Clickable coupling of carboxylic acids and amines at room temperature mediated by SO2F2: A significant breakthrough for the construction of amides and peptide linkages

Article abstract of DOI:10.1039/c9ob00699k

The construction of amide bonds and peptide linkages is one of the most fundamental transformations in all life processes and organic synthesis. The synthesis of structurally ubiquitous amide motifs is essential in the assembly of numerous important molecules such as peptides, proteins, alkaloids, pharmaceutical agents, polymers, ligands and agrochemicals. A method of SO₂F₂-mediated direct clickable coupling of carboxylic acids with amines was developed for the synthesis of a broad scope of amides in a simple, mild, highly efficient, robust and practical manner (>110 examples, >90% yields in most cases). The direct click reactions of acids and amines on a gram scale are also demonstrated using an extremely easy work-up and purification process of washing with 1 M aqueous HCl to provide the desired amides in greater than 99% purity and excellent yields.

Full text of DOI:10.1039/c9ob00699k

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DOI: 10.1039/C9OB00699K
ARTICLE
Clickable coupling of carboxylic acids and amines at room
temperature mediated by SO2F2: A significant breakthrough for
the construction of amides and peptide linkages
Received 00th January 20xx,
Accepted 00th January 20xx
Shi-Meng Wang, Chuang Zhao, Xu Zhang, Hua-Li Qin*
DOI: 10.1039/x0xx00000x
The construction of amide bonds and peptide linkages is one of the most fundamental transformations in all life processes
and organic synthesis. The synthesis of the structurally ubiquitous amide motifs is essential in assembly of numerous
important molecules such as peptides, proteins, alkaloids, pharmaceutical agents, polymers, peptides, ligands and
agrochemicals. A method of SO2F2 mediated direct clickable coupling of carboxylic acids with amines was developed for the
synthesis of a broad scope of amides in a simple, mild, high-efficiency, robust and practical manner (>110 examples, >90%
yields in most cases). The direct click reactions of acids and amines in grams-scale are also demonstrated using an extremely
easy work-up and purification process of washing with 1M aqueous HCl to provide the desired amides in greater than 99%
purity and excellent yields.
most common and predominating approach for amide
synthesis. As the most straightforward way for preparing
amides, the thermal amidation through the direct condensation
Introduction
As the fundamental structural unit of proteins, amide bonds
are the basis of all life processes. They also present in a vast
number of synthetic structures, such as polymers, biologically
active compounds and pharmaceutical products.1 The amide
moieties are also prevalent in up to 25% of all pharmaceuticals,2
for example (Fig. 1), Atorvastatin (a top selling drug worldwide
since 2003),3 Imatinib (a specific inhibitor of tyrosine kinase
enzymes),4 and Valsartan (a angiotensin-II receptor
antagonist).5 Indeed, amide formations are among the most
useful tools since it accounts for 16% of all reactions in the
synthesis of pharmaceuticals.6
of carboxylic acids and amines typically requires very harsh
conditions (T > 180 °C).8 To avoid the thermal conditions,
therefore, the pre- or in situ activations of the carboxylic acids
in the presence of stoichiometric “coupling” reagents have
become the most prevailing processes. The coupling reagents
such as carbodiimides, boronic acid derivatives, phosphonium
salts, uronium (or guanidinium) salts and many other coupling
reagents are highly efficient,9 as verified by the incredible
success of amides and peptides synthesis. However, most of the
amide synthesis processes through the use of organic coupling
agents generally suffer from large amount of organic waste
production, high-cost, hazardous-conditions, tedious workup
and purification which have significantly limited their industry
application. In fact, even some simple amides may resist
formation through coupling the corresponding acids with
amines because of the steric hindrance effects of the starting
materials and poor nucleophilicity of some electron-deficient
amines, especially the anilines, which will in turn force scientist
to use more exotic and expensive reagents and harsh conditions
for overcoming the synthetic issues.10 From green, sustainable
and processing-chemistry prospects, the ideal “perfect”
coupling reagent should be inorganic, which produces the
lowest amount of total organic carbon (TOC) in the waste
together with easy work-up and purification. Therefore, finding
a "perfect" coupling reagent capable of negating most of these
drawbacks while still allows smooth couplings of all types of
carboxylic acids with all types of amines would be highly
desirable for the synthesis of amides and peptide linkages in an
atom-economical and industry-applicable manner for
laboratorial and industrial chemistry, and this general coupling
method if achieved will unquestionably make a significant
COOH
N
N
HO
N
HO
N
HN
N
N
NH
F
N
O
O
O
N
N
H
NH
OH
N
O
N
Atorvastatin
imatinib
Valsartan
Figure 1. Representative drugs containing amide motifs.
Although many new strategies for amide formation from
nitriles, alcohols, aldehydes, or alkynes have been reported,7
direct condensation of a carboxylic acid and amine is still the
a. State Key Laboratory of Silicate Materials for Architectures; and School of
Chemistry, Chemical Engineering and Life Science, Wuhan University of
Technology, 205 Luoshi Road, Wuhan, 430070, P. R. China
b. Address here.
c. Address here.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Journal Name
breakthrough for the synthesis of the extremely important substrates for the formation of amide in the presence of N,N-
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amide moieties.
diisopropylethylamine (DIPEA) in MDOeIC: N10.10u39n/dCe9rOB0S0O6929FK2
atmosphere (balloon) at room temperature. Excitingly, within 5
h, the desired amide 5a was formed in 82% yield (Table 1, entry
1). Encouraged by this preliminary successful result, we further
screened a variety of common bases and conditions (see
supporting information for details). The examination indicated
that the performance of organic bases was superior to that of
inorganic bases which could partially be attributed to the
solubility of bases. DIPEA was found to be the ideal base for
constructing the desired amide 5a. The investigation of solvents
effect (Table 1, entry 1-6) revealed that in acetyl nitrile the
clickable amidation performed the best. One particular
importance in organic synthesis is reducing the amounts of
solvents for maximizing environmental and economic benefits.
Therefore, the influence of reaction concentrations for the
efficiency of amide formation also examined. Increasing the
concentration of 0.2 M to 0.5 M, the yields of amide 5a were
elevated from 85% to 95% (Table 1, entry 7-10). When the
concentrations were further increased to 0.6 M and 1.0 M the
yields of amide 5a were slightly decreased to 93% and 91%,
respectively (Table 1, entry 11-12) due to the uncomplete
dissolving starting materials. Therefore, 0.3 M was chosen as
the reaction concentration.
(a)
The formation and activity of aryl fluorosulfate
Nu
-OSO2F
leaving group
OH
O
SO2F2
Nu
O
S
F
base
O
O
S
S(VI)-F connector
O
Nu
O
(b) Proposed direct amidation mediated by SO2F2
O
R2
SO2F
R1
O
NH
R3
O
O
4
2
R2
SO2F2
base
R1
N
R1 OH
R3
1
O
5
R1
F
3
Scheme 1. The proposed direct amidation of carboxylic acids
with amines mediated by SO2F2
On the other hand, click chemistry comprises a series of
reactions that feature in mild conditions, high yields, rapid
kinetics and broad substrates scope,11 since the seminal work
by Sharpless.12 Many types of robust reactions meet the criteria
of “click chemistry” for assembly of various chemical
functionalities, such as the copper (I)-catalyzed azide-alkyne
cycloaddition (the CuAAC click reaction),12, 13 the Thiol-addition
chemistry (Thiol-ene, Thiol-yne),14 the cycloaddition reactions
(Diels–Alder and 1,3-dipolar-cycloadditions).15 In 2014, a new
family of click reactions, the sulfur(VI) fluoride exchange
(SuFEx), to create molecular connections with excellent
reliability and unprecedented efficiency through a sulfur(VI)
hub was introduced by the Sharpless group and has been widely
used in many research fields.16 Sulfuryl fluoride (SO2F2), a
colorless, odorless, inexpensive (about 1$/kg),17 abundant
(millions-kilograms annual production),17 and relatively inert
gas (stable up to 400 oC when dry) has recently attracted
significant attention as a S(VI)−F connective linkers for SuFEx
click chemistry and other transformations.16,17 Based on the
success of application of SO2F2 as an electrophile to react with
hydroxyl groups of phenols (or alcohols) for generating
fluorosulfates to be used as versatile building blocks with two
selectively addressable handles (-OSO2F, -F) for nucleophilic
substitutions and SuFEx click chemistry (Scheme 1a),16a, 18 we
envision that the hydroxyl groups of carboxylic acids 1 would
also proceed nucleophilic attack to SO2F2 in the presence of
base to form intermediates of carboxylic sulfurofluoridic
anhydrides 2 and/or acyl fluorides 3,19 both of which would
further undergo nucleophilic substitutions with amine 4 to
generate the desired amide product 5 with SuFEx clickable
efficiency. Notably, since SO2F2 is an inorganic reagent which
together with the base can be easily removed through simple
washing with aqueous HCl, therefore, the designed protocol
would offer an ideal strategy for amide bonds construction.
Table 1. Optimization of the amidation conditions.a
O
COOH
+
NH2
SO2F2
N
H
base (3 equiv.)
solvent
rt
4a
1a
5a
Concentration
(mol/L)
0.15
Yield b
(5a, %)
82
59
67
26
45
36
85
94
94
95
93
Entry
Base
Solvent
1
2
3
4
5
6
7
8
9
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
MeCN
dioxane
toluene
DMSO
NMP
0.15
0.15
0.15
0.15
0.15
0.20
0.30
0.40
DCM
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
10
11
12
0.50
0.60
1.0
91
a General conditions: a mixture of benzoic acid (1a, 0.3 mmol),
aniline (4a, 0.6 mmol) and DIPEA (3.0 mmol, 3 equiv) in MeCN
(reaction diluted to the specified concentration) under a SO2F2
atmosphere (balloon) was stirred at room temperature for 5 h.
b The yield was determined by HPLC using N-phenylbenzamide
(5a, tR = 3.807 min, λmax = 263.0 nm, water/methanol = 30 : 70
(v/v)) as the external standard.
With the optimized conditions in hand, we subsequently
explored the substrate scope and functional-group tolerance of
the amidation process by coupling of aniline 4a with a variety of
carboxylic acids 1 (Table 2). Accordingly, twenty-nine different
Results and discussion
To test the feasibility of the proposed process, we initially
examined benzoic acid (1a) and aniline (4a) as the model
2 | J. Name., 2012, 00, 1-3
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ARTICLE
acids were smoothly converted to the corresponding amides in corresponding fluorosulfate substituted amide (5ai) and vinyl
View Article Online
DOI: 10.1039/C9OB00699K
excellent to quantitative yields after the simple clickable moiety (5ap) were also tolerable to this process. Carboxylic
couplings. For aromatic carboxylic acids, both electron-donating acids possessing heteroarenes were also compatible, furnishing
(1b-1h) and electron-withdrawing (1j-1r) groups were the corresponding products 5aq-5at in satisfying yields.
compatible well. It was worth noting that the substitutions on Aliphatic and unsaturated acids reacted smoothly with 4v to
para-(1c, 1j), meta- (1d, 1k) and ortho- (1e, 1l) of carboxylic afford the corresponding products (5au-5ba) in excellent yields.
acids did not affect the efficiency of amidation. Interestingly, Remarkably, sterically hindered substrates 5ay and 5az, which
16a
phenolic hydroxy group (5s) which was reported
to be very typically required very harsh condition to synthesize, were
reactive to SO2F2 remained untouched during this process. In generated in quantitative yields using this method.
addition, heterocyclic carboxylic acids, including thiophene,
furan, and pyridine were also smoothly transformed to their Table 3. The scope of couplings of carboxylic acids with
corresponding amides in excellent to quantitative yields (5t-5x). aliphatic amine 4v.a
O
SO2F2 (balloon)
DIPEA (3 eq.)
O
Not surprisingly, aliphatic carboxylic acids (1y-1ac) were also
transformed smoothly into the corresponding amides, even
with the sterically hindering effects (5y-5ac). Carboxylic acid
possessing a reactive alkyne moiety 1ab was also converted to
the desired amide 5ab in quantitative yield.
R
N
O
N
H
4v
+
R
OH
MeCN (0.3 M)
rt, 5 h
5
1
O
O
O
N
O
N
N
N
N
Ph
N
O
F3CO
OHC
5ag
5ah
, 87%
5ae
5af
, 80%
, 99%
, 87%
5ad
, 99%
O
O
N
O
N
O
O
N
N
N
Table 2. The scope of couplings of carboxylic acids with
F
Cl
FO2SO
Br
(aromatic amine) aniline 4a. a
5al
5am
, 74%
5ak
, 92%
5ai
5aj
, 94%
O
, 97%
, 91%
O
SO2F2 (balloon)
O
NH2
O
DIPEA (3 eq.)
