A new and efficient catalytic isomerization of cis- and trans-epoxides

Article abstract of DOI:10.1016/S0040-4039(03)00465-9

We report new ruthenium-catalyzed cis-trans isomerization of various functionalized epoxides. Enantiospecific isomerization of chiral epoxides is achieved without loss of enantiopurity, and epimerization occurs only at the epoxide carbon of the activating group.

Full text of DOI:10.1016/S0040-4039(03)00465-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3143–3146
A new and efficient catalytic isomerization of cis- and
trans-epoxides
Ching-Yu Lo, Sitaram Pal, Arjan Odedra and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan 30043, ROC
Received 18 February 2003; accepted 20 February 2003
Abstract—We report new ruthenium-catalyzed cis–trans isomerization of various functionalized epoxides. Enantiospecific isomer-
ization of chiral epoxides is achieved without loss of enantiopurity, and epimerization occurs only at the epoxide carbon of the
activating group. © 2003 Elsevier Science Ltd. All rights reserved.
1
0
Since epoxides (oxirane) are readily available intermedi-
ates, numerous reactions have been developed to make
methyl-styrene oxide. In this study, we report a new
ruthenium-catalyzed cis–trans isomerization that is
applicable to various epoxides comprising a phenyl,
furanyl, alkynyl, alkenyl, ketone and aldehyde group.
1
,2
them useful in organic synthesis. The stereoselective
formation of a CꢀX bond (X=C, N, O, S) is readily
achieved via the ring-opening of a cis or trans epoxide
1
,2
by a suitable nucleophile. Despite the great popular-
ity of epoxides in organic reactions, there has been little1
success in the isomerization of cis and trans epoxides.
The thermal isomerization of epoxides can be applied
only to oxiranes of special types such as cyanostilbene
We examined isomerization with various ruthenium
11
catalysts, and found that TpRuPy Cl
(1) (Tp=
trispyrazolylborate, Py=pyridine, 4.0 mol%, toluene,
00°C, 12 h) was the most active for the isomerization
2
1
of cis-stilbene oxide (1.5 M) to its trans-isomer without
formation of byproduct (96% recovery yield). The equi-
librium ratio (trans/cis=24.0) was confirmed by a
reverse isomerization of trans-stilbene oxide using cata-
3
oxide and a,b-dicyanostilbene oxide (Scheme 1, Eq.
(
1)); the mechanism involves a carbonyl ylide intermedi-
ate. Photochemical isomerization of epoxides is only
known for a,b-diaryloxirane derivatives, and the forma-
tion of the intermediate carbonyl ylide or diradical
4
species depends on the presence of a suitable sensitizer.
This process is plagued by the formation of byproducts.
Although some epoxyketones undergo isomerization
catalyzed by sodium ethoxide, the recovery yields of
5
epoxides are very low. Common functionalized epox-
ides like aryl-, vinylepoxides or epoxyketones suffer
homolysis of CꢀO and CꢀC bonds upon thermolysis or
1,2
photolysis, to give complicated mixtures of products.
Metal-catalyzed reaction is a powerful tool in organic
synthesis. Most epoxides undergo catalytic rearrange-
ment to ketones or aldehydes in the presence of either
1,6–9
acidic or basic metal catalysts (Eq. (2)).
These rear-
rangement reactions have been intensively studied with
the mechanisms depicted in Scheme 1. Isomerization of
cis and trans epoxides was reported only for Ru(II)–
porphyrin complexes, but the scope is limited to b-
*
0
Corresponding author. E-mail: rsliu@mx.nthu.edu.tw
Scheme 1.
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00465-9

