Sulfur–Fluoride Exchange (SuFEx)-Mediated Synthesis of Sterically Hindered and Electron-Deficient Secondary and Tertiary Amides via Acyl Fluoride Intermediates

Article abstract of DOI:10.1002/chem.201701552

Amide bond formation is one of the most executed reactions in chemistry and biology. This is largely due to the ubiquity of the amide functional group in biological molecules, natural products and pharmaceutically important drugs. We report here the development of “SuFExAmide”: a new sulfur–fluoride exchange (SuFEx) click chemistry based protocol for the efficient amidation of carboxylic acids via acyl fluoride intermediates. We have developed benzene-1,3-disulfonyl fluoride as a cost effective, powerful and versatile coupling agent, which delivers challenging secondary and tertiary amides in excellent yields from sterically hindered and electron-deficient amines. The straightforward method offers significant benefits over existing protocols in terms of substrate scope, efficiency and ease of operation and is demonstrated by the synthesis of 44 amides, including GNF6702, an antiprotozoal drug candidate. In the majority of cases, the amide products are obtained in high yield without the need for excess reagents or chromatographic purification.

Full text of DOI:10.1002/chem.201701552

A Journal of
Accepted Article
Title: SuFEx Mediated Synthesis of Sterically Hindered and Electron-
Deficient Secondary and Tertiary Amides via Acyl Fluoride
Intermediates
Authors: John Edward Moses, Pallavi Sharma, Andrew Barrow,
Christian Spiteri, Christopher Smedley, and Marie-Claire Giel
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201701552
Link to VoR: http://dx.doi.org/10.1002/chem.201701552
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10.1002/chem.201701552
Chemistry - A European Journal
COMMUNICATION
SuFEx Mediated Synthesis of Sterically Hindered and Electron-
Deficient Secondary and Tertiary Amides via Acyl Fluoride
Intermediates
Christopher J. Smedley, Andrew S. Barrow, Christian Spiteri, Marie-Claire Giel, Pallavi Sharma and
John E. Moses*
Abstract: Amide bond formation is one of the most executed
reactions in chemistry and biology. This is largely due to the ubiquity
of the amide functional group in biological molecules, natural products
and pharmaceutically important drugs. We report here the
development of “SuFExAmide”: a new Sulfur Fluoride Exchange
(SuFEx) click chemistry based protocol for the efficient amidation of
carboxylic acids via acyl fluoride intermediates. We have developed
benzene-1,3-disulfonyl fluoride as a cost effective, powerful and
versatile coupling agent, which delivers challenging secondary and
tertiary amides in excellent yield from sterically hindered and electron-
deficient amines. The straightforward method offers significant
benefits over existing protocols in terms of substrate scope, efficiency
and ease of operation and is demonstrated by the synthesis of 44
amides, including GNF6702, an antiprotozoal drug candidate. In the
majority of cases, the amide products are obtained in high yield
without the need for excess reagents or chromatographic purification.
often fail, is in the preparation of sterically hindered and electron–
deficient amides.[4] The difficulties associated with the formation
of these amide classes often stems from steric hindrance along
the approach vector of the amine to the carbonyl, or by the poor
nucleophilicity of electron deficient amines. The deficit of available
methods for the synthesis of sterically hindered and electron
deficient amides has stimulated the development of a number of
creative new strategies.[4-6, 8] Bode and co-workers developed an
efficient direct coupling of isocyanates with Grignard reagents, but
this method is inevitably restricted to the synthesis of secondary
amides (Figure 1A).[5] Recently, Lear and Hayashi reported the
oxidative amidation of α-substituted malononitriles to access
sterically hindered amides via acyl nitrile intermediates (Figure
1B).[6] This novel approach, while wide in scope, requires the
preparation of the malononitrile starting materials via a two-step
synthesis, and results in the production of cyanide as a by-product
(Figure 1B).
A more desirable protocol, particularly for large-scale
industrial applications,[3] would tap into the vast resource of
available amine and carboxylic acid building blocks, while also
overcoming the issues associated with the activation of the
carboxylic acids by common coupling agents. Acyl fluorides offer
an attractive solution, particularly if they can be generated in situ
from the parent carboxylic acid and used directly in the amide
coupling reaction.
