Cu(I)-Induced Activation of Furan for Inverse Electron Demand ADAR with Alkenes toward Regioselective Synthesis of Tetrahydropyridine

Article abstract of DOI:10.1021/acs.joc.0c00279

The aza-Diels-Alder reaction of various alkenes and in situ formed 1-aza-1,3-dienes from the reaction of furan/pyrrole/thiophene and PhINTs for the regioselective synthesis of tetrahydropyridine (THP) derivatives was realized. The reaction was catalyzed by TpMe2Cu as a catalyst under very mild reaction conditions. Structurally different alkenes, along with an alkyne, have been utilized as dienophiles to afford a wide range of different THP derivatives up to 70% yield. The potential application of the envisaged method was also investigated by a gram-scale synthesis.

Full text of DOI:10.1021/acs.joc.0c00279

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Article
Cu(I)-Induced Activation of Furan for Inverse Electron Demand
ADAR with Alkenes toward Regioselective Synthesis of
Tetrahydropyridine
Prashant Shukla, Ambika Asati, Smita R. Bhardiya, Manorama Singh, Vijai K. Rai, and Ankita Rai*
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ABSTRACT: The aza-Diels−Alder reaction of various alkenes and in situ formed 1-aza-1,3-dienes from the reaction of furan/
pyrrole/thiophene and PhINTs for the regioselective synthesis of tetrahydropyridine (THP) derivatives was realized. The reaction
was catalyzed by TpMe2Cu as a catalyst under very mild reaction conditions. Structurally different alkenes, along with an alkyne, have
been utilized as dienophiles to afford a wide range of different THP derivatives up to 70% yield. The potential application of the
envisaged method was also investigated by a gram-scale synthesis.
In most of the cases, the synthesis of dihydropyridine
involves the following: multicomponent reactions,7 Morita−
Baylis−Hillman (MBH) reaction/adduct,8 Diels−Alder reac-
tion,5,9,10 noncatalyzed ring transformation,11 and C−H
activation/cyclization cascades.12 Among these, imine-diene
[4+2] cycloaddition9c−e,9 (a formal aza-Diels−Alder reac-
tion)13 is the most efficient, atom/step-economic method for
the construction of a THP ring. Particularly, inverse electron
demand Diels−Alder (DAINV) reactions are highly useful to
install a heteroatom in the product for the synthesis of six-
membered heterocycles. Electron-poor dienes containing a
nitrogen atom, i.e., 1-aza-1,3-dienes, have been well utilized in
the DAINV reaction for the synthesis of tetrahydropyridine.5,9a,b
Recently, furan has been utilized as a diene and dienophile
both; one molecule reacts with PhINTs to afford in situ 1-aza-
1,3-diene for formal [4+2] DAINV with another furan molecule
INTRODUCTION
■
Tetrahydropyridines (THPs) are basic structural motifs
present in various natural products1 viz., Arecoline I, a
nicotinic acid-based alkaloid possessing a stimulating effect,2
and Betanin II, a plant pigment used as a food additive,3 as well
as in synthetic bioactive molecule III with proinflammatory
protein inhibition activity4 and Awaine IV5 (Figure 1). From a
chemical viewpoint, tetrahydropyridines serve as a precursor
for the synthesis of valuable piperidine derivatives and are
important synthetic intermediates in organic syntheses.6
Owing to their chemical and biological interest, numerous
methods are developed for the synthesis of differently
substituted THPs.
for the synthesis of tetrahydropyridine.10a Perez et al. utilized
́
TpBr3Cu(NCMe) as the efficient catalyst for the synthesis of
1,2-dihydropyridine starting from 2-methyl/2,5-dimethylfuran
as a diene and dienophile both.10 However, they failed to
replace furan by other dienophiles except for ethylvinylether
under this condition. Although this pioneer work10 has a
restriction of using furan only as a dienophile, it opens up a
Received: February 18, 2020
Figure 1. Biologically important THP-containing molecules
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new direction to investigate novel dienophile substrates to
avoid the formation of bicyclic intermediates10 and further its
conversion into the target THP molecule. To bridge this
literature gap wherein, furan has been utilized as both dienes
and dienophiles,10 and in continuation of our research
program,14 especially C−H activation15 and nitrene transfer
reactions,16 we envisioned to develop an alternative and facile
synthetic strategy for the construction of a THP skeleton that
would utilize furan as diene for DAINV with a variety of
dienophiles. Herein, furan, thiophene, and pyrrole are utilized
as diene precursors for [4+2] cycloaddition with structurally
different alkenes/alkyne as dienophiles for the efficient
synthesis of THP derivatives (Scheme 1).
afford the product, while a poor yield was obtained using
CuI+bipy and TpBrCu(NCMe). Although the yield was
improved using [Cu(NCMe)4]PF4, TpBrAg, and TpMe3Ag
catalysts, TpMe2Cu was found to be the best in terms of yield
and conversion rate and was used in the present investigation
(Table 1). Furthermore, solvent screening for the present
model reaction was also undertaken (Table 2), and a relatively
Table 2. Solvent Screening for the Reaction of 2,5-Dimethyl
a
Furan, PhINTs, and 4-Methylstyrene
Scheme 1. Aza-Diene-Based [4+2] Cycloaddition for
Tetrahydropyridines
d
e
s. no.
catalyst
solvent
MeCN
toluene
THF
time (h)
yield (%)
1
2
2
3
4
5
6
7
TpMe2Cu
TpMe2Cu
TpMe2Cu
TpMe2Cu
TpMe2Cu
TpMe2Cu
TpMe2Cu
TpMe2Cu
TpMe2Cu
TpMe2Cu
TpMe2Cu
TpMe2Cu
TpMe2Cu
20
20
20
14
20
20
20
20
20
20
7
17
36
28
45
30
25
20
10
trace
45
30
45
35
DCM
Benzene
1,4-dioxane
DMSO
MeOH
H2O
DCM
DCM
DCM
DCM
8
9
RESULTS AND DISCUSSION
■
10
11
12
Our study commenced with catalyst screening using 2,5-
dimethyl furan, PhINTs, and 4-methylstyrene as model
substrates (Table 1). Initially, Cu(I) catalysts were chosen,
b
c
14
14
30
f
13
DCM
a
Table 1. Catalyst Screening for the Reaction of 2,5-
Dimethyl Furan, PhINTs, and 4-Methylstyrene
25.6 mg of catalyst was used throughout except entries 11 and 12.
a
b
c
d
35 mg of catalyst was used. 20 mg of catalyst was used. Stirring
e
time at room temperature. Yield of the isolated and purified product.
f
No reaction observed.