3
144
C.-Y. Lo et al. / Tetrahedron Letters 44 (2003) 3143–3146
1
2
lyst 1 under the same conditions. C Me RuPy Cl (4
5
5
2
mol%) was less active for the isomerization of cis-stil-
bene oxide and give a trans/cis ratio of 0.68 after
heating in toluene (100°C, 12 h). CpRuPy Cl (10
2
mol%), pyridine alone (10 mol%) and many basic
13
ruthenium complexes show no catalytic activity.
Table 1 shows various cis-epoxides that can be isomer-
ized by catalyst 1 (2–5 mol%) in toluene (100°C, 8–12
h). The resulting equilibrium ratios were verified by
reverse isomerization of pure trans-isomers using cata-
lyst 1. Recovery yields exceeded 95%, with negligible
amounts of byproduct. This isomerization is effective
for diverse substrates including alkynyl epoxide 2, and
vinyl- and (2-methoxycarbonyl)vinyl epoxides 3 and 4.
It is also applicable to cis-epoxides 5–9, bearing an
aldehyde, ketone, phenyl and furanyl group, respec-
tively (entries 4–8). Tertiary alkynyl epoxide 10 also
underwent isomerization using catalyst 1. Both the
forward and reverse isomerization of trans- and cis-iso-
mers of epoxide 10 confirm that cis-epoxide is more
stable than its trans-isomer. This result is consistent
Scheme 2.
lated from the reaction mixtures were determined to
14
with a calculation using the MM 2-program. The
acetylene group of 10 with a linear geometry is less
bulky than a methyl group. A higher loading of catalyst
have a (2S,3S) configuration based on comparison of
15,16
their [h]-values with those of authentic samples.
No
decrease in ee values was seen either for the trans-iso-
mers of 12 and 13 or for their recovered cis isomers.
Epimerization clearly occurs at the epoxide carbon of
the phenyl group of 12 and 13 during the catalytic
reaction. Similar results were seen for chiral tertiary
epoxide 14, the tertiary epoxide carbon of which under-
1
(5 mol%) is required for complete isomerization of
tertiary epoxide cis-11. We also prepared chiral epox-
ides 12–14 to investigate the nature of the mechanism
of isomerization. The trans-epoxides of 12 and 13 iso-
15
goes epimerization to form its cis-isomer without any
loss of its enantiopurity. Unfunctionalized cis-epoxide
Table 1. Catalytic isomerization of epoxides and their iso-
meric rations
1
5 fails to undergo isomerization even using a higher
loading of 1 (10 mol%).
Scheme 2 shows two possible mechanisms for isomer-
ization of cis–trans epoxides. Similar to Ru(II)–por-
10
phyrin complexes,
epoxide may coordinate to
TpRuPyCl to form species A which subsequently
undergoes CꢀO bond cleavage to form Ru(III)-radical
intermediate B. This radical species is stabilized by a
phenyl or other unsaturated functionalities. An alterna-
tive pathway involves an initial attack of the epoxide by
ruthenium metal (Scheme 2), to give Ru(IV)-intermedi-
ate species C, and Ru(IV)–oxetane D is obtained via
formation of a Ru(IV)ꢀO bond. Species D may be
prone to irreversible reductive elimination to complete
the reaction. Both processes rationalize the enantiospe-
cific isomerization of chiral epoxides 12–14. The success
of this process relies on the Tp group of catalyst 1,
17,18
which shows one crucial feature
—it increases the
basicity of Ru(II) to facilitate Ru(II)–Ru(III) or
Ru(II)–Ru(IV) interconversion. Further clarification of
the reaction mechanism requires additional work.
The ease of the isomerizations of epoxides provides new
routes in organic synthesis. As shown in Scheme 3,
cis-epoxide 4 provides access not only to syn-alcohol
1
6 (88% yield) but also to anti-alcohol 16. trans-Epox-
ide 4 was isolated in 80% yield using this approach
(
(
entry 3, Table 1), and further gave anti-alcohol 16
89%) upon treatment with NaN3 and NH Cl in
4
MeOH/H O. Catalyst 1 (2 mol%) also effected the
2