The amide bond is ubiquitous and plays a major role in the
composition of fundamental biological molecules, important
natural products and commercial drugs.[1] Amide bond forming
reactions are therefore among the most executed of all
transformations used in synthetic and medicinal chemistry
applications.[2]
The overwhelming majority of amide bonds are synthesized
through the dehydrative union of an amine with a carboxylic acid
upon the action of a coupling agent.[1] This approach has proven
highly successful, and a wealth of commercially available starting
materials (acids and amines) and many different commercial
coupling reagents are used regularly for the synthesis of amide
containing pharmaceuticals.[3] A recent review by Dunetz, Magano
and Weisenburger, focused on industrial pharmaceutical process
chemistry, highlighted the extensive use of coupling agents for
large-scale amide synthesis. Based upon the examples included
in their review, the top choices for acid activation by reagent are
EDC, SOCl2, CDI, and (COCl)2, followed by a second group
including isobutyl chloroformate (IBCF), T3P, and DCC.[3]
However, one of the biggest and unmet challenges in amide
bond forming chemistry, where even the best coupling reagents
A. Synthesis of sterically hindered and electron deficient secondary
C. Fluorouronium amide coupling
amides from isocyanates (Bode et al., 2012)
reagent BTFFH (Ulven et al., 2016)
O
-
R
F
PF6
N+
Et2O or THF,
r.t., 30 min
O
R'
N
R'MgBr
C
+
H
R
N
N
limited to 2o amides
upto 95% yield
BTFFH
B. Oxidative amidation of α-substituted malononitriles (Li, Lear and Hayashi, 2016)
O2 (1 atm)
Cs2CO3
O
O
CN
2 steps
R'NH2
[CN]-
O
R'
R
R
N
R
CN
R
CN
H
[CN]-
upto 95% yield
D. Acyl fluoride synthesis via sulfonyl fluorides (Steinkopf and Jaeger, 1930)
O
F
O
O
O
O
S
O
N
NH2
O
ONa
O
F
+
2
5
H
4
6
1
3
240 o
C
inseparable mixture
E. This work - SuFExAmide: Sulfur Fluoride exchange mediated synthesis of sterically hindered and
electron-deficient secondary and tertiary amides
O
S
O
R2
F
F
O
H
R2
R1
C. J. Smedley, A. S. Barrow, C. Spiteri, M. –C. Giel, P. Sharma,
Prof. Dr. J. E. Moses
Department of Chemistry and Physics,
La Trobe Institute for Molecular Science, La Trobe University,
Melbourne, Victoria, Australia
R2
R4
S
N
R1
R
R3
R4
O
O
N
R1
R
O
O
7
DBU, DIPEA,
MeCN, 50 oC, 17 h
R
X
R3
R3, R4 = H, Aryl, Alkyl
OH
R, R1, R2
=
2o & 3o amides
8 = X = -OSO2Ar
9 = X = F
F-
H, Aryl, Alkyl
upto 98% yield
E-mail: j.moses@latrobe.edu.au
Homepage: http://www.moseslabs.com
Figure 1. A) Grignard-isocyanate based coupling; B) Oxidative amidation of α-
substituted malononitriles via acyl nitriles; C) Fluoro-N,N,N′,N′-
bis(tetramethylene)formamidinium hexafluorophosphate (BTFFH); D) High
temperature synthesis of acyl fluorides using sulfonyl fluorides; E) SuFExAmide:
SuFEx mediated synthesis of amides via acyl fluoride intermediates.
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
This article is protected by copyright. All rights reserved.

10.1002/chem.201701552
Chemistry - A European Journal
COMMUNICATION
Frequently used for amide couplings of sterically hindered amino
acids, the relatively small size of the acyl fluoride minimises steric
hindrance with respect to the incoming nucleophile.[7] Ulven and
co-workers recently reported an efficient protocol involving the in
situ generation of acyl fluorides by the fluorouronium reagent
BTFFH at elevated temperatures, giving excellent yields of
sterically hindered secondary and tertiary amide products (Figure
1C).[8] Unfortunately, the method fails with arylacetic acid
substrates lacking a second a-substituent.