O
N
Ph
+
O
N
O
N
S
O
R
N
H
MeCN (0.3 M)
rt, 5 h
R
OH
O
O
O
N
N
1
4a
5
O2
N
5ao
5ap
, 74%
, 99%
5an
5ar
, 69%
, 60%
5aq
, 72%
O
O
O
O
Ph
Ph
Ph
N
Ph
Ph
N
N
N
N
O
O
O
O
H
H
H
H
H
N
O
Me
MeO
OMe
N
N
O
N
N
5a
5c
OMe 5d, 98%
, 99%
O
5b
, 92%
O
5e
, 99%
, 99%
O
N
Ph
N
5aw
, 99%
5as
5au
5av
, 99%
, 85%
5at
, 74%
O
, 95%
O
O
Ph
Ph
Ph
Ph
Ph
Ph
O
N
H
N
N
N
H
N
H
H
H
N
N
N
N
N
t-Bu
Ph
F3CO
Cl
H
O
O
5g
, 99%
5h
5j
, 99%
O
, 99%
O
5f
5i
, 99%
O
, 94%
O
O
5ax
5ba
, 70%
, 82%
O
5ay
5az
, 99%
, 99%
Ph
Ph
Ph
Ph
Ph
N
H
N
N
H
N
H
N
H
a Reaction conditions: a mixture of carboxylic acid (1, 1.0 mmol),
diethylamine (4v, 2.0 mmol) and DIPEA (3.0 mmol, 3 equiv) in
MeCN (0.3 M) under a SO2F2 atmosphere (balloon) was stirred
at room temperature for 5 h.
H
Cl
OHC
Br
MeOOC
5m
5n, 97%
5o, 87%
, 97%
5k
, 97%
O
5l
Cl
, 91%
O
O
O
O
N
Ph
Ph
Ph
Ph
N
N
H
N
N
H
H
H
H
O
MeO2
S
HO
NC
F3C
5s
5t
, 98%
, 99%
5p
5q
5r, 95%
, 87%
, 99%
To further explore the scope and functional-group
compatibility of amines for this clickable coupling reaction,
various amines 4 were examined for coupling with benzoic acid
1a. Excitingly, as illustrated in Table 4, most of the amines
provided the desired amides in excellent to quantitative yield
smoothly. Aromatic amines (anilines) bearing electron-donating
(6a-6c) or electron-withdrawing groups (6d-6h) generated their
corresponding amides efficiently in good to excellent yields. The
more electron deficient substrate 6e was obtained in relatively
decreased yield due to its strong electron-withdrawing
property. The heterocyclic amines 4i and 4j tolerated well to
provide the desired amides 6i and 6j in 73% and 85% yields
respectively. The sterically hindered aromatic amines 4k, 4l and
4m were smoothly transformed to their corresponding amides
6k, 6l and 6m in moderate yields. Aromatic secondary amines
4n and 4o were compatible under this the conditions to provide
their products in 90% and 51% yields respectively. Remarkably,
benzylic amine 4p were transformed to amide 6p in 75% yield
under the standard conditions, and it was elevated to
quantitative yield when the amount of amine was increased to
3.0 equivalent. Notably, heteroaromatic-benzylic amine 4q and
4r generated their corresponding amides 6q and 6r in satisfying
O
O
O
O
H
N
Ph
Ph
N
Ph
Ph
N
Ph
N
N
H
H
H
H
O
S
N
N
Ph
N
5y
, 97%
5u
5v
5x, 90%
, 98%
, 78%
5w
, 85%
O
NHPh
H
N
H
N
O
Ph
Ph
H
N
O
O
H
H
5z
5aa, 98%
, 88%
5ab
H
5ac
, 99%
, 80%
a Reaction conditions: a mixture of carboxylic acid (1, 1.0 mmol),
aniline (4a, 2.0 mmol) and DIPEA (3.0 mmol, 3 equiv) in MeCN
(0.3 M) under a SO2F2 atmosphere (balloon) was stirred at room
temperature for 5 h.
The general applicability of the simple, clickable amide bond
formation strategy was further evaluated with secondary
aliphatic amine 4v to evaluate the scope of carboxylic acids.
Accordingly, a variety of carboxylic acids were screened,
excitingly, the corresponding amides were generated in good to
excellent yields (Table 3). Electron-donating groups such as 2-
naphthyl (5ad), phenyl group (5ae), OMe (5af) and NMe2 (5ag),
and electron-withdrawing groups, such as halogen atoms (5aj-
5al), formyl group (5am) and NO2 (5an), were tolerated well on
the aryl rings. Phenolic hydroxy substrate was converted into
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Organic & Biomolecular Chemistry
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Journal Name
yields when the amines were added after the mixture of benzoic addition products. The primary amines provided corresponding
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acid 1a and DIPEA in MeCN stirred for 2 h under SO2F2 amides 6ah-6ak in moderate yields. EsDpOeIc:i1a0l.l1y0,3t9h/Ce9OstBe0r0ic6a99llKy
atmosphere, and the SO2F2 need to be pumped out of the very hindered 6ak was generated in 74% yield smoothly. Some
system because they were reported to be active enough to more reactive secondary amines (4al-4ao) were also testified
react with SO2F2 under the standard conditions.16a Aliphatic for couplings with acrylic acid, and their amides products were
amines 4s-4w were also testified with good to perfect generated in good to excellent yields (71% to 89%) without
compatibility. Propargyl amine 4s provided the desired amide in undergoing aza-Michael additions.
63% yield. Sterically hindered aliphatic primary amines 4t and
4u were smoothly transformed to their corresponding amides Table 5. The scope of couplings of amines with aliphatic
6t and 6u in 99% and 88% yields respectively. Secondary carboxylic acids. a
SO2F2
DIPEA (3 eq.)
R2
O
O
H
aliphatic amines 4v and 4w were converted to their amides in
the yields of 98% and 65% after coupling with benzoic acid 1a.
N
R2
+
R1
MeCN (0.3 M)
rt, 5 h
R
OH
R
N
R1
4
1
6
OMe
CN
O
O
O
O
O
Table 4. The scope of couplings of amines with aromatic
carboxylic acid 1a.a
O
N
N
N
H
N
H
H
N
H
H
OMe
6ab
, 98%
6z
6x
6y
, 84%
, 87%
, 90%
6aa
74%
O
O
SO2F2
H
R2
R2
N
DIPEA (3 eq.)
O
OH
+
N
R1
O
O
O
R1
MeCN (0.3 M)
rt, 5 h
N
N
H
N
H
N
H
N
H
1a
6
4
N
6ac
6ag
, 82%
, 81%
6af
6ad
, 99%
, 84%
6ae
, 70%
OMe
OPh
CN
NO2
Br
O
O
O
O
O
O
O
O
O
Ph
N
H
Ph
N
H
Ph
N
H
Ph
N
H
Ph
N
O
O
H
Ph
N
N
N
H
N
H
N
H
H
N
H
6a
6b
6c
6d
6e
6f
, 89%
, 98%
, 88%
, 77%
, 92%
O
, 60%
b
6ah
, 57%
6al,
71%
6ai
, 56%
6ak
6aj
, 74%
, 66%
CF3
N
O
O
O
O
O
O
N
Ph
N
H
O
O
Ph
N
Ph
N
H
Ph
N
H
O
N
Ph
Ph
Ph
Ph
N
H
Ph
N
H
H
N
N
b
6g
6h
6i
6j
6k
, 74%
, 99%
, 99%
, 73%
, 85%
Ph
6l,
53%
i-Pr
6ao
6am 71%
, 88%
O
6an,
89%
O
O
O
O
Ph
N
Ph
N
O
Ph
N
H
a Reaction conditions: a mixture of carboxylic acid (1aa or 1ad,
1.0 mmol), amine (4, 2.0 mmol) and DIPEA (3.0 mmol, 3 equiv)
in MeCN (0.3 M) under a SO2F2 atmosphere (balloon) was
Ph
Ph
N
H
Ph
N
H
Ph
N
H
N
c
Ph
i-Pr
6p,
75%
b
b
c
, 77%
6n
, 90%
6m,
6o,
6q
6r
60%
51%
, 73%
(99%b, 89%c
)
O
O
O
O
O
b
Ph
N
Ph
N
stirred at room temperature for 5 h. 3 equiv of amine was
Ph
N
Ph
N
H
Ph
N
H
O
H
used.
b
b
88%
6t
6v
6w
, 65%
, 99%
, 98%
6s,
6u,
63%
a Reaction conditions: a mixture of benzoic acid (1a, 1.0 mmol),
amine (4, 2.0 mmol) and DIPEA (3.0 mmol, 3 equiv) in MeCN (0.3
M) under a SO2F2 atmosphere (balloon) was stirred at room
temperature for 5 h. 3 equiv of amine was used. Reaction
conditions: a mixture of benzoic acid (1a, 1.0 mmol) and DIPEA
(3.0 mmol, 3 equiv) in MeCN (0.3 M) under SO2F2 atmosphere
(balloon) stirred at room temperature for 2 h and SO2F2 was
pumped out of the system, then amine (4, 2.0 mmol) was added
into the mixture and stirred for another 3 h.
Table 6. Application to peptide linkages constructions.a
O
SO2F2
O
H
R3
DIPEA (3 eq.)
R3
R1
N
+
N
R1 OH
b
c
MeCN (0.3 M)
rt, 5 h
R2
R2
1
2
7
O
O
O
O
OEt
OEt
Ph
OEt
O
OEt
O
NH
Ph
HN
O
HN
O
NH
Ph
HO
Ph
Ph
7c
7a
7b
7d
99%b, 98% ee
54%, 99% ee
80%b,c, >99% ee
99% b, >99% ee
O
HN Ph
To adequately demonstrate the generality and broad
substrates scope of the amidation process, we subsequently
examined the amidation of aliphatic carboxylic, the propionic
acid 1aa for coupling with various amines (Table 5). Aromatic
amines with either electron-donating (6x-6ab) or electron-
withdrawing (6ac-6ad) groups reacted with 1aa smoothly
providing the corresponding amides in good to excellent yields.
Sterically hindered aromatic amines and secondary aromatic
amine were transformed smoothly into the target amides 6ae
and 6af in 70% and 99% yield respectively. Aliphatic amine 4ag
bearing a pyridine moiety was also amenable to the amidation
system to provide amides 6ag in 82% yield. More importantly
and challengeably, acrylic acid, a non-aromatic carboxylic acid
bearing an activated terminal olefin functionality, which has
been proved to be very reactive with aliphatic amines to
undergo aza-Michael additions,20 proceeded the coupling
process very smoothly without formation of aza-Michael
O
H
O
H
Ph
OEt
O
Ph
N
N
Ph
HN
N
O
OMe
Boc
N
H
Boc
O
7f
7e
NH
b
86%c, >99% ee
7g
, 84%
7h
, 99%
83%, 95% ee
Boc
O
O
O
O
Ph
Ph
Ph
Ph
N
N
N
N
H
H
H
H
NH
HN
HN
HN
HN
Boc
Boc
Boc
HO
Boc
7k
7i
7j
7l
98%, 50% ee
85%, 68% ee
99%, 60% ee
92%, 50% ee
H
N
O
O
O
S
Ph
OMe
N
H
OEt
N
N
Boc
H
H
HN
O
NH
N
O
Boc
Boc
NH
Ph
O
7m
83%, 64% ee
c
c
NH
7o,
7p
, 70%
7n
93%
, 60%
EtOOC
Boc
a Reaction conditions: a mixture of carboxylic acid (1, 1.0 mmol),
amine (4, 2.0 mmol) and DIPEA (3.0 mmol, 3 equiv) in MeCN (0.3
M) under SO2F2 atmosphere (balloon) was stirred at room
temperature for 5 h. b Toluene was used as solvent. c 3 equiv of
amine was used.
4 | J. Name., 2012, 00, 1-3
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Page 5 of 14
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
Scheme 3. Application of the developed protVoiecwolArtficolerOntlhinee
DOI: 10.1039/C9OB00699K
The generality of the newly developed amidation protocol modification and synthesis of biologically active molecules
was also evaluated in the peptides-related synthesis for the
We were pleased to find that the described new methodology
possible assembly of one of the most important moieties in life is applicable to the synthesis and modification of biologically
and pharmaceutical industry. The results were summarized in active molecules (Scheme 3). Deferasirox 8 (an oral iron
Table 6. The amino esters of Alanine, Tyrosine, Phenylalanine, chelator) and Ibuprofen 10 (a nonsteroidal anti-inflammatory
Valine and Glycine generated their corresponding peptides 7a, drug) were successfully converted to their amide forms after
7b, 7c, 7d and 7g in up to quantitative yields (54% to 99%) after coupling with aniline 4a to afford 9 and 11 in quantitative yields.
coupling with benzoic acid 1a. The Boc- protected amino acids In addition, the synthesis of Boscalid 14, a fungicide was
of Proline, Glycine, Tryptophan, Tyrosine, Alanine, Leucine and achieved in 87% yield through coupling of the corresponding
Methionine were smoothly reacted with aniline 4a to generate carboxylic acid and amine using this method. Notably, the
the corresponding amides 7e and 7h-7m in excellent yields (83% synthesis of amide 17, a key precursor for the synthesis of
to 99%). And to our delight, the synthesis of dipeptides 7f, 7n, cholesterol drug Efaproxiral,21 was also accomplished in 99%
7o and 7p were also achieved with satisfying yields. It is very yield. Remarkably, the phenol group of carboxylic acid 15
worthy noting that the desired peptides 7a-7f was obtained in remained untouched during the amidation process.
very high enantiopurity (95%-99% ee) without undergoing
racemerization while slight to moderate racemization was
observed in 7i-7m.
