Direct Amidation of Carboxylic Acids through an Active α-Acyl Enol Ester Intermediate

Article abstract of DOI:10.1021/acs.joc.8b00819

The development of a highly efficient and simple protocol for the direct amidation of carboxylic acids is described employing ynoates as novel coupling reagents. The transformation proceeds in good to excellent yields via in situ α-acyl enol ester intermediates formation under mild reaction conditions. This useful method has been demonstrated for a range of substrates to provide a succinct access to structurally diverse amides, including key intermediates of glibenclamide, tiapride hydrochloride, and nateglinide, and can be conducted on a mole scale.

Full text of DOI:10.1021/acs.joc.8b00819

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Article
Direct Amidation of Carboxylic Acids through
an Active #-Acyl Enol Ester Intermediate
Xianjun Xu, Huangdi Feng, Liliang Huang, and Xiaohui Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00819 • Publication Date (Web): 06 Jun 2018
Downloaded from http://pubs.acs.org on June 6, 2018
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Direct Amidation of Carboxylic Acids through an Active αꢀAcyl Enol
Ester Intermediate
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Xianjun Xu,a Huangdi Feng,*a,b Liliang Huanga and Xiaohui Liu*a
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aCollege of Chemistry and Chemical Engineering, Shanghai University of Engineering Science,
333 Longteng Road, Shanghai, 201620, China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China
*Eꢀmail: hdfeng@sues.edu.cn; xhui1113@163.com
ABSTRACT
The development of a highly efficient and simple protocol for the direct amidation of carboxylic
acids is described employing ynoates as novel coupling reagents. The transformation proceeds in
good to excellent yields via in situ αꢀacyl enol ester intermediates formation under mild reaction
conditions. This useful method has been demonstrated for a range of substrates to provide a
succinct access to structurally diverse amides, including key intermediates of glibenclamide,
tiapride hydrochloride and nateglinide, and can be conducted on a mole scale.
INTRODUCTION
Amides represent an important functional group frequently found in numerous compounds of
relevance to natural products, medicinal chemistry, crop protection, material sciences and
biological systems.1 Among the myriad methods previously developed using boronic acid, borate
ester, and metal as a catalyst,2,3 aminolysis of activated carboxylic acid derivatives, such as acyl
chlorides, anhydrides or activated esters, is one of the most commonly used approaches for
construction of an amide bond. In these reactions, in situ generation of activated esters with
carbodiimides or phosphonium/uronium/aminium salts is currently a highly efficient and versatile
method.4 However, a significant drawback of this strategy is the high molecular weight of the
stoichiometric coupling reagents leading to poor overall atom economy. Therefore, the search for
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highly efficient coupling reagents with “ideal” atom economy is a matter of concern.5 Following
our recent studies on the acetylene chemistry,6 we would like to think about whether alkynes can
serve as a coupling agent for the construction of amides through enol esters species (Scheme 1)?
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Scheme 1. Envisioned Strategy for the Amide Synthesis
Recently, very nice examples of such transformation have appeared employing commercially
unavailable or unstable alkynes. In 2016, the Gooβen group reported a novel protocol for the
direct amidation of carboxylic acids using acetylene or ethoxyacetylene as an activating reagent
and catalyzed by the ruthenium complex (Scheme 2a, ethoxyacetylene is high sensitivity, and
expensive).7 Moreover, through employing ynamides as novel coupling reagents, a oneꢀpot,
twoꢀstep tandem approach for amides and peptides was described by Zhao and coꢀworkers
(Scheme 2b, more than 2 steps required to obtain ynamides, and difficult handling).8 Both
methods involved in the hydrocarboxylation of alkynes to form electronꢀrich enol esters
intermediate. Despite these significant advances, the direct amidation is still in its infancy.9 Active
αꢀacyl enol esters A, distinct structures containing multiple reactive sites, has been widely
explored as building blocks in synthetic transformations.10 However, to date, such
electronꢀdeficient enol esters have not previously been exploited as a source of acyl groups for
amidation. Taking into account the potential of this transformation, we became interested in
employing αꢀacyl enol esters A as acyl precursors. Herein, we report the first example of direct
amidation of carboxylic acids using ynoates as novel coupling reagents (Scheme 2c).
Scheme 2. Amide Bond Formation through Enol Esters Species
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RESULTS AND DISCUSSION
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To validate our hypothesis, the twoꢀstep, oneꢀpot strategy was initially investigated by the
treatment of phenylethylamine and αꢀacyl enol ester in situ generated from benzoic acid and ethyl
propiolate via Michaelꢀtype addition reaction in the presence of pyridine in toluene at room
temperature (Table 1).11 To our delight, the desired product Nꢀphenethylbenzamide 1 was isolated
in 47% yield (entry 1). Encouraged by these preliminary outcomes, we examined a range of
reaction parameters, including the solvent, base, coupling agent, and concentration. Among the
evaluation of solvents, acetonitrile was found to be the best solvent (entry 5), whereas
dichloromethane, 1,2ꢀdichloroethane (DCE), and tetrahydrofuran also gave good yields of the
corresponding product (entries 2−4). Other solvents such as methanol, and DMSO just provided
the amine 1 in 41% and 40% yields, respectively (entries 6 and 7). However, for water, only a
trace amount of product 1 was detected due to the procedure for the generation of key intermediate
αꢀacyl enol ester A is being blocked (entry 8). A subsequent investigation of bases showed that
both NEt3 and N,N,N’,N’ꢀtetramethylethaneꢀ1,2ꢀdiamine (TMEDA) retain top status (entries 9−11).
Interestingly, DMAP, which is commonly used in amidation, only afforded a low yield of the
targeted product along with unidentified byproducts (entry 12). Under identical conditions, strong
inorganic base KOt-Bu had a slight impact for this activator (entry 13). Further optimization of
regarding coupling agents illustrated that R1 substituent adversely affect the yield (entries 17 and
18). Meanwhile, R2 groups also played an essential role on the reaction efficiency (entries 14−16).