Given the issues and restricted scope of existing
protocols,[3] coupled with the cost of reagents and undesirable
side products, there remains a demand for the development of
new and efficient methods for the synthesis of challenging amide
bonds.[9]
As part of our research activities aimed at the development
of new amide bond forming reactions,[10] we report here the
development of “SuFExAmide”: a straightforward SuFEx click
chemistry[11-14] based protocol that enables the efficient synthesis
of sterically hindered and electron deficient amides via acyl
fluoride intermediates. Benzene-1,3-disulfonyl fluoride is
employed as an inexpensive condensing agent for the in situ
generation of acyl fluorides, that when used in combination with
bulky and/or electron-deficient amines, allows the facile synthesis
of secondary and tertiary amides in excellent yield.
O
S
O
F
F
S
O
O
H2N
O
O
O
O
O
O
F-
11a
S
SO2F
7
O
N
H
OH
F
DIPEA, DBU,
MeCN, 50 o
C
10
12
4
13a
νCO = 1726 cm-1
νCO = 1790 cm-1
νCO = 1816 cm-1
νCO = 1658 cm-1
Acyl Fluoride 4
Anhydride 12
Benzoic acid 10
Amide 13a
0
2000
4000
6000
Time (s)
Figure 2. The coupling reaction pathway observed by monitoring by the nC=O
carbonyl stretch using in situ FTIR (single point baseline correction at 1901 cm-
1). T = 0, benzoic acid (10, in anhydrous MeCN); T = 300, 1.0 eq DIPEA; T =
600, 0.5 eq DBU; T = 900, 1.0 eq reagent 7; T = 4600, 1.0 eq benzylamine
(11a).
O
S
O
F
F
S
O
O
O
O
R2
R2
HN
R1
+
7 (1.0 eq)
OH
R
N
R1
DIPEA (1.0 eq), DBU (0.50 eq),
MeCN, 50 oC, 17 h
13a-ra
10 (1.0 eq)
11 (1.0 eq)
O
O
O
N
H
N
H
N
H
To the best of our knowledge, there are no reports of the
practical application of sulfur fluoride exchange reagents in
amidation chemistry. In 1930, Steinkopf and Jaeger described the
conversion of sodium benzoate (1) into a mixture of benzoic
anhydride (3) and benzoyl fluoride (4) upon reaction with
benzenesulfonyl fluoride (2) at 240 °C. However, this mixture
could not be separated from the excess benzenesulfonyl fluoride
(2), and the products were “detected only by the smell and by the
conversion into benzanilide” (Figure 1D).[15] Yan and co-workers
O
13a
96%
13b
91%
13c
92%
O
O
O
N
H
N
Ph
N
H
NO2
Ph
13d
88%b
13e
98%
13f
86%
O
O
O
O
N
H
N
H
N
H
13g
89%
13h
85%
13i
85%c
more
recently
reported
1,1,2,2-tetrafluoro-2-(1,1,2,2-
fluoride
CF3
tetrafluoroethoxy)ethane-1-sulfonyl
O
O
O
(HCF2CF2OCF2CF2SO2F) as a condensing agent, although these
reactions proceed though the carboxylic-sulfonic mixed anhydride
intermediates, which likely explains the moderate yields obtained
and failure to react with secondary amines.[16]
N
H
N
H
N
H
13j
73%
13k
85%
13l
84%
O
N
O
O
N
H
N
H
While S-F bonds are thermodynamically very stable, they
can be activated to undergo SuFEx reactions by amine derived
catalysts.[11,12] We anticipated that under typical SuFEx
conditions, the formation of acyl fluorides would be possible under
significantly milder conditions than described by Steinkopf and
Jaeger. The combination of a suitable aromatic sulfonyl fluoride
reagent (e.g. 7), carboxylate and 3o amine catalyst would, in
principle, lead to the corresponding carboxylic-sulfonic mixed
anhydride 8, which in turn would exchange with the liberated
fluoride ion to form the acyl fluoride 9. Finally, attack of the in situ
generated acyl fluoride by the incoming amine nucleophile would
deliver the challenging amide products (Figure 1E).[16]
13m
78%
13n
90%
13o
89%
O
O
O
NO2
N
H
N
N
H
13p
80%
13q
96%
13r
87%
Scheme 1. Investigation of substrate scope of 10. [a] Reactions performed on
1.0 mmol scale, isolated yields, pre-formation of acyl fluoride intermediate for 1
h before addition of amine; [b] HCl salt of amine, 1.0 eq DIPEA added on amine
addition; [c] Heated at 80 °C.
