Iron Complex Catalyzed Selective C-H Bond Oxidation with Broad Substrate Scope

Article abstract of DOI:10.1021/acs.orglett.6b03359

The use of a peroxidase-mimicking Fe complex has been reported on the basis of the biuret-modified TAML macrocyclic ligand framework (Fe-bTAML) as a catalyst to perform selective oxidation of unactivated 3° C-H bonds and activated 2° C-H bonds with low catalyst loading (1 mol %) and high product yield (excellent mass balance) under near-neutral conditions and broad substrate scope (18 substrates which includes arenes, heteroaromatics, and polar functional groups). Aliphatic C-H oxidation of 3° and 2° sites of complex substrates was achieved with predictable selectivity using steric, electronic, and stereoelectronic rules that govern site selectivity, which included oxidation of (+)-artemisinin to (+)-10β-hydroxyartemisinin. Mechanistic studies indicate Fe^V(O) to be the active oxidant during these reactions.

Full text of DOI:10.1021/acs.orglett.6b03359

Letter
pubs.acs.org/OrgLett
Iron Complex Catalyzed Selective C−H Bond Oxidation with Broad
Substrate Scope
Sandipan Jana,†,§ Munmun Ghosh,†,§ Mayur Ambule,† and Sayam Sen Gupta*,‡
†Chemical Engineering Division, CSIR-National Chemical Laboratory, Pune 411008, India
‡Department of Chemical Sciences, Indian Institute of Science, Education and Research Kolkata, Mohanpur 741246, India
S
* Supporting Information
ABSTRACT: The use of a peroxidase-mimicking Fe complex
has been reported on the basis of the biuret-modified TAML
macrocyclic ligand framework (Fe−bTAML) as a catalyst to
perform selective oxidation of unactivated 3° C−H bonds and
activated 2° C−H bonds with low catalyst loading (1 mol %)
and high product yield (excellent mass balance) under near-
neutral conditions and broad substrate scope (18 substrates
which includes arenes, heteroaromatics, and polar functional
groups). Aliphatic C−H oxidation of 3° and 2° sites of
complex substrates was achieved with predictable selectivity
using steric, electronic, and stereoelectronic rules that govern
site selectivity, which included oxidation of (+)-artemisinin to
(+)-10β-hydroxyartemisinin. Mechanistic studies indicate FeV(O) to be the active oxidant during these reactions.
systems based on environmentally compatible and naturally
elective and predictable oxidation of alkyl C−H bonds in
Scomplex natural products under mild conditions presents a abundant metal iron remains a challenge.
major challenge in synthetic organic chemistry.1 Inspired by the
high catalytic efficiency for the hydroxylation of alkyl C−H
bonds by iron-containing enzymatic systems, chemists have
developed numerous synthetic Fe-based complexes2 including a
tetradentate N-donor ligand-bound FeII center with cis labile sites
(Fe−N4),3 a mimic of the enzyme Rieske dioxygenase. Using
these complexes, White4 in 2007 and subsequently Costas5 were
able to show the oxidation of aliphatic C−H bonds using H2O2 as
the oxidant on a preparative scale. In a series of reports, they
demonstrated that intermolecular aliphatic C−H oxidation of 3°
and 2° sites with predictable selectivity can be achieved using
steric, electronic, and stereoelectronic rules that govern site
selectivity.4,5 Although significant progress has been made in the
development of Fe complexes for alkyl C−H bond hydrox-
ylation, several formidable challenges still exist. These include (i)
expansion of the substrate scope to include structures derived
from aryl or heteroaromatic groups (Fe−N4 complexes
hydroxylate aromatic rings thus rendering the catalysts
inactive3d), (ii) expansion of the substrate scope to include
structures containing single polar functional groups, particularly
substrates that are sensitive to acid, (iii) selective oxidation of 3°
C−H bonds in the presence of 2° C−H bonds for substrates in
which the 3° C−H bonds are oriented in the axial position, and
(iv) reduction of catalyst loading to 2 mol % and lower during
oxidation to ensure that the reactions are economically feasible.
Although ruthenium- and manganese-based complexes have also
been used successfully for chemoselective C−H oxidations by
Du Bois, Bryliakov, and others,6 the development of catalytic
We focused our attention on a functional peroxidase mimic,
Fe−bTAML, a member of the broad class of catalysts called
TAML activators, developed by Collins in the mid-1990s.7−9
Upon addition of m-CPBA to Fe−bTAML, the peroxide-bound
FeIII complex formed the corresponding FeV(O) quantitatively at
room temperature,10 which is able to oxidize unactivated alkyl
C−H bonds via C−H abstraction. We hypothesized that the
lower electrophilicity of the FeV(O) due to the strongly σ-
donating deprotonated amide N atoms would make them more
selective toward aliphatic 3° C−H bonds and unreactive toward
aromatic rings. We herein report the ability of a NO2[Fe−
bTAML] complex (1) to catalyze highly stereoselective
oxidation of sp3 C−H bonds in the presence of the oxidant m-
CPBA (Scheme 1).11 We also demonstrate that 1 oxidizes a wide
range of substrates predictively, including substrates derived
Scheme 1. Schematic Diagram for Catalytic Hydroxylation of
Hydrocarbons by 1
Received: November 10, 2016
© XXXX American Chemical Society
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from benzene, containing polar functional groups as well as
complex natural products with low catalyst loadings (1−2 mol
%). Mechanistic studies indicate FeV(O)−bTAML to be the
active oxidant during these reactions.
