Chemoselective acylation of primary amines and amides with potassium acyltrifluoroborates under acidic conditions

Article abstract of DOI:10.1021/jacs.7b00059

Current methods for constructing amide bonds join amines and carboxylic acids by dehydrative couplings-processes that usually require organic solvents, expensive and often dangerous coupling reagents, and masking other functional groups. Here we describe an amide formation using primary amines and potassium acyltrifluoroborates promoted by simple chlorinating agents that proceeds rapidly in water. The reaction is fast at acidic pH and tolerates alcohols, carboxylic acids, and even secondary amines in the substrates. It is applicable to the functionalization of primary amides, sulfonamides, and other N-functional groups that typically resist classical acylations and can be applied to late-stage functionalizations.

Full text of DOI:10.1021/jacs.7b00059

Subscriber access provided by UB + Fachbibliothek Chemie | (FU-Bibliothekssystem)
Communication
Chemoselective acylation of primary amines and amides
with potassium acyltrifluoroborates under acidic conditions
Alberto Osuna Gálvez, Cedric P. Schaack, Hidetoshi Noda, and Jeffrey W. Bode
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Jan 2017
Downloaded from http://pubs.acs.org on January 24, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Chemoselective acylation of primary amines and amides with
potassium acyltrifluoroborates under acidic conditions
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Alberto Osuna Gálvez, Cédric P. Schaack, Hidetoshi Noda and Jeffrey W. Bode*
Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH–Zürich, 8093 Zürich, Switzerland
Supporting Information Placeholder
ABSTRACT: Current methods for constructing amide bonds
join amines and carboxylic acids by dehydrative couplings –
processes that usually require organic solvents, expensive and
often dangerous coupling reagents, and masking other
functional groups. Here we describe an amide formation
using primary amines and potassium acyltrifluoroborates
(KATs) promoted by simple chlorinating agents that
proceeds rapidly in water. The reaction is fast at acidic pH
and tolerates alcohols, carboxylic acids, and even secondary
amines in the substrates. It is applicable to the
functionalization of primary amides, sulfonamides and other
N–functional groups that typically resist classical acylations
and can be applied to late-stage functionalizations.
in the case of α-amino acid derivatives. We postulated that
simple amines could be employed by in situ activation of the
nitrogen atom. N-Chlorination of amines is a fast and well-
studied process that proceeds in water, 10 the preferred
solvent for the KAT ligation. The reagent could also oxidize
the acylboronate, as similar reactions are known for
organoborons.11
Scheme 1. Chemoselective amide formation with KATs.
Traditional coupling reagent-based amide formation
O
coupling agents
O
H2N
R
N
NBoc
basic conditions
DMF or CH2Cl2
H
R
OH
NBoc
carboxylic acid
amine
amide
KAT amide and imide formation (this work)
O
O
Amide bond formation is one of the most widely practiced
transformations of organic molecules.1 Nearly all amides are
produced by the condensation of an activated carboxylic
acid, or occasionally the acid itself, with an amine – processes
that typically require excess of organic solvent or high
reaction temperatures (Scheme 1). In the context of
pharmaceutical production, expensive – often dangerous –
coupling reagents are typically used in excess. These factors
contribute to the widely recognized desire for new amide-
O
" Cl+
"
H2N
R
N
H
R
BF3K
NH
NH
NH
acidic conditions
THF/H2O, rt
k ~ 10.5 M-1 s-1
primary amine
(chemoselective)
KAT reagent
amide
O
O
O
" Cl+
"
R
BF3K
H2N
R
N
acidic conditions
THF/H2O, 40 °C
2–12 h
H
NH
primary amide
(chemoselective)
KAT reagent
imide
In this report we document the coupling of primary amines
and potassium acyltrifluoroborates under aqueous
conditions, using inexpensive chlorinating agents to activate
the amine (Scheme 1). It operates chemoselectively at room
temperature in the presence of other functional groups
including carboxylic acids, alcohols, alkenes and secondary
amines. With slight modification of the reaction conditions,
it can also be applied to the acylation of primary amides,
ureas, sulfonamides and carbamates, which are typically
resistant to acylation under mild conditions.12
forming processes that operate cleanly under more
2 , 3
sustainable conditions.
