An iron catalyst for oxidation of alkyl C-H bonds showing enhanced selectivity for methylenic sites

Article abstract of DOI:10.1002/chem.201203281

Many are called but few are chosen: A nonheme iron complex catalyzes the oxidation of alkyl C-H bonds by using H₂O₂ as the oxidant, showing an enhanced selectivity for secondary over tertiary C-H bonds (see scheme). Copyright

Full text of DOI:10.1002/chem.201203281

DOI: 10.1002/chem.201203281
À
An Iron Catalyst for Oxidation of Alkyl C H Bonds Showing Enhanced
Selectivity for Methylenic Sites
Irene Prat, Laura Gꢀmez, Mercꢁ Canta, Xavi Ribas, and Miquel Costas*[a]
À
The selective functionalization of aliphatic C H bonds re-
mains one of the biggest challenges for modern synthetic
chemistry.[1] Despite being traditionally considered as inert,
À
alkyl C H bonds have been shown to exhibit distinct rela-
tive reactivity responding to innate electronic and steric fac-
tors.[2] Reagents and catalysts that engage in selective alkyl
À
C H bond oxidation reactions, without the aid of covalent
interactions, and that do not require excess substrate, are
quite exclusive,[3,4] and they generally show selectivity pat-
terns determined by this innate relative reactivity.[2] A par-
ticularly challenging problem is to find catalysts that over-
come this inherent bias in reactivity and oxidize methylenic
À
sites in the presence of more reactive tertiary C H
Scheme 1. Schematic representation of selected iron catalysts.
bonds.[4c,d] Nonactivated methylene sites are ubiquitous in
À
organic molecules, but their strong C H bond cannot be
À
oxidized by most of the traditional reagents employed in C
alyst affords analogous yields to 1 under substantially lower
catalyst loadings.
H oxidation, which instead operate in weaker sites such as
À
tertiary C H bonds or activated methylene sites (for exam-
ple, benzylic, or adjacent to a heteroatom).
Herein we describe an iron complex based on the triaza-
cyclononane ring [FeACTHNGUTERNNUG
(CF3SO3)2(Me,MePytacn)] (Me,MePytacn=
Nonheme iron oxygenases constitute a source of inspira-
1-(6-methyl-2-pyridylmethyl)-4,7-dimethyl-1,4,7-triazacyclo-
[5]
tion for the development of C H oxidation catalysts. This
nonane; 3Me,Me, Scheme 1) as a structurally distinct contribu-
À
À
class of enzymes exhibits a diverse reactivity, chemo-, regio-,
tion to the portfolio of iron complexes for preparative C H
À
and stereoselectivity in C H oxidation reactions, which
oxidation reactions. Most significantly, it exhibits a unique
enhanced preference for oxidizing methylenic sites, which
hints at the possibility of developing “enzymelike” iron-
based catalysts, with distinct electronic and/or spatial archi-
tectures, which could translate into novel selectivities. Fur-
thermore, the availability and lack of toxicity of this element
are especially attractive for catalysis.[6] However, despite of
À
expands the versatility of iron-based C H oxidation meth-
odologies.
ACTHNUTRGNEUNG
Complexes of general formula [FeII(CF3SO3)2(R,R’Pytacn)],
(Scheme 1) have been described as models for nonheme
the large number of studies devoted to iron-catalyzed C H
iron dependent oxygenases.[10] Experiments were devised to
À
oxidations,[7] synthetically useful yields in stereospecific oxi-
dation have been exclusively attained with two structurally
investigate whether these complexes could catalyze C H hy-
À
droxylation on a preparative scale. Towards this end, cis-4-
methylcyclohexyl-1-pivalate was chosen as a model sub-
strate, because it allows a fair comparison with the Fe cata-
lysts previously described.[8,9] Following a broad screening of
complexes (see Supporting Information), 3Me,Me was identi-
related catalysts, [Fe
bis(2-pyridylmethyl)-2,2’-bipyrrolidine) was described in the
pioneering work of White et al.[8] [Fe
(CF3SO3)2A(mcpp)], (2)
ACHTUNGNERT(NUNG CH3CN)2ACHTUNRTGE(NNGUN pdp)]ACTHUNGRTNE(NUGN SbF6)2 (pdp=N,N’-
A
CHTUNGTRENNUNG
(mcpp=N,N’-dimethyl-N,N’-bis{[(R)-4,5-pinenepyridin-2-yl]-
methyl}cyclohexane-1,2-diamine; Scheme 1) was developed
by us by introducing sterically demanding groups at the
ligand that provide isolation to the iron site.[9] The latter cat-
À
fied as an exceptional catalyst, providing C H oxidation
products in good yields. After optimization, best results
were obtained by using 3 mol% of catalyst, 3.6 equivalents
of H2O2 and 1.5 equivalents of acetic acid (Table 1, entry 3).
