Tuning Selectivity in Aliphatic C-H Bond Oxidation of N-Alkylamides and Phthalimides Catalyzed by Manganese Complexes

Article abstract of DOI:10.1021/acscatal.7b02151

Site selective C-H oxidation of N-alkylamides and phthalimides with aqueous hydrogen peroxide catalyzed by manganese complexes is described. These catalysts are shown to exhibit substantially improved performance in product yields and substrate scope in comparison with their iron counterparts. The nature of the amide and imide group and of the N-alkyl moiety are shown to be effective tools in order to finely tune site selectivity between proximal (adjacent to the nitrogen) and remote C-H bonds on the basis of steric, electronic, and stereoelectronic effects. Moreover, formation of the α-hydroxyalkyl product in good yield and with excellent product chemoselectivity was observed in the reactions of the pivalamide and acetamide derivatives bearing an α-CH₂ group, pointing again toward an important role played by stereoelectronic effects and supporting the hypothesis that these oxidations proceed via hydrogen atom transfer (HAT) to a high-valent manganese-oxo species. Good product yields and mass balances are obtained in short reaction times and under mild experimental conditions when relatively low loadings of an electron-rich manganese catalyst are used. The potential utility of these reactions for preparative purposes is highlighted in the site-selective oxidation of the pivalamide and phthalimide derivatives of substrates of pharmaceutical interest.

Full text of DOI:10.1021/acscatal.7b02151

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Article
Tuning Selectivity in Aliphatic C-H Bond Oxidation of N-
Alkylamides and Phthalimides Catalyzed by Manganese Complexes
Michela Milan, Giulia Carboni, Michela Salamone, Miquel Costas, and Massimo Bietti
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02151 • Publication Date (Web): 25 Jul 2017
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Tuning Selectivity in Aliphatic C−H Bond Oxidation of N-Alkylamides and Phthalimides
Catalyzed by Manganese Complexes
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Michela Milan1, Giulia Carboni2, Michela Salamone2, Miquel Costas1,* and Massimo Bietti2,*
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1 QBIS Research Group, Institut de Química Computacional i Catàlisi (IQCC) and Departament de
Química, Universitat de Girona, Campus Montilivi, Girona E-17071, Catalonia, Spain.
2 Dipartimento di Scienze e Tecnologie Chimiche, Università “Tor Vergata”, Via della Ricerca
Scientifica, 1 I-00133 Rome, Italy.
ABSTRACT. Site selective C−H oxidation of N-alkylamides and phthalimides with aqueous
hydrogen peroxide catalyzed by manganese complexes is described. These catalysts are shown to
exhibit substantially improved performance in product yields and substrate scope when compared
with their iron counterparts. The nature of the amide and imide group and of the N-alkyl moiety are
shown to be effective tools in order to finely tune site-selectivity between proximal (adjacent to the
nitrogen) and remote C−H bonds on the basis of steric, electronic and stereoelectronic effects.
Moreover, formation of the α-hydroxyalkyl product in good yield and with excellent product
chemoselectivity was observed in the reactions of the pivalamide and acetamide derivatives bearing
an α-CH2 group pointing again towards an important role played by stereoelectronic effects and
supporting the hypothesis that these oxidations proceed via hydrogen atom transfer (HAT) to a high
valent manganese-oxo species. Good product yields and mass balances are obtained in short
reaction times and under mild experimental conditions when using relatively low loadings of an
electron rich manganese catalyst. The potential utility of these reactions for preparative purposes is
highlighted in the site-selective oxidation of the pivalamide and phthalimide derivatives of
substrates of pharmaceutical interest.
