Catalyst-Free [4+2] Cycloaddition of Ynamides with 2-Halomethyl Phenols to Construct 2-Amino-4 H-Chromenes and α-Halo Enamides Simultaneously

Article abstract of DOI:10.1021/acs.joc.0c01258

We report the development of a facile protocol for the [4+2] cycloaddition of ynamides and 2-halomethyl phenols to afford the corresponding 2-amino-4H-chromenes and α-halo enamides under catalyst-free conditions. The reaction proceeds under mild condition

Full text of DOI:10.1021/acs.joc.0c01258

pubs.acs.org/joc
Article
Catalyst-Free [4+2] Cycloaddition of Ynamides with 2‑Halomethyl
Phenols To Construct 2‑Amino‑4H‑Chromenes and α‑Halo Enamides
Simultaneously
Hao Wen, Weibo Yan, Ping Chen,* Yu Li, and Yu Tang*
Cite This: https://dx.doi.org/10.1021/acs.joc.0c01258
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We report the development of a facile protocol for
the [4+2] cycloaddition of ynamides and 2-halomethyl phenols to
afford the corresponding 2-amino-4H-chromenes and α-halo
enamides under catalyst-free conditions. The reaction proceeds
under mild conditions and exhibits good tolerance toward various
functional groups and generates high yields. The plausible
mechanism involves the formation of an active intermediate
keteniminium as well as o-methylene quinone.
Ynamides have attracted growing attention as useful building
blocks.3 Notably, cycloaddition of ynamides with various
precursors provides an efficient and straightforward strategy to
construct heterocycles, such as pyridines,4 pyrroles,5 indoles,6
and carbolines.7 Recently, some elegant methods have been
reported for the synthesis of 2-amino-4H-chromenes via
cycloaddition of ynamides. For example, in 2016, Cao and
his co-workers8 developed ZnBr2-promoted formal [4+2]
annulation of ynamides with o-methoxybenzyl silyl ethers to
construct this framework (Scheme 1a). However, this method
suffered from certain salient drawbacks, for example, low yields
(41−65%), narrow substrate scopes, and 1.2 equiv Lewis acid
ZnBr2. Besides, Wang et al.9 reported an efficient method via
AlCl3-catalyzed [4+2] cycloaddition of ynamides with o-
quinone methides at −40 °C (Scheme 1b). However,
substrates of this reaction were limited to terminally
unsubstituted ynamides and o-quinone methides bearing
electron-donating groups. Maintaining the reaction temper-
ature at −40 °C and using a strong and moisture-sensitive
Lewis acid were necessary. Therefore, it is still deemed
worthwhile to explore green and efficient ways to synthesize 2-
amino-4H-chromenes. To the best of our knowledge, catalyst-
free reactions of ynamides are very rare. Herein, we developed
an efficient and concise catalyst-free approach to furnish this
INTRODUCTION
■
The 2-amino-4H-chromene skeleton belongs to the privileged
structural motifs in numerous natural products as well as
medicinal agents which exhibit diverse biological activities,
including antitumor, antibacterial, antioxidative, and anti-
hypertensive (Figure 1).1 For instance, 2-amino-4-aryl-4H-
chromene (HFI-437) is a high-affinity inhibitor of insulin-
regulated aminopeptidase, which has potential in the treatment
of neurodegenerative disease.1a Compound MX 58151 was
used as a tubulin inhibitor that binds at or close to the
colchicine site of β-tubulin.1b In addition, EPC2407 (crin-
obulin) is a potential vascular-targeting anticancer agent and
apoptosis inducer in the treatment of patients with advanced
solid tumors.1c HA 14-1 and sHA 14-1 could mitigate drug
resistance and synergize with a variety of cancer therapies in
leukemia cells.1d−f
Owing to the highly pronounced biological activities of 2-
amino-4H-chromenes, a multitude of effective protocols have
been developed to access 2-amino-4H-chromenes.2 Classic
methods for the syntheses of 2-amino-4H-chromene motifs
usually include two-component cascade reactions of salicyl-
aldehyde with active methylene compounds and three-
component reactions of aldehydes and phenols with
malononitriles using various catalysts such as ethylenediamine
diacetate, β-cyclodextrin, InCl3, Zr(KPO4)2, aminosilane-
modified Fe3O4 nanoparticles, and silica-bonded 2-hydroxy-
ethylammonium acetate via Knoevenagel condensation and
Michael addition. However, these methods show varying
degree success as well as limitations such as the requirement of
expensive catalysts, complex catalytic systems, complicated
operations, and low yields.
Received: May 26, 2020
https://dx.doi.org/10.1021/acs.joc.0c01258
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Figure 1. Biologically active molecules containing 4H-chromenes.
Scheme 1. Synthesis of 2-Amino-4H-Chromenes via Ynamides
class of molecules via formal [4+2] cycloaddition of ynamides
with readily available 2-halomethylphenols (Scheme 1c).
Furthermore, in this reaction, we have obtained α-halo
enamides in good yields which are versatile intermediates10
and readily converted into various functional groups by
halogen−metal exchange reactions. Although considerable
efforts have been made for the syntheses of α-halo enamides,11
most of them suffered from serious disadvantages such as
complex reaction conditions and tedious manipulation. On the
other hand, we recently reported a highly regio- and
stereoselective synthesis of α-halo enamides using aqueous
hydrogen halides in two-phase systems.12 Therefore, develop-
ing a green and simple method to synthesize α-halo enamides
is highly desirable.
yield from this reaction simultaneously. Then, different
inorganic bases were investigated, and Cs2CO3 gave the best
results (entries 2−7). Surprisingly, in the absence of a base in
this reaction, the desired product 3a was achieved in 53% yield,
and 4a was obtained in 23% yield (entry 8). Presumably,
because bases transformed 2-(bromomethyl)-4-nitrophenol 2a
into o-quinone methides, which easily formed dimers or
trimers, the use of bases lowered the yields of this reaction.
Next, evaluation of solvents disclosed that dichloromethane
(DCM) was the best choice (entries 8−15). Considering the
consumption of a stoichiometric amount of ynamide 2a, we
decided to increase the amount of ynamides. To our delight,
when the amount of ynamides 2a was increased to 1.5 equiv,
the yields of cycloaddition product 3a and (E)-α-bromoena-
mide 4a were increased to 76 and 59%, respectively (entry 16).
With the continuous increase of the amount of ynamide to 2.0
equiv, the yields of products 3a and 4a were increased to 91
and 81%, respectively (entry 17). Increasing the reaction
temperature has a beneficial effect on the reaction efficiency,
shortening the reaction time to 12 h (entry 18). In addition,
this transformation was catalyzed in the presence of 0.2 equiv
of Lewis acids, such as Sc(OTf)3, Fe(OTf)3, Cu(OTf)2, and
RESULTS AND DISCUSSION
■
Initially, 2-(bromomethyl)-4-nitrophenol 1a and ynamide 2a
were selected as model substrates to investigate the feasibility
of [4+2] cycloaddition. To our delight, the desired 2-amino-
4H-chromene 3a was obtained in 45% yield in the presence of
NaOH in CH2Cl2 at room temperature (rt) (Table1, entry 1).
Unexpectedly, (E)-α-bromoenamide 4a was isolated in 18%
B
https://dx.doi.org/10.1021/acs.joc.0c01258
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a b
,
Table 1. Condition Optimization of Ynamides 2a and 2-(Bromomethyl)-4-nitrophenol 1a
entry
base
solvent
temperature
3a yield (%)
4a yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
NaOH
CS2CO3
K2CO3
Na2CO3
NaHCO3
t-BuOK
MeONa
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
45
46
41
37
40
27
25
53
46
NR
NR
NR
42
31
37
76
91
93
18
23
21
17
18
5
9
23
37
NR
NR
NR
25
19
21
59
81
87
DMF
DMSO
MeOH
CH3CN
THF
toluene
DCM
DCM
DCM
c
16
d
17
e
18
reflux
a
Unless otherwise specified, reactions were conducted with 1a (0.15 mmol), 2a (0.15 mmol), and the base (0.165 mmol) in 2.0 mL of the solvent
b
c
at rt for 48 h. Isolated yield. Reactions were conducted with 1a (0.15 mmol) and 2a (0.225 mmol) in 2.0 mL of the solvent at rt for 48 h.
d
e
Reactions were conducted with 1a (0.15 mmol) and 2a (0.3 mmol) in 2.0 mL of the solvent at rt for 48 h. Reactions were conducted with 1a
(0.15 mmol) and 2a (0.3 mmol) in 2.0 mL of the solvent under reflux in an oil bath for 12 h.
Mg(OTf)2, giving lower yields of 3a and 4a, respectively (see
Table S1 in the Supporting Information for more details).
Therefore, the optimal reaction conditions were identified as
follows: 1a (0.15 mmol) and 2a (0.3 mmol) in refluxing DCM
for 12 h without any other catalysts, reagents, or additives.
With the optimal reaction conditions in hand, we began to
explore the scopes of the reaction first by varying the ynamides
(Scheme 2). When phenyl-terminated ynamides were
employed as reactants, both electron-donating and electron-
withdrawing groups were well tolerated, affording the desired
products 2-amino-4H chromenes 3a−3e in good to excellent
yields and (E)-α-bromoenamide 4a−4e in moderate to good
yields. Terminally unsubstituted ynamides 2g were also
compatible for this reaction to give [4+2] cycloaddition
products 3g in 72% yield. In this case, hydrolysis products 4g
were obtained instead of α-bromoenamide. Our assumption is
that the terminal ynamide was more unstable than internal
ynamides and readily underwent hydrolysis reaction. Similarly,
the tert-butyl-substituted ynamide was subjected to the optimal
conditions, furnishing the desired cycloaddition product 3h in
86% yield, and hydrolysis product 4h was obtained in 31%
yield. However, when N-Ns-protected ynamide 2i was
employed, the reaction proceeded smoothly, affording the
corresponding products 3i and 4i in good yields. Other alkyl
(cyclopropyl), thienyl-terminated, and N-alkyl-substituted
ynamides (2j−2l) afforded 3j−3l and 4j−4l with excellent
yields. Ynamide 2m incorporating the Boc group on the N
atom also tolerated during the smooth formation of the
corresponding products 3m and 4m in 95 and 93% yields,
respectively. In addition to N-sulfonyl ynamides, oxazolidinone
ynamide 2n was also an ideal substrate, which provided the
desired products 3n and 4n in moderate yields.
Next, various 2-bromomethyl phenol derivatives were also
investigated (Scheme 3). The nitro group on the phenyl had
no significant impact on the reaction, delivering the
corresponding products in excellent yields (5a−5d, 4a).
Besides, a list of aldehyde-containing 2-bromomethyl phenols
was examined and the corresponding products 5e−5g were
furnished in moderate yields under standard conditions.
