(3+2) Cycloadditions of Thiouronium Ylides: A Room-Temperature, One-Pot Approach to Dihydrothiophenes

Article abstract of DOI:10.1021/acs.joc.7b03255

A room-temperature (3+2) cycloaddition sequence for the synthesis of highly substituted dihydrothiophene derivatives has been developed. By utilizing structurally unique thiocarbonyl ylides, the reactivity of these traditionally high-energy intermediates can be modulated, enabling a synthetically useful transformation to proceed under mild conditions.

Full text of DOI:10.1021/acs.joc.7b03255

Note
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/joc
(
3+2) Cycloadditions of Thiouronium Ylides: A Room-Temperature,
One-Pot Approach to Dihydrothiophenes
James D. Neuhaus, Peter Angyal, Rik Oost, and Nuno Maulide*
̈
Institute of Organic Chemistry, University of Vienna, Wahringer Straße 38, 1090 Vienna, Austria
*
S Supporting Information
ABSTRACT: A room-temperature (3+2) cycloaddition se-
quence for the synthesis of highly substituted dihydrothio-
phene derivatives has been developed. By utilizing structurally
unique thiocarbonyl ylides, the reactivity of these traditionally
high-energy intermediates can be modulated, enabling a
synthetically useful transformation to proceed under mild conditions.
17b,18
mong the structurally broad family of sufur ylides, doubly
mostly relying on classical condensation chemistry.
Such
A
stabilized sulfonium ylides have recently attracted
considerable attention in synthesis. Given our group’s long-
routes often require high temperatures, and/or reagents that
limit functional group compatibility. The application of [3+2]
cycloadditions to the synthesis of dihydrothiophenes has
1
standing interest in these compounds following our original
1c
report on the concept of ylide transfer, we were keen to
investigate the applications of highly stabilized ylides bearing
alternative chemical structures. Thiocarbonyl ylides, formally
̈
hitherto restricted to the use of isothiomunchnones as 1,3-
19
dipoles.
Herein, we report a general and mild synthesis of highly
substituted 2-amino-4,5-dihydrothiophenes (3) via a formal
1
,3-dipoles, represent a conceptually distinct class of sulfonium
2
ylides, with unique reactivity. Reactions involving thiocarbonyl
(
3+2) cycloaddition reaction of nitroalkenes (1) and “push−
3
4
ylides include electrocyclizations, dimerization-type reactions,
pull” stabilized thiocarbonyl ylides (2) (Scheme 1). These
reactive 1,3-dipoles are formed in situ by the deprotonation of
thiouronium salts (5), which are easily accessed through the
combination of tetramethylthiourea and the appropriate alkyl
bromide.
5
6
1
,3 acid−base addition reactions, rearrangements, and
4a,7
cycloadditions.
A number of these transformations have
been developed to the stage where they have found use as key
steps in the syntheses of a number of natural products.
However, the high reactivity and instability of these compounds
place some limitations on their synthetic utility, and reactions
employing thiocarbonyl ylides often have to be very carefully
designed. The synthesis of these ylides, almost always
undertaken in situ for onward reactions, often requires either
very high temperatures or cryogenic cooling.
4c,7a,8
Scheme 1. Synthesis of 2-Amino-4,5-dihydrothiophenes via a
Formal (3+2) Reaction between Nitroolefins and in Situ-
Formed Thiocarbonyl Ylides
9
7b,8c,10
One of the
most common routes involves the use of alkyl azides, which
restricts the scale on which these reactions can safely be
undertaken. Although stabilization of the 1,3-dipole by addition
of electron-withdrawing and electron-donating groups is
1
1
possible, the design of thiocarbonyl ylides with enhanced
stability and lifetimes would enable the development of novel
transformations.
Heterocycles have long been considered privileged templates
in the search for biologically active molecules. A number of 4,5-
dihydrothiophenes, in particular 2-amino-4,5-dihydrothio-
phenes, have been investigated for a range of biological
1
2
13
12,14
effects, including anti-inflammatory, cytotoxic,
and
1
5
antimicrobial activity. The presence of a reactive sulfur
center, in addition to the double bond, means that these
structures can be employed as synthetic intermediates.
Examples include desulfurization with Raney nickel to generate
1
6
acyclic compounds and, in the case of 2-amino-4,5-
dihydrothiophenes, further condensation reactions to afford
16b,17
dihydrothiophene-fused nitrogen heterocycles.
A number
Received: January 7, 2018
of syntheses of 4,5-dihydrothiophenes have been developed,
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b03255
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Investigations began with the combination of malonate-
derived thiouronium salt 5a as the thiocarbonyl ylide precursor,
and various dipolarophiles. It soon emerged that Michael
acceptors were most effective in enabling a formal cyclo-
addition. Reactions with acrylonitrile, methyl vinyl ketone, and
ethyl propriolate all gave the (3+2) cycloaddition product,
albeit in low yields. When 2.0 equiv of nitrostyrene (1a) was
employed as the coupling partner, it was possible to isolate
dihydrothiophene 3a in 75% yield (Table 1, entry 1). By
Scheme 2. Substrate Scope of the Ylide Component
a
Table 1. Optimization of the Dihydrothiophene Synthesis
b
b
entry
base
solvent
CH Cl
yield (%)
consumption of 1a (%)
c
1
2
3
4
5
6
7
8
9
Et N
3
(75)
n/a
>99
>99
>99
43
2
2
Et N
3
CH Cl
95 (92)
<5
2
2
2
2
2
2
Li CO3
2
CH Cl
2
DBU
CH Cl
55
2
t-BuOK
pyridine
CH Cl
20
2
CH Cl
73
79
2
Et N
3
MeCN
DMSO
THF
87
>99
>99
>99
>99
>99
Et N
3
60
Et N
3
68
1
1
0
1
Et N
3
MeOH
toluene
92
a
Reaction conditions: 1a (0.2 mmol), 5 (0.3 mmol), Et N (0.3 mmol),
3
Et N
3
88
dichloromethane (1.0 mL), rt, 12 h.
a
Reaction conditions: 1a (0.2 mmol), 5a (0.3 mmol), base (0.3
b
mmol), solvent (1.0 mL), rt, 12 h. NMR yields using mesitylene as an
internal standard, unless inside parentheses. Reaction performed
c
using 5a (1.0 equiv), Et N (1.0 equiv), and 1a (2.0 equiv).
3
reversing the stoichiometry, we were able to increase this yield
to 92% (entry 2). Beyond this, a screen of both the base
(
entries 3−6) and the solvent (entries 7−11) offered no
improvement on the initial NEt /dichloromethane combina-
3
tion. This combination also made the purification extremely
straightforward, as no workup is required. Compared to those
of previously reported (3+2) cycloadditions, it is notable that
the conditions are extremely mild, proceeding at room
temperature with only the addition of a weak base.
Figure 1. X-ray diffraction structure of dihydrothiophene 4d, showing
trans relative stereochemistry.
