Aerobic amide bond formation with N-hydroxysuccinimide

Article abstract of DOI:10.1002/asia.201200017

Breathe easy: Molecular oxygen is one of the most abundant, atom-efficient, and economical oxidants. An aerobic oxidative amide formation from aldehydes and amines is reported. The method uses a catalytic amount of Co(OAc) ₂ and N-hydroxysuccinimide as reaction promoters. It is applicable to chiral substrates without loss of their optical purity. Copyright

Full text of DOI:10.1002/asia.201200017

DOI: 10.1002/asia.201200017
Aerobic Amide Bond Formation with N-hydroxysuccinimide
Haoyi Yao and Kana Yamamoto*[a]
The amide functionality is a ubiquitous motif seen in
pharmaceuticals, agrochemicals, and natural products.[1] The
synthesis of amides has been the subject of intense research,
and numerous methods have been developed. However,
cost-effective, high-yielding, and atom-efficient procedures
with a broad substrate scope have yet to be realized. The
most prevalent synthetic methods for amides rely on con-
densation of carboxylic acids and amines through stoichio-
metric activation, harsh conditions, or both.[2] A milder alter-
native approach is oxidative condensation of aldehydes or
alcohols with amines.[3] Recent examples of this strategy in-
clude: From aldehydes: hypervalent iodine (III) reagents;[4a]
sodium hydride with molecular oxygen;[4b] copper(II) cataly-
sis with tert-butylhydroperoxide (TBHP);[4c] metal-free con-
ditions with TBHP;[4d,e] palladium catalysis with hydrogen
peroxide;[4f] lanthanide-mediated conversions;[4g] and bio-
mimetic N-heterocyclic carbene catalyzed procedures.[5]
From alcohols: iridium(II)[6] and ruthenium(II)[7] mediated
dehydrogenative amide bond formations.
Most of these oxidative methods were studied with aro-
matic or unsaturated aldehydes and were only marginally ef-
fective when applied to aliphatic aldehydes. Some of them
required an excess of either of the coupling partners. We
have developed a new amide formation reaction that cir-
cumvents some of these limitations and is complementally
to the existing methods.
Apart from a few examples, the reported oxidative amide
formations rely on formation of hemiaminals or imines that
are subsequently oxidized to amide. This direct coupling is
dictated by the inherent reactivity of both components. In
order to alleviate such structural dependence, we opted for
oxidative formation of an activated acid intermediate
(Scheme 1, A!B), which would be displaced in situ by an
amine.[8]
Scheme 1. Two-step oxidative amide bond formation. Nitroxides, formed
in situ from NHS or NHPI, are the active species.
self-catalytically when treated with an aldehyde under simi-
lar oxidation conditions. We expected that subsequent dis-
placement with an amine would deliver an amide in a single
step (B!C). Alternatively, the NHPI ester might serve as
an equally efficient acylation reagent for amide formation.
Herein, we present realization of the concept.
The study was initiated by screening for suitable electron-
transfer mediators necessary for aerobic oxidation with
NHPI as a catalyst (Table 1). We have identified competing
formation of the corresponding acid, 4. Nevertheless, we
found that cobalt diacetate gave the desired NHPI ester 2 as
a major product (Table 1, entry 2). Further, replacing NHPI
with NHS under identical conditions provided the corre-
sponding NHS ester 3 in a comparable yield and selectivity
(Table 1, entry 5). Both reactions provided a mixture of the
ester and the acid in a ratio of approximately 3:1. We found
that ester 3 is slightly moisture sensitive,[11,12] yet reasoned it
could serve as an intermediate. Finally, the loading of cobalt
diacetate could be decreased to 0.5–1 mol% without affect-
ing the reaction outcome.
Next, we examined the feasibility of the second step, the
amine displacement [Scheme 2, Eq. (1)]. As expected, treat-
Table 1. Screening of electron-transfer mediators for aerobic oxidative
esterification of an aldehyde with NHPI.[a]
The N-hydroxysuccinimide (NHS) esters are valuable in-
termediates in amide (peptide) bond formation.[9] Because
the structurally related N-hydroxyphthalimide (NHPI) me-
diates various autoxidation reactions with molecular
oxygen,[10] we speculated that the NHS ester would form
Entry
Imide
Mediator
–
t [h]
Product
1
2
3
NHPI
NHPI
NHPI
NHPI
NHS
22
25
18
2.5
25
N.R.
Co
A
2 (40%)[d] +4
[a] H. Yao, Prof. Dr. K. Yamamoto
Department of Chemistry and School for Green Chemistry and Engi-
neering
FeCl3
MnCl2
4
4
4
5[c]
Co
N
3 (38%)[d] +4
The University of Toledo
Toledo, OH 43606 (USA)
E-mail: kana.yamamoto@utoledo.edu
[a] Conditions: 3-phenylpropionaldehyde (1.0 equiv), NHPI (1.1 equiv),
mediator, THF/MeCN (1.25:1 vol/vol), O2 (1 atm), room temperature.