low yield was obtained in polar protic solvents (MeOH, H2O),
as compared to aprotic solvents. This may be due to the
nucleophilic attack of MeOH and H2O to the aza-diene
intermediate formed by furan and PhINTs as well as a decrease
in its stabilization. Among different aprotic solvents, the yield
increases as the polarity of the solvent decreases, but a very
surprising result was obtained with DCM. This is because
PhINTs, which act as a nitrene source in the current synthetic
protocol, are highly soluble in DCM, where, in other aprotic
solvents, it is sparingly soluble, and hence, DCM was finally
chosen as the solvent for the present synthetic protocol. Thus,
the model experiment was successful; initially, the TpMe2Cu
catalyst was dissolved in 2,5-dimethyl furan in 2 mL of DCM,
and a yellow crystal of PhINTs was added to this greenish
solution, which changed into yellowish green and then a dark
green color after a few minutes. After continuing 15 min of
stirring, 4-methylstyrene was added to the solution to produce
the corresponding THP in a 45% yield. There was no effect of
increasing temperature on the yield; instead, the decom-
position of the final product was noticed. However, TsNH2
was also formed as a decomposed product in a negligible
amount. Herein, we report the unprecedented and efficient
construction of a tetrahydropyridine ring using furan/
thiophene/pyrrole, PhINTs, and alkenes/alkyne in a one-pot
procedure (Scheme 1).
c
entry
catalyst
time (h)
yield (%)
1
2
3
4
5
6
7
8
CuI
CuCl
20
20
25
22
25
22
25
20
14
20
20
20
26
b
15
b
10
b
30
45
36
30
CuI+PPh3
CuI+bipy
TpBr3Cu(NCMe)
TpBrCu(NCMe)
TpMsCu(NCMe)
[Cu(NCMe)4]PF4
TpMe2Cu
9
10
11
TpBrAg
TpMe3Ag
a
Reaction conditions: 0.075 mmol of TpMe2Cu, 10 mmol of 2,5-
dimethylfuran, 0.5 mmol of PhINTs, 50 mmol of 4-methylstyrene, 2
mL of DCM. No reaction observed. Yield of the isolated and
b
c
purified product.
and we were happy to get the desired product, albeit in a low
yield (Table 1, entries 1 and 2). Then, we turned our attention
on Cu-based hydrotrispyrazolylborate (Tpx) catalysts, which
were reported for the synthesis of tetrahydropyridine using
furan as diene precursors.10 Among various Cu-centric catalyst
systems screened for the formation of THP (Table 1), CuI
+PPh3, TpBr3Cu(NCMe), and TpMsCu(NCMe) failed to
After optimizing the reaction conditions, we explored the
substrate scope for the general validity of the envisaged
B
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cycloaddition process with a variety of furans 1 as a substrate
for the in situ formation of 1-aza-1,3-diene with PhINTs for
formal [4+2] cycloaddition with structurally different dien-
ophiles 2 to produce target tetrahydropyridines 3 (Schemes
2−4). The reaction of 2,5-dimethyl furan 1a occurred
source, we also obtained detosylated THP 3s, employing the
same reaction conditions (Scheme 3). Although the formation
of 3i and 3k does not involve the ADARINV reaction, electron-
poor dienophiles 2i and 2k were used just to check the
versatility of the envisaged protocol. However, we did not
isolate the corresponding THP using heteroaryl alkene, i.e., 2-
(2-nitrovinyl)furan as a dienophile under the envisaged
reaction conditions. Thus, the reported method worked well
with electron-rich, along with some moderate electron-poor,
dienophiles for the synthesis of THP 3.
Scheme 2. Substrate Scope of Styrene 2 for the Synthesis of
THP 3
It was noticed that the [4+2] cycloaddition is regioselective
with respect to the position of the substituent of dienophiles
either at C-2 or at C-3 in final product 3. When dienophile has
phenyl ring viz., 4-chlorostyrene (2a), 4-methylstyrene (2b),
styrene (2c), 4-bromostyrene (2d), 4-cyanostyrene (2e), 4-
fluorostyrene (2f), 4-methoxystyrene (2g), and phenylacety-
lene (2r), the corresponding THP contains an aryl substituent
at C-3 to the NTs group. This is because that regioselectivity
herein is driven presumably by steric hindrance. However, in
the case of β-nitrostyrene, the strong electron-withdrawing
nature of −NO2 directly attached to the double bond of
dienophile (2i), the electronic effect dominates over steric,
which favors the phenyl ring at the C-2 position by pushing
−NO2 away from NTs at C-3 of the corresponding THP (3i).
In the case of monosubstituted dienophile without an aryl ring,
viz., allyl bromide (2j), methyl acrylate (2k), acrylonitrile (2l),
and allyltrimethylsilane (2n), the substituent occupies the C-2
position of the corresponding THP (Scheme 3). Herein, an
electronic effect perhaps, operating the regioselectivity and due
to electron deficiency at the terminal carbon of alkene, either
flow of the electron in 2j, 2k, and 2l or the +I effect in 2n,
favors the product formation with substitution at the C-2
position. However, the carbon chain of octene in 2o was found
attached at the C-3 position in the corresponding product 3o,
smoothly with different substituted styrene 2 and afforded
the desired products in moderate to good yields (Scheme 2). A
range of styrenes 2 was examined as dienophiles, and it was
found that a variety of substituted styrenes including electron-
deficient were found to be suitable dienophiles for the
construction of target THP 3. However, 4-amino- and 4-
carboxyl-substituted styrene did not afford the desired product;
presumably, their alkene is either electron-rich or may not be
easily available because of resonance with the carbonyl group.
It is noteworthy that, in the case of 4-amino-substituted
styrene, the intermediate was detected after 30 min of stirring,
but the corresponding THP was not isolated. However, there
was no intermediate observed in the case of 4-carboxyl-
substituted styrene due to the high acidic environment of the
COOH group. The yield of the product with β-nitrostyrene is
the highest among all of these dienophiles. In addition to a
wide range of substituted styrene derivatives, other dienophiles
were also examined as given in Scheme 3, and the yield of the
corresponding THP was found to be good. We also performed
the reaction with alkyne (2r), and a 24% yield of
corresponding dihydropyridine 3r was obtained, which was
lower in comparison to alkenes (Scheme 3). This is because
alkynes are usually less nucleophilic than alkenes as the π
bonds are held more closely to the atom due to the more
electronegative nature of the sp-carbon than the sp2-carbon.
The bond length of alkynes is also shorter than alkenes. As
such, the electrons of an alkyne are generally less available than
an alkene. It is noteworthy that, using ammonia as a nitrene
Scheme 3. Substrate Scope of Dienophile 2 for the Synthesis
of THP 3
C
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which was again favored by the steric effect. However, in the
case of cyclopentene (2p) and cyclohexene (2q), no
regioselectivity was observed due to their symmetry at C-2/
C-3 positions, while the corresponding cis product (3m) was
formed in the case of cis-3-hexene (2m). All of the reactions
are highly stereoselective as we obtained only one regio-isomer
in all of the reactions. The regioselectivity of substituents in
THP 3 has been finally confirmed by their corresponding peak
cases (Scheme 4). As expected, the electronic effect of
substituents in furan affected the yield of product 3 and a
lower yield of 3t and 3u was obtained using 2-methyl- and 2-
formylfuran than that of 3c using 2,5-dimethylfuran, whereas
the yield of 3x from 2-n-butylfuran was comparable to 3c.
