2
Tetrahedron Letters
Figure 1. Structures of furanosteroids containing the
characteristic naphtho[1,8-bc]furan scaffold
The aim of this work is to describe the remarkable effects of
halogen substituents at C(2) positions on reaction pathway
switching in the intramolecular cycloaddition reaction of allenyl
2-halo-3-vinylcyclohex-2-enyl ethers. The 4,6,7,8-tetrahydro-
3H-naphtho[1,8-bc]furan (11) was synthesized by tandem [4+2]
cycloaddition/aromatization sequence.
A variety of propargyl 2-halo-3-vinylcyclohex-2-enyl ethers
used in cycloaddition reactions were prepared by the standard
procedures, and the synthetic routes are shown in Schemes 2 and
3. For the synthesis of the 2-chloro derivative, shown in Scheme
2, 2-chloroenone 3 was prepared from 1,3-cyclohexanedione
using the method reported by Shepherd.12 The 2-chloroenone 3
was vinylated, and the resulting alcohol was dehydrated to 2-
chlorodienone 4. The reduction of dienone 4 by NaBH4/CeCl3,13
and the propargylation of the resulting alcohol 5 provided the
requisite propargyl 2-chloro-3-vinylcyclohex-2-enyl ether (6).
Scheme 3. Synthetic routes for 2-bromo derivatives 10
using THF as a solvent led to the quick disappearance of the
starting materials at room temperature compared to the use of t-
BuOH (entries 1, 2, and 4). The resulting allenyl ether, which
was isomerized in THF, did not undergo a cycloaddition reaction
even when heated under reflux (66 °C); the alcohol 9a, which
could be produced by the hydrolyzed allenyl ether moiety, was
isolated after purification by silica gel column chromatography
(entry 3). The cycloaddition reaction of the corresponding
allenyl ether, from the propargyl ether 10a, in t-BuOH was
conducted under reflux conditions (82 °C), but not at room
temperature (entries 4, 5). Under reflux conditions in t-BuOH,
CH3CN (82 °C), and DMF (153 °C), the allenyl ether cyclized to
the intramolecular [4+2] adduct. The resulting cycloadduct
aromatized to give 4,6,7,8-tetrahydro-3H-naphtho[1,8-bc]furan
(11a) in good to high yield (entries 5-7).15 Apparently, the
cycloaddition of the C(2) halogen derivatives, 2-chloro 6, and 2-
bromo 10a and 10c, led only to
a
tandem [4+2]
cycloaddition/aromatization reaction, but did not lead to a
[2+2]/[3,3] reaction (entries 5, 8, 10, and 12). The C(4) dimethyl
derivative 10b was easily cyclized/aromatized at room
temperature without further heating.
The halogen effect and potential on intramolecular [4+2]
cycloaddition were explored using
a
B3LYP/6-31G(d)
calculation in Spartan 10,16,17 and the data are shown in Table 2.
The energy differences between s-cis and s-trans conformation,
∆E(s-cis)-(s-trans), of the C(2) bromo derivative (5.18 kcal) was
higher compared to non- or methyl-substituted derivatives, 3.23
and 3.84 kcal/mol, respectively. The data indicate that s-cis
conformation of the butadiene moiety may be severely disfavored
by the bromo substituent at the C(2) position because the C(2)
methyl derivative has been reported to disfavor s-cis
conformation of the moiety with highly repulsive interaction
between the methyl and vinyl group.18 The Diels-Alder
cycloaddition of 2-chlorofuran with ethylene has also been
previously reported that the halogen substitution led to an
increase of the reaction exothermicity and to stabilization of the
cycloadduct.6 Current intramolecular [4+2] cycloadditions of
non- and C(2) bromo-substituted derivatives were calculated to
have reaction enthalpies of –44.17 and –49.26 kcal/mol,
respectively. One possibility for the occurrence of the [4+2]
cycloaddition reaction of a C(2) bromo derivative, which may
disfavor s-cis conformation of the diene moiety, could involve
this increase in exothermicity upon bromo substitution. The
Scheme 2. Synthetic route for 2-chloro derivative 6
For synthesis of the 2-bromo derivatives, shown in Scheme 3, 2-
bromoenone 7, as
a starting material, was converted to
corresponding propargyl ethers 10 by the same synthetic route.
The configuration of 4,4-dimethyl-, but not 6,6-dimethyl-,
alcohol 9b were determined on the basis of the HMBC
experiment (data provided in supplementary material). A cross-
peak was detected in the HMBC spectrum between the dimethyl
protons and the sp2-carbon at the C(3) position; however, no
cross-peak was observed between the dimethyl protons and sp3-
carbon at C(1) position.
The data for base-catalyzed cycloaddition reaction of
propargyl ethers are shown in Table 1. Upon the treatment of the
propargyl ether with t-BuOK, the propargyl ether isomerized to
the corresponding allenyl ether14 prior to the cycloaddition
reaction because no reaction occurred upon heating the propargyl
ethers under similar reaction conditions without the base (data
not shown). The base-catalyzed rearrangement of propargyl
ethers to allenyl ethers proceeded smoothly in THF because
Hatae, Noriyuki