KEYWORDS: C−H oxidation, manganese and iron catalysts, hydrogen atom transfer,
stereoelectronic effects, selectivity, amides, phthalimides
INTRODUCTION
The selective functionalization of aliphatic C−H bonds in organic molecules represents one
of the main challenges of modern synthetic organic chemistry because of their inert character and
because selectivity is hampered by the multitude of C−H bonds, that differ only slightly in terms of
their electronic and steric properties. Increasing efforts have been devoted towards meeting this
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rewarding research goal, by pursuing metal catalyzed reactions that could implement site-selectivity
in C−H functionalization reactions.1-6
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A breakthrough towards the development of selective aliphatic C−H oxidation
methodologies for organic synthesis was disclosed in the studies of White and coworkers, using
nonheme nitrogen-ligated iron coordination complexes as catalysts, and hydrogen peroxide as
oxidant.7-8 Selectivity rules for the C−H oxidation reaction were clearly defined on the basis of
steric, electronic and stereoelectronic effects, and a reaction mechanism proceeding through an
initial hydrogen abstraction step was proposed.9-10 By taking into consideration these elements, a
reliable prediction of oxidation sites could be deduced in several substrates, including complex
natural products. Related manganese complexes have been more recently shown to follow the same
selectivity patterns, but their use remains much less explored.11-12 Catalyst dependent selectivity
distinct from the innate relative reactivity of C−H bonds can also be introduced by employing
highly structured catalysts.13-16 On one hand, sterically crowded catalysts favor oxidation of
secondary over tertiary C−H bonds, because, despite being weaker, the latter are sterically more
demanding.13-15 On the other hand, chiral bulky catalysts can also exhibit chirality dependent site
selectivity in the oxidation of steroids.13
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Amines represent an especially important class of organic compounds, that serve in
particular as the basic structure of a variety of natural products, bioactive molecules and organic
materials. The tolerance of this functional group to metal catalyzed oxidation reactions is however
particularly critical. Besides of their strong tendency to bind and deactivate metal centers, amines
can be also easily oxidized.17 Quite importantly, functionalization of amine substrates, when
achieved, selectively occurs at the strongly activated C−H that is α to the nitrogen center.18-30
Remote aliphatic C−H bond oxidation of amines with iron and manganese catalysts was recently
reported.31-33 In these works protonation of the amine, or formation of Lewis acid-base amine-BF3
adducts, electronically deactivated the amine moiety and the C−H bonds that are adjacent to the
nitrogen center, favoring selective oxidation at remote positions (Scheme 1a).
Along this vein, amide functionalities are also very interesting because, by decreasing
nucleophilicity at the nitrogen center, they can be employed as protecting groups for primary and
secondary amines, and the functionalization of these substrates can thus expand the structural
elaboration of amine-containing targets. Moreover, highly efficient C−H oxidation of
monosubstituted cyclohexanes has been recently described with manganese catalysts, where an N-
cyclohexyl amide moiety was the key to enable high levels of regio- and enantioselectivity,34
highlighting a very powerful role of this functional group in defining selective C−H oxidation
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reactions. In this study it was proposed that enantioselectivity arises in the C−H cleavage step via
hydrogen atom transfer (HAT) to a chiral high valent manganese-oxo species, followed by a fast
hydroxyl rebound towards the incipient carbon centered radical.
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a) Previous works
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H
R
R'
N
n
n
H
H
H
H
H
H+ or BF3
oxidation
R'
R
R'
or
R'
RHN
N
n
n
H
H
H
O(H)
R
N
Always remote oxidation
F3B
H
b) This work
OMe
Me
N
Me
O
H
α
-C-H oxidation
N
Mn
N
R
N
H
OTf
OTf
N
O
N
remote C-H oxidation
Me
Me
OMe
H
O
(S,S)-[Mn(OTf)2(dMMpdp)]
Scheme 1. The influence of medium (a) and structural (b) effects on site-selectivity in aliphatic
C−H bond functionalization of amine and amine-derived substrates
Besides the utility of the amide moiety as an amine protecting group, selective oxidation of
the aliphatic C−H bonds of these substrates is also of considerable interest in modern organic
synthesis. With secondary and tertiary amides bearing N-alkyl groups and with N-acyl cyclic
amines, oxidation generally occurs at the C−H bonds that are α to nitrogen yielding α-hydroxylated
products that are rapidly converted into imides, a useful functional group that has multiple
applications.26, 35-40 Quite importantly, isolation of the first formed α-hydroxy derivatives was only
achieved in a very limited number of cases,41-43 despite of the fact that such products can represent
versatile intermediates for further synthetic elaboration.44 Therefore, amide substrates constitute a
very promising platform for the development of selective C−H oxidation procedures, where control
over site (intramolecular) and product (intermolecular) selectivity can be particularly challenging
but highly rewarding.
