L-Proline derived mimics of the non-haem iron active site catalyse allylic oxidation in acetonitrile solutions

Article abstract of DOI:10.1016/j.tetlet.2012.12.095

Non-haem iron complexes are important reagents for the oxidative functionalisation of C-H bonds. Peptidomimetic ligands derived from l-proline, pyridine-2,6-dimethanol and pyridine-2,6-dicarboxylic acid have been combined with iron(II) triflate and hydrogen peroxide in acetonitrile. The resulting complexes convert cyclohexene into the allylic oxidation products, 2-cyclohexen-1-ol, 2-cyclohexen-1-one and 2-cyclohexenyl hydroperoxide in high turnover yields. A mechanism for product formation is proposed, in which the hydroperoxy radical (HOO) is the active oxidant.

Full text of DOI:10.1016/j.tetlet.2012.12.095

Tetrahedron Letters 54 (2013) 1236–1238
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
L-Proline derived mimics of the non-haem iron active site catalyse allylic
oxidation in acetonitrile solutions
⇑
Victoria J. Dungan, Belinda M.-L. Poon, Elizabeth S. Barrett, Peter J. Rutledge
School of Chemistry F11, The University of Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 May 2012
Revised 14 December 2012
Accepted 20 December 2012
Available online 29 December 2012
Non-haem iron complexes are important reagents for the oxidative functionalisation of C–H bonds.
Peptidomimetic ligands derived from L-proline, pyridine-2,6-dimethanol and pyridine-2,6-dicarboxylic
acid have been combined with iron(II) triflate and hydrogen peroxide in acetonitrile. The resulting
complexes convert cyclohexene into the allylic oxidation products, 2-cyclohexen-1-ol, 2-cyclohexen-1-
one and 2-cyclohexenyl hydroperoxide in high turnover yields. A mechanism for product formation is
Å
proposed, in which the hydroperoxy radical (HOO ) is the active oxidant.
Keywords:
Biomimetic chemistry
Catalysis
Ó 2012 Elsevier Ltd. All rights reserved.
C–H activation
Non-haem iron
Oxidation
Synthesis
The development of efficient, selective and environmentally be-
nign methods for the functionalisation of C–H bonds is an area of
considerable current interest.1 Iron has emerged as a key player
in this field due to its availability, affordability and capacity to
promote a range of oxidative chemistry.1 The ability of iron com-
plexes to drive oxidative transformations has long been apparent
in nature, where haem and non-haem iron enzymes catalyse reac-
tions including oxidative cyclisation, desaturation, hydroxylation,
epoxidation and dihydroxylation.5
substantial increase in the overall efficiency of oxidative turnover.
Alcohol 4 is tetradentate, so binding to iron should leave two
coordination sites available for oxidant binding, an arrangement
that mirrors oxygen binding at the non-haem iron active site.5
Ligands 5 and 6 are designed to bind iron in a pentadentate
manner, leaving one vacant site to be occupied by the oxidant.
Klein Gebbink and co-workers have observed this coordination
geometry crystallographically in complexes of diester 7.1
–3
,18
,4
9,20
,6
The combination of iron(II), ligand and hydrogen peroxide can
generate a number of possible oxidation products from cyclohex-
ene 8, via two general pathways (Scheme 1): biomimetic oxidation
reactions mediated by an iron–ligand complex to form the cis-diol
9 and/or epoxide 10 via high-valent iron-oxo intermediates (Path
Inspired by the biological example, chemists have used the non-
haem iron active site 1 as the starting point for the design of
effective iron-centred oxidation catalysts.5
–12
Amongst the most
effective of these biomimetic systems in the context of C–H activa-
tion are those based upon neutral, multidentate amine ligands
2
1–23
A);
or competing reactions via radical mechanisms affording
9
such as tris(2-pyridylmethyl)amine (TPA), pyridine-substituted
the allylic oxidation products, alcohol 11, ketone 12 and hydroper-
,4,7-triazacyclononane (TACN)10 and 2-({2-[1-(pyridin-2-ylmethyl)
oxide 13 (Path B).
24
1
12
pyrrolidin-2-yl]pyrrolidin-1-yl}methyl)pyridine (PDP).
