Chemoselective Tertiary C?H Hydroxylation for Late-Stage Functionalization with Mn(PDP)/Chloroacetic Acid Catalysis

Article abstract of DOI:10.1002/adsc.201901472

Aromatic and heterocyclic functionality are ubiquitous in pharmaceuticals. Herein, we disclose a new Mn(PDP) catalyst system using chloroacetic acid additive capable of chemoselectively oxidizing remote tertiary C(sp³)?H bonds in the presence of a broad range of aromatic and heterocyclic moieties. Although catalyst loadings can be lowered to 0.1 mol% under a Mn(PDP)/acetic acid system for aromatic and non-basic nitrogen heterocycle substrates, the Mn(PDP)/chloroacetic acid system generally affords 10–15% higher isolated yields on these substrates and is uniquely effective for remote C(sp³)?H hydroxylations in substrates housing basic nitrogen heterocycles. The demonstrated ability to perform Mn(PDP)/chloroacetic acid C(sp³)?H oxidations in pharmaceutically relevant complex molecules on multi-gram scales will facilitate drug discovery processes via late-stage functionalization. (Figure presented.).

Full text of DOI:10.1002/adsc.201901472

Title: Chemoselective Tertiary C—H Hydroxylation for Late-Stage
Functionalization with Mn(PDP)/Chloroacetic Acid Catalysis
Authors: Rachel Chambers, Jinpeng Zhao, Connor Delaney, and M.
Christina White
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901472
Link to VoR: http://dx.doi.org/10.1002/adsc.201901472

10.1002/adsc.201901472
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Chemoselective Tertiary C—H Hydroxylation for Late-Stage
Functionalization with Mn(PDP)/Chloroacetic Acid Catalysis
Rachel K. Chambers,a,b Jinpeng Zhao,a,b,c Connor P. Delaneya and M. Christina
Whitea,*
a
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States
These authors contributed equally to this work.
Current address: Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana, 46268.
b
c
Email: mcwhite7@illinois.edu
This paper is dedicated to Eric N. Jacobsen on the occasion of his 60th birthday for his inspirational work on the discovery
and study of practical reactions that illuminate new selectivity principles in catalysis.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Aromatic and heterocyclic functionality are ubiquitous in pharmaceuticals. Herein, we disclose a new Mn(PDP)
catalyst system using chloroacetic acid additive capable of chemoselectively oxidizing remote tertiary C(sp3)—H bonds in the
presence of a broad range of aromatic and heterocyclic moieties. Although catalyst loadings can be lowered to 0.1 mol% under
a Mn(PDP)/acetic acid system for aromatic and non-basic nitrogen heterocycle substrates, the Mn(PDP)/chloroacetic acid
system generally affords 10-15% higher isolated yields on these substrates and is uniquely effective for remote C(sp3)—H
hydroxylations in substrates housing basic nitrogen heterocycles. The demonstrated ability to perform Mn(PDP)/chloroacetic
acid C(sp3)—H oxidations in pharmaceutically relevant complex molecules on multi-gram scales will facilitate drug discovery
processes via late-stage functionalization.