Likewise, there is enormous
interest in chemoselective amide-forming ligations under
aqueous conditions,4,5 although the use of specialized starting
materials and conditions render them appropriate only for
high value products such as peptides or proteins.
In 2012, we disclosed the reaction of potassium
acyltrifluoroborates (KATs) and O-acylhydroxylamines.6 It
proceeds with fast kinetics and absolute chemoselectivity in
water, which makes it attractive for the bioconjugation of
proteins and peptides.7 The key starting materials, potassium
We chose potassium 4-fluorobenzoyltrifluoroborate 1a and
2-phenethylamine 2a in a mixture of aqueous buffer and
organic co-solvents as a model reaction for screening
conditions and halogenating agents. We identified N-
chlorosuccinimide (NCS) and related reagents, particularly
1,3-dichloro-5,5-dimethylhydantoin (DCH), as the most
effective choice.
8
acyltrifluoroborates, are robust salts that are already
becoming available – at the time of this submission, 19 KATs
were commercially available – and can be readily prepared
from aldehydes, enol ethers, organohalides or acyl chlorides.9
The O-acylhydroxylamines, however, require several steps to
prepare and are sometimes unstable compounds, especially
ACS Paragon Plus Environment

Journal of the American Chemical Society
Table 1. Substrate scope for the amide-forming reaction.a
Page 2 of 5
1
2
3
4
5
O
Me
Me
O
O
O
O
DCH (1.1 equiv)
Ph
R2
N
Cl
N
H
CF3
N
H
H2N R2
R1
N
H
N
R1
BF3K
Cl
THF / buffer pH 3
rt, 0.5-1 h
F
F
O
3b (74%)b
3a (92%)
1
2
3
DCH
(1.0 equiv)
(1.1 equiv)
6
7
8
9
RO
O
Ph
OH
OH
O
OR
OR
O
O
O
O
O
N
H
N
H
N
H
CO2Me
N
H
CO2Me
N
H
N
H
O
OR
F
CO2H
F
F
F
F
F
R = H
3c (81%)b
3d (80%)b
3g (95%)b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c
3f (70%)
3h (78%)
3e (66%)b,d
R = Ac
RO
O
NO2
O
O
O
O
O
N
N
O
O
NMe2
N
N
H
N
H
N
H
N
N
H
N
N
H
N
H
NH
OR
O
N
F
F
F
F
F
F
RO
R = H
3j (61%)e
3k (51%)f
3l (80%)g
c
3i (70%)
3m (70%)
3n (45%)d,g,h
R = Ac
O
O
Ph
O
O
O
F
N
H
O
Ph
Ph
N
H
N
Ph
Ph
F
O
N
H
Ph
Ph
N
H
N
H
N
H
O
O
O
MeO
F
F
H
3o (84%)
3p (64%)
3q (64%)
3r (88%)
3s (54%)
3t (36%)
F
NEt2
O
O
O
O
Ph
O
Ph
Ph
N
H
Ph
N
H
O
O
N
H
N
H
H
N
Ph
N
H
H
H
N
N3
O
N
TMS
O
Et2N
O
O
Et2N
S
O
2
O3S
O
O
O
3u (65%)
3v (62%)
3w (74%)
3x (69%)
3y (79%)
aPerformed on a 0.10 mmol scale with KATs 1 (1.1 equiv), amines 2 (1.0 equiv) and DCH (1.1 equiv) in 1:1 THF / pH 3 citrate
b
buffer (final conc. 0.10 M). Values in parentheses are isolated yields of the corresponding products 3a-3y. Amines used as HCl salts.
