Iron-catalyzed Cα-H oxidation of tertiary, aliphatic amines to amides under mild conditions

Article abstract of DOI:10.1002/anie.201507738

De novo syntheses of amides often generate stoichiometric amounts of waste. Thus, recent progress in the field has focused on precious metal catalyzed, oxidative protocols to generate such functionalities. However, simple tertiary alkyl amines cannot be used as starting materials in these protocols. The research described herein enables the oxidative synthesis of amides from simple, noncyclic tertiary alkyl amines under synthetically useful, mild conditions through a biologically inspired approach: Fe-catalyzed C_α-H functionalization. Mechanistic investigations provide insight into reaction intermediates and allow the development of a mild C_α-H cyanation method using the same catalyst system. The protocol was further applied to oxidize the drug Lidocaine, demonstrating the potential utility of the developed chemistry for metabolite synthesis. Let′s iron it out! The title reaction enables the oxidative synthesis of amides directly from tertiary, noncyclic alkyl amines under synthetically useful, mild conditions through a biologically inspired approach employing oxidative iron catalysis. Mechanistic studies suggest that hemiaminals are likely intermediates in this reaction and that the catalytic system can be employed for other C_α-H oxidations of amines.

Full text of DOI:10.1002/anie.201507738

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201507738
German Edition: DOI: 10.1002/ange.201507738
Amine Oxidation
À
Iron-Catalyzed Ca H Oxidation of Tertiary, Aliphatic Amines to
Amides under Mild Conditions
Christopher J. Legacy, Anqi Wang, Brian J. OꢀDay, and Marion H. Emmert*
Abstract: De novo syntheses of amides often generate stoi-
chiometric amounts of waste. Thus, recent progress in the field
has focused on precious metal catalyzed, oxidative protocols to
generate such functionalities. However, simple tertiary alkyl
amines cannot be used as starting materials in these protocols.
The research described herein enables the oxidative synthesis
of amides from simple, noncyclic tertiary alkyl amines under
synthetically useful, mild conditions through a biologically
À
inspired approach: Fe-catalyzed Ca
H functionalization.
Mechanistic investigations provide insight into reaction inter-
À
mediates and allow the development of a mild Ca H cyanation
Scheme 1. Fe-catalyzed synthesis of amides from aliphatic trialkyl-
amines.
method using the same catalyst system. The protocol was
further applied to oxidize the drug Lidocaine, demonstrating
the potential utility of the developed chemistry for metabolite
synthesis.
CYP enzymes with respect to tertiary alkyl amines, resulting
À
T
he synthesis of amides is one of the most important organic
in amide synthesis, oxidative dealkylation, or Ca H cyanation
depending on the chosen water content, oxidant loading, and
nucleophile in the reaction mixture.
reactions, due to their prevalence in materials (e.g. Kevlar),
biopolymers (e.g. proteins), and biologically active com-
pounds. However, classical syntheses of amides require the
activation of carboxylic acids to achieve the desired bond
formation and thus lack in atom economy.[1,2] Owing to the
importance of amides and the shortcomings of classical
methods, protocols for greener amide formations are highly
desirable.[1] In contrast to chemical syntheses, biological
To mimic the biological oxidant combination O2/NAD-
(P)H,[12] various oxidants were initially evaluated in combi-
nation with FeCl3 as catalyst precursor. Several common
oxidants with peroxide substructures and hypervalent iodine
reagents (see SI)[11a,13–27] were not effective in promoting the
desired transformation. However, employing the peroxide
esters PhCO3tBu or H3CCO3tBu resulted in low yields of the
desired amide 1 (Table 1, entries 1 and 2).
pathways catalyzed by Cytochrome P450 (CYP) achieve
amide formations through amine Ca H functionalizations.