Keywords: C—H hydroxylation; oxidation; chemoselective; site-selective; late stage functionalization
A. Aromatic and heteroaromatic functionality is common in pharmaceuticals
Introduction
H
H
O
O
O
Cl
Cl
O
H
The direct, atomistic change from C(sp3)—H to
C(sp3)—O can have a profound impact on the
physical and biological properties of pharmaceuticals
and complex bioactive molecules. With medicinal
chemists moving towards increasing the fraction sp3
(Fsp3) in small molecule therapeutics,[1] methods that
enable late stage C(sp3)—H hydroxylation are highly
desirable to avoid lengthy de novo syntheses when
accessing novel chemical space for molecule
derivatization and metabolite synthesis. The
N
S
N
N
O
O
N
H
H
H
O
B(OH)2
N
N
H
Glimepiride
Ixazomib
F3C
B. PDP catalysts for site-selective aliphatic C—H oxidation
This work
(SbF6)2
CF3
R
(SbF6)2
(SbF6)2
N
NCMe
NCMe
N
N
N
NCMe
NCMe
Mn
NCMe
NCMe
N
N
N
N
Fe
Mn
N
N
N
N
CF3
discovery of Fe(PDP) catalyst
1
in 2007
R
F3C
+ CH3COOH
+ ClCH2COOH
demonstrated for the first time that aliphatic C—H
bonds of the same bond type (3º or 2º) can be
preparatively and predictably distinguished based on
small differences in their steric, electronic, and
stereoelectronic properties.[2,3] Ligand modifications
leading to Fe(CF3-PDP) 2 demonstrated that the site
of oxidation can be altered by modifying the
catalyst.[4] Using these catalysts and the principles
that emerged, there has been an explosion of research
in the area of late stage oxidation for diversification
of drugs and natural products[3,4,5] and streamlining
synthesis[6]. Despite these advances, the majority of
methods are limited by chemoselectivity issues when
medicinally relevant aromatic and heteroaromatic
functionalities are present. The development of
+ ClCH2COOH
Fe(PDP) 1; R = H
remote 3º C—H [O]
Fe(CF3-PDP) 2;
Mn(PDP) 3
remote 3º C—H [O]
chemoselective
Mn(CF3-PDP) 4
remote 2º C—H [O]
remote 3º C—H [O]
chemoselective
R = 2,6-diCF3Ar
remote 2º C—H [O]
chemoselective
C. Divergent site-selectivities with Mn(CF3-PDP) vs. Mn(PDP) aliphatic C—H oxidation
previous work
this work
O
O
O
Mn(PDP) 3
ClCH2COOH
H2O2
Mn(CF3-PDP) 4
ClCH2COOH
O
O
O
H2O2
Cl
Cl
Cl
ref. 7
O
OH
58%
1.2:1 2º:3º
58%
3.4:1 3º:2º
Figure 1. PDP catalysts for site-selective aliphatic C—H
oxidation.
1
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10.1002/adsc.201901472
Advanced Synthesis & Catalysis
Table 1. Reaction Development.
methods that overcome this challenge stands to
further increase the impact of late stage C—H
functionalization in drug discovery (Figure 1.A).
We recently reported a small molecule Mn(CF3-
PDP) catalyst 4 using H2O2 oxidant and chloroacetic
acid additive to site-selectively oxidize strong
methylene bonds in the presence of more oxidatively
labile halogenated aromatic and heteroaromatic
functionality.[7] Non-haem Fe(PDP) 1 and Fe(CF3-
PDP) 2 catalysts were previously demonstrated to
site-selectively hydroxylate strong aliphatic C—H
bonds,[2,3,4] but showed no chemoselectivity for -
functionality unless deactivated with strongly
electron
withdrawing
groups
(i.e.
nitro,
trifluoromethyl, triflate). Alternatively, manganese
has a lower redox potential[8] which disfavours
undesired aromatic oxidation, while the increased
basicity of the manganese oxo[9] may promote C—H
abstraction. By combining manganese with the
sterically bulky CF3-PDP ligand design, which
additionally may disfavor the sterically demanding -
system oxidation,[10] Mn(CF3-PDP) 4 showed high
chemoselectivity for the oxidation of strong
methylene C(sp3)—H bonds. However, the later
ligand modification also limits the ability of Mn(CF3-
PDP) 4 to oxidize more sterically demanding 3º C—
H bonds. Indeed, within substrates containing both 3º
and 2º C—H sites available for oxidation, Mn(CF3-
PDP) 4 favors oxidation at the more accessible but
less electron rich 2º C—H bonds (Figure 1.C).[7] We
hypothesized investigating manganese catalyst
designs with less sterically demanding ligand
frameworks may allow us to access preparative
oxidation of 3º C—H bonds in the presence of
aromatic and heteroaromatic functionality.
Herein we disclose a chemoselective 3º C—H
hydroxylation with a Mn(PDP) 3/chloroacetic acid
catalytic system for late-stage functionalization that is
tolerant of
a wide variety of aromatic and
heterocyclic functionality (Figure 1.B).