Under these conditions, the tertiary alcohol was obtained
in 54% yield, >95% cis. The reaction is thus stereospecific.
Interestingly, the yield attained with 3Me,Me is only improved
with the highly elaborated catalyst 2 (Table 1, entry 5).
Other oxidants (tert-butyl hydrogen peroxide (TBHP),
Oxone and peracetic acid; Table 1, entries 6–8) that have
found use in iron-based oxidation catalysis were also tested.
[a] I. Prat, Dr. L. Gꢀmez, M. Canta, Dr. X. Ribas, Dr. M. Costas
Departament de Quꢁmica
Universitat de Girona
Campus de Montilivi, 17071, Girona (Spain)
Fax : (+34)972418150
E-mail: miquel.costas@udg.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203281.
1908
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Chem. Eur. J. 2013, 19, 1908 – 1913

COMMUNICATION
Table 1. Oxidation of cis-4-methylcyclohexyl pivalate by different cata-
dation of these three substrates and account for 4–13%
yield.
lysts.[a]
Oxidation of the methylene site in simple cycloalkanes
(Table 2, entries 5 and 6) was also accomplished, affording
the corresponding ketone products in 54–62% yields, pre-
sumably by means of a 2-step oxidation involving initial for-
mation of the corresponding alcohol, which is also obtained
in minor amounts. In agreement with this proposal, submit-
ting cyclohexanol to the standard experimental conditions
yielded cyclohexanone quantitatively. A more challenging
linear alkane such as n-hexane is also oxidized to a 1:1 mix-
ture of corresponding C2 and C3 ketones in a remarkable
57% combined yield (Table 2, entry 10). On the other hand,
methylene oxidation is sensitive to the electronic properties
Entry
Cat.
Cat. [mol%]/
Oxidant [equiv]/
AcOH [equiv]
Oxidant
A [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3Me,Me
3Me,Me
3Me,Me
1
1:1.2:0.5
(1:1.2:0.5)x3
3:3.6:1.5
3:3.6:1.5
3:3.6:1.5
H2O2
H2O2
H2O2
H2O2
31
51
54[d]
53
64
44
6
23
39
51
23
54
52
19
9
2
H2O2
3Me,Me
3Me,Me
3Me,Me
3Me,Me
3Me,Me
3Me,Me
3Me,Me
3Me,Me
1
3:3.6:1.5
3:3.6:1.5
CH3CO3H
Oxone
tBuOOH
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
À
of the C H bonds. This is shown in the oxidation of methyl
3:3.6:1.5
3:3.6:1.5[c]
5:3.6:1.5
hexanoate (Table 2, entry 11), which afforded preferential
oxidation at the most remote, electron-rich methylene site.
Modest yet significant steric effects are illustrated in the oxi-
dation of methylenic sites of 1,1-dimethylcyclohexane
(Table 2, entry 12). Ketone resulting from oxidation at the
sterically more demanding C2 site is obtained in 19% yield,
while C3 and C4 ketones are obtained in 26 and 13% yields,
respectively. These numbers, normalized for the number of
1:3.6:1.5
(2:2.4:9.0)[c] (1:1.2:0.5)[e]
3:3.6:0
3:3.6:0
3:3.6:0
2
[a] Equivalents refer to substrate. The reaction was performed by slow
syringe-pump addition, over 30 min, of a solution of H2O2 in acetonitrile
of catalyst and substrate at 08C in acetonitrile. [b] GC yield. [c] Catalyst
and H2O2 were simultaneously added through two parallel syringe pumps
over 30 min, into a solution of substrate at 08C in acetonitrile. [d] Meth-
ylenic site oxidation products were also detected with 9% yield. [e] A
third addition of catalyst, H2O2, and acetic acid was made.
À
C H bonds, indicate that C3 and C4 are equally reactive,
and slightly preferred over C2.
