Sulfonylation of five-membered heterocycles via an SNAr reaction

Article abstract of DOI:10.1021/jo401828b

An efficient, concise, and transition metal-free synthesis of functionalized sulfonylated five-membered heterocyclic compounds via an S _NAr reaction has been developed. Using commercially available sodium sulfinates as sulfonylation reagents, various five-membered heterocyclic sulfones were obtained in good yields.

Full text of DOI:10.1021/jo401828b

Article
pubs.acs.org/joc
Sulfonylation of Five-Membered Heterocycles via an SNAr Reaction
Shuai Liang, Ruo-Yi Zhang, Long-Yi Xi, Shan-Yong Chen,* and Xiao-Qi Yu*
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu,
610064, China
S
* Supporting Information
ABSTRACT: An efficient, concise, and transition metal-free
synthesis of functionalized sulfonylated five-membered hetero-
cyclic compounds via an SNAr reaction has been developed.
Using commercially available sodium sulfinates as sulfonylation
reagents, various five-membered heterocyclic sulfones were
obtained in good yields.
optimization studies. After stirring at 110 °C for 10 h under
air atmosphere, no product was found in 1,4-dioxane, water, or
toluene (Table 1, entries 1−3). In fact, the solubility of the
substrate is the cause of ineffectiveness of these three solvents.
Only trace amount of product was found in DMA (entry 4),
and this transformation was still sluggish even after 0.3 equiv of
Bu4NBr was added (entry 5). It should be mentioned that the
sulfonylation of pyridyl halides under the same condition
proceeded smoothly,34 which suggest that five-membered
heteroaromatic halides are poor coupling partners. Fortunately,
using DMSO as solvent, we obtained the product in 60% yield
(entry 6). The addition of Bu4NBr was not helpful for this
reaction (entry 7). When the dosage of 2a increased to 3 equiv,
the reaction afforded product in 72% yield (entry 8). Further
increasing 2a to 5 equiv, we isolated the product in 93% yield
(entry 9). Prolonging the reaction time to 20 h resulted in a
slightly increased yield (entry 10 vs entry 9). Reducing the
reaction time or lowering the reaction temperature resulted in
an obviously decreased yield (entry 11 or 12 vs entry 8).
With the optimized reaction condition in hand, we next
explored the scope of the reaction between various sulfinate
salts and heterocylic halides. Aryl sulfinates and alkyl sulfinates
afforded sulfones in excellent yields (Table 2, entries 1−7). It
seemed that the reactivity was influenced by the nucleophilic
ability of sulfinates. Sulfinates with electron-donating group on
the benzene ring performed better than those with electron-
withdrawing group (entries 1−3 vs entry 4). Interestingly,
chlorothiophene provided the product with the same high yield
as corresponding bromothiophene (entry 1 and entry 7). It
should be noted that chlorothiophenes often give notably lower
yields than bromothiophenes in a transition metal-catalyzed
system. Subsequently, we applied this method to a range of
five-membered heterocycles. This reaction has good compat-
ibility with various functional groups. Acetyl, ester, and even
aldehyde survived in this reaction (entries 1, 8, 9). When 2-
bromothiophene 1e was subjected to this reaction, only trace of
product was observed, which may be ascribed to its lower
INTRODUCTION
■
The heterocyclic sulfone moiety has been proven to be a useful
building block in medicinal chemistry. It exits widely in
medicinally active compounds, such as antagonists,1−4 enzyme
inhibitors,5−9 and antimicrobial agents.10−12 In addition to their
medicinal importance, heterocyclic sulfones are useful inter-
mediates in organic synthesis. For example, heterocyclic
sulfones serve as substrates in the Julia olefination to construct
double bonds13−15 (Figure 1).
Several approaches for preparation of aryl sulfones have been
reported. Traditional methods to prepare aryl sulfones include
the oxidation of sulfides16,17 and the sulfonylation of arenes in
the presence of strong acids.18,19 These traditional methods
have been replaced by more efficient routes through Pd or Cu
catalyzed cross-coupling reaction between sulfinate salts and
aryl halides, aryl boronic acids, or special arenes.20−32 Despite
significant advances in metal-catalyzed C−S bond formation
methods, only a few five-membered heteroaryl sulfones were
successfully prepared through cross-coupling reactions because
five-membered heteroaryl halides are notoriously poor coupling
partners.33 Furthermore, the sulfonylation of heterocycles
containing multiple heteroatoms remains a challenge. Recently,
metal-free protocols have attracted considerable attention.
Efficient methods for the synthesis of pyridyl, phenyl, and
vinyl sulfones have also been developed34−38 (Figure 2).
Herein, we describe a practical synthesis of five-membered
heterocyclic sulfones via the nucleophilic substitution of
halogenated or nitrated five-membered heterocycles with
sulfinate salts under metal-free conditions.
