Oxidative Amide Coupling from Functionally Diverse Alcohols and Amines Using Aerobic Copper/Nitroxyl Catalysis

Article abstract of DOI:10.1002/anie.201906130

The aerobic Cu/ABNO catalyzed oxidative coupling of alcohols and amines is highlighted in the synthesis of amide bonds in diverse drug-like molecules (ABNO=9-azabicyclo[3.3.1]nonane N-oxyl). The robust method leverages the privileged reactivity of alcohol

Full text of DOI:10.1002/anie.201906130

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Oxidative Amide Coupling from Functionally Diverse Alcohols and
Amines using Aerobic Copper/Nitroxyl Catalysis
Authors: Paige E. Piszel, Aristidis Vasilopoulos, and Shannon S Stahl
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906130
Angew. Chem. 10.1002/ange.201906130
Link to VoR: http://dx.doi.org/10.1002/anie.201906130
http://dx.doi.org/10.1002/ange.201906130

10.1002/anie.201906130
Angewandte Chemie International Edition
COMMUNICATION
Oxidative Amide Coupling from Functionally Diverse Alcohols and
Amines using Aerobic Copper/Nitroxyl Catalysis
Paige E. Piszel, Aristidis Vasilopoulos, and Shannon S. Stahl*
O
Abstract: The aerobic Cu/ABNO catalyzed oxidative coupling of
Ph
O
O
O
O
alcohols and amines is highlighted here in the synthesis of amide
bonds in diverse drug-like molecules (ABNO 9-
O
HN
NH
N
O
O
N
H
O
=
H
N
N
F
F
O
O
N
H
O
O
azabicyclo[3.3.1]nonane N-oxyl). The robust method leverages the
privileged reactivity of alcohols bearing electronegative heteroatoms
(O, F, N, Cl) in the b-position. The reaction tolerates over 20 unique
functional groups and is demonstrated on a 15 mmol scale under air.
Steric constraints of the catalyst allow for chemoselective amidation
of primary amines in the presence of secondary amines. All catalyst
components are commercially available, and the reaction proceeds
under mild conditions with retention of stereocenters in both reaction
partners, while producing only water as a by-product.
N
O
OMe
Ph
N
HN
AZD-7594
treatment of asthma and chronic
obstructive pulmonary disease
AdipoRON
ONX 0914
candidate for treatment of
autoimmune disorders
candidate for treatment of diabetes
and cardiovascular diseases
O
Target:
OH
O
Mild reaction conditions
Chemoselective
cat. [Cu]
cat. nitroxyl
X
X
H2NR’
+
NHR’
air or O2
R
R
Broad substrate scope and
functional group tolerance
X = O, F, N, Cl
Figure 1: a-Heteroatom-substituted amides in pharmaceuticals and targeted
strategy for their preparation.
Amide coupling reactions account for 16% of all reactions
performed in pharmaceutical syntheses.[1] Typical methods use
stoichiometric coupling reagents to activate a carboxylic acid for
nucleophilic attack by the amine coupling partner.[ 2 ] Several
catalytic methods for amide coupling have been reported, but
none yet exhibit the synthetic utility of methods that use
stoichiometric coupling reagents. Recent efforts have explored
catalytic methods for amide bond formation with reaction partners
other than carboxylic acids.[ 3 ] Prominent examples include
oxidative or dehydrogenative coupling of amines with primary
alcohols, which often produce only water or H2 as a by-product.
In spite of the potential appeal of these reactions,[ 4 ] the
precedents lack the functional-group compatibility, efficiency, or
synthetic reliability needed to compete with traditional amide
coupling methods. Herein, we demonstrate highly practical
applications of Cu/ABNO-catalyzed aerobic oxidative coupling of
primary alcohols and amines for the synthesis of diverse a-
heteroatom-substituted amides (ABNO = 9-azabicyclo[3.3.1]-
nonane N-oxyl).
