Combined Iron/Hydroxytriazole Dual Catalytic System for Site Selective Oxidation Adjacent to Azaheterocycles

Article abstract of DOI:10.1021/jacs.7b12864

This report details a new method for site-selective methylene oxidation adjacent to azaheterocycles. A dual catalysis approach, utilizing both an iron Lewis acid and an organic hydroxylamine catalyst, proved highly effective. We demonstrate that this method provides complementary selectivity to other known catalytic approaches and represents an improvement over current heterocycle-selective reactions that rely on stoichiometric activation.

Full text of DOI:10.1021/jacs.7b12864

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Communication
A Combined Iron/Hydroxytriazole Dual Catalytic System
for Site Selective Oxidation Adjacent to Azaheterocycles
Julian C Cooper, Chaosheng Luo, Ryohei Kameyama, and Jeffrey F Van Humbeck
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12864 • Publication Date (Web): 18 Jan 2018
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A Combined Iron/Hydroxytriazole Dual Catalytic System for Site
Selective Oxidation Adjacent to Azaheterocycles
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§
φ§
ꢀ
∝§*
Julian C. Cooper, Chaosheng Luo, Ryohei Kameyama, and Jeffrey F.Van Humbeck
§
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
ꢀ
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Nishikyoꢁku, Kyoto 615ꢁ8510, Jaꢁ
pan
Supporting Information Placeholder
positions where the pK of the benzylic CꢁH
issignificantlylowered. Several methods have been
shown to allow for selective oxidation at positions away
from
ABSTRACT:This report details a new method for siteꢁ
a
9
selective
methylene
oxidation
adjacent
to
azaheterocycles.A dual catalysis approach, utilizing both
an iron Lewis acid and an organic hydroxylamine
catalyst proved highly effective.We demonstrate thatthis
method provides complementary selectivity to other
known catalytic approaches and represents an
improvement over current heterocycleꢁselective
reactions that rely on stoichiometric activation.
the
Nitrogenꢁcontaining heterocyclesare key motifs
found in an array of pharmaceuticals, agrochemicals and
1
natural products. Specifically, over 250 FDAꢁapproved
1b
drugs include aromatic azaheterocycles.
New
techniquesthatpredictably diversify these substructures
2
in complex settingswill enablefurther discovery. For
example, systems that could oxidize heterobenzylic
3
sp CꢁH bonds in the presence of other reactive positions
would circumvent more common methods for the
synthesis
whichoftenrequire
ofcomplex
heterobenzylic
ketones,
3
multiꢁstep
sequences. Such
technology would also allow for lateꢁstage synthesis of
4
potential metabolites.
The overwhelming majority of known benzylic
oxidation methods cannot be used to site-selectively
5
oxidize adjacent to azaheterocycles. A comparison of
the reactivity of an alkylbenzene (1) and alkylpyridine
(2)shows why(Scheme 1), and we experimentally
confirm these following statements:We expected hydride
abstraction or single electron transfer (Scheme 1a) to be
selective for electron rich positions. A number of
Scheme 1. Knownsite selectivity of oxidation by
different mechanistic pathways (a–c) and our proposed
strategy (d).
6
hydrogen atom transfer (HAT) oxidations are known
7
(
Scheme 1b), but most HAT mediating agents typically
display modest to good selectivity for nucleophilic
positions. Heterobenzylic deprotonation is potentially
viable, but has only been demonstrated withactivated
10
azaheterocycle. An important advance was realized by
8
11
Leiand Zhuo in 2015 (Scheme 1c), where they
demonstratedthat azaheterocycles could be activatedby
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alkylation. Whilethis represented
improvement, the use of a stoichiometricelectrophilic
a
significant
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activator
may
limit
applications
in
Received: XX
Published: XX
complex settings. A fully catalytic system for
heterocycleꢁselective oxidation remains absent and is
highly desirable.
We envisioned a dualꢁcatalytic approach to address
this need (Scheme 1d). Thermodynamic and kinetic
studies have demonstrated that metal coordination can
modulate homolytic CꢁH, CꢁC, and XꢁH bond strength
and reactivity, and we aimed to use these effects to
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enforce siteꢁselectivity. We further aimed to fine tune
Table 2. Metal, ligand, and organic HAT
catalystevaluation.
selectivity by optimizing thestructure of a second
organic catalyst, inspired by the known HAT ability of
13
Nꢁhydroxyphthalimide (NHPI). Herein, we describe
the successful execution of this design plan.
Wefirst investigated known oxidation methods
(Table 1). DDQ is completely selective for ethylbenzene
(1) over ethylpyridine (2) (entry 1). A number of reports
have described the nonꢁcompetitive oxidation of
alkylheterocycles.They displayed either low reactivity
(
entry 2) or favored benzylic oxidation (entries 3ꢁ5) in
14
this competitive setting. Thestoichiometric alkylation
strategy of Zhuo and Lei (entry 6, 87:1) served as a
benchmark for our own investigations.
We were drawn to copper and iron for their benign
nature. Cu(OTf) and Fe(BF ) •6H O proved to be the
2
4 2
2
most effective of each element from several simple salts
tested (see Supporting Information). A selection of
multiꢁdentate ligands andpotential HAT catalysts were
investigated (Table 2) in a competition experiment