RESULTS AND DISCUSSION
■
Compared to pyridine and benzene, five-membered hetero-
cycles show intrinsically low reactivity toward nucleophilic
reagents because of their π-excessive character. Accordingly,
suitably located electron-withdrawing groups are necessary to
activate these substrates. Furthermore, the substitution
proceeds in general more readily at the α-position than at the
β-position to the heteroatom.39 In view of these rules, the
coupling of 2-acetyl-5-bromothiophene with sodium p-
toluenesulfinate was chosen as a model reaction for
Received: August 29, 2013
© XXXX American Chemical Society
A
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Figure 1. Examples of important five-membered heteroaryl sulfones.
When 2-bromo-5-nitrothiophene was subjected to this reaction,
disulfone 3o and 3p were isolated in good yield (entries 16,
17). 2-Nitrothiophene, like 2-bromothiophene, still remains
problematic (entry 18).
Then, we put our focus on the transformation of heterocyclic
halides containing multiple heteroatoms.40 The reaction of 2-
bromothiazole 4a with different sulfinates performed smoothly
(Table 3, entries 1−6). Other heterocycles with multiple
heteroatoms were further tested. 2-Bromobenzothiazole and 2-
clorobenzothiazole were efficiently transformed into sulfones in
the presence of sulfinate salts (entries 7 and 8). When methyl
sulfinate was used as the nucleophile, a mixture of 5i and
2(3H)-benzothiazolone was obtained (entry 9). 2-Bromo-N-
methylimidazole 4d and 8-bromocaffeine 4f were also good
substrates for this reaction (entries 10, 12, and 13). However,
5-chloro-N-methylimidazole 4e kept no change (entry 11).
Only trace amount of product was isolated for oxazole 4g
(entry 14). It was transformed into 2(3H)-benzoxazolone.
In support of the application of this method, we conducted
the reaction on a gram scale, and it also showed good
performance (Table 3, entry 5). The structure of 5e was
characterized by X-ray diffraction (Figure 3), which confirms
that the coupling occurs via C−S bond formation. To our
knowledge, synthesis of five-membered heterocyclic sulfones
containing multiple heteroatoms has hardly been studied, and
several products are reported for the first time; they may be
effective skeletons in medicines or organic synthesis.
Figure 2. Recent works for the synthesis of sulfones in metal-free
protocol.
reactivity toward nucleophilic reagents (entry 10). Even 3-
bromothiophene 1f did not undergo this transformation, which
may be due to the lower stability of its σ-adduct intermediate
(entry 11). These experimental results are consistent with the
SNAr mechanism of five-membered heteroaromatic substrates.
Furyl halides, for example, 1g, also underwent such trans-
formation, and afforded the product in moderate yield (entry
12). Interestingly, brominated indoles were good substrates for
this reaction, which provides a convenient synthetic method for
important indole derivatives (entries 13 and 14). Compound
3n is an analogue of compound A, which was found to be a
novel potent and highly selective HIV-1 nonnucleoside reverse
transcriptase inhibitor.5 1h has no electron-withdrawing group,
but it performed efficiently; it may ascribe to the formation of a
stable benzyl anion intermediate. We further found that an NO2
group could serve as the leaving group. 5-Nitrothiophene-2-
carboxaldehyde 1j gave sulfone 3i in moderate yield (entry 15).
Although the above experimental results are in accordance
with a metal-free SNAr mechanism, the effect of trace of metal
impurities and a radical mechanism should still be considered.
To study whether a metal or a radical intermediate is involved
in this reaction, several control experiments were carried out.
First, the reaction substrates were analyzed using inductively
a
Table 1. Optimization of the Reaction Conditions
entry
solvent
equiv. of 2a
yield (%)
entry
solvent
equiv. of 2a
yield (%)
b
1
2
3
4
5
6
1,4-dioxane
H2O
1.5
1.5
1.5
1.5
1.5
1.5
N.R
7
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1.5
3
58
N.R
8
72
93
Toluene
DMA
N.R
9
5
c
Trace
10
11
12
5
96
b
d
DMA
Trace
5
70
e
DMSO
60
5
31
a
b
c
d
e
Conditions: 1a, 0.3 mmol; 2a, 1.5−5 equiv; solvent, 2 mL; 110 °C; under air; 10 h. 0.3 equiv of Bu4NBr was added. For 20 h. 5 h. 70 °C.
B
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a
Table 2. Sulfonylation of Thiophenes, Furans, or Indoles
a
b
c
Conditions: 1a, 0.3 mmol; 2a, 5 equiv; DMSO, 2 mL; 110 °C; under air; 10−20 h. Compound 1 did not transform completely. Other 3-
substituted substrates gave the same results.
coupled plasma atomic emission spectroscopy (ICP-AES), 0.1
ppm of Pd, Cu, Fe, and other metal species were detected in
sulfinate (Table S1). Then, the reaction was carried out in the
presence of 200 ppm of Cu(OAc)2 or Pd(OAc)2. As shown in
Scheme 1, none of them promoted the reaction rate. We
further found that the yield had no change in Ar atmosphere,
and the addition of 0.5 equiv of TEMPO showed no inhibition
(Scheme 2). Based on these results, the effect of metal
impurities and a radical mechanism should be excluded.
undergoes such a transformation. However, if the intermediate
forms, it could afford the sulfonylation product.
