Epoxidation of electron deficient alkenes using tert-butyl hydroperoxide and 1,5,7-triazabicyclo[4.4,0]dec-5-ene and its Derivatives

Article abstract of DOI:10.1055/s-1999-2721

The title cyclic guanidine (4a) is an efficient promoter of enone epoxidation by tert-butyl hydroperoxide. Optimisation studies are reported and the procedure applied to cyclic and acyclic ketones, quinones and naphthoquinones. N-Substituted guanidine (4c) proved best for the epoxidation of 2-amidobenzoquinones. Preliminary asymmetric epoxidation studies are also discussed.

Full text of DOI:10.1055/s-1999-2721

LETTER
795
Epoxidation of Electron Deficient Alkenes Using tert-Butyl Hydroperoxide and
1,5,7-Triazabicyclo[4.4.0]dec-5-ene and its Derivatives
Thorsten Genski,a Gregor Macdonald,a Xudong Wei,a Norman Lewis,b Richard J. K. Taylora,*
aDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax:+44(0)1904-434523; E-mail rjkt1@york.ac.uk
bSmithKline Beecham Pharmaceuticals, Leigh, Tonbridge, Kent TN11 9AN, UK
Received 16 March 1999
have both been used to catalyse Michael additions,7 as
Abstract: The title cyclic guanidine (4a) is an efficient promoter of
have enantiopure C-substituted analogues.8 We were at-
enone epoxidation by tert-butyl hydroperoxide. Optimisation stud-
tracted to bicyclic guanidine bases 4 for several reasons.
Compounds 4a and 4b are commercially available and the
ies are reported and the procedure applied to cyclic and acyclic ke-
tones, quinones and naphthoquinones. N-Substituted guanidine (4c)
proved best for the epoxidation of 2-amidobenzoquinones. Prelimi- conversion of 4a into other N-substituted analogues is
well described.9 We felt that this gave the potential for
nary asymmetric epoxidation studies are also discussed.
tuning the reactivity of the bases and for preparing enan-
tiomerically pure analogues. In addition, the preparation
of solid-supported base is possible: this application was
reported during the course of our study.10
Key words: epoxidation, alkenes, guanidine
The epoxidation of electron deficient alkenes, a process of
great synthetic importance, can be achieved in a number
of ways.1 Many of these procedures utilise aqueous hydro-
gen peroxide and inorganic bases but in examples where
these conditions cause problems, the use of anhydrous
tert-butyl hydroperoxide (TBHP) and 1,8-diazabicyc-
lo[5.4.0]undec-7-ene (DBU, 3) in dichloromethane has
been recommended.2,3 We have made use of this proce-
dure during our studies on the total synthesis of manumy-
cin and related epoxyquinone antibiotics (Scheme 1).4 All
of the quinones 2 are very sensitive to alkali and undergo
rapid transformation to an unidentified black dyestuff un-
der standard alkaline peroxide conditions but the DBU
procedure was extremely fast and efficient.
We commenced this study by examining the epoxidation
of trans-chalcone using anhydrous TBHP (5.5 M in de-
cane) (Scheme 2 and Tables 1-3). We were delighted to
see that the oxidation proceeded smoothly in a range of
solvents using guanidine 4a as shown in Table 1. We also
established (Tables 1 and 2), that epoxidation proceeded
efficiently using sub-stoichiometric quantities of 4a but
that the reaction slows dramatically when less than 0.3
equivalents are employed. It should be noted that the reac-
tion proceeded to completion at a much faster rate when
one equivalent or more of 4a was employed but a lower
yield of product was obtained, presumably due to base-
promoted side reactions. Further studies showed that the
reaction still proceeded efficiently with just a slight excess
of oxidant (5.5 equiv. TBHP, 90% 5; 1.1 equiv. TBHP,
78% 5), and that guanidine 4a also catalysed epoxidation
with hydrogen peroxide and other peroxides, even in the
presence of water (Table 3).
Scheme 2
Table 1 Chalcone epoxidation with 0.3 eq. (4a) in several solvents
Scheme 1
In seeking to optimise this epoxidation procedure, we de-
cided to investigate the use of the corresponding 1,5,7-tri-
azabicyclo[4.4.0]dec-5-enes (4),5 a group of strong bases
with pKa (ca. 13)6 similar to or slightly greater than DBU.
The parent compound (4a) and its N-methyl derivative 4b
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T. Genski et al.
LETTER
Table 2 Variation of the equivalents of guanidine (4a) in CHCl3
Table 3 Variation of the oxidant
Scheme 3
In summary, we have shown that a number of cyclic
guanidines 4 promote the TBHP-mediated epoxidation of
electron deficient alkenes,16 and that enantiomerically
pure guanidines show promise in asymmetric epoxida-
tions.
We also examined the epoxidation of other substrates (Ta-
