Iron-catalyzed oxidative amidation of acylhydrazines with amines

Article abstract of DOI:10.1016/j.tetlet.2021.153316

A new approach for amide bond formation via a mild and efficient Iron-catalyzed cross-coupling reaction of acylhydrazines and amines using TBHP as oxidant is described. This protocol is compatible with a wide range of amines and acylhydrazines. In addition, the synthetic application of the reaction is presented.

Full text of DOI:10.1016/j.tetlet.2021.153316

Tetrahedron Letters 80 (2021) 153316
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Tetrahedron Letters
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Iron-catalyzed oxidative amidation of acylhydrazines with amines
⇑
Yi-Jie Wang, Guo-Yu Zhang, Adedamola Shoberu, Jian-Ping Zou
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Soochow University, 199 Renai Street, Suzhou, Jiangsu 215123, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach for amide bond formation via a mild and efficient Iron-catalyzed cross-coupling reaction
of acylhydrazines and amines using TBHP as oxidant is described. This protocol is compatible with a wide
range of amines and acylhydrazines. In addition, the synthetic application of the reaction is presented.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 26 March 2021
Revised 3 August 2021
Accepted 4 August 2021
Available online 11 August 2021
Keywords:
Amide
Acylhydrazine
Iron-catalyst
Radical reaction
Cross-coupling reaction
Introduction
[40]. Meanwhile, the groups of Luca and Singh independently
reported the successful cross-coupling of acyl radicals with N-
Amide bond formation is a fundamentally important process in
organic synthesis. These kinds of bonds are not only present in bio-
logical systems (e.g. proteins), but are also key compositions of
many valuable pharmaceuticals, agrochemicals and natural/syn-
thetic polymers [1–9]. Indeed, according to a survey, the amide
bond was one of the most abundant functional groups encountered
in known drug databases [10]. The most frequently employed
method for amide bond formation involves the direct coupling of
pre- or ‘‘in situ” activated carboxylic acids with amines in the pres-
ence of a stoichiometric ‘‘coupling” reagent. Although this strategy
has proven to be useful as evidenced by the incredible success with
peptide synthesis [11–16], drawbacks include the large amounts of
generated waste. Afterwards, the efforts were focused on the
improvement of reaction, and many progresses had been made,
particularly in the area of catalytic [17–27] and dehydrogenative
coupling reactions [28–31].
chloroamines (Scheme 1c) [41–43]. Furthermore, Dyson described
a Pd-catalyzed carbonylation protocol involving the oxidative cou-
pling of C(sp3)–H bonds with CO and amines (Scheme 1d) [44]. In
spite of these advances, there is still need to develop efficient
methods that does not involve 1) the use of pre-activated amines,
2) the use of aggressive/hazardous reagents and/or expensive pho-
tocatalysts, 3) the generation of toxic or irremovable byproducts.
Acylhydrazines are stable compounds that are easily prepared
from acids or esters. They have been widely used as synthons for
the preparation of pharmaceuticals, agrochemicals, polymers [45]
and peptide synthesis etc [46–49]. Nevertheless, the use of acylhy-
drazines as acyl radical precursors for synthetic purposes have
been less explored [50–53]. In continuation of our efforts on the
development of cross-coupling processes towards efficient car-
bon-heteroatom bond formation [54–57], herein, we report an
Fe-catalyzed cross-coupling of acyl radicals generated from acylhy-
drazines with amines to construct amide bonds (Scheme 1e).
Oxidative radical cross-coupling reaction has proven to be one
of the most powerful strategies for forging various chemical bonds
[32–38]. Within the context of amide bond formation, this strategy
has been succesfully applied using a variety of reagents. For
instance, Lei’s group disclosed the formation of amide bonds via
Results and discussion
We began by investigating the feasibility of an oxidative cou-
pling reaction between benzoylhydrazine 1a and 4-toluidine 2a
in CH3CN at 80 °C (Table 1). Initially, the reaction was conducted
in the presence of K2S2O8 oxidant (Table 1, entry 1). Fortunately,
the expected N-(p-tolyl)benzamide 3a was formed when the
amount of 2a was doubled, albeit in low yield (Table 1, entry 2).
No product was detected when TBHP was used in lieu of K2S2O8
(Table 1, entry 3). Although the same reaction afforded 3a in 35%
the coupling of acyl radicals generated from a-keto acids with ami-
nes (Scheme 1a) [39]. Furthermore, Wan and co-workers employed
