observa-
tions suggest that three metals which constitute a catalytic
system and a mixed solvent are needed to promote the present
reaction. When the amounts of catalysts were halved, the yield
of 3a (74%) was slightly decreased (entry 7). No reaction took
place under argon atmosphere in the absence of O2, because of
difficulty of regenerating Pd(II) from the reduced Pd(0) (entry
9). Several Lewis acids such as AlCl3, FeCl3, InCl3, SmCl3,
and YbCl3 were examined. FeCl3, YbCl3, and SmCl3 gave 3a
in 36%, 39%, and 10% yields, respectively, but AlCl3 and InCl3
led to a complex mixture of undesired polymeric products. Yb-
(OTf)3 and p-TsOH were found to be inert in the present
reaction.
6e
7
8f
74
9g
10h,i
11j
ndd
51
>99
>99
>99(91)
a A mixture of 1a (1 mmol) and 2a (6 mmol) in AcOH (0.5 mL) was
added to a solution of Pd(OAc)2, HPMo11V, and CeCl3·7H2O in MeOH
(1.0 mL) and AcOH (4.5 mL) over a period of 3.5 h at 70 °C followed by
stirring an additional 4.5 h at that temperature. b GLC yields based on 1a.
The number in parenthesis shows isolated yield. c A mixture of 1a and 2a
was added all at once to the catalytic solution without using syringe pump.
d Not detected by GLC. e H2O (1.0 mL) was used in place of MeOH. f 1a
(1 mmol) in AcOH was added to a solution of 2a (3 mmol), Pd(OAc)2,
HPMo11V, and CeCl3·7H2O in MeOH (1 mL) and AcOH (4.5 mL) over a
period of 2 h followed by stirring an additional 6 h. g Under Ar. h 2a (3
mmol) was used. i Trimethyl 1,3,5-benzenetricarboxylate (1.3%) was
formed. j 2a (7 mmol) was used.
yield (eq 2). Similarly, the reaction of the dimethyl acetal of 4,
4,4-dimethoxy-2-butanone (6), with 2a gave 5 in 93% yield (eq
3).
On the basis of these results, the furoate synthesis was
examined by a combination of various aldehydes with electron-
deficient alkenes (Table 2). The reaction of 2a with several alkyl
acrylates (1b-1e) afforded the corresponding alkyl furoates
(3b-3e) in fair to good yields (entries 1-4).
The reaction was successfully extended to several substrates
other than acrylates. Acetyl acetone (1f) reacted with 2a to form
2,5-dimethyl-3-acetylfuran (3f) in excellent yield (94%) (entry
5). 3,5-Heptanedione (1g) was less reactive, and the reaction at
90 °C for 15 h gave 2-ethyl-5-methyl-3-propionyl furan (3g) in
moderate yield (entry 6). Cyclic ketones such as 1,3-cyclohex-
anedione (1h) afforded 2-methyl-6,7-dihydro-5H-benzofuran-
4-one (3h) in moderate yield. It is important to note that
dimethyl acetal of 1a, methyl 3,3-dimethoxypropionate (1i),
reacted with 2a to afford 3a in quantitative yield as discussed
later (entry 10). The Pd(II)-catalyzed acetalization of 1a is
known to lead to acetal 1i.9 We reported that 1a easily undergoes
the acetalization to form 1i in quantitative yield by Pd(OAc)2
combined with molybdovanadophosphate.10
It is rather difficult to explain clearly the reaction pathway
for the formation of furoates from acrylates and aldehydes
catalyzed by Pd(II) and Lewis acid. A plausible reaction path
is shown in Scheme 1. It is reasonable to assume that the Pd-
(II)-catalyzed acetalization of acrylate 1a with methanol is a
key step to give acetal 1i and/or 1i′ which is a synthetic
equivalent of 1i. In fact, as shown in entry 10 in Table 2, the
reaction using 1i in place of 1a with 2a proceeded smoothly to
give 3a in quantitative yield. The aldol-type condensation of
the resulting 1i or 1i′ with 2a by CeCl3 affords an R,â-
unsaturated carbonyl condensate (A) on which subsequent
enolization by Pd(II) followed by intramolecular cyclization
produces methyl furoate 3a through Pd-H elimination from a
dihydrofuran intermediate (B). The fact that the reaction of 1a
with benzaldehyde (2d) lacking R-hydrogen was completed at
the stage of the formation of the condensate, methyl R-formyl-
cinnamate (3k), corresponding to the condensate A suggests
that the above-mentioned reaction pathway is probable (entry
In addition, when methyl vinyl ketone (4) was allowed to
react with 2a under similar catalytic reaction conditions, 2,5-
dimethyl-3-furaldehyde (5) was obtained exclusively in 92%
(9) Hosokawa, T.; Yamanaka, T.; Itotani, M.; Murahashi, S.-I. J. Org.