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Within this framework, we reasoned that amide moieties have the potential to be developed
into powerful directing groups for site-selective C−H functionalization because their electronic
properties and steric demand can be uniquely tuned. For example, the acyl moiety can be changed
from a strong electron withdrawing group such as trifluoroacetyl to the weaker acetyl one, and the
electron withdrawing character can be further increased by conversion into an imide derivative. On
the other hand, sterically demanding acyl moieties, such as pivaloyl, can be envisioned to impact on
the accessibility of the different C−H bonds of the substrate, translating into site-selectivity. With
these considerations in mind, in this work aliphatic C−H bond oxidation of N-alkylpivalamides,
acetamides, trifluoroacetamides and phthalimides bearing 1-pentyl, 2-(5-methylhexyl) and 1-(3-
methylbutyl) groups bound to nitrogen (structures S1-S12 displayed below in Table 1), has been
explored using iron and manganese catalysts and hydrogen peroxide as the oxidant. The three series
of substrates were chosen in order to allow a thorough evaluation of the role of structural and
electronic effects on the C−H functionalization selectivity, taking advantage of the methylenic C−H
bonds present in the N-pentyl derivatives (S1-S4), the combination of a tertiary α-C−H bond with a
tertiary δ-C−H bond in the N-2-(5-methylhexyl) derivatives (S5-S8), and the combination of an α-
CH2 group with a tertiary γ-C−H bond in the N-1-(3-methylbutyl) derivatives (S9-S12).
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The results obtained show that with manganese catalysts the nature of the amide and imide
group and of the N-alkyl moiety effectively tunes site-selectivity between proximal (adjacent to the
nitrogen) and remote C−H bonds on the basis of steric, electronic and stereoelectronic effects
(Scheme 1b). Good product yields and mass balances are obtained in short reaction times and under
mild experimental conditions when using relatively low loadings of an electron rich manganese
catalyst, highlighting the potential utility of these reactions for preparative purposes. Quite
importantly, in the reactions of the pivalamide and acetamide derivatives bearing a CH2 group α to
nitrogen, good yields and excellent selectivities were observed for the formation of the α-
hydroxyalkyl product.
RESULTS AND DISCUSSION
The oxidation of N-pentylpivalamide (S1) with hydrogen peroxide catalyzed by different
iron and manganese complexes was initially explored. Catalysts tested are based on chiral iron and
manganese complexes bearing tetradentate ligands, and with general formula [M(CF3SO3)2(L)] (L =
mcp, and pdp, mcp = N,N′-dimethyl N,N′-bis(2-pyridylmethyl)-1,2-trans-diamino cyclohexane, pdp
= N,N′-bis(2-pyridylmethyl)-2,2′-bipyrrolidine), whose structures are displayed in Scheme 2, all of
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which have been recently described to be particularly efficient in aliphatic C−H oxidation
reactions.7-8, 11-13, 16, 34, 45-48 The results of these reactions are shown in Table 1.
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Mx
R1
-H
-H
-H
-H
R2
-H
-H
-H
-H
R3
-H
Fe(pdp)
Mn(pdp)
Fe(mcp)
Mn(mcp)
Fe(dMMpdp)
Mn(dMMpdp)
Mn(dMMmcp)
Mn(Clmcp)
Fe(Me2Npdp)
Mn(Me2Npdp)
Fe(TIPSmcp)
Mn(TIPSmcp)
Mn(TIPSpdp)
R2
N
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R2
N
-H
R1
R3
R1
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-H
-H
-Me -OMe
-Me -OMe
-Me -OMe
-Me
-Me
-Me
-H
OTf
OTf
OTf
N
N
M
M
N
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OTf
-H
-H
-H
-H
-H
-H
-Cl
-NMe2
-NMe2
-H
N
N
-H
-H
R1
R3
-Si(iPr)3
-Si(iPr)3
-Si(iPr)3
R1
R3
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R2
-H
-H
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M(Xpdp)
Mn(BzImpdp) -BzIma
Mn(CF3mcp)
-H
-H -Ph(CF3)2
Scheme 2. Diagram of the iron and manganese complexes studied. aN-methylbenzimidazole instead
of pyridine.
Table 1. Oxidation of N-pentylpivalamide (S1) with Different Catalysts
Entry
Catalysts
Fe (pdp)
Conv %a
< 2%
64
Yield P1 %a
Yield P0 %a
1b
2
-
41
-
-
15
-
Mn (pdp)
Fe (mcp)
3b
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10
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4
Mn (mcp)
Fe (dMMpdp)
5b
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Mn (dMMpdp)
Mn (dMMmcp)
Mn (Clmcp)
99
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Fe (Me2Npdp)
Mn (Me2Npdp)
Fe (TIPSmcp)
Mn (TIPSmcp)
Mn (TIPSpdp)
Mn (BzImpdp)
Mn (CF3mcp)
Mn (dMMpdp)
9b
-
60
11
65
52
98
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10
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16c
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aConversions and yields determined from crude reaction mixtures by GC or 1H NMR. bReaction conditions: Fe catalyst
c
(3 mol %), H2O2 (2.5 equiv), AcOH (1.5 equiv) in CH3CN at 0 °C during 30 min. Cyclopropanecarboxylic acid was
used instead of acetic acid.
