Anthrone-derived NHPI analogues as catalysts in reactions using oxygen as an oxidant

Article abstract of DOI:10.1039/b812351a

An enantioselective synthesis of anthrone-derived NHPI analogues has been developed. One of these analogues, in combination with Co salts, was employed to catalyse the aerobic oxidation of benzylic compounds and diols. Exploratory studies using a racemic version of the catalyst were also conducted. Radical addition of dioxolanes or alcohols to activated alkenes with molecular oxygen as the terminal oxidant was also shown to be catalysed with NHPI analogues.

Full text of DOI:10.1039/b812351a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Anthrone-derived NHPI analogues as catalysts in reactions using
oxygen as an oxidant†
Juan Shen and Choon-Hong Tan*
Received 18th July 2008, Accepted 26th September 2008
First published as an Advance Article on the web 7th October 2008
DOI: 10.1039/b812351a
Table 1 Chiral bicyclic guanidine-catalysed Diels–Alder reactions be-
tween substituted anthrones and maleimides
An enantioselective synthesis of anthrone-derived NHPI
analogues has been developed. One of these analogues, in
combination with Co salts, was employed to catalyse the
aerobic oxidation of benzylic compounds and diols. Ex-
ploratory studies using a racemic version of the catalyst were
also conducted. Radical addition of dioxolanes or alcohols
to activated alkenes with molecular oxygen as the terminal
oxidant was also shown to be catalysed with NHPI analogues.
Entry
2 [R1, R2, R3, R4]
R5
4
Yield (%)a
ee (%)b
In recent years, N-hydroxyphthalimide (NHPI, Fig. 1) has been
recognized as a valuable catalyst for the aerobic oxidation of
organic compounds under mild conditions.1 Molecular oxygen,
which is environmentally benign and economical, would be
an ideal oxidant for the oxygenation of hydrocarbons. These
oxidations proceed via a phthalimide N-oxyl (PINO) radical
intermediate which is able to abstract hydrogen atoms from
organic compounds.2 The newly formed carbon centered radical
then readily reacts with molecular oxygen to give oxygenated
compounds. However, PINO is not stable under aerobic oxidation
conditions.2c,e
1
2
3
4
2a [Cl, Cl, H, H]
2a [Cl, Cl, H, H]
2b [H, H, Cl, Cl]
2b [H, H, Cl, Cl]
Me
Ph
Me
Ph
4a
4b
4c
4d
86
85
83
84
92
12
64
87
a Isolated yield. b Chiral HPLC.
oxidations. Herein, we report a new class of NHPI analogues
4a–d (Table 1), which were derived from anthrones. They were
investigated as catalysts for the asymmetric aerobic oxidation of
various organic compounds.
The Brønsted-basic bicyclic guanidine 1 has been reported by
our group to be an efficient catalyst for enantioselective Diels–
Alder reactions between various anthrones and activated olefins.4
It led us to evaluate 1 as a catalyst for the reactions of substituted
anthrones 2a–b with protected N-hydroxymaleimides 3a–b. High
enantioselectivity and high yield were achieved for adduct 4a
(Table 1, entry 1). Substituted anthrones 2a–b were prepared
from the reduction of their corresponding anthracenediones5 while
the N-hydroxymaleimides 3a–b were prepared from the retro-
Diels–Alder reaction of N-hydroxy-3,6-epoxy-1,2,3,6-tetrahydro-
phthalimide.6 The subsequent cleavage of the protecting group
from 4a was carried out by treatment with ethylamine in MeOH
to yield the anthrone-derived NHPI analogue 5 (Scheme 1).
Fig. 1 N-Hydroxyphthalimide (NHPI) and phthalimide N-oxyl (PINO)
radical intermediate.