Presumably, the more electron-rich nature of the diene
generated from 2,5-dimethylpyrrole and 2,5-dimethylthio-
phene is responsible for the improved yield of the
corresponding THPs 3v and 3w (Scheme 4). Furthermore,
the potential utility of the envisaged synthetic protocol for a
gram-scale synthesis was also investigated by setting a model
reaction using 15 times the amount of each substrate utilized in
the optimized reaction condition (Table 1). The reaction
afforded 1.24 g of the desired product in 43% yield without any
significant loss of its efficiency, thus demonstrating the
potential application of the protocol for the large-scale
synthesis of the target compound, tetrahydropyridines. The
structure of all of the synthesized products 3a−x was
1
positions in H NMR spectra.
Next, we also investigated the substrate scope of diene 1 for
the general validity of the reaction process, and hence, in
addition to 2,5-dimethylfuran, a series of different diene
precursors, viz., 2-methylfuran, 2-formylfuran, 2-n-butylfuran,
2,5-dimethyl pyrrole, and 2,5-dimethylthiophene, were taken as
shown in Scheme 4. These substrates were used to generate
Scheme 4. Substrate Scope of Diene 1 for the Synthesis of
THP 3
1
confirmed by their H NMR and 13C NMR spectra (ESI).
All compounds gave C, H, and N analyses within 0.38% and
satisfactory spectral (1H NMR, 13C NMR, and HRMS) data.
A general mechanism for the formation of THP using 2-
methyl furan and PhINTs in the presence of the TpMe2Cu
catalyst is proposed (Scheme 5), which includes three
Scheme 5. A Plausible Mechanism for the Formation of
THP through 1-Aza-1,3-diene B
consecutive steps: (I) aziridination of furan’s double bond
followed by its ring opening to generate intermediate A; (II)
intermediate A gets converted into B, catalyzed by H2O and/
or TpMe2Cu, (III) the aza-Diels−Alder reaction with a
dienophile to produce the corresponding THP (Scheme 5).
The formation of A could be explained through in situ
generated aziridine by a direct reaction of 2-methyl furan and
NTs (Figure 2). This was concluded because no intermediate
was observed before the generation of A. Presumably, nitrene
insertion on both double bonds of unsymmetrical 2-methyl
furan led to nonisolable aziridines 1 and 2, which further
underwent ring opening to afford intermediates A and B,
respectively (Figure 2). Although intermediate A is sterically
hindered, it has an electron-rich double bond than that of B,
and this is the reason that A dominated B during the initial
phase of the reaction.
the diene by reaction with PhINTs, and thus, in situ generated
dienes were employed in formal [4+2] cycloaddition with
styrene 2c as a dienophile and TpMe2Cu as a catalyst under
identical reaction conditions at room temperature. Interest-
ingly, a clean transformation took place, and a single spot of
the corresponding THPs 3t−3x was obtained in all of these
However, A finally converted into B via the transimination
reaction (Figure 2) catalyzed by water/moisture and/or a
D
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confirmed by their corresponding J values17 in their H NMR
spectra (Figure 4), which also shows peaks of some residual 2-
methyl furan and PhI generated from PhINTs along with these
two intermediates (Figure 4).
1
Figure 2. Formation of intermediates A and B.
TpMe2Cu catalyst, which is also acidic in nature. A control
experiment was performed by setting up a reaction between 2-
methyl furan (10 mmol) and PhINTs (0.5 mmol) in DCM at
1
Figure 4. H NMR spectrum (CDCl3, 500 MHz) of the reaction
mixture of 2-methylfuran and PhINTs in the presence of TpMe2Cu
after 15 min at room temperature.
1
room temperature without using catalyst TpMe2Cu. The H
NMR spectrum was taken after 45 min of stirring, but no
intermediate was detected. It clearly indicates that TpMe2Cu
plays a crucial role in an aziridine ring formation, which further
undergoes ring opening due to its instability. Furthermore, we
have performed another control experiment to study the
mechanistic study. To a mixture of TpMe2Cu (0.075 mmol)
and 2-methyl furan (10 mmol) in CH2Cl2 (2 mL) was added
PhINTs (0.5 mmol), and it was observed that the greenish
solution turned into yellowish green after the addition of
Next, the role of TpMe2Cu in transimination from A to B was
also confirmed by setting up a reaction of TpMe2Cu (0.075
mmol), 2-methyl furan (10 mmol), and PhINTs (0.5 mmol) in
2 mL of DCM, and after 15 min of stirring, both the
intermediates A and B were found in 1H NMR spectra (Figure
3a). The catalyst TpMe2Cu was separated from the reaction
mixture after 15 min through column chromatography (1%
EtOAc/hexane). After separation of TpMe2Cu, we run the
column from pure DCM to obtain the rest of the reaction
mixture, and again, a reaction was setup, using this residual
part, employing the same reaction conditions without a
catalyst.
1
PhINTs, which after few minutes turned into dark green. H
NMR of the reaction mixture was taken after 15 min, 1, 2, and
3 h of stirring (Figure 3a−d). It was noticed that the formation
of both the intermediates, viz., (2Z)-4-tosyliminopent-2-enal
(A) and (3E)-5-tosyliminopent-3-en-2-one (B), was confirmed
within 15 min of stirring (Figure 3a). However, intermediate B
overlaid A after 2 h (Figure 3c), and finally B was the only
intermediate observed in the reaction mixture after 3 h (Figure
3d). The structures of both intermediates (A and B) were
1
In H NMR after 3 h of stirring, we observed both the
intermediates A and B (Figure 3e). The 1H NMR spectra after
3 h, with (Figure 3d) and without (Figure 3e) using a catalyst,
were compared, and both the intermediates A and B were
observed after 3 h in the absence of a catalyst (Figure 3e) with
B predominating over A. This indicates that the catalyst
TpMe2Cu promotes the conversion of A to B, which was also
promoted by water from atmospheric moisture (Scheme 5).
The role of water in the reaction may be explained with the
help of controlled experiments (Figure 3). Herein, inter-
mediate B dominated over A (Figure 3e), i.e., even in the
absence of a catalyst; A underwent transimination into B,
which is possible presumably due to the presence of water
available from moisture (Figure 3e). However, this observation
is also supported by relevant previous work.10 Furthermore, a
plausible mechanism has also been given to explain how water
assisted the transimination of A into B (Figure 2).10 Thus, the
catalyst TpMe2Cu and water both promote the transimination
1
step, and hence, A completely disappeared after 3 h in the H
NMR spectra in the presence of a catalyst (Figure 3d), leading
to the complete transimination of A into B.
In conclusion, we have demonstrated a TpMe2Cu-catalyzed
[4+2] aza-Diels−Alder reaction for the synthesis of a variety of
THP using PhINTs as a nitrene source, styrenes and cyclic/
acyclic alkenes as a dienophile, and different furans/pyrrole/
thiophene as a source of 1-aza-1,3-dienes. The envisaged
Figure 3. Monitoring of the reaction mixture of 2-methyl furan and
PhINTs in the presence of a catalyst, TpMe2Cu: (a) at 15 min, (b) at 1
1
h, (c) 2 h, and (d) 3 h. (e) Monitoring of H NMR of the reaction
mixture after separation of the catalyst at 3 h.