Among them, methyl propiolate and ethyl propiolate were found to be the more effective for this
novel transformation (entries 9 and 14). Considering the cost and atom economy of the reaction,
methyl propiolate should be the most suitable in this case. It is noteworthy that the acidꢀtoꢀamine
ratio exerts a substantial effect on the product yield (entry 19). Intriguingly, lower loading of NEt3
is also remarkable but longer reaction time (entries 20 and 21) and a higher reaction temperature
(entry 22) for the formation of αꢀacyl enol ester intermediate is required.
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Table 1. Optimization of the One-Pot Synthesis of Amidea
Entry
1
Coupling agent
Solvent
toluene
Base [equiv]
pyridine [2.2]
Yield [%]b
47
R1 = H, R2 = OEt
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2
R1 = H, R2 = OEt
R1 = H, R2 = OEt
R1 = H, R2 = OEt
R1 = H, R2 = OEt
R1 = H, R2 = OEt
R1 = H, R2 = OEt
R1 = H, R2 = OEt
R1 = H, R2 = OEt
R1 = H, R2 = OEt
R1 = H, R2 = OEt
R1 = H, R2 = OEt
R1 = H, R2 = OEt
R1 = H, R2 = OMe
R1 = H, R2 = Me
R1 = H, R2 = OtꢀBu
R1 = Me, R2 = OEt
DCM
pyridine [2.2]
pyridine [2.2]
pyridine [2.2]
pyridine [2.2]
pyridine [2.2]
pyridine [2.2]
pyridine [2.2]
NEt3 [2.2]
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75
82
97
41
40
trace
98
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97
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21
98
87
78
n.d.
n.d.
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98
97
97
3
DCE
4
THF
5
acetonitrile
methanol
DMSO
water
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CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
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19c
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21d
22e
DABCO [2.2]
TMEDA [2.2]
DMAP [2.2]
KOt-Bu [2.2]
NEt3 [2.2]
NEt3 [2.2]
NEt3 [2.2]
NEt3 [2.2]
R1 = CO2Et, R2 = OEt CH3CN
NEt3 [2.2]
R1 = H, R2 = OMe
R1 = H, R2 = OMe
R1 = H, R2 = OMe
R1 = H, R2 = OMe
CH3CN
CH3CN
CH3CN
CH3CN
NEt3 [2.2]
NEt3 [1.1]
NEt3 [0.5]
NEt3 [0.3]
aReactions were performed by using benzoic acid (0.5 mmol), coupling agent
(0.55 mmol), and base in solvent (3.0 mL) for 30 min at room temperature; then
b
phenylethylamine (1.0 mmol) was added. Isolated yield, n.d. = not determined.
cPhenylethylamine (0.55 mmol) was used. 6 h for the first step. 14 h for the
first step, and reaction temperature: 60 oC.
d
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With the optimized reaction conditions in hand the scope of this oneꢀpot method was evaluated
with a wide range of amine derivatives (Table 2). Under the standard reaction conditions (Table 1,
entry 20), various phenylethylamines bearing electronꢀwithdrawing as well as electronꢀdonating
substituent underwent smooth to afford the corresponding amides (2−6) in good to excellent yields.
Notably, the 1,2ꢀamino alcohol was also found to be applicable for this approach to access the
desired product (7) tolerated free OH group. Similarly, a series of benzylamines provided the
expected amides (8−11) in excellent yields, surprisingly, the use of aniline didn't generate the
desired amidation product (12), and the exact cause is unclear. In the cases of aliphatic amines, the
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corresponding products (13−17) were achieved in excellent yields for all these examples. Also,
sterically hindered αꢀamino ester could be successfully applied to this protocol resulting in good
yield (18). However, the second amines such as diethylamine, morpholine, diallylamine, and
Nꢀmethylbenzylamine is not compatible, and only the pyrrolidine would participate in the
amidation and furnished the target products (19) in 79% yield. Gratifyingly, our method also
tolerates ammonium hydroxide to produce the benzamide (20) in high yield.
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Table 2. Substrate Scope for Various Aminesa
1, 98%, 30 min/10 min
5, 71%, 30 min/10 min
9, 92%, 30 min/25 min
13, 91%, 30 min/10 min
17, 93%, 30 min/10 min
2, 96%, 30 min/15 min
6, 91%, 30 min/10 min
10, 97%, 30 min/20 min
14, 91%, 30 min/10 min
18, 64%, 30 min/15 min
3, 86%, 30 min/15 min
7, 98%, 30 min/40 min
11, 96%, 30 min/40 min
15, 93%, 30 min/10 min
19, 79%, 30 min/10 min
4, 86%, 30 min/10 min
8, 96%, 30 min/30 min
O
N
H
12, n.d.
16, 98%, 30 min/10 min
20, 81%, 30 min/20 min
aReaction conditions: benzoic acid (0.5 mmol), amine (1.0 mmol), methyl propiolate (0.55 mmol), triethylamine
(0.55 mmol), in CH3CN (3.0 mL) at room temperature; The reaction times of the first step and the second step,
respectively; isolated yield; n.d. = not determined.
