The first, general, highly efficient method for preparing tetrasubstituted epoxides using HOF·CH3CN

Article abstract of DOI:10.1002/ejoc.200300082

Tetrasubstituted epoxides, and especially electron-depleted ones, generally are difficult to prepare. HOF·CH₃CN complex, probably the best oxygen transfer agent known today, epoxidizes tetrasubstituted alkenes at 0 °C in a matter of minutes or less in excellent yields. HOF·CH₃CN complex is very easy to prepare by bubbling diluted fluorine (commercial) through aqueous acetonitrile. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300082

FULL PAPER
The First, General, Highly Efficient Method for Preparing Tetrasubstituted
Epoxides Using HOF·CH3CN
Shlomo Rozen*[a] and Elizabeth Golan[a]
Dedicated to the memory of Prof. D. H. R. Barton
Keywords: Epoxidations / Fluorine / HOF·CH3CN / Olefins / Synthetic methods
Tetrasubstituted epoxides, and especially electron-depleted
very easy to prepare by bubbling diluted fluorine (commer-
ones, generally are difficult to prepare. HOF·CH3CN com- cial) through aqueous acetonitrile.
plex, probably the best oxygen transfer agent known today,
epoxidizes tetrasubstituted alkenes at 0 °C in a matter of
minutes or less in excellent yields. HOF·CH3CN complex is
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
Results and Discussion
The epoxidation of cis-2,3,4,5-tetramethyl-2-cyclopen-
tenone (1) is not known in the literature. We have attempted
its direct epoxidation with basic H2O2, but obtained only
the starting material. Prolonged treatment with MCPBA re-
sulted in a 2% yield of a material, which proved to be the
corresponding epoxide 2, with the rest being again the un-
changed starting material. Treating 1 with dimethyldioxir-
ane (DMDO) gave somewhat better results and 2 was ob-
tained in 25% yield after 24 hours of reaction at room tem-
perature. When this sterically hindered, electron-deficient
olefin was treated with HOF·CH3CN, however, it took only
1 min to convert it into the epoxide 2 with a yield ex-
ceeding 90%.
As with 1, the sterically hindered double bond of 4-
(ethoxycarbonyl)-2-ethyl-3-methylcyclohex-2-enone (3) has
never been epoxidized. In addition to the extensive steric
hindrance, this olefin is very deactivated toward electro-
philic attack by the two electron-withdrawing groups in
both α-positions. Using a twofold excess of the acetonitrile
complex of hypofluorous acid gave only traces of the corre-
sponding epoxide 4, but by employing a 15-fold excess of
this reagent we were able to obtain 4 in high yield.
The two double bonds of tetraphenylcyclopentadienone
(5) are somewhat less hindered and more electron-rich than
the ones described above and, indeed, the trans-diepoxide 6
has already been prepared by treating 5 with basic hydrogen
peroxide for several hours.[6] That reaction gave several by-
products, which were further manipulated to give the trans-
diepoxide 6 eventually in 60% yield. With a threefold excess
of HOF·CH3CN, 5 was converted into 6 in a single step.
Similarly, 2-cyclopentylidenecyclopetanone (7) and tetracy-
anoethylene (8) have been epoxidized in the past, the first
by treating it with DMDO for 24 h,[7] and the second by
Epoxides are essential intermediates and building blocks
in organic synthesis. Many methods have been developed
for the direct epoxidation of double bonds, mainly peracids,
hydrogen peroxide, and dialkyldioxiranes. Still, among the
tens of thousands of epoxides described, relatively few are
tetrasubstituted ones and even fewer are derived from elec-
tron-deficient tetrasubstituted alkenes. Clearly, a general
method for the preparation of such sterically hindered
epoxides is highly desirable.[1]
The HOF·CH3CN complex, easily prepared by bubbling
dilute fluorine through aqueous acetonitrile,[2] is considered
today as one of the best oxygen-transfer agents that organic
chemistry has to offer. The oxygen atom is strongly electro-
philic because it is weakly bound to the most electronega-
tive element — fluorine. The complex has been used for
epoxidations, hydroxylation of tertiary sp3-carbon centers,
for converting amines into the corresponding nitro deriva-
tives, thiophenes into the respective S,S-dioxides, sulfides
(including electron-depleted ones) into sulfones, and much
more.[3] It has also been successfully used for proving that,
under certain circumstances, the original mechanism Baeyer
suggested for the famous BaeyerϪVilliger rearrangement is
a viable one (although not correct when peracids are
used),[4] and for the preparation[5] of the elusive 1,10-phen-
anthroline N,N-dioxide. We report here on the first direct
and effective general method for preparing crowded tetra-
substituted epoxides from the corresponding olefins using
this unique reagent.