cFor purification, the reaction mixture was treated with Ac2O and pyridine in acetone. dIsolated yield over two steps. eNCS (2.0 equiv)
was used instead of DCH. fAmine was used as CF3CO2H salt. gPerformed with TCCA instead of DCH. hIsolated as a CF3CO2H salt.
groups (3j). Substrates having double bonds, which may be
sensitive to chlorinating agents, were also good substrates
(3k), although small amounts of halogenated byproducts
These were superior to brominating or iodinating agents, a
fact that we attributed to the poor stability of these
reagents.13 No amide formation was observed in the absence
were observed. Electron-rich anilines often gave complex
mixtures derived from ring chlorination or oxidation, but
electron-poor aryl and heteroarylamines could be smoothly
acylated using 1,3,5-trichloroisocyanuric acid (TCCA) as the
chlorinating agent (3l–3n). This is a notable contrast to
classical amide formations with coupling reagents, which
often fail with electron-deficient amines. 17 The reaction
conditions, including the chlorination step, also tolerated a
variety of KATs having different aryl, heteroaryl and alkyl
residues (3o–3r), as well as KATs with reactive groups such
as an aldehyde (3s) or an activated ester (3t). Coumarin and
sulforhodamine KATs (3u, 3v) afforded the corresponding
amide in good yields. KATs bearing azide and alkyne groups
(3w–3y) were suitable substrates as well.
Although it is well known that primary amides can be
chlorinated, we did not expect the resulting N-chloroamides
to react with KATs. However, by warming the reactions to
40 °C and replacing DCH with TCCA, 18 we identified
general conditions for acylation of primary amides under
aqueous, acidic conditions (Table 2). Aromatic (5a),
of halogenating source. The reaction was tolerant to a broad
variety of solvents in combination with acidic aqueous
buffers,14 and we selected 1:1 THF / pH 3 citrate buffer for
further studies. Experimentally, the reaction performed well
between pH 2 and 6, and we selected pH 3 as optimal in
terms of both rate and functional group compatibility. This
optimal value may be due to the pKa of N-chloroamines – in
the range of 0–2 – which are not likely to be protonated
under these conditions.15 Free amines or their salts can be
used directly in the reaction. After completion of the
reaction, any excess chloramine is quenched by the addition
of aqueous sodium bisulfite.16
With the optimized conditions in hand, we explored the
scope of the reaction. A wide variety of primary amines
underwent smooth amide formation using DCH as the
chlorinating agent (Table 1). We did not observe
epimerization of the α-carbon when optically active L-
phenylalanine methyl ester was used as substrate (product
3c, see the Supporting Information for details), although this
more sterically hindered amine required longer reaction
times than amines on primary carbons. The reaction is
chemoselective; it tolerates unprotected alcohols (3d, 3e),
phenols (3f), ketones (3g) and carboxylic acids (3h).
Acylation of primary amines occurs selectively in the
presence of tertiary (3i) and unprotected secondary amine
aliphatic (5b) and α,β-unsaturated amides (5h) were
effectively converted to the corresponding imides.
Carbamates (5c), ureas (5d, 5e), sulfonamides (5f) and
guanidines (5g) were also suitable partners for the reaction.
Remarkably, primary amides could be acylated even in the
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
presence of secondary amines (5i). KATs having triple bonds
This reaction is related to amide-formation from α-ketoacids
1
2
3
4
5
6
7
8
21
22
(5l), activated esters (5m), azide groups (5n) and coumarin-
bearing KATs (5o), afforded the corresponding imide in
moderate to good yields. There are relatively few methods
known for preparation of their mixed acyclic imides and
related compounds, which are interesting components of
bioactive natural products, pharmaceuticals, and catalysts.12,19
and hydroxylamines or N-iodoamines, and – more
generally – to the oxidative amidation of aldehydes with
amines.23 These reactions typically require the use of strong
24
25
oxidizing agents and/or transition metal catalysts,
although the direct coupling of aldehydes and amines with
NBS has been documented.26 Under our reaction conditions,
no amide product could be detected when
4-fluorobenzaldehyde was used in place of KAT 1a;
α-ketoacids also failed to give amides under these conditions.