Besides 2-bromomethyl phenol derivatives, 2-chlorophenols
bearing the acetyl or aldehyde group were employed as
substrates to successfully deliver cycloaddition product 5h and
5i in 73 and 79% yields, respectively, and (E)-α-chloro
enamides were obtained in moderate yields.
To demonstrate the applicability of this method in organic
synthesis, we carried out the reaction on a gram scale under
standard conditions, furnishing the desired products 3a and 4a
in 89 and 84% yields, respectively, while the reaction time was
extended to 24 h (Scheme 4).
To explore the mechanism of this reaction, control
experiments were carried out (Scheme 5). 1a was treated
with CH3OD, and 30% deuterium incorporation was observed
at the hydroxyl group of 1a′. Then, the reaction between 1a′
and ynamide 2a was performed under standard conditions, and
28% deuterium incorporation was found in 4a′. These results
indicated that hydrogen in the alkenyl group of 4a′ directly
comes from the hydroxyl group of 1a′ (eq 1, Scheme 5).
Chromene 3a was not detected using (E)-α-bromoenamide 4a
and 1a as substrates (eq 2, Scheme 5). Therefore, it was
impossible that 4a participated in the [4+2] cycloaddition
giving the desired product 3a (eq 2, Scheme 5). In addition,
treatment of 1a with 2.0 equiv of NaH for 0.5 h, followed by
reaction with 2a to give 3a in 43% yield along with less than
10% of 4a, proved that this transformation was probably
C
https://dx.doi.org/10.1021/acs.joc.0c01258
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a,b
Scheme 2. Substrate Scope of Ynamides
a
Unless otherwise specified, reactions were conducted with 1a (0.15 mmol) and 2 (0.3 mmol) in 2.0 mL of the solvent under reflux in an oil bath
b
for 12 h. Isolated yield.
achieved through the o-methylene quinone intermediate (eq 3,
Scheme 5).
α-halo enamide derivatives simultaneously in one step. Besides,
this strategy features simplicity, mild conditions, high yields,
and good functional group compatibility.
A plausible reaction mechanism was proposed based on our
experimental results (Scheme 6). Initially, one equivalent of
ynamide 2a acted as a base, which reacted with 1a, leading to
keteniminium A and o-methylene quinone B,13 respectively.
Subsequently, keteniminium A was nucleophilic-attacked by
Br− from the side of least steric hindrance to yield the
corresponding (E)-α-bromoenamide 4a. In the meanwhile, an
intermolecular [4+2] cycloaddition between o-methylene
quinone B and another equivalent of ynamide 2a was achieved
to afford 2-amino-4H-chromenes 3a.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise mentioned, all reactions
were performed in flame-dried glassware under air. Solvents were
distilled prior to use. Reagents were purchased from commercially
available sources and used without purification unless otherwise
noted. Chromatographic separations were performed using Kangbino
1
48−75 Å SiO2. H, 19F, and 13C NMR spectra were recorded on
Agilent ProPulse spectrometers using CDCl3 with tetramethylsilane
or a residual solvent as a standard unless otherwise noted. The
melting points were determined using a melting point apparatus and
were uncorrected/calibrated. Thin-layer chromatography (TLC)
analysis was performed using Kangbino glass-backed plates (60 Å,
250 μm) and visualized using UV and iodine stains. Low-resolution
mass spectra were obtained using an Agilent 1100 series LS/MSD. All
spectral data obtained for new compounds are reported here.
CONCLUSIONS
■
In conclusion, a novel and highly efficient catalyst-free
symbiotic reaction of 2-halomethylphenols and ynamides has
been developed. This method provides a general and
straightforward way to construct 2-amino-4H-chromenes and
D
https://dx.doi.org/10.1021/acs.joc.0c01258
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a,b
Scheme 3. Substrate Scope of 2-Halomethyl Phenols
a
Unless otherwise specified, reactions were conducted with 1 (0.15 mmol) and 2a (0.3 mmol) in 2.0 mL of the solvent under reflux in an oil bath
b
for 12 h. Isolated yield.
Scheme 4. Gram-Scale Reaction
Scheme 5. Control Experiments
E
https://dx.doi.org/10.1021/acs.joc.0c01258
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 6. Proposed Reaction Mechanism
General Procedure. General Procedure 1 for the Synthesis of
Ynamides (2a).14 CuCl2 (20 mol %), sulfonamide (2.0 equiv), and
Na2CO3 (2.0 equiv) were added to a three-necked round-bottomed
flask. The flask was purged with oxygen for 15 min, and a solution of
pyridine (2.0 equiv) in dry toluene (0.2 M) was added. A balloon
filled with oxygen was connected to the flask, and the stirred mixture
was heated in an oil bath at 70 °C. After 15 min, a solution of alkyne
(1.0 equiv) in anhydrous toluene (0.2 M) was added using a syringe
pump over 4 h. The mixture was allowed to stir at 70 °C for another 4
h and allowed to cool to rt. The reaction mixture was filtered through
a plug of silica gel, washed with ethyl acetate, and concentrated. The
crude residue was purified by flash chromatography over silica gel.
General Procedure 2 for the Synthesis of Ynamides (2b).15 To a
solution of phenylacetylene (1.0 equiv) in acetone (100 mL) were
added N-bromosuccinimide (1.1 equiv) and AgNO3 (10 mol %). The
resulting solution was stirred under nitrogen at rt for 6 h. After
removing excess acetone, the reaction mixture was quenched with
water, extracted with EtOAc three times, dried over MgSO4, and
concentrated under reduced pressure. The residue was eluted through
a short silica column (petroleum ether) to obtain the bromoalkyne.
To a dried flask were added N-phenylmethanesulfonamide (1.0
equiv), CuSO4·5H2O (0.5 equiv), 1,10-phenanthroline (30 mol %
equiv), K2CO3 (2.0 equiv), and bromoalkyne (1.2 equiv), and this
mixture was subsequently treated with anhydrous toluene (100 mL)
and the bromoalkyne. The flask was charged with nitrogen, and the
solution was heated at 80 °C overnight. After completion, the crude
reaction mixture was cooled to rt, filtered through Celite, and
concentrated in vacuo. Purification of the crude residue using silica gel
flash column chromatography yielded pure ynamide 1l as a white
solid.
Subsequently, a solution of KOH (230 mmol) in H2O (10 mL) was
added to the reaction mixture. After stirring for 5 h at 0 °C, H2O (20
mL) was added to the reaction mixture. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 20
mL). The combined organic layer was washed with brine and dried
over MgSO4. All volatiles were removed under reduced pressure. The
product was purified by SiO2 column chromatography.
To a dried flask were added N-methylmethanesulfonamide (4.85
mmol), CuSO4·5H2O (0.40 mmol), 1,10-phenanthroline (0.81
mmol), K2CO3 (10.01 mmol), and bromoalkyne (4.04 mmol), and
this mixture was subsequently treated with anhydrous toluene (100
mL) and the bromoalkyne. The flask was charged with nitrogen, and
the solution was heated at 80 °C in an oil bath overnight. After
completion, the crude reaction mixture was cooled to rt, filtered
through Celite, and concentrated in vacuo. Purification of the crude
residue using silica gel flash column chromatography yielded the pure
product as a white solid.
General Procedure 5 for the Synthesis of 2-Amino-4H-
Chromenes (3a) and α-Halo Enamides (4a). 2-(Bromomethyl)-4-
nitrophenol 1a (0.15 mmol), ynamide 2a (0.3 mmol), and dry
CH2Cl2 (2.0 mL) were added to a 10 mL sealed tube. The mixture
was stirred in reflux for 12 h. The reaction was monitored by TLC
until the starting material disappeared. Then, the solvent was removed
in vacuo, and the residue was purified by flash chromatography to give
the desired product.
Characterization of Products. N-Methyl-N-(phenylethynyl)-
methanesulfonamide (2a).12 Following general procedure 1, the
product was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 6/1 to petroleum ether/ethyl acetate
= 4/1) to afford the desired product 2a; white solid, mp 58−60 °C,
General Procedure 3 for the Synthesis of Ynamide 2g.7c To a
solution of N-(2-cyanophenyl)methanesulfonamide (30 mmol) in
dimethylformamide (DMF) (70 mL) was added Cs2CO3 (1.0 equiv).
The solution was stirred at rt for 30 min, and then, phenyl-
((trimethylsilyl)ethynyl)iodonium triflate (1.3 equiv) in DCM (30
mL) was added to the mixture and stirred until the reaction
proceeded to completion as monitored by TLC. The reaction mixture
was quenched by water and stirred for 30 min. The resulting mixture
was extracted with CH2Cl2, washed with water and brine, and dried
over anhydrous MgSO4. The mixture was filtered, and the solvent was
evaporated under reduced pressure; then, the residue was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 3/1 to petroleum ether/DCM = 1/1) to afford the desired
product as a white solid.
1
yield: 82% (380.65 mg); H NMR (500 MHz, CDCl3): δ 7.44−7.39
(m, 2H), 7.33−7.28 (m, 3H), 3.30 (s, 3H), 3.13 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 131.5, 128.3, 128.1, 122.3, 83.0, 69.5,
39.3, 36.8; mass spectrum [electrospray ionization (ESI)]: m/z (%
relative intensity) 232.0 (100) [M + Na]+.
N-Phenyl-N-(phenylethynyl)methanesulfonamide (2b).12 Fol-
lowing general procedure 1, the product was purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate =
6/1 to petroleum ether/ethyl acetate = 4/1) to afford the desired
1
product 2b; white solid, mp 67−68 °C, yield: 52% (458.6 mg); H
NMR (500 MHz, CDCl3): δ 7.62−7.58 (m, 2H), 7.49−7.44 (m, 4H),
7.41−7.36 (m, 1H), 7.34−7.30 (m, 3H), 3.17 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 138.7, 131.6, 129.5, 128.34, 128.32, 128.2,
125.6, 122.3, 82.0, 71.0, 36.9; mass spectrum (ESI): m/z (% relative
intensity) 294.0 (100) [M + Na]+.
General Procedure 4 for the Synthesis of Ynamide 2e.14,16 Under
an atmosphere of argon, a solution of triphenylphosphine (4.0 equiv)
and tetrabromomethane (2.0 equiv) in absolute CH2Cl2 (0.15 M) was
stirred at 0 °C for 30 min. The aldehyde was added over a period of 5
min, and the mixture was stirred at 0 °C for 1 h. After addition of
water, the layers were separated, and the aqueous layer was extracted
with CH2Cl2 (three times). The combined organic layers were dried
over MgSO4, and the solvent was removed under reduced pressure.
The crude product was dry-loaded on silica and subjected to flash
chromatography.