[a]
School of Chemistry, Raymond and Beverly Sackler Faculty of
Exact Sciences, Tel-Aviv University,
Tel-Aviv 69978, Israel
Fax: (internat.) ϩ 972-3/640-9293
E-mail: rozens@post.tau.ac.il
Eur. J. Org. Chem. 2003, 1915Ϫ1917
DOI: 10.1002/ejoc.200300082
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1915

S. Rozen, E. Golan
FULL PAPER
Scheme 1
Scheme 2
peracids or iodosobenzene, again with prolonged reaction
times.[8] We treated both 7 and 8 with HOF·CH3CN and
obtained the respective epoxides 9 and 10 in less than 3 min
with yields higher than 90% (Scheme 1).
HOF·CH3CN solution always contains some HF) we were
able to isolate it in only 70% yield. The α-hydroxycar-
bonium ion that is developed under these conditions is at-
tacked by water and acetonitrile leading to an additional
3% of the diol 22 and 17% of 9-hydroxy-10-acetamidodeca-
lin (23). Such an attack by acetonitrile on unstable car-
bonium ions has been described recently.[10]
In conclusion, we believe that the HOF·CH3CN complex
should be the reagent of choice whenever oxygen-transfer
reactions are the goal. Most of the objections to this re-
agent are based on mythical fears and prejudice concerning
F2. The good news is that 20 years ago fewer than ten or-
ganic laboratories ‘‘dared’’ to work with this element, but
currently there are more than 100. In addition, it is possible
to purchase pre-diluted fluorine, which simplifies the work
to the extent of opening and closing a single valve and plac-
ing a simple trap to absorb traces of unreacted fluorine.
Working with unsaturated anhydrides and other deriva-
tives where an oxygen atom is a part of a cyclic system
posed a problem, which at this stage we have been unable
to fully solve. Dimethylmaleic anhydride (11), octahydro-
phthalic anhydride (12), 5-(2-adamantylidene)-2,2-dimethyl-
1,3-dioxane-4,6-dione (13), and even the non-crowded ma-
leic anhydride itself, have never been directly epoxidized.
We treated all of them with large excesses of HOF·CH3CN,
but obtained only the unchanged starting materials. When
we opened these cyclic anhydrides, however, to form the
corresponding dimethyl esters 14Ϫ16 (heating under reflux
for 6 h with MeOH/Hϩ), they no longer resisted epoxid-
ation with HOF·CH3CN. Dimethyl 2,3-dimethyl-2,3-epoxy-
maleate (17), dimethyl 1,2-epoxycyclohexane-1,2-dicar-
boxylate (18), and the epoxy derivative 19 of dimethyl ada-
mantalidenemalonate were all obtained rapidly in high
yields (Scheme 2).
Experimental Section
The tetrasubstituted double bond of octahydronaph-
thalene (20) is not an electron-deficient one, so its reaction
with 1 mol-equiv. of HOF·CH3CN, leading to 9,10-epoxy-
decalin (21), was completed at Ϫ35 °C within 1Ϫ2 s.[9] Be-
1
General: H NMR spectra were recorded using a 200 MHz instru-
ment with CDCl3 as a solvent and Me4Si as an internal standard.
The proton broad-band decoupled 13C NMR spectra were re-
corded with a 360 MHz instrument at 90.5 MHz. Here, too, CDCl3
cause, however, this epoxide is very sensitive to acids (the served as the solvent with TMS as an internal standard. IR spectra
1916  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2003, 1915Ϫ1917

Tetrasubstituted Epoxides
FULL PAPER
were recorded in CHCl3 solution or in KBr pellets with a Bruker
Vector22 FTIR spectrophotometer. High-resolution mass spectra
were measured with a VG micromass 7070H instrument. MS and
GC-MS spectra were usually measured under CI conditions. In
many cases where the CI method could not detect the molecular
ion of the epoxide, we have successfully used Amirav’s supersonic
GC-MS method developed in our department. The main feature
of this method is to provide electron ionization while the sample is
cooled vibrationally in a supersonic molecular beam. This process
enhances the relative abundance of the molecular ions consider-
ably.[11] The spectral properties of all products presented in this
work are in excellent agreement with their structures, and are con-
sistent with those described in the literature. We are presenting here
only relevant data of the new compounds.
63.16, 169.28 ppm. HRMS (CI): calcd. for C8H13O5 189.07630;
found 189.07666 [M ϩ 1]ϩ. C8H12O5 (188.18): calcd. C 51.06, H
6.43; found C 51.01, H 6.16.