À
Oxidation of C H bonds can also lead to products arising
from a competition between hydroxylation and desaturation
1
reactions. H NMR analysis of a crude reaction mixture ob-
tained after oxidation of 4-methyl valeric acid (Table 2,
entry 13) under standard experimental conditions showed
the presence of C4 alcohol (32% yield), and 4,4’-dimethyl-g-
butyrolactone (9%). These products arise from an initial hy-
droxylation at C4. Following workup, 4,4’-dimethyl-g-butyr-
olactone was isolated in 42% yield. Besides hydroxylation,
products derived from a desaturation reaction are also ob-
served and include 4-methylpent-4-enoic acid (2%), the cor-
responding C4–C5 epoxide (2%), and 4-hydroxymethyl-4-
methyl-g-butyrolactone (11%). These products can be un-
derstood by assuming an initial desaturation, epoxidation of
the resulting olefin, and then intermolecular lactonization
through epoxide ring opening to yield 4-hydroxymethyl-4-
methyl-g-butyrolactone. Interestingly, the desaturation/hy-
droxylation product ratio depends on the nature of the iron
catalyst; with 3Me,Me it is 1:3.5, but 1 yields a substantially
larger discrimination towards hydroxylation (1:6.4).[13] The
origin of these differences is not understood at present.
Comparison between the regioselectivity in the oxidation
of cis- and trans-4-methylcyclohexyl-1-pivalate (Table 2, en-
tries 7 and 8) provides an illustration of the role of strain re-
Of these, only peracetic acid provides comparable product
yields and selectivity with regard to H2O2. We therefore re-
stricted our study to H2O2 as the more attractive oxidant.
Sequential addition of the catalyst, or higher catalyst load-
ings are not necessary (Table 1, compare entries 2 and 10),
and therefore the experimental procedure is largely simpli-
fied with respect to 1[8] and 2.[9] A further fundamental dif-
ference between the reactivity of these last two catalysts and
3Me,Me is that acetic acid appears not to be strictly required
for efficient catalysis (Table 1, compare entries 13–15).
Acetic acid has been shown to be a key additive to enhance
product yields in Fe-catalyzed oxidations,[11] by promoting
III
[12]
À
fast O O heterolysis of Fe -OOH intermediates. The ex-
ceptional behavior exhibited by 3Me,Me suggests that O O
À
lysis is remarkably facile for this catalyst.
The oxidation of a series of substrates using the above-de-
fined experimental conditions are shown in Table 2. Com-
bined product yields (with respect to the initial substrate)
range from 28 to 63%, adding 3Me,Me to the exclusive family
of iron catalysts that may find application in chemical syn-
thesis. Oxidation of 2,6-dimethyloctane occurs preferentially
at the two tertiary sites with a modest combined yield of
24%. An additional 4% is ketone byproduct (Table 2,
entry 1). On the other hand, when halide or ester groups are
À
lease effects in conditioning C H site selectivity. The terti-
ary C4 alcohol and C3 ketone were obtained in 39 and 22%
respective yields. As recently shown by Baran and Eschen-
moser,[14] breakage of tertiary C H sites in equatorial posi-
À
À
present, oxidation occurs preferentially at the remote C H
tions of cyclohexane skeletons is facilitated by strain release.
À
bond in 29–35% yields (Table 2, entries 2–4). This indicates
that the oxidant has an electrophilic nature. Products result-
ing from methylene oxidation were also observed in the oxi-
In the absence of this factor, tertiary C H bonds in axial po-
sitions are stronger, and their oxidation can compete with
[14]
À
that of secondary C H sites.
Chem. Eur. J. 2013, 19, 1908 – 1913
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www.chemeurj.org
1909

M. Costas et al.
Table 2. Alkane oxidation reactions catalyzed by 3Me,Me [a]
Entry Substrate
Products (Yield [%])[c]
.
Entry Substrate
12
Products (Yield [%])[c]
1
2 X=Br
(29)
(4)
(6)
(10)
(12)
3 X=OAc
4 X=OPiv
5 c-C6H12
6 c-C8H16
(31)
33[d] (35)
3[d] (4)
10[d] (13)
c-C6H11OH (1)
c-C8H15OH (6)
c-C6H10O (62)
c-C8H14O (54)
13
7
8
14
15
9
16
17
[b]
10 n-C6H14
11
[a] Catalyst (3 mol%), H2O2/substrate/AcOH (equiv); 3.6:1:1.5. [b] GC yield, unless otherwise stated. [c] Catalyst (3 mol%), H2O2/substrate/AcOH; 5.0:1:1.5.
[d] Isolated yield. [e] 1H NMR yields, using mesitylene as internal standard. [f] Catalyst (3 mol%), H2O2/substrate/AcOH (equiv) 1.5:1:1.5.