Results and Discussion
We began by investigating the hydroxylation of
tertiary substrate 5 containing a mildly electron-
deactivating para-chloro-substituted aromatic ring
with catalysts reported to hydroxylate 3º C—H bonds
in the presence of benzoate groups. Both cis-
[Ru(dtbpy)2Cl2][11] and Mn(OTf)2/bipy[12] catalysts
afforded moderate yields and chemoselectivities
under their reported conditions (Table 1.A, entry 1 –
2). Whereas Mn(CF3-PDP) 4 gave a comparable yield
and selectivity to these catalyst systems (entry 3),
expectedly Fe(PDP) 1 gave no desired 3º C—H
hydroxylation product 6 due to competitive aromatic
oxidation (entry 4).
(R,R)-Mn(PDP) and (S,S)-Mn(PDP) used interchangeably.
Isolated yields based on the average of 2-3 reactions.
a)Chemoselectivity (Sel.)
= 3º C—H oxidation/total
conversion. b)Substrate, catalyst and additive with slow
addition of H2O2 (in MeCN, 0.4 M) over 3 h. c)Iterative
addition of 5 mol% catalyst, 0.5 equiv. CH3COOH, 1.2
equiv. H2O2 every 10-15 min. d)Substrate, catalyst and
additive with slow addition of H2O2 over 1 h. e)Substrate,
catalyst, additive with slow addition of H2O2 (in MeCN,
2.5 M) over 1 h and reaction mixture stirred for an
additional 1 h. f)Substrate, catalyst, additive with slow
addition of H2O2 (in MeCN, 0.2 M) over 1 h.
Similar to our previous report, switching from iron
to
manganese
significantly
improved
2
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10.1002/adsc.201901472
Advanced Synthesis & Catalysis
chemoselectivity. Mn(PDP)
3
under identical
3º C—H oxidation to 73% yield (entry 5). Lowering
the temperature from 0 ºC to -36 ºC gave optimal
94%
iterative addition conditions gave significantly higher
yield (32%) of the desired 3º C—H oxidation product
6 with 81% chemoselectivity (entry 5). Switching
from an iterative addition protocol to a single
addition of Mn(PDP) 3 catalyst with slow addition of
H2O2 oxidant at room temperature further increased
the reactivity to a synthetically useful 52% yield of 3º
Table
2.
Mn(PDP)-Catalyzed
3º
C(sp3)—H
Hydroxylations in Aromatic and non-Basic Heteroaromatic
Compounds.
Condition Aa
Mn(PDP) 3 (0.1 mol%)
CH3COOH (14 equiv.)
alcohol
6
(entry 6). Reducing the reaction
temperature from room temperature to 0 ºC further
increased the yield for desired 3º oxidation,
presumably by avoiding catalase-like decomposition
of H2O2 by the manganese catalyst (entry 7).[13] We
questioned whether reducing the catalyst loading
would be feasible for the oxidation of weaker 3º C—
H2O2 (2.5 equiv.)
MeCN, 0 ºC, 1 h
H
OH
Condition Bb
Mn(PDP) 3 (10 mol%)
ClCH2COOH (15 equiv.)
n
n
X
X
1 equiv.
H2O2 (5 equiv.)
MeCN, -36 ºC, 3 h
H
bonds. Previously reported Mn(PDP)(OTf)2
O
OAc
F
OAc
CO2Me
catalysis for tertiary and secondary C—H oxidations
at very low catalyst loadings (0.1 mol%) were known
for simple aliphatic substrates, including substrates
containing benzoate moieties.[12,14] Using the reported
conditions with our Mn(PDP)(SbF6)2 3 catalyst, we
found that the desired product 6 was formed in
comparable yield and chemoselectivity to the 10
mol% catalyst loading conditions (entry 7 versus 8).
By modifying the reaction concentration, we found
the chemoselectivity could be further improved to
80% (entry 9). Chloroacetic acid, a key to the high
yielding conditions developed below (see Table 1.B),
under these low catalyst loading conditions (0.1
mol%), afforded a substantial decrease in yield (entry
10).
