Metal-free oxidative amide formation with N-hydroxysuccinimide and hypervalent iodine reagents

Article abstract of DOI:10.1016/j.tetlet.2012.07.024

An oxidative amide formation using N-hydroxysuccinimide and hypervalent iodine reagents was developed. The method enables a wide range of aldehydes and amines to be coupled under mild reaction conditions providing amide in good to excellent yield. The radical species in the reaction mixture was observed for the first time using ESR measurement, and along with other mechanistic investigations, a plausible mechanism of the reaction was proposed.

Full text of DOI:10.1016/j.tetlet.2012.07.024

Tetrahedron Letters 53 (2012) 5094–5098
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal-free oxidative amide formation with N-hydroxysuccinimide and
hypervalent iodine reagents
⇑
Haoyi Yao, Yun Tang, Kana Yamamoto
Department of Chemistry and School of Green Chemistry and Engineering, University of Toledo, 2801 W. Bancroft St., Toledo, OH 43606, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An oxidative amide formation using N-hydroxysuccinimide and hypervalent iodine reagents was devel-
oped. The method enables a wide range of aldehydes and amines to be coupled under mild reaction con-
ditions providing amide in good to excellent yield. The radical species in the reaction mixture was
observed for the first time using ESR measurement, and along with other mechanistic investigations, a
plausible mechanism of the reaction was proposed.
Received 15 June 2012
Revised 3 July 2012
Accepted 6 July 2012
Available online 21 July 2012
Published by Elsevier Ltd.
Keywords:
Hypervalent iodine
Amide
Oxidation
N-Hydroxysuccinimide
Electron spin resonance
Tandem reactions have drawn significant attention in recent
years as an attractive green alternative to traditional multi-step
processes. They avoid the isolation of intermediates and curtail
the number of overall synthetic steps.1 Among tandem reaction,
oxidative esterification or amide formation of alcohols or alde-
hydes has become popular as a promising synthetic tool serving
as an alternative to conventional approaches requiring carboxylic
acid isolation. Research during the past decade resulted in signifi-
cant progress in this field establishing a number of successful oxi-
dative esterifications. On the other hand, despite numerous
reported elegant strategies,2 oxidative amide formations are less
established: Most reported methods have limited substrate scope,
and some use excess of coupling partners or precious metal
catalysts. Current state of art methods in oxidative amide forma-
tion have been reviewed.3 Recently, we reported the first aerobic
oxidative amide formation method using a catalytic amount of
Co(OAc)2 in combination with N-hydroxysuccinimide (NHSI)
(Fig. 1).4,5 This approach involves the NHSI-mediated oxidative
formation of NHSI ester 3, which is sufficiently reactive to undergo
amine displacement providing amide 5. The reaction can be ap-
plied to both aliphatic and aromatic aldehydes, and the mild reac-
tion conditions enable chiral amines to be introduced without
racemization. However, sterically or electronically deactivated
substrates were shown to suffer from competitive formation of a
by-product, carboxylic acid 4. In addition, unsaturated aldehydes
were not applicable.
Figure 1. Aerobic oxidative amide formation.
⇑
Corresponding author. Tel.: +1 419 530 1507; fax: +1 419 530 4033.
E-mail address: kana.yamamoto@utoledo.edu (K. Yamamoto).
0040-4039/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.07.024