À
Oxidation of more complex molecules, such as p-acetoxy-
menthane (Table 2, entry 9), serves to illustrate an unusual
rial counterparts. Consequently, oxidation at secondary C H
sites in trans-dimethylcyclohexane and trans-decalin may be
expected to be competitive with that at tertiary sites, provid-
ed the oxidant exerts some steric demand.[2,8b,14] Indeed,
when these substrates were submitted to the standard oxida-
tion protocol using 3Me,Me as catalyst, we determined a non-
À
enhanced selectivity for secondary C H sites. Oxidation
mediated by 3Me,Me furnishes an approximate 2:1 mixture of
the C1 tertiary alcohol (A), and the ketone (K) resulting
from selective oxidation of methylene C2, in a combined
48% yield. Instead, under analogous conditions, 1[8] and 2[9]
selectively hydroxylate the spatially most exposed tertiary
À
À
normalized tertiary/secondary ratio (SACTHUNRGTENN[UG 38C H]/SACHTUNGTRENNUNG[28C H]
oxidation products) of 24:76 for trans-1,2-dimethylcyclohex-
ane and 4:96 for trans-decalin. Therefore, products arising
from oxidation at the 28 site are largely dominant, and the
extent of this selectivity finds very limited precedents in the
literature.[4c–d] We speculate that the methyl group in the a-
position of the pyridine ligand exerts some steric demand in
close proximity to the iron site at which oxidation occurs,
which enhances preferential oxidation of the spatially more
accessible secondary site with regard to the sterically more
À
C H site (C1), and the ketone appears as minor product
(A/K ca. 5:1 for 1 and 19:1 for 2).
cis-1,2-Dimethylcyclohexane and cis-decalin are preferen-
tially oxidized by 3Me,Me at the tertiary site (normalized terti-
ary/secondary ratios of ca.12 and ca.15) in 53 and 43% re-
spective combined yields (Table 2, entries 14 and 16). On
the other hand, trans-dimethylcyclohexane and trans-decalin
(Table 2, entries 15 and 17) contain sterically more protected
À
À
À
tertiary C H bonds. In addition, breakage of these axial C
H bonds does not liberate strain in the cyclohexane ring,
and because of that they are less reactive than their equato-
crowded tertiary C H bonds.
The synthetic value of 3Me,Me as a catalyst for the oxidation
of methylene sites in complex organic molecules is illustrat-
1910
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Chem. Eur. J. 2013, 19, 1908 – 1913

À
Iron-Catalyzed C H Oxidation
COMMUNICATION
ed by the oxidation of terpenoid substrates. (À)-Ambroxide
À
contains two tertiary C H sites and 14 methylenic sites
À
(Scheme 2, top). However, methylenic C H bonds adjacent
to the ether moiety were expected to be preferentially oxi-
dized, because they are activated by hyperconjugation ef-
fects.[2,8b] Indeed, ester (+)-sclareolide, resulting from selec-
tive oxidation of the activated methylenic site was obtained
in 68% yield.
À
Scheme 3. Regioselective C H oxidation reactions of (+)-neomenthyl
esters catalyzed by 1, 2, and 3Me,Me
. [a] Cat/H2O2/substrate/AcOH
3:360:100:150. [b] Cat/H2O2/substrate/AcOH 3:200:100:150. [c] GC yield.
[d] Recovered starting material. [e] Yield of isolated product.
Oxidation of (+)-neomenthyl acetate by 1 provides a 1:1
À
mixture of alcohol and ketone, resulting from tertiary C H
oxidation at C3, and methylene oxidation at C2, respective-
ly, in a combined 44% yield. Related selectivity and yields
were obtained with pivalate and trifluoroacetate derivatives.
By employing catalyst 2 oxidation occurs preferentially at
À
Scheme 2. Selective C H oxidation of terpenoid substrates. Top) (À)-
Ambroxide. Bottom) (+)-Sclareolide. [a] Yield of isolated product.
[b] GC yield.
À
tertiary C H (4:1 <A/K <5:1). Most remarkably, oxidation
with 3Me,Me effectively reverses selectivity and preferentially
occurs at the methylene site. (1:4.5 <A/K <1:2).