Cu/nitroxyl catalyst systems have been identified as highly
effective catalyst systems for aerobic alcohol oxidation,[6,7] and we
recently demonstrated that analogous catalyst systems could
support aerobic oxidative coupling of alcohols and amines.[4o] The
latter reactions, however, were subject to many of the synthetic
limitations noted above. The oxidative amidation begins with
alcohol oxidation to the aldehyde, followed by trapping by an
amine to form a hemiaminal, which is then oxidized further to the
corresponding amide (Scheme 1a). Insights from mechanistic
studies of Cu/nitroxyl-catalyzed alcohol oxidation[8 ] suggested
that b-heteroatom-substituted primary alcohols could be a
privileged substrate class for oxidative coupling due to their
enhanced acidity (e.g., the aqueous pKa values for EtOH,
ethylene glycol, and trifluoroethanol are 15.9,[9 ] 15.1,[10 ] and
12.4,[11] respectively). The previous studies showed that more
acidic alcohols undergo more rapid oxidation, owing to their more
favorable reaction with the CuII–hydroxide intermediate.[8b] For
example, competition studies showed that electron-deficient
benzyl alcohol derivatives undergo more rapid oxidation than
electron-rich analogs. In addition, the aldehyde intermediate with
an a-heteroatom substituent will have enhanced electrophilicity
that will promote formation of a hemiaminal and disfavor formation
of an imine (Scheme 1b),[12] which is not an intermediate in amide
Heteroatom-substituted
amides
and
a-substituted
derivatives, in particular (Figure 1), are an important class of
molecules due to their prevalence in pharmaceuticals and related
bioactive compounds.[5] For example, a recent survey of over
3500 pharmaceuticals revealed that the majority of alkyl amides
feature an oxygen or nitrogen atom a, b, or g to the carbonyl.[1b]
The heteroatom linkage at these positions has a beneficial effect
on bioactivity and/or pharmacological properties of the molecule
due to changes in enzyme binding and solubility. In light of these
considerations, new strategies to access such structures could
have broad impact.
a) Key steps in the oxidative coupling of alcohols and amines
OH
O
OH
O
catalyst
[O]
catalyst
[O]
R’
R’
H2NR’
H2NR’
R
N
R
N
R
R
H
H
- H2O
R’
R
N
b) Postulated origin of enhanced reactivity of β-heteroatom-substituted 1° alcohols
H
[*] P. E. Piszel, A. Vasilopoulos, Prof. S. S. Stahl
Department of Chemistry
University of Wisconsin-Madison
Madison, WI 53706 (USA)
O
OH
NHR’
O
X
X
X
lower pKa;
accelerated
Cu binding
R
R
R
enhanced
electrophilicity
improved hemi-
aminal stability
E-mail: stahl@chem.wisc.edu
Scheme 1. (a) General mechanism for the oxidative coupling of alcohols and
amines to prepare amides. (b) Basis for enhanced reactivity of b-heteroatom-
substituted alcohols in catalytic Cu/nitroxyl-catalyzed oxidative amidation.
Supporting Information for this article is given via a link at the end of the
document.
1
This article is protected by copyright. All rights reserved.

10.1002/anie.201906130
Angewandte Chemie International Edition
COMMUNICATION
formation. Improved reactivity in these fundamental steps should
allow these methods to be particularly effective for the preparation
of pharmaceutically relevant a-heteroatom-substituted amides.
The present study was initiated by testing the oxidative
amidation of tetrahydropyran-2-methanol with 3-phenylpropyl-
amine. Screening of multiple conditions and catalyst compositions
revealed that use of CuI/tBubpy (4,4’-di-tert-butyl-2,2’-bipyridine) in
combination with ABNO in MeCN produced the desired amide 8
(Scheme 2) in 94% yield under O2 (see Supporting Information for
full screening data). While an improved yield was obtained with
pure O2 as the source of oxidant, a yield of 77% was still retained
with air as the oxidant. This simplified 3-component catalyst
system provided the starting point to evaluate the scope and
functional group tolerance of the method with other alcohols and
amines.
