Simple and sustainable iron-catalyzed aerobic C-H functionalization of N, N-dialkylanilines

Article abstract of DOI:10.1021/ja402479r

Iron(III) chloride catalyzes the aerobic oxidation of tertiary anilines, including tetrahydroisoquinolines, to form reactive iminium ion intermediates that undergo Mannich reactions with silyloxyfurans, nitroalkanes, and other nucleophiles to give the cor

Full text of DOI:10.1021/ja402479r

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Article
Simple and Sustainable Iron-Catalyzed Aerobic
C-H Functionalization of N,N Dialkylanilines
Maxim O. Ratnikov, Xinfang Xu, and Michael P Doyle
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja402479r • Publication Date (Web): 04 Jun 2013
Downloaded from http://pubs.acs.org on June 5, 2013
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Simple and Sustainable Iron-Catalyzed Aerobic C-H Function-
alization of N,N-Dialkylanilines
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Maxim O. Ratnikov,† Xinfang Xu,† and Michael P. Doyle*
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20740, United States
Supporting Information Placeholder
aminals by O2. Hemiaminals are iminium ion reservoirs in Man-
ABSTRACT: Iron(III) chloride catalyzes the aerobic oxidation of
tertiary anilines, including tetrahydroisoquinolines, to form
nich reactions.8a Hence, we inquired if CuBr, FeCl3, or Co(OAc)2
could catalyze oxidative functionalization of an aliphatic C-H
bond adjacent to nitrogen of N,N-dialkylanilines in the most
atom economical fashion in the presence of a nucleophile.
reactive iminium ion intermediates that undergo Mannich
reactions with silyloxyfurans, nitroalkanes, and other
nucleophiles to give the corresponding butenolides , nitro
compounds, and α-substituted tetrahydroisoquinolines,
respectively, in good to excellent yields.
Initial investigations were carried out with 4-methyl-N,N-
dimethylaniline (1) in methanol under one atmosphere of O2.
The catalyst loading, solvent, concentration, temperature, and
the reaction time were kept the same as they were for the oxida-
tive Mannich reaction with TBHP.8a Evaluation of CuBr,
FeCl3•6(H2O), and Co(OAc)2 catalyzed oxidations 1 by O2 showed
that ferric chloride outperformed the other metal compounds,
forming the corresponding methoxy hemiaminal 2 in 50% yield
(eq. 1). Furthermore, ferric chloride showed the highest catalytic
activity among the studied metallic compounds reaching 71%
conversion with just 2.0 mole % (eq. 1). Presumably, a reduction
potential of Fe(III)/Fe(II) redox pair (+0.77V vs. NHE) matching a
potential of 1 (+0.97V vs. NHE)16 enables iron to shuttle electrons
to dioxygen better than Cu(II)/Cu(I) (+0.15V vs. NHE) and
Co(III)/Co(II) (+1.82V vs. NHE) redox pairs. Ferric chloride was
chosen for oxidative Mannich reactions with dioxygen.
Because of its natural abundance and electrochemical proper-
ties, iron as a catalyst is a desired goal for oxidative chemistry.1
Yet, despite its dominance in biological oxidations,2 iron cata-
lysts have been shadowed for many years by precious metals in
performance-driven catalytic oxidations of aliphatic C-H bonds,3
and these oxidations have commonly used peroxides4 rather
than dioxygen. Although many oxidative processes are of inter-
est, the oxidation of C-H bonds adjacent to nitrogen is one of the
most important and useful strategies for C-H functionalization
because this process forms iminium ions, substrates of Mannich
reactions,4f,5 that are widely used for the syntheses of natural
products and pharmaceuticals.6 The most efficient oxidative
Mannich reactions were developed for catalysis with rutheni-
um(II)7 and dirhodium(II)8 complexes and have relied on tert-
butyl hydroperoxide (TBHP) as the oxidant. Copper-based
methods with TBHP are mainly limited to oxidative reactions
with tetrahydroisoquinoline derivatives.4c,9 Here we report facile
vinylogous oxidative Mannich, aza-Henry reactions, and other
reactions of iminium ions with carbon nucleophiles catalyzed by
common ferric chloride in the absence of any additional ligands
with O2 as the oxidant.