With optimized conditions in hand, we moved on to
determine the range of stabilized thiocarbonyl ylides that could
be employed in the transformation (Scheme 2). Thiouronium
salts (5) were prepared via a simple nucleophilic substitution
between tetramethylthiourea and the respective alkyl bromide
in quantitative yields. Both of the malonate-derived substrates
reacted successfully in satisfactory to excellent yields (4a and
methyl (4g) group, the yield could be increased, at the expense
of the diastereomeric ratio. Use of a fluorenyl thiocarbonyl ylide
afforded product 4h in an excellent 95% yield. As expected,
reducing the level of stabilization even further, with only alkyl
or electron-neutral aryl groups, resulted in no product
formation, even when stronger bases were employed. An
interesting exception to the developing trend was the attempted
use of a dimedone-derived ylide (see 4k). In this instance, the
deprotonation was extremely fast and irreversible. However, the
ylide is so stabilized that it is completely inert under the
reaction conditions, and H NMR experiments showed no
decomposition of the ylide over multiple days, unlike ylide 2a,
which decomposed slowly over 24 h.
Exploration of the nitroolefin scope showed that a broad
range of substrates could be employed (Scheme 3). Both
electron-rich (examples 4l−4p) and electron-poor (4q−4u)
aryl groups were well tolerated. Included in this scope were
halide moieties that could be used for further functionalization
(4q−4t). Examples 4n and 4p showed that steric bulk in the
4
b). When one electron-withdrawing group was removed, the
yield dropped dramatically to 23% (4c); however, the
diastereocontrol was relatively high. Performing the reaction
at higher or lower temperatures let to no product formation at
all. This reduction in the stability of the thiocarbonyl
intermediate has been investigated previously (in the absence
of any coupling partner) by the group of Nozaki, and a number
1
9
of decomposition pathways have been identified.
Exchange of the ester group for either a ketone (4d) or a p-
nitrophenyl group afforded similar results (4e). The relative
stereochemistry of 4d (and by analogy those of 4c and 4e−4g)
was assigned using X-ray crystallographic analysis (Figure 1).
By further substitution of the ylide with either a phenyl (4f) or
B
DOI: 10.1021/acs.joc.7b03255
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
b
a
Scheme 3. Substrate Scope of the Nitroolefin Component
Scheme 4. One-Pot, Two-Step Procedure
a
Reaction conditions: tetramethylthiourea (0.3 mmol), diethyl
bromomalonate (0.3 mmol), dichloromethane (1.0 mL), rt, time 1;
then 1a (0.2 mmol), Et N (0.3 mmol), rt, time 2.
3
Scheme 5. Proposed mechanism
steps (path b). The elimination of dimethylamine from
intermediate 3 to afford dihydrothiophene 4 is entropically
favorable, and we believe that it provides the driving force for
the overall process.
In conclusion, we have developed a mild thiocarbonyl-ylide-
based (3+2) cycloaddition process for the synthesis of 2-amino-
22
a
b
Dropwise addition of the thiouronium salt. Reaction conditions: 1
0.2 mmol), 5a (0.3 mmol), Et N (0.3 mmol), dichloromethane (1.0
(
3
mL), rt, 12 h.
4
,5-dihydrothiophenes. A range of nitroolefins can be combined
with highly stabilized, push−pull 1,3-dipoles at room temper-
ature in good to excellent yields. The reaction is finely tuned
according to the stabilization of the thiocarbonyl ylide, with
reduced yields for less stabilized examples and a complete
shutdown of reactivity if the ylide is “overstabilized”. We hope
that the synthetic ease of this process can encourage further
investigations into what has been traditionally regarded as a
field involving high-energy, sensitive intermediates and harsh
reaction conditions.
ortho position could be tolerated with only a small decrease in
the yield. Heterocyclic nitroolefins could also be employed,
though in the case of the N-Boc-pyrrole substrate, the reaction
was found to be improved by a dropwise addition of the
thiouronium salt to the reaction mixture. This modified
procedure was also found to be useful in boosting the yield
of alkenyl example 4x. When alkyl nitroolefins were employed,
1
the yields were significantly reduced, which H NMR
experiments suggest is due to decomposition/oligomerization
20
of the nitroolefin under the action of triethylamine.
EXPERIMENTAL SECTION
All reactions were performed using oven-dried glassware and an
anhydrous solvent. Chromatography was performed on silica gel
As the in situ formation of 5a from tetramethylthiourea (6)
and diethyl bromomalonate (7) proceeded smoothly at room
temperature in dichloromethane, we were interested in probing
whether a one-pot, two-step procedure could be developed. In
the event, mixing tetramethylthiourea 6 and bromomalonate 7
for 12 h in dichloromethane (Scheme 4) followed by addition
of trimethylamine and nitrostyrene afforded an 87% yield of
cycloadduct 4a. Ancillary experiments with shorter reaction
times provided less satisfying results (Scheme 4).
■
(
230−400 mesh, Merck and Co.) with the indicated eluents. Thin-
layer chromatography was performed on silica plates. Compounds
were visualized by ultraviolet (254 nm) or potassium permanganate
staining. Mass spectra were obtained using a Finnigan MAT 8200 (70
eV) or an Agilent 5973 (70 eV) spectrometer, using electrospray
ionization (ESI). H and C NMR spectra were recorded using a
Bruker AV-400 (400 MHz) spectrometer, and F NMR spectra were
1
13
19
1
Scheme 5 details our proposed mechanism. H NMR studies
recorded at 101 MHz. Chemical shift values are reported in parts per
million with the solvent resonance as the internal standard (CHCl ,
have demonstrated that, for thiouronium salt 5a, the initial
deprotonation step is fast and irreversible, forming thiocarbonyl
ylide 2a, which is reasonably stable in solution for a number of
3
1
13
7
.26 for H, 77.0 for C). Data are reported as follows: chemical shifts
(parts per million), multiplicity (s, singlet; d, doublet; t, triplet; q,
2
1
quartet; br, broad; m, multiplet), coupling constants (hertz), and
integration. All starting materials were purchased from Aldrich or TCI
and used without further purification unless otherwise stated.
General Procedure 1 (GP1) for the Synthesis of Thiouro-
nium Salts. A solution of N,N,N′,N′-tetramethylthiourea (5 mmol)
hours. In the presence of a nitroolefin (1), this intermediate
2) undergoes a (3+2) cycloaddition, either in a concerted,
(
pericyclic manner (path a) or through a two-step process
comprising both Michael addition and 5-endotrig cyclization
C
DOI: 10.1021/acs.joc.7b03255
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
and alkyl bromide (5 mmol) in anhydrous CH Cl2 (50 mL) or
General Procedure 2 (GP2) for the (3+2) Cycloaddition. To
an oven-dried flask were added sulfonium salt (0.3 mmol),
nitrostyrene (0.2 mmol), and 1.0 mL of anhydrous CH Cl . To this
2
anhydrous acetone (50 mL) was stirred for 12 h at room temperature,
after which time the reaction mixture was concentrated in vacuo to
afford the reaction product. No further purification was necessary.