N-((4-Methoxyphenyl)ethynyl)-N-phenylmethanesulfonamide
(2c).12 Following general procedure 1, the product was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to afford the
desired product 2c; white solid, mp 96−97 °C, yield: 66% (427.7
mg); 1H NMR (500 MHz, CDCl3): δ 7.59 (d, J = 7.9 Hz, 2H), 7.48−
7.33 (m, 5H), 6.86 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H), 3.16 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 159.8, 138.9, 133.6, 129.4,
128.2, 125.5, 114.2, 114.0, 80.6, 70.7, 55.3, 42.7, 36.7; mass spectrum
To the vigorously stirred solution of 1,1-dibromoethene (5 mmol)
in CH2Cl2 (25 mL) at 0 °C, BnEt3Cl (4.4 mmol) was added.
(ESI): m/z (% relative intensity) 324.1 (100) [M + Na]+.
F
https://dx.doi.org/10.1021/acs.joc.0c01258
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
N-Phenyl-N-((4-(trifluoromethyl)phenyl)ethynyl)-
methanesulfonamide (2d). Following general procedure 1, the
product was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 4/1 to petroleum ether/ethyl acetate
= 3/1) to afford the desired product 2d; white solid; mp 114−115
(m, 1H), 7.30−7.26 (m, 4H), 7.25−7.22 (m, 2H), 2.44 (s, 3H),
1.37−1.31 (m, 1H), 0.83−0.78 (m, 2H), 0.69−0.65 (m, 2H);
13C{1H} NMR (150 MHz, CDCl3): δ 145.3, 140.1, 133.8, 130.0,
129.6, 128.9, 128.6, 126.8, 75.3, 70.0, 22.4, 9.5; mass spectrum (ESI):
m/z (% relative intensity) 334.1 (100) [M + Na]+.
1
°C; mp 98−99 °C; yield: 69% (469.2 mg); H NMR (500 MHz,
4 - M e t h y l - N - p h e n y l - N - ( t h i o p h e n - 3 - y l e t h y n y l ) -
benzenesulfonamide (2k).12 Following general procedure 1, the
product was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 4/1 to petroleum ether/ethyl acetate
= 3/1) to afford the desired product 2k; white solid, mp 150−151 °C,
CDCl3): δ 7.61−7.56 (m, 4H), 7.54 (d, J = 8.5 Hz, 2H), 7.48 (t, J =
7.8 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 3.18 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 138.3, 131.3, 129.67, 129.66 (q, J = 32.8 Hz),
128.7, 126.3 (q, J = 1.3 Hz), 125.7, 125.3 (q, J = 3.8 Hz), 123.9 (q, J =
272.1 Hz), 84.5, 74.1, 37.2; 19F NMR (470 MHz, CDCl3): δ −62.79.
High-resolution mass spectroscopy (HRMS) (ESI) m/z: [M + H]+
calcd for C16H13F3NO2S, 340.0614; found, 340.0609.
N-((2-Cyanophenyl)ethynyl)-N-methylmethanesulfonamide
(2e).12 Following general procedure 4, the product was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to afford the
desired product 2e; white solid, mp 54−55 °C, yield: 52% (491.6
mg); 1H NMR (500 MHz, CDCl3): δ 7.65−7.61 (m, 1H), 7.56−7.49
(m, 2H), 7.40−7.35 (m, 1H), 3.37 (s, 3H), 3.23 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 132.5, 132.4, 131.4, 127.9, 126.8, 117.8,
114.6, 89.5, 66.9, 39.2, 37.4; mass spectrum (ESI): m/z (% relative
intensity) 257.0 (100) [M + Na]+
N-((4-Chlorophenyl)ethynyl)-N-phenylmethanesulfonamide
(2f).12 Following general procedure 2, the product was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to afford the
desired product 2f; white solid, mp 112−114 °C, yield: 32% (314.9
mg); 1H NMR (500 MHz, CDCl3): δ 7.58 (d, J = 7.8 Hz, 2H), 7.49−
7.43 (m, 2H), 7.42−7.35 (m, 3H), 7.34−7.28 (m, 2H), 3.17 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 138.5, 134.2, 132.7, 129.6,
1
yield: 32% (240.6 mg); H NMR (500 MHz, CDCl3): δ 7.64−7.60
(m, 2H), 7.41−7.38 (m, 1H), 7.36−7.23 (m, 8H), 7.07 (d, J = 4.9 Hz,
1H), 2.45 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 144.9,
138.9, 133.0, 130.1, 129.5, 129.1, 128.9, 128.3, 128.2, 126.3, 125.2,
121.4, 82.3, 65.6, 21.7; mass spectrum (ESI): m/z (% relative
intensity) 376.1 (100) (M + Na)+.
N - ( 2 - C y a n o e t h y l ) - 4 - m e t h y l - N - ( p h e n y l e t h y n y l ) -
benzenesulfonamide (2l).7d Following general procedure 1, the
product was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 6/1 to petroleum ether/ethyl acetate
= 4/1) to afford the desired product 2l; white solid; mp 94−96 °C;
1
yield: 88% (570.0 mg); H NMR (500 MHz, CDCl3): δ 7.86 (d, J =
8.3 Hz, 2H), 7.42−7.37 (m, 4H), 7.34−7.30 (m, 3H), 3.75 (t, J = 7.2
Hz, 2H), 2.79 (t, J = 7.2 Hz, 2H), 2.48 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3): δ 145.5, 133.9, 131.6, 130.1, 128.39, 128.38, 127.8,
122.0, 116.4, 80.6, 71.9, 47.3, 21.7, 17.5.
tert-Butyl Phenyl(phenylethynyl)carbamate (2m). Following
1
general procedure 11; white solid; 42% (247.1 mg); H NMR (400
MHz, CDCl3): δ 7.56−7.51 (m, 2H), 7.42−7.37 (m, 4H), 7.31−7.23
(m, 2H), 1.57 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ 153.1,
139.8, 131.0, 128.9, 128.4, 127.5, 126.8, 124.8, 123.5, 83.8, 83.6, 70.2,
28.1; HRMS(ESI) m/z: [M + H]+ calcd for C19H20NO2, 294.1494;
found, 294.1491.
128.7, 128.5, 125.6, 120.8, 82.9, 69.9, 37.0. Mass spectrum (ESI): m/z
(% relative intensity) 328.0 (100) [M + Na]+.
3-(Phenylethynyl)oxazolidin-2-one (2n).12 Following general
procedure 1; white solid; mp 84−85 °C; yield: 62% (260.4 mg);
1H NMR (600 MHz, CDCl3): δ 7.47−7.41 (m, 2H), 7.32−7.28 (m,
N-Ethynyl-N-phenylmethanesulfonamide (2g). Following general
procedure 3, the product was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 6/1 to petroleum
ether/ethyl acetate = 4/1) to afford the desired product 2g; white
3H), 4.48 (t, J = 8.0 Hz, 2H), 3.98 (t, J = 8.0 Hz, 2H); 13C{1H} NMR
(150 MHz, CDCl3): δ 155.9, 131.6, 128.3, 128.2, 122.2, 79.0, 71.2,
63.1, 47.1; mass spectrum (ESI): m/z (% relative intensity) 210.1
(100) [M + Na]+.
1
solid; yield: 89% (288.0 mg); H NMR (500 MHz, CDCl3): δ 7.53
(d, J = 8.0 Hz, 2H), 7.44 (t, J = 7.7 Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H),
3.13 (s, 3H), 2.97 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ
138.0, 129.5, 128.6, 125.6, 75.8, 59.7, 36.7; HRMS (ESI) m/z: [M +
H]+ calcd for C9H10NO2S, 196.0432; found, 196.0423.
N-Methyl-N-(6-nitro-3-phenyl-4H-chromen-2-yl)-
methanesulfonamide (3a). Following general procedure 5, the
product was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 3a; white solid; mp 207−209 °C;
N-(3,3-Dimethylbut-1-yn-1-yl)-N-phenylmethanesulfonamide
(2h). Following general procedure 1, the product was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to afford the
desired product 2h; white solid; yield: 39% (196.56 mg); mp 86−87
1
yield: 93% (50.2 mg); H NMR (400 MHz, CDCl3): δ 8.07 (dd, J =
8.9, 2.7 Hz, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.44−7.36 (m, 4H), 7.34−
7.29 (m, 1H), 7.02 (d, J = 8.9 Hz, 1H), 3.89 (s, 2H), 3.02 (s, 3H),
2.81 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 143.9, 128.8,
128.2, 124.8, 124.0, 120.9, 116.8, 111.3, 39.7, 36.4, 31.0; HRMS
(APCI−orbitrap) m/z: [M + H]+ calcd for C17H17N2O5S, 361.0853;
found, 361.0850.
1
°C; H NMR (400 MHz, CDCl3): δ 7.52−7.48 (m, 2H), 7.43−7.37
(m, 2H), 7.35−7.29 (m, 1H), 3.05 (s, 3H),1.28 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ 139.3, 129.4, 128.0, 125.3, 79.2, 72.4,
35.8, 31.1, 27.7; HRMS (APCI−orbitrap) m/z: [M + H]+ calcd for
C13H18NO2S, 252.1053; found, 252.1054.
N-(3,3-Dimethylbut-1-yn-1-yl)-4-nitro-N-phenylbenzenesulfona-
mide (2i). Following general procedure 1, the product was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to afford the
desired product 2i; pale yellow solid; yield: 45% (323.1 mg); mp
N-(6-Nitro-3-phenyl-4H-chromen-2-yl)-N-phenylmethanesulfo-
namide (3b). Following general procedure 5, the product was purified
by column chromatography on silica gel (eluent: petroleum ether/
ethyl acetate = 2/1 to petroleum ether/ethyl acetate = 1/1) to afford
the desired product 3b; pale yellow solid; mp 80−82 °C; yield: 91%
(57.6 mg); 1H NMR (400 MHz, CDCl3): δ 8.11 (dd, J = 9.0, 2.7 Hz,
1H), 8.04−8.05 (m, 1H), 7.37−7.30 (m, 5H), 7.26−7.20 (m, 3H),
7.15−7.09 (m, 3H), 3.86 (s, 2H), 3.06 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 156.1, 144.1, 141.1, 139.1, 136.0, 129.4, 128.6,
128.3, 128.2, 127.9, 126.8, 124.9, 124.0, 121.1, 116.9, 113.0, 40.4,
31.4; HRMS (APCI−orbitrap) m/z: [M + H]+ calcd for
C22H19N2O5S, 423.1009; found, 423.1006.
1
144−146 °C; Rf = 0.55 (petroleum ether/ethyl acetate = 95:5); H
NMR (400 MHz, CDCl3): δ 8.33 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.8
Hz, 2H), 7.38−31 (m, 3H), 7.24−7.19 (m, 2H), 1.24 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3): δ 150.8, 140.9, 138.8, 129.6,
129.3, 128.6, 125.9, 123.9, 79.4, 72.2, 31.0, 27.6; HRMS (APCI−
orbitrap) m/z: [M + H]+ calcd for C18H19N2O4S, 359.1060; found,
359.1060.