Conclusions
In summary, a mild, simple, highly efficient, clickable and
O
1. SO2F2, DIPEA (3 eq.)
MeCN (0.3 M), rt, 5 h
NH2
COOH
robust protocol for assembly of amides and peptide linkages
through direct coupling of carboxylic acids with amines using
SO2F2 as easily removable coupling agent was discovered and
developed. Gram-scale reactions with simple aqueous-wash as
work-up provided the desired amides in nearly quantitative
yields and very high purity revealing this new method has
irreplaceably advantages over many other amides synthesis
procedures for practical processes. The robustness of this
method was proved though successful couplings of all types of
amines with all types of carboxylic acids in more than 110
examples (>90% in most cases). The modification and synthesis
of complicated biologically active molecules were also
accomplished. We anticipate that this method will practically
applicable to a wide range of fields involving amides and
peptides syntheses.
Ph
N
+
H
2. wash with 1 M HCl
1a
4a
5a
4.73 g, 96% yield, >99% purity
simple wash, no chromatography
1. SO2F2, DIPEA (3 eq.)
MeCN (0.3 M), rt, 5 h
H
NH2
N
Ph
COOH
+
O
2. wash with 1 M HCl
4a
1aa
5aa
4.25 g, 95% yield, >99% purity
simple wash, no chromatography
O
1. SO2F2, DIPEA (3 eq.)
MeCN (0.3 M), rt, 5 h
COOH
N
N
+
H
2. wash with 1 M HCl
1a
4v
6v
2.59 g, 97% yield, >99% purity
simple wash, no chromatography
Scheme 2. Gram scale reactions
In order to demonstrate the practicality of this method,
several gram-scale reactions were performed under standard
conditions as shown in Scheme 2. Remarkably, the pure
products 5a, 5aa and 6v were obtained in nearly quantitative
yields and greater than 99% purity directly after simple aqueous
workup, revealing that the new amidation procedure has
significant advantages over many current methods for further
practical applications.
Experimental
All reactions were carried out under an air atmosphere.
Unless otherwise specified, NMR spectra were recorded in
CDCl3 on a 500 MHz (for H), 471 MHz (for 19F), and 126 MHz
1
(for 13C) spectrometer. All chemical shifts were reported in ppm
relative to TMS (1H NMR, 0 ppm) and CFCl3 (19F NMR, 0 ppm) as
internal standards. The HPLC experiments were carried out on
a Waters e2695 instrument (column: J&K, RP-C18, 5 μm, 4.6 ×
150 mm), and the yields of the products were determined by
using the corresponding pure compounds as the external
standards. Enantiomeric excesses were determined on HPLC
using Chiralcel OD, IA or IC column with UV detector. Optical
rotations were measured on a Roudolph Autopl IV. Melting
points of the products were measured on a micro melting point
apparatus (SGW X-4) and uncorrected. High resolution mass
spectra (HRMS) were obtained on an Agilent 1260-6221 TOF
mass spectrometry. Reagents used in the reactions were all
purchased from commercial sources and used without further
purification.
O
O
SO2F2
DIPEA (3 eq.)
HN
HN
NH2
H
N
N
OH
N
+
N
N
MeCN (0.3 M)
rt, 5 h
H
H
O
O
O
4a
O
8
9, 98%
Deferasirox
Deferasirox amide
SO2F2
DIPEA (3 eq.)
NH2
O
O
+
Ph
MeCN (0.3 M)
rt, 5 h
OH
N
H
4a
10
11, 99%
(S)-ibuprofen amide
(S)-ibuprofen
O
O
H2
N
SO2F2
N
H
OH
DIPEA (3 eq.)
+
N
Cl
MeCN (0.3 M)
rt, 5 h
N
Cl
12
14, 87%
Boscalid
13
Cl
Cl
H
N
H
SO2F2
DIPEA (3 eq.)
Formal
synthesis
N
COOH
+
O
O
MeCN (0.3 M)
rt, 5 h
HO
HOOC
O
H2
N
HO
Efaproxiral
15
16
17, 99%
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
Page 6 of 14
ARTICLE
General procedure for amidation reaction of 1 with 2
Carboxylic acid (1, 1.0 mmol, 1.0 equiv), amine (2, 2.0 mmol, 2.0 ethyl acetate = 3 : 1 (v /v) as eluent for column chromatography.
equiv), DIPEA (3.0 mmol, 3.0 equiv) and MeCN (reaction mixture Brown oil, 225.0 mg, 99% yield. 1H NMR (500 MHz, CDCl3) δ 9.81
was diluted to 0.3 M) were added to an oven-dried 25 mL (s, 1H), 8.29 (dd, J = 7.8, 1.8 Hz, 1H), 7.68 (dd, J = 8.4, 0.9 Hz, 2H),
reaction flask equipped with a stirring bar and covered with a 7.48 (td, J = 7.7, 1.7 Hz, 1H), 7.36 (t, J = 8.0 Hz, 2H), 7.14-7.11
rubber stopper. Sulfuryl fluoride gas was introduced into the (m, 2H), 7.02 (d, J = 8.3 Hz, 1H), 4.03 (s, 3H).
stirred reaction mixture by slowly bubbling from a balloon. The 4-(Tert-Butyl)-N-phenylbenzamide (5f). [18g] Petroleum ether /
reaction mixture was stirred at room temperature for 5 h. After ethyl acetate = 5 : 1 (v /v) as eluent for column chromatography.
Journal Name
Petroleum ether /
[23]
2-Methoxy-N-phenylbenzamide (5e).
View Article Online
DOI: 10.1039/C9OB00699K
1
the reaction was completed, 1 M aqueous HCl solution (20 mL) White solid, 238.1 mg, 94% yield. H NMR (500 MHz, CDCl3) δ
was added to remove the excess amine and the reaction 7.90 (s, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.49
mixture was extracted with ethyl acetate (3 × 20 mL). The (d, J = 8.5 Hz, 2H), 7.36 (t, J = 8.0 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H),
extracts were dried over anhydrous Na2SO4, and concentrated 1.35 (s, 9H).
under reduced pressure. (For substrates 5v, 5w, 5x, 5as, 5at, 6i, N-Phenyl-[1,1'-biphenyl]-4-carboxamide (5g).[24] Petroleum
6j and 6ag, the reaction mixture was directly concentrated ether / ethyl acetate = 4 : 1 (v /v) as eluent for column
1
under vacuum without washing with aqueous HCl solution). The chromatography. White solid, 270.6 mg, 99% yield. H NMR
residue was purified by column chromatography on silica gel (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.84
using a mixture of petroleum ether and ethyl acetate as eluents (d, J = 8.4 Hz, 2H), 7.80 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 7.2 Hz, 2H),
to give the desired product.
7.51 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.9 Hz,
For substates 6q and 6r, carboxylic acid (1a, 1.0 mmol, 1.0 2H), 7.11 (t, J = 7.4 Hz, 1H).
equiv), DIPEA (3.0 mmol, 3.0 equiv) and MeCN (reaction mixture N-Phenyl-2-naphthamide (5h).[25] Petroleum ether / ethyl
was diluted to 0.3 M) were added to an oven-dried 25 mL acetate = 4 : 1 (v /v) as eluent for column chromatography.
1
reaction flask equipped with a stirring bar and covered with a White solid, 244.8 mg, 99% yield. H NMR (500 MHz, CDCl3) δ
rubber stopper. Sulfuryl fluoride gas was introduced into the 8.36 (s, 1H), 8.07 (s, 1H), 7.93-7.88 (m, 4H), 7.70 (d, J = 7.7 Hz,
stirred reaction mixture by slowly bubbling from a balloon. The 2H), 7.57 (dtd, J = 16.2, 6.9, 1.3 Hz, 2H), 7.39 (t, J = 8.0 Hz, 2H),
reaction mixture was stirred at room temperature until 7.17 (t, J = 7.4 Hz, 1H).
carboxylic acid was completely consumed (about 2 h). The N-Phenyl-4-(trifluoromethoxy)benzamide (5i).[25] Petroleum
sulfuryl fluoride gas was pumped out of the reaction system and ether / ethyl acetate = 3 : 1 (v /v) as eluent for column
1
then amine (4q or 4r, 2.0 mmol, 2.0 equiv) was added. The chromatography. White solid, 278.4 mg, 99% yield. H NMR
mixture was stirred at room temperature for 3 h and then was (500 MHz, CDCl3) δ 7.91 (d, J = 8.7 Hz, 2H), 7.82 (s, 1H), 7.62 (d,
directly concentrated under vacuum. The residue was purified J = 7.8 Hz, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H),
by column chromatography on silica gel using a mixture of 7.17 (t, J = 7.4 Hz, 1H). 19F NMR (471 MHz, CDCl3) δ -57.7 (s, 3F).
petroleum ether and ethyl acetate as eluents to give the desired 4-Chloro-N-phenylbenzamide (5j).[26] Petroleum ether / ethyl
product.
acetate = 3 : 1 (v /v) as eluent for column chromatography.
1
N-Phenylbenzamide (5a).[7d] Petroleum ether / ethyl acetate = White solid, 229.4 mg, 99% yield. H NMR (500 MHz, CDCl3) δ
5 : 1 (v /v) as eluent for column chromatography. White solid, 7.81 (d, J = 8.5 Hz, 2H), 7.77 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.46
1
195.3 mg, 99% yield. H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), (d, J = 8.5 Hz, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H).
7.86 (d, J = 7.4 Hz, 2H), 7.64 (d, J = 7.9 Hz, 2H), 7.53 (t, J = 7.3 Hz, 3-Chloro-N-phenylbenzamide (5k).[27] Petroleum ether / ethyl
1H), 7.46 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.9 Hz, 2H), 7.15 (t, J = 7.5 acetate = 3 : 1 (v /v) as eluent for column chromatography.
1
Hz, 1H).
White solid, 224.7 mg, 97% yield. H NMR (500 MHz, CDCl3) δ
4-Methyl-N-phenylbenzamide (5b).[7d] Petroleum ether / ethyl 7.87 (s, 1H), 7.84 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.8
acetate = 5 : 1 (v /v) as eluent for column chromatography. Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.37 (t, J
White solid, 211.1 mg, 99% yield. H NMR (500 MHz, CDCl3) δ = 7.9 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H).
7.79 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.37 2-Chloro-N-phenylbenzamide (5l).[28] Petroleum ether / ethyl
1
(t, J = 7.9 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), acetate = 3 : 1 (v /v) as eluent for column chromatography.
1
2.43 (s, 3H).
Brown solid, 210.8 mg, 91% yield. H NMR (500 MHz, CDCl3) δ
4-Methoxy-N-phenylbenzamide (5c).[7d] Petroleum ether / 7.93 (s, 1H), 7.75 (dd, J = 7.5, 1.7 Hz, 1H), 7.64 (d, J = 7.8 Hz, 2H),
ethyl acetate = 3 : 1 (v /v) as eluent for column chromatography. 7.44 (t, J = 7.8 Hz, 1H), 7.41-7.35 (m, 4H), 7.17 (t, J = 7.4 Hz, 1H).
White solid, 209.1 mg, 92% yield. H NMR (500 MHz, CDCl3) δ 4-Bromo-N-phenylbenzamide (5m).[25] Petroleum ether / ethyl
1
7.84 (d, J = 8.8 Hz, 2H), 7.82 (s, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.36 acetate = 3 : 1 (v /v) as eluent for column chromatography.
1
(t, J = 8.0 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), White solid, 267.8 mg, 97% yield. H NMR (500 MHz, CDCl3) δ
3.87 (s, 3H).
7.77 (s, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.64-7.61 (m, 4H), 7.38 (t, J
3-Methoxy-N-phenylbenzamide (5d).[22] Petroleum ether / = 7.9 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H).
[28]
ethyl acetate = 3 : 1 (v /v) as eluent for column chromatography. Methyl 4-(phenylcarbamoyl)benzoate (5n).
White solid, 222.7 mg, 98% yield. H NMR (500 MHz, CDCl3) δ ether / ethyl acetate = 2 : 1 (v /v) as eluent for column
7.97 (s, 1H), 7.64 (d, J = 7.7 Hz, 2H), 7.43 (s, 1H), 7.40-7.32 (m, chromatography. White solid, 247.6 mg, 97% yield. H NMR
Petroleum
1
1
4H), 7.15 (t, J = 7.4 Hz, 1H), 7.06 (d, J = 7.9 Hz, 1H), 3.84 (s, 3H). (500 MHz, CDCl3) δ 8.14 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.4 Hz,
6 | J. Name., 2012, 00, 1-3
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Page 7 of 14
Organic & Biomolecular Chemistry
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Journal Name
2H), 7.88 (s, 1H), 7.65 (d, J = 7.8 Hz, 2H), 7.38 (t, J = 8.0 Hz, 2H), N-phenylisonicotinamide (5x).