OH
OH
tBu
OH
9
10
ketoprofen derivative, 11
Cond. A: 53%
Cond. A: 54%
Cond. B: 60%
Cond. A: 35%
Cond. B: 43%
Cond. B: 71%
N
N
BzO
O
Ph
1
O
O
HO
7
6
Me
OH
OH
p-ClC6H4
12
13
14d
Cond. A: 36%c
Cond. B: 50%c
Cond. A: 44%, 3.2:1 3º:2º
Cond. B: 58%, 3.4:1 3º:2º Cond. B: 57%, ca. 11:1 C1:C6
Cond. A: 54%
HO
Cond. A: 51%
Cond. B: 62%
OAc
with Fe(PDP): 49%e
15
Condition B:
halogen-substituted aromatics:
We questioned if these extremely mild oxidation
conditions would be effective in more complex
molecular settings, particularly substrates containing
basic nitrogen functionality. It has been previously
demonstrated that such nitrogen functionality requires
complexation with a Brønsted acid having a non-
coordinating counterion (HBF4) to enable remote
aliphatic C—H oxidations with Fe or Mn(PDP)
OAc
OAc
OAc
F
OH
6, 69%
OH
OH
X
Cl
19, 56%
X =
18, 56%
Cl,
with 5 mol% 3, 6, 65%
Br, 16, 67%
F, 17, 66%
electron-neutral
electron-withdrawn
aromatics:
aromatics:
OH
OAc
OAc
OH
OH
OH
catalysis.[7,15] When a quinoline containing substrate 7
Cl
X
[14]
22, 73%
20, 69%
21, 35%
OCF3,
X =
was evaluated with both Mn(PDP)(OTf)2
and
CO2tBu, 23, 73%
Mn(PDP)(SbF6)2 3 catalysts, the low 0.1 mol%
catalyst loading conditions established in Table 1.A
were no longer competent at affording the desired
remote 3º C—H oxidation product 8 (Table 1.B, entry
1 – 2). Increasing the catalyst loading from 0.1 mol%
to 10 mol% restored reactivity, furnishing tertiary
alcohol 8 in an encouraging 33% yield with excellent
92% chemoselectivity (entry 3). Notably, no benzylic
oxidation is observed, likely due to the strong
inductively withdrawing nature of the protonated
quinoline. Increasing the oxidant loading from 2.5
equiv. to 5.0 equiv. provided synthetically useful
59% yield though with slightly diminished
chemoselectivity (entry 4). Electron deficient
chloroacetic acid additive was demonstrated to be
critical for optimal 2º C—H oxidation reactivity with
Mn(CF3-PDP) catalyst 4, possibly by increasing the
electrophilicity of the postulated manganese(oxo)
carboxylate intermediate.[7] Similarly, switching to
chloroacetic acid and extending the oxidant addition
time further increased the reactivity for Mn(PDP) 3 in
CN,
24, 76%
(R,R)-MnPDP and (S,S)-Mn(PDP) used interchangeably.
Isolated yields based on the average of 2-3 reactions.
a)Substrate, 0.1 mol% Mn(PDP) 3, 14 equiv. CH3COOH
additive with slow addition of 2.5 equiv. H2O2 (in MeCN,
0.2 M) over 1 h at 0 ºC. b)Substrate, 5-10 mol% Mn(PDP)
3, 15 equiv. ClCH2COOH additive with slow addition of
5.0 equiv. H2O2 (in MeCN, 0.4 M) over 3 h at -36 ºC.
c)Starting material recycled once. d)(S,S)-Mn(PDP) required
for optimal yield. e)See ref. 2a.
chemoselectivity while maintaining 70% yield (entry
6). In the majority of cases evaluated, the -36 ºC
conditions afforded higher yields (vide infra). Under
the optimized conditions B, we re-evaluated lowering
the catalyst loading. Lowering the catalyst from 10
mol% to 5 mol% maintained the preparative utility of
the reaction affording 55% yield of 8 (entry 7).
Lowering the catalyst loading further to 2.5 mol%
saw a significant diminishment in yield to 41% (entry
8). Re-investigation of 0.1 mol% catalyst 3 loading
3
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10.1002/adsc.201901472
Advanced Synthesis & Catalysis
under optimized conditions B furnished no product
(entry 9).
tetrahydroisoquinoline substrate evaluated under
Mn(PDP) 3/ chloroacetic acid catalysis at -36 ºC
afforded a modest 27% yield of the desired remote 3º
alcohol 27 with only a slight diminishment in yield at
0 ºC. Substrates containing electron neutral aromatic
moieties have not previously been demonstrated in
methylene C(sp3)—H oxidations with Mn(CF3-PDP)
4 catalysis due to competing aromatic oxidation. A
After establishing the optimal conditions for
Mn(PDP) 3 catalyzed 3º C—H hydroxylations, we
sought to investigate their generality. We initially
explored the 0.1 mol% 3 conditions (Table 1.A, entry
9, condition A) versus the 10 mol% 3 conditions
(Table 1.B, entry 6, condition B) on aromatic and
non-basic heteroaromatic substrates. Although
condition A (0.1 mol%) gave useful yields in the
majority of cases, a significant improvement was
observed with condition B (10 mol%). For example, a
derivative of biaryl NSAID ketoprofen afforded ca.