C.-Y. Lo et al. / Tetrahedron Letters 44 (2003) 3143–3146
3145
3
. (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1977, 16,
72; (b) Mukaiyama, T.; Kuwajima, J.; Ohno, K. Bull.
5
Chem. Soc. Jpn. 1965, 38, 54; (c) McDonald, H. H. J.;
Crawford, R. J. Can. J. Chem. 1972, 50, 428.
4. (a) Rau, H. Chem. Rev. 1983, 83, 535; (b) Inoue, Y.;
Yamasaki, N.; Shimoyama, H.; Tai, A. J. Org. Chem.
1993, 58, 1785; (c) Manring, L. E.; Peters, K. S. J. Am.
Chem. Soc. 1984, 106, 8077; (d) Griffin, G. W. Angew.
Chem., Int. Ed. Engl. 1971, 10, 537.
5. House, H. O.; Reif, D. J. J. Am. Chem. Soc. 1957, 79,
6491.
6
. The term ‘isomerization reaction’ is often misused in the
1,9a,b
literature.
Many so-called isomerization reactions are
actually rearrangement reactions. For instance, the base-
catalyzed isomerization of epoxide in Ref. 1a involves the
rearrangement of epoxide to allylic alcohol in the pres-
ence of a strong base.
Scheme 3.
transformation of trans-epoxide 17 into its cis-isomer
7
. For reviews on acid-mediated rearrangement of epoxides:
(
cis/trans=4.3) in 67% yield. Enyne metathesis of cis-
(
a) Rickborn, B. In Comprehensive Organic Synthesis,
19
isomer of 17 using Grubbs catalyst afforded function-
alized diene 18 in 62% yield.
CarbonꢀCarbon |-Bond Formation; Trost, B. M.; Flem-
ing, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, Chap-
ter 3.3, pp. 733–775; (b) Parker, R. E.; Issacs, N. S.
Chem. Rev. 1959, 59, 737.
. For representative examples of acid-catalyzed rearrange-
ment of epoxides, see: (a) Kita, Y.; Furukawa, A.; Futa-
mura, J.; Ueda, K.; Sawama, Y.; Hamamoto, H.;
Fujioka, H. J. Org. Chem. 2001, 66, 8779 and references
cited therein; (b) Jung, M. E.; D’Amico, D. C. J. Am.
Chem. Soc. 1995, 117, 7379 and references cited therein;
In summary, we found that the isomerization of cis-
trans epoxides can be achieved efficiently with ruthe-
nium catalyst 1 (2–5 mol%) under mild conditions. The
method is applicable to diverse functionalized epoxides.
The mechanism of isomerization involves cleavage of
the CꢀO bond at the epoxide carbon of the activating
group. S 2 attack of the epoxide by ruthenium is
proposed as the key step. This isomerization enhances
the usefulness of epoxides in organic synthesis.
8
N
(
5
c) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986,
1, 1922.
9
. The mechanism appears to vary for low-valence metal
catalysts, see: (a) Milstein, D.; Buchman, O.; Blum, J. J.
Org. Chem. 1977, 42, 2299; (b) Kulawiec, R. J. J. Org.
Chem. 1994, 59, 7195; (c) Alper, H.; Des Roches, D.;
Durst, T.; Legault, R. J. Org. Chem. 1976, 41, 3611; (d)
Suzuki, M.; Dda, Y.; Noyori, R. J. Am. Chem. Soc. 1979,
Supplementary material
Experimental procedures for catalytic reactions and
spectral data of new compounds 1–18.
1
2
01, 1623; (e) Eisenmann, J. L. J. Org. Chem. 1962, 27,
706.
Acknowledgements
10. Groves, J. T.; Ahn, K.-H.; Quinn, R. J. Am. Chem. Soc.
1
988, 110, 4217.
The authors wish to thank National Science Council,
Taiwan for support of this work.
1
1. Gemel, C.; Trimmel, G.; Slugovc, C.; Kremel, S.; Mere-
iter, K.; Schmid, R.; Kirchner, K. Organometallics 1996,
15, 3998.
References
12. The trans/cis equilibrium ratio of stilbene oxide was
found to be 31 upon photolysis at 23°C in pentane. See
Ref. 4b.
1
. For review of oxirane chemistry, see: Erden, I. In Com-
prehensive Heterocyclic Chemistry, 2nd ed.; Katritzky, A.
R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1996;
Vol. 1A, pp. 97–1369; (b) Sainsbury, M. In Three-, Four-,
and Five-membered Monoheterocyclic Compounds. Rodds’
Chemistry of Carbon Compounds, 2nd ed.; Second Sup-
plement to Volume IV, Heterocyclic Compounds; Part A,
Elsevier: Amsterdam, 1997.
. For representative examples, see: (a) Lautens, M.; Fag-
nou, K. Org. Lett. 2000, 2, 2319; (b) Sodergren, M. J.;
Andersson, P. G. J. Am. Chem. Soc. 1998, 120, 10760; (c)
Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50,
13. No catalytic activity was found for ruthenium catalysts
including TpRu(PPh ) Cl, C M Ru(PPh ) Cl, TpRu-
3
2
5
5
3 2
(COD)Cl, Cl Ru(PPh ) and C M Ru(COD)Cl.
2
3 3
5
5
14. The cis form of alkynylepoxide 10a has 0.89 kcal/mol less
in energy than its trans isomer based on MM2 program
(Pro 6.0 edition).
15. The trans-epoxide 12 given from isomerization of
(2S,3R)-cis-epoxide has [h] value −45.6 (83% ee, CHCl3,
c=0.50) consistent to that of authentic (2S,3S)-trans-
2
epoxide ([h]=−49.5, 89% ee, CHCl , c=0.50) reported in
3
16
literature. We also prepared authentic (2S,3S)-trans-
epoxides 13 and (2S,3R)-cis-epoxide 14, the [h] values of
which are used to identify absolute configurations of
products isomerized from (2S,3R)-trans-epoxides 13 and
(2S,3S)-cis-epoxide 14. For the details, see Supporting
information.
1
557; (d) Lin, K.-Q.; Li, Y.-M.; Chan, A. S. C. In
Principles and Applications of Asymmetric Synthesis;
Wiley: London, 2001; Chapter 4, pp. 159–220; (e) Pater-
son, I.; Berrisford, D. J. Angew. Chem., Int. Ed. Engl.
1
992, 31, 1179.

3
146
C.-Y. Lo et al. / Tetrahedron Letters 44 (2003) 3143–3146
1
1
6. Wang, Z.-M.; Zhou, W. S. Tetrahedron 1987, 43, 2935.
18. (a) Yeh, K.-L.; Liu, B.; Lo, C.-Y.; Huang, H.-L.; Liu,
R.-S. J. Am. Chem. Soc. 2002, 124, 6510; (b) Lo, C.-Y.;
Guo, H.; Lian, J.-J.; Shen, F.-M.; Liu, R.-S. J. Org.
Chem. 2002, 67, 3930.
7. For the stereoelectronic effect of the Tp group on coordi-
nation and reaction chemistry, see Ref. 10 and
Trofimenko, S. In Scorpinoates: Polypyrazolylborate Lig-
ands and Their Coordination Chemistry; Imperial Press,
19. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
1
999.
Lett. 1999, 1, 953.