ARTICLE
[31]
Petroleum ether / ethyl
View Article Online
7.18 (t, J = 7.4 Hz, 1H), 3.96 (s, 3H).
acetate = 2 : 1 (v /v) as eluent for colDumOI:n10c.h10r3o9m/Ca9tOoBg0ra06p9h9yK.
4-Formyl-N-phenylbenzamide (5o).[29] Petroleum ether / ethyl White solid, 178.4 mg, 90% yield. 1H NMR (500 MHz, DMSO-d6)
acetate = 2 : 1 (v /v) as eluent for column chromatography. δ 10.48 (s, 1H), 8.78 (dd, J = 4.4, 1.6 Hz, 2H), 7.86 (dd, J = 4.4, 1.6
1
White solid, 196.0 mg, 87% yield. H NMR (500 MHz, CDCl3) δ Hz, 2H), 7.77 (d, J = 7.6 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.14 (t, J
10.10 (s, 1H), 8.03-7.98 (m, 4H), 7.93 (s, 1H), 7.65 (d, J = 7.9 Hz, = 7.4 Hz, 1H).
2H), 7.39 (t, J = 8.0 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H).
2-([1,1'-Biphenyl]-4-yl)-N-phenylacetamide (5y).[32] Petroleum
4-Cyano-N-phenylbenzamide (5p).[30] Petroleum ether / ethyl ether / ethyl acetate = 2 : 1 (v /v) as eluent for column
1
acetate = 2 : 1 (v /v) as eluent for column chromatography. chromatography. White solid, 278.7 mg, 97% yield. H NMR
1
White solid, 193.4 mg, 87% yield. H NMR (500 MHz, CDCl3) δ (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.65-7.59 (m, 6H), 7.47-
7.96 (d, J = 8.3 Hz, 2H), 7.92 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.62 7.42 (m, 4H), 7.34 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.9 Hz, 2H), 7.04
(d, J = 7.9 Hz, 2H), 7.39 (t, J = 8.0 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H). (t, J = 7.4 Hz, 1H), 3.68 (s, 2H).
[25]
N-Phenyl-4-(trifluoromethyl)benzamide (5q).
Petroleum N-Phenylpivalamide (5z). [7d] Petroleum ether / ethyl acetate =
ether / ethyl acetate = 3 : 1 (v /v) as eluent for column 2 : 1 (v /v) as eluent for column chromatography. White solid,
1
1
chromatography. White solid, 262.6 mg, 99% yield. H NMR 156.0 mg, 88% yield. H NMR (500 MHz, DMSO-d6) δ 9.15 (s,
(500 MHz, CDCl3) δ 7.99 (d, J = 8.1 Hz, 2H), 7.81 (s, 1H), 7.76 (d, 1H), 7.63 (dd, J = 8.5, 1.0 Hz, 2H), 7.28 (t, J = 7.8 Hz, 2H), 7.03 (t,
J = 8.2 Hz, 2H), 7.64 (d, J = 7.9 Hz, 2H), 7.40 (t, J = 7.9 Hz, 2H), J = 7.4 Hz, 1H), 1.22 (s, 9H).
7.19 (t, J = 7.4 Hz, 1H). 19F NMR (471 MHz, CDCl3) δ -63.0 (s, 3F). N-Phenylpropionamide (5aa).
[26]
Petroleum ether / ethyl
4-(Methylsulfonyl)-N-phenylbenzamide (5r). Petroleum ether / acetate = 2 : 1 (v /v) as eluent for column chromatography.
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. White solid, 146.2 mg, 98% yield. 1H NMR (500 MHz, DMSO-d6)
White solid, 261.6 mg, 95% yield. 1H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 7.58 (d, J = 7.7 Hz, 2H), 7.27 (t, J = 7.8 Hz, 2H), 7.01
δ 10.48 (s, 1H), 8.17 (d, J = 8.5 Hz, 2H), 8.08 (d, J = 8.5 Hz, 2H), (t, J = 6.9 Hz, 1H), 2.31 (q, J = 7.6 Hz, 2H), 1.08 (t, J = 7.6 Hz, 3H).
7.77 (d, J = 7.6 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.14 (t, J = 7.4 Hz, N-Phenylbut-2-ynamide (5ab).[33] Petroleum ether / ethyl
1H), 3.28 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 164.9 (s), acetate = 2 : 1 (v /v) as eluent for column chromatography.
1
143.6 (s), 140.0 (s), 139.2 (s), 129.2 (s), 129.1 (s), 127.6 (s), 124.6 White solid, 157.6 mg, 99% yield. H NMR (500 MHz, CDCl3) δ
(s), 121.0 (s), 43.8 (s). Mp 207-208 oC. HRMS ESI (m/z): [M+Na]+ 7.64 (s, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.31 (t, J = 7.9 Hz, 2H), 7.11
calcd for C14H13NNaO3S: 298.0508; found: 298.0505.
(t, J = 7.4 Hz, 1H), 1.97 (s, 3H).
4-Hydroxy-N-phenylbenzamide (5s).[7d] Petroleum ether / ethyl (3r,5r,7r)-N-Phenyladamantane-1-carboxamide
(5ac).[31]
acetate = 2 : 1 (v /v) as eluent for column chromatography. Petroleum ether / ethyl acetate = 2 : 1 (v /v) as eluent for
1
White solid, 211.1 mg, 99% yield. 1H NMR (500 MHz, DMSO-d6) column chromatography. White solid, 204.3 mg, 80% yield. H
δ 10.41 (s, 1H), 8.14 (d, J = 8.8 Hz, 2H), 7.77 (dd, J = 8.0, 5.2 Hz, NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.64 (d, J = 7.6 Hz, 2H),
4H), 7.37 (t, J = 7.9 Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H).
7.27 (t, J = 8.0 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 2.02 (s, 3H), 1.91
N-phenylfuran-2-carboxamide (5t).[7d] Petroleum ether / ethyl (d, J = 2.8 Hz, 6H), 1.71 (d, J = 2.8 Hz, 6H).
acetate = 2 : 1 (v /v) as eluent for column chromatography. N,N-Diethyl-2-naphthamide (5ad).[34] Petroleum ether / ethyl
1
Brown solid, 183.5 mg, 98% yield. H NMR (500 MHz, CDCl3) δ acetate = 2 : 1 (v /v) as eluent for column chromatography.
8.09 (s, 1H), 7.65 (d, J = 7.7 Hz, 2H), 7.51 (s, 1H), 7.36 (t, J = 7.9 Yellow liquid, 226.4 mg, 99% yield. 1H NMR (500 MHz, CDCl3) δ
Hz, 2H), 7.24 (d, J = 3.5 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 6.55 (dd, 7.85 (dt, J = 6.7, 4.4 Hz, 4H), 7.54-7.48 (m, 2H), 7.47 (dd, J = 8.5,
J = 3.5, 1.7 Hz, 1H).
1.3 Hz, 1H), 3.60 (br s, 2H), 3.29 (br s, 2H), 1.28 (br s, 3H), 1.12
N-phenylthiophene-2-carboxamide (5u).[28] Petroleum ether / (br s, 3H).
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. N,N-Diethyl-[1,1'-biphenyl]-4-carboxamide
(5ae).[18g]
1
White solid, 199.2 mg, 98% yield. H NMR (500 MHz, CDCl3) δ Petroleum ether / ethyl acetate = 2 : 1 (v /v) as eluent for
7.88 (s, 1H), 7.64 (dd, J = 3.7, 1.1 Hz, 1H), 7.61 (d, J = 7.6 Hz, 2H), column chromatography. Colorless liquid, 252.0 mg, 99% yield.
7.53 (dd, J = 5.0, 1.1 Hz, 1H), 7.34 (t, J = 8.0 Hz, 2H), 7.14 (t, J = 1H NMR (500 MHz, CDCl3) δ 7.63-7.58 (m, 4H), 7.46-7.45 (m, 4H),
7.4 Hz, 1H), 7.10 (dd, J = 5.0, 3.8 Hz, 1H).
7.37 (t, J = 7.2 Hz, 1H), 3.57 (br s, 2H), 3.32 (br s, 2H), 1.30-1.10
N-phenylpicolinamide (5v).[31] Petroleum ether / ethyl acetate (m, 6H).
= 3 : 1 (v /v) as eluent for column chromatography. Brown solid, N,N-diethyl-4-methoxybenzamide (5af).[34] Petroleum ether /
154.6 mg, 78% yield. 1H NMR (500 MHz, CDCl3) δ 10.03 (s, 1H), ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography.
8.61 (s, 1H), 8.30 (d, J = 7.6 Hz, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.78 Colorless liquid, 179.6 mg, 87% yield. 1H NMR (500 MHz, CDCl3)
(d, J = 7.8 Hz, 2H), 7.48-7.46 (m, 1H), 7.39 (t, J = 7.9 Hz, 2H), 7.15 δ 7.31 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H),
(t, J = 7.4 Hz, 1H).
3.39 (br s, 4H), 1.15 (br s, 6H).
N-phenylnicotinamide (5w).[7d] Petroleum ether / ethyl acetate 4-(Dimethylamino)-N,N-diethylbenzamide (5ag).[35] Petroleum
= 2 : 1 (v /v) as eluent for column chromatography. White solid, ether / ethyl acetate = 2 : 1 (v /v) as eluent for column
1
1
168.5 mg, 85% yield. H NMR (500 MHz, CDCl3) δ 9.08 (s, 1H), chromatography. Light yellow liquid, 175.2 mg, 80% yield. H
8.75 (d, J = 3.4 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.12 (s, 1H), 7.64 NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 8.7
(d, J = 7.9 Hz, 2H), 7.42 (dd, J = 7.9, 4.8 Hz, 1H), 7.38 (t, J = 7.9 Hz, 2H), 3.42 (q, J = 6.0 Hz, 4H), 2.96 (s, 6H), 1.17 (t, J = 7.0 Hz,
Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H).
6H).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 14
ARTICLE
Journal Name
N,N-Diethyl-4-(trifluoromethoxy)benzamide (5ah). Petroleum 10.9 Hz, 1H), 5.78 (d, J = 17.6 Hz, 1H), 5.29 (d, J =V1ie0w.9ArtHiclze,O1nHlin)e,
ether / ethyl acetate = 2 : 1 (v /v) as eluent for column 3.53 (br s, 2H), 3.26 (br s, 2H), 1.23 (br s,D3OHI:),101..110139(/bCr9sO,B30H06).99K
chromatography. Colorless liquid, 227.8 mg, 87% yield. 1H NMR N,N-Diethylfuran-2-carboxamide (5aq).[38] Petroleum ether /
(500 MHz, CDCl3) δ 7.41 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.1 Hz, ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography.
2H), 3.54 (br s, 2H), 3.25 (br s, 2H), 1.25 (br s, 3H), 1.12 (br s, Colorless liquid, 119.6 mg, 72% yield. 1H NMR (500 MHz, CDCl3)
3H). 19F NMR (476 MHz, CDCl3) δ -57.8 (s, 3F). 13C NMR (126 δ 7.44 (d, J = 0.8 Hz, 1H), 6.98 (d, J = 3.4 Hz, 1H), 6.43 (dd, J =
MHz, CDCl3) δ 170.1 (s), 149.8 (s), 136.0 (s), 128.3 (s), 120.9 (s), 3.4, 1.7 Hz, 1H), 3.52 (br s, 4H), 1.22 (br s, 6H).
120.5 (q, J = 258 Hz), 43.5 (s), 39.6 (s), 14.3 (s), 13.0 (s). HRMS N,N-Diethylthiophene-2-carboxamide (5ar).[38] Petroleum
ESI (m/z): [M+H]+ calcd for C12H15F3NO2: 262.1049; found: ether / ethyl acetate = 3 : 1 (v /v) as eluent for column
1
262.1051.
chromatography. Light yellow liquid, 125.5 mg, 69% yield. H
N,N-Diethyl-4-hydroxybenzamide (5ai). Petroleum ether / NMR (500 MHz, CDCl3) δ 7.40 (dd, J = 5.0, 0.9 Hz, 1H), 7.31 (dd,
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. J = 3.6, 0.9 Hz, 1H), 7.01 (dd, J = 4.9, 3.7 Hz, 1H), 3.52 (q, J = 7.1
1
White solid, 186.8 mg, 97% yield. H NMR (500 MHz, CDCl3) δ Hz, 4H), 1.23 (t, J = 7.1 Hz, 6H).
7.49 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 3.54 (br s, 2H), N,N-Diethylisonicotinamide (5as).[40] Petroleum ether / ethyl
3.23 (br s, 2H), 1.24 (br s, 3H), 1.12 (br s, 3H). 19F NMR (476 MHz, acetate = 1 : 2 (v /v) as eluent for column chromatography.
CDCl3) δ 37.6 (s, 1F). 13C NMR (126 MHz, CDCl3) δ 169.29 (s), Colorless liquid, 151.8 mg, 85% yield. 1H NMR (500 MHz, CDCl3)
150.16 (s), 137.88 (s), 128.65 (s), 121.11 (s), 43.36 (s), 39.50 (s), δ 8.68 (d, J = 5.3 Hz, 2H), 7.28 (d, J = 5.9 Hz, 2H), 3.52 (q, J = 7.0
14.17 (s), 12.81 (s). HRMS ESI (m/z): [M+H]+ calcd for Hz, 2H), 3.17 (q, J = 7.0 Hz, 2H), 1.22 (t, J = 7.0 Hz, 3H), 1.09 (t, J
C12H15F3NO2: 242.0691; found: 242.0694.