2
2
solution was added slowly Et N (0.3 mmol), and the reaction mixture
3
2
-(1,3-Diethoxy-1,3-dioxopropan-2-yl)-1,1,3,3-tetramethylth-
was stirred for 12 h, before being concentrated in vacuo. The crude
mixture was purified by column chromatography (1:1 heptane/
EtOAc) to afford the dihydrothiophene product.
iouronium Bromide (5a). Obtained as a colorless oil via GP1 (1.85 g,
1
quantitative yield): H NMR (400 MHz, CDCl ) δ 4.81 (s, 1H),
.36−4.26 (m, 4H), 3.51 (s, 12H), 1.32 (t, J = 7.0 Hz, 6H); C{ H}
NMR (100 MHz, CDCl ) δ 172.4, 164.3, 64.0, 53.5, 45.0, 14.0; IR
film) 3387, 2984, 1727, 1609, 1505, 1465, 1396, 1370, 1300, 1256,
021 cm ; HRMS (ESI-TOF, m/z) ([M] ) calcd for C H N O S
3
13
1
4
General Procedure 3 (GP3) for the (3+2) Cycloaddition. To
3
an oven-dried flask were added nitrostyrene (0.2 mmol), Et N (0.3
3
(
1
2
mmol), and 1.0 mL of anhydrous CH Cl . To this mixture was added
2
2
−1
+
+
12 23 2 4
the solution of sulfonium salt (0.3 mmol) in 0.5 mL of CH Cl
2 2
91.1373, found 291.1374.
-[1,3-Bis(benzyloxy)-1,3-dioxopropan-2-yl]-1,1,3,3-tetrame-
thylthiouronium Bromide (5b). Obtained as a yellow oil via GP1
dropwise using a syringe pump over 6 h, and the reaction mixture was
stirred for an additional 6 h, before being concentrated in vacuo. The
crude mixture was purified by column chromatography (1:1 heptane/
EtOAc) to afford the dihydrothiophene product.
General Procedure 4 (GP4) for the Thiouronium Formation/
(3+2) Cycloaddition One-Pot Reaction. A solution of N,N,N′,N′-
tetramethylthiourea (0.3 mmol) and alkyl bromide (0.3 mmol) in
2
1
(
(
(
5
1
2.47 g, quantitative yield): H NMR (400 MHz, CDCl ) δ 7.35−7.29
m, 10H), 5.20 (s, 4H), 4.95 (s, 1H), 3.31 (s, 12H); C{ H} NMR
100 MHz, CDCl ) δ 171.7, 164.0, 134.0, 129.1, 128.9, 128.8, 69.4,
3.5, 44.9; IR (film) 3625, 3399, 1736, 1612, 1501, 1455, 1398, 1276,
261, 1169, 1113, 1061, 1001 cm ; HRMS (ESI-TOF, m/z) ([M] )
calcd for C H N O S 415.1686, found 415.1691.
3
13 1
3
−1
+
anhydrous CH Cl (1.0 mL) was stirred for 12 h at room temperature.
+
2
2
22
27
2
4
Then, nitrostyrene (0.2 mmol) was added, followed slowly by Et N
3
2
-(2-Ethoxy-2-oxoethyl)-1,1,3,3-tetramethylthiouronium Bro-
(0.3 mmol). After being stirred for a further 12 h, the reaction mixture
mide (5c). Obtained as a white solid via GP1 (1.49 g, quantitative
1
was concentrated in vacuo. The crude mixture was purified by column
chromatography (1:1 heptane/EtOAc) to afford the dihydrothiophene
product.
yield): H NMR (400 MHz, CDCl ) δ 4.23 (q, J = 7.0 Hz, 2H), 3.99
s, 2H), 3.49 (s, 12H), 1.30 (t, J = 7.0 Hz, 3H); C{ H} NMR (100
MHz, CDCl ) δ 174.3, 167.5, 62.97, 44.8, 36.1, 14.1; IR (film) 3491,
380, 2981, 2938, 1724,1603, 1505, 1463, 1395, 1304, 1261, 1191,
167, 1112, 1057, 1020 cm ; HRMS (ESI-TOF, m/z) ([M] ) calcd
for C H N O S 219.1162, found 219.1161.
3
13
1
(
3
Diethyl 5-(Dimethylamino)-4-nitro-3-phenylthiophene-2,2(3H)-
3
1
dicarboxylate (4a). Obtained as a yellow oil via GP2 (72.1 mg,
−1
+
1
9
7
2% yield): H NMR (400 MHz, CDCl ) δ 7.47−7.44 (m, 2H), 7.32−
+
3
9
19
2
2
.27 (m, 3H), 5.49 (s, 1H), 4.35 (dq, J = 10.5, 7.0 Hz, 1H), 4.27 (dq, J
1
,1,3,3-Tetramethyl-2-(2-oxo-2-phenylethyl)thiouronium Bro-
=
10.5, 7.0 Hz, 1H), 3.87 (dq, J = 10.5, 7.0 Hz, 1H), 3.74 (dq, J = 10.5,
mide (5d). Obtained as a yellow solid via GP1 (1.65 g, quantitative
1
7.0 Hz, 1H), 3.26 (s, 6H), 1.29 (t, J = 7.0 Hz, 3H), 0.95 (t, J = 7.0 Hz,
yield): H NMR (400 MHz, CDCl ) δ 8.16 (d, J = 7.5 Hz, 2H), 7.63
3
13
1
3
H); C{ H} NMR (100 MHz, CDCl ) δ 167.6, 164.6, 163.7, 136.9,
3
(
t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 5.12 (s, 2H), 3.45 (s,
2H); 13C{ H} NMR (100 MHz, CDCl ) δ 134.7, 131.2, 129.4, 129.2,
1
128.6, 128.34, 128.25, 118.9, 67.6, 63.2, 62.9, 56.0, 45.8, 13.8, 13.4; IR
1
1
1
3
(
1
film) 2983, 2936, 1736, 1590, 1430, 1372, 1290, 1274, 1245, 1211,
29.0, 125.4, 44.7, 34.6; IR (film) 3400, 3059, 2782, 1669, 1603, 1507,
−1
139, 1094, 1078, 1041, 1021 cm ; HRMS (ESI-TOF, m/z) ([M +
467, 1449, 1399, 1345, 1324, 1276, 1261, 1206, 1167, 1112, 1019
+
+
−
1
+
+
Na] ) calcd for C H N NaO S 417.1091, found 417.1099.
cm ; HRMS (ESI-TOF, m/z) ([M] ) calcd for C H N OS
18 22 2 6
1
3
19
2
Dibenzyl 5-(Dimethylamino)-4-nitro-3-phenylthiophene-2,2(3H)-
2
51.1213, found 251.1213.