coupled under the optimized conditions, and each coupling
resulted in >90% yield of the corresponding amide product. The
trifluoroethanol-derived product 3 was prepared in a 15 mmol
scale reaction using ambient air as the oxidant (92% isolated
yield). A number of other noteworthy results were obtained from
these reactions. The mild conditions allowed for preservation of
the Boc protecting group on the piperidine in 5. A high yield was
retained when using b-chloroethanol (6) as the substrate,
indicating that the amidation outcompetes SN2 displacement of a
primary alkyl chloride. In contrast, b-bromoethanol was not an
effective substrate due to competing SN2 reactivity. (The latter
result and other examples of unsuccessful substrates are
documented in the Supporting Information; see Tables S9 and
S10). Alcohols with alkyl ethers, aryl ethers, and acetonides at the
b position also were converted effectively to the corresponding
amide products (7, 8, 9, 11, 14). Boc-protected 2-(S)-
morpholinemethanol afforded the corresponding amide in 92%
yield (10). b-Nitrogen containing alcohols are more challenging
substrates, possibly reflecting their reduced electron-withdrawing
effect and/or deleterious chelation of the Cu center and inhibition
A variety of b-heteroatom-substituted alcohols were tested in
the oxidative coupling reaction with 3-phenylpropylamine
(Scheme 2a). Relevant b-heteroatom-substituted alcohol starting
materials are readily available from glycol derivatives, amino
alcohols, and halohydrins. Five b-fluorinated alcohols (1-5) were
5 mol% CuI
tBu
tBu
5 mol% tBubpy
3 mol% ABNO
OH
O
X
X
+
H2NR’
N
NHR’
0.2 M MeCN, r.t.,
1 atm O2, 4 h
O
N
N
R
R
tBubpy
ABNO
X = O, F, N, Cl
NMR yield (isolated yield)
a. Alcohols [a]
b. Amines [b]
O
O
O
O
O
F
F
F
O
O
F
O
N
N
3 Ph
3 Ph
N
F3C
N
3 Ph
H
H
H
H
F
F
F3C
N
F3C
N
F3C
N
1
2
3
H
O
H
H
O
O
quant. (98%)
quant. (99%)
quant. (99%)
15 mmol under air: (92%)[b,c]
tBuO
O
O
F
O
19
98% (96%)
20
96% (91%)
21
22
O
96% (94%)
94% (89%)
F3C
Cl
N
H
3 Ph
N
3 Ph
N
3 Ph
H
N
H
F
F
Boc
O
N
O
S
O
N
4
5
6
O
NH
S
95% (88%)
92% (90%)
97% (92%)
F3C
F3C
N
F3C
N
H
N
F3C
N
H
H
H
O
O
H
O
O
O
MeO
N
H
3 Ph
N
3 Ph
23
98% (92%)
24
98% (89%)
25
26
N
3 Ph
H
91% (80%)[d]
78% (70%)[c]
H
O
7
8
9
94% (90%)[d]
96% (92%)
92% (89%)
O
pharmaceutical and biologically active compounds
H
O
O
H
N
3 Ph
O
N
O
O
H
N
H
3 Ph
O
N
N
H
NH2
O
O
3 Ph
O
H
tBuO
O
H
O
O
F3C
N
H
Boc
N
N
H
F3C
F3C
N
OtBu
iPr
H
H
O
NH
10
11
12
N
F3C
OtBu
O
H
92% (86%)[d]
38% (38%)[d]
94% (91%)
O
O
O2N
O
O
O
O
27
(99%)[d]
28
29
quant. (98%)
30
O
N
H
O
N
3 Ph
80% (73%)[d]
89% (88%)
Asparagine
N
N
H
3 Ph
H
3 Ph
(+)-Dehydroabietylamine L-Leucine-4-Nitroanilide Benazepril Derivative
N
O
13
84% (80%)
14
15
80% (79%)[d]
N
93% (92%)
HO
O
O
O
Ph
O
pharmaceutical and biologically active compounds
H
N
O
HN
O
O
OtBu
O
O
F3C
N
N
N
O
O
H
O
H
F3C
N
O
O
F3C
N
H
N
H
N
H
H
O
N
F3C
N
O
3 Ph
O
H
N
H
H
H
N
N
N
Boc
N
N
3 Ph
3 Ph
H
H
H
O2N
F
31
quant. (98%)
Phenylalanine tBu Ester
33
32
34
16
17
18
quant. (96%)
Core of Tedizolid
94% (94%)[d]
94% (87%)
Saxagliptin
90% (90%)[d]
81% (81%)[d,e]
80% (75%)[d]
Alogliptin
Oseltamivir
Metronidazole
Boc-Alaninol
Scheme 2. Substrate scope of alcohols and amines for aerobic Cu/ABNO catalyzed a-heteroatom-substituted amide formation. Reactions at 0.5 mmol scale.
Calibrated 1H NMR yields using dimethyldiphenylsilane as an internal standard. tBubpy = 4,4'-di-tert-butyl-2,2'-bipyridine, ABNO = 9-Azabicyclo[3.3.1]nonane N-
oxyl. [a] 1 equiv alcohol with 1.1 equiv amine. [b] 1 equiv amine with 1.5 equiv alcohol. [c] Under air. [d] Catalyst loading: 10 mol% CuI, 10 mol% tBubpy, and 6
mol% ABNO. [e] DMF used as solvent.