CONCLUSIONS
■
In conclusion, we have developed an efficient approach for the
synthesis of five-membered heterocyclic sulfones, which have
been proven to be important in series of medicinally active
compounds. The reaction proceeds under mild conditions and
avoids the use of metal catalysts and other additives, which
make it significantly greener than current alternatives. Mean-
while, we have conducted several experiments to identify a
transition metal-free SNAr mechanism.
With the above results and proof in the literature,39 an
addition−elimination mechanism is proposed as shown in
Scheme 3. First, the addition of nucleophile 2a to the
heteroaromatic electrophile 1d generates σ-adduct intermediate
D. The intermediate is stabilized by an electron-withdrawing
group. Then, elimination of bromide gives the product 3i. The
formation of σ-adduct intermediate E, resulting from the
addition of 2a to 3-bromothiophene 1f, is difficult, so it hardly
EXPERIMENTAL SECTION
■
General Description. 1H NMR and 13C NMR spectra were
measured on a 400 MHz spectrometer (1H 400 MHz, 13C 100 MHz),
using CDCl3 as the solvent with tetramethylsilane (TMS) as the
internal standard Chemical shifts (δ) are reported in ppm, and
C
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coupling constants (J) are in Hertz (Hz). s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet. Mass spectra were recorded with
ESI mode. HRMS analysis was recorded on a Q-TOF mass
spectrometer with ESI mode. Chemicals were purchased or prepared
by literature.41,42 Anhydrous DMSO was used for reaction.
Table 3. Sulfonylation of Hetrocyclics Containing Multiple
Heteroatoms
a
General Procedure (3a for Example). To a 10 mL flask was
added 2-acetyl-5-bromothiophene (0.3 mmol), sodium p-toluenesulfi-
nate (1.5 mmol), and 2 mL anhydrous DMSO, and the reaction
mixture was stirred at 110 °C for 10 h. After cooling down to room
temperature, the reaction mixture was mixed with ethyl acetate (15
mL), then washed by brine (4 × 15 mL) to get rid of DMSO and
excess sodium sulfinates. After drying with Na2SO4, the ethyl acetate
extracts were concentrated in vacuum, and the residue was purified by
flash column chromatography on silica gel to give the product.
3a.31 White solid (78.0 mg, 93%). mp = 162.0−163.7 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
1
1:4). H NMR (CDCl3, 400 MHz): δ 7.87 (d, J = 7.6 Hz, 2 H), 7.63
(d, J = 4.0 Hz, 1 H), 7.55 (d, J = 4.0 Hz, 1 H), 7.33 (d, J= 7.6 Hz, 2
H), 2.54 (s, 3 H), 2.41 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
190.4, 150.2, 150.1, 145.2, 138.0, 132.6, 131.3, 130.2, 127.7, 26.9, 21.6
ppm. MS (ESI): m/z calcd. [M+1]+ = 281.4; Found 281.3.
3b.31 Light yellow solid (66.2 mg, 83%). mp = 131.6−131.9 °C.
Isolated by flash column chromatography (ethyl acetate/petroleum
1
ether = 1:4). H NMR (CDCl3, 400 MHz): δ 7.99 (d, J = 8.0 Hz, 2
H), 7.66−7.52 (m, 5 H), 2.54 (s, 3 H) ppm. 13C NMR (CDCl3, 100
MHz): δ 190.3, 150.4, 149.7, 140.9, 133.9, 132.9, 131.3, 129.5, 127.6,
26.9 ppm. MS (ESI): m/z calcd. [M+1]+ = 267.3; Found 267.3.
3c.43 White solid (85.2 mg, 96%). mp = 146.4−146.8 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
1
1:4). H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 8.8 Hz, 2 H), 7.62
(d, J = 4.0 Hz, 1 H), 7.55 (d, J = 4.0 Hz, 1 H), 7.00 (d, J = 9.2 Hz, 2
H), 3.87 (s, 3 H), 2.54 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
190.3, 164.0, 150.8, 149.8, 132.3, 132.2, 131.2, 130.0, 114.8, 55.7, 26.8
ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H13O4S2
297.0255; Found 297.0255.
3d.43 Light yellow solid (57.6 mg, 64%). mp = 112.0−112.6 °C.
Isolated by flash column chromatography (ethyl acetate/petroleum
1
ether = 1:4). H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 8.8 Hz, 2
H), 7.66 (d, J = 4.0 Hz, 1 H), 7.57 (d, J = 4.0 Hz, 1 H), 7.52 (d, J = 8.4
Hz, 2 H), 2.55 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ 190.2,
150.8, 149.2, 140.7, 139.5, 133.2, 131.3, 129.9, 129.1, 26.9 ppm.
HRMS (ESI-TOF) m/z: [M - H]− Calcd for C12H8ClO3S2 298.9603;
Found 298.9597.
