Scope and limitations of the double [4+3]-cycloadditions of 2-oxyallyl cations to 2,2′-methylenedifuran and derivatives

Article abstract of DOI:10.1021/jo020678s

The reactivity of various 2-oxyallyl cations toward 2,2′-methylenedifuran (1b), 2,2′-(hydroxymethyl)-difuran (1c), 2,2′-(trimethylsilylmethylene)difuran (1d), and di(2-furyl)methanone (1e) has been explored. Difuryl derivatives 1c, 1d, and 1e refused to undergo formal double [4+3]-cycloadditions. Conditions have been found to convert 1b into meso-1,1′-methylenedi[(1R,1′S,5S,5′R)-(3) and (±)-1,1′-methylenedi[(1RS,1′SR,5SR,5′RS)- 8-oxabicyclo[3.2.1]oct-6-en-3-one] (4) that do not require CF₃CH(OH)CF₃ as solvent. High yields of meso-1,1′-methylenedi[(1R,1′S,2S,2′R,4R,4′S, 5S,5′R)- (5) and (±).1,1′-methylenedi[(1RS,1′RS,2SR,2′SR, 4RS,4′RS,5SR,5′SR)-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6- en-3-one] (6) have been obtained when 1b was reacted with 2,4-dibromopentan-3-one (7h) and NaI/Cu.

Full text of DOI:10.1021/jo020678s

SCHEME 1
Scop e a n d Lim ita tion s of th e Dou ble
[4+3]-Cycloa d d ition s of 2-Oxya llyl Ca tion s
to 2,2′-Meth ylen ed ifu r a n a n d Der iva tives
Kai Torsten Meilert, Marc-Etienne Schwenter,
Yuli Shatz, Srinivas Reddy Dubbaka, and Pierre Vogel*
Institute of Molecular and Biological Chemistry,
Swiss Federal Institute of Technology, EPFL-BCH,
CH-1015 Lausanne-Dorigny, Switzerland
pierre.vogel@epfl.ch
Received October 30, 2002
Abstr a ct: The reactivity of various 2-oxyallyl cations
toward 2,2′-methylenedifuran (1b), 2,2′-(hydroxymethyl)-
difuran (1c), 2,2′-(trimethylsilylmethylene)difuran (1d ), and
di(2-furyl)methanone (1e) has been explored. Difuryl deriva-
tives 1c, 1d , and 1e refused to undergo formal double [4+3]-
cycloadditions. Conditions have been found to convert 1b
into meso-1,1′-methylenedi[(1R,1′S,5S,5′R)- (3) and (()-1,1′-
methylenedi[(1RS,1′SR,5SR,5′RS)-8-oxabicyclo[3.2.1]oct-6-
en-3-one] (4) that do not require CF3CH(OH)CF3 as solvent.
High yields of meso-1,1′-methylenedi[(1R,1′S,2S,2′R,4R,4′S,-
5S,5′R)- (5) and (()-1,1′-methylenedi[(1RS,1′RS,2SR,2′SR,-
4RS,4′RS,5SR,5′SR)-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-
en-3-one] (6) have been obtained when 1b was reacted with
2,4-dibromopentan-3-one (7h ) and NaI/Cu.
cloaddition to 1b giving, after reductive workup, a 45:55
mixture of diketones 3 and 4 in 60% yield. The meso
compound 3 could be converted into enantiomerically
pure pentadeca-1,3,5,7,9,11,13,15-octols6 via reaction
sequences implying the asymmetric Sharpless dihydrox-
ylation7 as the desymmetrization step. Racemic threo-4
can be converted into enantiomerically pure long-chain
polyols via reaction sequences involving an enzymatic
optical resolution.8
In this note we address the following questions: Can
one realize formal double [4+3]-cycloadditions to 2,2′-
methylenedifuran substituted at the methano linker such
as derivatives 1c-e? Can one exchange the expensive
CF3CH(OH)CF3 (HFIP) solvent used in the generation
of the 1,1,3-trichloro-2-oxyallyl cation for another solvent?