Ligands 4–6 have limited solubility in acetonitrile, so iron com-
We have previously utilised ligands 2–5 (Fig. 1) in combination
with iron(II) acetate, hydrogen peroxide and methanol as the
solvent to convert alkenes into oxidised products in low to moder-
plexes were prepared by combining the ligands with iron(II) tri-
2 3 2
flate [Fe(OTf) Á(CH CN) ] in anhydrous methanol and removing
the solvent in vacuo. The resulting complexes were then dissolved
in acetonitrile, in which they were readily soluble. Oxidative
turnover reactions were carried out by introducing the substrate,
cyclohexene (1000 equiv, used in excess to minimise over-oxida-
tion of initial oxidation products and protect the catalyst from
oxidative degradation) followed by slow addition of hydrogen
1
3–17
ate yields.
Here we report that the reactivity of these ligands is
significantly enhanced when used with iron(II) triflate in acetoni-
trile solution: this change of iron salt and solvent renders a
⇑
Corresponding author.
E-mail address: peter.rutledge@sydney.edu.au (P.J. Rutledge).
peroxide (10 equiv of
30 min). The reaction was stirred at room temperature overnight
a 30% aqueous solution, added over
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.095

V. J. Dungan et al. / Tetrahedron Letters 54 (2013) 1236–1238
1237
X
O
N
HO
HO
O
N
X
R1
2
His
Fe
Asp
O
O
CO
2
Li
CO
N
HO
Ph
2
H N
2
N
N
CO R
2
OH
2
N
N
Et
N
Ph
N
N
N
OH
N
HN
Ph
Ph
His
1
2
1
2
3
4
5 R = R = Li
6
7
1
2
R = Me, R = Li
1
2
R = R = Me
Figure 1. Generalized non-haem iron active site 1 (X = solvent or substrate-derived ligand) and ligand architectures 2–7 designed to mimic non-haem iron oxidase structure
and function.
OH
OH
O
O
OH
OH
Path A
Path B
+
O
+
+
9
10
8
11
12
13
Scheme 1. Potential oxidation products from turnover of cyclohexene 8: Path A is biomimetic oxidation to give cis-cyclohexane-1,2-diol 9 and/or cyclohexene oxide 10. Path
B is Fenton-type reactivity to allylic oxidation products alcohol 11, ketone 12 and hydroperoxide 13.
under argon (to exclude molecular oxygen).25 Reaction products
were isolated from the mixture and analysed by gas chromatogra-
phy (Table 1).
Ligands 4–6 all combine with iron(II) triflate to convert cyclo-
hexene into oxidised products (alcohol 11, ketone 12 and hydro-
peroxide 13) at levels well above the ligand-free combination of
iron(II) triflate and hydrogen peroxide. Neither diol 9 nor epoxide
iron(III)–alkylperoxo complex (LnFe –OOR) formed transiently
III
2
0
from diester 7, iron(II) and tert-butyl hydroperoxide. The iron(III)-
peroxo intermediate 14 can break down via four different pathways
givingrisetofivepossibleoxidants(Scheme2):theiron–hydroperoxy
intermediate L Fe –OOH 14; the hydroperoxy radical OOH; the
n
hydroxy radical OH; an iron(IV)-oxo species L
2
6
III
Å
Å
IV
n
Fe =O (15); or an
V
34
iron(V)-oxo species L
n
Fe =O (16). The nature of L dictates which
n
1
0 were observed under these conditions. Overall levels of product
of these pathways predominates, and thus controls the overall
outcome of the reaction.
With cyclohexene as substrate, iron–hydroperoxy 14, iron(IV)-
oxo 15 and iron(V)-oxo 16 species should all react to some extent
formation with ligands 4 and 5 were considerably higher than pre-
viously achieved using iron(II) acetate and methanol: under those
conditions, ligand 4 gave an overall yield of 31% (9:11:12,
2
(
%:7%:22%), while with ligand 5 the overall yield was 52%
with the p system of the alkene to give diol and/or epoxide prod-
9:11:12, 4%:6%:42%).16
ucts. Diol 9 and epoxide 10 were not observed in reactions of
4(Fe)–6(Fe) with cyclohexene 8 in acetonitrile, indicating that 14,
15 and 16 are not active oxidants in this system. Instead it seems
The allylic oxidation of cyclohexene to similar product combi-
nations of 11, 12 and 13 has previously been achieved using hydro-
gen peroxide or molecular oxygen with various transition metal
that L
n
Fe–OOH 14 breaks down via homolysis of the Fe–O bond
27
28
Å
catalysts including vanadium–pyrazine,
manganese–TACN,
(Scheme 2, path a). But which of the hydroperoxy radical ( OOH)
and hydroxy radical ( OH) is the active oxidant? Both these species
copper–cyclam, cobalt–salen and iron–porphyrin31 complexes.
