Oxidation of Indole Substrates by Oxodiperoxomolybdenum· Trialkyl(aryl)-phosphine Oxide Complexes

Article abstract of DOI:10.1021/jo0355350

A series of oxodiperoxo molybdenum complexes MoO₅· O=PR₃·L, where R = Me, Et, Pr, Bu, or Ph, have been synthesized. The X-ray crystal structures for the complexes with triethylphosphine oxide and tripropylphosphine oxide as ligands were obtained. These complexes oxidize indoles to various indolone products depending on the substitution pattern of the indole substrate.

Full text of DOI:10.1021/jo0355350

Oxid a tion of In d ole Su bstr a tes by
Oxod ip er oxom olybd en u m ‚Tr ia lk yl(a r yl)-
p h osp h in e Oxid e Com p lexes
Christine I. Altinis Kiraz, Thomas J . Emge, and
Leslie S. J imenez*
Department of Chemistry & Chemical Biology, Rutgers, The
State University of New J ersey, 610 Taylor Road,
Piscataway, New J ersey 08854-8087
F IGURE 1. Structure of mitomycin C and azidomitosene 1.
of developing a synthesis of the natural product, mito-
mycin C (Figure 1), we discovered that use of MoO5‚
HMPA oxidizes the C9-9a double bond of azidomitosene
1 to give a ∼2:1 mixture of the diastereomeric methoxy
ketones 7a and 7b in one step.12 Furthermore, the HMPA
ligand can be replaced by a trialkyl (or aryl) phosphine
oxide to form MoO5‚OdPR3‚L (L ) H2O or MeOH or Od
PR3) complexes which also convert 1 into a ∼2:1 mixture
of 7a /7b. In comparison to the MoO5‚HMPA complex,1,12
complexes 2-6 are more stable to room temperature and
moisture and do not decompose as readily upon exposure
to light. Herein we report the synthesis of a series of
oxodiperoxo molybdenum complexes where R ) Me, Et,
Pr, Bu, or Ph, the X-ray crystal structures for complexes
with triethylphosphine oxide and tripropylphosphine
oxide ligands, and their oxidation of 1 and several simple
indole substrates.
jimenez@rutchem.rutgers.edu
Received October 16, 2003
Abstr a ct: A series of oxodiperoxo molybdenum complexes
MoO5‚OdPR3‚L, where R ) Me, Et, Pr, Bu, or Ph, have been
synthesized. The X-ray crystal structures for the complexes
with triethylphosphine oxide and tripropylphosphine oxide
as ligands were obtained. These complexes oxidize indoles
to various indolone products depending on the substitution
pattern of the indole substrate.
From the onset of their discovery in the late 1960s,
oxodiperoxo molybdenum complexes have been used for
the oxidation of various functional groups.1,2 First char-
acterized by Mimoun and therefore referred to as Mi-
moun-type complexes, their most common use is as
epoxidation reagents for alkenes. However, an added
versatility of these compounds is their ability to oxidize
the C2-C3 double bond of indoles.3 Other reagents which
oxidize the indole C2-C3 double bond to various products
depending on the indole substitution pattern are di-
methyldioxirane,4 singlet oxygen,5 m-CPBA or MMPP,6
Co(salen),7 thallium(III) acetate,8 thallium(III) nitrate,9
N-chlorobenzotriazole,10 and DDQ.11 During the course
The oxodiperoxo molybdenum complexes were synthe-
sized by a modification of the method of Mimoun et al.1
and Vedejs and Larsen.13 Elemental analysis indicated
that MoO5‚OdPR3‚MeOH is formed for R ) Me (2) or Et
(3), MoO5‚OdPR3‚H2O for R ) n-Pr (4),14 and MoO5‚[Od
PR3]2 for R ) n-Bu (5) or Ph (6).14
All of these complexes oxidize 1 to a ∼2:1 mixture of
the diastereomers 7a /7b in a 60-75% combined yield
along with 10-25% of an undesired benzopyrrole byprod-
uct 12, except for 2 which is not soluble in the dichlo-
romethane/methanol solvent system used to run these
reactions. It is likely that oxodiperoxo molybdenum
complexes oxidize azidomitosene 1 through transient
formation of the epoxide 8, followed by formation of the
iminium ion 9. A second oxidation at C9 takes place
leading to the formation of intermediate 10 as outlined
in Scheme 1. The oxodiperoxo complexes of molybdenum
and tungsten (including MoO5‚HMPA‚H2O) have been
previously shown to oxidize secondary alcohols to the
corresponding ketones in modest yields.2e Methanolysis
of 10 then results in the diastereomeric mixture of
products 7a and 7b in 60-75% combined yield. When
the second oxidation at C9 does not take place, then loss
of a proton leads to the enolate 11, which is then
converted into the undesired benzopyrrole 12 by loss of
* Corresponding author.
(1) (a) Mimoun, H.; Seree, de Roch, I.; Sajus, L. Bull. Chim. Fr. 1969,
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1970, 26, 37-50. (c) Mimoun, H. Angew. Chem., Int. Ed. Engl. 1982,
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Furia, F.; Rossi, P.; Toboli, A.; Valle, G. J . Mol. Catal. 1993, 83, 95-
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5130. (e) J acobson, S. E.; Muccigrosso, D. A.; Meres, B. J . Org. Chem.
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Pharm. Bull. 1984, 32, 3945-3951. (b) Kawasaki, T.; Chien, C. C.;
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10.1021/jo0355350 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/21/2004
2200
J . Org. Chem. 2004, 69, 2200-2202