[b] Loading of 0.5 mol% instead of 10 mol%. [c] MeCN alone was used.
[d] Un-optimized yield.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200017.
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COMMUNICATION
Table 3. Screening of bases for one-step method.[a]
Scheme 2. Examination of the amine displacement.
ment of the isolated ester 2 with benzylamine gave the ex-
pected amide 5b as the major product. However, the reac-
tion was accompanied by a small amount of acid 4 as well as
benzylphthalimide 2a, which presumably formed as a result
of attack of the amine at the phthalimide ester. In contrast,
NHS ester 3 underwent smooth conversion to provide the
desired amide 5b [Eq. (2)]. Subsequent optimization studies
were therefore performed using NHS.
The two steps were then combined for the development
of a one-pot oxidative amide synthesis. Aldehyde 1a was
subjected to the same reaction conditions as used for NHS
ester synthesis, except in the presence of benzyl amine (con-
Entry
Base
Product
Yield [%][b]
1
2
NaHCO3
CaCO3
5a
–
–
80
N.R.
N.R.
14[d]
3
4[c]
NaHCO3
5a+4
[a] Conditions: 3-phenylpropionaldehyde (1.0 equiv), NHS (1.1 equiv),
Co(OAc)2·4H2O (1 mol%), base (1.1 equiv), amine HCl (1.5 equiv), mo-
AHCTUNGTRENNUNG
lecular sieves (5 ꢁ, 100 mg) in solvent (C=0.67m), 23 h. [b] Yields of iso-
lated product were based on 3-phenylpropionaldehyde. [c] 0.1 equiv of
NHS used. [d] 86% of 4 was also isolated.
ditions:
(1.1 equiv), CoACHTUNGTRENNUNG
3-phenylpropionaldehyde
(1.0 equiv),
NHS
A brief survey of bases revealed that NaHCO3 was the best
reaction promoter (Table 3). No amine oxidation was seen
under these reaction conditions. Interestingly, we found pre-
mixing of all components prior to amine addition to be es-
sential for successful reaction progress.
With improved procedures for successful amide formation
in hand, we then focused on evaluation of the substrate
scope. First, a set of structurally diverse amines was coupled
with aldehyde 1a using two methods (Table 4). A broad
range of amides were successfully formed with moderate to
good yield using these protocols (Table 4, entries 1–8). The
secondary amines gave modest to good yields (Table 4, en-
tries 3–4, 9–10, 12–15), even with the less reactive Weinreb
amine. The glycine methyl ester (Table 4, entry 11) resulted
in lower conversion after the typical reaction time. The
methyl ester functionality was retained intact in this reac-
tion.
(OAc)2·4H2O (1 mol%), benzylamine
(1.1 equiv), O2 (1 atm) in MeCN (0.67m)). However, the re-
action resulted in numerous products, the majority of which
derived from self- and cross-aldol condensation with the
substrate and benzaldehyde, which was formed by oxidation
of the amine.
One way to circumvent the formation of these products
was to add the amine to the reaction mixture after NHS
ester formation and purging the remaining oxidant. This
procedure can be done conveniently by displacing oxygen
gas with nitrogen. Addition of phenylethylamine after the
formation of the NHS ester gave the desired amide 5a and
acid 4 (Table 2, entry 1). Acid formation was, to some
Table 2. Two-step oxidative amide bond formation.[a]
Primary and secondary alcohols were also resistant to oxi-
dation.[13,14] Thus, trans-4-aminocyclohexanol and 2-amino-3-
phenylpropanol bearing hydroxy groups were chemoselec-
tively oxidized to form the corresponding amides (Table 4,
entries 6–8). In cases with amines with stereocenters at the
a-position (Table 4, entries 5, 7, 8, 12–15), we found that
their optical purity was retained.
Entry
Catalyst
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Molecular sieves [g]
5a/4[b]
[c]
1
2
N
–
1
3.9
E
0.1[d]
[a] Conditions: 3-phenylpropionaldehyde (1.0 equiv), NHS (1.1 equiv),
Co(OAc)2·4H2O (1 mol%), phenylethylamine (1.1 equiv) in MeCN
ACHTUNGTRENNUNG
Subsequently, the reaction scope of aldehydes was as-
sessed (Table 5). In general, the reaction proceeded well
with a wide range of aldehydes. The reaction was tolerant to
steric hindrance, giving good yields with secondary or terti-
ary aldehydes (Table 5, entries 2, 3). In contrast, the reaction
appeared to be sensitive to electronic factors. The aryl alde-
hydes with electron-donating substituents provided in-
creased acid formation, contributing to a decreased yield
(Table 5, entry 4). We observed that electron-withdrawing
substituents also retarded the reaction (Table 5, entry 5). It
is of note that the reaction proceeds well with saturated al-
dehydes and is thus complementary to known oxidative
amide bond formation methods, most of which proceed well
(0.67m), 22 h. [b] The ratio was determined from the yields of isolated
products. [c] Without molecular sieves. [d] With 100 mg of molecular
sieves (5 ꢁ).
extent, avoided by addition of molecular sieves (Table 2,
entry 2). This result suggested that the formation of 4, at
least partially, is due to water attack on the presumed inter-
mediate, NHS ester.