,1,3,3-Tetramethyl-2-(4-nitrobenzyl)thiouronium Bromide (5e).
dicarboxylate (4b). Obtained as a yellow oil via GP2 (69.3 mg, 67%
1
1
1
yield): H NMR (600 MHz, DMSO, 363 K) δ 7.38−7.28 (m, 13H),
Obtained as a yellow solid via GP1 (1.74 g, quantitative yield): H
NMR (400 MHz, CDCl ) δ 8.21 (d, J = 9.0 Hz, 2H), 7.87 (d, J = 9.0
Hz, 2H), 4.85 (s, 2H), 3.49 (s, 12H); C{ H} NMR (100 MHz,
CDCl ) δ 174.6, 147.7, 141.9, 130.8, 124.2, 45.0, 38.3; IR (film) 3398,
972, 2936, 1598, 1515, 1463, 1393, 1343, 1252, 1204, 1168, 1108,
057 cm ; HRMS (ESI-TOF, m/z) ([M] ) calcd for C H N O S
68.1114, found 268.1110.
2
nium Bromide (5f). Obtained as a yellow solid via GP1 (1.87 g,
7
.08−7.06 (m, 2H), 5.34 (s, 1H), 5.29 (d, J = 12.5 Hz, 1H), 5.25 (d, J
3
13
1
= 12.5 Hz, 1H), 4.78 (d, J = 12.5 Hz, 1H), 4.67 (d, J = 12.5 Hz, 1H),
1
3
1
.22 (s, 6H); 13C{ H} NMR (150 MHz, DMSO, 363 K) δ 167.7,
3
64.4, 163.5, 137.0, 135.4, 134.6, 128.94, 128.91, 12.85, 128.82,
2
1
2
−1
+
+
128.81, 128.72, 128.58, 128.50, 128.3, 118.1, 68.8, 68.6, 67.7, 56.3,
12
18
3
2
4
1
6.1; IR (film) 3027, 1737, 1590, 1453, 1430, 1373, 1291, 1261, 1232,
−1
+
199, 1139 cm ; HRMS (ESI-TOF, m/z) ([M + Na] ) calcd for
-(2-Ethoxy-2-oxo-1-phenylethyl)-1,1,3,3-tetramethylthiouro-
+
C H N NaO S 541.1404, found 541.1414.
28 26 2 6
1
quantitative yield): H NMR (400 MHz, CDCl ) δ 7.45 (m, 2H), 7.39
Ethyl (2S,3S)-5-(Dimethylamino)-4-nitro-3-phenyl-2,3-dihydro-
3
thiophene-2-carboxylate (4c). Obtained as a yellow oil via GP2
(
m, 3H), 5.32 (s, 1H), 4.20 (qd, J = 7.0, 1.0 Hz, 2H), 3.47 (s, 12H),
1
.20 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl ) δ 172.9,
(14.8 mg, 23% yield, co-eluted with a minor diastereomer): H NMR
1
1
3
1
3
(
400 MHz, CDCl ) δ 7.41−7.30 (m, 5H), 5.33 (d, J = 1.0 Hz, 1H),
68.5, 132.2, 129.9, 129.5, 128.6, 128.6, 63.5, 55.1, 44.9, 14.0; IR (film)
394, 2971, 2935, 1727, 1604, 1503, 1454, 1393, 1368, 1256, 1208,
167, 1110, 1057, 1019 cm ; HRMS (ESI-TOF, m/z) ([M] ) calcd
for C H N O S 295.1475, found 295.1475.
3
4
.30−4.22 (app. qd, J = 7.0, 1.0 Hz, 2H), 3.87 (d, J = 1.5 Hz, 1H), 3.29
1
−1
+
(
s, 6H), 1.31 (t, J = 7.0 Hz, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ
3
+
1
69.6, 165.9, 140.9, 128.9, 127.7, 126.6, 117.4, 62.6, 53.8, 51.2, 46.0,
15
23
2
2
2
-(1-Ethoxy-1-oxopropan-2-yl)-1,1,3,3-tetramethylthiouronium
14.0; IR (film) 2981, 2930, 1734, 1651, 1587, 1493, 1450, 1428, 1369,
−1
Bromide (5g). Obtained as a white solid via GP1 (1.56 g, quantitative
1291, 1271, 1179, 1095, 1028 cm ; HRMS (ESI-TOF, m/z) ([M +
1
+
+
yield): H NMR (400 MHz, CDCl ) δ 4.21−4.09 (m, 3H), 3.43 (s,
2H), 1.57 (d, J = 7.0 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H); C{ H}
NMR (100 MHz, CDCl ) δ 173.6, 170.4, 63.0, 45.4, 44.8, 16.8, 14.2;
IR (film) 3387, 2969, 2941, 1716, 1605, 1512, 1434, 1387, 1369, 1270,
209, 1180, 1113, 1059, 1002 cm ; HRMS (ESI-TOF, m/z) ([M] )
calcd for C H N O S 233.1318, found 233.1315.
Na] ) calcd for C H N NaO S 345.0879, found 345.0881.
3
15 18 2 4
13
1
1
[(2S,3S)-5-(Dimethylamino)-4-nitro-3-phenyl-2,3-dihydrothio-
phen-2-yl](phenyl)methanone (4d). Obtained as a yellow solid via
GP2 (14.2 mg, 20% yield, co-eluted with a minor diastereomer). Pure
3
−1
+
1
crystals of the major diastereomer were obtained after recrystallization
+
1
from acetone/heptane: H NMR (400 MHz, CDCl
) δ 7.89−7.86 (m,
10
21
2
2
3
2
-(9H-Fluoren-9-yl)-1,1,3,3-tetramethylthiouronium Bromide
2H), 7.64 (ddt, J = 8.0, 7.0, 1.5 Hz, 1H), 7.53−7.46 (m, 4H), 7.42−
7.38 (m, 2H), 7.34 (ddt, J = 8.5, 6.0, 1.5 Hz, 1H), 5.46 (d, J = 1.5 Hz,
1H), 4.71 (d, J = 1.5 Hz, 1H), 3.26 (s, 6H); C{ H} NMR (100 MHz,
(
5h). Obtained as a white solid via GP1 (1.88 g, quantitative yield):
1
13
1
H NMR (400 MHz, CDCl ) δ 7.74 (dd, J = 6.5, 2.0 Hz, 2H), 7.57−
3
7
.50 (m, 2H), 7.49−7.37 (m, 4H), 5.45 (s, 1H), 3.42 (s, 12H);
CDCl ) δ 191.7, 165.1, 141.4, 133.97, 133.87, 129.05, 129.03, 128.7,
3
1
3
1
C{ H} NMR (100 MHz, CDCl ) δ 173.1, 140.9, 140.5, 129.7, 128.8,
127.8, 126.9, 118.4, 52.51, 52.40, 45.9; IR (film) 3060, 3029, 2931,
3
−1
1
1
25.0, 120.7, 51.6, 45.2; IR (film) 3399, 1602, 1503, 1448, 1392, 1258,
167, 1109 cm ; HRMS (ESI-TOF, m/z) ([M] ) calcd for
C H N S 297.1420, found 297.1423.