The oxidative chlorination of the KAT to form an acyl
chloride was ruled out by control experiments.
Table 2. Substrate scope for the imide-forming reaction.
9
Cl
O
O
O
O
O
N
O
TCCA (0.36 equiv)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R1 BF3K
R1
N
H
R2
H2N
R2
N
N
THF / buffer pH 3
40 °C, 2-12 h
Cl
Cl
5
1
4
O
(1.0 equiv)
(1.1 equiv)
TCCA
O
O
O
O
O
O
Scheme 2. Late-stage functionalization of natural products.a
CO2Me
N
Ph
N
N
OtBu
H
H
H
NHFmoc
F
F
F
5a (65%)
5b (66%)
5c (43%)
H2N
NH2
HO
OH
1l (1 equiv)
DCH (2 equiv)
O
Exclusive mono acylation
of guanidine groups
(mixture of isomers)
O
N
O
O
O
O
HO
O
O
O
HN
Me
OH
S
NH
O
O
N
NHMe
THF / buffer pH 3
rt, 8 h
N
H
HO
HO
NH
NH2
O
N
N
N
H
O
H
H
Me
O
32%b,c
F
F
OH
NH2
F
Me
5f (68%)c
O
5e (80%)b
5d (60%)
• 1.5 H2SO4
KF3B
H
O
NH
O
O
O
O
H
N
Streptomycin
(5 equiv)
CO2Et
NHBz
N
H
N
H
N
H
Ph
N
H
1l
1l (1 equiv)
O
N
F
F
F
R
R = H
H2N
O
Exclusive mono acylation
of primary amines
(mixture of regio isomers)
HO
5g (75%)d
e
5h (57%)
HO
Me
NCS (3 equiv)
R = Boc 5i (44%)f,g
O
O
O
OH
NH2
H2N
Me
THF / buffer pH 3
rt, 5 h
O
O
HN
O
O
O
O
Me
HN
25%b
N
Ph
O
Me
O
Gentamicin C1
(5 equiv)
N
Ph
Ph
H
N
H
Ph
H
EtO2C
TMS
5j (54%)
5k (42%)
5l (57%)
O
Me
H2N
O
O
NH
Me
O
N
H
KF3B
O
O
O
Me
OH
H
N
O
NH
O
Me
O
O
O
F
F
N
H
Ph
O
O
112 O
H
N
N
H
Ph
C8H18
HN
NH2
F
O
N
H
Ph
6
N
H
N
H
O
O
O
N3
O
NH
HN
O
F
F
Exclusive
H
N
Et2N
O
O
6 (1 equiv)
NCS (10 equiv)
NH2 •H2SO4
NH2
mono-PEGylation
(mixture of
regioisomers)
O
NH2
5m (52%)
5n (40%)
5o (25%)
O
HO Me
THF / buffer pH 3
rt, 15 h
Polymyxin B
(10 equiv)
aPerformed on a 0.10 mmol scale with KATs 1 (1.1 equiv),
amides 4 (1.0 equiv) and TCCA (0.36 equiv) in 1:1 THF /
74%d
aPerformed on up to 0.10 mmol scale with KATs 6 or 1l
(1.0 equiv), natural products (5–10 equiv) and DCH or NCS
(3–10 equiv) in THF / pH 3 citrate buffer ([KAT] = 10–
25 mM) at rt. Products were isolated as a mixture of isomers
acylated on any of the nitrogen atoms marked in blue. bIsolated
yield (CF3CO2H salt) after preparative HPLC. cMixture of
C1/C3 acylated hemiaminal tautomers (1:1). dYield after
isolation by spin-filtration.
b
pH 3 citrate buffer (final conc. 0.10 M) at 40 °C. Performed
c
with DCH (1.1 equiv) instead of TCCA . Performed at 60 °C
in 1:1 MeCN, pH 3 citrate buffer (final conc. 0.10 M).
dGuanidine used as HCl salt eFor purification, the reaction
mixture was treated with Boc2O (1.5 mmol) and NaHCO3 (pH
7–8). fYield over two steps. gTCCA (0.66 equiv) was employed.