2
9
30
Å
Several iron-based catalysts have also been shown to form similar
combinations of the corresponding hydroperoxide, alcohol and ke-
are capable of abstracting the relatively weak allylic C–H in
À1
cyclohexene
(HOO–H) = 367 kJmol
[
D
H
DBE(C–H) = 351 kJmol
,
compared to
D
H
DBE
À1 35,36
tone products from cyclohexane.3
2,33
These reactions are generally
À1
and
DHDBE(HO–H) = 497 kJmol ].
Å
thought to be mediated by hydroxy ( OH) and/or hydroperoxy
OOH) radicals.
In the non-haem iron context, an iron complex (L
ide oxidant first form an iron-peroxo intermediate (L
4). Klein Gebbink and coworkers have observed the corresponding
The hydroxy radical can drive the corresponding reaction with
Å
À1
(
cyclohexane [
D
H
DBE(C–H) = 400 kJmol ] whereas the hydroper-
II
n
Fe ) and perox-
oxy radical cannot. Subjecting cyclohexane to reaction with 4(Fe)
or 5(Fe) and hydrogen peroxide under analogous conditions affords
cyclohexanol and cyclohexanone at levels equal to or below those
observed in control experiments without ligand [hydrogen perox-
ide/iron(II) triflate; data not shown]. Thus we propose that the
III
n
Fe –OOH,
3
4
1
Table 1
Å
hydroperoxy radical OOH is the primary oxidant in these systems:
Oxidation of cyclohexene by iron triflate complexes of ligands 4–6 in acetonitrile
in acetonitrile solution, the iron(II) triflate complexes of ligands
Entry
Liganda,b
11c,d (%)
12c,d (%)
13c,d (%)
Total yield (%)
4–6 catalyse the formation of hydroperoxy radicals from hydrogen
1
2
3
4
5
6
—
16
17
33
15
21
29
45
9
49
52
0
86
98
78
34
peroxide, and these reactive species drive the turnover of
e
4
10
1
2
O
2
a
Initial ratio catalyst:H
more details.
2
O
2
:substrate = 1:10:1000. See Supplementary data for
FeII
HO
L
L
n
+
HOO
b
a
d
b
Catalyst prepared in situ from ligand and iron(II) triflate in methanol; methanol
was then removed, the complex dissolved in acetonitrile, and the reaction run in
L
n
FeIII OOH
c
FeIV O + HO
15
n
1
4
acetonitrile.
c
Percentage yield relative to H
2 2
O , the limiting reagent. Turnover number (lmol
LnFeV
+
O HO
product produced per
lmol catalyst) can be derived by dividing these percentage
1
6
yields by 10. Percentage conversion of alkene = percentage yield/100.
d
Values shown are the averages of three repetitions.
Control experiments using only iron(II) salt and H
FeIII intermediate 14, which
n
Scheme 2. Potential breakdown pathways for the L
give rise to five potential oxidants in non-haem iron systems.
e
2
O
2
(i.e. no ligand).
34

1
238
V. J. Dungan et al. / Tetrahedron Letters 54 (2013) 1236–1238
O
OH
III
8
17
e
nF
L
II
e
nF
L
1
8
11
OH
OH
H
O
HOO HOOH
14
or
HOO
8
17
1
3
O
L
O
OH
O
n
F
e
III
O
-
H O
2
Ln
F
e
II
+
+ O
2
19
12
19
11
12
Å
Å
Scheme 3. Potential routes for formation of 11, 12 and 13 from cyclohexene 8: Abstraction of H from 8 by the hydroperoxy radical OOH would give 17, which could be
converted into hydroperoxide 13 by either a second hydroperoxy radical or complex 14. Redox conversion of 13 into 11 and 12 could proceed via intermediates 18 and 19,
37,38
with the iron complex functioning to decompose the hydroperoxide as observed by Gray and co-workers with porphyrin and salen complexes of iron.
ketone 12 may also arise from 13 via elimination of water.