Using benzoic acid (10) and benzylamine (11a) as model
coupling partners, we explored the amidation reaction with a
selection of candidate aromatic sulfonyl fluoride reagents in the
presence of DBU at room temperature (T1, SI). Benzene-1,3-
disulfonyl fluoride (7) was identified as the coupling agent of
choice.[17] Further optimization revealed the following coupling
conditions (T2, SI): 1.0 eq sulfonyl fluoride coupling agent 7, 0.5
eq DBU, 1.0 eq DIPEA, anhydrous MeCN (3.6 mL/mmol) at 50 °C,
stirring for 1 h before the addition of 1.0 eq of amine and further
stirring at 50 °C for 16 h.
The coupling of benzoic acid (10) with benzylamine (11a)
was next performed while simultaneously monitoring the course
of the reaction by in situ FTIR spectroscopy (see SI). Under the
optimised reaction conditions the formation of the sulfonic
anhydride 12 (1790 cm-1) was observed, followed by a significant
build-up in the concentration of acyl fluoride 4 and confirmed by a
sharp increase of the carbonyl stretch at 1816 cm-1. Upon addition
of the benzylamine (11a, 4600 seconds), the acyl fluoride stretch
diminished in concert with the appearance of the amide carbonyl
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10.1002/chem.201701552
Chemistry - A European Journal
COMMUNICATION
stretch at 1658 cm-1, thereby corroborating the proposed reaction
pathway (Figure 2).[18]
100 °C, giving the target GNF6702 in 77% yield without the need
for chromatographic purification.
The scope of the present protocol with a selection of amine
nucleophiles (11) was next investigated using benzoic acid as the
coupling partner. In most cases, analytically pure amide products
were obtained directly upon simple aqueous work-up (Scheme 1).
The reaction performed well with a number of substituted
benzylamines (11b-e), giving the electron-rich (13b-c), electron-
neutral (13a), electron-poor (13d) and hindered dibenzylamine
(13e) products in excellent yield (88-98%). Amidation with a
selection of challenging anilines could also be effected: the
synthesis of the electron-neutral (13f), electron-rich (13g-h), and
sterically hindered amide products (13i) all gave excellent yields.
The more challenging electron-poor 4-(trifluoromethyl)aniline was
also amenable to the reaction conditions, with the amide product
13j isolated in a reasonable 73% yield.
O
S
O
F
F
S
O
O
O
O
R'
R'
+
HN
R''
7 (1.0 eq)
R
N
R
OH
R''
DIPEA (1.0 eq), DBU (0.50 eq)
MeCN, 50 oC, 17 h
14 (1.0 eq)
15 (1.0 eq)
16a-ya
O
O
O
N
N
H
N
H
H
O
F
NC
16a
97%
16b
95%
16c
73%
O
O
O
N
H
NO2
N
H
N
H
O
16d
34%
16e
56%
16f
78%
O
H
N
O
O
N
N
H
O
Alkyne substituted anilines were also well tolerated (13k-l),
as were aliphatic amines (13m-q), each giving excellent yields of
product. Amide coupling of 10 with the electron-poor 5-nitroindole
(11r) gave 13r in an 87% yield. Scheme 2 illustrates the coupling
of a selection of carboxylic acids (14) and amines (15), to give a
diverse array of challenging secondary and tertiary amide
products 16a-y, in moderate to excellent yields. An electron rich
benzoic acid derivative performed well under the developed
conditions (16a), however lower yields were obtained with
electron-deficient carboxylic acids (16c-d). Notably, the products
16f and 16g were synthesised in significantly higher yields than
previously reported by Yan and co-workers [16f (78% vs. 15%)]
and [16g (81% vs. 0%)].[16] Arylacetic acid substrates with a single
a-substituent proved to be more challenging, however, even in
such instances, the SuFExAmide protocol gave moderate to good
yields for a range of products (16h-k), which contrasts with the
BTFFH coupling protocol described by Ulven and co-workers.[8]
The amidation of the hindered diphenylacetic acid with the
aromatic triazole moieties 15m and 15n occurred in 89% (16m)
and 86% (16n) yield, respectively. The coupling of the sterically
encumbered adamantane carboxylic acid with a range of bulky
and/or electron-deficient amines proceeded smoothly (16o-t) and