[3,4]
À
Recent efforts to synthetically mimic this reactivity and
achieve direct amine-to-amide conversions have employed
Cu or supported Ru catalysts for primary amines as sub-
strates.[5,6] Secondary cyclic amines can be converted into the
corresponding lactams by Au nanoparticles[7] or a Ru pincer
catalyst.[8] However, efficient amine-to-amide oxidations have
only been realized for primary, secondary, cyclic, or benzylic
amine substrates (Scheme 1).[5–10] Notably, these protocols
lack generality and are unreactive for functionalizations of
simple, acyclic tertiary alkyl amines.[11] Because of this gap in
the knowledge, our studies aimed at establishing a method-
ology for the challenging oxidation of tertiary, aliphatic
amines to amides. We report herein a versatile and tunable
iron-based catalyst system which imitates the reactivity of
Further studies were aimed at identifying suitable ligands
for Fe to promote the desired reactivity, which resulted in
identification of picolinic acid (2; Figure 1) as additive, which
Table 1: Reaction optimization and background.[a]
Entry Conditions
Yield
[%]
1
2
MeCO3tBu (2 equiv), 1008C
PhCO3tBu (2 equiv), 1008C
3
3
4
5
6
PhCO3tBu (4 equiv), 1008C
10
16
15
35
13
PhCO3tBu (4 equiv), 2 (5 mol%), 1008C
PhCO3tBu (3 equiv), 2 (5 mol%), 1008C
PhCO3tBu (3 equiv), 2 (5 mol%), 1008C
PhCO3tBu (3 equiv), 2 (5 mol%), 508C
7[b]
8
[*] C. J. Legacy, A. Wang, B. J. O’Day, Prof. M. H. Emmert
Department of Chemistry and Biochemistry
Worcester Polytechnic Institute
9[c]
10
11
12[c]
PhCO3tBu (3 equiv), 2 (5 mol%), H2O (11 equiv), 508C 58
no oxidant, 2 (5 mol%), H2O (11 equiv), 508C
no FeCl3·6H2O, 508C
no FeCl3·6H2O, 508C
0
15
0
100 Institute Road, Worcester, MA (USA)
E-mail: mhemmert@wpi.edu
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201507738.
[a] Conditions: Tri(n-propyl)amine (95 mL, 71 mg, 0.50 mmol,
1.00 equiv), FeCl3·6H2O (6.8 mg, 0.025 mmol, 5.0 mol%), pyridine
(1.80 mL), 24 h. [b] 5.0 mL pyridine. [c] Under N2 atmosphere.
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we oxidized NnBu3 under a N2 atmosphere, using 11 equiv of
H218O (97% 18O; Scheme 2B); notably, 89% incorporation of
18O into product 9 was observed. In contrast, subjecting the
product to the reaction conditions did not result in more than
3%
18O incorporation
(Scheme 2C),
which
makes
18O exchange in the product after amide formation unlikely.
Overall, these data suggest that 18O is introduced into the
product in an intermediate. Potential pathways are nucleo-
philic attack of H218O at a possible iminium intermediate or
direct amine hydroxylation by a 18O-labeled Fe–oxo species.
Furthermore, the reaction time (see SI) also has a distinct
influence on the yield, indicating that the optimal yield is
achieved after 8 h. Lower yields thereafter indicate that the
amide products are slowly decomposing under the reaction
conditions.
Figure 1. Ligands used in optimization.
provided 16% yield when used in a 1:1 ratio with FeCl3
(Table 1, entry 5). Lower or higher loadings of 2 resulted in
lower yields (Table S2 in the Supporting Information (SI)),
while other ligands (see Figure 1 and the SI) did not improve
the observed yield of amide (7–9%).
Interestingly, the FeCl3/2 catalyst system does not require
high temperatures and is active at 508C, forming 13% of
amide 1 (Table 1, entry 8; see SI for other temperatures
tested). In addition, optimizing the water content of the
reaction mixture at this temperature (Table 1, entry 9)
resulted in an even higher, synthetically useful 58% yield of
1. No product formation (Table 1, entry 10) was observed in
the absence of oxidant as well as in the absence of Fe under
a N2 atmosphere (Table 1, entries 9 and 12). However,
reactions in the absence of FeCl3 in air showed a background
reaction (15%; Table 1, entry 11), which could be suppressed
with 50 mol% TEMPO as radical scavenger (see SI).