18% higher isolated yield of alcohol 11 under 10 mol%
3 conditions B. Interestingly, a non-basic oxadiazole
heterocycle not requiring HBF4 protection furnished
alcohol 12 at the low Mn(PDP) 3 loadings of
condition A, signifying that the lack of reactivity of
these conditions with quinoline substrate 7 may be
related to its basicity and/or the Brønsted acid
complexation (vide infra). Highlighting the
orthogonality of Mn(PDP) 3 catalysis with Mn(CF3-
PDP) 4, a trans-cyclohexanol substrate housing
competing tertiary and secondary sites preferentially
oxidized the tertiary site under both conditions A and
B (3º:2º = 3.4:1, 13), whereas Mn(CF3-PDP) 4
favored formation of the methylene ketone (3º:2º =
1:1.2)[7]. Similarly, benzoate-protected menthol
furnished preparative yields and excellent 3º:2º
selectivity (14), with no observed oxidation at the
alternate C7 3º site. Interestingly, dioxirane[16] and
oxaziridines[17] oxidants are not reported to give any
selectivity on analogous menthol derived substrates
whereas radical azidation methods afford C7 products,
albeit in poor yields[18]. Archetypical citronellol-
derived substrate afforded substantially improved
yields of remote tertiary hydroxylated product 15
under Mn(PDP) 3 conditions B relative to its iron
counterpart with no observed diminishment in site-
selectivity.[2a] We additionally evaluated the more
forcing Mn(PDP) 3 oxidation conditions B with a
range of mildly electron-withdrawing halogen-
substituted aromatic substrates and gratifyingly found
uniformly preparative yields for tertiary C—H
oxidations (6, 16-24, Table 2). Consistent with
previous observations, Table 1.A substrate 5 afford
an ca. 10% increase in yield of tertiary hydroxylated
product 6 under conditions B (69%) and catalyst 3
could be lowered to 5 mol% with only a small
diminishment in yield (65%).
ketobemidone
analogue
containing
a
4-
chloroarylpiperidine pharmacophore afforded remote
oxidation product 28 in 68% yield under condition B.
Table 3. Mn(PDP)-Catalyzed 3º C(sp3) —H
Hydroxylations in Basic Heteroaromatic Compounds.
1) HBF4•OEt2
2) Mn(PDP) 3 (10 mol%)
R
R
ClCH2COOH (15 equiv.)
Het N
1 equiv.
Het N
H
OH
H2O2 (5 equiv.)
MeCN, -36 ºC, 3h
OH
OH
N
N
N
N
25, 52%
26, 70%
at 0 ºC, 58%a
at 0 ºC, 54%a
Cond. A: 0%b
Cond. A: 0%b
CN
OH
OH
N
N
Cl
28, 68%
27, 27%
at 0 ºC, 20%a
Cond. A: 0%b
(R,R)-Mn(PDP) and (S,S)-Mn(PDP) used interchangeably.
Isolated yields based on the average of 2-3 reactions.
a)Reactions runs at 0 ºC instead of -36 ºC. b)Substrate, 0.1
mol% catalyst, 14 equiv. CH3COOH additive with slow
addition of 2.5 equiv. H2O2 (in MeCN, 0.2 M) over 1 h at 0
ºC.
We hypothesized that analogous to Fe(PDP) 1
hydroxylations, Mn(PDP) 3 oxidations proceed via a
high valent metal oxidant that effects C—H
hydroxylations through a mechanism that does not
involve the generation of long-lived carbon centered
radical species.[3] To probe this, we evaluated the
oxidation of enantiomerically enriched substrate 29
under the general Mn(PDP) 3 catalysis condition B.