E
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36.0, 41.3, 50.3, 115.7, 126.7, 128.1, 129.4, 129.9, 132.2, 135.3, 138.4,
143.7, 144.8, 207.2. HRMS (ESI) m/z: [M + Na]+ calcd for
C22H25NO3SNa, 406.1452; found, 406.1434. Anal. Calcd for
C22H25NO3S: C, 68.90; H, 6.57; N, 3.65. Found: C, 68.59; H,
6.93; N, 3.38.
synthetic method is valuable, and the substrate scope is
hitherto unreported for the synthesis of structurally novel and
pharmaceutically important tetrahydropyridine scaffolds to
cater to the need of academia and industries.
Compound 3c. Eluent in chromatography: n-hexane/EtOAc 97:3.
Yellowish viscous oil. Yield: 101 mg, 55%. IR (KBr cm−1): ν 2918,
2911, 2905, 1706, 1666, 1325, 1149. 1H NMR (CDCl3, 500 MHz): δ
1.19 (s, 3H), 1.51 (s, 3H), 2.11 (s, 3H), 2.33 (d, 2H, J = 4.5 Hz), 2.38
(s, 1H), 2.93 (d, 1H, J = 7.0 Hz), 3.72 (dd, 1H, J = 7.0, 4.5 Hz),
7.15−7.17 (m, 2H), 7.21−7.25 (m, 3H), 7.27 (d, 2H, J = 8.0 Hz),
7.81 (d, 2H, J = 8.0 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 14.3,
21.8, 29.8, 36.1, 41.2, 53.6, 114.2, 126.7, 128.1, 128.5, 128.7, 129.9,
135.1, 135.2, 139.4, 144.8, 207.2. HRMS (ESI) m/z: [M + Na]+ calcd
for C21H23NO3SNa, 392.1295; found, 392.1274. Anal. Calcd for
C21H23NO3S: C, 68.27; H, 6.27; N, 3.79. Found: C, 68.07; H, 5.96;
N, 4.03.
EXPERIMENTAL SECTION
■
General Information. Reagents were obtained from commercial
suppliers and used without further purification unless otherwise
specified by a reference. All reactions were performed using oven-
dried glassware under a nitrogen atmosphere. Organic solutions were
concentrated using a Buchi rotary evaporator. Column chromatog-
raphy was carried out over silica gel (Merck 60−120 mesh), and TLC
was performed using silica gel GF254 (Merck) plates. IR spectra in
KBr were recorded on a Shimadzu 400−4000 cm−1 FTIR
spectrophotometer; 1H NMR spectra were recorded on a Bruker
AVIII 500 spectrometer in CDCl3/DMSO with chemical shift values
reported in ppm. All coupling constants (J) are reported in hertz
(Hz). 13C NMR spectra were recorded on the same instrument at 125
MHz in CDCl3/DMSO. ESI-HRMS spectral data were obtained using
Waters ESIMS model synaptic G2 high definition mass spectrometry.
Elemental analyses were carried out in a Coleman automatic carbon,
hydrogen, and nitrogen analyzer.
Compound 3d. Eluent in chromatography: n-hexane/EtOAc 97:3.
Yellowish viscous oil. Yield: 107 mg, 48%. IR (KBr cm−1): ν 2922,
1
2918, 2910, 1708, 1654, 1318, 1153, 608. H NMR (CDCl3, 500
MHz): δ 1.19 (s, 3H), 1.63 (s, 3H), 2.11 (s, 3H), 2.28 (d, 2H, J = 4.0
Hz), 2.37 (s, 1H), 2.92 (d, 1H, J = 7.0 Hz), 3.65 (dd, 1H, J = 7.0, 6.0
Hz), 7.02 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0 Hz), 7.35 (d, 2H, J
= 8.0 Hz), 7.79 (d, 2H, J = 8.0 Hz). 13C{1H} NMR (CDCl3, 125
MHz): δ 14.3, 21.8, 29.4, 36.2, 40.5, 53.9, 114.2, 122.5, 128.1, 128.4,
130.0, 131.9, 134.3, 134.9, 145.0, 147.4, 211.1. HRMS (ESI) m/z: [M
+ Na]+ calcd for C21H22BrNO3SNa, 470.0400; found, 470.0409. Anal.
Calcd for C21H22BrNO3S: C, 56.25; H, 4.95; N, 3.12. Found: C,
56.56; H, 4.59; N, 2.77.
General Procedure for the Synthesis of THP 3. TpMe2Cu
(0.075 mmol) was dissolved in furan (1, 10 mmol) and CH2Cl2 (2
mL). To this greenish solution, PhI = NTs (0.5 mmol) was added as
yellow crystals. The mixture became yellowish green in a few seconds,
which turned into a dark green solution after 10 min. After 15 min of
stirring, the appropriate olefin (2, 50 mmol) was added, and the
reaction mixture was stirred for 14 h at room temperature. After
completion of the reaction, the reaction mixture was diluted with
water (30 mL) and extracted with dichloromethane (3 × 15 mL). The
combined organic layers were dried over Na2SO4 and concentrated
under reduced pressure. The product was then purified by column
chromatography over silica gel to afford the analytically pure sample
of 3. The structure of all of the synthesized compounds 3 were
confirmed by their elemental and spectral analyses.
Typical Procedure for the Synthesis of THP (3b) on a Gram
Scale. TpMe2Cu (1.125 mmol) was dissolved in furan (1a, 150 mmol)
and CH2Cl2 (15 mL). To this greenish solution, PhI = NTs (7.5
mmol) was added as yellow crystals. The mixture became yellowish
green in a few seconds, which turned into a dark green solution after
10 min. After 15 min of stirring, the appropriate olefin (2b, 750
mmol) was added, and the reaction mixture was stirred for 14 h at
room temperature. After completion of the reaction, the reaction
mixture was diluted with water (50 mL) and extracted with
dichloromethane (3 × 30 mL). The combined organic layers were
dried over Na2SO4 and concentrated under reduced pressure. The
product was then purified by column chromatography over silica gel
to afford the analytically pure product 3b (1.24 g, 43% yield) as a
yellowish viscous oil.
Compound 3e. Eluent in chromatography: n-hexane/EtOAc 24:1.