featuring ethylpyridine (1) and ethylbenzene (2).
Cu(OTf)2 performed poorly independent of ligand
(
entries 1ꢁ3), whileFe(BF ) ꢁbased systems showeda
4 2
strikingdependence (entries 4ꢁ9). Tris(pyrazole)borate
11) is uniquely effective (entry 7, 74%, 44:1
(
selectivity):the closelyrelated tris(pyrazole)methane (12)
only delivered trace product (entry 8, 2.4%). Not all iron
sources showed such dependence: FeCl can deliver
modest yield (38%) even in the absence of ligand, and
only delivers slightly higher yield (44%) with ligand 11
included (TableS1, Supporting Information). Yield
andselectivityimprovedfurther with Fe(BF ) by tuning
HAT catalyst structure(entries 7, 10ꢁ12). 1ꢁHydroxyꢁ7ꢁ
azabenzotriazole (HOAt, 8) delivered optimal chemical
2
4
2
modest conversion (37%, entry 13), which may reflect
these iron(II) complexes’ ability to directly activate
yield and siteselectivity (entry 12,
selectivity). Reactions lacking a HAT catalyst still
showed
86%, 95:1
15
dioxygen. Still, the full system composed of
Fe(BF ) /11/8 clearly delivered the best performance.A
4 2
threeꢁsubstratecompetition
also
showed
that
heterocycleselectivity was high in the presence of
electronꢁrich and poor positions (Scheme 2, 1 vs. 14 vs.
Table 1. An evaluation of current oxidation
methodology.
1
5).These conditions typically result in full conversion
when secondary CꢁH bonds are present at the reactive
position. Primary or tertiary bonds return significant
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starting materials (25ꢁ40%, see Supporting Information).
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We applied our newly designed CꢁH oxidation
method to pyridines with multiple benzylic
appeared to have undergone oxidation at both reactive
position (entries 3, 6, 7, and 8 “X+O”). With the
exception of substitution at both biaryl ortho positions
(entry 8), useful results were obtained throughout (42ꢁ
90% yield, 19:1 or better selectivity). This was trueboth
1
4c, 16
positions.Avariant of Ishii’sconditions,
was used for
comparison, as a representativesystem that favors
electronꢁrich benzylic positions (Table 3). With our
conditions, we do not observe single oxidation at
theundesired aromatic position (site ‘O’). In cases where
smallamounts of byproduct could be isolated, the
structures
when
the
benzylicpositionswere
adjacent
to
separaterings (entries 1, 4ꢁ9) or located on the same ring
system (entries 2 and 3). These conditions are also
compatible with benzylic heteroatoms. A direct etherꢁtoꢁ
ester conversion is possible(entries 6 and 7), as well as
the conversion of anamide to an imide (vide infra).3ꢁ
ethylpyridine is entirely unreactive, while 2ꢁ
ethylpyridine is modestly reactive (25%, see
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SupportingInformation).Ishii’sconditions
theopposite selectivityin every case where reaction was
observed(entries 1, 3ꢁ5, 9).One
give
Scheme 2. Aromatic electronic effects on site selectivity.
Table
3.
Selective
oxidation
adjacent
to
othernoteworthybyproductwas observed in entry 9.
Cyclization to form a pyran (16)likely occurs during
pyridine/quinoline.
breakdown
of
an
Table 4. Oxidation of pyrimidines and quinazolines.
intermediate hydroperoxide. Measurable amounts (~3%)
of an analogous byproduct could also be observed in
entry 8.
We next investigated pyrimidines and quinazolines
(Table 4). Again, our conditions completely distinguish
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between reactive positions adjacent to separate rings
AUTHOR INFORMATION
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(
entries 3, 5ꢁ6) or on the same ring (entries 1, 4, 7ꢁ8).
Corresponding Author
jeffrey.vanhumbec1@ucalgary.ca
While cobaltꢁcatalyzed conditions were selective for the
heterobenzylic position in many cases, across the range
of substrates shown, ironꢁbased conditions were either
higher yielding or more selective—or both—in all cases.
As the heterocycle–iron interaction is disfavored by
steric congestion the oxidation systemsbegin to
converge, as would be expected (c.f. entry 2vs. 7 and8).
We have encountered two noteworthylimitations: As
*
Present Address
φDepartment of Chemistry, Colorado State University, Ft.
Collins, Colorado, USA 80523.
∝
Department of Chemistry, University of Calgary, 2500
University Dr NW, Calgary, Alberta, Canada, T2N 1N4
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with many dioxygenꢁbased systems, Nꢁdealkylation of
ORCID
17
alkylamines is observed.
Strongly chelating
Jeffrey Van Humbeck: 0000ꢁ0002ꢁ8910ꢁ4820
substituents (e.g. 2ꢁacetamido) are not currently
tolerated.
Funding Sources
Finally, we were pleasedto see our conditions
Financial support was provided by MIT. J.C.C. holds an
NSF graduate fellowship (NSFꢁGRFP). R.K. was supported
on a graduate exchange fellowship by JGP, Kyoto
University.
wereamenableto
pharmaceuticalagent:
direct
the
modificationof
antiꢁmuscarinic
a
agent
tropicamide could be directly oxidized at the
heterobenzylic position (Scheme 3). Inaddition to the
carbonyl product (18, 55% yield), trapping ofan initial
oxidation product by cyclization also produces
aninteresting cyclized derivative (19, 11% yield).
Cobaltꢁcatalyzed conditions only resulted in substrate
acetylation.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The organic and inorganic faculty at MITare thanked for
access to equipment, chemicals, and many helpful
discussions.
Scheme 3. Direct oxidation of tropicamide
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