To further explore the utility of this strategy, the scope of the reaction with respect to the
carboxylic acids was then tested, and it was found that this direct transformation is versatile and
robust (Table 3). Treatment of the benzoic acids, tolerating fluoro, nitro, methyl, and methoxy
substituents in different positions, with phenylethylamine led to the expected amides (21–27) in
good to excellent yields. Pleasingly, large steric hindrance group did not inhibit product formation,
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and successfully afforded 28 in slightly decreased yield (57%). In addition, not only a naphthalene
ring but also heterocyclic substrates, such as thiophene, pyridine, and indole could be employed
without any difficulties (29−32, 75−90% yield). However, when nicotinic acid was present, the
amidation did not occur (33). Next, we turned our attention to phenylacetic acids reacted smoothly
to produce the corresponding products (34−36) in 67−82% yield. Unexpectedly, no desired
product (37) was obtained with unknown side reactions when 2ꢀhydroxyꢀ2ꢀphenylacetic acid was
used. Highly efficient reaction was gained in the case of cinnamic acid delivered the desired
product (38) in excellent yield. Interestingly, isophthalic acid could also be successfully engaged
in this reaction providing the diamide (39) in 56% yield. A moderate yield (40, 41%) was observed
when cyclohexanecarboxylic acid was introduced as the starting material. Unfortunately, the target
products (41, 42, 43) were not obtained using NꢀBoc, Cbz, or Tos protected phenylalanines.
Moreover, the product (44) was not observed when a 2ꢀ((4ꢀmethylphenyl)sulfonamido)ꢀ
2ꢀphenylacetic acid was employed. In these unsuccessful examples, the acids were unable to react
with methyl propiolate to form αꢀacyl enol ester intermediates.
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Table 3. Reaction Scope of Carboxylic Acids a
21, 96%, 2 hb/30 min
25, 90%, 30 min/10 min
29, 75%, 30 min/10 min
33, n.d.
22, 65%, 4 h/10 min
26, 68%, 50 min/20 min
30, 96%, 2 h/10 min
34, 73%, 4 hb/30 min
23, 80%, 1 h/20 min
27, 94%, 50 min/20 min
31, 75%, 2 h/30 min
35, 82%, 2 h/30 min
24, 94%, 30 min/10 min
28, 57%, 2 h/20 min
32, 90%, 3 h/30 min
36, 67%, 2 h/10 min
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37, n.d.
41, n.d.
38, 96%, 3 h/10 min
39, 56%, 3 hb/30 min
40, 41%, 4 hb/30 min
42, n.d.
43, n.d.
44, n.d.
aReaction conditions: carboxylic acid (0.5 mmol), phenylethylamine (1.0 mmol), methyl propiolate (0.55 mmol),
and triethylamine (0.55 mmol), in CH3CN (3.0 mL) at room temperature; reaction times for the first and second
steps, respectively; isolated yield. bReaction temperature: 60 oC.
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Then, the synthetic value of this novel coupling reagent was emphasized by the construction of
the important amide frameworks (Scheme 3). As showed in (1), the reaction of less active
aliphatic acid with αꢀamino ester produced a 51% yield of amide 45 under modified reaction
conditions, which is a key intermediate for the synthesis of the drug glibenclamide.12 We also
directly synthesized an antipsychotic drug tiapride hydrochloride 46 in 48% yield (2). Meanwhile,
this coupling reagent was demonstrated in a gram scale amidation of 5ꢀchloroꢀ2ꢀmethoxybenzoic
acid. In this case, we obtained 1.89 grams of 47 in 85% yields with high chemoselectivity (3). In
the meantime, the product, could be readily converted into the drug molecule nateglinide,13 was
isolated without running a column chromatography paved the way for practical application.
Scheme 3. Synthetic Application.
CONCLUSIONS
In summary, we have described a new coupling reagent that is not only highly efficient but is also
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the “ideal” atom economic (mol wt = 84.07) for the direct synthesis of amides from various
carboxylic acids and amines. This reaction can be understood in one pot via in situ generation of
αꢀacyl enol esters. Excellent functional group tolerance, simple experimental operation, good to
excellent yields, and mild reaction conditions may make this transformation more attractive for an
easy access to the key intermediate of drug molecules. Research on further applications for this
novel coupling reagent is currently in progress in our laboratory.
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EXPERIMENTAL SECTION
General information. All of the chemicals were purchased and used as received unless
otherwise mentioned. Reactions were carried out in air using glassware and solvent that had not
been preꢀdried. Analytical thinꢀlayer chromatography (TLC) was performed and visualization of
the compounds was accomplished with UV light (254 nm) or iodine. Flash chromatography was
performed using 100–200 mesh silica gel with the indicated solvent system.
1
All H, 13C and 19F NMR spectra were recorded on a Bruker Avance III instrument (400 MHz
and 100 MHz, respectively). Chemical shifts (δ) are reported in ppm relative to the
tetramethylsilane (TMS) signal or residual protio solvent signal. Data for 1H NMR are recorded as
follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet or
unresolved, br = broad singlet, coupling constant(s) in Hz, integration). Data for 13C NMR and 19
F
NMR is reported in terms of chemical shift (δ, ppm).
General procedure for the synthesis of N-substituted benzamides. To a 10 mL
reaction tube were added benzoic acid (0.50 mmol), methyl acetylenate (0.55 mmol), and
triethylamine (1.10 mmol) in CH3CN (3 mL) under air. The tube was sealed and stirred at room
temperature for 30 min. Subsequently, amines (1.10 mmol) were added to the stirring solution, and
the resulting mixture was stirred at room temperature for another 10−30 min, monitoring with
TLC. Then 1N HCl solution (3 mL) was added into the mixture and extracted three times with
ethyl acetate. The combined organic layers were dried with anhydrous sodium sulfate and filtered.
The solvent was evaporated under reduced pressure and the residue was purified by silica gel flash
column chromatography (10−25% ethyl acetate in petroleum ether) to afford the desired product
1−20 as a white solid.
N-phenethylbenzamide (1). The product 1 (110.4 mg, 98% yield) was obtained as a white solid:
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1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.5 Hz,
2H), 7.31 (t, J = 7.3 Hz, 2H), 7.23 (t, J = 8.4 Hz, 3H), 6.40 (s, 1H), 3.69 (m, 6.9 Hz, 2H), 2.91 (t, J
= 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 167.6, 138.9, 134.6, 131.4, 128.8, 128.7, 128.5,
126.9, 126.5, 77.4, 77.1, 76.8, 41.2, 35.7.