8
1684, 1585, 1448, 1427, 1369, 1269, 1246, 1208, 1150, 1130 cm ;
−
1
+
+
+
HRMS (ESI-TOF, m/z) ([M + Na] ) calcd for C H N NaO S
19 18 2 3
+
377.0930, found 377.0929.
1
21
2
D
DOI: 10.1021/acs.joc.7b03255
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(
4S,5S)-N,N-Dimethyl-3-nitro-5-(4-nitrophenyl)-4-phenyl-4,5-di-
Diethyl 5-(Dimethylamino)-4-nitro-3-(p-tolyl)thiophene-2,2(3H)-
hydrothiophen-2-amine (4e). Obtained as a yellow solid via GP2
(
(
2
1
1
dicarboxylate (4l). Obtained as a yellow oil via GP2 (75.2 mg, 92%
1
1
14.8 mg, 20% yield, co-eluted with a minor diastereomer): H NMR
400 MHz, CDCl ) δ 8.25 (d, J = 9.0 Hz, 2H), 7.54 (d, J = 8.5 Hz,
yield): H NMR (400 MHz, CDCl
) δ 7.33 (d, J = 8.0 Hz, 2H), 7.10
3
(d, J = 8.0 Hz, 2H), 5.45 (s, 1H), 4.34 (dq, J = 10.5, 7.0 Hz, 1H), 4.26
(dq, J = 10.5, 7.0 Hz, 1H), 3.90 (dq, J = 10.5, 7.0 Hz, 1H), 3.76 (dq, J
3
H), 7.43−7.35 (m, 5H), 5.03 (d, J = 1.5 Hz, 1H), 4.46 (d, J = 1.5 Hz,
H), 3.38 (s, 6H); 13C{ H} NMR (100 MHz, CDCl ) δ 166.5, 148.5,
1
= 10.5, 7.0 Hz, 1H), 3.25 (s, 6H), 2.31 (s, 3H), 1.29 (t, J = 7.0 Hz,
3
3H), 0.98 (t, J = 7.0 Hz, 3H); 13C{ H} NMR (100 MHz, CDCl
1
) δ
47.7, 141.2, 129.1, 128.0, 127.5, 126.5, 124.6, 116.6, 59.3, 53.7, 46.2;
IR (film) 3063, 3029, 2926, 2852, 1706, 1654, 1586, 1517, 1493, 1451,
427, 1367, 1343, 1275, 1259, 1181, 1130, 1109, 1057 cm ; HRMS
ESI-TOF, m/z) ([M + Na] ) calcd for C H N NaO S 394.0832,
3
167.7, 164.7, 163.7, 138.0, 133.7, 129.0, 128.4, 119.0, 67.7, 63.1, 62.9,
−1
1
(
55.64, 45.8, 21.1, 13.8, 13.5; IR (film) 2983, 2936, 1735, 1588, 1513,
+
+
−1
1429, 1370, 1289, 1242, 1210, 1137, 1094, 1040, 1021 cm ; HRMS
18
17
3
4
+
+
(
ESI-TOF, m/z) ([M + Na] ) calcd for C H N NaO S 431.1247,
found 394.0814.
19 24 2 6
found 431.1247.
Ethyl (2S,3S)-5-(Dimethylamino)-4-nitro-2,3-diphenyl-2,3-dihy-
drothiophene-2-carboxylate (4f). Major diastereomer, obtained as a
yellow solid via GP2 (38.3 mg, 48% yield): H NMR (600 MHz,
Diethyl 5-(Dimethylamino)-3-(4-methoxyphenyl)-4-nitrothio-
1
phene-2,2(3H)-dicarboxylate (4m). Obtained as a yellow oil via
1
GP2 (77.3 mg, 91% yield): H NMR (400 MHz, CDCl ) δ 7.36 (d, J =
CDCl ) δ 7.67−7.60 (m, 2H), 7.54−7.30 (m, 8H), 5.54 (s, 1H), 3.80
3
3
8
.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 5.43 (s, 1H), 4.33 (dq, J = 10.5,
7.0 Hz, 1H), 4.24 (dq, J = 10.5, 7.0 Hz, 1H), 3.90 (dq, J = 10.5, 7.0 Hz,
H), 3.77 (dq, J = 10.5, 7.0 Hz, 1H), 3.77 (s, 3H), 3.24 (s, 6H), 1.28
(
dq, J = 10.5, 7.0 Hz, 1H), 3.75 (dq, J = 10.5, 7.0 Hz, 1H), 3.25 (s,
H), 0.85 (t, J = 7.0 Hz, 3H); 1 C{ H} NMR (150 MHz, CDCl ) δ
3
1
6
1
1
2
1
3
1
(
68.9, 166.2, 141.3, 138.2, 129.3, 128.9, 128.7, 128.5, 128.2, 127.3,
25.8, 71.2, 62.7, 57.3, 46.0, 13.5; IR (film) 3061, 3031, 2981, 2932,
242, 1729, 1580, 1445, 1427, 1370, 1286, 1265, 1231, 1186, 1129,
095, 1053, 1034 cm ; HRMS (ESI-TOF, m/z) ([M + Na] ) calcd
for C H N NaO S 421.1192, found 421.1193.
t, J = 7.0 Hz, 3H), 0.99 (t, J = 7.0 Hz, 3H); 13C{ H} NMR (100
1
MHz, CDCl ) δ 167.7, 164.7, 163.6, 159.5, 129.7, 128.8, 119.0, 113.7,
3
−1
+
67.8, 63.1, 62.9, 55.30, 55.23, 45.8, 13.8, 13.6; IR (film) 2983, 2936,
−1
+
1735, 1587, 1511, 1429, 1369, 1290, 1242, 1212, 1178, 1137 cm ;
21
22
2
4
+
+
HRMS (ESI-TOF, m/z) ([M + Na] ) calcd for C H N NaO S
Ethyl (2R,3S)-5-(Dimethylamino)-4-nitro-2,3-diphenyl-2,3-dihy-
19 24
2
7
4
47.1196, found 447.1192.