C−H bonds, resulting in the formation of both alcohol (7b, with
98% retention of configuration) and ketone (7c and 7d) at a ratio
of 76:24. The difference in reactivity between the cis (3a and 4a)
and trans isomers (7a, 8a, and 9a) can be attributed to the strain
release in the transition state for the cis isomers (3a and
4a).4b,5a,12,13 As predicted from the analysis, for substrates 3a and
4a, the corresponding tertiary alcohols, 3b and 4b, respectively,
were obtained in good yields (up to 85%), with high selectivity
and high retention of configuration (98%). For oxidation of the
corresponding trans isomers (Table 1, entries v and vi), the
selectivity toward 3° C−H bonds was much lower, and the
statistical advantage of the 2° C−H sites led to increased
oxidation of the methylenic C−H bonds, which is especially
prominent for 8a, resulting in higher ketone formation (8c and
8d) compared to 7b. In comparison, oxidation of 7a with the
Fe−(S,S,R)-MCPP complex resulted in 3-fold higher yields of
the ketones 7c and 7d.4b,5a The formation of ketone can also be
explained by two-step oxidation of the C−H bond by a two-
electron-transfer process. The second step, i.e., formation of
ketone from alcohol, is ∼100 times faster than oxidation of
alcohol from C−H bonds. We believe that generation of ketone
in the secondary position of cyclohexane derivatives can be
rationalized through this mechanism.14
All catalytic reactions were performed under optimized
conditions in which m-CPBA (2−5 equiv) was added using a
syringe pump at a rate of 100−200 μL/h to a solution of 1 (1−2
mol %) and substrate (0.1−0.2 mmol scale) in 80% CH3CN−
20% K2HPO4 (aq) solvent system. The time taken for the
reactions was around 2−12 h unless specifically mentioned.
Here, 3° C−H bonds are found to be preferentially oxidized in
the presence of statistically more important 2° C−H bonds, with
excellent mass balances and retention of configuration (RC). For
cis-dimethylcyclohexane (3a), cis-decalin (4a), and pivalate (9a),
hydroxylation predominantly occurred at 3° C−H centers (along
with 98% RC) (Table 1, entries i, ii, and vii). For substrate 5a,
Table 1. Regioselectivity and Diastereoselectivity for 3° C−H
Bond Oxidation with 1
Substituted aromatic rings frequently appear in both simple
and complex substrates; however, previous studies with metal-
based oxidants (Fe−N4 and RuCl3) have known problems with
deleterious arene oxidation.4,5a,6d With substrates 10a and 11a,
>50% yields of their corresponding 3° alcohols, 10b and 11b,
were observed, with <20% formation of the ketone (Table 2,
Table 2. Oxidation of 3° C−H Bonds with 1 in the Presence of
Polar Functional Groups, Arenes, and N-Heterocycles
*
0.2 mmol scale of 3a, 4a, 7a, and 8a was used; the rest were 0.1 mmol
scale; 2 mol % catalyst was used; selectivity was determined by GC.
For details and structure determination, see the SI.
*
All the substrates were 0.1 mmol scale; 1 mol % catalyst; selectivity
having an acetate group at the distal end, the selectivity toward
the 3° C−H bond hydroxylation was reduced as the desired
hydroxylated product 5b yielded 57% along with 19% ketone
formation (Table 1, entry iii). Electronic effects in the
regioselective oxidation of 3° C−H groups (substrate 6a)
exhibited characteristic patterns of an electrophilically active
species that is sensitive to inductive modulation of C−H bond
reactivity by the electron-withdrawing acetate group. The yield of
3° hydroxylation was 56%, with a C7 (6b) to C3 (6c)
hydroxylation ratio of 80:20 (Table 1, entry iv).
In cyclohexane derivatives, the stereochemical orientation of
the 3° C−H bonds (axial or equatorial) determines the
regioselective outcome of the reaction. For catalytic hydrox-
ylation of trans-dimethylcyclohexane 7a, the reaction was
comparatively slower with lower GC yield (68%) of the oxidized
product (Table 1, entry v) in contrast to that of 3a. Oxidation of
7a exhibits a significant amount of oxidation at the methylenic
was determined by GC. For details and structure determination, see
the SI.
entries i and ii). A bulky TBDPS group bearing substrate 15a
undergoes selective oxidation to give 15b (Table 3, entry ii).