2
This article is protected by copyright. All rights reserved.

10.1002/anie.201906130
Angewandte Chemie International Edition
COMMUNICATION
of catalytic turnover.[7b] Despite this challenge, tertiary amine (12)
was isolated in modest yield. Acylation of the b-nitrogen atom,
including conversion to a phthalimide (15) or Boc-protected amino
alcohol (17), led to product formation in high-yield. Similarly,
alcohols bearing b-heteroaromatic rings, oxazole (13) and
imidazole (16), formed the amidation product in 80% and 81%
isolated yields, respectively. The b-oxazolidinone of an alcohol
fragment in tedizolid (18) was well tolerated under the optimal
conditions. The antibiotic metronidazole is insoluble in acetonitrile
(16); however, conducting the reaction in DMF led to an 81% yield
of the desired product.[13]
trifluoroacetylation conditions with TFAA exhibited poor selectivity,
with preferential formation of the difunctionalized product.
a) Intermolecular Competition
Trifluoroacetylation
conditions
O
O
H2N
HN
+
+
F3C
N
H
F3C
N
1 equiv.
1 equiv.
Trifluoroacetylation Conditions:
2° amide
66%
3° amide
34%
TFAA, DBU, DCM [a]
TFAA, TMG, MeCN [b]
Cu/ABNO [c]
53%
34%
94%
6%
b) Intramolecular Competition
H2N
H
H
N
F3C
N
H2N
F3C
After assessing the alcohol substrate scope, we explored
different amine coupling partners (Scheme 2b). We elected 2,2,2-
trifluorethanol (TFE) as the coupling partner for coupling with
different amines, resulting in formation of the corresponding
trifluoroacetamide derivative.[14] An initial set of substrates (19-26)
was selected to probe the compatibility of various functional
groups, while a second set features an expanded set of functional
groups within specific pharmaceutically relevant molecules (27-
34). Functional groups in the first set include oxygen-containing
groups (ethers, tBu ester, and acetonide 19-22), and aromatic
heterocycles (thiophene, pyridine, and thiazole 23-25), all of
which formed the desired amide product in very good-to-excellent
yields. The catalyst system favors reaction with the primary amine
over the sterically encumbered secondary amine, leading to
formation of 26. The reaction tolerated a primary amide[15] and a
free tertiary alcohol (30 and 33; 89% and 94% yields, respectively),
showing that this protocol could have advantages over the use of
trifluoroacetic anhydride, which can lead to competitive
functionalization of other groups in a molecule.[16] Compatible
functional groups evident from reactions with the second set of
molecules include nitriles, alkenes, nitro groups, imides,
cyclopropyl rings, and lactams. The effectiveness of the reaction
with substrates as complex as the anti-diabetic drugs alogliptin
(32) and saxagliptin (33) and antiviral oseltamivir (34), all of which
underwent oxidative coupling in >90% yield, shows that this
oxidative coupling strategy represents a compelling complement,
and in some cases may be superior, to traditional amide coupling
reactions.[17]
Trifluoroacetylation
conditions
O
O
+
+
N
H
N
N
N
H
1 equiv.
O
CF3
O
CF3
Trifluoroacetylation Conditions:
2° amide
16%
3° amide
3%
di-functionalized
TFAA, DBU, DCM [a]
TFAA, TMG, MeCN [b]
Cu/ABNO [c]
29%
33%
2%
30%
3%
64%
1%
Scheme 3. Intermolecular (a) and Intramolecular (b) competition experiments
between a primary and secondary amine under optimized conditions and using
typical trifluoroacetylation protocols. [a] 1 equiv TFAA, 1.5 equiv DBU, DCM (0.6
M), 0 ºC to rt, overnight. [b] 1 equiv TFAA, 1.5 equiv TMG, MeCN (0.6 M), 0 ºC
to rt, overnight. [c] 1 equiv TFE, 10 mol% CuI, 10 mol% tBubpy, 6 mol% ABNO,
MeCN (0.2 M), air, rt,
4 h. TFAA = trifluoroacetic acid, DBU = 1,8-
Diazabicyclo[5.4.0]undec-7-ene, TMG = 1,1,3,3-Tetramethylguanidine, TFE =
2,2,2-trifluoroethanol.