= 7.0 Hz, 3H).
N,N-Diethyl-4-fluorobenzamide (5aj).[34] Petroleum ether / N,N-Diethylquinoline-6-carboxamide (5at). Petroleum ether /
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography.
1
1
Light yellow liquid, 177.8 mg, 91% yield. H NMR (500 MHz, Light brown liquid, 217.3 mg, 95% yield. H NMR (500 MHz,
CDCl3) δ 7.39-7.33 (m, 2H), 7.07 (d, J = 8.7 Hz, 1H), 7.05 (d, J = CDCl3) δ 8.91 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.10 (d,
8.6 Hz, 1H), 3.51 (br s, 2H), 3.25 (br s, 2H), 1.20 (br s, 3H), 1.12 J = 8.6 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.67 (dd, J = 8.6, 1.8 Hz,
(br s, 3H). 19F NMR (476 MHz, CDCl3) δ -111.4 (s, 1F).
1H), 7.40 (dd, J = 8.3, 4.2 Hz, 1H), 3.57 (br s, 2H), 3.26 (br s, 2H),
4-Chloro-N,N-diethylbenzamide (5ak).[36] Petroleum ether / 1.25 (br s, 3H), 1.10 (br s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.6
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. (s), 151.3 (s), 148.2 (s), 136.4 (s), 135.5 (s), 129.9 (s), 127.9 (s),
Colorless liquid, 198.0 mg, 94% yield. 1H NMR (500 MHz, CDCl3) 127.6 (s), 125.8 (s), 121.9 (s), 43.5 (s), 39.5 (s), 14.3 (s), 13.0 (s).
δ 7.36 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 3.52 (br s, 2H), HRMS ESI (m/z): [M+H]+ calcd for C14H17N2O: 229.1335; found:
3.23 (br s, 2H), 1.22 (br s, 3H), 1.10 (br s, 3H).
229.1333.
4-Bromo-N,N-diethylbenzamide (5al).[34] Petroleum ether / N,N-Diethylbut-2-ynamide (5au).[41] Petroleum ether / ethyl
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. acetate = 2 : 1 (v /v) as eluent for column chromatography.
1
White solid, 235.4 mg, 92% yield. H NMR (500 MHz, CDCl3) δ Yellow liquid, 149.8 mg, 74% yield. 1H NMR (500 MHz, CDCl3) δ
7.53 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 3.53 (br s, 2H), 3.55 (q, J = 7.1 Hz, 2H), 3.39 (q, J = 7.1 Hz, 2H), 1.98 (s, 3H), 1.19
3.24 (br s, 2H), 1.24 (br s, 3H), 1.11 (br s, 3H).
(t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H).
N,N-Diethyl-4-formylbenzamide (5am).[37] Petroleum ether / 2-([1,1'-Biphenyl]-4-yl)-N,N-diethylacetamide
(5av).[42]
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. Petroleum ether / ethyl acetate = 2 : 1 (v /v) as eluent for
Yellow liquid, 151.3 mg, 74% yield. 1H NMR (500 MHz, CDCl3) δ column chromatography. Colorless liquid, 234.1 mg, 99% yield.
10.00 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 3.53 1H NMR (500 MHz, CDCl3) δ 7.61-7.53 (m, 4H), 7.43 (t, J = 7.7 Hz,
(q, J = 6.5 Hz, 2H), 3.19 (q, J = 6.4 Hz, 2H), 1.23 (t, J = 6.2 Hz, 3H), 2H), 7.37-7.30 (m, 3H), 3.74 (s, 2H), 3.41 (q, J = 7.1 Hz, 2H), 3.33
1.08 (t, J = 6.7 Hz, 3H).
(q, J = 7.1 Hz, 2H), 1.14 (q, J = 7.3 Hz, 6H).
N,N-Diethyl-4-nitrobenzamide (5an).[34] Petroleum ether / N,N-Diethyl-3-phenylpropanamide (5aw).[43] Petroleum ether /
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. ethyl acetate = 3 : 1 (v /v) as eluent for column chromatography.
1
Yellow solid, 133.0 mg, 60% yield. H NMR (500 MHz, CDCl3) δ Colorless liquid, 204.1 mg, 99% yield. 1H NMR (500 MHz, CDCl3)
8.25 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 3.56 (q, J = 6.6 δ 7.28 (t, J = 7.5 Hz, 2H), 7.24-7.17 (m, 3H), 3.37 (q, J = 7.1 Hz,
Hz, 2H), 3.20 (q, J = 6.6 Hz, 2H), 1.25 (t, J = 6.6 Hz, 3H), 1.11 (t, J 2H), 3.22 (q, J = 7.1 Hz, 2H), 3.01-2.95 (m, 2H), 2.62-2.56 (m, 2H),
= 6.2 Hz, 3H).
N,N-Diethylbenzo[d][1,3]dioxole-5-carboxamide
1.15-1.09 (m, 6H).
(5ao).[38] N,N-Diethyl-4-(4-methoxyphenyl)butanamide
(5ax).
Petroleum ether / ethyl acetate = 2 : 1 (v /v) as eluent for Petroleum ether / ethyl acetate = 2 : 1 (v /v) as eluent for
column chromatography. Light yellow liquid, 220.9 mg, 99% column chromatography. Colorless liquid, 205.4 mg, 82% yield.
yield. 1H NMR (500 MHz, CDCl3) δ 6.90-6.82 (m, 2H), 6.79 (d, J = 1H NMR (500 MHz, CDCl3) δ 7.10 (d, J = 8.4 Hz, 2H), 6.82 (d, J =
7.7 Hz, 1H), 5.96 (s, 2H), 3.38 (br s, 4H), 1.15 (br s, 6H).
8.5 Hz, 2H), 3.78 (s, 3H), 3.36 (q, J = 7.1 Hz, 2H), 3.22 (q, J = 7.1
N,N-Diethyl-4-vinylbenzamide (5ap).[39] Petroleum ether / Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 2.28 (t, J = 7.5 Hz, 2H), 1.98-1.91
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. (m, 2H), 1.10 (dd, J = 13.2, 6.9 Hz, 6H).13C NMR (126 MHz, CDCl3)
Yellow liquid, 149.8 mg, 74% yield. 1H NMR (500 MHz, CDCl3) δ δ 172.1 (s), 158.0 (s), 134.1 (s), 129.5 (s), 113.9 (s), 55.4 (s), 42.1
7.42 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.71 (dd, J = 17.6, (s), 40.2 (s), 34.6 (s), 32.3 (s), 27.2 (s), 14.4 (s), 13.2 (s). HRMS
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
ESI (m/z): [M+H]+ calcd for C15H24NO2: 250.1802; found: N-(4-Bromophenyl)benzamide (6f). [18g] Petroleum ether / ethyl
View Article Online
250.1800.
acetate = 3 : 1 (v /v) as eluent for colDumOI:n10c.h10r3o9m/Ca9tOoBg0ra06p9h9yK.
White solid, 245.8 mg, 89% yield. H NMR (500 MHz, CDCl3) δ
1
N,N-Diethyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(5ay). Petroleum ether / ethyl acetate = 2 : 1 (v /v) as eluent for 7.86 (d, J = 7.1 Hz, 2H), 7.82 (s, 1H), 7.58-7.54 (m, 3H), 7.51-7.47
column chromatography. Colorless liquid, 229.8 mg, 99% yield. (m, 4H).
1H NMR (500 MHz, CDCl3) δ 7.15-7.07 (m, 3H), 6.93 (d, J = 7.2 N-(4-(Trifluoromethyl)phenyl)benzamide (6g).[7d] Petroleum
Hz, 1H), 4.04-3.98 (m, 1H), 3.56-3.38 (m, 4H), 2.94-2.85 (m, 1H), ether / ethyl acetate = 3 : 1 (v /v) as eluent for column
1
2.80-2.74 (m, 1H), 2.10-1.99 (m, 3H), 1.79-1.70 (m, 1H), 1.24 (t, chromatography. White solid, 262.6 mg, 99% yield. H NMR
J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.96 (d, J = 7.1 Hz, 2H),
δ 174.7 (s), 137.5 (s), 135.8 (s), 129.5 (s), 127.7 (s), 126.5 (s), 7.91 (d, J = 9.1 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.4 Hz,
126.1 (s), 43.9 (s), 42.6 (s), 40.7 (s), 29.4 (s), 27.7 (s), 21.7 (s), 2H), 7.36 (d, J = 8.5 Hz, 2H). 19F NMR (471 MHz, DMSO-d6) δ -
15.2 (s), 13.2 (s). HRMS ESI (m/z): [M+H]+ calcd for C15H22NO2: 57.1 (s, 3F).
232.1696; found: 232.1695.
(3r,5r,7r)-N,N-Diethyladamantane-1-carboxamide
Petroleum ether / ethyl acetate = 2 : 1 (v /v) as eluent for White solid, 219.1 mg, 99% yield. H NMR (500 MHz, CDCl3) δ
column chromatography. Colorless liquid, 234.1 mg, 99% yield. 7.99 (s, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.76 (s, 1H), 7.68 (d, J = 7.8
1H NMR (500 MHz, CDCl3) δ 3.41 (tt, J = 7.2, 3.6 Hz, 4H), 2.12- Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.30 (t, J
1.88 (m, 9H), 1.77-1.71 (m, 6H), 1.25 (t, J = 7.2 Hz, 4H), 1.12 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 6.1 Hz, 1H), 3.07 (s, 1H).
N-(3-Ethynylphenyl)benzamide (6h).[9n] Petroleum ether /
(5az).[44] ethyl acetate = 3 : 1 (v /v) as eluent for column chromatography.
1
= 7.0 Hz, 2H).
N-(Quinolin-3-yl)benzamide (6i).[45] Petroleum ether / ethyl
N-(2-(Diethylamino)-2-oxoethyl)benzamide (5ba). Petroleum acetate = 1 : 1 (v /v) as eluent for column chromatography.
ether / ethyl acetate = 2 : 1 (v /v) as eluent for column White solid, 181.2 mg, 73% yield. 1H NMR (500 MHz, DMSO-d6)
chromatography. Yellow solid, 163.0 mg, 70% yield. M.p. 75-77 δ 10.71 (s, 1H), 9.16 (d, J = 2.5 Hz, 1H), 8.86 (d, J = 2.3 Hz, 1H),
oC. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 7.2 Hz, 2H), 7.48 (t, J 8.05 (d, J = 7.1 Hz, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 7.9
= 7.4 Hz, 1H), 7.44-7.38 (m, J = 7.5 Hz, 3H), 4.22 (d, J = 3.9 Hz, Hz, 1H), 7.67 (t, J = 7.0 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.58 (q, J
2H), 3.43 (q, J = 7.1 Hz, 2H), 3.32 (q, J = 7.2 Hz, 2H), 1.21 (t, J = = 7.6 Hz, 3H).
7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ N-(Pyridin-3-yl)benzamide (6j).[18g] Petroleum ether / ethyl
167.3 (s), 167.2 (s), 134.1 (s), 131.7 (s), 128.6 (s), 127.2 (s), 41.8 acetate = 1 : 1 (v /v) as eluent for column chromatography.
1
(s), 41.2 (s), 40.7 (s), 14.1 (s), 13.0 (s). HRMS ESI (m/z): [M+H]+ White solid, 168.5 mg, 85% yield. H NMR (500 MHz, CDCl3) δ
calcd for C13H19N2O2: 235.1441; found: 235.1440.
8.68 (d, J = 2.4 Hz, 1H), 8.52 (s, 1H), 8.32 (d, J = 4.8 Hz, 1H), 8.30
N-(4-Methoxyphenyl)benzamide (6a).[7d] Petroleum ether / (dd, J = 8.4, 2.4 Hz, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.4
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.29 (dd, J = 8.3, 4.8 Hz, 1H).
1
White solid, 222.7 mg, 98% yield. H NMR (500 MHz, CDCl3) δ N-(2-Isopropylphenyl)benzamide (6k).[18g] Petroleum ether /
7.86 (s, 1H), 7.85 (d, J = 7.4 Hz, 2H), 7.52 (t, J = 7.8 Hz, 3H), 7.45 ethyl acetate = 3 : 1 (v /v) as eluent for column chromatography.
(t, J = 7.5 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 3.80 (s, 3H).
White solid, 177.1 mg, 74% yield. 1H NMR (500 MHz, DMSO-d6)
[18g]
N-(4-Phenoxyphenyl)benzamide (6b).