It is likely that a suitably designed chiral analogue of NHPI
should be of value for asymmetric catalysis. Einhorn et al.
reported the synthesis of axially chiral analogues of NHPI.3a
These analogues gave oxygenated products with moderate enan-
tioselectivities in several catalytic asymmetric oxidation reactions,
such as the desymmetrisation of 2-substituted indanes and the
kinetic resolution of racemic acetals. A second generation of C2-
symmetrical NHPI analogues based on diphenol was subsequently
developed and demonstrated to give moderate to high enantios-
electivities for the oxidative ring opening reactions of various N-
acyl oxazolidines.3b The enantioselectivities were highly dependent
on the substitution pattern of the catalysts. Such catalysts could
be useful for the synthesis of highly enantiomerically enriched
oxazolidines. These experiments represent the first examples
of chiral NHPI analogues catalysing enantioselective aerobic
Scheme 1 Synthesis of chiral anthrone-derived NHPI analogues.
A variety of benzylic compounds can be oxidised to their
corresponding oxygenated derivatives by molecular oxygen in the
presence of NHPI.7 When NHPI was replaced by racemic 5 in
some preliminary oxidation experiments, very similar results were
obtained. This indicated that 5 has the desired catalytic properties.
With optically pure 5 in hand, we attempted several asymmetric
Department of Chemistry, 3 Science Drive 3, National University of
Singapore, Singapore, 117543. E-mail: chmtanch@nus.edu.sg
† Electronic supplementary information (ESI) available: Experimental,
characterization of the oxidation products and NMR spectra. See DOI:
10.1039/b812351a
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oxidation reactions of benzylic compounds and a diol with 5 and
cobalt acetate as the co-catalyst.
intend to develop several other aerobic oxidation reactions using
our anthrone-derived NHPI analogues as catalysts. Subsequent
exploratory work was carried out using racemic catalyst 14
(Fig. 2).
The aerobic oxidation of 0.2 M of acenaphthene 6 in CH3CN
at 60 ◦C in the presence of 10 mol% of optically enriched
5 (92% ee) and Co(OAc)2 (1 mol%) gave alcohol 7a in 42%
yield. Asymmetric induction was negligible (4% ee) (eqn (1))
and significant over-oxidation was observed, leading to 35%
yield of acenaphthylen-1(2H)-one 7b. Indane is readily oxidised
to 1-indanone in good yield by NHPI-mediated oxidation.3,7
Indanes bearing two different substituents on C2 are interesting
substrates for asymmetric oxidations as they have two enantiotopic
benzylic carbons. Using similar reaction conditions, 2-methoxy-2-
phenylindane 8 was oxidised to ketone 9 in 48% yield and 8% ee
(eqn (2)). A slightly better result was observed with ethylbenzene
10. It was oxidised to 1-phenylethanol 11a in good yield and
13% ee (eqn (3)). Over-oxidation was also appreciable and 30%
of acetophenone 11b was obtained.
The proposed mechanism for the NHPI–O2–Co(II) oxidation
system suggests that the oxidation of NHPI to PINO is achieved
with a Co(III)peroxy-radical specie that was generated from the
Co(II) and O2.8 The PINO is responsible for abstracting the
benzylic hydrogen before the insertion of another molecule of O2
at that position. A non-zero enantioselectivity for the reactions
discussed above (eqn (1)–(4)) may indicate the formation of
relatively tight complexes between chiral NHPI–PINO derivatives
and the benzylic radical specie, possibly through non-covalent
interactions; the insertion of O2 should also be a rapid process.
Fig. 2 Racemic anthrone-derived NHPI catalyst 14.
Addition of aldehydes to terminal alkenes is an unique method
for the preparation of ketones.10 Direct hydroacylation of terminal
alkenes with aldehydes by transition-metal catalysts has been
reported (eqn (5)).10 The concomitant introduction of acyl or
hydroxy moieties to alkenes, referred to as hydroxyacylation, can
be achieved by a cascade reaction (eqn (6)). This provides a novel
route to b-hydroxy carbonyl compounds. Acyl radicals11 can easily
decarbonylate and react with O2 leading to carboxylic acids and
other undesired products.12 To overcome these drawbacks, 1,3-
dioxolanes were often employed as masked aldehydes and as the
source of the acyl group.13,14 Deprotection of the product, a b-
hydroxy ketal, under acidic conditions will provide the b-hydroxy
carbonyl compounds.