10 mol% CuI
10 mol% tBubpy
6 mol% ABNO
OH
O
X
X
+
H2NR
’
NHR
’
0.2 M MeCN, r.t.,
1 atm O2, 4h
R
R
X = O, F, N
NMR yield (isolated yield)
HO
NO2
O
F
O
O
N
H
O
H
N
NH
O
N
N
O
H
H
Boc
N
H
N
N
O
H
Boc
N
N
O
O
H
Boc
F
35
77% (70%)[a,b]
saxagliptin derivative
36
78% (76%)[c,d,e]
37
88% (87%)[a]
metronidazole derivative
benazepril F derviative
The chemoselective functionalization of the primary amine
over the secondary amine in substrate 26 prompted us to explore
this issue further.[ 18 ] Cu/nitroxyl catalyst systems show good
sterically controlled selectivity in oxidations of two different
alcohols,[7b,19] owing to the closed 6-membered transition state
involved in the H-transfer between bound alkoxide and nitroxyl
ligands.[ 20 ] We reasoned that analogous selectivity could be
achieved in reactions of hemiaminals derived from primary and
secondary amines due to the steric differences between these
O
Ph
H
O
O
39
H
N
H
OtBu
90% (89%)[c]
>20 : 1 d.r.
O
N
Boc
N
N
H
O
core of tedizolid derivative
38
72% (68%)[f,g]
Boc
Boc-Ala-Phe-OtBu
40
F
N
quant. (96%)[a]
PEGylated
O
O
O
O
O
benazepril F
O
N
H
H
O
41
quant. (99%)[a]
O
O
O
O
O
O
intermediates.
A
competition experiment between 3-
phenylpropylamine and piperidine in the presence of 1 equiv of
TFE exhibited >15:1 selectivity for the primary amine (94% yield)
over the secondary amine (Scheme 3a). In contrast, use of
traditional trifluoroacetylation conditions with trifluoroacetic
anhydride (TFAA)[21] resulted in low selectivity (primary:secondary
≤ 2:1), again favoring reaction with the primary amine. These
results were then extended to the reaction of 4-
Scheme 4. Synthesis of complex molecules using bioactive coupling partners
in Cu/ABNO catalyzed alcohol-amine coupling. Reactions at 0.5 mmol scale. [a]
1.1 equiv of alcohol used. [b] 5 mol% CuI, 5 mol% tBubpy, and 3 mol% ABNO.
[c] 1.1 equiv of amine used. [d] DMF used as solvent. [e] Catalyst loading
doubled. [f] 1.5 equiv of amine used. [g] 15 mol% CuI, 15 mol% tBubpy, and 9
mol% ABNO.
Finally, we sought to demonstrate that the coupling method
could be effective for cases in which both coupling partners exhibit
significant molecular complexity (Scheme 4). Reactions of this
type lack precedent among prior oxidative amidation methods.
(aminomethyl)piperidine
trifluoroacetylation of the primary amine was again achieved with
the Cu/ABNO catalyst system (primary:secondary > 30:1, with
(Scheme
3b).
Chemoselective
very little
difunctionalization; 64%
yield).
Traditional
3
This article is protected by copyright. All rights reserved.

10.1002/anie.201906130
Angewandte Chemie International Edition
COMMUNICATION
Each of the examples in Scheme 4 feature reactions in which both
reaction partners contain two or more heteroatom substituents.
Noteworthy examples include amide coupling with saxagliptin, as
the resulting amide product contains 10 unique heteroatoms (35).
Formation of a dipeptide was achieved via the coupling of a tBu-
ester amino acid with an N-Boc-protected amino alcohol (38).
Polyethylene glycols (PEGs) are a prominent class of b-
Acknowledgements
Financial support for this project was provided by a grant from the
National Institutes of Health (R01-GM100143). This material is
based upon work supported by the National Science Foundation
Graduate Research Fellowship Program under Grant No. DGE-
1747503 (PEP). Any opinions, findings, and conclusions or
recommendations expressed in this material are those of the
author(s) and do not necessarily reflect the views of the National
Science Foundation. Support was also provided by the Graduate
School and the Office of the Vice Chancellor for Research and
Graduate Education at the University of Wisconsin-Madison with
funding from the Wisconsin Alumni Research Foundation. NMR
instrumentation was supported by the NSF (CHE-1048642) and
by a generous gift from Paul J. and Margaret M. Bender. Mass
spectrometry instrumentation was supported by the NIH (1S10
OD020022-1).
heteroatom-substituted
alcohols,
and
PEGylation
of
pharmaceuticals can lead to enhanced pharmacological
properties by changing their solubility or membrane
permeability.[22,23] The Cu/ABNO-catalyzed method proved to be
effective in coupling mPEG–OH units with benazepril F,[ 24 ]
affording excellent product yields in both cases (40, 41).