Standard conditions for the reactions catalyzed by the manganese complexes involved
syringe pump delivery of H2O2 (3.0 equiv) to an acetonitrile solution of the catalyst (1 mol %) and
AcOH (13 equiv) in CH3CN at −40 °C during 30 min. Exploration of the simplest catalysts of the
series, Fe(pdp), Mn(pdp), Fe(mcp) and Mn(mcp) (entries 1-4) reveals that only the manganese
catalysts oxidize the substrate, with the bipyrrolidine Mn(pdp) catalyst being more efficient than
the cyclohexanediamine Mn(mcp) one. The negligible conversion observed with Fe(pdp) and
Fe(mcp) highlights the challenge that these substrates represent for the iron complexes. With the
two manganese catalysts the product deriving from C−H hydroxylation in α to nitrogen (P1) was
obtained in poor (10%, entry 4) to moderate (41%, entry 2) yield, together with smaller amounts of
pentanal. Despite of the electron withdrawing character of the amide group, the nitrogen atom in
pivalamide S1 is still sufficiently electron rich to activate the α-C−H bonds. No products deriving
from oxidation at C2-C5, nor from oxidation of the primary t-Bu C−H bonds were observed.
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Remarkably, no evidence for the formation of the corresponding imide, which is the most common
product resulting from oxidation of the C−H bonds that are α to nitrogen in N-alkylamides,38 was
observed. Pentanal presumably arises from oxidative C−N bond cleavage. Control experiments
showed that P1 does not convert into pentanal under the reaction conditions, indicating that the
latter is formed via a path that competes with α-C−H hydroxylation.49 Improved yields, from
moderate to good, were obtained when electron donating methyl and methoxy groups
(Mn(dMMpdp) and Mn (dMMmcp)) were introduced at pyridine positions 3, 4 and 5 of the
manganese complexes (entries 6 and 7). Making the catalyst more electron rich partially rescues
activity also in the case of iron catalysts, thus Fe(dMMpdp) provides oxidation products but in low
yield (entry 5), far from the values obtained with the manganese analogue (entry 6). On the other
hand, the more electron poor catalyst Mn(Clmcp) delivered only very low product yields (entry 8).
This apparent correlation between catalytic activity and electron donating ability of the ligand
follows that observed in epoxidation reactions.50-51 However, the use of the electron-rich
Fe(Me2Npdp) and Mn(Me2Npdp) catalysts, which have proven particularly active in olefin
epoxidation reactions,51 but are quite sensitive to harsh oxidation conditions, affords no product or
only 14% of the α-C−H hydroxylation product (entries 9 and 10). Improvement in product yield
was also observed by the use of manganese catalysts where bulky groups like the tris-
(isopropyl)silyl (TIPS) were introduced at positions 3 of the pyridine rings (entries 12-13). In this
case, the cyclohexanediamine system Mn(TIPSmcp) performs substantially better than the
bipyrrolidine one Mn(TIPSpdp), in line with our previous observations on the oxidation of N-
cyclohexyl amides.34 In addition, other manganese complexes were included in the catalyst
screening; namely Mn(BzImpdp), where the pyridine rings were replaced by N-methylbenzimidazole
(BzIm) rings, and Mn(CF3mcp) where 2,6-bis-trifluoromethylphenyl groups were appended to
position 3 of the pyridines of the mcp ligand (entries 14 and 15). None of these catalysts improved
the outcome of the reaction. Finally, cyclopropanecarboxylic acid was used instead of acetic acid in
reactions with the Mn(dMMpdp) catalyst (entry 16). This acid is sterically more demanding than
acetic acid and has recently proven particularly effective in regio and enantioselective C−H
oxidation of N-cyclohexyl amides with similar manganese catalysts.34 As compared to acetic acid,
the reaction furnished reduced yields of P1 and pentanal as the only products, in similar relative
ratios, although the mass balance of the reaction was particularly good. Therefore, on the basis of
this screening, Mn(dMMpdp) in combination with acetic acid was selected as the catalyst and
carboxylic acid partner of choice for the oxidation of the three series of N-alkylamide and
phthalimide substrates, in order to study in detail the effect of N-alkyl structure and of functional
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group structure and electronics on yield and site-selectivity of the reaction. The product
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distributions observed in the oxidation of the N-pentyl (S1-S4), N-2-(5-methylhexyl) (S5-S8) and
N-1-(3-methylbutyl) derivatives (S9-S12) catalyzed by Mn(dMMpdp) are displayed in Tables 2, 3
and 4, respectively.