3e.43 Light yellow solid (84.3 mg, 89%). mp = 121.9−122.0 °C.
Isolated by flash column chromatography (ethyl acetate/petroleum
ether = 1:4). 1H NMR (CDCl3, 400 MHz): δ 8.60 (s, 1 H), 8.01−7.89
(m, 4H), 7.70−7.56 (m, 4 H), 2.53 (s, 3H) ppm. 13C NMR (CDCl3,
100 MHz): δ 190.3, 150.4, 149.8, 137.7, 135.3, 132.9, 132.2, 131.3,
129.9, 129.6, 129.5, 129.4, 128.0, 127.9, 122.3, 26.8 ppm. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C16H13O3S2 317.0306; Found
317.0324.
3f.31 White solid (56.5 mg, 82%). mp = 87.8−88.1 °C. Isolated by
flash column chromatography (ethyl acetate/petroleum ether = 1:4).
1H NMR (CDCl3, 400 MHz): δ 7.65 (q, J = 4.0 Hz, 2 H), 2.62−2.56
(m, 4 H), 1.44−1.42 (m, 2 H), 1.15−1.13 (m, 2 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ 190.4, 150.1, 148.2, 132.9, 131.1, 34.0, 27.0, 6.9
ppm. HRMS (ESI-TOF) m/z: [M - H]− Calcd for C9H9O3S2
228.9993; Found 228.9994.
3g.44 White solid (48.9 mg, 80%). mp = 136.0−136.3 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
1
1:4). H NMR (CDCl3, 400 MHz): δ 7.70 (d, J = 4.0 Hz, 1 H), 7.65
(d, J = 4.0 Hz, 1 H), 3.20 (s, 3 H), 2.61 (s, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ 190.2, 150.5, 148.1, 133.3, 131.2, 45.8, 26.9
ppm. Ms (ESI): m/z Calcd. [M+1]+ = 205.3; Found 205.3.
3h.43 White solid (59.5 mg, 64%). mp = 92.7−95.0 °C. Isolated by
flash column chromatography (ethyl acetate/petroleum ether = 1:4).
1H NMR (CDCl3, 400 MHz): δ 7.87 (d, J = 8.4 Hz, 2 H), 7.67 (d, J =
4.0 Hz, 1 H), 7.60 (d, J = 4.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 4.35
(q, J = 7.2 Hz, 2 H), 2.42 (s, 3 H), 1.35 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ 160.9, 149.0, 145.0, 140.6, 138.2, 132.6,
a
Conditions: 1a, 0.3 mmol; 2a, 5 equiv; DMSO, 2 mL; 110 °C; under
b
c
air; 10−20 h. Gram scale. Compound 4 did not transform
d
completely. Based on1H NMR analysis.
D
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Figure 3. X-ray crystal structure of 5e. CCDC 965064 contains the supplementary Crystallographic data for this paper. Data can be obtained free of
charge from The Cambridge crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
= 8.0 Hz, 2 H), 2.43 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
Scheme 1. Sulfonylation of 2-Bromothiazole without or with
the Addition of Metals
182.8, 151.8, 148.8, 145.4, 137.7, 134.6, 132.5, 130.2, 127.8, 21.6 ppm.
HRMS (ESI-TOF) m/z: [M - H]− Calcd for C12H9O3S2 264.9993;
Found 264.9987.
3l.30 Light yellow solid (40.5 mg, 54%). mp = 114.8−116.7 °C.
Isolated by flash column chromatography (ethyl acetate/petroleum
ether = 1:4). 1H NMR (CDCl3, 400 MHz): δ 9.71 (s, 1 H), 7.93 (d, J
= 8.4 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.26 (d, J = 3.2 Hz, 1 H),
7.22 (d, J = 3.6 Hz, 1 H), 2.45 (s, 3 H) ppm. 13C NMR (CDCl3, 100
MHz): δ 178.4, 154.5, 154.4, 145.9, 135.6, 130.3, 128.4, 118.4, 117.3,
21.7 ppm. MS (ESI): m/z Calcd. [M+1]+ = 251.3; Found 251.2.
3m.43 White solid (69.6 mg, 81%). mp = 116.1−117.8 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
1
1:4). H NMR (CDCl3, 400 MHz): δ 8.88 (s, 1 H), 7.86 (d, J = 8.4
Hz, 2 H), 7.60 (d, J = 8.4 Hz, 1 H), 7.40−7.28 (m, 4 H), 7.18−7.14
(m, 1 H), 2.53 (s, 3 H), 2.39 (s, 3 H) ppm. 13C NMR (CDCl3, 100
MHz): δ 144.3, 139.0, 135.8, 129.9, 129.6, 129.4, 128.3, 127.0, 126.1,
120.7, 118.4, 112.1, 21.6, 8.9 ppm. HRMS (ESI-TOF) m/z: [M - H]−
Calcd for C16H14NO2S 284.0745; Found 284.0737.