The results described herein demonstrate that the Cu/ABNO
catalyst system exhibits broad scope and synthetic utility for the
oxidative coupling of alcohols and amines to form amides. The
reactions take advantage of the unique activating properties of b-
heteroatom-substituted alcohols to afford pharmaceutically
important a-substituted amides. The reaction yields, even with
complex substrates, are commonly >90%, suggesting that these
methods represent an important complement to traditional amide
coupling methods. For example, the efficiency and
chemoselectivity evident in the trifluoroacetylation of primary
amines suggests that this method offers an appealing alternative
to methods that use trifluoroacetic anhydride. More broadly, these
methods could find extensive use in medicinal chemistry,
enabling rapid diversification of simple building blocks or core
structures containing a primary alcohol or amine. And, the lack of
requirement for a stoichiometric coupling reagent offers potential
advantages in large scale amide coupling reactions.
Conflict of interest:
The authors declare no conflict of interest.
Keywords: amide coupling • copper • homogeneous catalysis •
aerobic oxidation • cross-coupling
[1] (a) J. S. Carey; D. Laffan; C. Thomson; M. T. Williams, Org. Biomol. Chem.
2006, 4, 2337–2347. (b) S. D. Roughley; A. M. Jordan, J. Med. Chem.
2011, 54, 3451–3479. (c) D. G. Brown; J. Boström, J. Med. Chem. 2016,
59, 4443–4458.
Lett. 2013, 54, 4922–4925. (k) N. Ortega; C. Richter; F. Glorius, Org. Lett.
2013, 15, 1776–1779 (l) X. Bantreil; N. Kanfar; N. Gehin; E. Golliard; P.
Ohlmann; J. Martinez; F. Lamaty, Tetrahedron 2014, 70, 5093–5099. (m)
X. Xie; H. V. Huynh, ACS Catal. 2015, 5, 4143–4151. (n) B. Kang; S. H.
Hong, Adv. Synth. Catal. 2015, 357, 834–840. (o) S. L. Zultanski; J. Zhao;
S. S. Stahl, J. Am. Chem. Soc. 2016, 138, 6416–6419. (p) S.
Selvamurugan; R. Ramachandran; G. Prakash; P. Viswanathamurthi; J.
G. Malecki; A. Endo, J. Organomet. Chem. 2016, 803, 119–127. (q) E. M.
Lane; K. B. Uttley; N. Hazari; W. Bernskoetter, Organometallics 2017, 36,
2020–2025. (r) A. Kumar; N. A. Espinosa-Jalapa; G. Leitus; Y. Diskin-
Posner; L. Avram; D. Milstein, Angew. Chem. Int. Ed. 2017, 56, 14992–
14996; Angew. Chem. 2017, 129, 15188–15192.
[2] (a) E. Valeur; M. Bradley, Chem. Soc. Rev. 2009, 38, 606–631. (b) H.
Lundberg; F. Tinnis; H. Adolfsson, Synlett 2012, 23, 2201–2204. (c) H.
Lundberg; F. Tinnis; H. Adolfsson, Chem. Eur. J. 2012, 18, 3822–3826.
(d) R. M. Lanigan; P. Starkov; T. D. Sheppard, J. Org. Chem. 2013, 78,
4512–4523. (e) B. Basavaprabhu; K. Muniyappa; N. R. Panguluri; P.
Veladi; V. V. Sureshbabu, New J. Chem. 2015, 39, 7746–7749.
[3] (a) C. A. G. N. Montalbetti; V. Falque, Tetrahedron 2005, 61, 10827–
10852. (b) K. Ekoue-Kovi; C. Wolf, Chem. Eur. J. 2008, 14, 6302–6315.
(c) V. R. Pattabiraman; J. W. Bode, Nature 2011, 480, 471–479 (d) C. L.
Allen; J. M. J. Williams, Chem. Soc. Rev. 2011, 40, 3405–3415. (e) A. M.
Whittaker; V. M. Dong, Angew. Chem. Int. Ed. 2015, 54, 1312–1315 (f) H.
Miyamura; H. Min; J.-F. Soulé; S. Kobayashi, Angew. Chem. Int. Ed. 2015,
54, 7564–7567; Angew. Chem. 2015, 127, 7674–7677. (g) T. T. Nguyen;
K. L. Hull, ACS Catal. 2016, 6, 8214–8218. (h) R. M. de Figueiredo; J.-S.
Suppo; J.-M. Campagne, Chem. Rev. 2016, 116, 12029–12122. (i) J. R.