with excellent conversions. To demonstrate the scalability of our
methodology, amides 16o and 16s were also synthesised in gram
quantities, with no degradation in yield. The synthesis of the
amide 16r resulted in a marginally improved yield of 81% when
compared to the methods of Bode (75%)[5] and Ulven (78%),
albeit at a comparatively higher temperature (80 oC).[8]
O
16g
81%
16h
82%
16i
66%
O
H
N
O
N
N
H
O
O
16j
61%
16k
60%
16l
92%
O
O
O
Ph
N
Ph
N
N
N
H
N
Ph
Ph
N
N
16m
89%
16n
86%
16o
81%
(81%, 1.07 g)b
O
O
O
N
S
N
H
N
H
N
H
N
16p
79%
16q
80%
16r
81%c
Literature yields: 788, 755
O
O
O
N
O
O
N
N
S
S
N
H
N
OEt
O
N
H
N
16s
70%
(80%, 1.20 g)b
16t
68%
16u
81%
N
N
O
N
O
H
N
S
S
H
N
O
O
O
O
16v
89%
16w
72%
16x
79%
O
N
H
N
H
O
Cl
To demonstrate the present coupling reaction as a protocol
with industrial and pharmaceutical relevance, we investigated the
synthesis of the drug candidate GNF6702. Recently reported as
an inhibitor of kinetoplastid proteasome, GNF6702 has been
O
O
N
O
O
16y
85%d
Scheme 2. Investigation of the substrate scope. [a] Reactions performed on
1.0 mmol scale, isolated yields, pre-formation of acyl fluoride intermediate for
1 h before addition of amine; [b] 5.55 mmol scale [c] Heated at 80 °C; [d]
Reaction performed on 0.5 mmol scale.
identified as
a promising treatment for Chagas disease,
leishmaniasis and sleeping sickness, and therefore a timely and
topical target.[19]
O
F
The synthesis of GNF6702 is reported in patent US
2015/0175613 A1,[20] and involves a final stage amide coupling of
the sterically hindered 2,4-dimethyloxazole-5-carboxylic acid (17)
with electron-deficient aniline 18, using HATU in DMF to give the
product in a modest 29.6% yield (Scheme 3). While HATU is used
routinely for the industrial synthesis of sterically hindered
amides,[3] the presented protocol proved superior for the
synthesis of GNF6702. Using modified reaction conditions to
account for the poor solubility of the substrates, the amide
coupling reaction between 17 and 18 was performed in DMF at
O
N
N
HO
N
N
N
N
O
Amide
Coupling
17
HN
GNF6702
+
O
NH2
N
N
N
N
US 2015/0175613 A1 (HATU), 29.6%
N
N
F
SuFExAmide, 77%
18
Scheme 3. Application of the presented protocol for the late stage amide
coupling synthesis of GNF6702.
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10.1002/chem.201701552
Chemistry - A European Journal
COMMUNICATION
Whereas the method proved successful with a range of
substrates, carboxylic acid substrates containing epimerisable a-
centers may not be compatible with the reaction conditions (See
SI).
Acknowledgements
We are grateful to the University of Nottingham for studentship
funding (C.J.S., A.S.B & M.-C.G.).
In summary, we have developed a new and robust protocol
for the synthesis of sterically hindered and electron-deficient
secondary and tertiary amides. The scalable protocol both
complements and improves upon existing methodology in terms
of substrate scope, ease of operation and efficiency. The
procedure, which exploits the unique properties of SuFEx click
chemistry, employs a new aromatic sulfonyl fluoride coupling
reagent, benzene-1,3-disulfonyl fluoride (7): an inexpensive,
bench stable and readily available reagent. The majority of the
amide products synthesised were obtained without the need for
additional purification, with the reagent waste removed by a
simple aqueous wash. Given the fidelity of the protocol, we
anticipate that our method will find wide application in the
synthesis of challenging secondary and tertiary amides for
several applications.
Keywords: • Acyl Fluoride • SuFEx Click Chemistry • Sterically
Hindered and Electron-Deficient Amides • Benzene-1,3-
disulfonyl fluoride
[1]
[2]
[3]
E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606–631.
S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451–3479.
J. R. Dunetz, J. Magano, G. A. Weisenburger, Org. Process Res. Dev.
2016, 20, 140–177.
[4]
a) V. R. Pattabiraman, J. W. Bode, Nature 2011, 480, 471–479, b) K. S.
