Trifluoroacetic acid catalyzed thiophenylmethylation and thioalkylmethylation of lactams and phenols via domino three-component reaction in water

Article abstract of DOI:10.1039/c3ra47874b

An efficient one-pot trifluoroacetic acid catalyzed thiophenylmethylation and thioalkylmethylation of lactams, isatins and phenols via domino three-component coupling (3CC) with thiols and formaldehyde in water has been described. The developed protocol has wide substrate-scope for a variety of thiols, lactams and isatins. Utility of the protocol for ortho-/para- thiophenylmethylation of phenols indicated that reaction proceeds through in situ formation of a thiophenylmethylium cation intermediate. LC-ESIMS-based mechanistic investigation further confirmed formation of this intermediate. For isatins, the N- versus O-thiophenylmethylation was confirmed by recording the X-ray crystal structure of compound 4e. Thionaphthyl analog 3e exhibited significant antiproliferative activity in MCF-7 cells (IC₅₀ 8 μM) via apoptosis-induction.

Full text of DOI:10.1039/c3ra47874b

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Trifluoroacetic acid catalyzed
thiophenylmethylation and thioalkylmethylation of
lactams and phenols via domino three-component
reaction in water†‡
Cite this: RSC Adv., 2014, 4, 14081
Ramesh Mudududdla,ab Rohit Sharma,ab Santosh K. Guru,c Manoj Kushwaha,d
Ajai P. Gupta,d Sonali S. Bharate,e Subrayashastry Aravinda,a Rajni Kant,f
ab
ab
Shashi Bhushan,bc Ram A. Vishwakarma
*
*
and Sandip B. Bharate
An efficient one-pot trifluoroacetic acid catalyzed thiophenylmethylation and thioalkylmethylation of
lactams, isatins and phenols via domino three-component coupling (3CC) with thiols and formaldehyde
in water has been described. The developed protocol has wide substrate-scope for a variety of thiols,
lactams and isatins. Utility of the protocol for ortho-/para-thiophenylmethylation of phenols indicated
that reaction proceeds through in situ formation of a thiophenylmethylium cation intermediate. LC-
ESIMS-based mechanistic investigation further confirmed formation of this intermediate. For isatins, the
N- versus O-thiophenylmethylation was confirmed by recording the X-ray crystal structure of
compound 4e. Thionaphthyl analog 3e exhibited significant antiproliferative activity in MCF-7 cells (IC50
8 mM) via apoptosis-induction.
Received 21st December 2013
Accepted 25th February 2014
DOI: 10.1039/c3ra47874b
www.rsc.org/advances
cycloaddition of in situ generated ortho-quinone methide with
styrene.5 Further, the 3CC of phenols with formaldehyde and
Introduction
Thiols are common building blocks in organic chemistry,1 and
play important roles in biological processes and are also used in
cell imaging and protein labelling.2 The thiophenylmethylation
reaction nds wide utility in organic chemistry and in the total
synthesis of natural products.3 Available protocols3,4 involve use
of organic solvents, and also the substrate-scope for these
protocols has not been established.
lactam gave amidoalkyl products 2 through Mannich-type
condensation.6 As a continuation of these results, herein we
investigated the reactivity of thiophenols in these 3CC reac-
tions. This resulted in development of simple and efficient tri-
uoroacetic
acid
catalyzed
one-pot
protocol
for
thiophenylmethylation and thioalkylmethylation of lactams,
isatins and phenols (Fig. 1). With the advances in green
chemistry, development of reactions in aqueous media is
gaining tremendous importance.7 The present protocol involves
use of water as a reaction medium containing 0.1% TFA as a
catalyst.
The three-component coupling (3CC) of phenols with form-
aldehyde and styrene produced avans 1 via [4 + 2]-Diels–Alder
aMedicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal
Road, Jammu-180001, India. E-mail: ram@iiim.ac.in; sbharate@iiim.ac.in; Fax:
+91-191-2569333; Tel: +91-191-2569111
bAcademy of Scientic and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Ra
Marg, New Delhi-110001, India
cCancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal
Road, Jammu-180001, India
dQuality Control and Quality Assurance Division, CSIR-Indian Institute of Integrative
Medicine, Canal Road, Jammu-180001, India
ePreformulation Laboratory, CSIR-Indian Institute of Integrative Medicine, Canal
Road, Jammu-180001, India
fX-ray Crystallography Laboratory, Post-Graduate Department of Physics and
Electronics, University of Jammu, Jammu-180006, India
† IIIM Publication number IIIM/1643/2014.