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Table 2. Oxidation of Different N-Pentyl Derivatives
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Yield PX %a
Entry/ Substrate (SX)
Conv %a
Yield P0 %a
(Isolated)
99
60 (48)
11
1
2
3
S1
S2
S3
89
64
40b
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13
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1
b
aConversions and yields determined from crude reaction mixtures by GC or H NMR. In a larger scale catalysis
experiment driven to complete substrate conversion, 36% yield of product P2 and 36% yield of the overoxidized imide
c
product were isolated together with pentanal (determined by GC) in 11% yield. Iterative addition (2x): cat (1 mol %),
H2O2 (3.0 equiv), AcOH (13 equiv) in CH3CN at -40 °C during 30 min.
Starting from the reactions of the N-pentyl derivatives, the results displayed in Table 2 show
that replacement of the sterically demanding pivaloyl (S1) for acetyl (S2) and for the more electron
withdrawing trifluoroacetyl (S3) (Table 2, entries 1-3) did not alter site selectivity, as clearly shown
for all three substrates by the formation of products P1, P2 and P3, respectively deriving from α-
C−H bond hydroxylation. Interestingly, the imide product was only observed in the oxidation of S2,
when the reaction was driven to full substrate conversion. Under these conditions formation of the
α-hydroxylation and imide products in a 1:1 ratio was observed, supporting the hypothesis of a
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higher reactivity of the substrate S2 as compared to first formed product P2 in the Mn(dMMpdp)
catalyzed reaction, and indicating that the imide product derives from overoxidation of P2.
Pentanal, that as mentioned above presumably derives from oxidative C−N bond cleavage, was
again identified in the reaction mixtures as side product. The decrease in conversion and product
yield observed on going from S1 and S2 to S3 is in line with the electrophilic character of the
intermediate manganese oxo complex and the electron withdrawing effect of the CF3 group that, as
compared to t-Bu and Me groups, deactivates the α-C−H bonds toward oxidation.
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Most interestingly, on going from the N-pentylamides to N-pentylphthalimide (S4), a
dramatic change in site selectivity was observed in the reactions catalyzed by Mn(dMMpdp) (Table
2, entry 4), where exclusive formation of the δ-ketoamide product resulting from oxidation at the
most remote methylene site of the pentyl moiety was detected. This behavior can be explained on
the basis of the increased electron withdrawing ability of the phthalimido group that, as compared to
the acyl ones, strongly deactivates the α-C−H bonds, as well as the β- and γ- ones, towards
oxidation, showing in particular that in these reactions site-selectivity can be drastically changed
through a simple synthetic modification of a parent amine substrate. The remote functionalization
observed in the reaction of S4 is in agreement with the results of recent studies on aliphatic C−H
bond oxidation of N-pentyl, N-cyclohexyl and N-cycloheptyl derivatives, where in all cases, the
phthalimido group provided the highest selectivity for the most remote methylene group.34, 52-54
However, in partial contrast to the present study, Alexanian and coworkers have recently shown that
sterically demanding amidyl radicals, generated photochemically from N-bromo and N-
chloroamides, react with N-pentylphthalimide leading, in addition to the δ-haloimide, to the
formation of sizable amounts (18-19%) of products deriving from halogenation at other sites.52-53
This comparison points towards an important role of the Mn(dMMpdp) catalyst in defining this
exquisite C−H oxidation selectivity that may reflect a higher steric demand of the reactive
manganese-oxo species as compared to the amidyl radicals, but it may also denote a higher and less
discriminate HAT reactivity of the later, a hypothesis that is well supported by the observation of
small amounts of products deriving from halogenation of the terminal methyl group.52-53
Moving then to the oxidation of the N-2-(5-methylhexyl) derivatives (S5-S8), characterized
by the presence of a tertiary α-C−H bond and a tertiary C−H bond at the remote δ-position, the
main product observed is in all cases the hydroxylated product PX that derives from oxidation at the
δ-C−H bond (Table 3, entries 1-4). This result is in sharp contrast with the oxidations of S1-S3, that
selectively occurred at the proximal α-methylene site (Table 2, entries 1-3). A second compound,
PX_a appears as a significant side product in the reactions of the least deactivated pivalamide (S5)
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and acetamide (S6) substrates and as a minor product in the reaction of the trifluoroacetamide one
(S7). Formation of this cyclic product can be explained on the basis of α-C−H oxidation of the first
formed product PX followed by cyclization. The observation that the relative importance of product
PX_a over PX increases with increasing conversion, together with the increased yield in PX_a
observed on going from S5 to S6, and the very low yield or lack of this product observed in the
reactions of S7 and S8, respectively, strongly support this hypothesis, reflecting the contribution of
steric (faster α-C−H oxidation of P6 as compared to P5) and electronic effects (slower α-C−H
oxidation of P7 as compared to P5 and P6) on the formation of this product.