A more complex case is the oxidation of (+)-sclareolide
(Scheme 2, bottom). In this case, electronic factors do not
The somewhat enhanced selectivity for methylenic sites
exhibited by 3Me,Me finds little precedent. In general, the rel-
À
À
particularly enhance any of the C H bonds, and tertiary
sites are sterically encumbered. Previous work on the oxida-
ative reactivity of alkyl C H bonds follows the order terti-
ary> secondary> primary, according to the relative strength
tion and halogenation of this substrate mediated by 1[8] and
of the C H bond. However, the steric crowding of C H
bonds also follow the order tertiary> secondary> primary,
and because of that it may be envisioned that preferential
reactivity of a secondary site with regard to a tertiary C H
bond requires a sterically demanding C H oxidation re-
À
À
Mn–porphyrin catalysts[15] have shown that C H regioselec-
À
tivity responds basically to steric differentiation among C1,
C2, and C3 (Scheme 2, bottom). Indeed, oxidation of
(+)-sclareolide under our standard experimental conditions
furnishes C2 and C3 ketones as major products in respective
26 and 35% product yields. Oxidation of such substrates is
interesting because it shows that 3Me,Me is a valuable tool for
late-stage oxidation of methylene sites and that it operates
with lower catalyst loading than 1.[8b]
À
À
agent. Precedents for this switch are rare and include a
bulky divanadium polyoxometallate catalyst that oxidises
hydrocarbon molecules with large secondary/tertiary selec-
ity.[4c] Enhanced selectivity towards secondary sites has
ACHUTNGRENtNUG ivACHTUNGTRENNUGN
also been recently documented for a sterically impeded iron
catalyst structurally related to 1 and 2.[4d] Both of these cata-
lysts were only tested in simple hydrocarbon substrates, and
substantially differ from 3Me,Me because they operate at
much lower substrate conversion levels.
A more challenging problem would be to use 3Me,Me to
divert regioselectivity in the C H oxidation of a complex or-
ganic molecule towards a methylene site, complementing se-
lectivities attained with 1 and 2. (+)-Neomenthyl esters con-
tain four tertiary and six secondary different C H sites
(Scheme 3) and were identified as illustrative substrate
À
Single-crystal X-ray structures of
1
)
and [FeII-
À
[16]
A
E
U
allow
a
À
probes to demonstrate the dependence between C H regio-
selectivity and the nature of the iron catalyst.
comparative analysis of the respective active sites (Figure 1).
This analysis shows that in the case of 1,[17] the two labile cis
Chem. Eur. J. 2013, 19, 1908 – 1913
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1911

M. Costas et al.
M.C., and Consolider Ingenio/CSD2010-00065. I.P. and M.C thank the
MICINN and Generalitat de Catalunya, respectively, for Ph.D. grants.
M.C. and X.R. thank the Generalitat de Catalunya for 2009SGR637 and
ICREA Acadꢃmia Awards. Catexcel is acknowledged for a generous gift
of tritosyltriazacyclononane.
Keywords: bioinspired catalysis · homogeneous catalysis ·
À
hydrogen peroxide · iron · C H oxidation
Figure 1. Ball and stick diagram of the X-ray structures of 1[17] (left), and
(H2O)Me,Me (right). Triflate and water ligands have been omitted, leaving
À
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stantially more shielded by the methyl groups of the pyri-
dine and the TACN macrocycle. Therefore, we propose that
the enhanced selectivity for methylene sites exhibited by
3Me,Me is very likely to originate from a steric discrimination
towards the more accessible secondary site. A cautious note
is that unlike 1, the two labile sites in 3Me,Me are not equiva-
lent. Shielding appears to be particularly evident for O1,
while O2 is more exposed.
In conclusion, the present work describes an iron catalyst
À
that mediates the oxidation of alkyl C H bonds with prod-
uct yields that may be amenable for synthetic purposes.
Product yields and turnover numbers obtained with 3Me,Me
are comparable to those obtained with the most active non-
heme iron catalysts reported to date.[8,9] However, 3Me,Me dif-
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hanced selectivity towards methylene sites. Oxidizing species
generated from the reaction of 3Me,Me with H2O2 are highly
À
À
[7] For examples of Fe-catalyzed C H oxidations, see: a) Y. Hitomi, K.
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À
This is a quite unique characteristic, as other C H oxidants,
such as organic peroxides,[3a,c] Ru-based reagents,[3d,e] and
even metalloporphyrins,[18] show a strong preference for oxi-
À
dizing tertiary C H bonds, or activated secondary sites. Be-
cause of this, 3 not only adds to the selected family of iron
À
catalysts that could mediate C H oxidation with synthetic
applications, but in addition it may also open distinct paths
À
for regioselective C H functionalization and complements
existing methods.
Experimental Section
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Financial support by the European Research Council for project ERC-
29910, the MCYT of Spain through project CTQ2009–08464/BQU to
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Received: September 13, 2012
Revised: October 30, 2012
Published online: December 19, 2012
Chem. Eur. J. 2013, 19, 1908 – 1913
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