A new synthesis of 8-oxabicyclo[3.2.1]octan-2-one and its use for the preparation of cycloheptane annulated furans

Article abstract of DOI:10.1055/s-0029-1218371

Two novel syntheses of 8-oxabicyclo[3.2.1]octan-2-one are described, making this key intermediate readily available in preparative amounts. On chain elongation with various oxophosphonates this compound is converted to α,β-unsaturated ketones, which, on t

Full text of DOI:10.1055/s-0029-1218371

LETTER
3349
A New Synthesis of 8-Oxabicyclo[3.2.1]octan-2-one and Its Use for the
Preparation of Cycloheptane Annulated Furans
S
ynthesis of Furan
e
-Fused
C
yc
n
loheptanols ning Hopf,* K. G. Abhilash
Institute of Organic Chemistry, Technical University of Braunschweig, Hagenring 30, 38106 Braunschweig, Germany
Fax +49(531)3915388; E-mail: h.hopf@tu-bs.de
Received 7 October 2009
In memoriam Professor Dr. Hans-Dieter Martin
Scheme 1. Since a direct Vilsmeier formylation of ethyl
furoate 1 provided the desired aldehyde 5 in 20% yield
only (reaction conditions: 100 °C, 8 h), an indirect route
was employed. This involves chloromethylation to 2,2,3
Abstract: Two novel syntheses of 8-oxabicyclo[3.2.1]octan-2-one
are described, making this key intermediate readily available in pre-
parative amounts. On chain elongation with various oxophospho-
nates this compound is converted to a,b-unsaturated ketones,
which, on treatment with BF3·OEt2, cyclize to furanocycloheptanols conversion to the acetoxy derivative 3,4 selective cleavage
of the acetoxy group,5 and oxidation of the resulting alco-
with a substitution pattern not reported previously.
hol 4. For the oxidation of 4 PCC was used initially which
gave 80% yield after a difficult workup and chromato-
graphic purification. On the other hand, IBX was found to
be a highly efficient oxidant in this case, providing a near
quantitative yield of 5 after a simple filtration.6 The Wittig
olefination to 6 (mixture of diastereomers) and reduction
to 7 also proceeded with excellent yields. The Dieckmann
cyclization was carried out by treatment with NaH in re-
fluxing THF. The decarboxylation of the resulting keto
ester 8 yielded the oxabicycle 9 in 90% yield.
Key words: bicyclic ketones, Wittig–Horner reactions, hetero-
cycles, furan synthesis, annulated furan derivatives
In spite of the ease of preparation and its functionally en-
riched, strained structure, 8-oxabicyclo[3.2.1]octan-2-one
(9, Scheme 1) has received only scant attention in organic
synthesis. The only report on its chemistry was by Davies
et al., who utilized it for the synthesis of tropanone.1 The
presence of the carbonyl function near to the oxygen
bridge suggests that the molecule could be useful for an-
nulation reactions through suitable derivatization. Herein
we report the results of our investigations in this direction.
The Horner–Wadsworth–Emmons (HWE) adducts of 9
with 2-oxoalkyl phosphonates were found to undergo a
novel acid-catalyzed rearrangement leading to an efficient
synthesis of cycloheptane-annulated furans.
To make the preparation of 9 still more facile, a second
route to this ketone was developed; this is presented in
Scheme 2. The Wittig product 11, available easily from
furfural 10 could be readily formylated under Vilsmeier
conditions. Alkaline iodine oxidation was utilized for the
direct conversion of the thus prepared aldehyde 12 to the
methyl ester 13.7 Reduction to 14 followed by cyclization
to 15 and finally decarboxylation to 9 proceeded smoothly
as in the previous case (63% over six steps, compared to
47% over eight steps for the first route, Scheme 1).
To prepare 9 we first used a synthesis which resembles
Davies’ approach1 in the initial and final steps, but differs
in its central section. This protocol is summarized in
ii
iii
i
OAc
Cl
EtO2C
EtO2C
vi
EtO2C
EtO2C
iv
O
1
O
3
O
2
v
O
OH
CO2Et
O
EtO2C
CO2Et
EtO2C
O
O
5
O
6
O
4
EtO2C
vii
viii
O
O
EtO2C
O
7
8
9
Scheme 1 Synthetic route to 9. Reagents and conditions: i. (CH2O)n, ZnCl2, dry HCl, CHCl3, r.t., 83%; ii. NaOAc, AcOH, Ac2O, 120 °C,
90%; iii. (a) NaOEt (cat.), EtOH, r.t., 24 h, (b) H+ (ion-exchange resin), 85%; iv. IBX, EtOAc, reflux, 3 h, 99%; v. Ph3P=CHCO2Et, THF, r.t.,
2 h, 98%; vi. Pd/C, H2, EtOAc, 99%; vii. NaH, THF, reflux, 6 h, 85%; viii. HOAc–H2O–H2SO4 (8:8:1), reflux, 2.5 h, 90%.
SYNLETT 2009, No. 20, pp 3349–3351
x
x
.x
x
.2
0
0
9
Advanced online publication: 18.11.2009
DOI: 10.1055/s-0029-1218371; Art ID: G31209ST
© Georg Thieme Verlag Stuttgart · New York