Consistent with oxidation results with other chiral
substrates (e.g. 13, 14), Mn(PDP) 3 oxidation of 29
proceeds with stereoretention to afford 3º alcohol 30
(eq. 1). This result is in contrast to electrochemical[19]
and iron and manganese porphyrin catalyzed C—H
functionalizations which proceed via long lived
radicals[18,20,21] where ablation of stereochemistry at
tertiary sites is observed.
Consistent with previous observations, Mn(PDP) 3
C—H hydroxylations of substrates housing basic
nitrogen moieties requiring Brønsted acid protection
were uniquely effective under conditions B, with no
desired product being observed under the low catalyst
loading (0.1 mol%) conditions A (Table 3). The
temperature influence on yield was substrate
(R,R)-Mn(PDP) 3 (10 mol%)
ClCH2COOH (15 equiv.)
Me
Me
H
OH
OBz
OBz
H2O2 (5 equiv.)
MeCN, 3 h, -36 ºC
29
97% e.e.
30, 43%, 2:1 3º:2º
97% e.e.
Equation 1. Stereoretention Study.
dependent: whereas
a
benzimidazole substrate
afforded slightly higher yield of 25 under the 0 ºC
conditions, the analogous imidazole substrate gave ca.
16% higher yield of 26 at -36 ºC. A challenging
The chemoselectivity and reactivity observed with
Mn(PDP) catalysis in the presence of
3
4
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10.1002/adsc.201901472
Advanced Synthesis & Catalysis
pharmaceutically
relevant
aromatic
and
heteroaromatic moieties provides an opportunity for
late-stage diversification of drug scaffolds.
Evaluation of an efavirenz derivative 31, the parent
compound being a WHO essential medicine for HIV,
afforded tertiary hydroxylated product 32 in 53%
isolated yield under condition B with no protection of
the non-basic carbamate nitrogen. In addition to
demonstrating high chemoselectivity for the -
systems of an aromatic and alkyne moiety, Mn(PDP)
3 tertiary oxidation also displayed preferential
reactivity for tertiary C—H bond oxidation versus
oxidation alpha to the heterocyclic nitrogen. Previous
Mn(CF3-PDP) 4 methylene oxidation of a hexanoyl
efavirenz derivative had also shown -system
tolerance when the alpha-nitrogen site was blocked
with a carbonyl moiety (vide infra, Fig. 3.B).[7]
Warming the reaction to 0 ºC or using the low
Mn(PDP) 3 catalyst loading condition A (0.1 mol%)
afforded product 32 with comparable diminishments
in yield to those noted in Table 2.
A. Efavirenz derivative
OH
H
H
H
Mn(PDP) 3 (x mol%)
acid (x equiv.)
Figure 3. Scale-up C—H Oxidations of Bioactive
Molecules.
a
a
N
O
Cl
N
Cl
O
O
H2O2 (x equiv.)
MeCN
O
CF3
32
H2O2 (equiv.) Temp. (ºC) Yield (%)
facilitate drug discovery processes. We examined
both Mn(PDP) 3 and Mn(CF3-PDP) 4 catalysts for
6.0 mmol scale tertiary and methylene oxidations of
pharmaceutically relevant substrates. Compound 35,
with a 4-fluoroarylpiperidine, a pharmacophore found
in opioids, such as ketobemidone and haloperidol,
was initially evaluated on a 0.3 mmol scale to explore
lower Mn(PDP) 3 catalyst loadings under condition B
that would be particularly relevant for large scale
oxidations (Figure 3.A). Using Mn(PDP) 3 condition
B (10 mol%), remote oxidation product 36 was
isolated in an optimal 66% yield. The catalyst loading
of Mn(PDP) 3 can be reduced to 5 mol% while
maintaining a preparatively useful 60% yield.
Underscoring the significance of the chloroacetic acid
additive, a switch to acetic acid under otherwise
CF3
31
3 (mol %)
Acid (equiv.)
ClCH2COOH (15)
ClCH2COOH (15)
AcOH (14)
10
10
0.1
5.0
5.0
2.5
-36
0
53
43
46
0
B. Cycloheximide derivative
Me
O
Me
O
H
Mn(PDP) 3 (10 mol%)
ClCH2COOH (15 equiv.)