Chem. 1995, 60, 6159 and refs cited therein.
(10) Yokota, T.; Fujibayashi, S.; Nishiyama, Y.; Sakaguchi, S.; Ishii,
Y. J. Mol. Catal. A: Chem. 1996, 114, 113.
J. Org. Chem, Vol. 72, No. 23, 2007 8821

Tamaso et al.
TABLE 2. Furoate Synthesis from 1 and Aldehydes (2)a
SCHEME 1. A Plausible Reaction Patha for the Formation
of 3a from 1a and 2a
a Schemes in the brackets show a conceivable path.
of 1a with 2a to obtain the condensate A was examined under
various conditions, but we failed in isolating the A. However,
the reaction of 1g with 2a to obtain an alternative condensate
A′ was carried out (eq 4). As expected, 4-propylidene-3,5-
heptanedione (A′), which is assumed to be a precursor to furan
derivative 3g, was obtained in 26% yield along with furan 3g
(20%). The isolated A′ is then subjected to react under the
influence of Pd(OAc)2/HPMo11V to give 3g in 43% yield (eq
5). However, the cyclization of A′ to 3g was not induced by
CeCl3‚7H2O alone in the absence of Pd(OAc)2 and HPMo11V.
This shows that the palladium species was an essential
component for the furoate formation.
a A mixture of 1 (1 mmol) and 2 (7 mmol) in AcOH (0.5 mL) was added
to a solution of Pd(OAc)2 (0.3 mmol), HPMo11V (23 µmol), and
CeCl3‚7H2O (0.3 mmol) in MeOH (1.0 mL) and AcOH (4.5 mL) over a
period of 3.5 h at 80 °C, followed by stirring an additional 4.5 h at that
temperature. b GLC yields based on 1. The numbers in parentheses show
isolated yields. c Pd(acac)2 was used instead of Pd(OAc)2. d 2a (10 mmol)
was used. e Reaction was carried out at 60 °C. f The reaction was carried
out at 90 °C for 15 h. g 1i (1 mmol) in AcOH (0.5 mL) and MeOH (0.5
mL) was added to a solution of 2a (3 mmol), Pd(OAc)2 (0.1 mmol),
HPMo11V (7.5 µmol), and CeCl3‚7H2O (0.1 mmol) in MeOH (1.0 mL)
and AcOH (4.5 mL). h The reaction was carried out at 60 °C for 2 h, and
2d (60 mmol) was used. i E:Z ) 33:67.
In conclusion, we have developed a direct route to substituted
furans, which are very attractive compounds in organic syn-
thesis, from cheap starting materials such as acrylates and
aldehydes by using Pd(II) and CeCl3 as key catalysts. This
reaction would provide a very convenient synthetic route to
various polysubstituted furoate derivatives.
12). Finally, the reduced Pd(0) was reoxidized to Pd(II) by the
action of the HPMo11V/O2 reoxidation system.11
The reaction of 4 with 2a seemed to proceed in a similar
reaction pathway through the Ce enolate (7) as a transient
intermediate.
Experimental Section
Compounds 3a,12 3b,6 3f,13 3g,14 3h,15 3k,16 and 517 were reported
previously.
Experimental Procedures. A Typical Reaction was Carried
out as Follows (Table 1, entry 11). To a solution of Pd(OAc)2
(45 mg, 0.20 mmol, 20 mol %), H4PMo11VO40‚28H2O (HPMo11V)
(12) Divald, S.; Chun, M. C.; Joullie, M. M. J. Org. Chem. 1976, 41,
2835.
(13) (a) Arcadi, A.; Cerichelli, G.; Chiarini, M.; Di Giuseppe, S.;
Marinelli, F. Tetrahedron Lett. 2000, 41, 9195. (b) Qian, C.-Y. J. Heterocycl.
Chem. 1994, 31, 1219.
(14) Padwa, A.; Chiacchio, U.; Kline, D. N.; Perumattam, J. J. Org.
Chem. 1988, 53, 2238.
In the aforementioned reaction pathway, the condensate A is
thought to be a precursor to the furoate 3a. Thus, the reaction
(11) (a) Yokota, T.; Tani, M.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc.
2003, 125, 1476. (b) Tani, M.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2004,
69, 1221.