H2
C
H3C
CH3
H3C
N
N
OMe
cat.
(1)
O2 (1 atm.),
MeOH,
40 oC, 2 h
Me
Me
2
1
75% conv., 32% yield
61% conv., 42% yield
71% conv., 50% yield
CuBr (5.0 mol %)
Co(OAc)2 (10.0 mol %)
FeCl3. 6(H2O) (2.0 mol %)
Copper(I) salts have been employed in catalytic aerobic oxida-
tive functionalizations by indoles, nitroalkanes, and isocyanides,
but they have been generally limited to reactions that occur at
the 1-position of tetrahydroisoquinolines.4c-f,10 Iron(0) and iron(II)
complexes were used as reagents11 or catalysts12 in cytochrome
P-450 inspired demethylation2a,13 of tertiary amines. Iron(II) and
iron(III) salts were investigated for the oxidative Mannich reac-
tions of N,N-dialkylanilines and tetrahydroisoquinolines with
carbon nucleophiles but they were only reported to be effective
with TBHP14 or di-tert-butylperoxide15 as the oxidant. Our recent
investigations of oxidative Mannich reactions8a with TBHP that
included those catalyzed by CuBr, FeCl3•6(H2O), and Co(OAc)2
suggested that 4-substituted N,N-dimethylanilines could under-
go oxidation in methanol to the corresponding methoxy hemi-
With FeCl3 as the catalyst, siloxyfuran 3, a known precursor of
γ-butyrolactones,17 was chosen as a nucleophile for the oxidative
vinylogous Mannich reaction. The ubiquitous γ-butyrolactone
fragments are widely used in synthesis18 and appear in pharma-
ceuticals,19 natural products,20 and biomass processing.21 The
Mannich adduct 4 was isolated in 72% yield using just 1.2 equiva-
lents of 3, with one atmosphere of O2, and 2.0 mole % of
FeCl3•6(H2O) (eq. 2).
This initial success prompted elaboration of reaction condi-
tions suitable for a large scope of N,N-dialkylanilines in the ferric
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The scope of the oxidative vinylogous Mannich reaction was
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3
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examined under the optimized conditions with representative
N,N-dialkylanilines which afforded butenolide products in 49-
87% yield (Table 2). Electron rich N,N-dimethylanilines formed
Mannich adducts in greater than 84% yield (entries 1-3). The
moderately electron deficient 4-fluoro-N,N-dimethylaniline af-
forded 7 in 66% yield (entry 4). The presence of two methyl
groups in the ortho positions of the aromatic ring of aniline fur-
nished butenolide 9 in 66% yield (entry 6). Unsymmetrical N-
chloride oxidative Mannich reaction by O2 (Table 1). Optimiza-
tion of FeCl3 loading for the oxidative vinylogous Mannich reac-
tion of 1 and 3 in methanol showed that conversions above 90%
could be achieved with just 2.0 mole % of ferric chloride (entries
1 and 2). The yield of 4 remained around 70% in the presence of
2.0 and 5.0 mole % of FeCl3 but fell to 10% with 10.0 mole %
loading of FeCl3 (entries 1-3), presumably because of a more
rapid alcoholysis of 3. Refluxing methanol decreased conversion
of 4 to 60% (entry 4). The use of air as the oxidant furnished 4 in
only 36% yield compared to 70% yield with only dioxygen (entry
5). In ethanol the oxidative Mannich reaction of 1 with 3 cata-
lyzed by 2.0 mole % of FeCl3 afforded an 80% conversion and a
94% isolated yield of 4 based on consumed 1 (entry 6). The use
of 5.0 mole % of FeCl3 furnished 4 in only 5% yield because of
rapid ethanolysis of siloxyfuran 3 (entry 7); that oxidation must
be significantly faster than alcoholysis of the silyloxyfuran, which
is also catalyzed by ferric chloride, is evident in this result. When
soluble FeCl2 was used in place of FeCl3 or with FeCl2:FeCl3 in a
10:1 ratio under the same conditions, the oxidative Mannich
product 4 was formed in less than 5% yield, and a majority of the
unoxidized 1 was recovered (entries 8-9). This latter result sug-
gests that dioxygen bound to iron(II) does not initiate the oxida-
tive Mannich reaction.