Scheme 2. Experiments for Mechanism
3n.43 Light yellow solid (39.1 mg, 38%). mp = 153.2−153.5 °C.
Isolated by flash column chromatography (ethyl acetate/petroleum
ether = 1:2). 1H NMR (CDCl3, 400 MHz): δ 9.49 (s, 1 H), 8.56 (d, J
= 8.0 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.46−7.36 (m, 3 H), 7.25 (d,
J = 7.2 Hz, 2 H), 4.40 (q, J = 7.2 Hz, 2 H), 2.38 (s, 3 H), 1.37 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ 159.0, 143.6,
140.3, 134.1, 129.2, 127.7, 127.3, 126.4, 126.3, 123.6, 122.7, 119.5,
112.1, 62.4, 21.6, 14.1 ppm. HRMS (ESI-TOF) m/z: [M - H]− Calcd
for C18H16NO4S 342.0800; Found 342.0806.
Scheme 3. Proposed Mechanism
3o.43 White solid (72.9 mg, 62%). mp = 151.2−152.2 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
1
1:1). H NMR (CDCl3, 400 MHz): δ 7.84 (d, J = 8.4 Hz, 4 H), 7.52
(s, 2 H), 7.34 (d, J = 8.4 Hz, 4 H), 2.43 (s, 6 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ 150.7, 145.5, 137.6, 132.0, 130.3, 127.8, 21.7
ppm. HRMS (ESI-TOF) m/z: [M - H]− Calcd for C18H15O4S3
391.0132; Found 391.0138.
3p.45 White solid (36.7 mg, 51%). mp = 171.7−172.5 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
1:2). 1H NMR (CDCl3, 400 MHz): δ 7.72 (s, 2 H), 3.24 (s, 6 H) ppm.
13C NMR (CDCl3, 100 MHz): δ 149.2, 132.9, 45.9 ppm. HRMS (ESI-
TOF) m/z: [M - H]− Calcd for C6H7O4S3 238.9506; Found 238.9510.
5a.43 White solid (60.2 mg, 84%). mp = 129.3−129.8 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
132.3, 130.1, 127.6, 62.0, 21.6, 14.2 ppm. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C14H15O4S2 311.0412; Found 311.0412.
1
1:2). H NMR (CDCl3, 400 MHz): δ 7.98 (d, J = 8.4 Hz, 2 H), 7.94
3i.43 White solid (78.2 mg, 98%). mp = 126.9−127.6 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
(d, J = 2.8 Hz, 1 H), 7.64 (d, J = 2.8 Hz, 1 H), 7.36 (d, J = 7.6 Hz, 2
H), 2.43 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ 167.6, 145.6,
145.2, 135.8, 130.1, 128.7, 125.6, 21.7 ppm. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C10H10NO2S2 240.0153; Found 240.0142.
1
1:4). H NMR (CDCl3, 400 MHz): δ 9.93 (s, 1 H), 7.89 (d, J = 8.4
Hz, 2 H), 7.71 (d, J = 4.0 Hz, 1 H), 7.67 (d, J = 3.6 Hz, 1 H), 7.85 (d, J
E
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5b.43 White solid (60.2 mg, 73%). mp = 129.4−130.2 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
5m.43 White solid (77.1 mg, 67%). mp = 221.0−223.3 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
1:1). H NMR (CDCl3, 400 MHz): δ 8.66 (s, 1 H), 8.05−7.93 (m, 4
H), 7.74−7.65 (m, 2 H), 4.36 (s, 3 H), 3.51 (s, 3 H), 3.37 (s, 3 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ 155.4, 151.2, 146.6, 146.4,
135.7, 135.4, 132.0, 130.6, 130.1, 129.9, 129.7, 128.1, 122.7, 39.3, 30.0,
28.2 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H17N4O4S
385.0971; Found 385.0962.
1
1
1:2). H NMR (CDCl3, 400 MHz): δ 8.72 (s, 1 H), 8.06−7.90 (m, 5
H), 7.68−7.63 (m, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ 145.3,
135.7, 135.6, 132.2, 130.7, 129.8, 129.7, 129.7, 128.0, 127.8, 125.8,
123.0 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C13H10NO2S2 276.0153; Found 276.0138.
5c.46 Colorless oil (33.7 mg, 69%). Isolated by flash column
chromatography (ethyl acetate/petroleum ether = 1:2). 1H NMR
(CDCl3, 400 MHz): δ 8.04 (d, J = 3.2 Hz, 1 H), 7.74 (d, J = 3.2 Hz, 1
H), 3.33 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ 166.2, 144.9,
125.8, 42.7 ppm. Ms (ESI): m/z Calcd. [M+1]+ = 164.2; Found 164.2.
5d.43 White solid (50.5 mg, 89%). mp = 70.8−72.5 °C. Isolated by
flash column chromatography (ethyl acetate/petroleum ether = 1:2).