‡ Electronic supplementary information (ESI) available: Spectroscopic data scans,
biology data and protocols, LC-ESIMS data. CCDC 975544. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ra47874b
Fig. 1 Our previous work on phenols (reaction of phenols with
formaldehyde and styrene/vinyl lactams) and the present work on
thiols.
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formed (entry 12). As reported by Abdel-Ghany and coworkers,4a
we attempted this 3CC reaction in dioxane as a solvent without
addition of any catalyst; however no product was formed (entry
13). When this reaction was carried out using lactam instead of
N-vinyl lactam using optimized reaction conditions (entry 11),
similar results were obtained. Since N-vinyl lactam undergoes
acid and heat-mediated devinylation to produce lactam, which
participates in thiophenylmethylation reaction, all further
investigations were performed using lactams.
As the reaction also proceeded without water as a medium, it
is clear that water only acts a reaction medium and do not
participate in reaction mechanism.
The scope of this 3CC protocol was investigated for variety of
aromatic and aliphatic thiols and various lactams. Results are
shown in Fig. 2. The reaction proceeded smoothly with both
aromatic as well as aliphatic thiols, producing 64–90% yields of
thiophenyl/thioalkyl methylated products.
The substitution of various electron-donating (3b, 3c, 3g, and
3h) as well as electron-withdrawing groups (3d, 3i, and 3n) on
thiophenol was also well tolerated. Furthermore, the thio-
naphthol also participated well in this reaction producing cor-
responding thiophenylmethylated products in excellent yields
(products 3e, 3j and 3o).
In case of lactams as well as isatins, there are two possible
positions for alkylation. For lactams, it was possible to differ-
entiate N- versus O-alkylation simply by checking the presence
or absence of amidic carbonyl (–N–CO–) stretching frequency in
IR spectrum. All alkylated products of lactams showed presence
Results and discussion
The present study was initiated with the reaction of thiophenol
5a with formaldehyde 6 and N-vinyl caprolactam 7 in presence
of 50% w/w silica–HClO4 (Table 1, entry 1). In this reaction,
thiophenylmethylated lactam 3a was formed and not the ortho-
amidoalkyl product, as it was formed with phenols.6 Similar to
our earlier reports,6,8 it was noticed that the formation of
product 3a proceeds via acid and heat mediated devinylation of
N-vinyl lactam 7, which is followed by the 3CC of lactam with
thiol 5a and formaldehyde 6. The preference of 3CC on
SH-functionality over ortho-CH demonstrates higher nucleo-
philicity of SH- group than ortho-CH position in this reaction.
Next, the catalyst and solvent optimization study was carried
out. The silica–HClO4 catalyst produced 60% yield of product 3a
in ACN; however no improvements in reaction yield was
observed when further solvent optimization was carried out
using other solvents such as DCM, MeOH and DMF. Next, the
reaction in acetic acid and formic acid was investigated, which
produced poor yields (10 and 30%, respectively) of product 3a
(entries 2 and 3). In the presence of 10 mol% TFA, reaction
moved efficiently producing 80% of the product (entry 4). Next,
we attempted to use water as a reaction medium for this reac-
tion. The use of 10% TFA in water produced 3a in excellent yield
(entry 5). Further optimization of the TFA amount and reaction
time (entries 5–11) indicated that 0.1% TFA in water at 80 ꢀC for
30 min was able to produce desired product in good yield (entry
11). Continuation of reaction for additional time (entries 9 and
10) does not let to signicant improvement in product yield.
Thus, entry 11 was considered as optimized reaction condition.