A more detailed study of the influence of water on
product formation is shown in Scheme 2. Interestingly, very
low and very high water loadings do not promote amide
formation (Scheme 2A). Observation of a strong dependence
of product formation on the water content suggests that H2O
is inherently involved in the mechanism of the reaction and
possibly the source of the O atom incorporated into the amide
product. In order to trace the source of incorporated oxygen,
The significant dependence of amide formation on the
H2O concentration in the reaction medium further suggests
that amide formation—just as in biological systems—is only
À
one possible outcome of the Ca H oxidation of amines and
depends on the concentration of water and oxidation
equivalents present at the catalytically active site. Thus, we
analyzed a crude reaction mixture after 24 h by GCMS to gain
a better understanding of potential side products. Interest-
ingly, both double oxidation products and dealkylation
products were observed (for details see the SI). Based on
this observation, we postulated that the selectivity for amide
formation versus dealkylation should be determined by the
relative rates of dealkylation versus oxidation of a common
hemiaminal intermediate. To test this hypothesis, we per-
formed a series of experiments in which the H2O/pyridine
ratio was systematically changed from 1:17 to 1:0.2
(Scheme 3).
Scheme 3. Selectivity of product formation versus H2O loading.
Interestingly, a clear dependence of product selectivity on
the H2O concentration was observed, with higher amounts of
water favoring the formation of dealkylation product. Further
optimizations (see SI, Table S8) afforded the dealkylation
product N,N-dibutylamine in 64% yield; other substrates also
undergo oxidative dealkylation under these conditions (see
SI, Table S9). Overall, these studies suggest a reaction
mechanism similar to the mechanism postulated for CYP-
catalyzed oxidations of amines (Scheme 4).[28] This mecha-
nism accounts for the formation of both amide (C) and
oxidative dealkylation product (D) through a common hemi-
aminal intermediate (B). Accessing B from the amine
Scheme 2. a) Water addition, b) H218O incorporation, and c) back-
ground studies.
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Table 2: Substrate scope of amide formation with simple amines.[a]
Entry Substrate Product Conditions GC Yield
(isolated)
24 equiv
H2O, 2 h
1[b]
2
NEt3
52%
11 equiv
H2O, 6 h
N(nPr)3
N(nBu)3
63%
64%
Scheme 4. Mechanistic hypothesis. Path A represents a direct hydroxyl-
ation pathway; path B would be a stepwise electron and proton
abstraction.
11 equiv
H2O, 24 h (57%)
3
15 equiv 71%
4
N[(CH2)4CH3]3
H2O, 48 h (63%)
1 equiv 59%
substrate can proceed through two different pathways:
Path A suggests a radical rebound mechanism, while path B
proceeds through sequential electron and proton transfers.
The presence of a hemiaminal intermediate in our
reactions is further supported by in-situ FTIR detection of
5
N(CH2Ph)3
Et2NPh
H2O, 24 h (58%)
30 equiv
41%
6[c]
H2O, 6 h
a
reaction intermediate with characteristic hemiaminal
6 equiv
21%
bands[29] at n˜ = 1400, 1450, and 1600 cmÀ1. Based on these
data, we reasoned that amide synthesis should also proceed
under the established conditions when a hemiaminal is
accessible through a different pathway. To this end, a mixture
of di(n-propyl)amine and propionaldehyde (Scheme 5) was
subjected to the reaction conditions. After minor optimiza-
tions, amide 1 was obtained in 54% yield, suggesting that
hemiaminals are likely intermediates of oxidative amide
formation.
7
8
iPr2NEt
H2O, 24 h
9 equiv
29%
PhCH2N(nPent)2
H2O, 24 h
5 equiv
H2O, 24 h
9
HN(CH2Ph)2
54% (46%)
[a] Conditions: 2-picolinic acid (3.1 mg, 0.025 mmol, 5.0 mol%),
FeCl3·6H2O (0.025 mmol, 5.0 mol%), PhCO3tBu (280 mL, 291 mg,
1.50 mmol, 3.00 equiv), H2O (1 to 30 equiv), amine (0.50 mmol,
1.0 equiv), 508C, sealed vial. [b] 3.5 equiv PhCO3tBu. [c] 4 equiv
PhCO3tBu, 708C.
developed amine oxidation protocol might give access to
À
other Ca H functionalizations beyond amide formations.