1H NMR (CDCl3, 400 MHz): δ 8.06 (d, J = 3.2 Hz, 1 H), 7.72 (d, J =
3.2 Hz, 1 H), 2.82−2.75 (m, 1 H), 1.51−1.49 (m, 2 H), 1.18−1.16 (m,
2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ 166.1, 145.1, 125.6, 31.8,
6.5 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C6H8NO2S2
189.9996; Found 190.0006..
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR, MS (EI) spectra for new
compounds, and ICP-AES analysis of sulfinate salt. This
material is available free of charge via the Internet at http://
pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: chensy@scu.edu.cn. Tel. & Fax: (86)-28-85415886.
*E-mail: xqyu@scu.edu.cn. Tel. & Fax: (86)-28-85415886.
■
5e.47 White solid (1.1g, 82%). mp = 122.5−124.3 °C. Isolated by
flash column chromatography (ethyl acetate/petroleum ether = 1:2).
1H NMR (CDCl3, 400 MHz): δ 8.12−8.10 (m, 2 H), 7.96 (d, J = 3.2
Hz, 1 H), 7.67−7.55 (m, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
167.1, 145.3, 138.9, 134.3, 129.5, 128.7, 125.9 ppm. MS (ESI): m/z
Calcd. [M+1]+ = 226.3; Found 226.1.
Notes
The authors declare no competing financial interest.
5f.48 White solid (31.1 mg, 40%). mp = 136.6−138.1 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
ACKNOWLEDGMENTS
■
1
This work was financially supported by the National Program
on Key Basic Research Project of China (973 Program,
2013CB328900) and the National Science Foundation of
China (Grant No. 2120210 7 and 21021001).
1:2). H NMR (CDCl3, 400 MHz): δ 8.04 (d, J = 8.8 Hz, 2 H), 7.97
(d, J = 3.2 Hz, 1 H), 7.69 (d, J = 2.8 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 2
H) ppm. 13C NMR (CDCl3, 100 MHz): δ 166.7, 145.4, 141.3, 137.3,
130.1, 129.8, 126.0 ppm. MS (ESI): m/z Calcd. [M+1]+ = 260.7;
Found 260.7.
5g.49 White solid (60.6 mg, 70%). mp = 129.9−131.8 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
REFERENCES
(1) Crosignani, S.; Pret
■
1
̂
re, A.; Jorand-Lebrun, C.; Fraboulet, G.;
1:2). H NMR (CDCl3, 400 MHz): δ 8.15 (d, J = 7.6 Hz, 1 H), 8.04
Seenisamy, J.; Augustine, J. K.; Missotten, M.; Humbert, Y.; Cleva, C.;
Abla, N.; Daff, H.; Schott, O.; Schneider, M.; Burgat-Charvillon, F.;
Rivron, D.; Hamernig, I.; Arrighi, J.-F.; Gaudet, M.; Zimmerli, S. C.;
Juillard, P.; Johnson, Z. J. Med. Chem. 2011, 54, 7299.
(2) Ivachtchenko, A. V.; Golovina, E. S.; Kadieva, M. G.; Kysil, V. M.;
Mitkin, O. D.; Tkachenko, S. E.; Okun, I. M. J. Med. Chem. 2011, 54,
8161.
(d, J = 7.6 Hz, 2 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.54 (m, 2 H), 7.37 (d, J
= 7.2 Hz, 2 H), 2.43 (s, 3H) ppm. 13C NMR (CDCl3, 100 MHz): δ
167.7, 152.9, 145.9, 137.0, 135.5, 130.2, 129.0, 127.7, 127.4, 125.5,
122.2, 21.7 ppm. MS (ESI): m/z Calcd. [M+1]+ = 290.4; Found 290.3.
5h.50 Light yellow solid (76.0 mg, 78%). mp = 154.3−156.0 °C.
Isolated by flash column chromatography (ethyl acetate/petroleum
ether = 1:2). 1H NMR (CDCl3, 400 MHz): δ 8.77 (s, 1 H), 8.15−7.89
(m, 6 H), 7.67−7.51 (m, 4H) ppm. 13C NMR (CDCl3, 100 MHz): δ
167.4, 152.9, 137.0, 135.7, 135.3, 132.2, 131.1, 129.9, 129.8, 129.7,
128.0, 127.8, 127.5, 125.5, 123.1, 122.2 ppm. MS (ESI): m/z Calcd.
[M+1]+ = 326.4; Found 326.3.
(3) Liu, K. G.; Robichaud, A. J.; Bernotas, R. C.; Yan, Y.; Lo, J. R.;
Zhang, M.-Y.; Hughes, Z. A.; Huselton, C.; Zhang, G. M.; Zhang, J. Y.;
Kowal, D. M.; Smith, D. L.; Schechter, L. E.; Comery, T. A. J. Med.
Chem. 2010, 53, 7639.