Can one generate double adducts of 1b with other
2-oxyallyl cation intermediates than the 1,1,3-trichloro-
2-oxyallyl cation?
As we shall see, conditions have now been found for
the synthesis of 3 and 4 that use toluene as solvent
instead of HFIP. We report also that 2,2′-methylenedi-
furan (1b) can be reacted with 2,4-dibromopentan-3-one
(7h ) to provide diketones 5 and 6. The three 2,2′-
methylenedifuran derivatives 1c-e substituted at the
methano linker by a hydroxyl, a silyl, and an oxo group,
respectively, refused to yield products of double cycload-
ditions with 2-oxyallyl cation derivatives.
The simultaneous two-direction chain elongation fol-
lowed by kinetic or chiral desymmetrization is a very
attractive strategy for the construction of complicated
compounds of biological interest.1 We have used such
strategy in our combinatorial approach to the synthesis
of antitumor anthracyclines and analogues2 based on the
double Diels-Alder addition of 2,3,5,6-tetramethylidene-
7-oxabicyclo[2.2.1]heptane derivatives.3 More recently we
have shown that double cycloaddition of diethyl (2E,5E)-
4-oxohepta-2,5-dionate to 2,2′-ethylenebis[3,4-dimethyl-
furylfuran] (1a ) gives a single adduct 2 that could be
converted to complicated bicyclic and tricyclic polypro-
pionates.4In parallel, we have investigated the formal
[4+3]-cycloaddition of 2,2′-methylenedifuran (1b) and
found conditions under which the 1,1,3-trichloro-2-oxy-
allyl cation (generated by base induced elimination of HCl
from 1,1,3,3-tetrachloroacetone5) leads to a double cy-
(1) Hoye, T. R.; Peck, D. R.; Swanson, T. A. J . Am. Chem. Soc. 1984,
106, 2738. Harada, T.; Kagamihara, S.; Tanaka, S.; Sakamoto, K.; Oku,
A. J . Org. Chem. 1992, 57, 1637. Poss, C. S.; Schreiber, S. L. Acc. Chem.
Res. 1994, 27, 9. Rychnovsky, S. D.; Griesgraber, G.; Kim, J . J . Am.
Chem. Soc. 1994, 116, 2621. Cheˆnevert, R.; Courchesne, G. Tetrahedron
Lett. 1995, 6, 2093. Magnusson, S. R. Tetrahedron 1995, 51, 2167.
Oppolzer, J .; De Brabander, J .; Walther, W.; Bernardinelli, G. Tetra-
hedron Lett. 1995, 36, 4413. Shepherd, J . N.; Na, J .; Myles, D. C. J .
Org. Chem. 1997, 62, 4558. Perkins, M. V.; Sampson, R. A. Tetrahedron
Lett. 1998, 39, 8367. Hanessian, S.; Ma, J .; Wang, W. Tetrahedron Lett.
1999, 40, 4627. Ward, D. E.; Guo, C.; Sasmal, P. K.; Man, C. C.; Sales,
M. Tetrahedron Lett. 2000, 2, 1325.
The 2,2′-methylenedifuran derivative 1c was obtained
by condensation of (2-furyl)lithium9 onto furfuraldehyde
(2) Vogel, P.; Carrupt, P.-A. Tetrahedron Lett. 1974, 4532. Dienes,
Z.; Vogel, P. J . Org. Chem. 1996, 61, 6958.
(3) Vogel, P. Curr. Org. Chem. 1998, 2, 255.
(6) Schwenter, M.-E.; Vogel, P. Chem. Eur. J . 2000, 6, 4091.
Schwenter, M.-E.; Vogel, P. J . Org. Chem. 2001, 66, 7869.
(7) Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(4) Marchionni, C.; Vogel, P.; Roversi, P. Tetrahedron Lett. 1996,
37, 4149; Marchionni, C.; Meilert, K.; Vogel, P.; Schenk, K. Synlett
2000, 1111. Marchionni, C.; Vogel, P. Helv. Chim. Acta 2001, 84, 431.