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N-(4-fluorophenethyl)benzamide (2). The product 2 (116.3 mg, 96% yield) was obtained as a
white solid:1H NMR (400 MHz, DMSOꢀd6) δ 8.56 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H),
7.38–7.21 (m, 2H), 7.12 (t, J = 8.9 Hz, 2H), 3.49 (m, 2H), 2.85 (t, J = 7.3 Hz, 2H); 19F NMR (471
MHz, DMSOꢀd6) δ ꢀ117.17 (s).13C NMR (100 MHz, DMSOꢀd6) δ 166.6, 162.4, 160.0, 136.1,
136.1, 135.0, 131.5, 130.9, 130.8, 128.7, 127.5, 115.5, 115.3, 41.2, 40.6, 40.3, 40.1, 39.9, 39.7,
39.5, 39.3, 34.6.
N-(4-chlorophenethyl)benzamide (3). The product 3 (111.4 mg, 86% yield) was obtained as a
white solid: 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.5 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.39
(t, J = 7.5 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.37 (s, 1H), 3.66 (m, 2H),
2.89 (t, J = 7.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 167.6, 137.4, 134.5, 132.3, 131.5, 130.1,
128.7, 128.6, 126.8, 77.4, 77.0, 76.7, 41.1, 35.0.
N-(3-methoxyphenethyl)benzamide (4). The product 4 (108.8 mg, 86% yield) was obtained as a
white solid: 1H NMR (400 MHz, CDCl3) δ 7.77–7.62 (m, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.38 (t, J =
7.5 Hz, 2H), 7.24 (m, 1H), 6.80 (m, 3H), 6.36 (s, 1H), 3.77 (s, 3H), 3.69 (m, 2H), 2.90 (t, J = 7.0
Hz, 2H). 13C NMR (100 MHz, CDCl3) 167.5, 159.9, 140.5, 134.6, 131.4, 129.6, 128.5, 126.8,
121.1, 114.4, 112.0, 77.4, 77.1, 76.7, 55.1, 41.1, 35.7.
N-(3,4-dimethoxyphenethyl)benzamide (5). The product 5 (100.7 mg, 71% yield) was obtained as
1
a white solid: H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.5 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H),
7.39 (t, J = 7.5 Hz, 2H), 6.81 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 11.2 Hz, 2H), 6.43 (s, 1H), 3.83 (d, J
= 13.9 Hz, 6H), 3.68 (m, 2H), 2.87 (t, J = 7.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 167.5,
149.0, 147.7, 134.6, 131.5, 131.3, 128.5, 126.8, 120.6, 112.0, 111.4, 77.5, 77.1, 76.8, 55.9, 55.8,
41.3, 35.2.
N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)benzamide (6). The product 6 (122.2 mg, 91% yield) was
obtained as a white solid: 1H NMR (400 MHz, DMSOꢀd6) δ 8.54 (s, 1H), 7.91–7.63 (m, 2H), 7.51
(m, 1H), 7.45 (m, 2H), 6.82 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 7.9 Hz, 1H), 5.97 (s, 2H), 3.46 (m,
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2H), 2.78 (t, J = 7.3 Hz, 2H). 13C NMR (100 MHz, DMSOꢀd6) δ 166.6, 147.6, 145.9, 135.1, 133.8,
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131.5, 128.7, 127.5, 122.0, 109.4, 108.5, 101.1, 41.5, 40.6, 40.3, 40.1, 39.9, 39,7, 39.5, 39.3, 35.2.
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N-(2-hydroxy-2-phenylethyl)benzamide (7). The product 7 (118.4 mg, 98% yield) was obtained as
a white solid: 1H NMR (400 MHz, DMSOꢀd6) δ 8.54 (s, 1H), 7.94–7.76 (m, 2H), 7.52 (t, J = 7.2
Hz, 1H), 7.46 (t, J = 7.9 Hz, 2H), 7.36 (m, 4H), 7.26 (t, J = 7.7 Hz, 1H), 5.56 (d, J = 4.1 Hz, 1H),
4.81 (m, 1H), 3.51 (m, 1H), 3.38–3.26 (m, 1H). 13C NMR (100 MHz, DMSOꢀd6) δ 166.9, 144.2,
135.0, 131.5, 128.6, 128.5, 127.6, 127.5, 126.4, 71.6, 48.1, 40.5, 40.3, 40.1, 39.9, 39.7, 39.5, 39.3.
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N-benzylbenzamide (8). The product 8 (102.3 mg, 96% yield) was obtained as a white solid: H
NMR (400 MHz, CDCl3) δ 7.87–7.69 (m, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.8 Hz, 2H),
7.30 (d, J = 4.1 Hz, 4H), 7.26 (m, 1H), 6.89 (s, 1H), 4.57 (d, J = 5.8 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 167.5, 138.3, 134.3, 131.5, 128.7, 128.5, 127.8, 127.5, 127.0, 77.4, 77.1, 76.8, 44.0.
N-(4-methoxybenzyl)benzamide (9). The product 9 (110.7 mg, 92% yield) was obtained as a
yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.5 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.29
(t, J = 7.5 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 6.62 (s, 1H), 4.44 (d, J = 5.6
Hz, 2H), 3.68 (s, 4H). 13C NMR (100 MHz, CDCl3) δ 167.4, 159.0, 134.5, 131.4, 130.4, 129.2,
128.5, 127.0, 114.1, 77.4, 77.1, 76.8, 55.2, 43.5.
N-(4-fluorobenzyl)benzamide (10). The product 10 (110.5 mg, 97% yield) was obtained as a white
solid: 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.3 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.38 (t, J =
7.6 Hz, 2H), 7.32–7.22 (m, 2H), 7.20 (s, 1H), 6.98 (t, J = 8.7 Hz, 2H), 4.53 (d, J = 5.1 Hz, 2H). 19F
NMR (471 MHz, CDCl3) δ ꢀ116.17 (s). 13C NMR (100 MHz, CDCl3) δ 167.6, 163.3, 160.9, 134.2,
131.5, 129.4, 129.3, 128.5, 127.0, 115.5, 115.3, 77.4, 77.1, 76.8, 43.2.
