Fe-Catalysed oxidative C-H/N-H coupling between aldehydes and simple amides

Article abstract of DOI:10.1039/c4cc01447b

A novel oxidative coupling of aldehydes with simple amides, most likely involving a radical process, was achieved through the use of an iron catalyst. Various amides were utilized as substrates to easily construct imides by coupling with aldehydes. A catalytic cycle involving the benzoyl halide intermediate is proposed based on our experimental results. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01447b

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Fe-Catalysed oxidative C–H/N–H coupling
between aldehydes and simple amides†
Jing Wang,a Chao Liu,a Jiwen Yuana and Aiwen Lei*ab
Cite this: Chem. Commun., 2014,
50, 4736
Received 25th February 2014,
Accepted 19th March 2014
DOI: 10.1039/c4cc01447b
www.rsc.org/chemcomm
A novel oxidative coupling of aldehydes with simple amides, most likely
involving a radical process, was achieved through the use of an iron
catalyst. Various amides were utilized as substrates to easily construct
imides by coupling with aldehydes. A catalytic cycle involving the benzoyl
halide intermediate is proposed based on our experimental results.
(1)
Recently, we initiated a program toward the aldehyde C–H
activation for preparing various carbonyl compounds.10 During the
course of our research, we were pleased to discover that an aldehyde
could be converted to the corresponding acyl chloride in the presence
of FeCl2 and TBHP (eqn (2)). Due to the unstable property of the
corresponding acyl chloride, the stoichiometric reaction was detected
by in situ IR.11 The kinetic profile of the reaction clearly revealed a new
component A which increased in intensity as the reaction proceeded
(Fig. 1(A)); this new component was assigned to be benzoyl chloride
by comparison with an authentic sample (Fig. 1(B)). This indicated
that acyl chloride could be prepared in situ with aldehydes and FeCl2
in the presence of TBHP. We envisioned that this acyl chloride
generation from aldehyde could be utilized in the direct synthesis
of imides from aldehydes and amides. Consequently, FeCl2 com-
bined with TBHP was initially applied to test the oxidative coupling of
aldehydes with amides to construct imides.
The oxidative coupling between R1H and R2H,1 which avoids the
use of organo halides (or halide equivalents) and organometallic
reagents, possesses practical advantages for applications and has
attracted much attention in recent years. Many advancements have
been made in this emerging field, in which main efforts have been
put on the oxidative cross coupling between two C–H bonds for the
construction of C–C bonds. In comparison, the direct oxidative
coupling between C–H and N–H for the construction of C–N bonds
has been less reported.2 The mainly utilized NH nucleophiles were
amines3 and special amides (such as picolinamide4 or primary
amides5). However, to the best of our knowledge, no reports have
been demonstrated by using simple chainlike secondary amides as
the nucleophiles to oxidatively couple with aldehydes for the
construction of imides.6
Imides7 are present in biologically active molecules and have
been targets of interest for the synthesis of pharmaceuticals8 such as
variotin, aniracetam, and several heterocycles,9 which are present in
abundance in biologically active natural products. As we know, the
use of acyl halides as acylation reagents is a common strategy to
construct imides,7a whereas the method is problematic due to the
unstable and corrosive properties of the corresponding acyl halides.
Comparatively, an aldehyde would be the elegant acylation reagent,
due to its wide availability and no release of halide waste. Herein, we
report a Fe-catalysed oxidative coupling approach for the construc-
tion of imides via acylation of simple amides with aldehydes as the
acylation reagents (eqn (1)).
(2)
a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan,
Hubei 430072, P. R. China. E-mail: aiwenlei@whu.edu.cn;
Fax: +86-27-68754067; Tel: +86-27-68754672
b National Research Center for Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang, Jiangxi 330022, P. R. China
Fig. 1 (A) Kinetic profile of the reaction. (B) IR spectra of component A
(blue curve) and the authentic sample of benzoyl chloride (red curve).
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc01447b
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Table 1 Impact of reaction parameters on Fe-catalysed oxidative cou-
pling of N-benzylacetamide with benzaldehydea
Entry
[M]
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
FeCl2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
AIBN
BPO
DCE
DCE
DCE
DCE
28
80
n.d.
Trace
n.d.