Petroleum ether / δ 9.92 (s, 1H), 7.99 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.53
ethyl acetate = 3 : 1 (v /v) as eluent for column chromatography. (t, J = 7.4 Hz, 2H), 7.37 (d, J = 7.3 Hz, 1H), 7.28 (td, J = 7.1, 2.5 Hz,
White solid, 254.6 mg, 88% yield. 1H NMR (500 MHz, DMSO-d6) 1H), 7.25-7.20 (m, 2H), 3.18 (dt, J = 13.7, 6.9 Hz, 1H), 1.16 (d, J =
δ 10.29 (s, 1H), 7.97 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 7.0 Hz, 2H), 6.9 Hz, 6H).
7.59 (t, J = 7.1 Hz, 1H), 7.53 (t, J = 7.4 Hz, 2H), 7.37 (t, J = 7.6 Hz, N-(2,6-Dimethylphenyl)benzamide (6l).[7d] Petroleum ether /
2H), 7.11 (t, J = 7.3 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 7.00 (d, J = ethyl acetate = 3 : 1 (v /v) as eluent for column chromatography.
8.0 Hz, 2H).
White solid, 92.4 mg, 41% yield (119.4 mg, 53% yield when 3
N-(Naphthalen-1-yl)benzamide (6c).[18g] Petroleum ether / equiv of amine was used). 1H NMR (500 MHz, DMSO-d6) δ 9.77
ethyl acetate = 3 : 1 (v /v) as eluent for column chromatography. (s, 1H), 8.01 (d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.53 (t, J
White solid, 190.4 mg, 77% yield. 1H NMR (500 MHz, DMSO-d6) = 7.4 Hz, 2H), 7.13 (s, 3H), 2.19 (s, 6H).
δ 10.45 (s, 1H), 8.12 (d, J = 7.1 Hz, 2H), 8.03-7.98 (m, 2H), 7.88 N-(2,6-Diisopropylphenyl)benzamide (6m).[7d] Petroleum ether
(d, J = 8.1 Hz, 1H), 7.65-7.62 (m, 2H), 7.59-7.55 (m, 5H).
/ ethyl acetate = 3 : 1 (v /v) as eluent for column
N-(4-Cyanophenyl)benzamide (6d).[18g] Petroleum ether / ethyl chromatography. White solid, 115.4 mg, 41% yield (168.8 mg,
acetate = 2 : 1 (v /v) as eluent for column chromatography. 60% yield when 3 equiv of amine was used). 1H NMR (500 MHz,
1
White solid, 204.5 mg, 92% yield. H NMR (500 MHz, CDCl3) δ CDCl3) δ 7.91 (d, J = 7.1 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.48 (t, J
8.13 (s, 1H), 7.88-7.86 (m, 2H), 7.81-7.79 (m, 2H), 7.65-7.63 (m, = 7.6 Hz, 2H), 7.46 (s, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 7.7
2H), 7.65 (tt, J = 7.4, 1.1 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H).
Hz, 2H), 3.15 (dt, J = 13.7, 6.9 Hz, 2H), 1.22 (d, J = 6.9 Hz, 12H).
N-(4-Nitrophenyl)benzamide (6e).[18g] Petroleum ether / ethyl N-Methyl-N-phenylbenzamide (6n).[7d] Petroleum ether / ethyl
acetate = 2 : 1 (v /v) as eluent for column chromatography. acetate = 3 : 1 (v /v) as eluent for column chromatography.
1
Yellow solid, 145.3 mg, 60% yield. 1H NMR (500 MHz, DMSO-d6) White solid, 190.1 mg, 90% yield. H NMR (500 MHz, CDCl3) δ
δ 10.79 (s, 1H), 8.26 (d, J = 9.1 Hz, 2H), 8.07 (d, J = 9.2 Hz, 2H), 7.19 (d, J = 7.1 Hz, 2H), 7.13-7.09 (m, 3H), 7.06-7.00 (m, 3H),
7.98 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.5 Hz, 6.92 (d, J = 7.4 Hz, 2H), 3.39 (s, 3H).
2H).
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
N,N-Diphenylbenzamide (6o).[23] Petroleum ether / ethyl N-(m-Tolyl) propionamide (6y).[48] Petroleum ether / ethyl
View Article Online
acetate = 3 : 1 (v /v) as eluent for column chromatography. acetate = 2 : 1 (v /v) as eluent for columnDcOhIr:o10m.1a0t3o9g/Cra9OphB0y0. 6P9a9leK
White solid, 90.2 mg, 33% yield (112.1 mg, 41% yield when 3 yellow solid, 146 mg, 90% yield. 1H NMR (500 MHz, CDCl3) δ 7.61
equiv of amine was used). 1H NMR (500 MHz, DMSO-d6) δ 7.42 (br s, 1H), 7.39 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.6 Hz,
(d, J = 8.5 Hz, 2H), 7.34-7.29 (m, 5H), 7.26-7.18 (m, 8H).
1H), 6.90 (d, J = 7.3 Hz, 1H), 2.37 (q, J = 7.6 Hz, 2H), 2.31 (s,
N-Benzylbenzamide (6p).[9n] Petroleum ether / ethyl acetate = 3H),1.23 (s, 3H).
2 : 1 (v /v) as eluent for column chromatography. White solid, N-(o-Tolyl) propionamide (6z).[48] Petroleum ether / ethyl
147.9 mg, 70% yield (209.2 mg, 99% yield when 3 equiv of amine acetate = 2 : 1 (v /v) as eluent for column chromatography. Pale
was used). 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 7.2 Hz, 2H), yellow solid, 136 mg, 84% yield. 1H NMR (500 MHz, CDCl3) δ 7.71
7.50 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.35 (d, J = 4.4 Hz, (d, J = 7.5 Hz, 1H), 7.19-7.16 (m, 3H), 7.06 (t, J = 7.1 Hz, 1H), 2.39
4H), 7.31 (dd, J = 7.8, 3.6 Hz, 1H), 6.50 (s, 1H), 4.64 (d, J = 5.7 Hz, (q, J = 7.1 Hz, 2H), 2.22 (s, 3H),1.24 (t, J = 7.5 Hz, 3H).
2H).
N-(Naphthalen-1-yl) propionamide (6aa). [49]Petroleum ether /
N-(Pyridin-2-ylmethyl)benzamide (6q).[46] Petroleum ether / ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography.
ethyl acetate = 1 : 1 (v /v) as eluent for column chromatography. Pink solid, 146 mg, 74% yield. 1H NMR (500 MHz, CDCl3) δ 7.86-
Pale yellow solid, 76.4 mg, 36% yield. 1H NMR (500 MHz, CDCl3) 7.80 (m, 3H), 7.76 (d, J = 6.6 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.45
δ 8.53 (d, J = 4.7 Hz, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.72 (s, 1H), (s, 2H), 7.38 (t, J = 7.3 Hz, 1H), 2.44 (q, J = 7.0 Hz, 2H), 1.25 (t, J
7.66 (td, J = 7.7, 1.7 Hz, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.41 (t, J = = 6.7 Hz, 3H).
7.5 Hz, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 7.1, 5.2 Hz, 1H), N-(2-Methoxyphenyl) propionamide (6ab).[48] Petroleum ether
4.74 (d, J = 4.9 Hz, 2H).
/ ethyl acetate = 2 : 1 (v /v) as eluent for column
1
N-(Furan-2-ylmethyl)benzamide (6r).[46] Petroleum ether / chromatography. Orange liquid, 175 mg, 98% yield. H NMR
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. (500 MHz, CDCl3) δ 8.38 (d, J = 7.8 Hz, 1H), 7.79 (br s, 1H), 7.02
1
White solid, 76.5 mg, 38% yield. H NMR (500 MHz, CDCl3) δ (t, J = 6.8 Hz, 1H), 6.94 (td, J = 7.7, 1.0 Hz, 1H), 6.86 (d, J = 8.1 Hz,
7.78 (d, J = 7.3 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 3.86 (s, 3H), 2.41 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).
2H), 7.37 (d, J = 1.0 Hz, 1H), 6.53 (s, 1H), 6.33 (t, J = 2.5 Hz, 1H), N-(4-Cyanophenyl) propionamide (6ac).[50] Petroleum ether /
6.29 (d, J = 3.1 Hz, 1H), 4.63 (d, J = 5.5 Hz, 2H).
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography.
N-(Prop-2-yn-1-yl)benzamide (6s).[9n] Petroleum ether / ethyl White powder, 140 mg, 81% yield. H NMR (500 MHz, DMSO-
acetate = 2 : 1 (v /v) as eluent for column chromatography. d6) δ 10.28 (s, 1H), 7.77 (d, J = 8.9 Hz, 2H), 7.73 (d, J = 8.7 Hz,
White solid, 84.4 mg, 53% yield (100.3 mg, 63% yield when 3 2H), 2.37 (q, J = 7.4 Hz, 2H), 1.08 (t, J = 7.7 Hz, 3H).
equiv of amine was used). 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J N-(3-Ethynylphenyl) propionamide (6ad). Petroleum ether /
1
= 7.1 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 6.47 ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography.
1
(s, 1H), 4.25 (dd, J = 5.2, 2.6 Hz, 2H), 2.28 (t, J = 2.6 Hz, 1H).
Brown solid, 145 mg, 84% yield. Mp. 78-80℃. H NMR (500
N-((3S,5S,7S)-adamantan-1-yl)benzamide (6t).[9k] Petroleum MHz, CDCl3) δ 7.64 (br s, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.26-7.20
ether / ethyl acetate = 2 : 1 (v /v) as eluent for column (m,
1
chromatography. White solid, 252.8 mg, 99% yield. H NMR 2H), 3.05 (s, 1H), 2.38 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.7 Hz, 3H).
(500 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.27 13C NMR (126 MHz, CDCl3) δ 172.4 (s), 138.1 (s), 129.0 (s), 127.9
(t, J = 8.1 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 2.02-2.01 (m, 3H), 1.90 (s), 123.4 (s), 122.8 (s), 120.5 (s), 83.2 (s), 77.4 (s), 30.7 (s), 9.6
(d, J = 2.9 Hz, 6H), 1.71-1.70 (m, 6H).
N-(Tert-butyl)benzamide (6u).
(s). HRMS ESI (m/z): [M+H]+ calcd for C11H11NO: 174.0913;
Petroleum ether / ethyl found: 174.0916.
[9j]
acetate = 3 : 1 (v /v) as eluent for column chromatography. N-(2-Isopropylphenyl) propionamide (6ae). Petroleum ether /
White solid, 99.3 mg, 56% yield (156.0 mg, 88% yield when 3 ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography.
equiv of amine was used). 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J Pale pink solid, 133 mg, 70% yield. Mp. 61-63 oC. 1H NMR (500
= 7.1 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H), 7.39 (t, J = 7.4 Hz, 2H), 5.97 MHz, CDCl3) δ 7.64 (br s, 1H), 7.28 (s, 1H), 7.18-7.17 (m, 3H),
(s, 1H), 1.46 (s, 9H).
3.03 (hept, J = 6.5 Hz, 1H), 2.41 (q, J = 7.2 Hz, 2H), 1.28-1.23 (m,
N,N-Diethylbenzamide (6v).[9j] Petroleum ether / ethyl acetate 9H). 13C NMR (126 MHz, CDCl3) δ 172.4 (s), 140.7 (s), 134.2 (s),
= 3 : 1 (v /v) as eluent for column chromatography. White solid, 126.3 (s), 126.0 (s), 125.6 (s), 125.1 (s), 30.5 (s), 28.0 (s), 23.0 (s),
173.7 mg, 98% yield. 1H NMR (500 MHz, CDCl3) δ 7.37-7.33 (m, 9.9 (s). HRMS ESI (m/z): [M+H]+ calcd for C12H17NO: 192.1383;
5H), 3.53 (s, 2H), 3.23 (s, 2H), 1.15 (d, J = 71.1 Hz, 6H).
Morpholino(phenyl)methanone (6w).
found: 192.1382.
[7d]
Petroleum ether / N-Methyl-N-phenylpropionamide (6af).[51] Petroleum ether /
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography.
1
White solid, 124.3 mg, 65% yield. H NMR (500 MHz, CDCl3) δ Orange solid, 161.6 mg, 99% yield. 1H NMR (500 MHz, CDCl3) δ
8.12 (dd, J = 8.3, 1.3 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.41 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 7.7 Hz,
7.8 Hz, 2H), 3.80 (t, J = 4.7 Hz, 4H), 3.44 (t, J = 4.9 Hz, 4H).
2H), 3.26 (s, 3H), 2.08 (q, J = 6.2 Hz, 2H), 1.05 (t, J = 7.2 Hz, 3H).
N-(4-Methoxyphenyl) propionamide (6x).[47] Petroleum ether / N-(Pyridin-3-ylmethyl) propionamide (6ag).[52] Petroleum
ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography. ether / ethyl acetate = 1 : 2 (v /v) as eluent for column
1
White solid, 155 mg, 87% yield. 1H NMR (500 MHz, CDCl3) δ 7.69 chromatography. Orange liquid, 135 mg, 82% yield. H NMR
(br s, 1H), 7.39 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 3.76 (s, (500 MHz, CDCl3) δ 8.47 (s, 1H), 8.41 (d, J = 4.1 Hz, 1H), 7.64 (d,
3H), 2.33 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H).