Diethyl 3-(2,4-Dimethoxyphenyl)-5-(dimethylamino)-4-nitrothio-
phene-2,2(3H)-dicarboxylate (4n). Obtained as a yellow oil via GP2
drothiophene-2-carboxylate (4f′). Minor diastereomer, obtained as
1
a yellow solid via GP2 (26.3 mg, 33% yield): H NMR (600 MHz,
CDCl ) δ 7.14−7.00 (m, 10H), 5.70 (s, 1H), 4.33 (dq, J = 11.0, 7.0
3
1
(
52.7 mg, 58% yield): H NMR (400 MHz, CDCl ) δ 7.33 (d, J = 9.0
3
Hz, 1H), 4.29 (dq, J = 11.0, 7.0 Hz, 1H), 3.35 (s, 6H), 1.26 (t, J = 7.0
Hz, 3H); 1 C{ H} NMR (150 MHz, CDCl ) δ 172.0, 165.0, 137.3,
3
1
Hz, 1H), 6.45−6.42 (m, J = 8.5 Hz, 2H), 6.04 (s, 1H), 4.34 (dq, J =
0.5, 7.0 Hz, 1H), 4.27 (dq, J = 10.5, 7.0 Hz, 1H), 3.90 (dq, J = 10.5,
.0 Hz, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.72 (dq, J = 10.5, 7.0 Hz,
3
1
7
1
1
4
1
33.8, 130.1, 128.8, 128.2, 128.0, 127.8, 127.4, 127.3, 68.8, 63.1, 59.0,
6.0, 14.0; IR (film) 3060, 3029, 2977, 2930, 2242, 1726, 1583, 1521,
447, 1429, 1371, 1287, 1263, 1216, 1188, 1135, 1094, 1078, 1052
H), 3.24 (s, 6H), 1.29 (t, J = 7.0 Hz, 3H), 0.99 (t, J = 7.0 Hz, 3H);
13
1
−
1
+
C{ H} NMR (100 MHz, CDCl
3
) δ 167.8, 165.0, 164.0, 160.7, 158.6,
cm ; HRMS (ESI-TOF, m/z) ([M + Na] ) calcd for
+
129.2, 119.0, 118.1, 104.5, 98.9, 67.4, 62.9, 62.7, 55.9, 55.3, 48.2, 45.6,
C H N NaO S 421.1192, found 421.1189.
2
1
22
2
4
1
1
3.8, 13.5; IR (film) 2983, 2937, 1735, 1584, 1506, 1461, 1439, 1372,
Ethyl (2R,3S)-5-(Dimethylamino)-2-methyl-4-nitro-3-phenyl-2,3-
dihydrothiophene-2-carboxylate (4g). First diastereomer obtained
as a yellow solid via GP2 (12.8 mg, 19% yield): H NMR (600 MHz,
−1
291, 1245, 1208, 1139, 1033 cm ; HRMS (ESI-TOF, m/z) ([M +
+
+
1
Na] ) calcd for C H N NaO S 477.1302, found 477.1304.
20 26 2 8
Diethyl 3-[2-(Benzyloxy)phenyl]-5-(dimethylamino)-4-nitrothio-
CDCl ) δ 7.47−7.44 (m, 2H), 7.32−7.26 (m, 3H), 4.70 (s, 1H), 3.83
3
phene-2,2(3H)-dicarboxylate (4p). Obtained as a yellow oil via GP2
(
6
dq, J = 10.5, 7.0 Hz, 1H), 3.77 (dq, J = 10.5, 7.0 Hz, 1H), 3.30 (s,
1
H), 2.00 (s, 3H), 0.92 (t, J = 7.0 Hz, 3H); 13C{ H} NMR (150 MHz,
1
(73.1 mg, 73% yield): H NMR (600 MHz, DMSO, 363 K) δ 7.58 (d,
J = 7.5 Hz, 2H), 7.43−7.40 (m, 3H), 7.34 (t, J = 7.5 Hz, 1H), 7.26
ddd, J = 8.5, 7.5, 1.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.93 (t, J = 7.5
Hz, 1H), 6.13 (s, 1H), 5.16 (d, J = 12.0 Hz, 1H), 5.13 (d, J = 12.0 Hz,
H), 4.31 (dq, J = 10.5, 7.0 Hz, 1H), 4.24 (dq, J = 10.5, 7.0 Hz, 1H),
CDCl ) δ 170.0, 166.9, 138.5, 128.4, 128.2, 128.1, 118.6, 64.3, 62.4,
1.4, 46.0, 30.4, 13.6; IR (film) 3029, 2978, 2931, 2869, 1717, 1585,
448, 1425, 1393, 1368, 1289, 1245, 1198, 1175, 1139, 1100, 1064,
010 cm ; HRMS (ESI-TOF, m/z) ([M + Na] ) calcd for
3
(
6
1
1
1
3
(
−
1
+
.81 (dq, J = 10.5, 7.0 Hz, 1H), 3.65 (dq, J = 10.5, 7.0 Hz, 1H), 3.15
+
C H N NaO S 359.1036, found 359.1036.
13
1
1
6
20
2
4
s, 6H), 1.22 (t, J = 7.0 Hz, 3H), 0.84 (t, J = 7.0 Hz, 3H); C{ H}
Ethyl (2S,3S)-5-(Dimethylamino)-2-methyl-4-nitro-3-phenyl-2,3-
NMR (150 MHz, DMSO, 363 K) δ 168.2, 164.8, 164.2, 157.0, 137.8,
129.6, 129.2, 128.6, 128.0, 127.7, 126.6, 121.0, 118.3, 113.3, 70.5, 67.2,
dihydrothiophene-2-carboxylate (4g′). Second diastereomer ob-
1
tained as a yellow solid via GP2 (12.1 mg, 18% yield): H NMR
6
1
(
3.3, 62.9, 48.9, 45.9, 14.0, 13.5; IR (film) 3064, 2983, 2936, 1734,
(
600 MHz, CDCl ) δ 7.40−7.31 (m, 5H), 5.24 (s, 1H), 4.29 (q, J =
.0 Hz, 2H), 3.30 (s, 6H), 1.33 (t, J = 7.0 Hz, 3H), 1.22 (s, 3H);
C{ H} NMR (150 MHz, CDCl ) δ 173.0, 166.5, 137.6, 128.79,
28.75, 128.1, 121.8, 120.1, 62.9, 59.1, 58.0, 45.9, 20.5, 14.1; IR (film)
028, 2960, 2927, 2870, 1727, 1583, 1450, 1429, 1371, 1289, 1261,
225, 1136, 1102, 1057, 1015 cm ; HRMS (ESI-TOF, m/z) ([M +
Na] ) calcd for C H N NaO S 359.1036, found 359.1034.
3
−1
585, 1492, 1451, 1429, 1373, 1274, 1240, 1139, 1021 cm ; HRMS
7
+
+
ESI-TOF, m/z) ([M + Na] ) calcd for C H N NaO S 523.1509,
1
3
1
25 28 2 7
3
found 523.1509.