H
OAc
OAc
Me
H
Me
OH
H2O2 (5 equiv.)
O
O
MeCN, 3 h, -36oC
N
O
N
O
Cl
Cl
34, 63%a
33
Figure 2. Late Stage C—H Oxidation of Pharmaceutical
optimal condition
B
furnished
a
comparable
Derivatives. a)Starting material recycled once.
diminishment in yield to decreasing the catalyst
loading to 2.5 mol% (42% vs 43%). Expectedly, the
0.1 mol% catalyst loading condition A afforded no
product with this basic piperidine substrate. From
these studies, we concluded the optimal conditions
for reaction scale-up would use 5 mol% catalyst
loading with chloroacetic acid additive. Following
piperidine protection using the HBF4 protection
strategy,[15] a 1.7 g (6.0 mmol) C—H hydroxylation
of 35 using 5 mol% Mn(PDP) 3 afforded 1.0 g (3.4
mmol) of tertiary hydroxyl product 36 in 56% yield.
We additionally examined the previously reported
Mn(CF3-PDP) 4 methylene oxidation of HIV-1 drug
efavirenz derivative 37. A similar reduction in
Mn(CF3-PDP) 4 loading from 10 mol% to 5 mol% on
a small scale (0.2 mmol) oxidation resulted in only
minor reduction in yield (58%  50%, see
Supporting Information). On a 2.5-gram scale (6
mmol), Mn(CF3-PDP) 4 at 5 mol% afforded ca. 41%
yield of 38 with 27% recovered starting material 37
Additionally, we evaluated an aryl-substituted
cycloheximide derivative 33, the parent compound
having broad antimicrobial activity, for remote
tertiary oxidation on the cyclohexanone core.
Consistent with previous observations, the imide
functionality was tolerated with no Brønsted acid
complexation.[15] Notably, Mn(PDP) 3 catalysis using
general condition B was tolerant of the newly
introduced aniline moiety, albeit electronically
deactivated, furnishing the tertiary hydroxylated
product 34 in excellent 63% yield.
Given the ability of Mn(PDP) 3 and Mn(CF3-PDP)
4 to catalyze chemoselective tertiary and methylene
C—H oxidations to access metabolites and perform
late-stage functionalization on medicinally relevant
candidates, we wanted to evaluate the ability to
perform these oxidation reactions on scales that
5
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10.1002/adsc.201901472
Advanced Synthesis & Catalysis
A 40 ml vial was charged with substrate (0.3 mmol, 1.0
equiv.), Mn(PDP) 3 (27.9 mg, 0.03 mmol, 10 mol%),
ClCH2CO2H (425 mg, 4.5 mmol, 15.0 equiv.) and a stir bar.
Acetonitrile (MeCN, 0.6 mL, 0.50 M) was added along the
wall to ensure all compounds were washed beneath the
solvent level and the vial was sealed with a screw cap
fitted with a PTFE/silicone septum. The vial was cooled to
-36 °C with a 1,2-dichloroethane/dry ice bath. A separate
solution of H2O2 (102 mg, 1.5 mmol, 5.0 equiv., 50% wt.
in H2O, purchased from Sigma-Aldrich) in MeCN (3.75
mL, 0.4 M) was loaded into a 10 mL syringe fitted with a
25 G needle and added dropwise to the stirring reaction via
a syringe pump over 3 h (1.25 mL h−1 addition rate) while
maintaining the reaction vial at -36 °C. Upon completion,
the reaction was concentrated in vacuo to a minimum
amount of solvent. The residue was dissolved in DCM and
washed with sat. NaHCO3 solution (caution: CO2 released)
to remove ClCH2CO2H. The aqueous layer was extracted
with DCM twice. The combined organic layer was dried
with Na2SO4, filtered and concentrated. The crude mixture
was purified by flash column chromatography to afford the
desired oxidation product. If this method gave low
conversion, an alternative addition protocol was used. See
Supporting Information Methods C and D.
(see Supporting Information). A simple recycle of the
recovered starting material 37 afforded 1.3 grams (3.1
mmol) of remote oxidation product 38 in 52% overall
yield.