10 | J. Name., 2012, 00, 1-3
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J = 8.0 Hz, 1H), 7.22 (dd, J = 7.8, 4.9 Hz, 1H), 6.92 (br s, 1H), 4.37 1.52 (d, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H). [α]D = +18.7 (c =
View Article Online
DOI: 10.1039/C9OB00699K
(d, J = 5.9 Hz, 2H), 2.21 (q, J = 7.6 Hz, 2H), 1.09 (t, J = 7.7 Hz, 3H). 1.0, CHCl3), >99% ee was determined by chiral HPLC (chiralcel
N-Benzylacrylamide (6ah).[53] Petroleum ether / ethyl acetate = OD-H, n-hexane/2-propanol = 80/20, 0.5 mL/min, 254 nm). tR =
2 : 1 (v /v) as eluent for column chromatography. White solid, 9.92 min (minor) and 12.32 min (major). Authentic samples
92 mg, 57% yield. 1H NMR (500 MHz, CDCl3) δ 7.33 (t, J = 7.3 Hz, were independently prepared from L- and D-amino acids and
2H), 7.29-7.26 (m, 3H), 6.30 (dd, J = 16.9, 1.2 Hz, 1H), 6.12 (dd, their mixture was used as reference racemate.
J = 16.9, 10.2 Hz, 2H), 5.64 (dd, J = 10.2, 1.2 Hz, 1H), 4.49 (d, J = Ethyl benzoyl-L-tyrosinate (7b).[60] Petroleum ether / ethyl
5.7 Hz, 2H).
acetate = 2 : 1 (v /v) as eluent for column chromatography.
N-Cyclohexylacrylamide (6ai).[54] Petroleum ether / ethyl White solid, 310.3 mg, 99% yield. H NMR (500 MHz, CDCl3) δ
acetate = 2 : 1 (v /v) as eluent for column chromatography. 7.74 (d, J = 7.3 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz,
White solid, 85 mg, 56% yield. 1H NMR (500 MHz, CDCl3) δ 6.24 2H), 7.29-7.27 (m, 4H), 6.74 (s, 1H), 5.06 (dd, J = 12.9, 6.2 Hz,
(dd, J = 17.1 Hz, 1.3 Hz, 1H), 6.08 (dd, J = 17.1, 10.2 Hz, 1H), 5.74 1H), 4.22 (q, J = 6.9 Hz, 2H), 3.30 (ddd, J = 19.4, 14.0, 5.9 Hz, 2H),
(br s, 1H), 5.58 (dd, J = 10.3, 1.1 Hz, 1H), 3.86-3.79 (m, 1H), 1.95- 1.26 (t, J = 7.1 Hz, 3H). [α]D25 = -43.2 (c = 0.10, CH3OH), >99% ee
1.91 (m, 2H), 1.72-1.68 (m, 2H), 1.62-1.60 (m, 1H), 1.40-1.31 (m, was determined by chiral HPLC (chiralcel OD-H, n-hexane/2-
1
2H), 1.19-1.11 (m, 3H).
propanol = 80/20, 0.5 mL/min, 254 nm). tR = 14.79 min (minor)
N-(1-Phenylethyl) acrylamide (6aj).[54] Petroleum ether / ethyl and 23.29 min (major). Authentic samples were independently
acetate = 2 : 1 (v /v) as eluent for column chromatography. prepared from L- and D-amino acids and their mixture was used
1
Yellow liquid, 115 mg, 66% yield. H NMR (500 MHz, CDCl3) δ as reference racemate.
7.32 (d, J = 4.4 Hz, 4H), 7.25 (t, J = 4.3 Hz, 1H), 6.34 (br s, 1H), Ethyl benzoyl-L-phenylalaninate (7c).[59] Petroleum ether /
6.26 (dd, J = 17.0, 1.3 Hz, 1H), 6.12 (dd, J = 17.0, 10.3 Hz, 1H), ethyl acetate = 2 : 1 (v /v) as eluent for column chromatography.
1
5.60 (dd, J = 10.3, 1.3 Hz, 1H), 5.19 (hept, J = 7.4 Hz, 1H), 1.50 White solid, 294.4 mg, 99% yield. H NMR (500 MHz, CDCl3) δ
(d, J = 6.8 Hz, 3H).
7.73 (d, J = 7.1 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.6 Hz,
N-((3S,5S,7S)-adamantan-1-yl) acrylamide (6ak).[55] Petroleum 2H), 7.30-7.27 (m, 2H), 7.26-7.22 (m, 1H), 7.15 (d, J = 8.2 Hz, 2H),
ether / ethyl acetate = 2 : 1 (v /v) as eluent for column 6.61 (d, J = 7.2 Hz, 1H), 5.07 (dt, J = 7.5, 5.7 Hz, 1H), 4.21 (q, J =
chromatography. White solid, 151.6 mg, 74% yield.1H NMR (500 7.1 Hz, 2H), 3.26 (qd, J = 13.8, 5.7 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).
25
MHz, CDCl3) δ 6.24 (dd, J = 16.9, 1.5 Hz, 1H), 6.15 (dd, J = 17.0, [α]D = -35.1 (c = 0.10, CH3OH), 98% ee was determined by
10.0 Hz, 1H), 6.06 (s, 1H), 5.59 (dd, J = 10.1, 0.8 Hz, 1H), 1.93- chiral HPLC (chiralcel OD-H, n-hexane/2-propanol = 90/10, 1.0
1.61 (m, 15H).
mL/min, 254 nm). tR = 8.93 min (minor) and 11.58 min (major).
N,N-Dimethylacrylamide (6al).[56] Petroleum ether / ethyl Authentic samples were independently prepared from L- and D-
acetate = 2 : 1 (v /v) as eluent for column chromatography. amino acids and their mixture was used as reference racemate.
1
Colorless liquid, 70 mg, 71% yield. H NMR (500 MHz, CDCl3) δ Ethyl benzoyl-L-valinate (7d).[61] Petroleum ether / ethyl
6.54 (dd, J = 16.8, 10.4 Hz, 1H), 6.24 (dd, J = 16.7, 1.9 Hz, 1H), acetate = 2 : 1 (v /v) as eluent for column chromatography.
1
5.62 (dd, J = 10.6, 2.0 Hz, 1H), 3.04 (s, 3H), 2.97 (s, 3H).
White solid, 134.6 mg, 54% yield. H NMR (500 MHz, CDCl3) δ
N,N-Diethylacrylamide (6am).[57] Petroleum ether / ethyl 7.81 (d, J = 7.1 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.5 Hz,
acetate = 2 : 1 (v /v) as eluent for column chromatography. 2H), 6.65 (d, J = 8.0 Hz, 1H), 4.77 (dd, J = 8.6, 4.8 Hz, 1H), 4.29-
Yellow liquid, 90 mg, 71% yield. 1H NMR (500 MHz, CDCl3) δ 6.52 4.18 (m, 2H), 2.42-2.04 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.01 (dd,
(dd, J = 16.8, 10.5 Hz, 1H), 6.32 (dd, J = 16.6, 2.0 Hz, 1H), 5.64 J = 12.7, 6.9 Hz, 6H). [α]D25 = +22.0 (c = 0.10, CHCl3). 99% ee was
(dd, J = 10.5, 1.9 Hz, 1H), 3.43 (q, J = 7.0 Hz, 2H), 3.37 (q, J = 7.0 determined by chiral HPLC (chiralcel OD-H, n-hexane/2-
Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H).
propanol = 90/10, 1.0 mL/min, 254 nm). tR = 5.36 min (minor)
N,N-Dipropylacrylamide (6an).[56] Petroleum ether / ethyl and 6.62 min (major). Authentic samples were independently
acetate = 2 : 1 (v /v) as eluent for column chromatography. Pale prepared from L- and D-amino acids and their mixture was used
1
yellow liquid, 137 mg, 89% yield. H NMR (500 MHz, CDCl3) δ as reference racemate.
6.53 (dd, J = 16.6, 10.4 Hz, 1H), 6.32 (dd, J = 16.8, 2.0 Hz, 1H), Tert-butyl (S)-2-(phenylcarbamoyl)pyrrolidine-1-carboxylate
5.64 (dd, J = 10.4, 1.9 Hz, 1H), 3.33 (t, J = 7.5 Hz, 2H), 3.26 (t, J = (7e).[62] Petroleum ether / ethyl acetate = 2 : 1 (v /v) as eluent
7.6 Hz, 2H), 1.59 (hept, J = 7.6 Hz, 4H), 0.90 (dd, J = 12.9, 7.2 Hz, for column chromatography. White solid, 241.0 mg, 83% yield.
6H).
1H NMR (500 MHz, CDCl3) δ 9.47 (s, 1H), 7.51 (d, J = 7.7 Hz, 2H),
N,N-Dibenzylacrylamide (6ao).[58] Petroleum ether / ethyl 7.30 (s, 2H), 7.08 (s, 1H), 4.47 (s, 1H), 3.39 (d, J = 26.7 Hz, 2H),
acetate = 2 : 1 (v /v) as eluent for column chromatography. 2.55 (s, 1H), 2.04-1.72 (m, 3H), 1.49 (s, 9H). [α]D25 = -136.0 (c =
1
Yellow liquid, 220 mg, 88% yield. H NMR (500 MHz, CDCl3) δ 0.10, CHCl3). 95% ee was determined by chiral HPLC (chiralcel
7.38-7.26 (m, 8H), 7.18 (d, J = 7.2 Hz, 2H), 6.32 (dd, J = 16.8, 10.4 OD-H, n-hexane/2-propanol = 90/10, 1.0 mL/min, 254 nm). tR =
Hz, 1H), 6.50 (dd, J = 16.8, 2.2 Hz, 1H), 5.74 (dd, J = 10.4, 2.1 Hz, 5.31 min. (minor) and 6.49 min. (major). Authentic samples
1H), 4.67 (s, 2H), 4.53 (s, 2H).
were independently prepared from L- and D-amino acids and
Ethyl benzoyl-L-alaninate (7a).[59] Petroleum ether / ethyl their mixture was used as reference racemate.
acetate = 3 : 1 (v /v) as eluent for column chromatography. Ethyl (tert-butoxycarbonyl)glycyl-L-phenylalaninate (7f).[63]
1
White solid, 177.0 mg, 80% yield. H NMR (500 MHz, CDCl3) δ Petroleum ether / ethyl acetate = 2 : 1 (v /v) as eluent for
7.80 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.5 Hz, column chromatography. Colorless oil, 301.4 mg, 86% yield. 1H
2H), 6.79 (s, 1H), 4.78 (p, J = 7.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), NMR (500 MHz, CDCl3) δ 7.25 (d, J = 7.4 Hz, 2H), 7.21 (t, J = 7.2
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Organic & Biomolecular Chemistry
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Journal Name
Hz, 1H), 7.10 (d, J = 6.9 Hz, 2H), 6.68 (s, 1H), 5.25 (s, 1H), 4.83 Tert-butyl-(4-methyl-1-oxo-1-(phenylamino)pentVainew-2A-rticle Online
(dd, J = 13.6, 6.1 Hz, 1H), 4.13 (dd, J = 14.6, 7.4 Hz, 2H), 3.81- yl)carbamate (7l).[62] Petroleum ether / DetOhI:y1l0a.1c0e3t9a/tCe9O=B200:6199(Kv
3.70 (m, 2H), 3.09 (t, J = 5.3 Hz, 2H), 1.42 (s, 9H), 1.20 (t, J = 7.2 /v) as eluent for column chromatography. White solid, 281.9
25
Hz, 3H). [α]D = -14.7 (c = 0.10, MeOH). >99% ee was mg, 92% yield. 1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.60
determined by chiral HPLC (chiralcel IC, n-hexane/2-propanol = (d, J = 7.8 Hz, 2H), 7.29 (t, J = 7.9 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H),
80/20, 1.0 mL/min, 254 nm). tR = 8.96 min (major) and 13.58 6.99 (d, J = 8.0 Hz, 1H), 4.13 (dd, J = 13.7, 9.0 Hz, 1H), 1.67-1.62
min (minor). Authentic samples were independently prepared (m, 1H), 1.56-1.50 (m, 1H), 1.44 (dd, J = 8.3, 5.6 Hz, 1H), 1.38 (s,
25
from L- and D-amino acids and their mixture was used as 9H), 0.89 (dd, J = 6.3, 4.2 Hz, 6H). [α]D = +36.6 (c = 0.10,
reference racemate.
MeOH). 50% ee was determined by chiral HPLC (chiralcel IA, n-
Methyl benzoylglycinate (7g).[64] Petroleum ether / ethyl hexane/2-propanol = 80/20, 1.0 mL/min, 254 nm). tR = 4.65 min
acetate = 3 : 1 (v /v) as eluent for column chromatography. (minor) and 5.66 min (major). Authentic samples were
1
White solid, 162.3 mg, 84% yield. H NMR (500 MHz, CDCl3) δ independently prepared from L- and D-amino acids and their
7.80 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, mixture was used as reference racemate.
2H), 6.82 (s, 1H), 4.23 (d, J = 5.1 Hz, 2H), 3.78 (s, 3H).