(5) Fo¨hlisch, B. J . Chem. Res. 1981, 246.
(8) Csa´ky¨, A.; Vogel, P. Tetrahedron: Asymmetry 2000, 11, 4935.
10.1021/jo020678s CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/01/2003
2964
J . Org. Chem. 2003, 68, 2964-2967

SCHEME 2
First, these studies did not bring any improvements. A
mediocre yield in 3 + 4 (16%) was obtained for the
reaction of 7b with 1b after reductive workup with Zn/
Cu/NH4Cl/MeOH.21 In most cases polymeric material was
found together with low yields of monocycloadducts. One
of them, 9, was isolated in 16% yield, when 1b was
reacted with 1,1,3,3-tetrabromoacetone (7f) in the pres-
ence of Et2Zn in toluene at 0 °C. An acceptable yield of a
46:54 mixture of 3 + 4 (40%, 63% per cycloaddition) was
obtained on reacting 1,3-dibromo-1,3-dichloroacetone (7e)
with 1b in toluene in the presence of Et2Zn. With 1,3-
dibromo-1,3-diethoxyacetone (7g), the same mixture was
obtained in 30% yield under the same conditions. Thus,
procedures are now available that do not use the expen-
sive HFIP as solvent.
With the 2,2′-methylenedifuran substituted at the
methano linker we failed to detect any trace of the
corresponding products of double [4+3]-cycloaddition. In
the case of di(2-furyl)methanone (1e), the “classical” basic
conditions with 1,1,3,3-tetrachloroacetone (7a ), Et3N, and
HFIP, only polymeric material was obtained. The method
using 1,1,3,3-tetrabromoacetone (7f) and Et2Zn gave 40%
yield of monoadduct 10. The endo relative configuration
of the 2- and 4-bromo substituent was established by its
(56% yield). The preparation of the silylated derivative
1d has already been described.10 Di(2-furyl)methanone
(1e) was obtained by reaction of (2-furyl)lithium9 with
N,N-dimethylcarbamate (53%).
One of the main difficulties with the search of optimal
conditions for the double cycloadditions of 1 with 2-oxy-
allyl cation derivatives is the necessity to use an excess
of the latter reagent rather than an excess of the furan
derivative, as is the case under well-established condi-
tions for the [4+3]-cycloadditions of simple furans.11
Furthermore, furans are acid sensitive and polymerize
readily in the presence of electrophilic reagents.
Because of the high synthetic potential of the 2,2′-
methylenedifuran (1b) we have searched for conditions
that do not require the expensive HFIP solvent as in our
initial procedure.6 This led us to explore the possibility
of using other oxyallyl cation precursors than 1,1,3,3-
tetrachloroacetone. Exploratory experiments were done
with 7b-h ,12-15 using basic conditions promoted by
different bases (Et3N, TMEDA) in various solvents
(HFIP, CF3CH2OH, CH3NO2, CCl3CN, CH3CN, DMSO,
toluene, CH2Cl2), as well as reductive conditions pro-
moted by different reducing agents (Et2Zn, Fe(CO)9, Zn,
SnCl2, Cu) in aprotic solvents (toluene, dioxane, benzene,
MeCN, THF), and applying established procedures.5,6,16-20
3
1H NMR spectrum (vicinal coupling J H,H coupling con-
stants and 2D-NOESY).
With 2,4-dibromopentan-3-one (7h ) and in the presence
of NaI/Cu in CH3CN,20 2,2′-methylenedifuran (1b) gave
an excellent yield (90%) of a 1:1 mixture of diketones 5
and 6 that were readily separated in 44% and 41% yield,
respectively, by flash chromatography. These two com-
pounds are potential precursors in the synthesis of long-
chain polypropionates, assuming the methods developed
for the asymmetric synthesis of 1,3-polyols based on 3
and 4 can be applied to 5 and 6. The relative endo
configuration of the four methyl substituents in 5 and 6
has been determined by their 1H NMR data and con-
firmed by 2D-NOESY.