Trace
24
FeBr2
Fe(OAc)2
Fe(OTf)2
None
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
DCE
Benzene
Toluene
CH3CN
DCE
DCE
DCE
31
9
10
11
Trace
n.d.
Trace
n.d. = no desired product. TBHP = tert-butyl hydroperoxide, DTBP =
2-(tert-butylperoxy)-2-methylpropane, BPO = benzoic peroxyanhydride,
a
AIBN = azobisisobutyronitrile. Unless otherwise noted, the reaction was
carried out with 1a (0.5 mmol), 2a (1.5 mmol), oxidant (1.0 mmol), catalyst
(0.025 mmol), solvent (2.0 mL), 60 1C, 16 h, Ar. b The yield was determined
by GC analysis with dibenzo[b,d]furan as the internal standard.
We started our investigation by utilizing the reaction of
N-benzylacetamide 1a with benzaldehyde 2a as a model reaction
to test different reaction conditions. Selected data are listed in
Table 1. To our delight, as expected, a 28% GC yield of the desired
product 3aa was obtained by using 5 mol% FeCl2 as the catalyst
(Table 1, entry 1), indicating that a catalytic cycle was operating
under current conditions. Considering that acyl bromide is more
active than acyl chloride, FeBr2 was further tested. Indeed, the yield
of 3aa showed a remarkable improvement and an 80% yield of 3aa
was obtained (Table 1, entry 2). When FeBr2 was replaced by non-
halide containing iron salts such as Fe(OAc)2 or Fe(OTf)2, none or a
Scheme 1 Substrate scope of Fe-catalysed oxidative coupling of amide
with various aldehydes. a The reaction was carried out with 1 (0.50 mmol),
2 (1.50 mmol), TBHP (1.0 mmol of a 70% aqueous solution), FeBr2
(0.025 mmol), DCE (2.0 mL), 60 1C, 16 h, Ar. Yields shown are for isolated
b
products. The remainder of the starting materials was observed.
trace amount of desired product was obtained (Table 1, entries 3 C–I bond.12 However, the benzaldehyde bearing iodine group could
and 4), indicating that Fe catalyst precursors containing halogens be well tolerated in this oxidative coupling reaction (Scheme 1, 3ah).
were crucial for the coupling process. Without catalysts, no desired Other halo substituents, such as F, Cl, and Br, were also well
product was obtained (Table 1, entry 5). Solvent screening showed that tolerated (Scheme 1, 3ad, 3ae, 3af, 3ag, 3ai, and 3aj). These C–X
the desired product could be obtained in benzene or toluene, but only groups provided the possibility for further functionalization. The
in low yields which may result from the poor solubility of FeBr2 in benzaldehyde bearing o-Br afforded a relatively low yield, which may
these solvents (Table 1, entries 6 and 7). A 31% GC yield of the desired result from the steric hindrance effect (Scheme 1, 3ae). This ortho-
product 3aa was obtained in coordinating solvent CH3CN (Table 1, position effect has also been observed in the benzaldehydes bearing
entry 8). TBHP gave excellent yield for this oxidative coupling reaction. p-Cl, p-F, o-Cl, and o-F (Scheme 1, 3af, 3ag, 3ai, and 3aj). The
However, other oxidants such as DTBP, AIBN and BPO showed less or benzaldehyde derivative bearing an electron-withdrawing substituent
no efficiency (Table 1, entries 9–11). A ratio of 1 : 3 for 1a and 2a was such as the CF3 group gave moderate yield (Scheme 1, 3ak). The
found to be ideal and the product could be obtained in excellent yield. benzaldehyde derivative bearing an electron-donating substituent
From these experiments, we determined the optimized conditions to such as the OMe group afforded a lower yield (Scheme 1, 3al). It
be: FeBr2 (5 mol%), TBHP (2 equiv.), DCE, 60 1C, 16 h.
was noteworthy that the reaction with the aliphatic aldehyde
With the optimized conditions in hand, we started employing also proceeded well under the standard conditions to give the
other substrates in this Fe-catalysed oxidative coupling of aldehydes corresponding imide in a moderate yield (Scheme 1, 3am).
with amides to synthesize imides. First of all, various aldehydes were
Encouraged by these promising results, we further applied
employed to couple with N-benzylacetamide 1a. The results are the optimized conditions to test the substrate scope of amides.
summarized in Scheme 1. Benzaldehyde substituted with alkyl Aromatic amides afforded the corresponding imides in good
groups, such as o- and p-Me, reacted smoothly to afford the yields (Scheme 2, 3ba–3fa). Aromatic amides with electron-
corresponding imides in good yields (Scheme 1, 3ab and 3ac). donating substituents such as Me and OMe worked well under
Normally, Fe salts have been reported to react with the aromatic the optimized reaction conditions (Scheme 2, 3ca, 3da, 3ea, and 3fa).
