previously unknown tandem hydroformylation/acetalization
of alkenediols (Scheme 1).
For the synthesis of benzoannelated tetrahydrofuro[2,3b]
furans we used o-hydroxy cinnamyl alcohols 8 as starting
compounds, which can be easily prepared starting from
coumarins.12 Unlike the aliphatic pentenediols, these cin-
namyl alcohols undergo regioselective hydroformylation, as
shown by Nozaki et al.13 for the formation of phenyl-
substituted tetrahydrofuran-2-ols. Under optimized condi-
tions, the desired cis-2,3,3a,8a-tetrahydrofuro[2,3b]benzofuran
(9a)14 is obtained starting from the unsubstituted diol 8a in
69% yield (Scheme 2) at 60 °C using the Rh(acac)(CO)2/
PPh3 catalyst system with 1,4-dioxane as the solvent.
Scheme 1
Scheme 2
Starting with pent-2-ene-1,5-diol (1a)9 as a model com-
pound, we obtained perhydrofuro[2,3b]furan (2a) in up to
72% yield. The optimal reaction conditions are found at a
reaction temperature of 120 °C and a total pressure of 60
bar syngas (CO:H2 ) 3:1) using the catalyst system [Rh-
(cod)Cl]2/PPh3 with dichloromethane as the solvent.10
A
coupling constant of 5.0 Hz for the bridgehead protons
demonstrates the exclusive formation of cis-fused bicycles.
Under nonoptimized conditions, several byproducts can
be observed, among them the hydrogenation product 5a,
tetrahydropyran-2-ol (6a), which is formed via a rhodium-
catalyzed double-bond migration to the enol and addition of
the second hydroxy group to the enol forming the hemi-
acetal. The saturated diol 5a was only observed when the
phosphine ligand was omitted. Furthermore, a regioisomeric
hydroformylation product 7a can be formed, which under-
goes only hemiacetalization. This regioisomer was only
observed when using 1,4-dioxane as the solvent.
This reaction sequence can also be applied to substituted
alcohols. The 1,5-diphenyl-substituted alkenediol 1b11 affords
the desired furofuran 2c in 55% yield. The 2,2,5,5-tetra-
methyl-substituted furofuran 2c is obtained in 48% yield
starting from the alkenediol 1c.11
Similar to the aliphatic olefins, isomerization and hydro-
genation products are observed and their ratio increases if
the reaction is performed at higher reaction temperatures in
the absence of phosphine ligands.
Substituents at the double bond or at the aliphatic alcohol
moiety enable the formation of substituted tetrahydrofuro-
benzofurans. Since these cinnamyl alcohols are less reactive
than the unsubstituted olefin 8a, we examined their reactions
only at 120 °C.
Under these conditions 2,3,3a,8a-tetrahydro-3-methylfuro-
[2,3b]benzofuran (9b) is obtained in 47% yield starting from
the trisubstituted olefin 8b. The substituted tetrahydrofuro-
[2,3b]benzofuran 9b is obtained as a 7:1 mixture of two
diastereomers, where the heterocyclic rings are cis-fused.
Analogously, the tandem hydroformylation acetalization
of 2-((Z)-3-hydroxy-3-methylbut-1-enyl)-phenol (8c) gives
access to 2,3,3a,8a-tetrahydro-2,2-dimethylfuro[2,3b]-benzo-
furan (9c) in 62% yield. Under milder reaction conditions
at 60 °C, only the hemiacetal 10c as a 1:1 mixture of two
The decline of the yields can be attributed both to steric
shielding of the double bond and to side reactions of the
higher-substituted alcohols, especially dehydration of the diol
and subsequent reactions to be expected thereof. Thus, further
optimization is required here for each individual substrate.
(9) de Leon, C. Y.; Ganem, B. Tetrahedron 1997, 53, 7731.
(10) Typical procedure. A solution of 512 mg (5.0 mmol) of pent-2-
ene-1,5-diol (1a), 12 mg (25 µmol) of [Rh(cod)Cl]2, and 40 mg (150 µmol)
of PPh3 in 10 mL of dichloromethane is heated for 20 h at 120 °C in an
autoclave under an atmosphere of 45 bar carbon monoxide and 15 bar
hydrogen. Purification of the crude product by column chromatography on
basic alumina with MTBE followed by ethanol as eluants gives 411 mg
(3.6 mmol) of perhydrofuro[2, 3b]furan (2a).
(12) (a) Wang, B.; Zhang, H.; Zheng, A.; Wang, W. Bioorg. Med. Chem.
1998, 6, 417. (b) Alberola, A.; Ortega, A. G.; Pedrosa, R.; Bragado, J. L.
P.; Amo, J. F. R. J. Heterocycl. Chem. 1983, 715. (c) Boyd, D. R.; Sharma,
N. D.; Boyle, R.; Evans, T. A.; Malone, J. F.; McCombie, K. M.; Dalton,
H.; Chima, J. J. Chem. Soc., Perkin Trans. 1 1996, 1757.
(13) Nozaki, K.; Li, W.; Horiuchi, T.; Takaya, H. Tetrahedron Lett. 1997,
38, 2611.
(14) Alema´n, A.; Donate, P. M.; da Silva, R.; da Silva, G. V. J. J. Org.
Chem. 1999, 64, 5712.
(11) Guijarro, A.; Yus, M. Tetrahedron 1994, 50, 13269.
290
Org. Lett., Vol. 4, No. 2, 2002