Table 2. Substrate scope of the FeCl3 catalyzed aerobic
oxidative vinylogous Mannich reaction of N,N-dialkyl-
anilines with siloxyfuran 3.
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entry methoda
product
isolated yield, %b
85
1
A
2
A
87
Table 1. Optimization of conditions of the FeCl3 catalyzed
oxidative vinylogous Mannich reaction with siloxyfuran 3.
3
A
B
84
66
4
5
6
B
A
72
cat.
load,
mol %
66
T,
°C
conv.
, %a
yield,
%
entry
oxidant solvent
b,c
1
2
2.0
5.0
O2
O2
O2
O2
air
O2
O2
O2
O2
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
EtOH
40
40
40
65
40
40
40
40
40
92
96
94
60
76
70
72
10
5
7
A
A
49
3
10.0
2.0
4
5
2.0
36
94
5
6
7
8d
2.0
80
100
<5
5.0
8
50c
10.0
10.0
EtOH
-
9e
EtOH
<5
-
a Method A: 2.0 mole % of FeCl3•6H2O in ethanol. Method B: 5.0 mol
a
1
b
Determined by H NMR spectroscopy from the ratio of the absorp-
% of FeCl3 • 6H2O in methanol. Isolated yield after column chromatog-
raphy on silica gel. c Diastereomer ratio is 3:1.
tion (2.89 ppm, s, 6H) corresponding to 1 and that of biphenyl (7.60 ppm,
b
d, J = 7.2 Hz, 4H) that was used as an internal standard. Isolated yield
c
after column chromatography on silica gel. Yield calculated based on
methyl-N-ethylaniline underwent selective reaction at only the
N-methyl group (entry 7), and the oxidative Mannich reaction of
N-phenyltetrahydroisoquinoline 15 occurred as expected at the
1-position with 11 isolated in 50% yield. These observations and
d
the amount of consumed 1. 99.99% Pure FeCl2 (10.0 mol%) was used
e
instead of FeCl3•6H2O. 99.99% Pure FeCl2 (10.0 mol%) and FeCl3•6H2O
(1.0 mol%) was used instead of FeCl3•6H2O.
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results are not unlike those found with TBHP as the oxidant un-
tions with indole, 1-methyl indole, and 1-methylpyrrole occurred
der Rh2(cap)4 catalysis.8b
under the standard conditions employed for the oxidative vi-
nylogous Mannich reaction to give high conversions but moder-
ate yields of the coupled products. Dimethyl malonate gave
moderate conversion and moderate isolated yield based on con-
sumed 15 even with 10 eq of the nucleophile. Reactions per-
formed in the presence of HFIP resulted in the same percentage
conversions and isolated yields as those performed in the ab-
sence of HFIP (see Supporting Information). Oxidation of
N-phenyltetrahydroisoquinoline 15 to form the corresponding
amide was a competing reaction, and the yield of this product
increased with increasing water content. As is also evident from
prior investigations with TBHP,9 phenylacetylene does not un-
dergo coupling with 15 under the mild conditions employed for
iron(III) catalyzed aerobic oxidations.