(4) Hartz, R. A.; Arvanitis, A. G.; Arnold, C.; Rescinito, J. P.; Hung,
K. L.; Zhang, G.; Wong, H.; Langley, D. R.; Gilligan, P. J.; Trainor, G.
L. Bioorg. Med. Chem. Lett. 2006, 16, 934.
(5) La Regina, G.; Coluccia, A.; Brancale, A.; Piscitelli, F.; Gatti, V.;
Maga, G.; Samuele, A.; Pannecouque, C.; Schols, D.; Balzarini, J.;
Novellino, E.; Silvestri, R. J. Med. Chem. 2011, 54, 1587.
(6) Becker, D. P.; Barta, T. E.; Bedell, L. J.; Boehm, T. L.; Bond, B.
R.; Carroll, J.; Carron, C. P.; DeCrescenzo, G. A.; Easton, A. M.;
Freskos, J. N.; Funckes-Shippy, C. L.; Heron, M.; Hockerman, S.;
Howard, C. P.; Kiefer, J. R.; Li, M. H.; Mathis, K. J.; McDonald, J. J.;
Mehta, P. P.; Munie, G. E.; Sunyer, T.; Swearingen, C. A.; Villamil, C.
I.; Welsch, D.; Williams, J. M.; Yu, Y.; Yao, J. J. Med. Chem. 2010, 53,
6653.
5i.51 White solid (it is an inseparable mixture containing 5i and
2(3H)-benzothiazolone, identified by GC-MS, and a ratio of 2:1 via 1H
NMR. Totally 47.5 mg, the yield for only 5i after calculation: 55%).
Isolated by flash column chromatography (ethyl acetate/petroleum
ether = 1:4). For only 5i: 1H NMR (CDCl3, 400 MHz): δ 8.21 (d, J =
7.6 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.62 (m, 2 H), 3.41 (s, 3 H)
ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C8H8NO2S2
213.9996; Found 213.9991.
5j.43 White solid (48.1 mg, 68%). mp = 155.6−156.5 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
1
1:1). H NMR (CDCl3, 400 MHz): δ 7.92 (d, J = 8.4 Hz, 2 H), 7.35
(d, J = 8.0 Hz, 2 H), 7.09 (d, J = 1.2 Hz, 1 H), 6.94 (d, J = 1.2 Hz, 1
H), 3.97 (s, 3 H), 2.43 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
145.2, 143.4, 136.7, 129.9, 129.4, 128.2, 125.5, 35.2, 21.7 ppm. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C11H13N2O2S 237.0698; Found
237.0680.
(7) Nuti, E.; Panelli, L.; Casalini, F.; Avramova, S. I.; Orlandini, E.;
Santamaria, S.; Nencetti, S.; Tuccinardi, T.; Martinelli, A.; Cercignani,
G.; D’Amelio, N.; Maiocchi, A.; Uggeri, F.; Rossello, A. J. Med. Chem.
2009, 52, 6347.
(8) Du, W.; Hardouin, C.; Cheng, H.; Hwang, I.; Boger, D. L. Bioorg.
Med. Chem. Lett. 2005, 15, 103.
5l.43 White solid (75.1 mg, 72%). mp = 208.9−209.7 °C. Isolated
by flash column chromatography (ethyl acetate/petroleum ether =
1
1:1). H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 8.4 Hz, 2 H), 7.39
(9) Young, S. D.; Amblard, M. C.; Britcher, S. F.; Grey, V. E.; Tran,
T. O.; Lumma, W. C.; Huff, J. R.; Schleif, W. A.; Emini, E. E.; O’Brien,
J. A.; Pettibone, D. J. Bioorg. Med. Chem. Lett. 1995, 5, 491.
(10) Padmavathi, V.; Thriveni, P.; Sudhakar Reddy, G.; Deepti, D.
Eur. J. Med. Chem. 2008, 43, 917.
(d, J = 8.4 Hz, 2 H), 4.30 (s, 3 H), 3.52 (s, 3 H), 3.37 (s, 3 H), 2.46 (s,
3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ 155.5, 151.2, 146.7, 146.5,
146.3, 135.6, 130.2, 128.6, 109.8, 34.2, 30.0, 28.2, 21.8 ppm. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C15H17N4O4S 349.0971; Found
349.0961.
F
dx.doi.org/10.1021/jo401828b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(11) Hussain, I.; Yawer, M. A.; Lalk, M.; Lindequist, U.; Villinger, A.;
Fischer, C.; Langer, P. Bioorg. Med. Chem. 2008, 16, 9898.
(12) Chen, C.-J.; Song, B.-A.; Yang, S.; Xu, G.-F.; Bhadury, P. S.; Jin,
L.-H.; Hu, D.-Y.; Li, Q.-Z.; Liu, F.; Xue, W.; Lu, P.; Chen, Z. Bioorg.
Med. Chem. 2007, 15, 3981.
(51) Yu, B.; Liu, A.-H.; He, L.-N.; Li, B.; Diao, Z.-F.; Li, Y.-N. Green
Chem. 2012, 14, 957.
(13) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563 and
references cited therein..
(14) Surprenant, S. C.; Chan, W. Y.; Berthelette, C. Org. Lett. 2003,
5, 4851.
(15) Li, N.-S.; Scharf, L.; Adams, E. J.; Piccirilli, J. A. J. Org. Chem.