Alternatively, competitive oxidation of the amine was
avoided by replacing it with the corresponding amine hydro-
chloride salt. In the presence of a mild base, amine displace-
ment occurred as the amine was converted to the free base.
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Aerobic Amide Bond Formation
Table 4. Scope of amine substrates for one- or two-step method.[a]
Table 5. Scope of aldehyde substrates with one-step method.[a]
Entry
Aldehyde
Product
Yield [%]
80
1
1b
1c
5p
2
3
4
5q
5r
5s
76
58
49
12
Entry
Amine
Method[c]
Product
Yield [%]
1e
1
2
A/B
A/B
5a
5b
78/80
76/57
5
1 f
5t
<10[b]
3
4
A
5c
5d
80
A/B
56/48
[a] One-step method (method A of Table 5). [b] The starting material
was recovered (75%).
5
6
A
A
5e
5 f
67[d]/48[d]
49
7
8
A
5g
5h
28[d]
A/B
33[d]/36[d]
9
B
B
5i
5j
33
52
10
11
12
13
B
5k
5l
28
A
A
44[d,e]
36[d,e]
Scheme 3.
Amide formation with chiral aldehydes. Boc=tert-butoxycarbonyl;
Tempo=2,2,6,6-tetramethylpiperidine-1-oxy radical, TCICA=trichloroi-
socyanuric acid.
5m
14
15
A
A
5n
5o
29[d–f]
36[d–f]
A mild aerobic oxidative method of amide formation for
aliphatic and aromatic aldehydes was developed. The proce-
dure represents the first example that utilizes NHS as a dual
promoter of aldehyde oxidation and amine displacement.
The reaction was shown to tolerate a variety of functional
groups, such as unprotected primary and secondary alcohols,
esters, amides, as well as optically active amines and alde-
hydes with stereocenters at a-positions. Investigations of the
reaction mechanism, as well as extension of the chemistry to
other transformations, are currently underway in our group.
[a] Conditions: 3-phenylpropionaldehyde (1.0 equiv), NHS (1.1 equiv),
Co(OAc)2·4H2O (1 mol%), amine (1.1equiv), molecular sieves (5 ꢁ,
ACHTUNGTRENNUNG
100 mg) in solvent (C=0.67m), 18–24 h. [b] Yields of isolated products
were based on 3-phenylpropionaldehyde. [c] Method A: one-step
method. Method B: two-step method. [d] Optical purity of the isolated
amides was retained (>99% ee, see the Supporting Information).
[e] Acids were also isolated. [f] Esters were also isolated (12–24%).
with unsaturated or aromatic aldehydes but less efficiently
with saturated aldehydes.
Finally, we examined the applicability of the reaction to
the amide formation with a chiral aldehyde. Thus, N-Boc-l-
alaninol 6 was oxidized to aldehyde 7 under either Swern or
Tempo[15] oxidation conditions (Scheme 3). The amide for-
mation with glycine methyl ester underwent with complete
retention of optical purity to smoothly provide the corre-
sponding dipeptides 8. Their optical purity was confirmed
by comparison of the optical rotation of the product with
the reported value (see the Supporting information).
Acknowledgements
This work was supported by the funding from the University of Toledo
(K.Y., New Faculty Start Up Fund; University of Toledo Summer Re-
search Award, 2010). We thank Dr. Yong-Wah Kim for assistance with
NMR analyses.
Keywords: amides · oxidation · oxygen · peptide coupling ·
synthetic methods
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Haoyi Yao and Kana Yamamoto
COMMUNICATION
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Published online: && &&, 0000
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COMMUNICATION
Amide Formation
Haoyi Yao,
Kana Yamamoto*
&&&& — &&&&
Aerobic Amide Bond Formation with
N-hydroxysuccinimide
Breathe easy: Molecular oxygen is one
of the most abundant, atom-efficient,
and economical oxidants. An aerobic
oxidative amide formation from alde-
hydes and amines is reported. The
method uses a catalytic amount of Co-
AHCTUNGERTG(NNUN OAc)2 and N-hydroxysuccinimide as
reaction promoters. It is applicable to
chiral substrates without loss of their
optical purity.
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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These are not the final page numbers! ÞÞ