acyl radical precursors (generated from aldehyde) as coupling part-
ners with formamides to construct new amide bonds (Scheme 1b)
⇑
Corresponding author.
E-mail address: jpzou@suda.edu.cn (J.-P. Zou).
https://doi.org/10.1016/j.tetlet.2021.153316
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Yi-Jie Wang, Guo-Yu Zhang, A. Shoberu et al.
Tetrahedron Letters 80 (2021) 153316
Table 2, a variety of amines, including aromatic/aliphatic and pri-
mary/secondary substrates were suitable to the reaction. In the
case of anilines bearing para- or meta-electron-donating groups
such as methyl or methoxy, the reaction furnished the correspond-
ing products in good yields (3a, 3c and 3f). However, the yields of
anilines bearing ortho-substituents were noticeably affected by
steric hindrance as exemplified by products 3d and 3 g. Moreover,
this effect was more pronounced with the bulky 2-tert-butyl group
(3e). In addition, the reactions of anilines bearing electron-with-
drawing halogen groups afforded the desired products (3h-3j) in
moderate yields (55 ~ 61%), however, 4-nitroaniline could only
afford the corresponding product 3l in trace amount, probably
due to the greater electron-pulling effect of the –NO2 group. It is
noteworthy that the steric effect was more pronounced for ortho-
brominated aniline (3k, 28%). Furthermore, aliphatic amines were
found to be viable substrates. For instance, benzylamine and n-
hexylamine afforded the corresponding products 3m and 3n in
75% and 92% yields, respectively. Notably, the reaction of the sec-
ondary alkylated arylamine, N-methylaniline occurred smoothly
to give the desired amide 3o in 85% yield; meanwhile the sec-
ondary dialkylamines such as piperidine and diethylamine fur-
nished the desired products 3p, 3q in lower 38% and 35% yields,
respectively, it may attribute to the steric hindrance of amines;
but the reaction of the secondary diarylamine such as dipheny-
lamine did not give the desired product 3r. Unfortunately, amines
both in which the amine nitrogen atom is electron-deficient such
as benzamide, 4-methylbenzenesulfonamide, phthalimide and
heteroaromatic amines like 2-aminopyridine, pyrrole were largely
unreactive under standard conditions (3s ~ 3w).
Scheme 1. Amide bond formation.
yield when carried out at 120 °C, the efficiency was still not satis-
factory (Table 1, entry 4). Pleasingly, the use of FeCl3 as oxidant
resulted in a remarkable 84% yield of 3a (Table 1, entry 6). How-
ever, the requisite use of 4 equiv of FeCl3 is not desirable from an
economic standpoint. To this end, further optimizations were car-
ried out towards rendering the reaction catalytic. Fortunately, the
use of a catalytic amount of FeCl3 and 6 equiv of TBHP afforded
3a in 82% yield (Table 1, entry 7). Notably, the reaction efficiency
was still relatively maintained when conducted at room tempera-
ture (Table 1, entry 8), which might be beneficial in the case of
amino acids. Further attempts to improve reaction efficiency by
increasing the amount of amine were unsuccessful (Table 1, entries
9–10). Moreover, the catalytic behavior of other metal salts (such
as Ag and Cu) was investigated; while AgNO3 was ineffective, CuCl2
displayed good catalytic behavior, albeit in comparably lower
yields (Table 1, entries 11–13).
Next, we turned attention to investigating the scope of the reac-
tion with respect to a variety of acylhydrazines (Table 3). In con-
trast to the amine coupling partners, the reactions of
acylhydrazines were not noticeably influenced by either steric or
electronic factors. Both electron-rich and electron-deficient sub-
strates afforded good yields of the corresponding coupling prod-
ucts (4a-4g), it is noteworthy that the reaction of 4-
nitrobenzoylhydrazine gave the desired product 4h in 66% yield.
Notably, aliphatic acylhydrazines are also compatible under stan-
dard conditions to give the corresponding products (4i-4n) in good
yields.
With the optimized reaction conditions in hand, the scope of
the reaction with respect to amines was explored. As shown in
Table 1
Optimization of the reactiona.
Entry
1a:2a
Catalyst (10 mol%)
Oxidant (equiv)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
1:1
1:2
1:1
1:1
1:1
1:1
1:1
1:1
1:1.5
1:2
1:1
1:1
1:1
–
–
–
–
–
–
K2S2O8 (4)
K2S2O8 (4)
TBHP (6)
TBHP (6)
FeCl3 (4)
FeCl3 (4)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
K2S2O8 (4)
K2S2O8 (4)
24
24
24
2
24
2
2
12
2
trace
15
N.D.c
35d
85
84
FeCl3
FeCl3
FeCl3
FeCl3
CuCl2
CuCl2
AgNO3
82
70e
79
9
10
11
12
13
2
68
80
70
trace
24
24
24
a Reactions conditions: 1a (1 mmol%) and 2a (1 mmol) in CH3CN (5 mL) at 80° C under argon atmosphere. b Isolated yield. c N.D. means not detected. d at 120 °C. e at 25 °C.
2