This study suggests that only the most stable (“softest”)
electrophilic intermediate 12 or 14 generated by het-
erolysis of polyhaloketones 7 or under reductive condi-
tions (Scheme 3) is able to generate products of formal
[4+3]-cycloaddition competitively with the polymeriza-
tion of 2,2′-methylenedifuran (1b).
Among the different methods reported for the [4+3]-
cycloaddition of furan, only those involving the 1,1,3-
trichloro-2-oxyallyl, 1,3-dichloro-2-oxyallyl, and 1,3-
dimethyl-2-oxyallyl species generate products of double
cycloaddition with 1b. The substituted derivatives 1c-d
refuse to undergo the double cycloaddition for steric or/
and electronic reasons. Alcohol 1c polymerizes very
readily due to its ability to be ionized into a cationic
species. In the case of ketone 1e, conjugation of a furan
and carbonyl moiety retards the cycloadditions.
Conditions have now been found that allow for the
conversion of 2,2′-methylenedifuran (1b) into the valu-
able meso-1,1′-methylenedi[(1R,1′S,5S,5′R)-8-oxabicyclo-
[3.2.1]oct-6-en-3-one] (3) and (()-1,1′-methylenedi[(1RS,-
1′SR,5SR,5′RS)-8-oxabicyclo[3.2.1]oct-6-en-3-one] (4) that
do not require HFIP as solvent, but toluene. We have
shown that formal double [4+3]-cycloadditions of 2-oxy-
(9) Brandsma, L.; Verkruijsse, H. D.; Keegstra, M. A. Synth.
Commun. 1989, 19, 1047.
(10) Schwenter, M.-E.; Schenk, K.; Scopelliti, R.; Vogel, P. Hetero-
cycles 2002, 57, 1513.
(11) For recent reviews, see: Mann, J . Tetrahedron 1986, 42, 4611.
Hosomi, A.; Tominga, Y. Comprehensive Organic Synthesis; Fleming,
I., Ed.; Pergamon Press: Oxford, UK, 1991; Vol. 5, p 593. Rigby, J .
H.; Pigge, C. F. Org. React. 1997, 51, 351. Harmata, M. Recent Res.
Dev. Org. Chem. 1997, 1, 523. Dell, C. P. J . Chem. Soc., Perkin Trans.
1 1998, 3873. Ou, L.; Bai, D. Huaxue J inzhan 2000, 12, 51. El-Wareth,
A.; Sarhan, A. O. Curr. Org. Chem. 2001, 5, 827.
(12) Zincke, T.; Kegel, O. Chem. Ber. 1889, 22, 1478. UK-1,140,-
434; Patent Office, 1966, 1-3.
(13) 7b and 7c are commercially available. 7e has been prepared
by bromination of 1,3-dichloroacetone in CH2Cl2 by Br2 catalyzed by
HBr 48%. 7g has been prepared by oxidation of 1,3-diethoxypropan-
2-ol with PCC in CH2Cl2 and bromination of the corresponding ketone
in PBr3 with Br2.
(14) Zincke, T.; Kegel, O. Chem. Ber. 1890, 23, 230.
(15) Rappe, C. Acta Chem. Scand. 1962, 16, 2467.
(16) Mann, J .; Barbosa, L. C. d. A. Synthesis 1996, 31.
(17) Fukuzawa, S.; Sakai, S. Bull. Chem. Soc. J pn 1989, 62, 2348.
(18) Takaya, H.; Makino, S.; Hayakawa, Y.; Noyori, R. J . Am. Chem.
Soc. 1978, 100, 1765.
(19) Hoffmann, H. M. R.; J oshi, N. N. Tetrahedron Lett. 1986, 27,
687.
(20) Ashcroft, M. R.; Hoffmann, H. M. R. Org. Synth. 1978, 58, 17.
Montan˜a, A. M.; Ribes, S.; Grima, P. M.; Garcia, F. Acta Chem. Scand.
1998, 52, 453.
(21) LeGoff, E. J . Org. Chem. 1964, 29, 2048.