Yang, A. E. Nibbs, Y. E. Türkmen, V. H. Rawal, J. Am. Chem. Soc. 2013,
135, 16050–16053; c) K.S. Yang, V.H. Rawal, J. Am. Chem. Soc. 2014,
136, 16148–16151; d) Y. Rao, X. Li, S.J. Danishefsky, J. Am. Chem. Soc.
2009, 131, 12924–12926; f) Z. Z. Brown, C. E. Schafmeister, J. Am.
Chem. Soc. 2008, 130, 14382–14383.ꢀ
[5]
[6]
[7]
[8]
[9]
a) G. Schäfer, C. Matthey, J. W. Bode, Angew. Chem. Int. Ed. 2012, 51,
9173–9175; b) G. Schäfer, J. W. Bode, Chimia 2014, 68, 252–255.
J. Li, M. J. Lear, Y. Hayashi, Angew. Chem. Int. Ed. 2016, 55, 9060–
9064.
Experimental Section
a) C. A. G. N. Montalbetti, V. Falque, Tetrahedron 2005, 61, 10827–
10852; b) M. M. Joullié, K. M. Lassen, ARKIVOC 2010, 8, 189–250.
M. E. Due-Hansen, S. K. Pandey, E. Christiansen, R. Andersen, S. V. F.
Hansen, T. Ulven, Org. Biomol. Chem. 2016, 14, 430–433.
Synthesis of benzene-1,3-disulfonyl fluoride (7): To a solution of
potassium hydrogen bifluoride (24.0 g, 308 mmol) in H2O (65 mL)
was added a solution of benzene-1,3-disulfonyl chloride (18.4 g,
66.9 mmol) in MeCN (130 mL) and the reaction mixture stirred at
room temperature for 3 h. The product was extracted into EtOAc
(300 mL), washed with brine (2 x 300 mL), dried over anhydrous
MgSO4 and the solvent removed under reduced pressure. The
crude residue was filtered through a pad of silica (50% EtOAc in
petroleum ether) to give the target product as an off-white solid
(14.6 g, 90%); m.p. 39-42 °C [lit: 38-39 °C][21]; IR ⱱmax (CHCl3)/cm-
A number of one-pot amide coupling protocols for the synthesis of amino
acids involving acyl fluoride intermediates have been developed,
although many of the coupling reagents involved are expensive and
create undesirable side products: a) C. Kaduk, H. Wenschuh, M.
Beyermann, K. Forner, L. A. Carpino, M. Bienert, Lett. Pept. Sci. 1996,
2, 285–288; b) G. S. Lal, G. P. Pez, R. J. Pesaresi, F. M. Prozonic, H.
Cheng, J. Org. Chem. 1999, 64, 7048–7054; c) L. A. Carpino, A. El-
Faham, J. Am. Chem. Soc. 1995, 117, 5401–5402; d) G. A. Olah, M.
Nojima, I. Kerekes, Synthesis 1973, 8, 487–488.
1
1: 3075, 1469, 1433, 832; H NMR (400 MHz, CDCl3) δH = 8.67
(app. t, J = 1.8 Hz, 1 H), 8.43 (dd, J = 8.0, 1.8 Hz, 2 H), 8.00 (app.
t, J = 8.0 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δC = 135.3 (d, 2JC-
F = 28 Hz), 134.8, 131.6, 128.6; 19F NMR (376 MHz, CDCl3) δ =
66.7 ppm.
[10] a) P. Sharma, A. D. Moorhouse, J. E. Moses, Synlett 2011, 16, 2384–
2386; b) G. Carbone, J. Burnley, J. E. Moses, Chem. Commun. 2013, 49,
2759–2761.
[11] J. Dong, L. Krasnova, M. G. Finn, K. B. Sharpless, Angew. Chem. Int.
Ed. 2014, 53, 9430–9448.
[12] S. Li, P. Wu, J. E. Moses, K. B. Sharpless, Angew. Chem. Int. Ed. 2017,
56, 2903–2908.