Dimethyl 1,2-Epoxycyclohexane-1,2-dicarboxylate (18): Obtained
from 15 (2 g) at room temperature in a 5-min reaction by using 3
mol-equiv. of HOF·CH3CN. Yield: 1.83 g (85%). IR: ν˜ ϭ 1743
cmϪ1 1H NMR: δ ϭ 1.38Ϫ1.55 (m, 4 H), 2.00Ϫ2.07 (m, 2 H),
.
2.29Ϫ2.36 (m, 2 H), 3.74 (s, 6 H) ppm. 13C NMR: δ ϭ 18.58,
24.94, 52.3, 62.68, 169.01 ppm. HRMS (CI): calcd. for C10H15O5
215.09195; found 215.09202 [M ϩ 1]ϩ. C10H14O5 (214.22): calcd.
C 56.07, H 6.59; found C 55.79, H 6.68.
Epoxy Derivative of Dimethyl Adamantylidenemalonate (19): Ob-
tained from 16 (1 g) at 0 °C in a 2-min reaction by using 2 mol-
equiv. of HOF·CH3CN. Yield: 0.99 g (93%); m.p. 87 °C (from
General Procedure for Working with Fluorine: Fluorine is a strong
oxidant and a very corrosive substance. It should be used only with
an appropriate vacuum line, such as the one described in ref.[12] For
the occasional user, however, various premixed mixtures of F2 in
inert gases are commercially available, simplifying the process. If
elementary precautions are taken, work with fluorine is relatively
simple and we have had no bad experiences working with it.
1
MeOH). IR: ν˜ ϭ 1749 cmϪ1. H NMR: δ ϭ 1.71Ϫ2.08 (m, 14 H),
3.83 (s, 6 H) ppm. 13C NMR: δ ϭ 26.41, 26.68, 33.08, 35.18, 35.80,
36.22, 52.89, 67.34, 74.27, 165.39 ppm. HRMS (CI): calcd. for
C15H21O5 281.13890; found 281.13810 [M ϩ 1]ϩ. C15H20O5
(280.32): calcd. C 64.27, H 7.19; found C 64.02, H 7.30.
9,10-Epoxydecalin (21) and 9-Hydroxy-10-acetamidodecalin (23):
Obtained by treating 20 (0.9 g) with HOF·CH3CN at Ϫ35 °C for
5 s. The main compound obtained was the known 21.[9] Yield: 0.7 g
(70%). The main byproduct was 23. Yield: 0.24 g (17%); m.p. 170
General Procedure for Producing the Oxidizing Agent
؊
HOF·CH3CN Complex: Mixtures of 10Ϫ15% F2 in nitrogen were
used in this work. They were passed at a rate of about 400 mL/min
through a cold (Ϫ10 °C) mixture of CH3CN (60 mL) and H2O
(6 mL). The development of the oxidizing power was monitored by
treating aliquots with an acidic aqueous solution of KI. The liber-
ated iodine was then titrated with thiosulfate. Typical concen-
trations of the oxidizing reagent were around 0.4Ϫ0.6 mol/L.
1
°C (from CH3CN). IR: ν˜ ϭ 1666 cmϪ1. H NMR: δ ϭ 1.35Ϫ1.69
(m, 15 H) 2.02 (s, 3 H), 2.37 (m, 1 H), 2.42 (br. s, 1 H), 4.94 (s, 1
H) ppm. 13C NMR:
δ ϭ 58.89, 70.19, 168.61 ppm. MS
(supersonic): m/z ϭ 211 [Mϩ]. C12H21NO2 (211.31): calcd. C 68.21,
H 10.02, N 6.63; found C 67.67, H 9.85, N 6.64.
General Procedure for Epoxidations: The olefin (usually 4Ϫ8 mmol)
was dissolved in CH2Cl2, usually at room temperature (see text).
The HOF·CH3CN solution, kept at a similar or lower temperature,
was added in one portion to the reaction mixture and, after seconds
or a few minutes (see below), the reaction was stopped by adding
NaHCO3. The organic material was extracted with CH2Cl2, washed
with water, and dried with MgSO4. The crude product was usually
purified by vacuum flash chromatography using silica gel 60-H
(Merck). Unless otherwise stated, all products are oils.
Acknowledgments
This work was supported by the Israel Science Foundation founded
by the Israel Academy of Sciences and Humanities.
[1]
The challenge for developing such a method was presented to
one of us (S. R.) by the late Prof. D. H. R. Barton a few days
before his death.
A detailed procedure for the preparation and handling of
[2]
HOF·CH3CN can be found in: S. Dayan, Y. Bareket, S. Rozen,
cis-2,3-Epoxy-2,3,4,5-tetramethylcyclopentanone (2): Obtained from
1 (1 g) at 0 °C in a 1-min reaction by using 1.1 mol-equiv. of
Tetrahedron 1999, 55, 3657Ϫ3664.