3350
H. Hopf, K. G. Abhilash
LETTER
iii
i
ii
O
O
CO2Me
iv
CO2Me
O
11
O
12
O
10
v
CO2Me
CO2Me
MeO2C
MeO2C
MeO2C
O
O
13
14
O
O
9
O
O
vi
15
Scheme 2 Alternate synthesis of 9. Reagents and conditions: i. Ph3P=CHCO2Me, THF, r.t., 2 h, 98%; ii. DMF, POCl3, 0 °C to r.t. (12 h), then
60 °C (2 h), 90%; iii. I2, KOH, MeOH, 0 °C to r.t., 1 h, 95%; iv. Pd/C, H2, EtOAc, 99%; v. NaH, THF, reflux, 6 h, 85%; vi. AcOH–H2O–H2SO4
(8:8:1), reflux, 2.5 h, 90%.
The oxoalkyl phosphonates required for the HWE reac- In order to confirm the proposed structure, further deriva-
tion with 9 were synthesized following a reported proce- tizations were carried out. Thus 18a underwent mesyla-
dure.8 In an initial experiment diethyl (2-oxo- tion followed by acylation at the furan 3-position as
propyl)phosphonate was added dropwise to an ice-cold expected. Furthermore, oxidation as well as catalytic hy-
suspension of NaH in dry THF under nitrogen. After com- drogenation proceeded smoothly (Scheme 4).
plete addition the solution was stirred for one hour at room
temperature. To this a solution of the ketone 9 in THF was
added and allowed to stir at room temperature for 24
O
hours. After workup and chromatographic purification the
O
O
O
i
ii
HWE adduct was obtained as a mixture of the cis- and
trans-isomers in 92% yield. The rearrangement of the
HWE adduct was initially carried out with excess PTSA
in refluxing benzene. After 30 minutes of reaction time
followed by workup and chromatographic purification,
the furan 18a9 was isolated in 80% yield (Scheme 3). The
structure of 18a was assigned on the basis of the spectro-
scopic data. In the IR spectrum of 18a, the hydroxyl group
exhibited a broad peak at 3333 cm–1. In the 1H NMR spec-
trum the furyl proton was visible as a singlet at d = 5.73
ppm. The methyl group resonated as a singlet at d = 2.19
and the hydroxyl bound CH was visible as a triplet of trip-
let at d = 3.87 ppm. Matching resonances in the 13C NMR
spectrum were also observed.
18a
MsO
HO
19
MsO
20
O
O
O
iii
iv
21
HO
HO
22
O
18a
Scheme 4 Further functionalization of 18a. Reagents and conditi-
ons: i. MsCl, Et3N, CH2Cl2, 0 °C to r.t., 1 h, 95%; ii. Ac2O, BF3·OEt2,
CH2Cl2, 0 °C to r.t., 2 h, 70%; iii. IBX, EtOAc, reflux, 3 h, 80%; iv.
Pd/C, H2, EtOAc, 4 h, 95% (mixture of diastereomers).
A limited study of different acidic reagents proved that
BF3·OEt2 is the most efficient catalyst for the cyclization.
The reaction could be easily extended to various phospho-
nates leading to a general synthesis of furanocyclohep-
tanols. The results are presented in Table 1. Interestingly,
the cinnamyl and the furyl substituents were not tolerated
under the acidic conditions.
O
O
9
O
O
P
O
i
EtO
O
+
OEt
16a
17a
In conclusion, the present method offers a novel and effi-
cient route for the synthesis of furanocycloheptanols. It is
to be noted that furanocycloheptanols with the particular
substitution pattern were not reported previously.
O
ii
HO
18a
Acknowledgment
Scheme 3 HWE reaction followed by rearrangement to the furan.
Reagents and conditions: i. NaH, THF, 0 °C to r.t., 24 h, 92%; ii.
PTSA, benzene, reflux, 30 min, 80%.
K.G.A. thanks the Alexander von Humboldt Foundation for a post-
doctoral fellowship.
Synlett 2009, No. 20, 3349–3351 © Thieme Stuttgart · New York