At the current stage of development, the amide and imide-
formation is limited to primary amines and amides.
Morpholine did not react under the standard conditions.
This appears to be a steric effect, rather than a mechanistic
Mechanistically, we favor direct interaction of the N-
chloroamine and the KAT carbonyl group – as in the case of
O-benzoylhydroxylamines6 – over an interaction of the
nucleophile with the boron and subsequent acyl migration.
As a control experiment, N-chlorobutylamine was freshly
prepared from n-butylamine and NCS in CDCl3; its purity
and concentration were determined by NMR. This reacted
rapidly with KAT 1a, yielding quantitatively the
corresponding amide (see the Supporting Information for
details). Although this experiment does not completely rule
out the involvement of other pathways, it favors our
mechanistic hypothesis. This protocol was used to determine
the reaction rate for amide-formation at pH 3 to be
~10 M-1s-1,27 which is several orders of magnitude faster than
limitation,
as
an
excess
of
the
preformed
N−chloromorpholine undergoes acylation with KATs under
neat conditions (see the Supporting Information for details).
We also applied this method to the late-stage
functionalization of more complex molecules (Scheme 2).
Streptomycin bears two guanidino groups in addition to one
aldehyde and one secondary amine, yet acylation occurred
chemoselectively on the guanidino groups. Alkyne KAT 1l
was coupled to gentamicin C1 to give a mixture of adducts,
exclusively on the primary amines. By using a 5 kDa PEG-
KAT 6 as the limiting reagent, we obtained a mixture of
mono-PEGylated derivatives of polymyxin B – which has five
28
amidation using activated esters at room temperature.
20
primary amines – in good yield.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
In summary, we have developed
a
mild, rapid and
(7) Noda, H.; Erős, G.; Bode, J. W. J. Am. Chem. Soc. 2014, 135, 5611–
5614.
1
2
3
4
5
6
7
8
chemoselective acylation of in situ generated N-chlorinated
amines or amides using KAT reagents. As the key starting
materials – potassium acyltrifluoroborates – are becoming
widely available, we believe this method will emerge as an
attractive alternative to classical acylation chemistry by being
completely tolerant to the presence of water, fast at acidic
pH, and offering unique chemoselectivity over many
different functional groups, including secondary amines.
(8) Noda, H.; Bode, J. W. J. Am. Chem. Soc. 2015, 137, 3958–3966.
(9) (a) Molander, G. A.; Raushel, J.; Ellis, N. M. J. Org. Chem. 2010, 75,
4304–4306. (b) Dumas, A. M.; Bode, J. W. Org. Lett. 2012, 14, 2138–
2141. (c) Erős, G.; Kushida, Y.; Bode, J. W. Angew. Chem. Int. Ed. 2014,
53, 7604–7607. (d) He, Z.; Zajdlik, A.; Yudin, A. K. Acc. Chem. Res. 2014,
47, 1029–1040. (e) Liu, S. M.; Mazunin, D.; Pattabiraman, V. R.; Bode, J.
W. Org. Lett. 2016, 18, 5336–5339.
(10) (a) Antelo, J. M.; Arce, F.; Parajó, M. Int. J. Chem. Kinet. 1995, 27,
637–647. (b) Qiang, Z.; Adams, C. D. Environ. Sci. Technol. 2004, 38,
1435–1444. (c) Zhong, Y. L.; Zhou, H.; Gauthier, D. R.; Lee, J.; Askin, D.;
Dolling, U. H.; Volante, R. P. Tetrahedron Lett. 2005, 46, 1099–1101.