1
3
1
Diethyl 5-(Dimethylamino)-3-(4-fluorophenyl)-4-nitrothiophene-
2
,2(3H)-dicarboxylate (4q). Obtained as a yellow oil via GP2 (67.6
−1
1
mg, 82% yield): H NMR (400 MHz, CDCl ) δ 7.44 (dd, J = 8.5, 5.5
3
+
+
16
20
2
4
Hz, 2H), 6.99 (app. t, J = 8.5 Hz, 2H), 5.47 (s, 1H), 4.34 (dq, J = 10.5,
N,N-Dimethyl-4′-nitro-3′-phenyl-3′H-spiro[fluorene-9,2′-thio-
7
1
.0 Hz, 1H), 4.26 (dq, J = 10.5, 7.0 Hz, 1H), 3.91 (dq, J = 10.5, 7.0 Hz,
H), 3.78 (dq, J = 10.5, 7.0 Hz, 1H), 3.26 (s, 6H), 1.29 (t, J = 7.0 Hz,
phen]-5′-amine (4h). Obtained as a yellow solid via GP2 (76.1 mg,
1
9
1
7
7
1
3
1
5% yield): H NMR (600 MHz, CDCl , 363 K) δ 7.87 (d, J = 7.5 Hz,
13
1
3
3H), 0.99 (t, J = 7.0 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ
3
H), 7.81 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.49 (td, J =
.5, 1.0 Hz, 1H), 7.41 (td, J = 7.5, 1.0 Hz, 1H), 7.34−7.27 (m, 4H),
.05 (br. s, 2H), 6.88 (td, J = 7.5, 1.0 Hz, 1H), 6.19 (d, J = 7.5 Hz,
1
67.5, 164.5, 163.5, 162.5 (d, JC−F = 247.0 Hz), 132.9 (d, JC−F = 3.0
Hz), 130.3 (d, JC−F = 8.5 Hz), 118.8, 115.2 (d, JC−F = 21.5 Hz), 67.5
19
1
(
d, JC−F = 1.0 Hz), 63.3, 63.0, 55.2, 45.8, 13.8, 13.5; F{ H} NMR δ
H), 4.79 (s, 1H), 3.39 (s, 6H); 13C{ H} NMR (150 MHz, CDCl ,
1
3
−113.7; IR (film) 2983, 2937, 1734, 1588, 1508, 1429, 1369, 1288,
63 K) δ 168.2, 151.2, 140.7, 140.0, 139.1, 138.0, 129.73, 129.72
29.48, (129.0) (this carbon peak was not observed, even at 363 K,
because of peak broadening due to restricted rotation; a rough
−1
1
272, 1241, 1160, 1137, 1097, 1039, 1021 cm ; HRMS (ESI-TOF,
+
+
m/z) ([M + Na] ) calcd for C H FN NaO S 435.0997, found
18
21
2
6
4
35.0994.
2
3
estimate was obtained via a high-temperature HSQC experiment ),
28.5, 128.2, 127.1, 126.9, 121.9, 120.9, 120.7, 117.9, 64.0, 61.8, 46.4;
IR (film) 3488, 3059, 2929, 1954, 1579, 1286, 1262, 1191, 1145, 1032
Diethyl 3-(3-Chlorophenyl)-5-(dimethylamino)-4-nitrothiophene-
1
2,2(3H)-dicarboxylate (4r). Obtained as a yellow solid via GP2 (59.2
1
mg, 69% yield): H NMR (400 MHz, CDCl ) δ 7.44−7.42 (m, 1H),
3
−
1
+
cm ; HRMS (ESI-TOF, m/z) ([M + Na] ) calcd for
7.35 (dt, J = 7.0, 2.0 Hz, 1H), 7.28−7.22 (m, 2H), 5.45 (s, 1H), 4.34
(dq, J = 10.5, 7.0 Hz, 1H), 4.26 (dq, J = 10.5, 7.0 Hz, 1H), 3.91 (dq, J
+
C H N NaO S 423.1138, found 423.1136.
4
2
20
2
2
E
DOI: 10.1021/acs.joc.7b03255
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
=
10.5, 7.0 Hz, 1H), 3.81 (dq, J = 10.5, 7.0 Hz, 1H), 3.26 (s, 6H), 1.29
Diethyl (E)-5-(Dimethylamino)-4-nitro-3-styrylthiophene-2,2(3H)-
13
1
(
t, J = 7.0 Hz, 3H), 1.00 (t, J = 7.0 Hz, 3H); C{ H} NMR (100
dicarboxylate (4x). Obtained as a yellow solid via GP3 (47.9 mg, 57%
1
MHz, CDCl ) δ 167.3, 164.6, 163.2, 137.0, 133.1, 129.5, 128.4, 127.5,
yield): H NMR (400 MHz, CDCl
3
) δ 7.38−7.35 (m, 2H), 7.32−7.22
3
1
2
1
26.3, 119.1, 67.0, 63.3, 63.1, 53.9, 45.8, 13.9, 13.4; IR (film) 2982,
927, 2855, 1736, 1590, 1430, 1372, 1286, 1246, 1211, 1168, 1139,
096, 1040 cm ; HRMS (ESI-TOF, m/z) ([M + Na] ) calcd for
(m, 3H), 6.81 (d, J = 15.5 Hz, 1H), 6.19 (dd, J = 15.5, 9.0 Hz, 1H),
5.05 (d, J = 9.0 Hz, 1H), 4.32 (dq, J = 10.5, 7.0 Hz, 1H), 4.24 (dq, J =
−
1
+
1
1
1
0.5, 7.0 Hz, 1H), 4.16 (q, J = 7.0 Hz, 2H), 3.22 (s, 6H), 1.28 (s, 3H),
.17 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 167.3, 164.9, 163.3,
1
35
21
+
C H ClN NaO S 451.0701, found 451.0700.
3
1
8
2
6
36.5, 134.9, 128.5, 127.9, 126.6, 122.2, 116.7, 67.4, 63.3, 63.2, 54.3,
Diethyl 3-(4-Chlorophenyl)-5-(dimethylamino)-4-nitrothiophene-
2
,2(3H)-dicarboxylate (4s). Obtained as a yellow solid via GP2 (57.5
45.8, 14.0, 13.8; IR (film) 3727, 3705, 3626, 2961, 2926, 1735, 1587,
1
−1
mg, 67% yield): H NMR (400 MHz, CDCl ) δ 7.39 (d, J = 8.5 Hz,
1446, 1428, 1369, 1234, 1136, 1020 cm ; HRMS (ESI-TOF, m/z)
3
+
+
2
1
3
0
1
4
1
H), 7.26 (d, J = 8.5 Hz, 2H), 5.44 (s, 1H), 4.33 (dq, J = 10.5, 7.0 Hz,
H), 4.25 (dq, J = 10.5, 7.0 Hz, 1H), 3.91 (dq, J = 10.5, 7.0 Hz, 1H),
.78 (dq, J = 10.5, 7.0 Hz, 1H), 3.24 (s, 6H), 1.28 (t, J = 7.0 Hz, 3H),
([M + Na] ) calcd for C20H N NaO S 443.1247, found 443.1256.