Yellowish viscous oil. Yield: 124 mg, 63%. IR (KBr cm−1): ν 2928,
1
2924, 2921, 2250, 1707, 1660, 1322, 1153. H NMR (CDCl3, 500
MHz): δ 1.19 (s, 3H), 2.11 (s, 3H), 2.57 (s, 3H), 2.76 (d, 2H, J = 4.0
Hz), 2.85−2.90 (m, 1H), 3.69 (d, 1H, J = 7.0 Hz), 4.10 (dd, 1H, J =
12.5, 7.0 Hz), 7.10 (d, 2H, J = 8.0 Hz), 7.55 (d, 2H, J = 8.5 Hz), 7.79
(d, 2H, J = 8.0 Hz), 7.94 (d, 2H, J = 8.0 Hz). 13C{1H} NMR (CDCl3,
125 MHz): δ 14.3, 20.4, 29.4, 31.9, 45.5, 53.9, 110.0, 117.8, 117.9,
126.5, 129.6, 130.1, 133.1, 133.9, 138.9, 143.5, 151.5, 207.2. HRMS
(ESI) m/z: [M + Na]+ calcd for C22H22N2O3SNa, 417.1248; found,
417.1231. Anal. Calcd for C22H22N2O3S: C, 66.98; H, 5.62; N, 7.10.
Found: C, 67.16; H, 5.81; N, 6.84.
Compound 3f. Eluent in chromatography: n-hexane/EtOAc 24:1.
Yellowish viscous oil. Yield: 102 mg, 53%. IR (KBr cm−1): ν 2927,
1
2922, 2920, 1707, 1670, 1326, 1158, 1107. H NMR (CDCl3, 500
MHz): δ 1.19 (s, 3H), 1.53 (s, 3H), 2.11 (s, 3H), 2.29 (d, 2H, J = 4.5
Hz), 2.38 (s, 1H), 2.90 (d, 1H, J = 7.0 Hz), 3.70 (dd, 1H, J = 7.0, 4.5
Hz), 6.91 (d, 2H, J = 8.5 Hz), 7.12 (d, 2H, J = 8.5 Hz), 7.28 (d, 2H, J
= 8.0 Hz), 7.80 (d, 2H, J = 8.5 Hz). 13C{1H} NMR (CDCl3, 125
MHz): δ 14.3, 21.9, 29.9, 36.2, 40.5, 50.4, 115.7, 115.9, 128.1, 128.5,
130.0, 131.1, 135.1, 143.9, 145.0, 161.9, 207.5. HRMS (ESI) m/z: [M
+ H]+ calcd for C21H23FNO3S, 388.1382; found, 388.1393. Anal.
Calcd for C21H22FNO3S: C, 65.10; H, 5.72; N, 3.61. Found: C, 65.30;
H, 5.42; N, 3.95.
Compound 3a. Eluent in chromatography: n-hexane/EtOAc 97:3.
Yellowish viscous oil. Yield: 100 mg, 50%. IR (KBr cm−1): ν 2906,
1
Compound 3g. Eluent in chromatography: n-hexane/EtOAc 24:1.
2904, 2903, 1708, 1324, 1153, 709. H NMR (CDCl3, 500 MHz): δ
Yellowish viscous oil. Yield: 87 mg, 44%. IR (KBr cm−1): ν 2916,
1.20 (s, 3H), 1.56 (s, 3H), 2.12 (s, 3H), 2.29 (d, 2H, J = 4.5 Hz), 2.39
(s, 1H), 2.93 (d, 1H, J = 7 Hz), 3.68 (dd, 1H, J = 7.0, 4.5 Hz), 7.10
(d, 2H, J = 8.5 Hz), 7.28 (d, 2H, J = 8 Hz), 7.48 (d, 2H, J = 8.5 Hz),
7.80 (d, 2H, J = 8 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 14.3,
21.8, 29.9, 36.2, 40.5, 53.6, 119.3, 128.0, 128.1, 129.0, 130.0, 133.8,
134.4, 135.0, 145.0, 147.3, 207.3. HRMS (ESI) m/z: [M + Na]+ calcd
for C21H22ClNO3SNa, 426.0905; found, 426.0908. Anal. Calcd for
C21H22ClNO3S: C, 62.44; H, 5.49; N, 3.47. Found: C, 62.80; H, 5.28;
N, 3.27.
1
2906, 2895, 2843, 1707, 1667, 1320, 1232, 1149. H NMR (CDCl3,
500 MHz): δ 2.01 (s, 3H), 2.22 (s, 3H), 2.29 (s, 3H), 2.33 (d, 2H, J =
6.0 Hz), 2.36 (s, 1H), 3.25 (d, 1H, J = 8.0 Hz), 3.67−3.73 (m, 1H),
3.74 (s, 3H), 7.09 (d, 2H, J = 8.5 Hz), 7.22 (d, 2H, J = 8.5 Hz), 7.55
(d, 2H, J = 8.0 Hz), 7.65 (d, 2H, J = 8.0 Hz). 13C{1H} NMR (CDCl3,
125 MHz): δ 14.3, 21.7, 29.9, 36.8, 42.9, 54.8, 55.4, 114.0, 114.2,
127.4, 128.1, 129.6, 135.8, 138.9, 143.4, 144.0, 157.5, 207.6. HRMS
(ESI) m/z: [M + Na]+ calcd for C22H25NO4SNa, 422.1401; found,
422.1407. Anal. Calcd for C22H25NO4S: C, 66.14; H, 6.31; N, 3.51.
Found: C, 65.96; H, 6.61; N, 3.87.
Compound 3b. Eluent in chromatography: n-hexane/EtOAc 24:1.
Yellowish viscous oil. Yield: 86 mg, 45%. IR (KBr cm−1): ν 2922,
1
Compound 3h. Eluent in chromatography: n-hexane/EtOAc 24:1.
2919, 2911, 2909, 1706, 1660, 1323, 1151. H NMR (CDCl3, 500
Yellowish viscous oil. Yield: 119 mg, 56%. IR (KBr cm−1): ν 2980,
MHz): δ 1.19 (s, 3H), 1.51 (s, 3H), 2.11 (s, 3H) 2.25 (s, 3H), 2.32
(d, 2H, J = 4.5 Hz), 2.37 (s, 1H), 2.91 (d, 1H, J = 7), 3.68 (dd, 1H, J
= 7.0, 4.5 Hz), 7.04 (s, 4H), 7.26 (d, 2H, J = 8.0 Hz), 7.80 (d, 2H, J =
8.0 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 14.3, 21.3, 21.8, 29.9,
1
2956, 2940, 2843, 1728, 1709, 1658, 1328, 1243, 1152. H NMR
(CDCl3, 500 MHz): δ 1.19 (s, 3H), 1.46 (s, 3H), 2.11(s, 3H), 2.37 (s,
1H), 2.58 (d, 1H, J = 4.0 Hz), 3.71−3.76 (m, 2H), 3.79 (s, 3H), 7.16
F
https://dx.doi.org/10.1021/acs.joc.0c00279
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(d, 2H, J = 8.5 Hz), 7.26 (d, 2H, J = 8.5 Hz), 7.45 (d, 2H, J = 8.5 Hz),
7.75 (d, 2H, J = 8.0 Hz), 9.59 (d, 1H, J = 8.0 Hz). 13C{1H} NMR
(CDCl3, 125 MHz): δ 14.3, 21.7, 29.9, 32.1, 50.4, 55.4, 67.3, 114.0,
114.6, 126.7, 127.0, 129.9, 130.3, 139.2, 140.3, 151.5, 161.9, 203.9,
207.0. HRMS (ESI) m/z: [M + H]+ calcd for C23H26NO5S, 428.1531;
found, 428.1515. Anal. Calcd for C23H25NO5S: C, 64.62; H, 5.89; N,
3.28. Found: C, 64.34; H, 6.22; N, 3.13.
(d, 2H, J = 8.0 Hz), 7.62 (d, 2H, J = 8.0 Hz). 13C{1H} NMR (CDCl3,
125 MHz): δ 1.2, 14.3, 21.7, 29.1, 29.9, 36.0, 43.5, 60.3, 106.8, 127.2,
130.1, 134.8, 138.2, 144.4, 210.6. HRMS (ESI) m/z: [M + Na]+ calcd
for C19H29NO3SSiNa, 402.1534; found, 402.1520. Anal. Calcd for
C19H29NO3SSi: C, 60.12; H, 7.70; N, 3.69. Found: C, 59.87; H, 7.88;
N, 3.37.