Scheme 5. Amide formation from propionaldehyde and HNnPr2.
Thus, we added NaCN as nucleophile to a reaction mixture
with Me2NPh as substrate and obtained 16% unoptimized
yield of the a-aminonitrile 10 (Scheme 6). Further optimiza-
tions of H2O and oxidant loading as well as switching to KCN
as CNÀ source in combination with 30 mol% of 18-crown-6 to
solubilize KCN afforded 80% yield of 10, suggesting that
iminium intermediates (A; Scheme 4) are readily accessible
with the developed catalyst system.
To explore the scope of the developed catalytic system,
several tertiary amine substrates were tested under the
reaction conditions. The yields shown in Table 2 are opti-
mized for each substrate with respect to reaction time, H2O
and oxidant loading, and reaction temperature. For aliphatic,
tertiary amines, the obtained yields increased with the alkyl
chain length and the highest yield was observed for tri(n-
pentyl)amine (71%; Table 2, entry 4). Tribenzylamine was
also successfully employed (59%; Table 2, entry 5), suggest-
ing that the protocol is generally applicable for aliphatic and
benzylic amine substrates. The unsymmetrical amines
EtNiPr2, PhNEt2, and BnN(nPent)2 all provided lower yields
(21–41%; Table 2, entries 6–8). However, no starting materi-
als or dealkylation products were observed in these reactions,
suggesting that other side reactions are rapid with these
substrates (see SI). One secondary amine (Bn2NH; Table 2,
entry 9) was also oxidized using the protocol (54% GC yield
and 46% yield of isolated product). Unfortunately, other
secondary aliphatic amines (such as HN(nPent)2 or HNnBu2)
showed exclusively dealkylation products or amides
PhCONR2, which are likely derived from nucleophilic
attack of the amines at the oxidant. As the only tested aniline
substrate showed only low yields, we decided to test if other
À
Scheme 6. Ca H cyanation with an analogous catalytic system.
À
Finally, one goal for the Ca H functionalization of amines
is to mimic CYP activity to access putative metabolites.
Generally, establishing the identity of amine metabolites is
important, since such compounds can have altered biological
activities compared to the original amines.[30] Both amides and
dealkylation products are common metabolites.[31,32] In order
to demonstrate the feasibility of using the developed amine
oxidation protocols for the direct synthesis of metabolites, we
subjected the active pharmaceutical ingredient Lidocaine to
À
Ca H functionalizations would proceed more readily with
this type of substrate. We reasoned that modifications of the
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Scheme 7. Oxidation of Lidocaine, the pharmaceutically active ingre-
dient in Lidoderm.
The dealkylation product has previously been identified
as metabolite;[33] conversely, the biological relevance of the
amide product has not been reported. However, the change in
À
addition of 14 mass units by Ca H oxidation would be
analogous to the mass change caused by methylation, another
common metabolic reaction.[30] We thus conclude that the
developed amine oxidation protocol provides not only a pro-
tocol for the unprecedented synthesis of amides from tertiary
aliphatic amines, but also a method to distinguish between the
two metabolic pathways of methylation and amine to amide
oxidation, as the mild conditions enable the use of more
complex substrates than simple tertiary amines.
Overall, the studies detailed above show that PhCO3tBu
À
can be successfully employed in amine Ca H functionaliza-
tions and that the resulting Fe-catalyzed protocols show
À
promise for novel C H bond functionalizations of aliphatic,
benzylic, and aromatic amine substructures, which are
common in biologically active molecules. Thus, the protocol
can be expected to expedite the synthesis of oxidative
metabolites relevant for toxicity studies of pharmaceutically
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À
Keywords: C H functionalization · iron catalysis ·
metabolite synthesis · oxidation · reaction mechanism
How to cite: Angew. Chem. Int. Ed. 2015, 54, 14907–14910
Angew. Chem. 2015, 127, 15120–15123
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Received: September 23, 2015
Published online: October 16, 2015
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