LETTER
Synthesis of Furan-Fused Cycloheptanols
3351
Table 1 Generality of the Reactiona
(4) Gonis, G.; Amstutz, E. D. J. Org. Chem. 1962, 27, 2946.
(5) Finan, P. A. J. Chem. Soc. 1963, 3917.
(6) (a) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
(b) For the preparation of IBX, see: Frigerio, M.;
Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537.
(7) Yamada, S.; Morizono, D.; Yamamoto, K. Tetrahedron Lett.
1992, 33, 4329.
R
R
O
O
O
O
O
ii
i
P
O
O
+
EtO
R
OEt
(8) Corbel, B.; L’Hostil-Kervella, I.; Haelters, J.-P. Synth.
Commun. 1996, 26, 2561.
9
16
17
18
HO
(9) Representative Procedure
Entry
R
Yield (%)
Furan
To a suspension of NaH (67 mg, 60% suspension in oil, 1.67
mmol, 1.05 equiv) in dry THF (10 mL), cooled to 0 °C, was
added a solution of diethyl (2-oxopropyl)phosphonate (339
mg, 1.75 mmol, 1.1 equiv) in dry THF (10 mL) dropwise
under nitrogen. After complete addition the reaction mixture
was allowed to stir for 1 h at r.t. To this solution the ketone
9 (200 mg, 1.59 mmol, 1 equiv) was added, and the mixture
was allowed to stir for 24 h at r.t. The reaction was quenched
by the addition of H2O (50 mL) and worked up with Et2O
(4 × 50 mL). The combined extracts were dried over anhyd
Na2SO4 and concentrated. The residue was purified by
column chromatography (Et2O–pentane, 1:1) to afford the
HWE adduct 17a (242 mg, 92%). To the HWE adduct (100
mg, 0.6 mmol, 1 equiv) in dry CH2Cl2 (15 mL), was added
BF3·OEt2 (128 mg, 0.9 mmol, 1.5 equiv), and the solution
was allowed to reflux for 6 h. The reaction was quenched by
the addition of sat. NaHCO3 solution and worked up by
CH2Cl2 extraction. The combined extracts were dried over
anhyd Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography (Et2O–pentane, 1:1) to
afford the furan 18a (82 mg, 82%) as a white amorphous
solid.
HWE adductb
17a (92)
17b (91)
17c (97)
17d (90)
17e (96)
17f (90)
17g (62)
17i (64)
1
2
3
4
5
6
7
8
9
Me
Et
18a (82)
18b (80)
18c (86)
18d (80)
18e (77)
18f (77)
18g (60)
0
Pr
Ph
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
cinnamyl
2-furyl
17j (72)
0
a Reaction conditions: i. NaH, THF, 0 °C to r.t., 24 h. ii. BF3·OEt2,
CH2Cl2, reflux, 6–10 h.
b Mixture of E- and Z-isomers, in roughly equal amounts.
Compound 18a: white amorphous solid; mp 55–57 °C. IR
(diamond ATR): nmax = 3333, 2941, 2920, 2981, 2581, 1578,
1493, 1442, 1251, 1022, 957, 904, 802 cm–1. 1H NMR (200
MHz, CDCl3): d = 1.53–1.76 (m, 2 H), 1.86 (br s, 1 H),
1.95–2.10 (m, 2 H), 2.19 (s, 3 H), 2.25–2.40 (m, 2 H), 2.47–
2.65 (m, 2 H), 2.77–2.90 (m, 1 H), 3.87 (tt, 1 H, J1 = 2.8 Hz,
J2 = 9.1 Hz), 5.73 (s, 1 H). 13C NMR (50 MHz, CDCl3):
d = 13.2, 21.0, 23.1, 34.9, 37.0, 73.4, 108.7, 120.4, 147.9,
150.0. HRMS (EI): m/z calcd for C10H14O2: 166.09938;
found: 166.09902.
References and Notes
(1) Davies, W. A. M.; Pinder, A. R.; Morris, I. G. Tetrahedron
1962, 18, 405.
(2) Schmuck, C.; Machon, U. Eur. J. Org. Chem. 2006, 4385.
(3) Moldenhauer, O.; Trautmann, G.; Irion, W.; Pfluger, R.;
Döser, H.; Mastaglio, D.; Marwitz, H. Liebigs Ann. Chem.
1953, 580, 169.
Synlett 2009, No. 20, 3349–3351 © Thieme Stuttgart · New York

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