Compound 3o. Eluent in chromatography: n-hexane/EtOAc 24:1.
Yellowish viscous oil. Yield: 79 mg, 42%. IR (KBr cm−1): ν 2922,
2917, 2908, 2894, 1707, 1650, 1490, 1462, 1458, 1449, 1446, 1321,
Compound 3i. Eluent in chromatography: n-hexane/EtOAc 24:1.
Yellowish viscous oil. Yield: 144 mg, 70%. IR (KBr cm−1): ν 2930,
1
1
2925, 2917, 1707, 1668, 1560, 1372, 1327, 1152. H NMR (CDCl3,
1147. H NMR (DMSO, 500 MHz): δ 0.93 (s, 13H), 1.58 (s, 1H),
500 MHz): δ 1.51 (s, 3H), 2.12 (s, 3H), 2.17 (s, 3H), 2.34 (d, 1H, J =
4.5 Hz), 4.75 (d, 1H, J = 14.5 Hz), 5.61 (dd, 1H, J = 14.5, 10.0 Hz),
5.90 (dd, 1H, J = 10.0, 4.5 Hz), 7.16 (d, 2H, J = 7.0 Hz), 7.23−7.30
(m, 5H), 7.48 (d, 2H, J = 6.5 Hz). 13C{1H} NMR (CDCl3, 125
MHz): δ 10.9, 13.9, 29.9, 37.9, 58.6, 84.9, 106.3, 126.9, 128.5, 129.0,
129.2, 129.4, 133.5, 136.4, 139.7, 148.4, 208.9. HRMS (ESI) m/z: [M
+ H]+ calcd for C21H23N2O5S, 415.1327; found, 415.1309. Anal.
Calcd for C21H22N2O5S: C, 60.85; H, 5.35; N, 6.76. Found: C, 61.25;
H, 5.60; N, 7.07.
2.03 (s, 3H), 2.16 (s, 3H), 2.40 (s, 3H), 2.42 (d, 2H, J = 4.5 Hz), 4.45
(dd, 1H, J = 11.0, 4.5 Hz), 4.89 (s, 1H), 7.45 (d, 2H, J = 8.0 Hz), 7.77
(d, 2H, J = 8.5 Hz). 13C{1H} NMR (DMSO, 125 MHz): δ 13.6, 18.1,
20.9, 21.0, 28.4, 42.3, 59.6, 107.0, 126.9, 130.2, 133.2, 137.5, 144.2,
209.1. HRMS (ESI) m/z: [M + Na]+ calcd for C21H31NO3SNa,
400.1921; found, 400.1913. Anal. Calcd for C21H31NO3S: C, 66.81 H,
8.28; N, 3.71. Found: C, 67.14; H, 8.04; N, 3.92.
Compound 3p. Eluent in chromatography: n-hexane/EtOAc 49:1.
Yellowish viscous oil. Yield: 66 mg, 40%. IR (KBr cm−1): ν 2912,
1
Compound 3j. Eluent in chromatography: n-hexane/EtOAc 49:1.
2908, 2902, 1708, 1642, 1320, 1140 cm−1. H NMR (CDCl3, 500
Yellowish viscous oil. Yield: 110 mg, 57%. IR (KBr cm−1): ν 2918,
MHz): δ 0.78−0.83 (m, 2H), 1.19 (s, 2H), 1.46 (s, 2H), 1.56 (s, 3H),
1.66 (s, 3H), 1.90 (s, 1H), 2.00 (s, 1H), 2.36 (s, 3H), 3.24 (dd, 1H, J
= 17.5, 9.0 Hz), 5.29 (d, 1H, J = 9.0 Hz), 7.22 (d, 2H, J = 8.5 Hz),
7.65 (d, 2H, J = 8.0 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 13.8,
21.7, 24.0, 27.1, 29.6, 29.9, 31.1, 46.9, 55.7, 112.9, 127.4, 129.6, 133.4,
138.9, 143.4, 207.2. HRMS (ESI) m/z: [M + H]+ calcd for
C18H24NO3S, 334.1476; found, 334.1459. Anal. Calcd for
C18H23NO3S: C, 64.84; H, 6.95; N, 4.20. Found: C, 65.13; H,
6.74; N, 4.52.
1
2911, 2909, 1707, 1664, 1322, 1149, 608. H NMR (CDCl3, 500
MHz): δ 1.19 (s, 3H), 1.53 (s, 3H), 1.84 (dd, 2H, J = 22.5, 10.5 Hz),
1.95 (s, 3H), 2.35 (s, 1H), 2.44−2.52 (m, 1H), 2.95 (d, 2H, J = 9.5
Hz), 4.04 (d, 1H, J = 7 Hz), 7.47 (d, 2H, J = 7.5 Hz), 7.81 (d, 2H, J =
7.0 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 14.3, 21.2, 29.9, 32.1,
40.4, 49.2, 54.3, 112.6, 127.0, 129.3, 134.7, 136.4, 144.2, 208.2.
HRMS (ESI) m/z: [M + H]+ calcd for C16H21BrNO3S, 386.0425;
found, 386.0410. Anal. Calcd for C16H20BrNO3S: C, 49.75; H, 5.22;
N, 3.63. Found: C, 50.00; H, 5.51; N, 3.27.
Compound 3q. Eluent in chromatography: n-hexane/EtOAc 97:3.
Compound 3k. Eluent in chromatography: n-hexane/EtOAc 97:3.
Yellowish viscous oil. Yield: 61 mg, 35%. IR (KBr cm−1): ν 2913,
Yellowish viscous oil. Yield: 105 mg, 60%. IR (KBr cm−1): ν 2917,
2909, 2905, 1708, 1660, 1321, 1150 cm−1. H NMR (CDCl3, 500
1
1
2911, 2909, 1740, 1706, 1667, 1323, 1150. H NMR (CDCl3, 500
MHz): δ 0.77−0.83 (m, 2H), 1.10−1.19 (m, 2H), 1.31−1.37 (m,
2H), 1.47−1.61 (m, 2H), 1.73 (s, 3H), 1.93−2.00 (m, 1H), 2.10−
2.17 (m, 1H), 2.38 (s, 3H), 2.91 (s, 3H), 3.14 (s, 1H), 4.51 (d, 1H, J
= 7.0 Hz), 7.28 (d, 2H, J = 8.0 Hz), 7.76 (d, 2H, J = 8.0 Hz). 13C{1H}
NMR (CDCl3, 125 MHz): δ 14.3, 21.8, 23.0, 24.8, 28.8, 29.9, 31.2,
32.2, 40.0, 56.0, 117.6, 127.8, 129.8, 130.0, 136.1, 144.2, 208.0.