Tert-butyl-(4-(methylthio)-1-oxo-1-(phenylamino)butan-2-
Tert-butyl (2-oxo-2-(phenylamino)ethyl)carbamate (7h).[65] yl)carbamate (7m). [62] Petroleum ether / ethyl acetate = 3 : 1 (v
Petroleum ether / ethyl acetate = 2 : 1 (v /v) as eluent for /v) as eluent for column chromatography. White solid, 269.3
1
column chromatography. White solid, 247.8 mg, 99% yield. H mg, 83% yield. 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 7.50 (d,
NMR (500 MHz, CDCl3) δ 8.55 (s, 1H), 7.50 (d, J = 7.8 Hz, 2H), J = 7.9 Hz, 2H), 7.29 (t, J = 6.5 Hz, 2H), 7.08 (t, J = 7.4 Hz, 1H),
7.29 (t, J = 7.9 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H), 5.59 (t, J = 5.3 Hz, 5.50 (d, J = 0.5 Hz, 1H), 4.47 (s, 1H), 2.61 (dd, J = 12.4, 6.6 Hz,
1H), 3.94 (d, J = 4.0 Hz, 2H), 1.46 (s, 9H).
2H), 2.18 (td, J = 13.5, 6.7 Hz, 1H), 2.10 (s, 3H), 2.01 (dd, J = 14.3,
Tert-butyl-(3-(1H-indol-3-yl)-1-oxo-1-(phenylamino)propan-2- 7.0 Hz, 1H), 1.44 (s, 9H). [α]D25 = -5.9 (c = 0.10, MeOH). 64% ee
yl)carbamate (7i).[62] Petroleum ether / ethyl acetate = 2 : 1 (v was determined by chiral HPLC (chiralcel IA, n-hexane/2-
/v) as eluent for column chromatography. White solid, 322.6 propanol = 90/10, 1.0 mL/min, 254 nm). tR = 10.97 min (major)
mg, 85% yield. 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.95 (s, and 12.17 min (minor). Authentic samples were independently
1H), 7.67 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.28 (d, J = prepared from L- and D-amino acids and their mixture was used
7.8 Hz, 2H), 7.23 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.6 Hz, 1H), 7.10 as reference racemate.
(t, J = 7.5 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 6.98 (s, 1H), 5.39 (s, Tert-butyl-2-((2-methoxy-2-oxoethyl)carbamoyl)pyrrolidine-
1H), 4.63 (s, 1H), 3.30 (d, J = 31.0 Hz, 2H), 1.42 (s, 9H). [α]D25 = - 1-carboxylate (7n).[66] Petroleum ether / ethyl acetate = 3 : 1 (v
26.3 (c = 0.10, CHCl3). 68% ee was determined by chiral HPLC /v) as eluent for column chromatography. Colorless oil, 171.8
(chiralcel IA, n-hexane/2-propanol = 80/20, 1.0 mL/min, 254 mg, 60% yield. 1H NMR (500 MHz, CDCl3) δ 5.05 (dt, J = 8.2, 3.9
nm). tR = 8.98 min (major) and 14.90 min (minor). Authentic Hz, 1H), 4.70 (dd, J = 51.9, 17.7 Hz, 1H), 4.44 (dd, J = 38.3, 17.7
samples were independently prepared from L- and D-amino Hz, 1H), 3.79 (s, 3H), 3.64-3.53 (m, 1H), 3.50-3.39 (m, 1H), 2.43-
acids and their mixture was used as reference racemate.
1.88 (m, 5H), 1.40 (s, 9H).
Tert-butyl-(3-(4-hydroxyphenyl)-1-oxo-1-(phenylamino)
Ethyl (tert-butoxycarbonyl)glycyl-valinate (7o). Petroleum
propan -2-yl)carbamate (7j).[62] Petroleum ether / ethyl acetate ether / ethyl acetate = 3 : 1 (v /v) as eluent for column
1
= 2 : 1 (v /v) as eluent for column chromatography. White solid, chromatography. Colorless oil, 281.2 mg, 93% yield. H NMR
1
352.9 mg, 99% yield. H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), (500 MHz, CDCl3) δ 6.80 (s, 1H), 5.42 (s, 1H), 4.48 (s, 1H), 4.15 (t,
7.39 (d, J = 7.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.31-7.26 (m, 2H), J = 6.7 Hz, 2H), 3.79 (qd, J = 16.4, 4.6 Hz, 2H), 2.13 (dq, J = 13.4,
7.23 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 7.2 Hz, 1H), 5.40 (d, J = 8.0 6.7 Hz, 1H), 1.41 (s, 9H), 1.23 (t, J = 7.1 Hz, 3H), 0.90 (d, J = 6.8
Hz, 1H), 4.57 (s, 1H), 3.29-3.16 (m, 1H), 3.08 (dd, J = 13.6, 7.1 Hz, Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
25
1H), 1.39 (s, 9H). [α]D = -61.4 (c = 0.10, CHCl3). 60% ee was 171.7 (s), 169.4 (s), 156.1 (s), 80.3 (s), 61.2 (s), 57.0 (s), 44.5 (s),
determined by chiral HPLC (chiralcel IA, n-hexane/2-propanol = 31.3 (s), 28.3 (s), 18.9 (s), 14.2 (s). HRMS ESI (m/z): [M+H]+ calcd
80/20, 1.0 mL/min, 254 nm). tR = 6.91 min (major) and 9.94 min for C14H27N2O5: 303.1914; found: 303.1917.
(minor). Authentic samples were independently prepared from Ethyl (tert-butoxycarbonyl)-tryptophyl-phenylalaninate (7p).
L- and D-amino acids and their mixture was used as reference Petroleum ether / ethyl acetate = 2 : 1 (v /v) as eluent for
racemate.
column chromatography. Pale yellow solid, 335.7 mg, 70% yield.
Mp 105-107 oC. 1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.66 (d,
Tert-butyl-(1-oxo-1-(phenylamino)propan-2-yl)carbamate
(7k).[62] Petroleum ether / ethyl acetate = 3 : 1 (v /v) as eluent J = 7.9 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.22-7.09 (m, 5H), 7.01
for column chromatography. White solid, 259.0 mg, 98% yield. (s, 1H), 6.85 (d, J = 6.9 Hz, 2H), 6.27 (s, 1H), 5.14 (s, 1H), 4.71 (s,
1H NMR (500 MHz, CDCl3) δ 8.75 (s, 1H), 7.50 (d, J = 7.9 Hz, 2H), 1H), 4.45 (s, 1H), 4.06 (t, J = 6.1 Hz, 2H), 3.29 (s, 1H), 3.15 (dd, J
7.29 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.10-7.04 (m, 1H), = 14.5, 7.0 Hz, 1H), 2.95 (d, J = 5.9 Hz, 2H), 1.42 (s, 9H), 1.17 (t, J
5.41 (d, J = 5.2 Hz, 1H), 4.40 (s, 1H), 1.45 (s, 9H), 1.43 (d, J = 7.1 = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.5 (s), 171.2 (s),
Hz, 3H). [α]D25 = +12.6 (c = 0.10, MeOH). 50% ee was determined 170.9 (s), 155.4 (s), 136.3 (s), 135.8 (s), 129.3 (s), 128.4 (s), 127.5
by chiral HPLC (chiralcel IA, n-hexane/2-propanol = 80/20, 1.0 (s), 126.9 (s), 123.3 (s), 122.3 (s), 119.8 (s), 118.9 (s), 111.2 (s),
mL/min, 254 nm). tR = 5.62 min (minor) and 6.32 min (major). 110.6 (s), 80.1 (s), 61.4 (s), 55.2 (s), 53.3 (s), 38.0 (s), 28.3 (s),
Authentic samples were independently prepared from L- and D- 14.0 (s). HRMS ESI (m/z): [M+H]+ calcd for C27H34N3O5:
amino acids and their mixture was used as reference racemate. 480.2493; found: 480.2490.
12 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 13 of 14
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
4
M. W. N. Deininger, B. J. Druker, Pharmacol. Rev., 2003, 55,
4-((3Z,5E)-3,5-bis(6-oxocyclohexa-2,4-dien-1-ylidene)-1,2,4-
View Article Online
401.
M. de Gasparo, S. Whitebread, Regul. DPOepI:t1.0, .11093995/,C599O,B3000369. 9K
S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451.
For representative reviews, see (a) C. L. Allen, J. M. J. Williams,
Chem. Soc. Rev., 2011, 40, 3405. (b) R. M. de Figueiredo, J.-S.
Suppo, J.-M. Campagne, Chem. Rev. 2016, 116, 12029. For
representative examples, see (c) C. W. Cheung, M. L. Ploeger,
X. Hu, Nat. Commun. 2016, 8, 14878. (d) G. Li, M. Szostak, Nat.
Commun. 2018, 9, 4165. (e) T. Xu, F. Sha, H. Alper, J. Am.
Chem. Soc. 2016, 138, 6629. (f) A. O. Gálvez, C. P. Schaack, H.
Noda, J. W. Bode, J. Am. Chem. Soc. 2017, 139, 1826. (g) C.
Qin, P. Feng, Y. Ou, T. Shen, T. Wang, N. Jiao, Angew. Chem.
Int. Ed. 2013, 52, 7850.
triazolidin-1-yl)-N-phenylbenzamide (9). White solid, 439.53
5
6
7
1
mg, 98% yield. H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H),
8.08-8.06 (m, 3H), 7.84-7.65 (m, 8H), 7.60 (d, J = 8.5 Hz, 1H),
7.55 (d, J = 8.5 Hz, 1H), 7.40 (t, J = 8.4 Hz, 1H), 7.36 (t, J = 7.8 Hz,
2H), 7.12 (t, J = 7.3 Hz, 1H), 7.05 (t, J = 8.7 Hz, 1H). 13C NMR (126
MHz, DMSO-d6) δ 164.7 (s), 160.9 (s), 158.1 (s), 156.7 (s), 149.8
(s), 148.8 (s), 147.1 (s), 139.5 (s), 139.3 (s), 136.0 (s), 134.3 (s),
133.3 (s), 132.3 (s), 131.0 (s), 130.3 (s), 129.6 (s), 129.1 (s), 127.7
(s), 124.9 (s), 124.4 (s), 124.2 (s), 123.1 (s), 123.0 (s), 121.0 (s),
o
120.3 (s), 117.7 (s), 114.0 (s). Mp 94-95 C. HRMS ESI (m/z):
[M+H]+ calcd for C27H21N4O3: 449.1608; found: 449.1610.
(S)-2-(4-isobutylphenyl)-N-phenylpropanamide (11).[67] White
solid, 278.6 mg, 99% yield. 1H NMR (500 MHz, CDCl3) δ 7.41 (d,
J = 7.9 Hz, 2H), 7.28-7.25 (m, 4H), 7.16 (d, J = 7.9 Hz, 2H), 7.10
(s, 1H), 7.06 (t, J = 7.4 Hz, 1H), 3.70 (q, J = 7.1 Hz, 1H), 2.48 (d, J
= 7.2 Hz, 2H), 1.87 (dp, J = 13.5, 6.7 Hz, 1H), 1.59 (d, J = 7.2 Hz,
3H), 0.92 (d, J = 6.6 Hz, 6H). [α]D25 = +59.1 (c = 0.10, CH2Cl2).
2-Chloro-N-(4'-chloro-[1,1'-biphenyl]-2-yl)nicotinamide
8
9
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J. Cossy, C. Pale-Grosdemange, Tetrahedron Lett. 1989, 30,
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1
(14).[31] White solid, 298.6 mg, 87% yield. H NMR (500 MHz,
CDCl3) δ 8.43 (dd, J = 4.7, 1.9 Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H),
8.15 (s, 1H), 8.13 (dd, J = 7.7, 1.8 Hz, 1H), 7.45-7.41 (m, 3H), 7.36-
7.32 (m, 3H), 7.26 (d, J = 4.2 Hz, 2H).
N-(3,5-dimethylphenyl)-2-(4-hydroxyphenyl)acetamide
1
(17).[68] White solid, 252.8 mg, 99% yield. H NMR (500 MHz,
CDCl3) δ 7.44 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.16 (s,
1H), 7.09 (s, 2H), 6.76 (s, 1H), 3.71 (s, 2H), 2.27 (s, 6H).
Conflicts of interest
There are no conflicts to declare.
10 (a) K. S. Yang, A. E. Nibbs, Y. E. Türkmen, V. H. Rawal, J. Am.
Chem. Soc., 2013, 135, 16050. (b) K. S. Yang, V. H. Rawal, J.
Am. Chem. Soc., 2014, 136, 16148. (c) Y. Rao, X. Li, S. J.
Danishefsky, J. Am. Chem. Soc., 2009, 131, 12924. (d) Z. Z.
Brown, C. E. Schafmeister, J. Am. Chem. Soc., 2008, 130,
14382. (e) J. Li, M. J. Lear, Y. Hayashi, Angew. Chem. Int. Ed.
2016, 55, 9060.
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Acknowledgements
We are grateful to the National Natural Science Foundation of
China (Grant No. 21772150), and Wuhan University of
Technology for their continuous encouragement towards the
research and financial support.
12 V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. Int. Ed. 2002, 41, 2596.
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