SCHEME 1
SCHEME 2
reported previously for oxidation of 13 with MoO5‚HMPA.3
Oxidation of 1-methylindole 15 gives a mixture of three
products. Intermediate 16 gives rise to a methanolysis
product 17 and an electrophilic aromatic substitution
(EAS) product 18. Ketone 17 is obtained as a ∼10:1 17/
20 mixture (∼19%), while 18 is obtained as a ∼1:2 17/18
mixture (∼12%). As attempts to completely separate
these compounds were not successful, tentative structural
TABLE 1. Oxid a tion of th e C9-9a Dou ble Bon d of 1
% yield of % yield
oxidant
7a + 7b
of 12
1
assignments were made based on the H and 13C NMR
MoO5‚R3PdO‚L
R ) Me; L ) MeOHa (2) (unrecryst)
10
80
major
25
15
12
and mass spectral data. Further oxidation of 18 by loss
of a hydride equivalent would result in the formation of
intermediate 19, which gives rise to an EAS product 20
(46%).15 Oxidation of 1,2-dimethylindole 21 results in the
formation of an EAS product 2216 exclusively in a 90%
yield, while 1-methyl-2-phenylindole 23 gives both a
methanolysis product 2417 (33%) and an EAS product 2518
(54%) (Scheme 3). The greater steric hindrance invoked
by the phenyl group at the 2 position may slow the EAS
reaction and allow the solvolysis reaction to become
competitive. The mitosene 1, which is also an indole
substituted at the 1 and 2 positions, is apparently too
sterically hindered to produce an EAS product, and thus
only the methanolysis products 7a and b are observed.
R ) Me; L ) MeOHa (2) (recryst from MeOH)
R ) Et; L ) MeOH (3) (recryst from MeOH)
R ) n-Pr; L ) H2O (4) (unrecryst)
R ) n-Pr; L ) H2O (4) (recryst from MeOH)
R )n-Bu; L ) OdP(n-Bu)3 (unrecryst)b(5)
R) Ph; L ) OdPPh3 (6) (unrecryst)c
72
75
65
71
62
10
22
a
Crystalline and crude material were insoluble in the CH2Cl2/
b
MeOH solvent system. Unable to obtain crystals due to the waxy
nature of 5. c Unable to obtain crystals and oxidant not very
soluble in the CH2Cl2/MeOH solvent system.
azide and methanesulfonic acid. Table 1 shows the yields
of the diastereomers 7a and b and the benzopyrrole
byproduct 12 obtained when 1 was oxidized with 6-8
equiv of the oxodiperoxo molybdenum complexes 2-6 in
a 1:1 mixture of CH2Cl2/MeOH at 0-2 °C for about 12 h.
(15) Shen, X.; Lind, J .; Eriksen, R. E.; Merenyi, G. J . Chem. Soc.,
Perkin Trans. 2 1990, 597-603.
Some representative oxidations on indoles with various
substitution patterns at C2 and C3 were carried out in
1:1 CH2Cl2/MeOH at 0 °C with the oxodiperoxo molyb-
denum complexes 3 and 4 (Scheme 2). Oxidation of
1-acetyl-2-methylindole 13 with 3 resulted in a 52% yield
of the hydroxy ketone 14. A similar result had been
(16) Astolfi, P.; Greci, L.; Rizzoli, C.; Sgarabotto, P.; Marrosu, G. J .
Chem. Soc., Perkin Trans. 2 2001, 1634-1640.
(17) Ling, K.-Q. Chin. J . Chem. 1996, 265-270.
(18) (a) Carloni, P.; Eberson, L.; Greci, L.; Stipa, P.; Tosi, G. J . Chem.
Soc., Perkin Trans. 2 1991, 1779-1783. (b) Berti, C.; Greci, L.;
Andruzzi, R.; Trazza, A. J . Org. Chem. 1985, 50, 368-373.
J . Org. Chem, Vol. 69, No. 6, 2004 2201

SCHEME 3
C2 to give an intermediate 27 which tautomerizes to the
indolone product 2819 in a low yield (20%).
The oxodiperoxo molybdenum complexes are useful in
their ability to oxidize the C2-C3 double bond of indoles
to indolone iminium species such as 10, 16, or 19. The
isolated products can be predicted to occur via solvolysis
or EAS of these intermediates. In contrast, the oxidant
dimethyldioxirane (DMDO) is unable to effect oxidation
of 1 to 10 and results in a different product, the C9a
hydroxy analogue of 7a .4b DMDO appears to oxidize the
enol form of 11 (Scheme 1) while the oxodiperoxo
molybdenum complexes seem unable to effect this type
of oxidation, losing azide and MsOH to form the ben-
zopyrrole byproduct 12 instead. Thus these two different
classes of reagents appear to oxidize indoles by compli-
mentary reaction pathways.
Ack n ow led gm en t. We thank the National Science
Foundation (CHE-0316199) and Schering-Plough Re-
search Institute, Kenilworth, NJ , for support of this
research.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystal data,
oxodiperoxomolybdenum complex preparation, and experi-
mental procedures and compound characterization for the
oxidations of indoles 1, 15, 21, 23, and 26 are reported. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0355350
(19) (a) Kato, T.; Inada, A.; Morita, Y.; Miyamae, H. Chem. Pharm.
Bull. 1985, 33, 5270-77. (b) Suyama, T.; Kato, t.; Morita, Y. Miyamae,
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When indoles are substituted at the 1 and 3 positions as
in 1,3-dimethylindole 26, oxidation apparently occurs at
2202 J . Org. Chem., Vol. 69, No. 6, 2004