N-(1-phenylethyl)benzamide (11). The product 11 (107.5 mg, 96% yield) was obtained as a white
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solid: H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.1 Hz, 2H), 7.51 (t, J = 8.0 Hz, 1H), 7.40 (m,
6H), 7.34–7.27 (m, 1H), 6.52 (s, 1H), 5.36 (m, 1H), 1.62 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 166.6, 143.2, 134.6, 131.4, 128.7, 128.5, 127.4, 126.9, 126.2, 77.3, 77.0, 76.7, 49.2,
21.7.
N-(3-methoxypropyl)benzamide (13). The product 13 (87.1 mg, 91% yield) was obtained as a oil:
1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.6 Hz, 2H), 7.46 (t, J = 6.7 Hz, 1H), 7.39 (t, J = 7.7 Hz,
2H), 7.21 (s, 1H), 3.54 (m, 4H), 3.35 (s, 3H), 1.95–1.79 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
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167.4, 134.7, 131.1, 128.3, 126.9, 77.5, 77.2, 76.9, 71.8, 58.7, 38.6, 28.9.
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N-butylbenzamide (14). The product 14 (80 mg, 91% yield) was obtained as a oil: 1H NMR (400
MHz, CDCl3) δ 7.88–7.68 (m, 2H), 7.46 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 6.62 (s, 1H),
3.42 (m, 2H), 1.64–1.51 (m, 2H), 1.38 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 167.4, 134.7, 131.1, 128.3, 126.9, 77.5, 77.2, 76.9, 71.8, 58.7, 38.6, 28.9.
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N-(cyclopropylmethyl)benzamide (15). The product 15 (81.2 mg, 93% yield) was obtained as a
white solid: 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.3 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H), 7.37
(t, J = 7.6 Hz, 2H), 6.93 (s, 1H), 3.37–3.16 (m, 2H), 1.05 (m, 1H), 0.49 (m, 2H), 0.23 (d, J = 4.9
Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 167.6, 134.7, 131.2, 128.3, 127.0, 77.5, 77.1, 76.8, 44.8,
10.7, 3.4.
N-(cyclohexylmethyl)benzamide (16). The product 16 (106.3 mg, 98% yield) was obtained as a
white solid: 1H NMR (400 MHz, CDCl3) δ 7.87–7.70 (m, 2H), 7.45 (t, J = 7.3 Hz, 1H), 7.37 (t, J =
7.5 Hz, 2H), 6.83 (s, 1H), 3.25 (t, J = 6.5 Hz, 2H), 1.71 (m, 5H), 1.60–1.49 (m, 1H), 1.30–1.07 (m,
3H), 0.94 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 167.8, 134.9, 131.1, 128.4, 127.0, 77.5, 77.1,
76.8, 46.2, 37.9, 30.9, 26.4, 25.8.
N-(4-(tert-butyl)cyclohexyl)benzamide (17). The product 17 (120.8 mg, 93% yield) was obtained
as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.1 Hz, 2H), 7.39 (t, J = 6.7 Hz, 1H),
7.32 (t, J = 7.4 Hz, 2H), 6.09 (s, 1H), 3.80 (s, 1H), 2.04 (d, J = 9.3 Hz, 2H), 1.74 (d, J = 10.7 Hz,
2H), 1.18–0.98 (m, 4H), 0.98–0.83 (m, 1H), 0.78 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 166.8,
135.0, 131.1, 128.4, 126.9, 77.3, 77.0, 76.7, 49.3, 47.3, 33.6, 32.3, 27.5, 26.1.
Methyl benzoylphenylalaninate (18). The product 18 (90 mg, 64% yield) was obtained as a white
solid: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.34 (t, J =
7.5 Hz, 2H), 7.27–7.12 (m, 3H), 7.06 (d, J = 6.5 Hz, 2H), 6.55 (d, J = 7.1 Hz, 1H), 5.10–4.95 (m,
1H), 3.68 (s, 3H), 3.18 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 172.0, 166.8, 135.9, 133.9, 131.7,
129.3, 128.6, 127.4, 127.0, 77.3, 77.0, 76.7, 53.5, 52.4, 37.9.
Phenyl(pyrrolidin-1-yl)methanone (19). The product 19 (69.1 mg, 79% yield) was obtained as a
yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 2H), 7.31 (d, J = 4.8 Hz, 3H), 3.45 (s, 4H), 1.83
(s, 4H). 13C NMR (100 MHz, CDCl3) δ 137.2, 129.7, 128.1, 127.0, 77.4, 77.1, 76.8, 49.2, 46.5,
29.6, 25.4.
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Benzamide (20). The product 20 (48.7 mg, 81% yield) was obtained as a white solid: H NMR
(400 MHz, CDCl3) δ 7.84 (d, J = 8.1 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 6.9 Hz, 2H),
6.40 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 169.9, 133.4, 132.0, 128.6, 127.3, 77.3, 77.0, 76.7.
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General procedure for the evaluation of carboxylic acids. To a 10 mL reaction tube were
added carboxylic acid (0.50 mmol), methyl acetylenate (0.55 mmol), and triethylamine (1.10
mmol) in CH3CN (3 mL) under air. The tube was sealed and stirred at room temperature or 60 oC
for 30 min to 4 hours. After cooling to room temperature, the phenylethylamine (1.10 mmol) was
added to the stirring solution, and the resulting mixture was stirred at room temperature for
another 10−30 min, monitoring with TLC. Then 1N HCl solution (3 mL) was added into the
mixture and extracted three times with ethyl acetate. The combined organic layers were dried with
anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the
residue was purified by silica gel flash column chromatography (10−25% ethyl acetate in
petroleum ether) to afford the desired product 21−40 as a white solid.