J . Org. Chem, Vol. 68, No. 7, 2003 2965

SCHEME 3
mg, 3.50 mmol) at - 40 °C. After 24 h under stirring, the solution
was allowed to warm to room temperature. After one night under
stirring, 7e (384 mg, 1.35 mmol) was added dropwise and
allowed to react for 3 h. This latter addition was repeated. The
solution was diluted with EtOAc (10 mL) and quenched by sat.
NH4Cl in methanol (10 mL). The solvents were removed and
the brown residue was dissolved in sat. NH4Cl in methanol (30
mL). Zn/Cu couple (1 g) was added portionwise to the vigorously
stirred mixture. After stirring at room temperature for 4 d, the
precipitate was filtered off on Celite and the solvent evaporated.
The residue was taken up in Et2O (20 mL) and silica gel (5 g)
was added. After 20 min under stirring, filtration, rinsing with
Et2O, and evaporation, the brown residue was deposited over
silica gel. Flash chromatography (silica gel, Et2O/PE 3:1) afforded
141 mg (40%) of 3 and 4 as a 45:55 mixture. Spectral data of
this mixture were identical with those reported for these
compounds.6
allyl cation intermediates to 2,2′-methylenedifuran are
not possible yet with derivatives substituted at the
methano linker between the two furyl groups. By using
2,4-dibromopentan-3-one and 2,2′methylenedifuran (1b),
meso-1,1′-methylenedi[(1R,1′S,2S,2′R,4R,4′S,5S,5′R)- (5)
and (()-1,1′-methylenedi[(1RS,1′RS,2SR,2′SR,4RS,4′RS,-
5SR,5′SR)-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-
one] (6) are obtained in good yields.
Exp er im en ta l Section
Gen er a l Rem a r k s. See ref 22. Flash column chromatography
(FC) was performed on Merck silica gel (230-400 mesh, no.
9385). Thin-layer chromatography (TLC) was carried out on
silica gel (Merck aluminum foils). 1H NMR and 13C NMR signal
assignments were confirmed by coupled 13C NMR, 2D-COSY,
HMQC, or HSQC, and when required by 2D-NOESY spectra. J
values are given in hertz.
m eso-1,1′-Meth ylen ed i[(1R,1′S,2S,2′R,4R,4′S,5S,5′R)-2,4-
d im eth yl-8-oxa bicyclo[3.2.1]oct-6-en -3-on e] (5) a n d (()-1,1′-
Meth ylen ed i[(1RS,1′RS,2SR,2′SR,4RS,4′RS,5SR,5′SR)-2,4-
d im eth yl-8-oxa bicyclo[3.2.1]oct-6-en -3-on e] (6). Anhydrous
acetonitrile (30 mL), followed by flame dried NaI (18 g, 120
mmol) and 1c (740 mg, 5 mmol) were added to freshly activated
Cu powder (3.8 g, 60 mmol). The mixture was heated to reflux
and 2,4-dibromopentan-3-one (4.84 g, 20 mmol) was added
dropwise over 30 min. As the reaction proceeded the solution
turned into a yellow suspension. After 1 h under reflux, the
solvent was evaporated under reduced pressure and the remain-
ing mixture diluted with water (25 mL) and CH2Cl2 (25 mL).
The solution was stirred for 10 min and then filtrated on Celite.
The aqueous layer was extracted with CH2Cl2 (30 mL, 3 times).
The combined organic layers were dried (MgSO4) and concen-
trated under reduced pressure to yield a yellow oil. Flash
chromatography (silica gel, CH2Cl2/Et2O/PE 54:6:40) gave 703
mg of 5 (44%) and 625 mg of 6 (41%). Both fractions can be
recrystallized from hexane to give white crystals.
2,2′-(Hyd r oxym eth yl)d ifu r a n (1c). To a solution of furan
(500 mg, 7.34 mmol) in anhydrous ether (5 mL) was added
dropwise a 1.6 M solution of BuLi in THF (4.58 mL, 7.34 mmol).