Conclusion
We describe the development of the first general
conditions for chemoselective Mn(PDP) 3 catalyzed
tertiary C(sp3)—H hydroxylations in substrates
containing
a
broad range of aromatic and
heteroaromatic functionality. Systematic evaluation
of the previously reported[14] low loading conditions
for Mn(PDP) 3 (0.1 mol%) using acetic acid additive
illuminated that these conditions afford moderate to
good hydroxylation yields for simple halogenated
aromatics and non-basic heterocyclic substrates but
prove ineffective for molecules containing basic-
nitrogen heterocycles. The general oxidation
conditions reported in this work using Mn(PDP) 3
catalysis at higher catalyst loadings (5-10 mol%) in
combination with chloroacetic acid additive are
uniquely effective in the remote C—H hydroxylation
of medicinally important substrates housing basic
nitrogen functionality that must be masked with
Brønsted acid complexation prior to C—H oxidation.
Moreover, these conditions afford 10-15% higher
yields in halogenated aromatic and non-basic
heteroaromatic substrates. Given the relative
abundance of manganese and the ease of preparation
of Mn(PDP) 3 catalyst, we believe these general
conditions will find widespread use in late stage
Detailed experimental procedures and characterization data
for all new compounds are described in the supporting
information.
Crystallographic data for (S,S)-Mn(PDP) 3 can be obtained
free of charge from www.ccdc.cam.ac.uk/structures/ with
deposit number CCDC 1869257.
Crystallographic data for (S,S)-Mn(CF3-PDP) 4 can be
obtained
free
of
charge
from
www.ccdc.cam.ac.uk/structures/ with deposit number
CCDC 1964541.
diversification
of
pharmaceutically
relevant
molecules and the rapid identification of metabolites.
Acknowledgements
The authors thank L. Zhu and D. Olsen for assistance with NMR
spectroscopy, D. Gray and T. Woods for X-Ray crystallographic
studies.
Experimental Section
General Procedure for C—H Oxidation Condition A
Using 0.1 mol% Mn(PDP) Catalyst
Notes
A 40 mL vial was charged with substrate (0.3 mmol, 1.0
equiv), Mn(PDP) 3 (5 mM stock solution, 60 L, 0.3 mol,
0.001 equiv.), CH3COOH (0.24 mL, 4.2 mmol, 14.0
equiv.) and a stir bar. Acetonitrile (MeCN, 0.6 mL, 0.5 M)
was added and the vial was sealed with a screw cap fitted
with a PTFE/silicone septum. The vial was cooled to 0 ºC
with an ice/water bath. A separate solution of H2O2 (51.0
mg, 0.75 mmol, 2.5 equiv., 50% wt. in H2O, purchased
from Sigma Aldrich) in MeCN (3.75 mL, 0.2 M) was
loaded into a 10 mL syringe fitted with a 25G needle and
added dropwise to the stirring reaction via syringe pump
over 1 h (3.75 mL h−1 addition rate) while maintaining the
reaction vial at 0 ºC. Upon completion of addition, the
reaction was concentrated in vacuo to a minimum amount
of solvent. The residue was dissolved in DCM and washed
with sat. NaHCO3 solution. The aqueous layer was
extracted with DCM twice. The combined organic layer
was dried with Na2SO4, filtered and concentrated. The
crude mixture was purified by flash column
chromatography to afford the desired oxidation product.
ORCID
M. Christina White: 0000-0002-9563-2523
Rachel K. Chambers: 0000-0002-5747-9855
Jinpeng Zhao: 0000-0001-8006-137X
Connor P. Delaney: 0000-0002-6885-6011
Funding Sources
Financial Support for this work was provided by the NIH NIGMS
Maximizing Investigator’s Research Award MIRA (R35
GM122525). RKC was partially funded by a Sir Keith Murdoch
Scholarship from the American Australian Association.
Competing Interest
The University of Illinois has filed a patent application on the
Mn(CF3-PDP) catalyst for C—H oxidation in aromatic
molecules.
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6
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10.1002/adsc.201901472
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
FULL PAPER
Chemoselective Tertiary C—H Hydroxylation with
Mn(PDP)/Chloroacetic Acid Catalysis
Adv. Synth. Catal. Year, Volume, Page – Page
Rachel K. Chambers,a,b Jinpeng Zhao,a,b,c Connor P.
Delaneya and M. Christina Whitea,*
8
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