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was conducted. However, only a 7% GC yield of the desired
product was obtained (eqn (4)), thus providing evidence that
the iron cation also played an important role in the catalytic
cycle and promotes the reaction efficiency.
(4)
To further assess the nature of the iron cation, the reaction
between 1b and 2a with FeBr2 or FeBr3 as the precatalyst was
investigated. The results are shown in eqn (5). Using FeBr2 as the
catalyst precursor, the reaction provided the desired product in an
89% GC yield. The reaction using FeBr3 as the catalyst precursor
gave an 88% GC yield. Similar results indicated that Fe(III) might be
involved in the catalytic cycle for this oxidative coupling.
Scheme 2 Substrate scope of Fe-catalysed oxidative coupling of amides
a
with benzaldehyde. The reaction was carried out with 1 (0.50 mmol), 2
(1.50 mmol), TBHP (1.0 mmol of
a 70% aqueous solution), FeBr2
(5)
(0.025 mmol), DCE (2 mL), 60 1C, 16 h, Ar. Yields shown are for isolated
b
products. The remainder of the starting materials was observed.
It is worth noting that an o-Me substituent has little negative
steric effect, affording the coupling product in an excellent
yield (Scheme 2, 3ca and 3fa). Unfortunately, aromatic amides
with electron-withdrawing substituents were not suitable for
the reaction under the standard conditions. Aliphatic amides
proceeded well in this oxidative coupling reaction (Scheme 2,
3ga, 3ha and 3ia). The desired product was obtained in 67%
isolated yield when a cyclic amide was applied (Scheme 2, 3ja).
To our delight, a substrate with the propionyl group also
worked well in this transformation (Scheme 2, 3la).
When investigating the mechanism of this Fe-catalysed oxi-
dative coupling of amides with aldehydes, the single electron
transfer (SET) process is considered. Generally, the aldehyde
could be easily converted to the corresponding acyl radical in the
presence of peroxides. Therefore, a radical-trapping experiment
was carried out. A 78% isolated yield of TEMPO-adduct aldehyde
4 was obtained when TEMPO was introduced into the reaction,
while the formation of 3aa was completely suppressed (eqn (3)).
This result provided good evidence that the acyl radical was
formed under the standard conditions.
Based on the above results, a plausible mechanism was
proposed in Scheme 3. In the first step, FeBr2 was oxidized by
TBHP to generate a Fe(III) species, bromine and an alkyloxy
radical which then abstracts hydrogen from the aldehyde to
generate the acyl radical. Subsequently, the acyl radical abstracts
a bromine atom from bromine to produce the acyl bromide. The
addition of an amide to acyl bromide afforded the desired
product along with an equivalent amount of hydrogen bromide
which may be oxidized by TBHP to recover the bromide source.
We have developed the first Fe-catalysed oxidative coupling
of amides with aldehydes to construct imides. By using a
simple catalytic system consisting of FeBr2,13 TBHP, and DCE,
a variety of amides and aldehydes could be directly transformed
into imides in moderate to good yields. Moreover, various
(3)
To elucidate the role of FeBr2 in the reaction, the reaction
Scheme 3 Proposed mechanism.
between 1b and 2a in the presence of a catalytic amount of Br2
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This work opens up a new approach for the construction of imides.
Preliminary mechanistic studies revealed that benzoyl halide might
be formed from the aldehyde and a catalytic amount of halide
source. Further studies on the mechanism are currently underway
and will be reported in due course.
This work was supported by the 973 Program (2012CB725302),
the National Natural Science Foundation of China (21025206,
21272180 and 21302148), and the Program for Changjiang Scholars
and Innovative Research Team in University (IRT1030) and the
Research Fund for the Doctoral Program of Higher Education of
China (20120141130002).
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