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Table 3. Oxidation of Different N-2-(5-methylhexyl) Derivatives
Yield PX %a
(isolated)
Yield PX_a %a
(isolated)
Entry
1
Substrate
Conv %a
93
77 (52)
41 (36)
84 (58)
13
34 (33)b
2
S5
S6
S7
99
90
2
3
1
b
aConversions and yields determined from crude reaction mixtures by GC or H NMR. P6_a was isolated with 11%
yield of a non-identified impurity that could not be separated.
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The lack of products deriving from tertiary α-C−H bond oxidation in S5-S7 can be
reasonably explained on the basis of the operation of stereoelectronic effects. As described in a
recent time-resolved kinetic study on HAT from N-alkylamides to a representative oxygen centered
radical such as cumyloxyl (CumO•), a ∼9-fold decrease in the kH value for HAT from the α-C−H
bonds was measured on going from N-ethylpivalamide to N-isopropylpivalamide.55 It was proposed
that the introduction of a methyl group on the α-carbon increases the energy barrier required to
reach the most suitable conformation for HAT where the α-C−H bonds are aligned with the amide
π-system (structure A in Scheme 3), accounting for the observed decrease in reactivity.
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H
CH3
O
C
tBu
O
tBu
O
CH(CH3)2
H
C
H
C
H
tBu
N
H
H3C
CH3
H3C
A
B
Scheme 3. Conformational equilibrium for rotation around the N−CH(CH3)2 bond in N-
isopropylpivalamide.
Along these lines, a similar explanation can be put forward to account for the regioselectivity
observed in the present study in the Mn(dMMpdp) catalyzed oxidation of S5-S7. Quite importantly,
this observation supports the hypothesis that the reactions of alkanamides with CumO• and the
oxidations catalyzed by manganese complexes described in this work involve a common HAT step.
Of notice, an analogous regioselective oxidation of a trifluoroacetamide substrate strictly
related to S7, namely N-(2-(6-methylheptyl)trifluoroacetamide, with the [Fe(pdp)(CH3CN)2](SbF6)2
catalyst was previously described and rationalized on the basis of the electron withdrawing α-C−H
deactivation determined by the trifluoroacetyl group.7 The current results indicate instead that
stereoelectronic effects are at the basis of the observed regioselectivity.
Along the same vein, a very recent study on the aliphatic α-C−H functionalization of N-Boc
protected ethyl methyl amine and isopropyl methyl amine via the combination of photoredox, nickel
and HAT catalysis, pointed towards steric effects as a rationale for the predominant alkylation of
the primary α-C−H bonds of the methyl groups over the weaker secondary and tertiary ones.56 Also
in this case, stereoelectronic effects can be reasonably invoked to account for this peculiar
selectivity, pointing once again towards the very important role played by these effects in governing
site-selectivity in HAT based functionalization of aliphatic C−H bonds that are α to sp2 nitrogen
atoms, such as those of amide and carbamate substrates.
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Particularly relevant in the context of the oxidation of N-2-(5-methylhexyl) derivatives is the
observation that with the phthalimide derivative S8 the reaction progresses with excellent yield and
mass balance (Table 3, entry 4), leading to exclusive oxidation at the remote tertiary position, with
no formation of the secondary oxidation product P8_a.