The solution was heated under reflux for 15 min, while a white
suspension appears. After the mixture was cooled to -50 °C,
furfural (775 mg, 8.07 mmol) was added dropwise and the
solution was left under stirring overnight. The reaction was
quenched by addition of brine (5 mL). The aqueous layer was
extracted by EtOAc (10 mL, twice). The organic phase was dried
(MgSO4) and distilled under reduced pressure (bp 160 °C, 1
mBar) and gave 683 mg (56%) of 1f, which decomposes at room
1
temperature, but can be stored at -80 °C. H NMR (400 MHz,
CDCl3): δ 7.46 (m, 2H), 6.36 (dd, 2H, 3J ) 1.8, 3J ) 3.3), 6.30
3
4
3
(dd, 2H, J ) 3.3, J ) 0.6), 5.80 (d, 1H, J ) 5.1), 2.48 (d, 1H,
3J ) 5.1).
Di(2-fu r yl)m eth a n on e (1e). To a solution of furan (500 mg,
7.34 mmol) in anhydrous ether (5 mL) was added dropwise a
1.6 M solution of BuLi in THF (4.58 mL, 7.34 mmol). The
solution was heated under reflux for 15 min, while a white
suspension appears. After the mixture was cooled to -25 °C,
N,N-dimethylethylcarbamate (268 mg, 3.67 mmol) was added
dropwise and the solution was allowed to warm to 20 °C and
left under stirring for 1 h. The reaction was quenched with a
saturated aqueous solution of NH4Cl (8 mL) and the aqueous
layer was extracted with CH2Cl2 (10 mL, twice). The organic
phase was dried (MgSO4) and purified by flash chromatography
(silica gel, Et2O/PE 1:1) and gave 320 mg (53%) of 1e as a
colorless oil. The product was precipitated in PE as a white solid.
Data for 5: Mp 132-135 °C. 1H NMR (400 MHz, CDCl3) δ
6.31 (d, 2H, 3J ) 6.0), 6.18 (dd, 2H, 3J ) 6.0, 3J ) 1.7), 4.82 (dd,
2H, 3J ) 4.7, 3J ) 1.7), 2.78 (q, 2H, 3J ) 7.0), 2.73 (qd, 2H, 3J )
7.0, 3J ) 4.7), 2.39, 2.38 (2d, 2H, 2J ) 15.6), 1.06, 0.95 (2d, 12H,
3J ) 7.0). Anal. Calcd for C19H24O4: C, 72.13, H, 7.65. Found:
C, 72.07, H, 7.75.
Data for 6: Mp 162-166 °C. 1H NMR (400 MHz, CDCl3) δ
6.28 (d, 2H, 3J ) 6.1), 6.05 (dd, 2H, 3J ) 6.1, 3J ) 1.7), 4.78 (dd,
2H, 3J ) 4.6, 3J ) 1.7), 2.74 (qd, 2H, 3J ) 7.0, 3J ) 4.6), 2.68 (q,
3
3
2H, J ) 7.0), 2.37 (s, 2H), 1.06, 0.96 (2d, 12H, J ) 7.0). Anal.
Calcd for C19H24O4: C, 72.13, H, 7.65. Found: C, 72.07, H, 7.60.
3
3
1H NMR (400 MHz, CDCl3): δ 7.68 (dd, 2H, J ) 1.8, J ) 1.6),
7.56 (dd, 2H, 3J ) 3.7, 3J ) 1.8), 6.61 (dd, 2H, 3J ) 3.7, 4J )
1.6). Anal. Calcd for C9H6O3: C, 66.67, H, 3.73. Found: C, 66.69,
H, 3.78.