(11) (a) Brown, H. C.; Lane, C. F. J. Am. Chem. Soc. 1970, 92 (1968),
6660–6661. (b) Thiebes, C.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A.
Synlett 1998, 141–142. (c) Szumigala, R. H.; Devine, P. N.; Gauthier, D.
R.; Volante, R. P. J. Org. Chem. 2004, 69, 566–569.
(12) (a) Hurd, C. D.; Prapas, A. G. J. Org. Chem. 1958, 24, 388–392.
(b) Mumm, O.; Hesse, H.; Volquartz, H. Chem. Ber. 1915, 48, 379–391.
(c) Schwarz, J. J. Org. Chem. 1972, 37, 2906–2908. (d) Schnyder, A.;
Indolese, A. F. J. Org. Chem. 2002, 67, 594–597. (e) Li, H.; Dong, K.;
Neumann, H.; Beller, M. Angew. Chem. Int. Ed. 2015, 54, 10239–10243.
(f) Sperry, J. Synthesis 2011, 22, 3569–3580. (g) Li, X.; Danishefsky, S. J. J.
Am. Chem. Soc. 2008, 130, 5446–5448. (h) Bates, R. B.; Fletcher, F. A.;
Janda, K. D.; Miller, W. A. J. Org. Chem. 1984, 49, 3038. (i) Tomizawa, T.;
Orimoto, K.; Niwa, T.; Nakada, M. Org. Lett. 2012, 14 , 6294–6297. (j)
Chan, J.; Baucom, K. D.; Murry, J. a. J. Am. Chem. Soc. 2007, 129, 14106–
14107. (k) Bian, Y.-J.; Chen, C.-Y.; Huang, Z.-Z. Chem. Eur. J. 2013, 19,
1129–1133.
(13) Worley, S. D.; Williams, D. E.; Barnela, S. B. Water Res. 1987, 21,
983–988.
(14) We have previously documented the better performance of KAT
reagents under acidic pH. See ref. 7 for details.
(15) Calvo, P.; Crugeiras, J.; Ríos, A. J. Org. Chem. 2009, 74, 5381–
5389.
(16) Hermant, B. M.; Basu, O. D.; Ph, D.; Eng, P. J. Environ. Eng. 2013,
139, 522–529.
(17) Schäfer, G.; Matthey, C.; Bode, J. W. Angew. Chem. Int. Ed. 2012,
51, 9173–9175.
(18) Hiegel, G. A.; Hogenauer, T. J.; Lewis, J. C. Synth. Commun.
2005, 35, 2099–2105.
(19) (a) Koehn, F. E.; Longley, R. E.; Reed, J. K. J. Nat. Prod. 1992, 55,
613–619. (b) Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L. J.
J. Am. Chem. Soc 2003, 125, 7754–7755. (c) Nicolaou, K. C.; Mathison,
C. J. N. Angew. Chem. Int. Ed. 2005, 44, 5992–5997. (d) Habibi, Z.;
Salehi, P.; Zolfigol, M. A.; Yousefi, M. Synlett 2007, 5, 812–814. (e)
Pacher, T.; Raninger, A.; Lorbeer, E.; Brecker, L.; But, P. P.-H.; Greger, H.
J. Nat. Prod. 2010, 73, 1389–1393.
(20) Studies were also performed on the naturally occurring peptide
leupeptin. Crude HPLC showed a clean trace with two overlapping peaks
with the expected product mass; however, we could not fully characterize
the amide product.
(21) Bode, J. W.; Fox, R. M.; Baucom, K. D. Angew. Chem. Int. Ed.
2006, 45, 1248–1252.
(22) Cho, C.-C.; Liu, J. N.; Chien, C. H.; Shie, J. J.; Chen, Y. C.; Fang, J.
M. J. Org. Chem. 2009, 74, 1549–1556.
(23) For a review on the field, see: Ekoue-Kovi, K.; Wolf, C. Chem. Eur.