N-(Cyclopropylethynyl)-4-methyl-N-phenylbenzenesulfonamide
(2j).12 Following general procedure 1, the product was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to afford the
desired product 2j; white solid, mp 103−105 °C, yield: 41% (410.8
mg);1H NMR (600 MHz, CDCl3): δ 7.58−7.55 (m, 2H), 7.33−7.30
N-(3-(4-Methoxyphenyl)-6-nitro-4H-chromen-2-yl)-N-phenylme-
thanesulfonamide (3c). Following general procedure 5, the product
was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 3c; yellow solid, mp 130−132
°C, yield: 92% (62.4 mg);1H NMR (400 MHz, CDCl3): δ 8.11 (dd, J
G
https://dx.doi.org/10.1021/acs.joc.0c01258
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
= 8.9, 2.7 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.33−7.27 (m, 2H),
7.26−7.23 (m, 3H), 7.17−7.14 (m, 2H), 7.11 (d, J = 9.0 Hz, 1H),
6.92−6.85 (m, 2H), 3.83 (s, 2H), 3.82 (s, 3H), 3.08 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 159.4, 156.1, 144.0, 140.7, 139.1, 129.4,
129.1, 128.3, 128.1, 126.8, 125.0, 124.0, 121.1, 116.8, 113.9, 112.6,
55.4, 40.41, 31.41; HRMS (APCI−orbitrap) m/z: [M + H]+ calcd for
C23H21N2O6S, 453.1115; found, 453.1113.
N-(6-Nitro-3-(4-(trifluoromethyl)phenyl)-4H-chromen-2-yl)-N-
phenylmethanesulfonamide (3d). Following general procedure 5,
the product was purified by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl
acetate = 1/1) to afford the desired product 3d; white solid; mp 193−
195 °C; yield: 85% (62.6. mg); 1H NMR (400 MHz, CDCl3): δ 8.14
(d, J = 8.8 Hz, 1H), 8.05 (s, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.46 (d, J =
7.8 Hz, 2H), 7.27−7.21 (m, 3H), 7.18−7.07 (m, 7.0 Hz, 3H), 3.87 (s,
2H), 3.11 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.7,
144.3, 142.0, 139.7, 138.9, 130.2 (q, J = 32.4 Hz), 129.6, 128.53,
128.46, 126.5, 125.6 (q, J = 4.1 Hz), 125.0, 124.2, 124.1 (q, J = 271.3
Hz), 120.7, 117.0, 111.7, 40.4, 31.0; 19F NMR (376 MHz, CDCl3): δ
−62.47 (s, 3F); HRMS (APCI−orbitrap) m/z: [M + H]+ calcd for
C23H18F3N2O5S, 491.0883; found, 491.0878.
N-(3-(tert-Butyl)-6-nitro-4H-chromen-2-yl)-4-nitro-N-phenylben-
zenesulfonamide (3i). Following general procedure 5, the product
was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 3i; white solid; mp 202−204 °C;
1
yield: 83% (63.4 mg); H NMR (400 MHz, CDCl3): δ 8.25 (d, J =
8.4 Hz, 2H), 8.10−8.03 (m, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.47−7.42
(m, 2H), 7.35−7.27 (m, 3H), 6.60 (d, J = 9.0 Hz, 1H), 3.80−3.50 (m,
2H), 1.26 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.9,
150.4, 144.6, 143.9, 139.8, 138.3, 129.8, 129.6, 127.8, 124.81, 124.79,
124.0, 123.6, 121.6, 121.5, 115.1, 35.1, 29.6, 28.1; HRMS (APCI−
orbitrap) m/z: [M + H]+ calcd for C25H24N3O7S, 510.1330; found,
510.1327.
N-(3-Cyclopropyl-6-nitro-4H-chromen-2-yl)-4-methyl-N-phenyl-
benzenesulfonamide (3j). Following general procedure 5, the
product was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 3j; pale yellow solid; mp 204−
1
206 °C; yield: 88% (61.0 mg); H NMR (400 MHz, CDCl3): δ 8.02
(d, J = 8.9 Hz, 1H), 7.97 (s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.38−7.21
(m, 8H), 6.78 (d, J = 8.9 Hz, 1H), 3.21 (s, 2H), 2.44 (s, 3H), 2.11−
2.00 (m, 1H), 0.80−0.5 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3):
δ 156.4, 144.1, 143.5, 139.5, 139.3, 136.5, 129.3, 128.5, 128.1, 127.4,
125.1, 123.8, 120.2, 116.4, 113.3, 25.4, 21.8, 11.5, 3.3; HRMS
(APCI−orbitrap) m/z: [M + H]+ calcd for C25H22N2O5S, 463.1322;
found, 463.1321.
N-(3-(2-Cyanophenyl)-6-nitro-4H-chromen-2-yl)-N-methylme-
thanesulfonamide (3e). Following general procedure 5, the product
was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 3e; white solid; mp 99−101 °C;
1
4-Methyl-N-(6-nitro-3-(thiophen-3-yl)-4H-chromen-2-yl)-N-phe-
nylbenzenesulfonamide (3k). Following general procedure 5, the
product was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 3k; yellow solid, mp 200−202
°C, yield: 94% (71.1 mg); 1H NMR (400 MHz, CDCl3): δ 8.11−8.05
(m, 2H), 7.57−7.52 (m, 3H), 7.48 (dd, J = 3.0, 1.4 Hz, 1H), 7.37 (dd,
J = 5.1, 3.0 Hz, 1H), 7.27 (s, 1H), 7.23−7.17 (m, 3H), 7.13−7.10 (m,
2H), 6.86 (d, J = 8.8 Hz, 1H), 3.91 (s, 2H), 2.45 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 155.7, 144.4, 143.9, 140.6, 139.0, 136.2,
135.6, 129.3, 129.2, 128.63, 128.2, 127.4, 127.0, 125.6, 125.0, 123.9,
123.7, 120.8, 116.4, 108.5, 30.6, 21.8; HRMS (APCI−orbitrap) m/z:
[M + H]+ calcd for C26H21N2O5S2, 505.0886; found, 505.0883.
N-(2-Cyanoethyl)-4-methyl-N-(6-nitro-3-phenyl-4H-chromen-2-
yl)benzenesulfonamide (3l). Following general procedure 5, the
product was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 3l; white solid; mp 163−165 °C;
yield: 95% (67.7 mg); 1H NMR (400 MHz, CDCl3): δ 8.08−8.00 (m,
2H), 7.74 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 7.0 Hz, 2H), 7.45−7.32
(m, 5H), 6.84−6.76 (m, 1H), 3.95 (s, 2H), 3.40 (t, J = 7.2 Hz, 2H),
2.48 (s, 3H), 2.3−2.20 (t, J = 7.2 Hz, 2H); 13C{1H} NMR (100 MHz,
CDCl3): δ 155.7, 145.0, 144.0, 139.1, 135.9, 135.6, 129.9, 129.0,
128.6, 128.4, 127.8, 124.9, 124.0, 120.7, 117.0, 116.5, 114.4, 45.1,
31.4, 21.8, 17.5; HRMS (APCI−orbitrap) m/z: [M + H]+ calcd for
C25H22N3O5S, 476.1275; found, 476.1273.
yield: 74% (42.7 mg); H NMR (400 MHz, CDCl3): δ 8.11 (dd, J =
9.0, 2.7 Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H),
7.66 (td, J = 7.7, 1.2 Hz, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.45 (td, J =
7.7, 1.1 Hz, 1H), 7.05 (d, J = 9.0 Hz, 1H), 3.92 (s, 2H), 3.10 (s, 3H),
2.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.7, 144.2,
142.3, 140.7, 133.5, 133.1, 130.7, 128.7, 124.9, 124.2, 120.3, 118.2,
117.1, 111.6, 109.8, 38.9, 36.0, 31.0; HRMS (APCI−orbitrap) m/z:
[M + H]+ calcd for C18H16N3O5S, 386.0605; found, 386.0604.
N-(3-(4-Chlorophenyl)-6-nitro-4H-chromen-2-yl)-N-phenylme-
thanesulfonamide (3f). Following general procedure 5, the product
was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 3f; pale yellow solid; mp 212−
214 °C; yield: 81% (55.4 mg); 1H NMR (400 MHz, CDCl3): δ 8.12
(dd, J = 9.0, 2.7 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.35−7.25 (m,
7H), 7.15−7.11 (m, 3H), 3.83 (s, 2H), 3.10 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 155.8, 144.1, 141.4, 138.9, 134.3, 134.0, 129.6,
129.4, 128.8, 128.5, 126.6, 125.0, 124.1, 120.8, 116.9, 111.9, 40.4,
31.2; HRMS (APCI−orbitrap) m/z: [M + H]+ calcd for
C22H18ClN2O5S, 457.0620; found, 457.0617.
N-(6-Nitro-4H-chromen-2-yl)-N-phenylmethanesulfonamide
(3g). Following general procedure 5, the product was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 3/1 to petroleum ether/ethyl acetate = 2/1) to afford the
desired product 3g; pale yellow solid; mp 114−116 °C; yield: 72%
(37.4 mg); 1H NMR (500 MHz, CDCl3): δ 8.08 (dd, J = 8.9, 2.5 Hz,
1H), 8.01 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.43 (t, J = 7.6
Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 5.33 (t, J =
3.8 Hz, 1H), 3.65 (d, J = 3.8 Hz, 2H), 3.17 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 156.3, 144.1, 144.0, 139.2, 129.7, 128.5, 126.9,
125.1, 123.8, 120.1, 117.2, 101.0, 40.3, 25.4; HRMS (APCI−orbitrap)
m/z: [M + H]+ calcd for C16H15N2O5S, 347.0696; found, 347.0694.