1,3-Dibr om o-1,3-d ich lor oa ceton e (7e). In a two-necked
flask surmounted by a cooler connected to two basic traps, HBr
(48%, 4 mL, 1 mL per mmol of ketone) was added dropwise to a
solution of 1,3-dichloroacetone (5 g, 0.04 mol) in 50 mL of CH2-
Cl2. At room temperature, Br2 (4.04 mL, 0.08 mol) was added
dropwise via dropping funnel. After 6 days under stirring, the
solution was extracted with a saturated aqueous solution of
NaHCO3 (100 mL, twice) and until decoloration with a 10%
aqueous solution of NaHSO3. After evaporation to dryness, the
crude product was distilled under reduced pressure (bp 65-67
°C, 4 mBar) and gave 9.45 g (58%) of an irritating yellowish
liquid. 1H NMR (400 MHz, CDCl3): δ 6.50, 6.46 (2s).
m eso-1,1′-Meth ylen ed i[(lR,l′S,5S,5′R)-3-oxo-8-oxa bicyclo-
[3.2.1]oct -6-en e-1-yl] (3) a n d 1,1′-Met h ylen ed i[(lRS,l′SR,-
5SR,5′RS)-3-oxo-8-oxa bicyclo[3.2.1]oct-6-en e-1-yl] (4). To a
1.1 M solution of Et2Zn (5.87 mL, 6.46 mmol) in toluene
containing 1b (200 mg, 1.35 mmol) was added dropwise 7e (999
(22) Kraehenbuel, K.; Picasso, S.; Vogel, P. Helv. Chim. Acta 1998,
81, 1439.
2966 J . Org. Chem., Vol. 68, No. 7, 2003

1,3-Dibr om o-1,3-d ieth oxya ceton e (7g). To a solution of 1,3-
diethoxypropan-2-ol (1.82 g, 19.04 mmol) and dry molecular
sieves (3 Å, 10 g) in anhydrous CH2Cl2 (100 mL) was added PCC
(10 g, 46.40 mmol). The mixture was stirred for 5 h and quenched
by addition of Et2O (100 mL) and silica gel (25 g). After filtration
over a Celite path, the solvents were removed under reflux with
cooling at -20 °C. Purification by flash chromatography (silica
gel, PE/EtOAc 3:1) afforded 2.75 g (99%) of 1,3-diethoxypopan-
2-one.
1H, 3J ) 1.8, 4J ) 0.4), 6.49 (dd, 1H, 3J ) 1.7, 3J ) 6.0), 6.43 (d,
1H, 3J ) 6.0), 6.36 (dd, 1H, 3J ) 1.8, 4J ) 3.1), 6.30 (dd, 1H,
3J ) 3.1, 4J ) 0.4), 6.17 (dd, 1H, 3J ) 1.7, 3J ) 4.8), 4.81 (d, 1H,
2
2
3J ) 4.8), 4.70 (s, 1H), 3.51 (d, 1H, J ) 15.5), 3.36 (d, 1H, J )
15.5). Anal. Calcd for C12H10Br2O3: C, 39.81, H, 2.78. Found:
C, 39.75, H, 2.80.
(1S,5R)-1-(2-Fu r oyl)-8-oxabicyclo[3.2.1]oct-6-en -3-on e (10).
To an ice-cooled solution of 1h (240 mg, 1.48 mmol) and 2e (720
mg, 1.92 mmol) in anhydrous benzene (25 mL) was added
dropwise a 1 M solution of Et2Zn (2.2 mL, 2.2 mmol) in hexane.
After being stirred overnight at 20 °C (TLC, Et2O/PE 1:1), the
reaction was quenched with EtOAc (15 mL) and a saturated
aqueous solution of NH4Cl (15 mL). The organic layer was
filtrated over a Celite path and dried (Na2SO4). After solvent
evaporation, the brown residue was redissolved in a sat. NH4Cl
solution in MeOH (6 mL) and freshly prepared Zn/Cu couple (1
g) was added portionwise. After 5 days (TLC, Et2O/PE 9:1), the
solution was filtrated over a Celite path. After solvent evapora-
tion and redissolution in EtOAc (30 mL), the organic layer was
extracted with Na2EDTA (10 mL, twice) and washed with brine
(10 mL, twice). The solution was dried over Na2SO4 and the
solvents evaporated. Purification by flash chromatography (silica
gel, Et2O/PE 8:2) afforded 129 mg (40%) of 10 as a white solid.