[3]
S. Rozen, Acc. Chem. Res. 1996, 29, 243Ϫ248.
S. Rozen, Y. Bareket, M. Kol, Tetrahedron 1993, 49,
8169Ϫ8178. Baeyer’s mechanism was presented in: A. Baeyer,
V. Villiger, Ber. Dtsch. Chem. Ges. 1899, 32, 3625, and then was
disqualified in: W. E. von Doering, E. Dorfman, J. Am. Chem.
Soc. 1953, 75, 5595.)
S. Rozen, S. Dayan, Angew. Chem. Int. Ed. 1999, 38,
3471Ϫ3473.
G. Rio, B. Muller, F. Lareze, C. R. Acad. Sci. Paris, Ser. C
1
HOF·CH3CN. Yield: 1.02 g (92%). IR: ν˜ ϭ 1739 cmϪ1. H NMR:
[4]
δ ϭ 1.02 and 1.22 (d, J ϭ 8 Hz, each 3 H), 1.37 and 1.45 (s, each
3 H), 1.67 and 1.99 (br. dq, J1 ϭ 8, J2 ϭ 2.5 Hz, each 1 H) ppm.
13C NMR: δ ϭ 213.9, 69.8, 65.6, 43.1, 41.8, 13.4, 12.5, 11.5,
8.2 ppm, MS (EI): m/z ϭ 154 [Mϩ]. C9H14O2 (154.21): calcd. C
70.10, H 9.15; found C 69.58, H 9.05.
[5]
[6]
Ethyl
2-Epoxy-3-ethyl-2-methyl-4-oxocyclohexane-1-carboxylate
1969, 268, 1157Ϫ1159.
(4): Obtained from 3 (1.5 g) at room temperature in a 10-min reac-
tion by using 15 mol-equiv. of HOF·CH3CN. Yield: 1.37 g (85%).
[7]
W. Adam, L. Hadjiarapoglou, A. Smerz, Chem. Ber. 1991,
1
IR: ν˜ ϭ 1705, 1732 cmϪ1. H NMR: δ ϭ 1.02 (t, J ϭ 8 Hz, 3 H),
124, 227Ϫ232.
[8]
R. M. Moriarty, S. C. Gupta, H. Hu, D. R. Berenschot, K. B.
1.27 (t, J ϭ 8 Hz, 3 H), 1.50 (s, 3 H), 1.53 (m, 1 H), 1.81 (m, 1 H),
2.17Ϫ2.42 (m, 4 H), 3.12 (m, 1 H), 4.19 (q, J ϭ 8 Hz, 2 H) ppm.
13C NMR: δ ϭ 9.3, 14.04, 18.33, 19.61, 19.97, 33.12, 45.97, 61.08,
64.82, 68.02, 172.27, 204.46 ppm. HRMS: calcd. for C12H18O4
226.12051; found 226.12026 [Mϩ]. C12H18O4 (226.27): calcd. C
63.70, H 8.02; found C 63.75, H 7.67.
White, J. Am. Chem. Soc. 1981, 103, 686Ϫ688.
[9]
This epoxide has been prepared by treating 20 with DMDO
for 24 h: S. E. Denmark, D. C. Forbes, D. S. Hays, J. S. DePue,
R. G. Wilde, J. Org. Chem. 1995, 60, 1391Ϫ1407.
R. D. Chambers, A. M. Kenwright, M. Parsons, G. Sandford,
[10]
J. S. Moilliet, J. Chem. Soc., Perkin Trans. 1 2002, 2190Ϫ2197.
[11] [11a]
S. Dagan, A. Amirav, J. Am. Soc. Mass. Spectrom. 1995,
Dimethyl 2,3-Dimethyl-2,3-epoxymaleate (17): Obtained from 14
(1.5 g) at 0 °C in a 10-min reaction by using 5 mol-equiv. of
[11b]
6, 120Ϫ131.
A. Amirav, A. Gordin, N. Tzanani, Rapid
Commun. Mass Spectrom. 2001, 15, 811Ϫ820.
S. Dayan, M. Kol, S. Rozen, Synthesis 1999, 1427Ϫ1430.
Received February 8, 2003
1
HOF·CH3CN. Yield: 1.47 g (90%). IR: ν˜ ϭ 1744 cmϪ1. H NMR:
[12]
δ ϭ 3.75 (s, 6 H), 1.60 (s, 6 H) ppm. 13C NMR: δ ϭ 15.13, 52.61,
Eur. J. Org. Chem. 2003, 1915Ϫ1917
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1917