Alternatively
3
9,40
cyclohexene to the alcohol 11, ketone 12 and hydroperoxide 13
products observed, via intermediates 17–19 (Scheme 3).
In conclusion, the iron(II) triflate complexes of non-haem li-
gands 4–6 catalyse high levels of oxidative turnover of cyclohexene
18. A new route to compound 4 was developed starting from pyridine-2,6-
dicarboxylic acid. Our previous synthesis starting from pyridine–2,6-
dimethanol is more direct (two steps vs five to the key bromide
intermediate), but the overall yields of that intermediate are almost identical
(43.7% vs 43.1%) and the diacid starting material is significantly cheaper than
the diol. For more details see the Supplementary data.
8
into the alcohol 11, ketone 12 and hydroperoxide 13 in acetoni-
19. Gosiewska, S.; Cornelissen, J. J. L. M.; Lutz, M.; Spek, A. L.; van Koten, G.; Klein
Å
trile solutions. We propose that the hydroperoxy radical OOH is
the primary oxidant and that hydroperoxide 13 is a common inter-
mediate in the formation of 11 and 12. Further work (including ki-
netic studies, spectroscopic characterisation of intermediates and
Gebbink, R. J. M. Inorg. Chem. 2006, 45, 4214–4227.
20. Gosiewska, S.; Permentier, H. P.; Bruins, A. P.; Koten, G. V.; Klein Gebbink, R. J.
M. Dalton Trans. 2007, 3365–3368.
21. Rohde, J. U.; In, J. H.; Lim, M. H.; Brennessel, W. W.; Bukowski, M. R.; Stubna, A.;
Munck, E.; Nam, W.; Que, L. Science 2003, 299, 1037–1039.
22. Martinho, M.; Blain, G.; Banse, F. Dalton Trans. 2010, 39, 1630–1634.
1
8
experiments with H
2
O
2
) is required to confirm this proposal
23. Lee, Y.-M.; Hong, S.; Morimoto, Y.; Shin, W.; Fukuzumi, S.; Nam, W. J. Am. Chem.
Soc. 2010, 132, 10668–10670.
and to fully elucidate the mechanism of these transformations.
2
4. Sawyer, D. T.; Sobkowiak, A.; Matsushita, T. Acc. Chem. Res. 1996, 29, 409–416.
Acknowledgment
25. Representative turnover procedure: iron(II) triflate (31 mg, 0.07 mmol) was
dissolved in degassed, dry MeOH (1.2 mL). A portion (0.2 mL) of this solution
was added via cannula to a solution of ligand (4 mg, 0.01 mmol) in MeOH
This work was supported by a Bridging Support Grant from the
University of Sydney.
(
0.2 mL) under argon. The resultant orange solution was stirred for 1 h at room
temperature under an atmosphere of argon, after which time the MeOH was
removed under vacuum to give the resulting complex as a brown oil. This oil
was redissolved in MeCN (10 mL) and cyclohexene (1.01 mL, 10 mmol) was
Supplementary data
2 2 2
added. H O (30% solution in H O, 13 lL, 0.1 mmol) in MeCN (1 mL) was added
over 30 min via syringe pump. The solution was stirred at room temperature
under argon for 16 h, then concentrated in vacuo, diluted with EtOAc and
passed through a short silica column. Decane was added as an internal
standard and the products were analysed by gas chromatography.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
1
2.095. These data include MOL files and InChiKeys of the most
26. Samples were analysed on a Hewlett-Packard 5890 Series II gas chromatograph
using an HP-1 ms column (30 m  0.25 mm ID, 0.25
and Hewlett-Packard 5890A gas chromatograph with
25 m  0.22 mm ID, 0.25 m), each equipped with a split/splitless capillary
l
m; S/N US2469051H)
important compounds described in this article.
a
a
BP-20 column
(
l
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