N-(3-(tert-Butyl)-6-nitro-4H-chromen-2-yl)-N-phenylmethane-
sulfonamide (3h). Following general procedure 5, the product was
purified by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate = 1/1) to
afford the desired product 3h; white solid; mp 144−146 °C; yield:
86% (52.0 mg); 1H NMR (400 MHz, CDCl3): δ 8.11−8.05 (m, 2H),
7.58 (d, J = 7.7 Hz, 2H), 7.37 (t, J = 7.9 Hz, 2H), 7.28−7.22 (s, 1H),
6.99 (d, J = 9.3 Hz, 1H), 3.64 (q, J = 24.8 Hz, 2H), 3.06 (s, 3H), 1.18
(s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 156.6, 143.9, 140.5,
138.4, 129.7, 126.6, 124.7, 123.9, 122.8, 122.0, 121.0, 115.8, 40.0,
34.9, 29.4, 27.9; HRMS (APCI−orbitrap) m/z: [M + H]+ calcd for
C20H23N2O5S, 403.1322; found, 403.1321.
t. ert-Butyl (6-Nitro-3-phenyl-4H-chromen-2-yl)(phenyl)-
carbamate (3m). Following general procedure 5, the product was
purified by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate = 1/1) to
afford the desired product 3m; yellow liquid; yield: 95% (63.1 mg);
1H NMR (400 MHz, CDCl3): δ 8.01−8.03 (m, 2H), 7.31−7.17 (m,
7H), 7.14−7.03 (m, 4H), 3.88 (s, 2H), 1.37 (s, 9H); 13C{1H} NMR
(100 MHz, CDCl3): δ 156.8, 152.9, 143.8, 142.1, 140.2, 136.8, 128.7,
128.6, 127.9, 127.0, 126.0, 124.7, 124.7, 123.9, 121.4, 117.0, 82.1,
30.7, 28.1; HRMS (ESI) (m/z): [M−C5H8O2 + H]+ calcd for
C21H17N2O3, 345.1234; found, 345.1231.
3-(6-Nitro-3-phenyl-4H-chromen-2-yl)oxazolidin-2-one (3n).
Following general procedure 5, the product was purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate =
2/1 to petroleum ether/ethyl acetate = 1/1) to afford the desired
1
product 3n; pale yellow solid, mp 100−102 °C, 59% (29.9 mg); H
NMR (400 MHz, CDCl3): δ 8.09−8.01 (m, 2H), 7.40−7.32 (m, 5H),
7.04 (d, J = 8.9 Hz, 1H), 4.30 (dd, J = 8.7, 7.3 Hz, 2H), 3.91 (s, 2H),
H
https://dx.doi.org/10.1021/acs.joc.0c01258
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
3.66 (dd, J = 8.7, 7.3 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ
156.2, 156.0, 143.8, 137.5, 136.1, 129.0, 128.3, 127.1, 124.0, 120.7,
117.1, 111.0, 62.8, 44.9, 30.7; HRMS (APCI−orbitrap) m/z: [M +
H]+ calcd for C18H15N2O5, 339.0976; found, 339.0976.
yellow liquid; yield: 37% (11.8 mg); 1H NMR (400 MHz, CDCl3): δ
7.50−7.46 (m, 3H), 7.31−7.27 (m, 2H), 3.45 (s, 3H), 1.95 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 171.7, 136.1, 130.3, 130.2,
129.8, 42.2, 25.2.
(E)-N-(1-Bromo-2-phenylvinyl)-N-methylmethanesulfonamide
(4a).11h Following general procedure 5, the product was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to afford the
desired product 4a; white solid; mp 89−91 °C; yield: 87% (38.0 mg);
1H NMR (400 MHz, CDCl3): δ 7.58−7.54 (m, 2H), 7.38−7.30 (m,
3,3-Dimethyl-N-(methylsulfonyl)-N-phenylbutanamide (4h). Fol-
lowing general procedure 5, the product was purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate =
4/1 to petroleum ether/ethyl acetate = 3/1) to afford the desired
product 4h; colorless oil; yield: 31% (12.5 mg); 1H NMR (400 MHz,
CDCl3): δ 7.51−7.44 (m, 3H), 7.29−7.22 (s, 2H), 3.44 (s, 3H), 2.00
(s, 2H), 0.98 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 173.4,
136.0, 130.09, 130.06, 130.0, 48.1, 42.0, 31.8, 29.6; HRMS (APCI−
orbitrap) m/z: [M + H]+ calcd for C13H20NO3S, 270.1158; found,
270.1157.
(E)-N-(1-Bromo-3,3-dimethylbut-1-en-1-yl)-4-nitro-N-phenyl-
benzenesulfonamide (4i). Following general procedure 5, the
product was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 6/1 to petroleum ether/ethyl acetate
= 4/1) to afford the desired product 4i; white solid; mp 139−141 °C;
yield: 58% (38.1 mg);1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.9
Hz, 2H), 7.88 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.40−
7.27 (m, 3H), 6.16 (s, 1H), 1.16 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ 150.9, 150.5, 143.0, 140.0, 130.6, 129.5, 127.9, 124.4,
123.7, 114.5, 36.5, 29.6; HRMS (ESI) m/z: [M + H2O-H]− calcd for
C18H20N2O5BrS, 455.0282; found, 455.0272.
3H), 6.88 (s, 1H), 3.07 (s, 3H), 2.98 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 137.4, 133.6, 129.3, 128.9, 128.8, 120.6, 37.5, 36.6.
(Z)-N-(1-Bromo-2-phenylvinyl)-N-phenylmethanesulfonamide
(4b).12 Following general procedure 5, the product was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to afford the
desired product 4b; white solid, mp 135−136 °C, 90% (47.4 mg); Rf
= 0.5 (20% EtOAc/petroleum ether);1H NMR (500 MHz, CDCl3): δ
7.60−55 (m, 4H), 7.38−7.31 (m, 5H), 7.31−7.26 (m, 1H), 7.08 (s,
1H), 3.16 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 138.9,
138.6, 133.4, 129.5, 129.2, 128.7, 128.6, 127.4, 123.7, 118.0, 39.1.
(E)-N-(1-Bromo-2-(4-methoxyphenyl)vinyl)-N-phenylmethane-
sulfonamide (4c). Following general procedure 5, the product was
purified by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to
afford the desired product 4c; colorless liquid; yield: 90% (51.4 mg);
1H NMR (400 MHz, CDCl3): δ 7.61−7.57 (m, 2H), 7.56−7.51 (m,
(E)-N-(1-Bromo-2-cyclopropylvinyl)-4-methyl-N-phenylbenzene-
sulfonamide (4j). Following general procedure 5, the product was
purified by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to
afford the desired product 4j; white solid; mp 110−112 °C; yield:
2H), 7.38−7.32 (m, 2H), 7.29−7.26 (m, 1H), 6.98 (s, 1H), 6.87−
6.83 (m, 2H), 3.78 (s, 3H), 3.16 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 160.3, 139.0, 138.3, 130.4, 129.7, 127.3, 126.0, 123.4,
115.5, 114.2, 55.4, 39.2; HRMS (APCI−orbitrap) m/z: [M + H]+
calcd for C16H17BrNO3S, 382.0107; found, 382.0105.
1
86% (52.1 mg); Rf = 0.6 (30% EtOAc/petroleum ether); H NMR
(500 MHz, CDCl3): δ 7.77−7.74 (m, 2H), 7.39−7.32 (m, 5H),
7.30−7.26 (m, 2H), 5.48 (d, J = 10.1 Hz, 1H), 2.44 (s, 3H), 2.05−
1.96 (m, 1H), 0.96−0.82 (m, 2H), 0.62−0.46 (m, 2H). 13C{1H}
NMR (125 MHz, CDCl3): δ 145.1, 144.3, 139.2, 135.9, 129.3, 129.2,
128.8, 128.2, 127.4, 114.3, 21.6, 12.9, 7.2; HRMS (ESI) m/z: [M +
Na]+ calcd for C16H16BrNO3SNa, 403.9926; found, 403.9927.
(E)-N-(1-Bromo-2-(thiophen-3-yl)vinyl)-4-methyl-N-phenylben-
zenesulfonamide (4k). Following general procedure 5, the product
was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 6/1 to petroleum ether/ethyl acetate
= 4/1) to afford the desired product 4k; white solid, mp 154−156 °C,
(E)-N-(1-Bromo-2-(4-(trifluoromethyl)phenyl)vinyl)-N-phenylme-
thanesulfonamide (4d). Following general procedure 5, the product
was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 6/1 to petroleum ether/ethyl acetate
= 4/1) to afford the desired product 4d; white solid; mp 142−144
°C; yield: 74% (46.5 mg); 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J
= 8.2 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.35
(t, J = 8.0 Hz, 2H), 7.29 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 3.15 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 138.8, 137.1, 136.8, 130.8
(q, J = 32.6 Hz), 129.8, 128.9, 127.8, 125.8 (q, J = 3.8 Hz), 123.9 (q, J
= 271.0 Hz), 123.8, 120.4, 39.1; 19F NMR (376 MHz, CDCl3): δ
−62.71 (s, 3F); HRMS (APCI−orbitrap) m/z: [M + H]+ calcd for
C16H14BrF3NO2S, 419.9875; found, 419.9871.
1
yield: 91% (62.1 mg); Rf = 0.7 (20% EtOAc/petroleum ether); H
NMR (500 MHz, CDCl3): δ 7.76 (d, J = 8.2 Hz, 2H), 7.71−7.68 (m,
1H), 7.61 (d, J = 4.4 Hz, 1H), 7.44−7.38 (m, 2H), 7.35−7.32 (m,
1H), 7.31−7.24 (m, 5H), 7.06 (s, 1H), 2.44 (s, 3H). 13C{1H} NMR
(125 MHz, CDCl3): δ 144.7, 139.1, 135.0, 134.9, 133.0, 129.30,
129.27, 129.2, 128.0, 127.5, 127.0, 126.0, 125.8, 117.6, 21.7; HRMS
(ESI) m/z: [M + Na]+ calcd for C19H16BrNO2S2Na, 455.9698; found,
455.9695.
(E)-N-(1-Bromo-2-(2-cyanophenyl)vinyl)-N-methylmethanesul-
fonamide (4e). Following general procedure 5, the product was
purified by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to
afford the desired product 4e; colorless liquid; yield: 59% (27.8 mg);
1H NMR (400 MHz, CDCl3): δ 8.00−7.93 (m, 2H), 7.67−7.54 (m,
(E)-N-(1-Bromo-2-phenylvinyl)-N-(2-cyanoethyl)-4-methylbenze-
nesulfonamide (4l). Following the general procedure, the product
was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 6/1 to petroleum ether/ethyl acetate
= 4/1) to afford the desired product 4l; white solid; mp 115−117 °C;
2H), 7.44−7.35 (m, 1H), 7.22 (s, 1H), 3.06 (s, 3H), 2.98 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 136.9, 133.3, 133.1, 132.8,
129.1, 128.6, 125.0, 117.6, 112.1, 37.3, 37.0; HRMS (APCI−orbitrap)
m/z: [M + H]+ calcd for C11H12BrN2O2S, 314.9797; found, 314.9796.
