Synthesis of 2-alkylidenetetrahydrofurans by Ru-catalyzed regio- and stereoselective codimerization of dihydrofurans with α,β-unsaturated esters

Article abstract of DOI:10.1039/b509578f

2-(1-Alkoxycarbonyl)alkylidenetetrahydrofurans were readily synthesized by the codimerization of 2,3- or 2,5-dihydrofurans with α,β-unsaturated esters using a zerovalent Ru catalyst, Ru(cod)(cot), with high regio- and stereoselectivity. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b509578f

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Synthesis of 2-alkylidenetetrahydrofurans by Ru-catalyzed regio- and
stereoselective codimerization of dihydrofurans with a,b-unsaturated
esters{
Hiroshi Tsujita, Yasuyuki Ura, Kenji Wada, Teruyuki Kondo and Take-aki Mitsudo*
Received (in Cambridge, UK) 8th July 2005, Accepted 9th August 2005
First published as an Advance Article on the web 9th September 2005
DOI: 10.1039/b509578f
RhCl(PPh3)3, IrCl(CO)(PPh3)2 and Pd(PPh3)4, 3a was not
obtained at all.
2-(1-Alkoxycarbonyl)alkylidenetetrahydrofurans were readily
synthesized by the codimerization of 2,3- or 2,5-dihydrofurans
with a,b-unsaturated esters using a zerovalent Ru catalyst,
Ru(cod)(cot), with high regio- and stereoselectivity.
The effect of the reaction temperature on the codimerization of
1a with 2a was examined, and 160 uC was revealed to be suitable.
The yield of 3a was decreased at over 160 uC (60% at 170 uC and
51% at 180 uC). The use of other solvents with high boiling point
such as diglyme and mesitylene resulted in a lower yield of 3a
(32 and 35%).
2-Alkylidenetetrahydrofurans are versatile synthetic building
blocks for natural products such as macrotetrolide antibiotics1
and for artificial biologically active substances.2 A large number of
preparative methods for 2-(1-alkoxycarbonyl)alkylidenetetrahy-
drofurans have been reported so far, and are roughly classified into
the following categories: acid or base-mediated cyclizations,3,4
cross-Claisen condensation by nucleophilic reactions of ester
enolates with lactones,5 selenium6 or iodine7-involved cyclizations,
and transition metal-catalyzed reactions.8–10 Most of these
methods, however, have an essential drawback inasmuch as
undesirable byproducts such as inorganic salts are produced. On
the other hand, codimerization of unsaturated hydrocarbons is an
attractive carbon–carbon bond forming method with high atom
efficiency. In the course of our investigation on ruthenium-
catalyzed selective codimerization of alkenes,11 we found a highly
regio- and stereoselective codimerization of dihydrofurans with
a,b-unsaturated esters catalyzed by low-valent ruthenium com-
plexes, which provides a novel and unique synthetic route to 2-(1-
alkoxycarbonyl)alkylidenetetrahydrofurans.12
Under the optimized reaction conditions, the scope of the
codimerization of dihydrofurans with a,b-unsaturated esters was
investigated (Table 2). The reaction of 1a with 2-aryl-2,3-
dihydrofurans proceeded nicely to give the corresponding codimers
(runs 2 and 3). Remarkably, b-substituted unsaturated esters such
as methyl cinnamate (2b), methyl crotonate (2c) and dimethyl
fumarate (2d) were also applicable to the present catalytic system
(runs 5–7). Dimethyl maleate worked as well as 2d to afford the
identical codimer 3g in 68% yield. The use of 2,5-dihydrofuran
instead of 1a in the codimerization with 2a gave 3a in 62% yield. In
this case, isomerization of the substrate prior to the codimerization
would occur. On the other hand, the codimerization of 1a with
a-substituted and b,b-disubstituted acrylates, 2(5H)-furanone,
vinylketones, acrylonitrile and acrylamides, did not proceed under
the present reaction conditions. Six-membered unsaturated cyclic
ethers such as 3,4-dihydro-2H-pyran and 1,4-dioxene, and n-butyl
vinyl ether did not give the corresponding codimers in the reaction
with 2a, either.
The reaction of 2,3-dihydrofuran (1a) with ethyl acrylate (2a)
was first examined. A zerovalent ruthenium catalyst, Ru(cod)(cot)
[cod 5 1,5-cyclooctadiene, cot 5 1,3,5-cyclooctatriene], was found
to catalyze the codimerization efficiently in a polar solvent,
N,N-dimethylacetamide (DMA) at 160 uC, affording 2-(1-
ethoxycarbonyl)ethylidenetetrahydrofuran (3a) exclusively in 70%
yield. Catalytic activity of several low-valent ruthenium complexes
for the codimerization of 1a with 2a was then surveyed (Table 1).
Another zerovalent ruthenium complex, Ru(cot)(dmfm)2
[dmfm 5 dimethyl fumarate],13 was also effective to give 3a
(run 3). Ru(cyclooctadienyl)2, Ru3(CO)12 and RuHCl(CO)(PPh3)3
A deuterium-labeling experiment was conducted to elucidate
the reaction mechanism with deuterium-incorporated dimethyl
Table 1 Codimerization of 2,3-dihydrofuran with ethyl acrylate
catalyzed by several ruthenium complexesa
showed moderate catalytic activity (runs 4,
5 and 6).
CpRuCl(PPh3)2, Cp*RuCl(cod) [Cp* 5 pentamethylcyclopenta-