H. Yao et al. / Tetrahedron Letters 53 (2012) 5094–5098
5095
Figure 3. Kinetic isotope effect measured with Singleton method.
8
iodine reagents or the conditions catalytic in PhI(OAc)2 were less
effective (see the Supplementary data).
To gain further insights into this reaction, a series of mechanis-
tic studies were performed using stoichiometric PhI(OAc)2 (Fig. 3).
Again utilizing 1a as a representative aldehyde, the kinetic isotope
effect (KIE) of the substitution of the aldehyde hydrogen with deu-
terium was examined using the method of Singelton.9 A mixture of
aldehyde 1a and the deuterated aldehyde 1a0 was subjected to the
reaction conditions, however the reaction was quenched before its
full conversion, and the recovered starting material was analyzed
for the ratio of parent and deuterated substrates. A large kinetic
isotope effect (ꢀ9.3) was measured for this reaction, indicating
that the abstraction of the aldehyde hydrogen is rate limiting in
the formation of the NHSI ester. The recorded KIE higher than
the theoretical maximum may be due to a quantum tunneling,
which has been observed in related oxidative reactions that use
nitroxide catalysts.10
To verify the presence of a radical intermediate, a series of elec-
tron spin resonance (ESR) experiments were performed under var-
ious conditions. When PhI(OAc)2 and NHSI were mixed in a 2:1
ratio, a clean ESR signal corresponding to the reported succinimide
N-oxy (SINO) radical A11 was observed (Fig. 4(a)). The signal for
this radical diminished within ꢀ10 min in the absence of reactant,
confirming its non-persistent nature.6a,12 In a separate 1H NMR
experiment, the same mixture showed immediate consumption
of PhI(OAc)2 and the formation of PhI and AcOH upon mixing of
the two reagents. Successive addition of benzaldehyde or aldehyde
1a to this mixture diminished the original ESR signal, and new sig-
nals began to emerge as shown in (b) and (c), respectively. We
attributed these spectra to hemiaminal radicals B and C. Both rad-
icals are elusive and diminish within a few minutes. Acyl radical
formation from free aldehyde was another possibility,13,14 however
it was not observed under our experimental conditions.
Figure 2. Aerobic oxidative amide formation.
Herein, we report the successful use of an alternative terminal
oxidant, hypervalent iodine reagents (PhI(OAc)2 or IBX) to effec-
tively suppress this unwanted side reaction. These oxidants effi-
ciently lead to amide formation via a two-step tandem reaction,
delivering significantly higher yields than previously reported.
Our new method also possesses broader scope demonstrated by
the coupling with an
a,b-unsaturated aldehyde, pivaldehyde, and
aniline. In addition, a plausible mechanism is proposed based on
detailed mechanistic investigation.
At the onset of our investigation, pathways to form carboxylic
acid byproducts under the original aerobic conditions4 were con-
sidered. We speculated that the reaction of NHSI with aldehydes
A proceeds through an intermediate radical, analogous to the
known nitroxide-mediated oxidations (Fig. 2).6 This led us to two
possible reaction pathways that could generate carboxylic acids
involving either the reaction of radical intermediate B with molec-
ular oxygen, or by hydrolysis of NHSI ester C. Investigation into the
stability of ester C revealed these derivatives to be highly stable to
hydrolytic conditions (see the Supplementary data), which led us
to assume that the radical mediated oxidative pathway is more
likely.
Thus, we embarked on screening for alternative oxidants that
suppress this undesirable side reaction (Scheme 1). Aldehyde 1a
was used as a test substrate, and was treated with 1 equiv of NHSI
and various oxidants. The reaction mixture was analyzed by deter-
mining the ratio of the amount of produced ester 3a and acid 4a by
1H NMR analyses. While the majority of the oxidants showed an
increased level of acid formation when compared to molecular
oxygen, two hypervalent iodine reagents, PhI(OAc)2 and IBX, exclu-
sively provided the desired NHSI ester 3a.7 Using other hypervalent
On the basis of the foregoing studies, a plausible mechanism of
the oxidative NHSI ester formation is proposed (Fig. 2). Mixing of
PhI(OAc)2 and NHSI results in the rapid formation of SINO.15 Addi-
tion of aldehyde A led to the presumably reversible formation of
hemiaminal A0. A slow (rate-determining) hydrogen abstraction
of the aminal hydrogen by SINO provides the observed hemiaminal
radical B, which rapidly undergoes the second oxidation with
PhI(OAc)2, either by direct oxidation or mediated by NHSI, to pro-
vide ester C.16
With improved reaction conditions to deliver the ester C now
identified, we examined its compatibility to coupling with primary
amines. Subjecting phenethylamine 2a to 1 equiv each of aldehyde
Scheme 1. The screening results of alternative oxidants.

5096
H. Yao et al. / Tetrahedron Letters 53 (2012) 5094–5098
Table 1
Tandem amide formation using hypervalent iodine reagents
Entry
1
Aldehyde
Conditions
Yielda (%)
90
NHSI (1.1 equiv), PhI(OAc)2 (1 equiv), MeCN, rt, 3–5 min; 2a (1 equiv)
2
3
NHSI (1.2 equiv), IBX (1 equiv), EtOAc, 90 °C, 2.5 h; 2a (2 equiv)
NHSI (2.5 equiv), IBX (2.2 equiv), EtOAc, 90 °C, 4.5 h; 2a (3 equiv)
42
57
4
NHSI (2.5 equiv), IBX (2.2 equiv), EtOAc, 90 °C, 3.5 h; 2a (4 equiv), 23.5 h
70
a
Isolated yield.
1a, NHSI, and PhI(OAc)2 resulted in a rapid reaction that delivered a
multitude of unidentified products. To circumvent what we believe
to be competitive amine oxidation, consumption of the oxidant
needs to be completed before introduction of the amine coupling
partner. As such we observed that addition of amine 2a to the
reaction mixture after formation of the active ester led to smooth
displacement of NHSI with the amine to deliver the desired amide
5a in excellent yield (Table 1, entry 1). Due to the extremely fast
formation of the active ester, amine addition can be made immedi-
ately after addition of the other reagents making it a practical
alternative to available oxidative amide formations. In most cases,
an amine was added after stirring for 2–3 min.
(c) + phenylpropionaldehyde
(a) PhI(OAc)2 + NHSI (1:1)
(b) + benzaldehyde
Aldehyde
Addition
O
O
O
OH
OH
N
N
O
N
O
O
O
O
O
A
C
B
succinimide N-oxy (SINO)
Figure 4. ESR measurements of the reaction mixture.
Scheme 2. Oxidative amide formation with a catalytic amount of NHSI using PhI(OAc)2 oxidant.