Typical procedure for the preparation of N-benzylbenzamide
(13a): To a solution of benzoic acid (10) (1.00 mmol) and
benzene-1,3-disulfonyl fluoride (7) (242 mg, 1.00 mmol) in
anhydrous MeCN (3.6 mL) was added DIPEA (174 µL, 1.00
mmol) and DBU (75 µL, 0.50 mmol) and the reaction mixture
stirred at 50 °C for 1 h. Benzylamine (11a) (1.00 mmol) was added
and the reaction mixture stirred at 50 °C for a further 16 h. After
cooling to room temperature, the reaction mixture was extracted
with EtOAc (20 mL) and washed sequentially with sat. NaHCO3
(aq) (20 mL), 1.0M HCl(aq) (20 mL) and H2O (20 mL).The organic
layer was dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure to give the product as a colourless solid
(204 mg, 96%); m.p. 103 °C [lit: 96-97 °C][22]; IR ⱱmax (CHCl3)/cm-
1: 3067, 3009, 1658, 1603, 1581, 1519, 1487, 1275, 1146, 1076;
1H NMR (400 MHz, CDCl3) δH = 7.83–7.78 (m, 2 H), 7.54–7.48 (m,
1 H), 7.47–7.41 (m, 2 H), 7.40–7.35 (m, 4 H), 7.35–7.28 (m, 1 H),
6.43 (br. s., 1 H), 4.67 (d, J = 5.6 Hz, 2 H); 13C NMR (101 MHz,
CDCl3) δC = 167.3, 138.2, 134.3, 131.5, 128.7, 128.5, 127.9,
127.6, 126.9, 44.1; HRMS (ESI+): calculated for C14H14N1O1
[M+H+]: m/z = 212.1070, m/z found 212.1081.
[13] J. Yatvin, K. Brooks, J. Locklin, Chem. Eur. J. 2016, 22, 16348-16354.
[14] A. Dondoni, A. Marra, Org. Biomol. Chem. 2017, 15, 1549-1553.
[15] W. Steinkopf, P. Jaeger, J. Prakt. Chem. 1930, 128, 63–79.
[16] Z. Yan, W. Tian, F. Zeng, Y. Dai, Tetrahedron Lett. 2009, 50, 2727–2729.
[17] The superior coupling ability of this reagent can be supported by the
highly electron-withdrawing potential of an m-SO2F subsitutent
compared to the other candidates examined (s-Hammett coefficient
+0.89).
[18] A number of acyl fluorides were prepared using the developed protocol
by omitting the amine addition step (see SI).
[19] S. Khare, A. S. Nagle, A. Biggart, Y. H. Lai, F. Liang, L. C. Davis, S. W.
Barnes,ꢀ C. J. N. Mathison, E. Myburgh, M. –Y. Gao, J. R. Gillespie, X.
Liu, J. L. Tan, M. Stinson, I. C. Rivera, J. Ballard, V. Yeh, T. Groessl, G.
Federe, H. X. Y. Koh, J. D. Venable, B. Bursulaya, M. Shapiro, P. K.
Mishra, G. Spraggon, A. Brock, J. C. Mottram, F. S. Buckner,ꢀ S. P. S.
Rao, B. G. Wen, J. R. Walker, T. Tuntland, V. Molteni, R. J. Glynne, F.
Supek, Nature 2016, 537, 229–233.
[20] A. Biggart, F. Liang, C. J. N. Mathison, V. Molteni, A. S. Nagle, F. Supek,
V. Yeh, US 2015/0175613 A1, 2015.
[21] W. Steinkopf, J. Prakt. Chem. 1927, 117, 1–82.
[22] N. Wang, X. Zou, J. Ma, F. Li, Chem. Commun. 2014, 50, 8303–8305.
This article is protected by copyright. All rights reserved.

10.1002/chem.201701552
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Christopher J. Smedley, Andrew S.
Barrow, Christian Spiteri, Marie-Claire
Giel, Pallavi Sharma and John E. Moses*
Page No. – Page No.
SuFEx
Mediated
Synthesis
of
Sterically Hindered and Electron-
Deficient Secondary and Tertiary
The perfect couple: A new SuFEx click chemistry based protocol for the efficient
amidation of carboxylic acids via acyl fluoride intermediates, using benzene-1,3-
disulfonyl fluoride as a condensing reagent. SuFExAmide has broad substrate scope
and is well suited for the synthesis of challenging, sterically hindered and electron-
deficient secondary and tertiary amides. The majority of the 44 examples of amide
products described here were obtained in high yield without the need for excess
reagents or chromatographic purification.
Amides
via
Acyl
Fluoride
Intermediates
This article is protected by copyright. All rights reserved.