1
2
3
4
5
6
7
8
The generality of ferric chloride for catalysis of the oxidative
functionalization of C-H bonds adjacent to nitrogen with O2 as
the oxidant (Table 2) was assessed with nitromethane for the
aza-Henry reaction. Prior studies of TBHP or photolytic catalytic
oxidation reported efficient functionalization with N-
aryltetrahydroisoquinolines but only limited success with dial-
kylanilines.23 Consistent with this limitation, treatment of 1 in
nitromethane as solvent under the optimized conditions de-
scribed for aerobic oxidation with silyloxyfuran 3 in Table 2 gave
no aza-Henry or double addition products even with 10 mole %
of the iron(III) catalyst. Further increases in catalyst loading re-
turned only trace amounts of 13a, and addition of 0.5 mL of
methanol to the reaction mixture with stirring for 1-2 hour led to
the quantitative recovery of 1. The absence of oxidation of N,N-
diallkylaniline 1 indicated catalyst inhibition by the reactant
amine. However, performing the same reaction in ethanol as
solvent using 10 equiv of nitromethane gave 44% conversion and
a 32% isolated yield of 13a within 24 h. Efforts to trigger the iron
catalyzed reaction with various additives in nitromethane as
solvent revealed that weak acids promoted the oxidation to give
the desired product while organic bases did not (see Supporting
Information). With the addition of only a 1.0 equiv of 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP), the oxidative aza-Henry product
13a was obtained in 71% yield based on consumed 1 (eq 3, R = H),
and these conditions were optimal for the aza-Henry reaction.24
Formation of the double addition product 14a, which was as
high as 2:98 for 14a:13a in reactions without HFIP, was success-
fully minimized under these conditions.25
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Consistent with the compatibility of ferric chloride with ter-
tiary anilines and tetrahydroisoquinolines, as well as with the
previously established mechanism for the oxidative Mannich
reactions of these amines,8a we propose that the initiation step is
electron transfer between ferric chloride and the amine to pro-
duce radical cation 22 and iron(II) chloride (Scheme 1). This pro-
posal is compatible with the potentials of the Fe(III)/Fe(II) (+0.77V
vs. NHE) and amine/radical cation redox pairs (+0.79V-+1.08V vs.
NHE).26 The fate of the amine radical cation in arriving at the
iminium ion product is less certain, but hydrogen atom abstrac-
tion from the radical cation that produces the iminium ion di-
rectly is plausible, either directly27 or through iron(II)-bound di-
oxygen.1g The resulting peroxo species could then enter Haber-
Scheme 1. Plausible mechanism for ferric chloride cata-
lyzed aerobic oxidative C-H functionalization reactions.
The acid promoted Fe(III)/O2 conditions of the oxidative Man-
nich (aza-Henry) reaction were also effective for reaction of di-
methylaniline 1 with nitroethane (eq. 3, R = Me). Further investi-
gations
of
this
transformation
with
N-phenyl-
tetrahydroisoquinoline 15 and nitromethane, as well as ni-
troethane, showed higher reactivity for this reactant compared
to N,N-dialkylanilines, and the Mannich adducts 16 and 17 were
formed with high conversion in 83% and 75% isolated yield, re-
spectively, under optimized conditions (eq. 4). Addition of HFIP
minimized oxidation of 15 to the corresponding amide formed
by oxidation at the alpha position. The diastereomeric ratio for
17 was 2.0, which is between those reported for the copper(I)
bromide catalyzed oxidation by TBHP23a and the iridium(III) pho-
toredox catalysis of the same reaction.23b
Weiss or Fenton-like chemistry to complete the process.28 The
requirement of mild acid to effect the oxidative aza-Henry reac-
tion, either to inhibit coordination of iron(III) with the amine
reactant or to activate the nitroalkane, suggests that these con-
ditions may make possible a variety of other oxidative Mannich
To ascertain that this iron-catalyzed aerobic C-H functionali-
zation is generally applicable to a broad range of nucleophiles,
we examined the oxidative transformation of N-phenyl-
tetrahydroisoquinoline (15) in the presence of representative
nucleophiles whose coupling reactions due to TBHP oxidations
of 15 have been widely reported.4c,4f,7,9 As noted in eq 5, reac-
reactions that have previously been reported using TBHP.4c-
f,7a,9,14,29
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The oxidative protocol that we have reported allows facile
† Maxim O. Ratnikov and Xinfang Xu have contributed equally to
1
2
3
4
5
6
7
8
functionalization of an aliphatic C-H bond adjacent to nitrogen
with siloxyfuran, nitroalkanes, and other nucleophiles using a
commodity catalyst (FeCl3) and an atom-efficient oxidant (O2).