J. 2008, 14, 6302–6315.
(24) Achar, T. K.; Mal, P. J. Org. Chem. 2015, 80, 666–672.
(25) Cadoni, R.; Porcheddu, A.; Giacomelli, G.; De Luca, L. Org. Lett.
2012, 14, 5014–5017.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
Supporting
Information.
Experimental
procedures,
supplementary results and spectroscopic data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
bode@org.chem.ethz.ch.
Funding Sources
This research was supported by ETH Zürich.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Gábor Erős, Dmitry Mazunin, Sizhou M. Liu and Dino Wu
(ETH Zürich) are acknowledged for fruitful discussions and
preparation of starting materials.
REFERENCES
(1) (a) Greenburg, A., Breneman, C. M., Liebman, J. F., Eds.; The Am-
ide Linkage: Selected Structural Aspects in Chemistry, Biochemistry and
Materials Science; Wiley, New York, 2000. (b) Roughley, S. D.; Jordan, A.
M. J. Med. Chem. 2011, 54, 3451–3479.
(2) (a) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, Jr., J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. a.;
Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411–420. (b)
Monks, B. M.; Whiting, A. In Sustainable Catalysis; Dunn, P. J. Hii, K. K.
Krische, M. J. Williams, M. T., Eds.; Wiley, New York, 2013; pp. 89–110.
(3) For catalytic amide-forming processes, see: (a) Pattabiraman, V. R.;
Bode, J. W. Nature 2011, 480, 471–479. (b) Al-Zoubi, R. M.; Marion, O.;
Hall, D. G. Angew. Chem. Int. Ed. 2008, 47, 2876–2879. (c) Yoo, W. J.; Li,
C. J. J. Am. Chem. Soc. 2006, 128, 13064–13065. (d) Gunanathan, C.;
Ben-David, Y.; Milstein, D. Science 2007, 317, 790–792. (e) Chan, W.-K.;
Ho, C.-M.; Wong, M.-K.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 14796–
14797. (f) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798–
13799. (g) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796–
13797. (h) Shen, B.; Makley, D. M.; Johnston, J. N. Nature 2010, 465,
1027–1032. (i) Soulé, J. F.; Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc.
2011, 133, 18550–18553. (j) Shackleford, J. P.; Shen, B.; Johnston, J. N.
Proc. Natl. Acad. Sci. 2012, 109, 44–46.
(4) (a) Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Kent, S. B. H. Sci-
ence 1994, 266, 776–779. (b) Hackenberger, C. P. R.; Schwarzer, D. An-
gew. Chem. Int. Ed. 2008, 47, 10030–10074.
(5) For non-chemoselective amide-forming processes in water, see: (a)
MacMillan, D. S.; Murray, J.; Sneddon, H. F.; Jamieson, C.; Watson, A. J. B.
Green Chem. 2013, 15, 596–600. (b) Gabriel, C. M.; Keener, M.; Gallou,
F.; Lipshutz, B. H. Org. Lett. 2015, 17, 3968–3971.
(26) Markó, I. E.; Mekhalfia, A. Tetrahedron Lett. 1990, 31, 7237–
7240.
(27) Measured by UV-Vis and HPLC techniques (8.3 M–1s–1 and
12.1 M–1s–1 respectively).
(6) Dumas, A. M.; Molander, G. A.; Bode, J. W. Angew. Chem. Int. Ed.
2012, 51, 5683–5686.
(28) Cline, G. W.; Hanna, S. B. J. Org. Chem. 1988, 53, 3583–3586.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
O
O
Cl+
H2N
N
BF3K
aq. acidic conditions
rt, < 1 h
H
amide
k ∼10 M-1 s-1
primary amines
KAT reagents
(aromatic, aliphatic)
8
9
O
O
O
O
Cl+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
BF3K
H2N
N
H
aq. acidic conditions
40 ºC, 2 – 12 h
KAT reagents
primary amides
mixed imide
ACS Paragon Plus Environment