(15) Tang, E.; Huang, X.; Xu, W.-M. Tetrahedron 2004, 60, 9963.
(16) Han, X.; Widenhoefer, R. A. J. Org. Chem. 2004, 69, 1738.
(17) Comins, D. L.; Killpack, M. O. J. Org. Chem. 1987, 52, 104.
8822 J. Org. Chem., Vol. 72, No. 23, 2007

Direct Synthesis of Substituted Furoates
(38 mg, 15 µmol, 1.5 mol %), and CeCl3‚7H2O (75 mg, 0.20 mmol,
20 mol %) in a mixed solvent of methanol (1.0 mL) and acetic
acid (4.5 mL) was added a solution of 1a (86 mg, 1 mmol) and 2a
(407 mg, 7 mmol) in acetic acid (0.5 mL) over a period of about
3.5 h by using a syringe pump under O2 (1 atm), and the mixture
was stirred at 70 °C for an additional 4.5 h. After the reaction,
GLC and GC-MS analyses were performed. The conversions and
yields of products were estimated from the peak areas, based on
the GC internal standard technique. Solvent was removed under
reduced pressure, neutralized with sodium bicarbonate, and ex-
tracted with diethyl ether (50 mL). The product, methyl 5-methyl-
3-furoate (3a), was isolated as a pure form by Kugelrohr distillation
in 91% yield.
Reaction of Methyl Vinyl Ketone (4) with Propanal (2a) in
the Presence of Pd(OAc)2/HPMo11V/CeCl3 (eq (2)). To a solution
of Pd(OAc)2 (67 mg, 0.30 mmol, 30 mol %), H4PMo11VO40‚28H2O
(HPMo11V) (50 mg, 23 µmol, 2.3 mol %), and CeCl3‚7H2O (112
mg, 0.30 mmol, 30 mol %) in acetic acid (4.5 mL) was added a
solution of 4 (70 mg, 1 mmol) and 2a (581 mg, 10 mmol) in acetic
acid (0.5 mL) over a period of about 4.5 h by using a syringe pump
under O2 (1 atm), and the mixture was stirred at 60 °C for an
additional 3.5 h. After the reaction, GLC and GC-MS analyses
were performed. The conversions and yields of products were
estimated from the peak areas, based on the GC internal standard
technique. Solvent was removed under reduced pressure, neutralized
with sodium bicarbonate, and extracted with diethyl ether (50 mL).
The product, 2,5-dimethyl-3-furaldehyde (5), was isolated as a pure
form by Kugelrohr distillation in 86% yield.
VO40‚28H2O (HPMo11V) (50 mg, 23 µmol, 2.3 mol %), and CeCl3‚
7H2O (112 mg, 0.30 mmol, 30 mol %) in acetic acid (4.5 mL) was
added a solution of 6 (132 mg, 1 mmol) and 2a (581 mg, 10 mmol)
in acetic acid (0.5 mL) over a period of about 4.5 h by using a
syringe pump under O2 (1 atm), and the mixture was stirred at
60 °C for an additional 3.5 h. GLC and GC-MS analyses of the
reaction mixture showed that 5 was formed in 93% yield.
Reaction of 4-Propylidene-3,5-heptadione (A′) in the Presence
of Pd(OAc)2/HPMo11V (eq (5)). To a solution of Pd(OAc)2 (67
mg, 0.30 mmol, 30 mol %) and H4PMo11VO40‚28H2O (HPMo11V)
(50 mg, 23 µmol, 2.3 mol %) in acetic acid (4.5 mL) was added a
solution of 4-propylidene-3,5-heptadione (A′) (168 mg, 1 mmol)
in acetic acid (0.5 mL) over a period of about 2.5 h by using a
syringe pump under O2 (1 atm), and the mixture was stirred at
70 °C for an additional 5.5 h. GLC and GC-MS analyses of the
reaction mixture showed that 3g was formed in 43% yield.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan, and “High-Tech Research Center” Project for Private
Universities: matching fund subsidy from the Ministry of
Education, Culture, Sports, Science and Technology, Japan,
2005-2009.
Supporting Information Available: Experimental procedures
and spectral data of 3, 5, and A′. This material is available free of
charge via the Internet at http://pubs.acs.org.
Reaction of 4,4-Dimethoxy-2-butanone (6) with Propanal (2a)
in the Presence of Pd(OAc)2/HPMo11V/CeCl3 (eq (3)). To a
solution of Pd(OAc)2 (67 mg, 0.30 mmol, 30 mol %), H4PMo11-
JO701635F
J. Org. Chem, Vol. 72, No. 23, 2007 8823