24 2 6
Diethyl 5-(Dimethylamino)-4-nitro-3-phenethylthiophene-
2
,2(3H)-dicarboxylate (4y). Obtained as a yellow solid via GP2
1
.98 (t, J = 7.0 Hz, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 167.4,
1
(35.5 mg, 42% yield): H NMR (400 MHz, CDCl ) δ 7.29−7.25 (m,
3
3
2
(
H), 7.20−7.16 (m, 3H), 4.54 (dd, J = 10.5, 4.5 Hz, 1H), 4.34−4.17
m, 4H), 3.16 (s, 6H), 2.96 (ddd, J = 14.5, 10.5, 6.0 Hz, 1H), 2.81
64.5, 163.4, 135.7, 134.1, 129.9, 128.5, 118.6, 67.3, 63.3, 63.1, 55.3,
5.8, 13.8, 13.5; IR (film) 2983, 2936, 1734, 1588, 1491, 1429, 1371,
286, 1241, 1209, 1138, 1089, 1039, 1015 cm ; HRMS (ESI-TOF,
−1
(ddd, J = 14.5, 10.5, 6.0 Hz, 1H), 2.09 (dtd, J = 13.0, 10.5, 6.0 Hz,
+
35
+
1H), 1.98 (dddd, J = 13.0, 10.5, 6.0, 4.5 Hz, 1H), 1.30 (t, J = 7.0 Hz,
m/z) ([M + Na] ) calcd for C H ClN NaO S 451.0701, found
18
21
2
6
1
3
1
6
H), 1.27 (t, J = 7.0 Hz, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ
4
51.0698.
3
67.5, 165.3, 164.8, 142.0, 128.35, 128.18, 125.8, 118.2, 68.9, 63.26,
Diethyl 3-(2-Bromophenyl)-5-(dimethylamino)-4-nitrothiophene-
3.09, 50.2, 45.8, 32.6, 31.6, 13.92, 13.77; IR (film) 2983, 2935, 1735,
2
,2(3H)-dicarboxylate (4t). Obtained as a yellow solid via GP2 (73.8
−1
1
1589, 1451, 1428, 1370, 1284, 1250, 1211, 1132, 1095, 1030 cm ;
mg, 78% yield): H NMR (400 MHz, CDCl ) δ 7.57−7.51 (m, 2H),
3
+
+
HRMS (ESI-TOF, m/z) ([M + Na] ) calcd for C H N NaO S
7
1
3
.23 (td, J = 7.5, 1.0 Hz, 1H), 7.09 (td, J = 7.5, 1.5 Hz, 1H), 6.23 (s,
H), 4.34 (dq, J = 10.5, 7.0 Hz, 1H), 4.28 (dq, J = 10.5, 7.0 Hz, 1H),
20 26
2
6
4
45.1404, found 445.1401.
.88 (dq, J = 10.5, 7.0 Hz, 1H), 3.69 (dq, J = 10.5, 7.0 Hz, 1H), 3.22
s, 6H), 1.28 (t, J = 7.0 Hz, 3H), 0.97 (t, J = 7.0 Hz, 3H); 13C{ H}
1
(
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b03255.
■
NMR (100 MHz, CDCl ) δ 167.3, 164.6, 163.2, 137.0, 133.2, 129.5,
3
S
1
28.4, 127.5, 126.3, 119.0, 67.0, 63.3, 63.1, 53.9, 45.8, 13.9, 13.4; IR
(film) 3728, 3703, 3627, 2983, 2924, 2854, 1737, 1589, 1466, 1431,
−1
1
376, 1290, 1252, 1211, 1141, 1119, 1095, 1053, 1029 cm ; HRMS
+
81
+
(
ESI-TOF, m/z) ([M + Na] ) calcd for C H BrN NaO S
NMR spectra for all reported compounds (PDF)
1
8
21
2
6
4
97.0175, found 497.0177.
X-ray data for compound 4d (CIF)
Diethyl 5-(Dimethylamino)-4-nitro-3-(4-nitrophenyl)thiophene-
2
,2(3H)-dicarboxylate (4u). Obtained as a yellow oil via GP2 (71.2
1
AUTHOR INFORMATION
Corresponding Author
*E-mail: nuno.maulide@univie.ac.at.
ORCID
Nuno Maulide: 0000-0003-3643-0718
Author Contributions
J.D.N. and P.A. contributed equally to this work.
mg, 81% yield): H NMR (400 MHz, CDCl ) δ 8.17 (d, J = 9.0 Hz,
■
3
2
1
3
0
1
4
1
H), 7.68 (d, J = 9.0 Hz, 2H), 5.58 (s, 1H), 4.36 (dq, J = 10.5, 7.0 Hz,
H), 4.28 (dq, J = 10.5, 7.0 Hz, 1H), 3.92 (dq, J = 10.5, 7.0 Hz, 1H),
.78 (dq, J = 10.5, 7.0 Hz, 1H), 3.28 (s, 6H), 1.30 (t, J = 7.0 Hz, 3H),
.97 (t, J = 7.0 Hz, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 167.1,
1
3
64.2, 163.3, 147.7, 144.9, 129.6, 123.5, 117.9, 66.8, 63.6, 63.3, 55.5,
6.0, 13.8, 13.5; IR (film) 2983, 2936, 1735, 1589, 1521, 1430, 1371,
347, 1274, 1243, 1211, 1139, 1095, 1039, 1020 cm ; HRMS (ESI-
−
1
+
+
TOF, m/z) ([M + Na] ) calcd for C H N NaO S 462.0942, found
4
1
8
21
3
8
Notes
62.0939.
The authors declare no competing financial interest.
Diethyl 5′-(Dimethylamino)-4′-nitro-[2,3′-bithiophene]-
2
′,2′(3′H)-dicarboxylate (4v). Obtained as a yellow solid via GP2
1
ACKNOWLEDGMENTS
(
60.1 mg, 75% yield): H NMR (400 MHz, CDCl ) δ 7.18 (dd, J =
■
3
5
1
7
1
.0, 1.0 Hz, 1H), 7.09 (d, J = 3.0 Hz, 1H), 6.93 (dd, J = 5.0, 3.5 Hz,
H), 5.79 (s, 1H), 4.33 (dq, J = 10.5, 7.0 Hz, 1H), 4.24 (dq, J = 10.5,
.0 Hz, 1H), 4.04 (dq, J = 10.5, 7.0 Hz, 1H), 3.94 (dq, J = 10.5, 7.0 Hz,
Support of this research by the DFG (Grant MA 4861/4-2)
and by the GE Foundation Scholar-Leaders Program is
acknowledged. The authors are grateful to the University of
Vienna for continued support of our research programs. Ing. A
Roller (University of Vienna) is acknowledged for assistance
with crystallographic structure determination.
H), 3.25 (s, 6H), 1.27 (t, J = 7.0 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H);
1
3
1
C{ H} NMR (100 MHz, CDCl ) δ 167.3, 164.3, 163.5, 139.6, 127.3,
3
1
3
1
26.7, 125.0, 119.4, 68.1, 63.3, 63.2, 51.6, 45.8, 13.8, 13.6; IR (film)
728, 3704, 3626, 3598, 2923, 2853, 2332, 1736, 1651, 1590, 1430,
373, 1276, 1374, 1277, 1261, 1140, 1094, 1035 cm ; HRMS (ESI-
−1
+
+
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4
■
16
20
2
6 2
23.0653.
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3
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F
DOI: 10.1021/acs.joc.7b03255
J. Org. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.joc.7b03255
J. Org. Chem. XXXX, XXX, XXX−XXX