(E)-N-(1-Bromo-2-(4-chlorophenyl)vinyl)-N-phenylmethanesul-
fonamide (4f). Following general procedure 5, the product was
purified by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to
afford the desired product 4f; white solid; mp 119−121 °C; yield:
1
yield: 88% (53.3 mg); H NMR (400 MHz, CDCl3): δ 7.82 (d, J =
8.2 Hz, 2H), 7.71−7.63 (m, 2H), 7.42−7.30 (m, 5H), 7.05 (s, 1H),
3.98−3.85 (m, 1H), 3.3−3.15 (m, 1H), 2.65−2.45 (m, 2H), 2.45 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 145.6, 140.7, 133.5,
133.1, 130.0, 129.8, 129.2, 117.7, 116.7, 45.5, 21.8, 16.8; HRMS
(APCI−orbitrap) m/z: [M + H]+ calcd for C18H18BrN2O2S,
405.0267; found, 405.0264.
1
73% (44.6 mg); Rf = 0.5 (20% EtOAc/petroleum ether); H NMR
(500 MHz, CDCl3): δ 7.57−7.48 (m, 4H), 7.40−7.34 (m, 2H),
7.33−7.28 (m, 3H), 7.02 (s, 1H), 3.16 (s, 3H). 13C{1H} NMR (125
MHz, CDCl3): δ 138.8, 137.3, 135.0, 131.8, 129.8, 129.7, 129.0,
127.6, 123.6, 118.5, 39.0. HRMS (ESI) m/z: [M + Na]+ calcd for
C15H13BrClNO2SNa, 407.9431; found, 407.9434.
(E)-tert-Butyl (1-Bromo-2-phenylvinyl)(phenyl)carbamate (4m).
Following general procedure 5, the product was purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate =
6/1 to petroleum ether/ethyl acetate = 4/1) to afford the desired
N-(Methylsulfonyl)-N-phenylacetamide (4g).17 Following general
procedure 5, the product was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 6/1 to petroleum
ether/ethyl acetate = 4/1) to afford the desired product 4g; pale
1
product 4m; yellow liquid; yield: 93% (52.0 mg); H NMR (400
MHz, CDCl3): δ 7.43−7.21 (m, 10H), 6.88 (s, 1H), 1.35 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3): δ 151.7, 139.1, 134.6, 133.3,
I
https://dx.doi.org/10.1021/acs.joc.0c01258
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
129.0, 128.7, 127.7, 126.5, 124.6, 121.0, 82.8, 28.0; HRMS (ESI) m/z:
[M−C5H8O2 + H]+ calcd for C14H13BrN, 274.0226; found, 274.0226.
(E)-3-(1-Bromo-2-phenylvinyl)oxazolidin-2-one (4n). Following
general procedure 5, the product was purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate
= 6/1 to petroleum ether/ethyl acetate = 4/1) to afford the desired
product 4n; white solid, mp 103−105 °C, 47% (20.4 mg); Rf = 0.3
(20% EtOAc/petroleum ether); 1H NMR (500 MHz, CDCl3): δ
7.37−7.30 (m, 5H), 6.96 (s, 1H), 4.45 (t, J = 8.0 Hz, 3H), 3.74 (t, J =
8.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 155.3, 135.5,
133.7, 128.84, 128.83, 127.9, 116.4, 62.7, 45.2; HRMS (ESI) m/z: [M
+ Na]+ calcd for C11H10BrNO2Na, 289.9787; found, 289.9793.
N-Methyl-N-(7-nitro-3-phenyl-4H-chromen-2-yl)-
methanesulfonamide (5a). Following general procedure 5, the
product was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 5a; yellow solid; mp 148−150
°C; yield: 93% (50.2 mg); 1H NMR (400 MHz, CDCl3): δ 7.91 (dd, J
= 8.4, 2.2 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.45−7.36 (m, 4H),
7.34−7.29 (m, 1H), 7.27−7.23 (s, 1H), 3.90 (s, 2H), 3.01 (s, 3H),
2.90 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 151.6, 147.6,
141.5, 136.3, 129.4, 128.8, 128.1, 127.6, 127.5, 119.0, 111.6, 110.5,
39.8, 36.4, 31.2; HRMS (APCI−orbitrap) m/z: [M + H]+ calcd for
C17H17N2O5S, 361.0853; found, 361.0851.
N-Methyl-N-(5-nitro-3-phenyl-4H-chromen-2-yl)-
methanesulfonamide (5b). Following general procedure 5, the
product was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 5b; yellow solid; mp 144−146
°C; yield: 94% (50.8 mg); 1H NMR (400 MHz, CDCl3): δ 7.77 (dd, J
= 8.2, 1.3 Hz, 1H), 7.45−7.35 (m, 4H), 7.34−7.28 (m, 2H), 7.22−
7.19 (m, 1H), 4.13 (s, 2H), 3.01 (s, 3H), 2.80 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 152.6, 148.4, 140.8, 136.4, 128.8, 128.1, 128.0,
127.7, 121.5, 120.4, 116.6, 110.6, 39.8, 36.4, 29.5; HRMS (APCI−
orbitrap) m/z: [M + H]+ calcd for C17H17N2O5S, 361.0853; found,
361.0851.
N-(6-(tert-Butyl)-8-formyl-3-phenyl-4H-chromen-2-yl)-N-methyl-
methanesulfonamide (5f). Following general procedure 5, the
product was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 5f; yellow liquid; yield: 51%
(30.5 mg); 1H NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 7.65−
7.55 (m, 2H), 7.45−7.25 (m, 5H), 3.84 (s, 2H), 3.09 (s, 3H), 2.96 (s,
3H), 1.26 (s, 9H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 189.7,
150.7, 146.9, 141.6, 137.4, 132.9, 128.8, 128.0, 124.6, 123.1, 121.6,
111.7, 39.3, 36.6, 34.7, 31.5, 30.4; HRMS (APCI−orbitrap) m/z: [M
+ H]+ calcd for C22H26NO4S, 400.1577; found, 400.1576.
N-(6-Bromo-8-formyl-3-phenyl-4H-chromen-2-yl)-N-methylme-
thanesulfonamide (5g). Following general procedure 5, the product
was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 5g; yellow liquid; yield 73%
(46.1 mg); 1H NMR (400 MHz, CDCl3): δ 10.27 (s, 1H), 7.79 (d, J
= 2.4 Hz, 1H), 7.46−7.44 (m, 1H), 7.42−7.39 (m, 4H), 7.34−7.30
(m, 1H), 3.83 (s, 2H), 3.03 (s, 3H), 2.87 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 187.1, 151.8, 141.3, 137.2, 136.3, 131.2, 128.8,
128.2, 127.5, 125.0, 123.7, 116.6, 111.7, 39.5, 36.4, 30.6; HRMS
(APCI−orbitrap) m/z: [M + H]+ calcd for C18H17BrNO4S, 422.0056;
found, 422.0057.
N-(6-Acetyl-3-phenyl-4H-chromen-2-yl)-N-methylmethanesulfo-
namide (5h). Following general procedure 5, the product was purified
by column chromatography on silica gel (eluent: petroleum ether/
ethyl acetate = 2/1 to petroleum ether/ethyl acetate = 1/1) to afford
the desired product 5h; yellow liquid; yield 73% (39.1 mg); 1H NMR
(400 MHz, DMSO-d6): δ 7.83−7.89 (m, 2H), 7.47−7.43 (m, 2H),
7.40−7.35 (m, 2H), 7.31−7.26 (m, 1H), 7.15 (d, J = 9.1 Hz, 1H),
3.85 (s, 2H), 2.99 (s, 3H), 2.91 (s, 3H), 2.51 (s, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6): δ 197.0, 154.9, 141.6, 137.3, 133.4, 130.1,
129.0, 128.9, 128.0, 127.9, 120.5, 116.5, 111.1, 39.7, 36.6, 30.3, 27.1;
HRMS (APCI−orbitrap) m/z: [M + H]+ calcd for C19H20NO4S,
358.1108; found, 358.1106.
N-(8-Formyl-6-nitro-3-phenyl-4H-chromen-2-yl)-N-methylme-
thanesulfonamide (5i). Following general procedure 5, the product
was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 5i; pale yellow solid; mp 120−
122 °C; yield: 79% (46.0 mg); 1H NMR (400 MHz, CDCl3): δ 10.34
(s, 1H), 8.57 (d, J = 2.8 Hz, 1H), 8.23 (dt, J = 2.7, 1.0 Hz, 1H), 7.45−
7.41 (m, 4H), 7.39−7.34 (m, 1H), 3.97 (s, 2H), 3.05 (s, 3H), 2.86 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 186.5, 156.7, 143.6,
141.2, 135.6, 129.2, 129.0, 128.6, 127.4, 124.6, 123.87, 123.1, 112.1,
39.6, 36.4, 30.8; HRMS (APCI−orbitrap) m/z: [M + H]+ calcd for
C18H17N2O6S, 389.0802; found, 389.0800.
N-(7-Cyano-3-phenyl-4H-chromen-2-yl)-N-methylmethanesulfo-
namide (5c). Following general procedure 5, the product was purified
by column chromatography on silica gel (eluent: petroleum ether/
ethyl acetate = 2/1 to petroleum ether/ethyl acetate = 1/1) to afford
the desired product 2w; white solid; mp 148−150 °C; yield: 58%
1
(29.6 mg); H NMR (400 MHz, CDCl3): δ 7.43−7.29 (m, 6H),
7.23−7.17 (m, 2H), 3.86 (s, 2H), 3.00 (s, 3H), 2.86 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 151.5, 141.4, 136.5, 129.7, 128.8, 128.1,
127.7, 127.5, 125.8, 119.7, 118.2, 111.6, 110.7, 39.7, 36.4, 31.2;
HRMS (APCI−orbitrap) m/z: [M + H]+ calcd for C18H17N2O3S,
341.0954; found, 341.0956.
N-(6-Bromo-3-phenyl-4H-chromen-2-yl)-N-methylmethanesul-
fonamide (5d). Following general procedure 5, the product was
purified by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate = 1/1) to
afford the desired product 5d; colorless liquid; yield: 54% (31.8 mg);
1H NMR [400 MHz, dimethyl sulfoxide- d6 (DMSO-d6)]: δ 7.46−
7.33 (m, 6H), 7.30−7.23 (m, 1H), 7.02 (d, J = 8.5 Hz, 1H), 3.78 (s,
2H), 2.98 (s, 3H), 2.88 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-
d6): δ 150.6, 141.8, 137.4, 131.7, 131.0, 128.8, 127.9, 127.9, 123.1,
118.6, 115.9, 39.7, 36.6, 30.2; HRMS (APCI−orbitrap) m/z: [M +
H]+ calcd for C17H17BrNO3S, 394.0107; found, 394.0105.
(E)-N-(1-Chloro-2-phenylvinyl)-N-methylmethanesulfonamide
(6). Following general procedure 5, the product was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to afford the
desired product 6; white oil; yield: 71% (28.4 mg); Rf = 0.8 (30%
EtOAc/petroleum ether); 1H NMR (500 MHz, CDCl3): δ 7.59−7.56
(m, 2H), 7.39−7.29 (m, 3H), 6.70 (s, 1H), 3.15 (s, 3H), 3.02 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3): δ 132.8, 132.5, 129.13, 129.09,
128.8, 128.7, 38.1, 35.8; HRMS (ESI) m/z: [M + Na]+ calcd for
C10H12ClNO2SNa, 268.0169; found, 268.0170.