Dunetz; J. Magano; G. Weisenburger, Org. Process Res. Dev. 2016, 20,
140–177.
[5] (a) E. M. Huber; M. Basler; R. Schwab; W. Heinemeyer; C. J. Kirk; M.
Groettrup; M. Groll, Cell 2012, 148, 727–738. (b) W. L. Holland; P. E.
Scherer, Science 2013, 342, 1460–1461. (c) M. Golden; N. P. R. Mon; V.
Nandialath; A. Muthusamy; R. Neppalli; R. H. Vasudev (Astra Zeneca),
WO 2016124722, 2016.
[6] For reviews, see: (a) B. L. Ryland; S. S. Stahl, Angew. Chem. Int. Ed.
2014, 53, 8824–8838; Angew. Chem. 2014, 126, 8968–8983 (b) Y. Seki;
K. Oisaki; M. Kanai, Tet. Lett. 2014, 55, 3738–3746. (c) Q. Cao; L. M.
Dornan; L. Rogan; N. L. Hughes; M. J. Muldoon, Chem. Commun. 2014,
50, 4524 (d) K. C. Miles; S. S. Stahl, Aldrichimica Acta 2015, 48, 8–10.
[7] For leading references, see: (a) P. Gamez; I. W. C. E. Arends; R. A.
Sheldon; J. Reedijk, Adv. Synth. Catal. 2004, 346, 805–811 (b) E. T. T.
Kumpulainen, A. M. P. Koskinen, Chem. Eur. J. 2009, 15, 10901–10911.
(c) J. M. Hoover; S. S. Stahl, J. Am. Chem. Soc. 2011, 133, 16901–16910.
(d) J. E. Steves; S. S. Stahl, J. Am. Chem. Soc. 2013, 135, 15742–15745.
(e) Y. Sasano; S. Nagasawa; M. Yamazaki; M. Shibuya; J. Park; Y.
Iwabuchi, Angew. Chem. Int. Ed., 2014, 53, 3236–3240.
[4] (a) C. Gunanathan; Y. Ben-David; D. Milstein, Science 2007, 317, 790–
792. (b) L. U. Nordstrøm; H. Vogt; R. Madsen, J. Am. Chem. Soc. 2008,
130, 17672–17673. (c) J. H. Dam; G. Osztrovszky; L. U. Nordstrøm; R.
Madsen, Chem. Eur. J. 2010, 16, 6820–6827. (d) Y. Zhang; C. Chen; S.
C. Ghosh; Y. Li; S. H. Hong, Organometallics 2010, 29, 1374–1378. (e) A.
Prades; E. Peris; M. Albrecht, Organometallics 2011, 30, 1162–1167. (f)
N. D. Schley; G. E. Dobereiner; R. H. Crabtree, Organometallics 2011, 30,
4174–4179. (g) C. Chen; Y. Zhang; S. H. Hong, J. Org. Chem. 2011, 76,
10005–10010. (h) J.-F. Soulé; H. Miyamura; S. Kobayashi, J. Am. Chem.
Soc. 2011, 133, 18550–18553. (i) X. Bantreil; C. Fleith; J. Martinez; F.
Lamaty, ChemCatChem 2012, 4, 1922–1925. (j) S. C. Ghosh; J. S. Y.
Ngiam; A. M. Seayad; D. T. Tuan; C. W. Johannes; A. Chen, Tetrahedron
[8] (a) J. M. Hoover; B. L. Ryland; S. S. Stahl, ACS Catal. 2013, 3, 2599–
2605. (b) J. M. Hoover; B. L. Ryland; S. S. Stahl, J. Am. Chem. Soc. 2013,
135, 2357–2367.
4
This article is protected by copyright. All rights reserved.

10.1002/anie.201906130
Angewandte Chemie International Edition
COMMUNICATION
(c) J. Feng; Z. Zhang; M. B. Wallace; J. A. Stafford; S. W. Kaldor; D. B.
Kassel; M. Navre; L. Shi; R. J. Skene; T. Asakawa; K. Takeuchi; R. Xu; D.
R. Webb; S. L. Gwaltney, J. Med. Chem. 2007, 50, 2297–2300.
[18] For previous studies directed toward chemoselective acylation of amines,
see the following: (a) S.-I. Murahashi; T. Naota; N. Nakajima, Chem. Lett.