9
Finally, the oxidation of N-1-(3-methyl)butyl derivatives S9-S12 was evaluated. In this case,
the proximal position is a methylenic site, that was envisioned to compete with the oxidation of a
tertiary C−H bond at a remote γ-position. In line with the previous observations (Tables 2 and 3), in
the reactions of the pivalamide (S9) and acetamide (S10) derivatives the α-CH2 position is activated
toward oxidation, and the proximal hydroxylated products P9_b and P10_b were preferentially
obtained in good isolated yield (Table 4, entries 1 and 3), while the remote oxidized products P9_c
and P10_c were observed only in low or very low amount. This can be explained on the basis of a
stronger activation of the α-C−H bonds as compared to the remote tertiary C−H bonds determined
by the presence of the amide nitrogen atom. It is possible to notice that the presence of the bulkier
pivaloyl group as compared to acetyl can reduce the extent of α-oxidation, however a good to
excellent selectivity for this oxidation site was observed for both substrates (PX_b:PX_c = 4.7:1
and 33:1; Table 4, entries 1 and 3, respectively). The formation of P9_b and P10_b, with no
evidence of overoxidation to the corresponding imide products, highlights once again the ability of
this catalyst to perform oxidation of amide C−H bonds with very high levels of product selectivity.
The origin of this unusual chemoselectivity can be explained on the basis of the stereoelectronic
effects discussed above (see Scheme 3), where α-hydroxylation increases the energy barrier
required to reach the most suitable conformation for HAT from this position where the α-C−H
bonds are aligned with the amide π-system. It can also be proposed that intramolecular hydrogen-
bonding between the α-hydroxyl and carbonyl groups plays a role in this respect, preventing
optimal overlap of the α-C-H bond with the amide π system.
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On the other hand, the presence of EWG groups led to a dramatic change in site selectivity. The
predominant or exclusive formation of the product deriving from remote tertiary C−H bond
hydroxylation PX_c was obtained with the trifluoroacetamide or phthalimide substrates (S11 and
S12, respectively, Table 4, entries 5 and 7) with modest to good isolated yields and very good to
outstanding levels of selectivity (PX_b:PX_c from 1:22 to <1:99, Table 4, entries 5 and 7,
respectively). Very striking is the observation that the phthalimide derivative S12 undergoes
exclusive oxidation at the remote position, highlighting once again the powerful role of this
functional group in governing site-selectivity.
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Table 4. Oxidation of Different N-1-(3-methylbutyl) Derivatives
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10
11
12
13
14
15
Yield PX_b %a
(isolated)
Yield PX_c %a
(isolated)
Selectivity
PX_b / PX_cb
Entry
1
Substrate
Conv %a
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17
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20
21
22
23
24
25
26
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28
29
30
31
32
33
34
35
36
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93
66 (64)
7
4.7:1
S9
2c
<2
95
<2
91
55
-
-
-
S9
66 (65)
1
-
33:1
3
S10
4c
-
7
-
S10
S11
S11
77 (48)
1:22
1:6.5
5
6c
11
36
1
b
c
aConversions and yields determined from crude reaction mixtures by GC or H NMR. Normalized Ratio. Reaction
conditions: Fe(pdp) (3 mol %), H2O2 (2.5 equiv), AcOH (1.5 equiv) in CH3CN at 0 °C during 30 min.
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Finally, the poor performance of the iron analogues of the Mn(pdp) and Mn(dMMpdp)
catalysts was further investigated. It was noticed that with the Fe(pdp) and Fe(dMMpdp) catalyst
catalytic oxidation of amide substrates bearing activated α-C−H bonds (S1, S9 and S10) did not
proceed or provided very low product yields (Table 1, entries 1 and 5; Table 4, entries 2 and 4).
Instead, oxidation of amide substrates where oxidation takes place preferentially at remote positions
(S4, see Supporting Information, and S11, Table 4, entry 6) occurred with improved (albeit still
modest) yields. We reasoned that the α-hydroxylated product may inhibit the catalyst, presumably
by chelation through the O-carbonyl and the α-OH groups. Consistent with this proposal, no
oxidation products were obtained when a typical catalytic oxidation reaction of S10 (50 equiv with
respect to the catalyst) with Fe(pdp) was performed in the presence of P10 (50 equiv with respect
to the catalyst). Furthermore, reaction mixtures of the oxidation of S1, S9 and S10 with the iron
catalysts rapidly turned intense purple/blue following addition of hydrogen peroxide, suggesting the
immediate formation of iron species that exhibit low energy charge transfer transitions. Charge
transfer from extended π systems of the ligand to a FeIII center are usually associated with these
spectroscopic features.57-61 In addition, high resolution mass spectrometry monitoring of the
reaction of Fe(pdp) with S10 under standard conditions showed cluster ions at m/z = 261.1294 that
can be assigned to {[Fe(pdp)(S10)+O-H]}+2 ions. Taken together, these observations suggest that
P10 chelates and effectively deactivates the iron catalysts, while manganese counterparts do not
appear to be affected suggesting that they are more labile and less sensitive to chelation.