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2-Fluoro-N-phenethylbenzamide (21). The product 21 (116.4 mg, 96% yield) was obtained as a
white solid: 1H NMR (400 MHz, CDCl3) δ 8.06 (t, J = 7.9 Hz, 1H), 7.42 (m, 1H), 7.35–7.27 (m,
2H), 7.22 (m, 4H), 7.10–6.99 (m, 1H), 6.82 (s, 1H), 3.83–3.67 (m, 2H), 2.93 (t, J = 7.1 Hz, 2H).
19F NMR (471 MHz, CDCl3) δ ꢀ114.43 (s). 13C NMR (100 MHz, CDCl3) δ 163.2, 161.8, 159.3,
138.8, 133.1, 133.0, 131.9 128.7, 128.6, 126.5, 124.7, 116.0, 115.8, 77.4, 77.1, 76.8, 41.3, 35.6.
4-Nitro-N-phenethylbenzamide (22). The product 22 (77.2 mg, 65% yield) was obtained as a white
solid: 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.9 Hz, 2H), 7.75 (d, J = 8.9 Hz, 2H), 7.25 (t, J =
7.2 Hz, 2H), 7.21–7.11 (m, 3H), 6.29 (s, 1H), 3.66 (m, 2H), 2.87 (t, J = 6.9 Hz, 2H). 13C NMR
(100 MHz, CDCl3) δ 165.5, 149.5, 140.2, 138.5, 128.8, 128.7, 128.0, 126.7, 123.7, 77.3, 77.0,
76.7, 41.4, 35.4.
4-Methyl-N-phenethylbenzamide (23). The product 23 (95.6 mg, 80% yield) was obtained as a
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white solid: H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 7.2 Hz, 2H),
7.30–7.17 (m, 5H), 6.45 (s, 1H), 3.71 (m, 2H), 2.94 (t, J = 7.0 Hz, 2H), 2.40 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 167.6, 141.8, 139.0, 131.7, 129.1, 128.8, 128.6, 126.9, 126.5, 77.4, 77.1,
76.7, 41.2, 35.7, 21.3.
4-Methoxy-N-phenethylbenzamide (24). The product 24 (120.1 mg, 94% yield) was obtained as a
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white solid: 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 2H), 7.37–7.27 (m, 2H), 7.23 (m,
3H), 6.88 (d, J = 8.7 Hz, 2H), 6.71 (s, 1H), 3.81 (s, 3H), 3.74–3.59 (m, 2H), 2.92 (t, J = 7.1 Hz,
2H). 3C NMR (100 MHz, CDCl3) δ 167.2, 162.1, 139.1, 128.8, 128.7, 128.6, 126.8, 126.4, 113.7,
77.5, 77.1, 76.8, 55.3, 41.2, 35.8.
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3-Methoxy-N-phenethylbenzamide (25). The product 25 (114.3 mg, 90% yield) was obtained as a
white solid: 1H NMR (400 MHz, CDCl3) δ 7.40–7.19 (m, 8H), 7.02 (d, J = 10.4 Hz, 1H), 6.59 (s,
1H), 3.81 (s, 3H), 3.75–3.63 (m, 2H), 2.93 (t, J = 7.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ
167.5, 159.8, 139.0, 136.2, 129.5, 128.7, 128.6, 126.4, 118.9, 117.5, 112.4, 77.6, 77.2, 76.9, 55.3,
41.3, 35.7.
3,5-Dimethoxy-N-phenethylbenzamide (26). The product 26 (97.0 mg, 68% yield) was obtained as
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a white solid: H NMR (400 MHz, CDCl3) δ 7.22 (t, J = 7.6 Hz, 2H), 7.14 (m, 3H), 6.74 (d, J =
2.2 Hz, 2H), 6.45 (t, J = 1.9 Hz, 1H), 6.34 (s, 1H), 3.68 (d, J = 1.4 Hz, 6H), 3.58 (m,2H), 2.82 (t, J
= 7.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 167.5, 160.8, 138.9, 136.8, 128.7, 128.6, 126.5,
104.9, 103.6, 77.5, 77.1, 76.8, 55.4, 41.3, 35.6.
3,4-Dimethyl-N-phenethylbenzamide (27). The product 27 (119.1 mg, 94% yield) was obtained as
a white solid: 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.34 (t, J = 7.2
Hz, 2H), 7.26 (t, J = 7.5 Hz, 3H), 7.16 (d, J = 7.8 Hz, 1H), 6.41 (s, 1H), 3.71 (m, 2H), 2.94 (t, J =
7.0 Hz, 2H), 2.29 (d, J = 4.9 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 167.7, 140.3, 139.1, 136.7,
132.2, 129.6, 128.8, 128.6, 128.3, 126.4, 124.2, 77.5, 77.2, 76.9, 41.2, 35.8, 19.7, 19.6.
2-(Phenethylcarbamoyl)phenyl acetate (28). The product 28 (80.7 mg, 57% yield) was obtained as
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a white solid: H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H),
7.36–7.19 (m, 6H), 7.06 (d, J = 8.1 Hz, 1H), 6.37 (s, 1H), 3.70 (m, 2H), 2.91 (t, J = 6.8 Hz, 2H),
2.08 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.9, 165.6, 147.9, 138.8, 131.7, 129.7, 128.7, 128.1,
126.6, 126.2, 123.1, 77.3, 77.0, 76.7, 41.0, 35.4, 20.7.