HRMS (ESI) m/z: [M + H]+ calcd for C19H26NO3S, 348.1633;
found, 348.1619. Anal. Calcd for C19H25NO3S: C, 65.68; H, 7.25; N,
4.03. Found: C, 65.47; H, 6.94; N, 3.71.
MHz): δ 2.15 (s, 3H), 2.19 (dd, 2H, J = 10.5, 7.0 Hz), 2.22 (s, 3H),
2.35 (s, 3H), 3.11 (s, 1H), 3.41 (t, 1H, J = 7.0 Hz), 3.92 (s, 3H), 4.69
(d, 1H, J = 5.5 Hz), 7.22 (d, 2H, J = 8.0 Hz), 7.62 (d, 2H, J = 8.0 Hz).
13C{1H} NMR (CDCl3, 125 MHz): δ 14.3, 21.7, 29.5, 29.9, 54.9,
58.6, 60.2, 111.4, 127.6, 129.9, 133.4, 137.6, 144.1, 170.0, 207.5.
HRMS (ESI) m/z: [M + Na]+ calcd for C17H21NO5SNa, 374.1037;
found, 374.1018. Anal. Calcd for C17H21NO5S: C, 58.10; H, 6.02; N,
3.99. Found: C, 58.40; H, 6.35; N, 3.80.
Compound 3r. Eluent in chromatography: n-hexane/EtOAc 49:1.
Compound 3l. Eluent in chromatography: n-hexane/EtOAc 97:3.
Yellowish viscous oil. Yield: 44 mg, 24%. IR (KBr cm−1): ν 2920,
Yellowish viscous oil. Yield: 103 mg, 65%. IR (KBr cm−1): ν 2928,
1
1
2918, 2909, 1706, 1641, 1635,1321, 1148. H NMR (DMSO, 500
2922, 2919, 2240, 1709, 1663, 1319, 1155. H NMR (CDCl3, 500
MHz): δ 1.88 (s, 3H), 2.01 (s, 3H), 2.60 (s, 3H), 3.76 (d, 1H, J = 7.0
Hz), 5.00 (d, 1H, J = 7.0 Hz), 5.52 (s, 1H), 6.86−6.94 (m, 5H), 7.17
(d, 2H, J = 8.5 Hz), 7.88 (d, 2H, J = 8.0 Hz). HRMS (ESI) m/z: [M
+ Na]+ calcd for C21H21NO3SNa, 390.1139; found, 390.1126. Anal.
Calcd for C21H21NO3S: C, 68.64 H, 5.76; N, 3.81. Found: C, 68.35;
H, 6.10; N, 3.51.
MHz): δ 2.00 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H), 3.23 (s, 1H), 4.90
(dd, 2H, J = 9.5, 5.0 Hz), 5.29 (d, 1H, J = 7.0 Hz), 6.12 (t, 1H, J = 5.0
Hz), 7.22 (d, 2H, J = 8.0 Hz), 7.51 (d, 2H, J = 8.0 Hz). 13C{1H}
NMR (CDCl3, 125 MHz): δ 13.8, 22.1, 29.6, 29.9, 43.9, 55.7, 112.9,
116.4, 127.4, 129.3, 132.9, 138.9, 144.3, 208.2. HRMS (ESI) m/z: [M
+ Na]+ calcd for C16H18N2O3SNa, 341.0935; found, 341.0918. Anal.
Calcd for C16H18N2O3S: C, 60.36; H, 5.70; N, 8.80. Found: C, 60.08;
H, 6.02; N, 8.57.
Compound 3s. Eluent in chromatography: n-hexane/EtOAc 24:1.
Yellowish viscous oil. Yield: 68 mg, 63%. IR (KBr cm−1): ν 2909,
1
2904, 1706, 1642. H NMR (CDCl3, 500 MHz): δ 0.81 (d, 2H, J =
Compound 3m. Eluent in chromatography: n-hexane/EtOAc 97:3.
Yellowish viscous oil. Yield: 75 mg, 43%. IR (KBr cm−1): ν 2924,
7.0 Hz), 1.20 (s, 3H) 1.30 (d, 1H, J = 7.5 Hz), 1.58 (s, 3H), 1.97 (dd,
1H, J = 14.0, 7.5 Hz), 2.11 (s, 1H), 7.71 (t, IH, J = 8.0 Hz), 8.18 (d,
2H, J = 8.0 Hz), 8.44 (d, 2H, J = 8.0 Hz), 10.07 (s, 1H). 13C{1H}
NMR (CDCl3, 125 MHz): δ 14.3, 22.9, 29.6, 29.9, 32.1, 114.3, 124.7,
128.8, 130.6, 134.8, 137.6, 189.9. HRMS (ESI) m/z: [M + Na]+ calcd
for C14H17NONa, 238.1207; found, 238.1206. Anal. Calcd for
C14H17NO: C, 78.10 H, 7.96; N, 6.51. Found: C, 77.74; H, 8.24;
N, 6.72.
1
2920, 2917, 2884, 2874, 1707, 1648, 1473, 1470, 1322, 1152. H
NMR (CDCl3, 500 MHz): δ 0.82 (t, 6H, J = 5.5 Hz), 1.55 (s, 4H),
2.01 (s, 1H), 2.11 (s, 3H), 2.18 (s, 3H), 2.23 (s, 3H), 2.36 (s, 1H),
3.42 (dd, 1H, J = 14.0, 7.0 Hz), 4.95 (d, 1H, J = 7.0 Hz), 7.15 (d, 2H,
J = 8.0 Hz), 7.65 (d, 2H, J = 8.0 Hz). 13C{1H} NMR (125 MHz;
CDCl3): δ 13.8, 14.3, 14.6, 21.7, 22.1, 22.9, 29.9, 36.8, 55.8, 58.6,
112.9, 127.4, 129.6, 135.9, 138.9, 143.4, 207.3. HRMS (ESI) m/z: [M
+ Na]+ calcd for C19H27NO3SNa, 372.1608; found, 372.1606. Anal.
Calcd for C19H27NO3S: C, 65.30; H, 7.79; N, 4.01. Found: C, 65.01;
H, 7.98; N, 4.22.
Compound 3t. Eluent in chromatography: n-hexane/EtOAc 97:3.