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With these results in hand we decided to probe the versatility of this approach in the
oxidation of more complex bioactive molecules bearing primary amine moieties as a main structural
feature. For this purpose, pivalamide and phthalimide derivatives of drug molecules such as
pregabalin (Lyrica) and the antiviral drug rimantadine (Flumadine), whose structures are shown in
Scheme 4, were chosen as substrates.
As expected, the Mn(dMMpdp) catalyst performs the oxidation of these molecules in
satisfactory yields, with site selectivity that can be predicted on the basis of the amine
derivatization. In line with the results shown in Table 4, oxidation of the pivalamide derivative of
pregabalin (S13, Scheme 4) occurs preferentially at the most activated CH2 position that is α to
nitrogen, yielding amido γ-lactone compound P13_a derived from cyclization of the first formed
product, that results from hydroxylation at this methylenic site, with the carboxylic group.
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a
Scheme 4. Oxidation of bioactive molecules. Iterative addition (3x): cat (2 mol %), H2O2 (3.5
equiv), AcOH (13 equiv) in CH3CN at -40 °C during 30 min. Isolated yields.
The oxidized amido δ-lactone product resulting from hydroxylation at the remote tertiary
C−H site (P13_b) was observed only in lower amount (P13_a/P13_b = 3.9). No evidence for
functionalization at the tertiary C−H bond that is β to both the amido and carboxyl groups was
observed, in line with the deactivation of this site determined by the presence of the latter group. On
the other hand, when pregabalin is derivatized with the strong electron withdrawing phthalimido
group (S14, Scheme 4), oxidation catalyzed by Mn(dMMpdp) provides exclusively the amido δ-
lactone product (P14) deriving from remote tertiary C−H hydroxylation, in good isolated yield
(60%). On the other hand, the nature of the amine protecting group did not alter site selectivity in
the oxidation of rimantadine derivatives S15 and S16 (Scheme 4). In both cases, products deriving
from hydroxylation of two and/or three tertiary C−H bonds of the adamantane skeleton were
observed. Moreover, removal of the methyl group that is α to nitrogen (S17, Scheme 4), did not
change the reaction regioselectivity. Product P17, resulting from hydroxylation of two adamantane
tertiary C−H bonds, is the mayor product, along with a smaller amount of the trihydroxylated one.
Products deriving from oxidation at the α-C−H bonds were not observed, pointing towards the
strong activation of adamantane tertiary C−H bonds and suggesting moreover an important
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contribution of steric and stereoelectronic effects imposed by the presence of the bulky adamantly
4
5
moiety towards deactivation of the α-CH2 site.
6
7
8
CONCLUSIONS
9
The present work describes the oxidation of aliphatic amides and phthalimides with aqueous
H2O2 using manganese catalysts. Amides are demonstrated to be superior functional groups for
modulating site selectivity in these reactions, playing an activating or deactivating role on proximal
C−H bonds on the basis of electronic, steric and stereoelectronic factors. The phthalimido group
constitutes a unique case because its powerful electron withdrawing character strongly deactivates
proximal C−H bonds and consistently directs oxidation towards the most remote position. Also
remarkably, amides that present a methylenic site that is α to nitrogen are hydroxylated at this
position with excellent product chemoselectivity, providing a straightforward entry into this
challenging class of molecules. This hydroxylation reaction is remarkable because most oxidation
methods reported in the literature consistently lead to the imide product and highlights in particular
the powerful role of the manganese catalyst in governing selectivity. Presumably, the HAT nature
of the current reactions and the associated stereoelectronic effects lay at the basis of this unusual
chemoselectivity. Taken together, the current work discloses a site- and product selective and
predictable C−H oxidation methodology with potential applicability to molecules of interest in
modern organic chemistry, including substrate platforms of pharmaceutical relevance.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free of charge on the ACS
Publications website. Experimental details on the preparation and characterization of the catalysts,
experimental procedures for the catalytic reactions, spectroscopic data for the products.
AUTHOR INFORMATION
Corresponding Authors
*bietti@uniroma2.it
*miquel.costas@udg.edu
ACKNOWLEDGMENTS
M.C. acknowledges financial support from MINECO of Spain (CTQ2015-70795-P) and the Catalan
DIUE of the Generalitat de Catalunya (2009SGR637). M.C. thanks an ICREA-Academia award.
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