N-phenethyl-2-naphthamide (29). The product 29 (103.5 mg, 75% yield) was obtained as a white
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solid: H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.05–6.91 (m, 3H), 6.87 (d, J = 8.6 Hz, 1H),
6.72–6.55 (m, 2H), 6.55–6.41 (m, 2H), 6.37 (d, J = 5.5 Hz, 3H), 5.50 (s, 1H), 2.88 (m, 2H), 2.09 (t,
J = 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 167.5, 138.9, 134.7, 132.6, 131.9, 128.9, 128.8,
128.7, 128.4, 127.7, 127.6, 127.3, 126.7, 126.6, 123.5, 77.3, 77.0, 76.7, 41.3, 35.7.
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N-phenethylthiophene-2-carboxamide (30). The product 30 (110.5 mg, 96% yield) was obtained
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as a white solid: H NMR (400 MHz, CDCl3) δ 7.37 (m, 1H), 7.34 (m,1H), 7.25 (t, J = 7.2 Hz,
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2H), 7.16 (m, 3H), 7.02–6.90 (m, 1H), 6.04 (s, 1H), 3.61 (m, 2H), 2.84 (t, J = 7.0 Hz, 2H). 13C
NMR (100 MHz, CDCl3) δ 161.8, 139.0, 138.8, 129.7, 128.8, 128.7, 127.9, 127.5, 126.6, 77.3,
77.0, 76.7, 41.1, 35.7.
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N-phenethylpicolinamide (31). The product 31 (85 mg, 75% yield) was obtained as a white solid:
1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 4.2 Hz, 1H), 8.14 (d, J = 7.8 Hz, 2H), 7.79 (t, J = 8.5
Hz, 1H), 7.35 (m, 1H), 7.29–7.21 (m, 2H), 7.21–7.12 (m, 4H), 3.67 (m,2H), 2.88 (t, J = 7.3 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ 163.7, 149.5, 147.4, 138.9, 137.9, 128.7, 128.6, 126.4, 126.2,
122.6, 77.3, 77.0, 76.7, 40.8, 35.8.
N-phenethyl-1H-indole-2-carboxamide (32). The product 32 (117.8 mg, 90% yield) was obtained
as a white solid: 1H NMR (400 MHz, DMSOꢀd6) δ 11.56 (s, 1H), 8.58 (t, J = 5.6 Hz, 1H), 7.62 (d,
J = 8.0 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.35–7.24 (m, 4H), 7.19 (m, 2H), 7.12 (s, 1H), 7.04 (t, J
= 7.5 Hz, 1H), 3.55 (m, 2H), 2.89 (t, J = 7.4 Hz, 2H). 13C NMR (100 MHz, DMSOꢀd6) δ 161.5,
139.9, 136.8, 132.3, 129.1, 128.8, 127.5, 126.5, 123.6, 121.9, 120.1, 112.7, 102.7, 40.9, 40.4, 40.1,
39.9, 39.7, 39.4, 39.3, 35.7.
N-phenethyl-2-phenylacetamide (34). The product 34 (87.4 mg, 73% yield) was obtained as a
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white solid: H NMR (400 MHz, CDCl3) δ 7.37–7.12 (m, 8H), 7.02 (d, J = 7.9 Hz, 2H), 5.44 (s,
1H), 3.51 (s, 2H), 3.45 (m, 2H), 2.72 (t, J = 6.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 170.8,
138.7, 134.8, 129.4, 128.9, 128.6, 128.5, 127.2, 126.4, 77.3, 77.0, 76.7, 43.8, 40.7, 35.5.
N-phenethyl-2-(p-tolyl)acetamide (35). The product 35 (103.4 mg, 82% yield) was obtained as a
white solid: 1H NMR (400 MHz, CDCl3) δ 7.30–7.14 (m, 3H), 7.11 (d, J = 7.8 Hz, 2H), 7.08–6.95
(m, 4H), 5.43 (s, 1H), 3.48 (s, 2H), 3.44 (m, 2H), 2.71 (t, J = 6.8 Hz, 2H), 2.34 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 171.3, 138.6, 136.9, 131.6, 129.7, 129.3, 128.7, 128.5, 126.4, 77.3, 77.0,
76.7, 43.3, 40.7, 35.4, 21.1.
2-(2-iodophenyl)-N-phenethylacetamide (36). The product 36 (121.3 mg, 67% yield) was obtained
as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.7 Hz, 1H), 7.40–7.10 (m, 5H), 7.06
(d, J = 6.7 Hz, 2H), 6.96 (t, J = 8.5 Hz, 1H), 5.49 (s, 1H), 3.66 (s, 2H), 3.47 (m, 2H), 2.75 (t, J =
6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 169.4, 139.8, 138.6, 138.3, 130.8, 129.2, 128.8, 128.7,
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128.6, 126.4, 101.2, 77.4, 77.1, 76.8 ,48.6, 40.7, 35.4.
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N-phenethylcinnamamide (38). The product 38 (120.4 mg, 96% yield) was obtained as a white
solid: 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 15.6 Hz, 1H), 7.49 (m, 2H), 7.38–7.28 (m, 5H),
7.24 (t, J = 8.2 Hz, 3H), 6.53 (d, J = 6.7 Hz, 1H), 6.50 (d, J = 15.7 Hz, 1H), 3.68 (m, 2H), 2.93 (t,
J = 7.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 166.2, 140.9, 138.9, 134.9, 129.6, 128.7, 128.6,
127.8, 126.5, 120.9, 77.4, 77.1, 76.8, 41.0, 35.7.
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N1,N3-diphenethylisophthalamide (39). The product 39 (103.4 mg, 56% yield) was obtained as a
white solid: 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.71 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.6
Hz, 1H), 7.25 (s, 4H), 7.15 (t, J = 8.5 Hz, 6H), 6.43 (s, 2H), 3.72–3.53 (m, 4H), 2.85 (t, J = 6.9 Hz,
4H). 13C NMR (100 MHz, CDCl3) δ 166.9, 138.6, 134.7, 129.8, 128.9, 128.7, 128.7, 126.6, 125.5,
77.3, 77.0, 76.7, 41.4, 35.6.