1987, 879–882. (b) A. O. Gálvez; C. P. Schaack; H. Noda; J. W. Bode, J.
Am. Chem. Soc. 2017, 139, 1826–1829. (c) F. Piazzolla; A. Temperini,
Tetrahedron Lett. 2018, 59, 2615–2621.
[9] W. N. Olmstead, Z. Margolin, F. G. Bordwell, J. Org. Chem. 1980, 45,
3295–3299.
[10] E. P. Serjeant, B. Dempsey. Ionisation Constants of Organic Acids in
Aqueous Solution, Pergamon Press, 1979, 22.
[11] F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456–463.
[12] See, for example: G. Blond; T. Billard; B. R. Langlois, J. Org. Chem. 2001,
66, 4826–4830.
[13] N. A. Kasim; M. Whitehouse; C. Ramachandran; M. Bermejo; H.
Lennernäs; A. S. Hussain; H. E. Junginger; S. A. Stavchansky; K. K.
Midha; V. P. Shah; G. L. Amidon, Mol. Pharm. 2004, 1, 85–96.
[14] P. G. M. Wuts; T. W. Greene, Greene’s Protecting Groups in Organic,
Fourth Edition, Wiley-VCH, 2006, 781–783.
[19] X. Xie; S. S. Stahl, J. Am. Chem. Soc. 2015, 137, 3767–3770.
[20] B. L. Ryland, S. D. McCann, T. C. Brunold, S. S. Stahl, J. Am. Chem. Soc.
2014, 136, 12166–12173.
[21] Trifluoroacetylation conditions obtained from: A. Welle; F. Billard; J.
Marchand-Brynaert, Synthesis 2012, 44, 2249–2254.
[15] A recent report showed that Cu/nitroxyl catalyst systems can promote
imide formation from amides: K. Kataoka; K. Wachi; X. Jin; K. Suzuki; Y.
Sasano; Y. Iwabuchi; J.-Y. Hasegawa; N. Mizuno; K. Yamaguchi Chem.
Sci. 2018, 9, 4756–4768.
[22] J. M. Harris; R. B. Chess, Nat. Rev. Drug Discov. 2003, 2, 214–221.
[23] S. M. Ryan; G. Mantovani; X. Wang; D. M. Haddleton; D. J. Brayden,
Expert Opin. Drug Discov. 2008, 5, 371–383.
[24] For discovery of benazepril F, see: W. H. Parsons; A. A. Patchett; M. K.
Holloway; G. M. Smith; J. L. Davidson; V. J. Lotti; R. S. L. Chang, J. Med.
Chem. 1989, 32, 1681–1685.
[16] J. M. Tedder, Chem. Rev. 1955, 55, 787–827.
[17] For discoveries of the drugs, see: (a) A. Moscona, N. Engl. J. Med. 2005,
353, 1363–1373. (b) D. J. Augeri; J. A. Robl; D. A. Betebenner; D. R.
Magnin; A. Khanna; J. G. Robertson; A. Wang; L. M. Simpkins; P. Taunk;
Q. Huang; S.-P. Han; B. Abboa-Offei; M. Cap; L. Xin; L. Tao; E. Tozzo; G.
E. Welzel; D. M. Egan; J. Marcinkeviciene; S. Y. Chang; S. A. Biller; M. S.
Kirby; R. A. Parker; L. G. Hamann, J. Med. Chem. 2005, 48, 5025–5037.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.201906130
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Cu/ABNO-catalyzed oxidative amidation is
shown to be highly effective in the cross
coupling of complex alcohols and amines.
The reactions exploiting the unique
reactivity of b-heteroatom-substituted
alcohols to enable access to diverse
products with pharmaceutically relevant
functional groups.
P. E. Piszel, A. Vasilopoulos, S. S.
Stahl*
OH
O
cat. [Cu]/ABNO
40 examples
+
X
X
H2NR’
aerobic
X = O, F, N, Cl
NHR’
R
R
O
H
Page No. – Page No.
HO
O
5
O
MeO
NH
O
O
H
Oxidative Amide Coupling from
Functionally Diverse Alcohols and
Amines using Aerobic
F3C
NH
O
F3C
N
N
H
H
N
N
Boc
NH
complex
molecules
H
chemoselectivity
PEGylation
Copper/Nitroxyl Catalysis
6
This article is protected by copyright. All rights reserved.