(5)
(1)
(6)
A mixture of 1,3-dioxolane 15a and methyl acrylate 16a was
allowed to react under O2 (1 atm) in the presence of catalyst 14
(10 mol%) and a small amount of Co(OAc)2 (1 mol%) at room
temperature for 5 h (Table 2, entry 1). The b-hydroxy ketal 17a
was obtained in 60% yield. Acrylonitrile 16b was also found to
serve as a good acceptor for 15a, giving cyanohydrin 17b in good
yield (entry 2). 2-Methyl-1,3-dioxolane 15b, also provided the
corresponding hydroxy-acylated products 17c–d in good yields
(entries 3 and 4).
(2)
(3)
a-Hydroxy-g-lactones are valuable synthetic precursors to
compounds such as a,b-butenolides, which have potent biological
activities.15 They are also useful as monomers of biodegradable
polymers and as fine chemicals. Ishii et al. reported the catalytic
generation of an a-hydroxy carbon radical using NHPI in
(4)
Table 2 Hydroxyacylation of alkenes using 1,3-dioxolanes and dioxygen
It has been shown that NHPI in combination with Co(II)
salts is also an efficient method for the oxidation of alcohols
to their corresponding carbonyl compounds.9 Our experiments
with compounds 6, 8 and 10 also demonstrated that the 5–Co(II)
catalyst system is able to oxidise alcohols with ease under mild
conditions. 1,2-Diphenylethanediol 12 was oxidised to benzoin
13a in 45% yield and 10% ee with 32% of the over-oxidised product,
benzil 13b (eqn (4)). Optimisation of the reaction may be possible
through the variation of reaction temperature and reaction time.
The chiral induction in the previous oxidation reactions was
moderate. However, these results clearly indicate that asym-
metric catalysis mediated by optically active 5 is possible. We
Entry
10 [R1]
Y
4
Yield (%)a
1
2
3
4
15a [H]
15a [H]
15b [Me]
15b [Me]
16a [CO2Me]
16b [CN]
16a [CO2Me]
16b [CN]
17a
17b
17c
17d
60
56
58
52
a isolated yield.
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combination with cobalt acetate under O2 (1 atm).16 Trapping the
generated radicals with a,b-unsaturated esters leads to a-hydroxy-
g-lactones which are difficult to obtain by conventional methods.
This new method for the construction of a-hydroxy-g-lactones is
general for a variety of alcohols and a,b-unsaturated esters.
Catalyst 14–Co(OAc)2 was employed in the radical reaction
between isopropyl alcohol 18 and methyl acrylate 16a under O2
(1 atm). This reaction occurred at room temperature to give 19 in
65% yield in 8 h (eqn (7)).
2 (a) R. Arnaud, A. Milet, C. Adamo, D. Einhorn and J. Einhorn,
J. Chem. Soc., Perkin Trans. 2, 2002, 1967–1972; (b) R. Amorati,
M. Lucarini, V. Mugnaini, G.-F. Pedulli, F. Minisci, F. Recupero, F.
Fontana, P. Astolfi and L. Greci, J. Org. Chem., 2003, 68, 1747–1754;
(c) N. Koshino, B. Saha and J. H. Espenson, J. Org. Chem., 2003, 68,
9364–9370; (d) N. Koshino, Y. Cai and J. H. Espenson, J. Phys. Chem.
A, 2003, 107, 4262–4267; (e) B. Saha, N. Koshino and J. H. Espenson,
J. Phys. Chem. A, 2004, 108, 425–431.
3 (a) C. Einhorn, J. Einhorn, C. Marcadal-Abbadi and J.-L. Pierre, J.
Org. Chem., 1999, 64, 4542–4546; (b) M. Nechab, D. N. Kumar, C.
Philouze, C. Einhorn and J. Einhorn, Angew. Chem., Int. Ed., 2007, 46,
3080–3083.
4 J. Shen, T. T. Nguyen, Y.-P. Goh, W. Ye, X. Fu, J. Xu and C.-H. Tan, J.
Am. Chem. Soc., 2006, 128, 13692–13693.