A two-necked round-bottom flask fitted with a dropping funnel
and condenser was charged with 1,3-diethoxypropanone (500 mg,
3.42 mmol) and PBr3 (500 µL). The solution was cooled to 0 °C
and Br2 (440 µL, 8.55 mmol) was added dropwise. The solution
was stirred for 15 h and allowed to warm to 20 °C. The reaction
was diluted with CH2Cl2 (30 mL) and quenched with sat.
Na2S2O5 (10 mL). The organic layer was washed with a saturated
aqueous solution of NaHCO3 (5 mL, twice). The combined
organic layer was dried (Na2SO4) and the solvents removed
1
under vacuum: 956 mg (93%) of 7g, colorless oil. H NMR (400
MHz, CDCl3): δ 6.49, 6.47 (s, 2H), 4.07, 4.04, 3.73, 3.71 (q, 4H,
3J ) 7.0), 1.38 (t, 6H, 3J ) 7.0).
{[2,2-Dich lor o-1-(d ich lor om et h yl)vin yl]oxy}t r im et h yl-
sila n e (8). To a solution of 7a (5 g, 25 mmol) and trimethyl-
chlorosilane (2.98 g, 27.5 mmol) in anhydrous ether (40 mL) was
added dropwise anhydrous Et3N (4.18 mL, 30 mmol). After the
solution was stirred overnight, the white suspension was
filtrated and the solvent evaporated. Distillation under reduced
pressure (bp 110-115 °C, 5 mBar) in a Kugelrohr afforded 5.1
g (87%) of 8 as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ
6.81 (s, 1H), 0.38 (s, 9H).
4
3
1H NMR (400 MHz, CDCl3): δ 7.70 (dd, 1H, J ) 0.8, J ) 1.6),
7.60 (dd, 1H, 4J ) 0.8, 3J ) 3.5), 6.57 (dd, 1H, 3J ) 1.6, 3J )
3.5), 6.44 (d, 1H, 3J ) 5.9), 6.37 (dd, 1H, 3J ) 5.9, 3J ) 1.9), 5.31
(dt, 1H, 3J ) 1.8, 3J ) 5.4), 2.89 (d, 1H, 3J ) 16.7), 2.83 (dd, 1H,
3J ) 16.7, 3J ) 5.4), 2.79 (d, 1H, 3J ) 16.7), 2.42 (d, 1H, 3J )
16.7).
Ack n ow led gm en t . We thank the Swiss National
Science Foundation, the Fonds Herbette (Lausanne),
and the Office Fe´de´ral de l’Enseignement et de la
Science (Bern, European COST D13/010/01 action). We
thank also Mr. Martial Rey and Franscisco Sepu´lveda
for technical help.
(1R,2S,4R,5S)-2,4-Dibr om o-1-(2-fu r ylm eth yl)-8-oxabicyclo-
[3.2.1]oct-6-en -3-on e (9). A 1 M solution of Et2Zn (1.83 mL,
2.02 mmol) in toluene was added dropwise to a solution of 1c
(200 mg, 1.34 mmol), TMSCl (211 mg, 1.94 mmol), and 2e (701
mg, 1.87 mmol) in 10 mL of anhydrous toluene at 0 °C. The
solution was allowed to warm to 20 °C and was stirred overnight
(TLC, Et2O/PE 1:1). After dilution with EtOAc, the reaction was
quenched with a saturated aqueous solution of NH4Cl (10 mL).
The aqueous phase was extracted with EtOAc (5 mL, twice). The
combined organic extracts were filtrated over a Celite path and
dried (MgSO4). The brown residue was purified by flash chro-
matography (silica gel, Et2O/PE 1:4) to afford 75 mg (16%) of a
white solid that decomposes slowly at 20 °C, but can be stored
at -80 °C for weeks. 1H NMR (400 MHz, CDCl3): δ 7.41 (dd,
1
Su p p or tin g In for m a tion Ava ila ble: Detailed H and 13C
NMR spectra and signal assignments, IR and MS spectra of
all described compounds, as well as complementary data to
the initial publications for 7a , 7d , and 7f. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O020678S
J . Org. Chem, Vol. 68, No. 7, 2003 2967