N-phenethylcyclohexanecarboxamide (40). The product 40 (103.4 mg, 82% yield) was obtained as
a white solid: 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.3 Hz, 2H), 7.27–7.14 (m, 3H), 5.60 (s,
1H), 3.49 (t, J = 9.9 Hz, 2H), 2.80 (t, J = 6.9 Hz, 2H), 2.01 (m, 1H), 1.78 (t, J = 13.8 Hz, 4H),
1.70–1.53 (m, 1H), 1.39 (m, 2H), 1.31–1.11 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 176.0, 139.0,
128.7, 128.5, 126.4, 77.4, 77.0, 76.7, 45.5, 40.3, 35.7, 29.6, 25.7.
Preparation of compound 45. To
a
10 mL reaction tube were added
4ꢀisopropylcyclohexaneꢀ1ꢀcarboxylic acid (0.50 mmol), methyl acetylenate (0.55 mmol), and
o
triethylamine (1.10 mmol) in CH3CN (3 mL) under air. The tube was sealed and stirred at 60 C
for 5 hours. After cooling to room temperature, the methyl phenylalaninate (1.10 mmol) was
added to the stirring solution, and the resulting mixture was stirred at room temperature for
another 3 hours, monitoring with TLC. Then 1N HCl solution (3 mL) was added into the mixture
and extracted three times with ethyl acetate. The combined organic layers were dried with
anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the
residue was purified by silica gel flash column chromatography (10−25% ethyl acetate in
petroleum ether) to give methyl (4ꢀisopropylcyclohexaneꢀ1ꢀcarbonyl) phenylalaninate 45 (83.9 mg,
51% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.28–7.11 (m, 3H), 7.00 (d, J = 6.7 Hz,
2H), 5.88 (d, J = 7.4 Hz, 1H), 4.82 (m, 1H), 3.65 (s, 3H), 3.05 (m, 2H), 2.05–1.87 (m, 1H), 1.79 (t,
J = 13.1 Hz, 2H), 1.70 (d, J = 12.1 Hz, 2H), 1.31 (m,3H), 0.93 (m, 3H), 0.77 (d, J = 6.8 Hz, 6H);
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13C NMR (100 MHz, CDCl3) δ 175.6, 172.2, 135.9, 129.3, 128.4, 127.0, 77.3, 77.0, 76.7, 52.7,
52.2, 45.4, 43.2, 37.8, 32.7, 29.7, 29.4, 29.0, 28.9, 19.7.
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Preparation of compound 46. To
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10 mL reaction tube were added
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2ꢀmethoxyꢀ5ꢀ(methylsulfonyl)benzoic acid (0.50 mmol), methyl acetylenate (0.55 mmol), and
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o
triethylamine (1.10 mmol) in CH3CN (3 mL) under air. The tube was sealed and stirred at 60 C
for 3 hours. Then, N1,N1ꢀdiethylethaneꢀ1,2ꢀdiamine (1.10 mmol) was added to the stirring solution,
o
and the resulting mixture was stirred at 60 C for another 2 hours, monitoring with TLC. Finally,
the solvent was evaporated under reduced pressure and the residue was purified by silica gel flash
column chromatography (5−10% methyl alcohol in dichloromethane) to give
Nꢀ(2ꢀ(diethylamino)ethyl)ꢀ2ꢀmethoxyꢀ5ꢀ(methylsulfonyl)benzamide 46 (78.2 mg, 48% yield) as a
1
yellow oil: H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.65 (s, 1H), 8.02 (d, J = 11.2 Hz, 1H),
7.13 (d, J = 8.8 Hz, 1H), 4.10 (s, 3H), 3.75 (m, 2H), 3.06 (s, 3H), 2.97 (t, J = 5.6 Hz, 2H), 2.88 (m,
4H), 1.24 (t, J = 7.2 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 163.8, 161.3, 133.1, 131.9, 122.7,
112.0, 77.3, 77.0, 76.7, 56.6, 51.9, 47.6, 44.5, 36.9, 10.3.
Preparation of compound 47. To
a
10 mL reaction tube were added
5ꢀchloroꢀ2ꢀmethoxybenzoic acid (0.50 mmol), methyl acetylenate (0.55 mmol), and triethylamine
o
(1.10 mmol) in CH3CN (3 mL) under air. The tube was sealed and stirred at 60 C for 40 min.
Subsequently, the 4ꢀ(2ꢀaminoethyl)benzenesulfonamide (1.10 mmol) was added to the stirring
solution, and the resulting mixture was stirred at 60 oC for another 2 hours, monitoring with TLC.
o
Then the reaction was cooled to 0 C using the ice water for 30 min, and a white solid
5ꢀchloroꢀ2ꢀmethoxyꢀNꢀ(4ꢀsulfamoylphenethyl)benzamide 47 (1.89 g, 85% yield) was obtained by
the filtration: 1H NMR (400 MHz, DMSOꢀd6) δ 8.27 (t, J = 5.5 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H),
7.64 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 11.7 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.31 (s, 2H), 7.16 (d,
J = 8.9 Hz, 1H), 3.81 (s, 3H), 3.53 (m, 2H), 2.91 (t, J = 7.0 Hz, 2H). 13C NMR (100 MHz,
DMSOꢀd6) δ 164.0, 156.1, 144.1, 142.6, 131.9, 129.9, 129.6, 126.1, 125.3, 124.8, 114.6, 56.7,
35.0.
ACKNOWLEDGMENTS
We are grateful for the generous financial support by the Natural Science Foundation of Shanghai
(15ZR1418800), the China Postdoctoral Science Foundation (2016M601681), the Opening Project
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of Shanghai Key Laboratory of Chemical Biology, and the Shanghai University of Engineering
Science (nhrcꢀ2015ꢀ15).
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ASSOCIATED CONTENT
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI: .
NMR spectra for compounds 1−11, 13−32, 34−36, 38−40, 45−47 (PDF)
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