Given the exceptional simplicity of the reported procedure, we
anticipate that ligand free FeCl3 catalyzed oxidations by O2 will
be applied to a wide range of transformations, as we have illus-
trated with indols, pyrroles and methyl malonate, and will be
considered as possible pathways of corrosive degradations.30
this work.
ACKNOWLEDGMENT
Support for these investigations from the National Science
Foundation (CHE - 1212446) is gratefully acknowledged. MOR
thanks the Department of Education for a GAANN fellowship.
REFERENCES
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General Procedure for FeCl3 Catalyzed Oxidative Vinylo-
gous Mannich Reactions of N,N-Dialkylanilines with Silyloxy-
furan 3 in Ethanol. To a solution of the N,N-dialkylaniline (0.5
mmol) and siloxyfuran 3 (0.25 mmol, 0.5 equiv, 60 mg) in ethanol
(1.5 mL), FeCl3 • 6(H2O) (10 µmol, 2.0 mol %, 2.7 mg) was added
at room temperature. The vial was equipped with a balloon con-
taining only O2, and the resulting solution was stirred at 40 °C for
5 hours. A second portion of siloxyfuran 3 (0.50 mmol, 1 equiv.,
120 mg) was added to the solution and the reaction mixture was
stirred overnight at 40 °C under the atmosphere of O2. The reac-
tion mixture was then concentrated under reduced pressure, and
the reaction product was isolated by column chromatography on
silica gel.
General Procedure for the FeCl3 Catalyzed Oxidative Man-
nich Reaction of N,N-Dimethylanilines and 2-Phenyl-1,2,3,4-
tetrahydroisoquinoline in Nitroalkanes. To an oven-dried flask
containing a magnitic stirring bar, the amine (1.0 mmol), FeCl3 •
6(H2O) (20 mol %, 54.0 mg), nitroalkane (1.0 mL) and 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP, 0.1 mL) were added in sequence.
The vial was equipped with a balloon containing only O2, and the
resulting solution was stirred at 40 °C for 5 days. The reaction
mixture was then quenched with Et3N (0.3 mL) and concentrated
under reduced pressure, and the reaction product was isolated
by column chromatography on silica gel. The reactions of ni-
troethane and 15 were run for 7 days; and other reactions with
nitroalkanes were run for 5 days.
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General Procedures for the FeCl3 Catalyzed Oxidative
Mannich Reactions of 2-Phenyl-1,2,3,4-tetrahydroiso-
quinoline with Representative Nucleophiles in Ethanol. To a
solution of 2-phenyl-1,2,3,4-tetrahydroisoquinoline (1.0 mmol,
209 mg) and nucleophiles (2.0 mmol, 2.o equiv) in ethanol (2.0
mL), FeCl3 • 6(H2O) (20 mol %, 54.0 mg), was added at room
temperature. The vial was equipped with a balloon containing
only O2, and the solution was stirred at 40 °C for 5 days. The
reaction mixture was then quenched with Et3N (0.3 mL) and
concentrated under reduced pressure, and the reaction product
was isolated by column chromatography on silica gel.
ASSOCIATED CONTENT
Supporting Information
General procedures, summary of conditions for optimization,
and spectral characterization of previously unknown substrates
are included. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
mdoyle3@umd.edu
Notes
The authors declare no competing financial interests.
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