H. Yao et al. / Tetrahedron Letters 53 (2012) 5094–5098
5097
Table 2
and/or a longer reaction time were required (entry 2). One advan-
tage of the use of IBX is its capability to oxidize primary alcohol to
aldehyde, which extends the substrate scope (entries 3–4).17
NHSI can be recycled multiple times after release by the amine
displacement (Scheme 2). Thus, when using 0.3 equiv of NHSI,
addition of 0.3 equiv each of the oxidant followed by the amine,
in three separate operations furnished the desired amide in 81%
yield (Eq. 1). Alternatively, to limit the oxidation of the amine,
amine hydrochloride salt can be used. In the presence of a suitable
base, the amine may be gradually neutralized such that it under-
goes displacement at a rate that competes with its oxidation. This
approach provided the desired compound with a maximum yield
of 60% using 20 mol% of NHSI (Eq. 2).
We examined the scope and limitation of this approach using
stoichiometric PhI(OAc)2. Table 2 shows the amide formation with
various amines and aldehydes. Initially, 3-phenylpropionaldehyde
1a was examined with various amines (entries 1–7). Good to excel-
lent yields were obtained with primary amines (entries 1, 3, 5, and
7). As expected, primary alcohols were compatible under the reac-
tion conditions (entries 5, 7, 10, 13, and 14). Secondary amines also
delivered good yields including synthetically important Weinreb
amine (entry 2). Less reactive aniline also provided good yield of
the amide (entry 6).
In the reaction of unsaturated aldehyde 1b, the corresponding
unsaturated amides were obtained without affecting the double
bond (entries 8–11). Sterically hindered pivaldehyde 1c also re-
acted smoothly under the reaction conditions (entries 12–14).
The yields with these substrates are generally lower than that of
1a, although still giving respectable yields for these challenging
substrates. We have also examined aryl aldehydes with electron
donating or electron-withdrawing groups (entries 15–17), and
were pleased to find that these substrates participated in the
amide formation under identical conditions. Finally, all the opti-
cally pure amines examined retained their optical purity (entries
3, 5, 10, 11, 13, and 14).
In conclusion, an oxidative and metal-free amide formation was
developed. Hypervalent iodine reagents, PhI(OAc)2 and IBX both
served as stoichiometric oxidants and provided the intermediate,
active ester in good to excellent yields. A plausible mechanism of
the active ester formation was proposed based on a series of mech-
anistic investigations. The reaction was extended to tandem amide
formation reaction by successive addition of reagents in one-pot,
which demonstrated the recyclability of NHSI. Because of the mild
nature of the oxidant,8,18 this oxidative amide formation is widely
applicable for the synthesis of structurally diverse amines and
Scope of aldehydes and amines
Entry
1
Aldehyde
Product
Yieldb (%)
90
O
O
Ph
Ph
H
Ph
N
H
1a
5a
O
O
2
3
4
70
Ph
N
5b
O
O
84a
60
Ph
Ph
N
H
Ph
5c
N
5d
O
O
55a
OH
5
Ph
Ph
N
H
5e
Ph
6
7
8
69
74
84
N
H
5f
5g
O
O
O
Ph
Ph
H
Ph
Ph
N
H
1b
5h
O
9
56
N
5i
OH
O
O
10
Ph
67a
Ph
N
H
5j
OH
Ph
11
57a
Ph
O
N
H
5k
O
Ph
12
13
14
62
H
N
H
5l
1c
O
O
OH
66a
54a
N
H
5m
5n
aldehydes, including aniline, pivaldehyde, and
a,b-unsaturated
OH
N
H
aldehyde. The current method showed clear advantages to our pre-
vious methods, demonstrating simplicity, readily available re-
agents, and broad scope of applicable substrates.
O
O
O
Ph
H
N
H
15
16
17
58
61
72
Acknowledgments
MeO
O2N
MeO
O2N
O2N
1d
5o
O
This work was supported by funding from the University of To-
ledo (K.Y., New Faculty Start Up Fund; University of Toledo Sum-
mer Research Award, 2010). We thank Dr. Yong-Wah Kim for
assistance with ESR analyses. We also thank Dr. Chao Hang of Bris-
tol-Myers Squibb for helpful discussions on isotope effect
experiments.
Ph
H
N
H
5p
1e
O
N
5q
Supplementary data
a
>99% ee (see the Supplementary data).
Isolated yield.
b
Supplementary data (The spectral data for compounds 5f–5k,
5m, 5n, and 5g; Stability testing of ester 3a; Full data for oxidant
screening; ESR spectral data; NMR data for kinetic isotope effect
measurements.) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.024.
An analogous amide formation procedure using IBX was also
examined. The formation of the active ester using this reagent
was not as rapid as using PhI(OAc)2, and a higher temperature

5098
H. Yao et al. / Tetrahedron Letters 53 (2012) 5094–5098
5. Non-catalyzed oxidative formation of amides using PhI(OAc)2 has been
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