Strikingly, substrate 12a, which possesses an isonicotinate group,
was smoothly oxidized only at the 3° C−H center to yield 12b in
74% yield (Table 2, entry iii). The excellent mass balance
observed in these reactions is indicative of exclusive arene
tolerance. The ability to oxidize these sites in the presence of the
basic heteroaromatic nitrogen groups without the use of
Bronsted and Lewis acids to in situ protect the heteroatomic
nitrogen from N-oxide formation is unprecedented among iron
complexes.15,16 Thus, the oxidation of substrates containing
arenes (ester and carbamate) and heteroarenes addresses one of
the key shortcomings of Fe−N4 complexes for the chemo-
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Table 3. Use of Steric Effects To Direct 3° C−H Bond
Oxidation with 1
Table 4. Oxidation of 3° C−H Bonds in Complex Natural
Products and Their Derivatives by 1
*
For reaction with 18a, 5 mol % of catalyst and 5 equiv of m-CPBA
were used; time taken was 18 h; all of the substrates were 0.2 mmol
scale; 17a requires 2 mol % of catalyst.
*
All of the substrateswere 0.1 mmol scale except 14a (0.2 mmol); 2
mol % catalyst was used; selectivity was determined by GC. For details
and structure determination, see the SI; RSM stands for recovered
starting material.
Table 5. Oxidation of Substrates with Activated 2° and
Benzylic C−H Bonds by 1
selective oxidation of C−H bonds. High product yield (80%) and
mass balance were also observed for acid-sensitive NHBoc
bearing substrate 13a (Table 2, entry iv).
The role of sterics in the regioselectivity of C−H oxidation in
multiple 3° C−H bonds was investigated for 14a, 15a, and 16a
(Table 3, entries i−iii). For menthyl acetate (14a), hydroxylation
at both 3° C−H positions occurs, leading to the formation of
products 14b and 14c in 55% overall yield at a ratio of 3:1 in favor
of the more sterically accessible 3° C−H bond (15% ketone was
also observed). This result demonstrates that the planar nature of
1 cannot efficiently distinguish between two 3° C−H bonds
using sterics as was demonstrated by White for a sterically
hindered Fe−N4 complex that led to the formation of 14b and
14c in a ratio of 11:1.4a However, when the bulky TBDPS was
used as the protecting group for the menthol −OH (substrate
15a), 15b was exclusively formed, demonstrating that bulky
neighboring groups can be used to direct the selectivity between
electronically similar 3° C−H bonds. Moreover, as previously
observed by White,4a we were unable to oxidize the sterically
inaccessible natural product picrotoxin (16a) (Table 3, entry iii).
In this reaction, 95% of the starting material was recovered,
indicating functional group tolerance of 1.
Natural products containing unactivated methylene sites
include (+)-cedryl acetate (17a), a derivative of cedrol. It was
hydroxylated very selectively at the least sterically hindered 3°
C−H bond to give 17b (Table 4, entry i); the crystal structure is
provided in the SI. The puckered structure of 17a and release of
steric strain may be responsible for its very high yield (80%),
unlike using Fe−(S,S,R)-mcpp.5b Antimalarial drug (+)-artemi-
sinin (18a) having five 3° C−H bonds along with the fragile
endoperoxide moiety forms (+)-10β-hydroxyartemisinin (18b)
in 38% yield (Table 4, entry ii).
*
All of the substrates were 0.1 mmol scale, 1 mol % of catalyst was
used; selectivity was determined by GC. For details and structure
determination, see the SI
predominantly oxidized to the ketone along with minor
hydroxylation at the 3° C−H bond adjacent to the isopropyl
group. Finally, papaverine (21a) (Table 5, entry iii), an opium
alkaloid, was oxidized at the benzylic position to form the
corresponding ketone 21b in 68% yield without formation of
papaverine N-oxide.
The very high selectivity observed indicated the involvement
of a high-valent iron−oxo intermediate instead of organic
radicals, as observed previously.2d,3a,17,18 Recently, we showed
the formation of an extensively characterized (HRMS,
Mossbauer, EPR, resonance Raman, and EXAFS) FeV(O)
species at room temperature.10 Addition of m-CPBA (6 × 10−5
M) to a solution of 5 × 10−5 M of 1 led to the complete formation
of 2. The formation of FeV(O), 2, a violet-colored species, was
well characterized by UV−vis spectroscopy (characteristic peak
at 585 nm, Figure S1) and ESI-MS (mass to charge ratio:
474.0613, Figure S2). Subsequent addition of excess substrate
19a ambroxide (25 × 10−3 M) led to an immediate color change,
and within a few minutes, the starting FeIII complex 1 was
completely regenerated (Figure S3-A).