ble 4). Cyclohexenone oxide (6) and naphthoquinone ox-
ide (7) were both produced in high yields using catalytic
amounts of guanidine 4a. In addition, this procedure was
employed in the synthesis of deoxypreussomerin A.11
However, epoxidation of quinones 1a-c proceeded rather
violently under these conditions with the reaction mixture
turning black within seconds and only low yields (33-
45%) of epoxides 2a-c being isolated. Use of the N-meth-
yl guanidine 4b gave slightly better yields but the reaction
was still very fast. We therefore prepared the N-benzhydr-
yl guanidine 4c12 and found that with this catalyst the ep-
oxidation of these sensitive quinones proceeded more
slowly and in much higher yields (60% - 68%).
Acknowledgement
We are grateful to the EPSRC for the award of a Research Fel-
lowship (X. W.) and a CASE Studentship (G. M.) and the DAAD
and Elsevier Science Ltd for studentship support (T. G.).
References and Notes
(1) Meth-Cohn, O.; Moore, C.; Taljaard, H. C. J. Chem. Soc.,
Perkin Trans. I 1988, 2663 and references therein.
(2) Schlessinger, R. H.; Bebernitz, G. R.; Lin, P.; Poss, A. J. J.
Am. Chem. Soc. 1985, 107, 1777;
Yadav, V. K.; Kapoor, K. K. Tetrahedron 1995, 51, 8573.
(3) For other aprotic epoxidation procedures see references 1, 2
and:
Table 4 Variation of the substrates
Yadav, V. K.; Kapoor, K. K. Tetrahedron Lett. 1994, 35,
9481;
Still, W. C. J. Am. Chem. Soc. 1979, 101, 2493 and references
therein.
(4) Taylor, R. J. K.; Alcaraz, L.; Kapfer-Eyer, I.; Macdonald, G.;
Wei, X.; Lewis, N. Synthesis 1998, 775;
Alcaraz, L.; Macdonald, G.; Ragot, J. P.; Lewis, N.; Taylor, R.
J. K. J. Org. Chem. 1998, 63, 3526.
(5) McKay, A. F.; Kreling, M.-E. Can. J. Chem. 1957, 35, 1438.
(6) Raczynska, E. D.; Maria, P.-C.; Gal, J.-F.; Decouzon, M. J.
Phys. Org. Chem. 1994, 7, 725 and references cited therein.
(7) Horváth, A. Tetrahedron Lett. 1996, 37, 4423.
(8) Alcázar, V.; Morán, J. R.; de Mendoza, J. Tetrahedron Lett.
1995, 36, 3941.
(9) Alder, R. W.; Mowlam, R. W.; Vachon, D. J.; Weisman, G. R.
Chem. Commun. 1992, 507; see also reference 11.
(10) Subba Rao, Y. V.; De Vos, D. E.; Jacobs, P. A. Angew. Chem.
Int. Ed. Engl. 1997, 36, 2661.
We have also prepared a range of enantiomerically pure
guanidines (e.g. 4d-g, Scheme 3).13,14 Preliminary studies
illustrate the potential of these reagents, although consid-
erable optimisation is clearly required. Thus, for example,
epoxidation of enone 8 with TBHP in the presence of 4d
gave a predominance of epoxide (-)-(9) {[a]D - 65 (c 0.98,
CHCl3); 35% ee}, a valuable building block in antibiotic
synthesis.4,15 The enantiomer of 4d was also prepared and
this was used to produce (+)-9 with a similar enantiomeric
purity.
(11) Ragot, J. P.; Steeneck, C.; Alcaraz, M.-L.; Taylor, R. J. K.
Taylor J. Chem. Soc.,Perkin Trans. I 1999, 1073.
(12) Kosasayama, A.; Konno, T.; Higashi, K.; Ishikawa, F. Chem.
Pharm. Bull. 1979, 27, 841; we prepared 4c directly by
alkylation of 4a with benzhydryl bromide.
1
(13) All new compounds were fully characterised by high field H
and 13C NMR spectroscopy and by elemental analysis or high
resolution mass spectrometry.
Synlett 1999, No. 6, 795–797 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Epoxidation of Electron Deficient Alkenes Using tert-Butyl Hydroperoxide
797
(14) 4d-f were prepared from 4a by reaction with the
corresponding epoxide; 4g was prepared by deprotonation of
4b and trapping with camphor.
(15) Macdonald, G.; Alcaraz, L.; Lewis, N. J.; Taylor, R. J. K.
Tetrahedron Lett. 1998, 39, 5433.
(16) Representative procedure:1,5,7-Triazabicyclo[4.4.0]dec-5-
ene (4a) (81 mg, 0.58 mmol) was added to a stirred solution of
2-methyl-1,4-naphthoquinone (100 mg, 0.58 mmol) and
anhydrous tert-butyl hydroperoxide in decane (5.5 M, 0.55
mL, 3.03 mmol) in dichloromethane (4 mL) at RT. After 2 min
the reaction had gone to completion (tlc) whereupon the
mixture was diluted with dichloromethane (15 mL) and
extracted with saturated aqueous iron(II) sulfate solution
(2 x 15 mL). The organic layer was dried over magnesium
sulfate, filtered and concentrated in vacuo. Purification by
column chromatography on silica gel using petrol ether-ethyl
acetate (5:1) as the eluent gave 2,3-epoxy-2-methyl-1,4-
naphthoquinone (7) (98.4 mg, 90%) as colourless needles,
m.p. 96 °C (lit.17 95-98 °C) with consistent spectroscopic data.
(17) Jackson-Mülly, M.; Zsindely, J.; Schmid, H. Helv. Chim. Acta
1976, 59, 664.
Article Identifier:
1437-2096,E;1999,0,06,0795,0797,ftx,en;L03799ST.pdf
Synlett 1999, No. 6, 795–797 ISSN 0936-5214 © Thieme Stuttgart · New York