Yellowish viscous oil. Yield: 83 mg, 47%. IR (KBr cm−1): ν 2924,
1
2916, 1730, 1653, 1323, 1153. H NMR (CDCl3, 500 MHz): δ 1.19
(s, 3H), 2.11 (s, 3H), 2.33 (d, 2H, J = 4.5 Hz), 2.37 (s, 1H), 2.93 (d,
1H, J = 7.5 Hz), 3.72 (dd, 1H, J = 7.0, 5.0 Hz), 7.15−7.24 (m, 5H),
7.27 (d, 2H, J = 8.0 Hz), 7.81 (d, 2H, J = 8.0 Hz), 9.97 (s, 1H).
13C{1H} NMR (CDCl3, 125 MHz): δ 14.3, 21.8, 36.1, 41.2, 54.4,
114.2, 126.7, 128.1, 128.5, 128.7, 129.9, 135.1, 135.2, 139.5, 144.8,
196.9. HRMS (ESI) m/z: [M + Na]+ calcd for C20H21NO3SNa,
Compound 3n. Eluent in chromatography: n-hexane/EtOAc 97:3.
Yellowish viscous oil. Yield: 57 mg, 30%. IR (KBr cm−1): ν 2924,
1
2921, 2916, 2911, 2907, 2901, 1708, 1660, 1460, 1322, 1147. H
NMR (CDCl3, 500 MHz): δ 1.00 (s, 9H), 1.45 (d, 2H, J = 5.5 Hz)
1.60 (s, 3H), 1.80 (dd, 2H, J = 12.5, 4.5 Hz), 2.08 (s, 3H), 2.21 (s,
3H), 2.27−2.33 (m, 1H), 2.37 (s, 1H), 4.45 (d, 1H, J = 6.5 Hz), 7.25
G
https://dx.doi.org/10.1021/acs.joc.0c00279
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
378.1139; found, 378.1124. Anal. Calcd for C20H21NO3S: C, 67.58;
H, 5.95; N, 3.94. Found: C, 67.85; H, 5.75; N, 4.18.
Authors
Prashant Shukla − School of Physical Sciences, Jawaharlal
Nehru University, New Delhi 110067, India
Compound 3u. Eluent in chromatography: n-hexane/EtOAc 24:1.
Yellowish viscous oil. Yield: 74 mg, 40%. IR (KBr cm−1): ν 2929,
1728, 1722, 1645, 1329, 1154 cm−1. 1H NMR (CDCl3, 500 MHz): δ
2.11 (s, 3H), 2.33 (d, 2H, J = 4.5 Hz), 2.37 (s, 1H), 2.93 (d, 1H, J =
7.0 Hz), 3.72 (dd, 1H, J = 6.5, 4.5 Hz), 7.16 (d, 2H, J = 7.5 Hz),
7.39−7.47 (m, 5H), 7.92 (d, 2H, J = 8.0 Hz), 9.75 (s, 1H), 9.97 (s,
1H). 13C{1H} NMR (CDCl3, 125 MHz): δ 21.9, 36.1, 41.2, 53.8,
126.7, 127.4, 128.0, 128.6, 129.1, 130.2, 133.6, 134.1, 134.4, 149.1,
166.3, 192.3. HRMS (ESI) m/z: [M + Na]+ calcd for
C20H19NO4SNa, 392.0931; found, 392.0915. Anal. Calcd for
C20H19NO4S: C, 65.02; H, 5.18; N, 3.79. Found: C, 65.33; H,
5.48; N, 3.57.
Compound 3v. Eluent in chromatography: n-hexane/EtOAc 97:3.
Yellowish viscous oil. Yield: 106 mg, 58%. IR (KBr cm−1): ν 3317,
2928, 2923, 2909, 1643, 1324, 1150. 1H NMR (CDCl3, 500 MHz): δ
1.20 (s, 3H), 1.38 (s, 3H), 2.13 (s, 3H), 2.15 (d, 2H, J = 7.0 Hz), 2.18
(s, 1H), 2.84 (d, 1H, J = 4.0 Hz), 3.11 (dd,1H, J = 5.5, 4.0 Hz), 7.18
(d, 2H, J = 7.5 Hz), 7.47−7.49 (m, 5H), 7.54 (br, s, 1H), 7.59 (d, 2H,
J = 7.5 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 14.3, 22.9, 29.9,
36.7, 37.3, 48.8, 114.3, 126.4, 128.7, 128.8, 129.0, 131.1, 135.3, 136.0,
139.5, 143.0, 168.0. HRMS (ESI) m/z: [M + Na]+ calcd for
C21H24N2O2SNa, 391.1455; found, 391.1436. Anal. Calcd for
C21H24N2O2S: C, 68.45 H, 6.56; N, 7.60. Found: C, 68.64; H,
6.78; N, 7.92.
Compound 3w. Eluent in chromatography: n-hexane/EtOAc 97:3.
Yellowish viscous oil. Yield: 115 mg, 60%. IR (KBr cm−1): ν 2922,
2918, 2909, 1656, 1319, 1152, 1148. 1H NMR (CDCl3, 500 MHz): δ
1.20 (s, 3H), 1.57 (s, 3H), 2.11 (s, 3H), 2.33 (d, 2H, J = 4.0 Hz), 2.37
(s, 1H), 2.93 (d, 1H, J = 7.0 Hz), 3.72 (dd,1H, J = 7.0, 4.5 Hz), 7.15−
7.24 (m, 5H), 7.27 (d, 2H, J = 8.0 Hz), 7.81 (d, 2H, J = 8.0 Hz).
13C{1H} NMR (CDCl3, 125 MHz): δ 14.4, 21.5, 39.6, 42.2, 44.1,
57.0, 114.6, 126.1, 128.2, 128.5, 128.7, 129.5, 133.3, 135.8, 140.7,
146.1, 253.3. HRMS (ESI) m/z: [M + Na]+ calcd for
C21H23NO2S2Na, 408.1067; found, 408.1046. Anal. Calcd for
C21H23NO2S2: C, 65.42 H, 6.01; N, 3.63. Found: C, 65.11; H,
5.74; N, 3.84.
Ambika Asati − Department of Chemistry, Guru Ghasidas
Vishwavidyalaya, Bilaspur, Chhattisgarh 495009, India
Smita R. Bhardiya − Department of Chemistry, Guru Ghasidas
Vishwavidyalaya, Bilaspur, Chhattisgarh 495009, India
Manorama Singh − Department of Chemistry, Guru Ghasidas
Vishwavidyalaya, Bilaspur, Chhattisgarh 495009, India;
orcid.org/0000-0001-5872-6160
Vijai K. Rai − Department of Chemistry, Guru Ghasidas
Vishwavidyalaya, Bilaspur, Chhattisgarh 495009, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c00279
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The SERB, DST, New Delhi, for the INSPIRE Faculty
Research Award (IFA12-CH-61), and JNU, for UPE-II (217),
are acknowledged for financial assistance and AIRF, JNU, for
providing microanalyses and spectra. P.S. thanks UGC for the
Junior Research Fellowship (23/06/2013(i)EU-V).
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Synthetic procedures and H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
Ankita Rai − School of Physical Sciences, Jawaharlal Nehru
University, New Delhi 110067, India; orcid.org/0000-
0002-2962-7427; Email: ankitarai@mail.jnu.ac.in
H
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