2-(Bromomethyl)-4-nitrophenol (1a′). The product was purified
by column chromatography on silica gel (eluent: petroleum ether/
ethyl acetate = 6/1 to petroleum ether/ethyl acetate = 4/1) to afford
the desired product 1a′; 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J =
2.7 Hz, 1H), 8.14 (d, J = 2.7 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 6.92
(d, J = 8.9 Hz, 0.7H), 4.54 (s, 2H).
N-(8-Formyl-6-methyl-3-phenyl-4H-chromen-2-yl)-N-methylme-
thanesulfonamide (5e). Following general procedure 5, the product
was purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 2/1 to petroleum ether/ethyl acetate
= 1/1) to afford the desired product 5e; yellow solid; mp 64−66 °C;
yield: 45% (24.1 mg); 1H NMR (400 MHz, CDCl3): δ 10.31 (s, 1H),
7.48−7.37 (m, 5H), 7.33−7.28 (m, 1H), 7.15 (s, 1H), 3.81 (s, 2H),
3.02 (s, 3H), 2.95 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 188.8, 150.7, 141.4, 136.8, 135.6, 133.6, 129.1, 128.7,
127.9, 127.6, 123.5, 121.0, 111.6, 39.4, 36.5, 30.8, 20.6; HRMS
(APCI−orbitrap) m/z: [M + H]+ calcd for C19H20NO4S, 358.1108;
found, 358.1107.
(E)-N-(1-Bromo-2-phenylvinyl)-N-methylmethanesulfonamide
(4a′). The product was purified by column chromatography on silica
gel (eluent: petroleum ether/ethyl acetate = 6/1 to petroleum ether/
ethyl acetate = 4/1) to afford the desired product 4a′; yield: 85%
1
(37.1 mg); H NMR (400 MHz, CDCl3): δ 7.58−7.53 (m, 2H),
7.38−7.31 (m, 3H), 6.89 (s, 0.72H), 3.08 (s, 3H), 2.99 (s, 3H).
J
https://dx.doi.org/10.1021/acs.joc.0c01258
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Activity Relationship and Molecular Mechanisms of Ethyl 2-Amino-4-
(2-ethoxy-2-oxoethyl)-6-phenyl-4H-chromene-3-carboxylate (sHA
14-1) and Its Analogues. J. Med. Chem. 2009, 52, 5937−5949.
(e) Wang, J.-L.; Liu, D.; Zhang, Z.-J.; Shan, S.; Han, X.; Srinivasula, S.
M.; Croce, C. M.; Alnemri, E. S.; Huang, Z. Structure-based discovery
of an organic compound that binds Bcl-2 protein and induces
apoptosis of tumor cells. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 7124−
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01258.
■
sı
NMR spectra for all compounds (PDF)
́
7129. (f) Manero, F.; Gautier, F.; Gallenne, T.; Cauquil, N.; Gree, D.;
AUTHOR INFORMATION
Corresponding Authors
■
́
Cartron, P.-F.; Geneste, O.; Gree, R.; Vallette, F. M.; Juin, P. The
Small Organic Compound HA14-1 Prevents Bcl-2 Interaction with
Bax to Sensitize Malignant Glioma Cells to Induction of Cell Death.
Cancer Res. 2006, 66, 2757−2764.
Ping Chen − Key Laboratory of Marine Drugs, Chinese Ministry
of Education, School of Medicine and Pharmacy, Ocean
University of China, Qingdao 266003, P. R. China;
Email: chenping8315@126.com
Yu Tang − Key Laboratory of Marine Drugs, Chinese Ministry of
Education, School of Medicine and Pharmacy, Ocean University
of China, Qingdao 266003, P. R. China; Laboratory for
Marine Drugs and Bioproducts, Qingdao National Laboratory
for Marine Science and Technology, Qingdao 266237, P. R.
China; orcid.org/0000-0001-8224-4639; Email: tangyu@
ouc.edu.cn
(2) (a) Kolla, S. R.; Lee, Y. R. Efficient one-pot synthesis of b-
phosphono malonates and 2-amino-4H-chromen-4-ylphosphonate
derivatives by ethylenediamine diacetate-catalyzed three-component
reactions. Tetrahedron 2012, 68, 226−237. (b) Reddy, C.;
́
Vijaykumar, J.; Gree, R. Tris(pentafluorophenyl)borane-Catalyzed
Alkylation of 1,3-Dicarbonyl Compounds with Benzylic Alcohols:
Access to Oxygenated Heterocycles. Synthesis 2010, 3715−3723.
(c) Fan, J.; Wang, Z. Facile Construction of Functionalized 4H-
chromene via Tandem Benzylation and Cyclization. Chem. Commun.
2008, 42, 5381−5383. (d) Safari, J.; Javadian, L. Ultrasound Assisted
the Green Synthesis of 2-amino-4H-chromene Derivatives Catalyzed
by Fe3O4-functionalized Nanoparticles with Chitosan as a Novel and
Reusable Magnetic Catalyst. Ultrason. Sonochem. 2015, 22, 341−348.
(e) Sobhani, S.; Honarmand, M. Silica-Bonded 2-Hydroxyethylam-
monium Acetate as an Efficient and Recyclable Catalyst for the
Synthesis of 2-Amino-4H-chromen-4-yl Phosphonates and b-
Phosphonomalonates. Catal. Lett. 2013, 143, 476−485.
Authors
Hao Wen − Key Laboratory of Marine Drugs, Chinese Ministry
of Education, School of Medicine and Pharmacy, Ocean
University of China, Qingdao 266003, P. R. China
Weibo Yan − Key Laboratory of Marine Drugs, Chinese Ministry
of Education, School of Medicine and Pharmacy, Ocean
University of China, Qingdao 266003, P. R. China
Yu Li − Key Laboratory of Marine Drugs, Chinese Ministry of
Education, School of Medicine and Pharmacy, Ocean University
of China, Qingdao 266003, P. R. China
(3) For selected recent reviews on ynamides, see: (a) Evano, G.;
Coste, A.; Jouvin, K. Ynamides: Versatile Tools in Organic Synthesis.
Angew. Chem., Int. Ed. 2010, 49, 2840−2859. (b) Evano, G.;
Theunissen, C.; Lecomte, M. Ynamides: Powerful and Versatile
Reagents for Chemical Synthesis. Aldrichim Acta 2015, 48, 59−70.
(c) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang,
Y.; Hsung, R. P. Ynamides: A Modern Functional Group for the New
Millennium. Chem. Rev. 2010, 110, 5064−5106. (d) Wang, X.-N.;
Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B. L.; Hsung,
R. P. Ynamides in Ring Forming Transformations. Acc. Chem. Res.
2014, 47, 560−578. (e) Dodd, R. H.; Cariou, K. Ketenimines
Generated from Ynamides: Versatile Building Blocks for Nitrogen-
Containing Scaffolds. Chem.Eur. J. 2018, 24, 2297−2304. (f) Pan,
F.; Shu, C.; Ye, L.-W. Recent Progress towards Gold-Catalyzed
Synthesis of N-Containing Tricyclic Compounds Based on Ynamides.
Org. Biomol. Chem. 2016, 14, 9456−9465. (g) Zhou, B.; Tan, T.-D.;
Zhu, X.-Q.; Shang, M.; Ye, L.-W. Reversal of Regioselectivity in
Ynamide Chemistry. ACS Catal. 2019, 9, 6393−6406.
(4) (a) Zhang, J.; Zhang, Q.; Xia, B.; Wu, J.; Wang, X.-N.; Chang, J.
Metal-Free [2+2+2] Cycloaddition of Ynamides with Nitriles to
Construct 2,4-Diaminopyridines. Org. Lett. 2016, 18, 3390−3393.
(b) Wang, Y.; Song, L.-J.; Zhang, X.; Sun, J. Metal-Free [2+2+2]
Cycloaddition of Ynamides and Nitriles: Mild and Regioselective
Synthesis of Fully Substituted Pyridines. Angew. Chem., Int. Ed. 2016,
55, 9704−9708. (c) Xie, L.-G.; Shaaban, S.; Chen, X.; Maulide, N.
Metal-Free Synthesis of Highly Substituted Pyridines by Formal
[2+2+2] Cycloaddition under Mild Conditions. Angew. Chem., Int. Ed.
2016, 55, 12864−12867. (d) Garcia, P.; Evanno, Y.; George, P.;
Sevrin, M.; Ricci, G.; Malacria, M.; Aubert, C.; Gandon, V.
Regioselective Cobalt-Catalyzed Formation of Bicyclic 3- and 4-
Aminopyridines. Org. Lett. 2011, 13, 2030−2033. (e) Karad, S. N.;
Liu, R.-S. Regiocontrolled Gold-Catalyzed [2+2+2] Cycloadditions of
Ynamides with Two Discrete Nitriles to Construct 4-Amino-
pyrimidine Cores. Angew. Chem., Int. Ed. 2014, 53, 9072−9076.
(f) Chen, Y.-L.; Sharma, P.; Liu, R.-S. Sulfonamides-directed Gold-
catalyzed [2+2+2]-Cycloadditions of Nitriles with Two Discrete
Ynamides to Construct 2,4-Diaminopyridine cores. Chem. Commun.
2016, 52, 3187−3190. (g) Xie, L.-G.; Niyomchon, S.; Mota, A. J.;
Gonzalez, L.; Maulide, N. Metal-free intermolecular formal cyclo-
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01258
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21772181) and the NSFC-Shandong Joint Fund for Marine
Science Research Centers (U1606403) for financial support.
The Fundamental Research Funds for the Central Universities
(201612013) and the Qingdao Scientific and Technological
Innovation Center for Marine Biomedicine Development grant
(2017-CXZX01-1-1) for financial support are also gratefully
acknowledged.
REFERENCES
■
(1) (a) Albiston, A. L.; DiWakarla, S.; Fernando, R. N.; Mountford,
S. J.; Yeatman, H. R.; Morgan, B.; Pham, V.; Holien, J. K.; Parker, M.
W.; Thompson, P. E.; Chai, S. Y. Identification and Development of
Specific Inhibitors for Insulin-regulated Aminopeptidase as a New
Class of Cognitive Enhancers. Br. J. Pharmacol. 2011, 164, 37−47.