2013, 78, 5970.
(16) Truce, W. E.; Klinger, T. C.; Brand, W. W. In Organic Chemistry
of Sulfur; Oae, S., Ed.; Plenum Press: New York, 1977.
(17) Oae, S. Organic Sulfur Chemistry; CRC Press: Boca Raton, FL,
1992; Chapter 6.
(18) Ueda, M.; Uchiyama, K.; Kano, T. Synthesis 1984, 323.
(19) Graybill, B. M. J. Org. Chem. 1967, 32, 2931.
(20) Kar, A.; Sayyed, I. A.; Lo, W. F.; Kaiser, H. M.; Beller, M.; Tse,
M. K. Org. Lett. 2007, 9, 3405.
(21) Huang, F.; Batey, R. A. Tetrahedron 2007, 63, 7667.
(22) Baskin, J. M.; Wang, Z. Org. Lett. 2002, 4, 4423.
(23) Suzuki, H.; Abe, H. Tetrahedron Lett. 1995, 36, 6239.
(24) Zhu, W.; Ma, D. J. Org. Chem. 2005, 70, 2696.
(25) Bian, M.; Xu, F.; Ma, C. Synthesis 2007, 19, 2951.
(26) Reeves, D. C.; Rodriguez, S.; Heewon, L.; Haddad, N.;
Krishnamurthy, D.; Senayake, C. H. Tetrahedron Lett. 2009, 50, 2870.
(27) Cacchi, S.; Fabrizi, G.; Goggoamani, A.; Parisi, L. M.; Bernini, R.
J. Org. Chem. 2004, 69, 5608.
(28) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Parisi, L. M. Org. Lett.
2002, 4, 4719.
(29) Wu, Z.-Y.; Song, H.-Y.; Cui, X.-L.; Pi, C.; Du, W.-W.; Wu, Y.-J.
Org. Lett. 2013, 15, 1270.
(30) Bandgar, B. P.; Bettigeri, S. V.; Phopase, J. Org. Lett. 2004, 6,
2105.
(31) Yuan, Y.-Q.; Guo, S.-R. Synlett 2011, 18, 2750.
(32) Saidi, O.; Marafie, J.; Ledger, A. E. W.; Liu, P. M.; Mahon, M. F.;
Kociok-Kohn, G.; Whittlesey, M. K.; Frost, C. G. J. Am. Chem. Soc.
̈
2011, 133, 19298.
(33) Su, M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2012, 51, 4710.
(34) Maloney, K. M.; Kuethe, J. T.; Linn, K. Org. Lett. 2011, 13, 102.
(35) Umierski, N.; Manolikakes, G. Org. Lett. 2013, 15, 188.
(36) Chawl, R.; Kapoor, R.; Singh, A. K.; Yadav, L. D. S. Green Chem.
2012, 14, 1308.
(37) Liang, S.; Zhang, R.-Y.; Wang, G.; Chen S.-Y.; Yu, X.-Q. Eur. J.
Org. Chem. [Online early access]. DOI: 10.1002/ejoc.201301101.
(38) Ulman, A.; Edward Urankar, E. J. Org. Chem. 1989, 54, 4691.
(39) Terrier, F. Modern Nucleophilic Aromatic Substitution; Wiley-
VCH, 2013.
(40) For a related transformation from 2-clorobenzothiazol derivative
and its application in synthesis, see: Mizukawa, Y.; Fujimori, T.; Kato,
Y. U.S. Patent Appl.20070117031, 24 May 2007.
(41) Boga, C.; Vecchio, E. D.; Forlani, L.; Todesco, P. E. J.
Organomet. Chem. 2000, 601, 233.
(42) Rad, M. N. S.; Behrouz, S.; Nekoei, A.-R. Synlett 2012, 23, 1191.
(43) These are new compounds.
(44) Renato, N.; Michelangelo, G.; Caterina, A.; Liliana, L.;
Domenico, S. J. Chem. Res. 1993, 7, 274.
(45) Clark, P. D.; Mesher, S. T. E.; Primak, A. Phosphorus, Sulfur and
Silicon and the Related Elements 1996, 114, 99.
(46) Yamanaka, H.; Ohba, S.; Sakamoto, T. Heterocycles 1990, 31,
1115.
(47) Kikelj, D.; Urleb, U. Science of Synthesis 2002, 11, 627.
(48) Noguchi, T.; Hashimolo, Y.; Mori, T.; Kano, S.; Miyazaki, K.
Yakugaku Zasshi 1968, 88, 1437.
(49) Heinz, B. Helv. Chim. Acta 1974, 57, 1912.
(50) Miyazawa, T.,; Yasufuku, K.; Nishihata, T.; Imamura, K.;
Matsumoto, K.; Watanabe, T. Jpn. Kokai Tokkyo Koho 1988, JP
63284104 A 19881121.
G
dx.doi.org/10.1021/jo401828b | J. Org. Chem. XXXX, XXX, XXX−XXX