Yi-Jie Wang, Guo-Yu Zhang, A. Shoberu et al.
Tetrahedron Letters 80 (2021) 153316
Table 2
(c = 0.32, CHCl3))) (Scheme 2a); then, the reaction was extended
Scope of aminesa.
to
D-phenylalanine 2ac, but the expected product 3ac was not
detected, it may attribute to the presence of a free carboxylic acid
group (Scheme 2b); therefore, the ester 2ad derived from 2ac was
then applied to the reaction, the expected product 3ad was
obtained in 75% yield, it also remained its optically pure (methyl
benzoyl-
D
-phenylalaninate [a]2D0 = À30.72 (c = 0.2, CHCl3 (lit. value:
23
[58] methyl benzoyl-L-phenylalaninate [
a]
= +35.1 (c = 0.60,
D
CHCl3)) (Scheme 2c). Finally, the reaction of optically pure aminoa-
cylhydrazine 2ag and aminoacid ester 2ad both of them derived
from D-phenylalanine 2ac was carried out, the expected product
3ae was obtained in 51% yield, it also remained its optically pure
(methyl (tert-butoxycarbonyl)- D-phenylalanyl-D-phenylalaninate
23
[a]
= À28.72 (c 10 mg/mL CHCl3) (lit. value: methyl (tert-butoxy-
D
25
carbonyl)-L-phenyl- alanyl-L-phenylalaninate [
a]
= +26 (c 10 mg/
D
mL, CHCl3) (Scheme 2d) [59].
In order to gain an insight into the reaction mechanism, some
control experiments were carried out (Scheme 3). Firstly, the addi-
tion of the radical trapping agent, 2,2,6,6-tetramethyl- 1-
piperidinyloxy (TEMPO, 4.0 equiv) to the reaction of benzoylhy-
drazine 1a with aniline 2b significantly inhibited the formation
of 3b; instead the compound 5, presumably formed from a benzoyl
radical capture by TEMPO was detected by LC–MS (Scheme 3a).
Meanwhile, in the absence of aniline 2b, the reaction of benzoylhy-
drazine 1a with TEMPO (2.0 equiv) under the standard conditions
afforded compound 5 in 92% yield (Scheme 3b). In order to know
whether benzoyl radical formed could be further oxidized to the
corresponding benzoyl cation [52], the same reaction as
Scheme 3b was performed in the solvent CH3CN:CH3OH (4:1)
and CH3OH. The results indicated that two cases afforded com-
pound 5 in 90% and 60% yield, respectively; while benzoic methyl
ester 6, presumably formed from a benzoyl cation capture by CH3-
OH, was not detected (Scheme 3c). In addition, compound 5 was
still isolated in 13% yield in the absence of FeCl3 catalyst
(Scheme 3d). These results implicate the possible participation of
benzoyl radical intermediate in the reaction, not including benzoyl
cation one.
Table 3
Scope of acylhydrazinesa.
Furthermore, the synthetic applicability of this protocol was
demonstrated by the reaction of optically pure aminoacid ester.
Benzoylhydrazine 1a underwent oxidative coupling with the L-
tryptophan ester 2ab under standard conditions to furnish product
3ab in 65% yield. Notably, the same reaction when carried out at
25 °C produced 3ab in 55% yield, 3ab remained its optically pure
On the basis of results obtained and related literature [60–66], a
plausible mechanism for this reaction is depicted in Scheme 4. As
illustrated in Table 1, since FeIII salt is critical for the cross-coupling
of acyl radical and amine, then it is reasonable that the iron cata-
lyst is largely responsible for mediating this process. Initially, FeCl3
20
23
([
a]
= +60.12 (c = 0.2, CHCl3 (lit. value: [58] [
a]
= +57.13
D
D
Scheme 2. Synthetic application.
Scheme 3. Control experiments.
3

Yi-Jie Wang, Guo-Yu Zhang, A. Shoberu et al.
Tetrahedron Letters 80 (2021) 153316
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
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Appendix A. Supplementary data
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