(b) Kasibhatla, S.; Gourdeau, H.; Meerovitch, K.; Drewe, J.; Reddy,
S.; Qiu, L.; Zhang, H.; Bergeron, F.; Bouffard, D.; Yang, Q.; Herich, J.;
Lamothe, S.; Cai, S. X.; Tseng, B. Discovery and Mechanism of Action
of a Novel Series of Apoptosis Inducers with Potential Vascular
Targeting Activity. Mol. Cancer Ther. 2004, 3, 1365−1374. (c) Cai, S.;
Drewe, J.; Kemnitzer, W. Discovery of 4-Aryl-4H-Chromenes as
Potent Apoptosis Inducers Using a Cell- and Caspase-Based Anti-
Cancer Screening Apoptosis Program (ASAP): SAR Studies and the
Identification of Novel Vascular Disrupting Agents. Anti-Cancer Agents
Med. Chem. 2009, 9, 437−456. (d) Das, S. G.; Doshi, J. M.; Tian, D.;
Addo, S. N.; Srinivasan, B.; Hermanson, D. L.; Xing, C. Structure-
K
https://dx.doi.org/10.1021/acs.joc.0c01258
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
additions enable an orthogonal access to nitrogen heterocycles. Nat.
Commun. 2016, 7, 10914.
Regio- and Stereoselective Hydrohalogenation of Ynamide Compo-
nents in 1,3-butadiynes with in Situ Generated HX. Tetrahedron Lett.
2014, 55, 2130−2133. (e) Maity, P.; Klos, M. R.; Kazmaier, U.
Syntheses of α-Stannylated and α-Iodinated Enamides via Molybde-
num-Catalyzed Hydrostannation. Org. Lett. 2013, 15, 6246−6249.
(f) Prabagar, B.; Nayak, S.; Mallick, R. K.; Prasad, R.; Sahoo, A. K.
Triphenylphosphine Promoted Regio and Stereoselective α-Halogen-
ation of Ynamides. Org. Chem. Front. 2016, 3, 110−115. (g) Kim, S.
W.; Um, T.-W.; Shin, S. Brønsted acid-catalyzed α-halogenation of
ynamides from halogenated solvents and pyridine-N-oxides. Chem.
Commun. 2017, 53, 2733−2736. (h) Zeng, X.; Lu, Z.; Liu, S.;
Hammond, G. B.; Xu, B. Triphenylphosphine Promoted Regio and
Stereoselective α-Halogenation of Ynamides. J. Org. Chem. 2017, 82,
13179−13187.
(12) Cao, W.; Chen, P.; Wang, L.; Wen, H.; Liu, Y.; Wang, W.;
Tang, Y. A Highly Regio- and Stereoselective Syntheses of α-Halo
Enamides, Vinyl Thioethers, and Vinyl Ethers with Aqueous
Hydrogen Halide in Two-Phase Systems. Org. Lett. 2018, 20,
4507−4511.
(13) (a) Bai, W.-J.; David, J. G.; Feng, Z.-G.; Weaver, M. G.; Wu, K.-
L.; Pettus, T. R. R. The Domestication of ortho-Quinone Methides.
Acc. Chem. Res. 2014, 47, 3655−3664. (b) Singh, M. S.; Nagaraju, A.;
Anand, N.; Chowdhury, S. Ortho-Quinone methide (o-QM): a
Highly Reactive, Ephemeral and Versatile Intermediate in Organic
Synthesis. RSC Adv. 2014, 4, 55924−55959. (c) Zielke, K.; Waser, M.
Formal (4+1)-Addition of Allenoates to o-Quinone Methides. Org.
Lett. 2018, 20, 768−771. (d) Liang, M.; Zhang, S.; Jia, J.; Tung, C.-
H.; Wang, J.; Xu, Z. Synthesis of Spiroketals by Synergistic Gold and
Scandium Catalysis. Org. Lett. 2017, 19, 2526−2529.
(14) Hamada, T.; Ye, X.; Stahl, S. S. Copper-Catalyzed Aerobic
Oxidative Amidation of Terminal Alkynes: Efficient Synthesis of
Ynamides. J. Am. Chem. Soc. 2008, 130, 833−835.
(15) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.;
Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. A Copper-
Catalyzed C−N Bond Formation Involving sp-Hybridized Carbons. A
Direct Entry to Chiral Ynamides via N-Alkynylation of Amides. J. Am.
Chem. Soc. 2003, 125, 2368−2369.
(16) Nie, X.; Wang, G. Synthesis and Self-Assembling Properties of
Diacetylene-Containing Glycolipids. J. Org. Chem. 2006, 71, 4734−
4741.
(17) Coman, S.; Florea, M.; Parvulescu, V.; David, V.; Medvedovici,
A.; Devos, D.; Jacobs, P.; Poncelet, G.; Grange, P. Metal-triflate ionic
liquid systems immobilized onto mesoporous MS41 materials as new
and efficient catalysts for N-acylation. J. Catal. 2007, 249, 359−369.
(5) (a) Zhu, L.; Yu, Y.; Mao, Z.; Huang, X. Gold-Catalyzed
Intermolecular Nitrene Transfer from 2H-Azirines to Ynamides: A
Direct Approach to Polysubstituted Pyrroles. Org. Lett. 2015, 17, 30−
33. (b) Cao, Z.; Zhu, J.; Liu, L.; Pang, Y.; Tian, L.; Sun, X.; Meng, X.
AgNTf2-catalyzed formal [3+2] cycloaddition of ynamides with
unprotected isoxazol-5-amines: efficient access to functionalized 5-
amino-1H-pyrrole-3-carboxamide derivatives. Beilstein J. Org. Chem.
2019, 15, 2623−2630. (c) Dutta, S.; Mallick, R. K.; Prasad, R.;
Gandon, V.; Sahoo, A. K. Alkyne Reactivity Preferred over Ynamide:
Regioselective Radical Cyclization of Yne-Ynamides. Angew. Chem.,
Int. Ed. 2019, 58, 2289−2294. (d) Chen, C.; Cui, S. Iterative
Assembly of Nitrile Oxides and Ynamides: Synthesis of Isoxazoles and
Pyrroles. J. Org. Chem. 2019, 84, 12157−12164.
(6) (a) Dunetz, J. R.; Danheiser, R. L. Synthesis of Highly
Substituted Indolines and Indoles via Intramolecular [4+2] Cyclo-
addition of Ynamides and Conjugated Enynes. J. Am. Chem. Soc.
2005, 127, 5776−5777. (b) Yao, P.-Y.; Zhang, Y.; Hsung, R. P.; Zhao,
K. A Sequential Metal-Catalyzed C-N Bond Formation in the
Synthesis of 2-Amido-indoles. Org. Lett. 2008, 10, 4275−4278.
̈
(c) Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.; Rottlander, M.;
Skrydstrup, T. Highly Regioselective Au(I)-Catalyzed Hydroamina-
tion of Ynamides and Propiolic Acid Derivatives with Anilines. Org.
Lett. 2009, 11, 4208−4211.
(7) (a) Cao, J.; Xu, Y.; Kong, Y.; Cui, Y.; Hu, Z.; Wang, G.; Deng,
Y.; Lai, G. Synthesis of δ-Carbolines via a Pd-Catalyzed Sequential
Reaction from 2-Iodoanilines and N-Tosyl-enynamines. Org. Lett.
2012, 14, 38−41. (b) Dassonneville, B.; Witulski, B.; Detert, H.
[2+2+2] Cycloadditions of Alkynylynamides − A Total Synthesis of
Perlolyrine and the First Total Synthesis of “Isoperlolyrine”. Eur. J.
Org. Chem. 2011, 2836−2844. (c) Wang, G.; You, X.; Gan, Y.; Liu, Y.
Synthesis of δ- and α-Carbolines via Nickel-Catalyzed [2+2+2]
Cycloaddition of Functionalized Alkyne-Nitriles with Alkynes. Org.
Lett. 2017, 19, 110−113. (d) Wen, H.; Cao, W.; Liu, Y.; Wang, L.;
Chen, P.; Tang, Y. Metal-Free [2+2+2] Cycloaddition of Ynamide-
Nitriles with Ynamides: A Highly Regio- and Chemoselective
Synthesis of δ-Carboline Derivatives. J. Org. Chem. 2018, 83,
13308−13324.
(8) Chen, L.; Yu, L.; Deng, Y.; Zheng, Z.-J.; Xu, Z.; Cao, J.; Xu, L.-
W. C-H Functionalization/C-O Bond Cleavage of Benzyl Silyl Ethers
with Ynamides for the Chemoselective Synthesis of Skeletally Diverse
Compounds. Adv. Synth. Catal. 2016, 358, 480−485.
(9) Yang, Y.; Liu, H.; Peng, C.; Wu, J.; Zhang, J.; Qiao, Y.; Wang, X.-
N.; Chang, J. AlCl3-Catalyzed Annulations of Ynamides Involving a
Torquoselective Process for the Simultaneous Control of Central and
Axial Chirality. Org. Lett. 2016, 18, 5022−5025.
(10) (a) Lander, P. A.; Hegedus, L. S. Asymmetric Synthesis of a-
Amino Acids by Copper-Catalyzed Conjugate Addition of Grignard
Reagents to Optically Active Carbamatoacrylates. J. Am. Chem. Soc.
1994, 116, 8126−8132. (b) Flynn, A. B.; Ogilvie, W. W.
Stereocontrolled Synthesis of Tetrasubstituted Olefins. Chem. Rev.
2007, 107, 4698−4745. (c) Fujino, D.; Yorimitsu, H.; Osuka, A.
Regiocontrolled Palladium-Catalyzed Arylative Cyclizations of
Alkynols. J. Am. Chem. Soc. 2014, 136, 6255−6258. (d) Endo, N.;
Iwasawa, T. Stereo-defined synthesis of differentially all-carbon
tetrasubstituted alkenes derived from (E)-1-bromo-2-iodoalkenes.
Tetrahedron 2017, 73, 5833−5840.
(11) (a) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale, H.;
Frederick, M. O.; Shen, L.; Zificsak, C. A. Highly Stereoselective
Synthesis of Novel r-Haloenamides via a Mild and Efficient
Hydrohalogenation of Ynamides. Org. Lett. 2003, 5, 1547−1550.
(b) Sato, A. H.; Ohashi, K.; Iwasawa, T. Regio- and stereospecific
synthesis of (E)-a-iodoenamide moieties from ynamides through
iodotrimethylsilane-mediated hydroiodation. Tetrahedron Lett. 2013,
54, 1309−1311. (c) Ohashi, K.; Mihara, S.; Sato, A. H.; Ide, M.;
Iwasawa, T. Synthesis of 1-haloethenamides from Ynamide through
Halotrimethylsilane-mediated Hydrohalogenation. Tetrahedron Lett.
2014, 55, 632−635. (d) Ide, M.; Ohashi, K.; Mihara, S.; Iwasawa, T.
L
https://dx.doi.org/10.1021/acs.joc.0c01258
J. Org. Chem. XXXX, XXX, XXX−XXX