dienyl], RuH2(PPh3)4, [RuCl2(CO)3]2 and Ru(CO)3(PPh3)2 were
ineffective for the present codimerization. With 8–10 group
transiton metal catalysts such as Fe3(CO)12, Co2(CO)8,
Run
Catalyst
Yieldb (%)
1
2
3c
4
5
6
7
a
None
Ru(cod)(cot)
Ru(cot)(dmfm)2
Ru(cyclooctadienyl)2
Ru3(CO)12
0
70
70
50
45
31
5
Department of Energy and Hydrocarbon Chemistry, Graduate School of
Engineering, Kyoto University, Nishikyo-ku, Kyoto, 615-8510, Japan.
E-mail: mitsudo@scl.kyoto-u.ac.jp; Fax: +81 75 383 2507;
Tel: +81 75 383 2506
{ Electronic supplementary information (ESI) available: Experimental
section. See http://dx.doi.org/10.1039/b509578f
RuHCl(CO)(PPh3)3
CpRuCl(PPh3)2
b
Ru catalyst (0.030 mmol as
a
metal atom).
GLC yields.
c
dmfm 5 dimethyl fumarate.
5100 | Chem. Commun., 2005, 5100–5102
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A proposed mechanism is shown in Scheme 1. Alkylruthenium
complex 5 would be formed by the insertion of a,b-unsaturated
ester 2 into the Ru–H bond of the catalytically active ruthenium
hydride species 4. At this stage, an electron-withdrawing
alkoxycarbonyl group should be placed at the a-position.
Successive insertion of 1 into the Ru–C bond in 5 gives
tetrahydrofuranylruthenium species 6, where an electronic factor
seems to be predominant to control the insertion direction. The
intermediate 6 is followed by b-hydrogen elimination to afford 7,
and isomerization of the formed dihydrofuran gives 2-alkylidene-
tetrahydrofuran 3, along with the regeneration of ruthenium
hydride 4. It is noted that (E)-3h is more thermally stable than (Z)-
3h by 4.97 kcal mol21, calculated by a DFT method at the
B3LYP/6-31G** level (Fig. 1). The decrease of deuterium
incorporation in eqn (1) can be explained by the existence of the
rapid equilibria between 4 and 5, and, 4 and 8. Under these
equilibria, a certain percentage of the deuterium in 2d-d2 would be
transferred into the dihydrofuran at the early stage of the reaction.
A metallacycle mechanism can be considered as an alternative
pathway; in this case, however, linear codimers should be obtained
rather than the branched ones such as 3a–3d, because the
alkoxycarbonyl group would prefer to occupy the a-position in
the metallacycle intermediate. Moreover, the decrease of deuterium
incorporation in eqn (1) cannot be explained by this mechanism.
Table 2 Ru(cod)(cot)-catalyzed codimerization of 2,3-dihydrofurans
with a,b-unsaturated esters
Run R1 R2
R3 Product
Et
Yielda (%)
3a 70 (59)
1
H
H
H
H
H
Ph
2
Ph
Et
3b 39 (26)
3c 79 (65)
3d 72 (55)
3e 44 (19)
3b,,c Np
Et
4
5
H
H
tBu
Me
6
7
a
H
H
Me
Me
3f
(11)
CO2Me Me
3g 64 (55)
b
GLC yields. Isolated yields are shown in parentheses. Np 5
c
1-Naphthyl. 48 h.
fumarate (2d-d2). The codimer 3g-d2 was isolated in 50% yield with
29 and 36% deuterium incorporations as shown in eqn (1). The
decrease of the deuterium incorporating ratio in 3g-d2 implies that
a rapid H/D exchange occurred during the reaction, that is
promoted by an in situ-generated ruthenium hydride species. We
believe that the hydride should be supplied from a cod ligand in
Ru(cod)(cot) or an olefinic hydrogen of a,b-unsaturated esters via
C–H activation.
Scheme 1 A possible mechanism.
(1)
Fig. 1
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In summary, we have developed a novel synthetic method for 2-
(1-alkoxycarbonyl)alkylidenetetrahydrofurans by a simple codi-
merization of dihydrofurans with a,b-unsaturated esters. Further
mechanistic study and application of the present reaction to
organic synthesis are now in progress.{
We thank financial support in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science,
Sports and Culture, Japan.
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Notes and references
{ General procedure: A mixture of 2,3-dihydrofuran (1a, 351 mg, 5.0 mmol),
ethyl acrylate (2a, 100 mg, 1.0 mmol), Ru(cod)(cot) (9.4 mg, 0.030 mmol)
and N,N-dimethylacetamide (3.0 mL) were placed in a 20 mL Pyrex glass
flask equipped with a magnetic stirring bar and a reflux condenser under an
argon atmosphere. The reaction mixture was then stirred at 160 uC for 20 h.
After removal of the solvent, the crude product was purified by flash
column chromatography (ethyl acetate–hexane 5 1 : 10) and Kugelrohr
distillation (110 uC at 10 Torr) to give the corresponding codimer 3a (93 mg,
59%) as a colorless oil; IR (neat): 1692, 1646, 1455, 1304 cm21; 1H NMR
(CDCl3, 400 MHz): d 4.14 (t, J 5 7.0 Hz, 2H), 4.08 (q, J 5 6.8 Hz, 2H),
2.99 (dt, J 5 1.5, 7.8 Hz, 2H), 2.03–1.96 (m, 2H), 1.74 (t, J 5 1.5, 3H), 1.21
(t, J 5 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d 170.0 (C), 169.1 (C),
97.5 (C), 71.2 (CH2), 59.5 (CH2), 31.0 (CH2), 24.7 (CH2), 14.6 (CH3), 11.4
(CH3); MS (EI) m/z 170 (M+). Anal. Calc. for C9H14O3: C, 63.51; H, 8.29.
Found: C, 63.33; H, 8.11%.
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