5 H. Prinz, W. Wiegrebe and K. Mu¨ller, J. Org. Chem., 1996, 61, 2853–
2856.
(7)
6 M. Akiyama, K. Shimizu, S. Aiba and F. Banba, J. Chem. Soc., Perkin
Trans. 1, 1980, 2122–2125.
In conclusion, we have developed an enantioselective synthesis
of anthrone-derived NHPI analogues. One of these analogues,
in combination with Co salts, was employed to catalyse the
aerobic oxidation of benzylic compounds and diols. However,
low enantioselectivities were observed. Exploratory studies using
a racemic version of the catalyst were also conducted. Radical
addition of dioxolanes or alcohols to activated alkenes with
molecular oxygen as the terminal oxidant was shown to be
catalysed with the NHPI analogues. Asymmetric versions of these
reactions will be investigated.
7 (a) Y. Ishii, K. Nakayama, M. Takeno, S. Sakaguchi, T. Iwahama and
Y. Nishiyama, J. Org. Chem., 1995, 60, 3934–3935; (b) C. Einhorn, J.
Einhorn, C. Marcadal and J. L. Pierre, Chem. Commun., 1997, 447–
448; (c) M. Nechab, C. Einhorn and J. Einhorn, Chem. Commun., 2004,
1500–1501; (d) G. Yang, Q. Zhang, H. Miao, X. Tong and J. Xu, Org.
Lett., 2005, 7, 263–266.
8 C. Annunziatini, M. F. Gerini, O. Lanzalunga and M. Lucarini, J. Org.
Chem., 2004, 69, 3431–3438.
9 (a) T. Iwahama, S. Sakaguchi, Y. Nishiyama and Y. Ishii, Tetrahedron
Lett., 1995, 36, 6923–6926; (b) T. Iwahama, Y. Yoshino, T. Keitoku,
S. Sakaguchi and Y. Ishii, J. Org. Chem., 2000, 65, 6502–6507; (c) F.
Rajabi and B. Karimi, J. Mol. Catal. A: Chem., 2005, 232, 95–99.
10 C.-H. Jun, J.-B. Hong and D.-Y. Lee, Synlett, 1999, 1, 1–12.
11 C. Chatgilialoglu, D. Crich, M. Komatsu and I. Ryu, Chem. Rev., 1999,
99, 1991–2070.
Acknowledgements
12 T. Punniyamurthy, B. Bhatia and J. Iqbal, J. Org. Chem., 1994, 59,
850–853.
This work was supported by grants (R-143-000337-112 and R-
143-000-342-112) and a scholarship (to JS) from the National
University of Singapore. Financial support from the Medicinal
Chemistry Program is also acknowledged.
13 (a) H.-S. Dang and B. P. Roberts, Tetrahedron Lett., 1999, 40, 8929–
8933; (b) A. Gross, L. Fensterbank, S. Bogen, R. Thouvenot and M.
Malacria, Tetrahedron, 1997, 53, 13797–13810.
14 (a) K. Hirano, T. Iwahama, S. Sakaguchi and Y. Ishii, Chem.
Commun., 2000, 2457–2458; (b) T. Kagayama, S. Sakaguchi and Y.
Ishii, Tetrahedron Lett., 2005, 46, 3687–3689.
15 (a) Y. S. Rao, Chem. Rev., 1976, 76, 625–694; (b) H. M. R.
Hoffman and J. Rabe, Angew. Chem., Int. Ed. Engl., 1985, 24, 94–
110.
Notes and references
1 (a) Y. Ishii, S. Sakaguchi and T. Iwahama, Adv. Synth. Catal., 2001,
343, 379–427; (b) F. Recupero and C. Punta, Chem. Rev., 2007, 107,
3800–3842.
16 T. Iwahama, S. Sakaguchi and Y. Ishii, Chem. Commun., 2000, 613–
614.
4098 | Org. Biomol. Chem., 2008, 6, 4096–4098
This journal is
The Royal Society of Chemistry 2008
©