Finally, substrates bearing activated methylenic and benzylic
C−H bonds were explored. Ambroxide (19a) was selectively
oxidized among nine possible sites of oxidation to give the
lactone (+)-(3R)-sclareolide, 19b, in 90% yield (Table 5, entry i).
Here, oxidation of the α-ethereal C−H bond occurred
exclusively without any further oxidation (even after 10 equiv
of m-CPBA addition). This is in contrast to the oxidation by PDP
complexes reported by White and Costas where formation of
oxosclareolide takes place.4b,5a,b For ibuprofen methyl ester
(20a) (Table 5, entry ii), the benzylic position was
To gain a better understanding on the progress of the reaction,
we employed a reaction protocol in which ambroxide oxidation
was initiated by the addition of m-CPBA (10−3 M; 10 equiv) to a
solution of 1 (10−4 M) and substrate (3 × 10−2 M). After every
60 s, a further aliquot of 10 equiv of m-CPBA was added, which
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was continued until the color of the solution completely bleached
out. The progress of the reaction was monitored by GC−MS (for
product sclaral and sclareolide determination) and UV−vis/ESI-
MS (to determine reactive intermediates). GC−MS studies at
the end of this reaction showed formation of a mixture of sclaral
and sclareolide (4:1) (Figure S4). The UV−vis (Figure S3-A)
and GC−MS studies indicated a positive correlation between the
FeIII recovered after each cycle and FeV(O) formed initially at the
start of the cycle with the gradual increase in the TON indicating
that FeV(O) remains the primary oxidant under aerobic
conditions (Figure S3-B). In conclusion, we have reported a
rationally designed iron biuret modified TAML complex (1) that
mostly outperforms state-of-the-art Fe-based oxidation catalysts
in terms of selectivity toward unactivated 3° C−H bonds, catalyst
loading, product yield, and substrate scope. Specifically, this
system can oxidize 3° C−H bonds in substrates bearing arene
rings, N-based heterocycles, and acid-sensitive substrates, which
addresses a serious drawback of Fe-based catalysts reported to
date. Moreover, these reactions exhibit excellent retention of
configuration while dealing with substrates like dimethylcyclo-
hexane and decalin, irrespective of its stereochemistry (cis or
trans). Apart from these, the high selectivity toward 3° C−H
bonds is manifested in the selective oxidation of 3° C−H bonds
in complex molecules, like natural products such as cedryl acetate
and artemisinin without oxidation of methylenic C−H bonds.
Thus, 1 displays great promise in the quest to develop reagents
for selective oxidation of alkyl C−H bonds in complex natural
products under mild conditions.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03359.
̈
General considerations and materials, characterization
data of 2, mechanistic approach for ambroxide oxidation,
synthetic procedures and characterization of unreported
substrates, procedure of catalytic hydroxylation reaction,
characterization data and NMR spectra of products, GC
and chiral GC of selected compounds, crystal structure of
17b (ORTEP diagram), and references (PDF)
174, 361−390.
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Commun. 2011, 47, 8016−8018.
(10) Ghosh, M.; Singh, K. K.; Panda, C.; Weitz, A.; Hendrich, M. P.;
Collins, T. J.; Dhar, B. B.; Sen Gupta, S. J. Am. Chem. Soc. 2014, 136,
9524−9527.
(11) The catalytic reactions were attempted using the Fe−bTAML
complex bearing a nitro group in the aromatic ring to provide much
higher operational stability and faster reaction rates. The product yields
for the oxidations dramatically increase for the nitro-substituted
complex in comparison to the unsubstituted complex. Detailed
mechanistic work will be reported.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sayam.sengupta@iiserkol.ac.in.
ORCID
Sayam Sen Gupta: 0000-0002-3729-1820
Author Contributions
§S.J. and M.G. contributed equally to this work.
Notes
(16) Pattanayak, S.; Sen Gupta, S. Manuscript in revision. (Note: We
believe it is due to the propensity of FeV(O), 2, to exist as a 5-coordinate
complex in solution, as observed from XAS studies, which prevents
binding of pyridine nitrogen to the Fe-center, leading to its oxidation.)
(17) Mayer, J. M. In Biomimetic Oxidations Catalyzed by Transition
Metal Complexes; Meunier, B., Ed; Imperial College Press: London,
1999; Chapter 2.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.S.G. acknowledges SERB EMR/2014/0016 for funding. S.J.
acknowledges UGC New Delhi for funding. We thank Miquel
Costas for helpful discussions.
(18) Kim, J.; Harrison, R. G.; Kim, C.; Que, L. J. Am. Chem. Soc. 1996,
118, 4373−4379.
DEDICATION
■
This paper is dedicated to Professor Terrence J. Collins.
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