When the reaction was performed only in water, no product was
Table 1 Solvent and catalyst optimization studiesa
Entry Reaction medium
Temp. (ꢀC) Time (h) %Yieldb of 3a
1
50 mol% w/w
80
8
60
silica–HClO4 in ACN
10 mol% AcOH
10 mol% HCOOH
10 mol% TFA
10% TFA in water
10% TFA in water
10% TFA in water
1% TFA in water
0.1% TFA in water
0.1% TFA in water
0.1% TFA in water
Water
2
3
4
5
6
7
8
9
10
11c
12
13
80
80
80
80
rt
6
6
2
2
1
12
2
2
1
0.5
10
30
80
80
0
rt
0
80
80
80
80
80
80
80
80
78
76
0
24
12
Dioxane
0
Fig. 2 Thiophenylmethylation and thioalkylmethylation of lactams
(reaction time and yields are mentioned in the parentheses). Reagents
and conditions: thiol 5 (1.0 mmol), lactam 8 (1.2 mmol), formaldehyde
6 (3.0 mmol), 0.1% TFA in water, 80 ꢀC, 0.5–1 h.
a
Reagents and conditions: thiol 5a (1.0 mmol), N-vinyl lactam 7 (1.2
b
c
mmol), formaldehyde 6 (3.0 mmol). Isolated yield. Optimized
reaction condition.
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of stretching frequency of ꢁ1650 cmꢂ1 in IR spectrum indi- This nding further suggested that nucleophilicity of SH is
cating N-alkylation. Further, this observation was supported by higher than ortho-CH.
1H and 13C NMR data.
Further, in order to support the formation of intermediate I,
Next we investigated the 3CC reaction of thiophenols 5 and and also to investigate the scope of this protocol for thio-
formaldehyde 6 with isatins 9 as nucleophiles. Like lactams and phenylmethylation of –CH activated phenols, the reaction of
N-vinyl lactams, the thiophenylmethylated isatins 4a–e were thiophenols with formaldehyde 6 and o-cresol 13 was studied.
formed in excellent yields (Fig. 3). In this case, two possible In this reaction, a pair of two products were formed, one with
positions for alkylation cannot be differentiated only with IR para-substituted o-cresols 14aa–14ba and other with ortho-/
data as products contain additional –C]O group. Further, both para-disubstituted o-cresols 14ab–14bb, the former being a
possible products have similar expected NMR values. Thus, in major product. The occurrence of thiophenylmethylation at 4,
order to conrm the structure of the obtained products, X-ray 6-positions of o-cresol, indicates that the reaction sequence
crystallography study for one of the analog 4e was carried out. should be involving formation of thiophenylmethylium cation I,
The molecular conformation of 4e in crystals is shown in Fig. 4. followed by subsequent electrophilic substitution on o-cresol at
Next, the reactivity of thiophenol 5c with formaldehyde 6 and 4,6-positions (Fig. 6).
styrene 10 in presence of 50 mol% silica–HClO4 was investi-
Next, in order to conrm the formation of thio-
gated. The silica–HClO4 catalyst was chosen for this reaction, in phenylmethylium cation I intermediate, the reaction between
order to follow the exactly same protocol as we reported earlier 4-methoxy thiophenol, formaldehyde and caprolactam was
for phenols.5 The expected styrene-linked product 12 was not monitored by LC-ESIMS. The proposed mechanism for forma-
formed; instead a thiophenol dimer 11 was produced. The tion of N-thiophenylmethylated product 3c is depicted in
formation of thiophenol dimer 11 occurred presumably via Fig. 7b. The LCMS spectra depicted in Fig. 7a showed formation
formation of thiophenylmethylium cation intermediate I. The of thiophenylmethylium cation I with m/z 153 [M]+ at tR 13.3
styrene 10 has not participated and not played any role in this min, which eventually led to formation of product 3c (m/z 266
reaction, which was further conrmed by performing control [M + H]+ at tR 21.5 min). Apart from these peaks, LCMS analysis
reaction (reaction in the absence of styrene 10). When this 3CC also indicated formation of lactam dimer 16 (m/z 239 [M + H]+ at
reaction was performed in presence of 0.1% TFA in water, it also 11.5 min), and interestingly an ortho-thioquinone methide II
led to formation of product 11 and not the thioavan 12 (Fig. 5). (m/z 153 [M + H]+ at 15.7 min), which further produced ortho-
amidoalkyated product 15 (m/z 266 [M + H]+ at 20.9 min). The
product 15 was formed in very minor amount, and thus could
not be isolated. In order to rule out the possibility of formation
of I through hydrolysis of product 3c, the HPLC analysis of the
reaction mixture at different time intervals was carried out. The
HPLC analysis (Fig. 7a insets) performed at 2 min, showed
41 : 42 ratio of I: 3c, which was further changed to 11 : 78 ratio
at 30 min, indicating that the thiophenylmethylium cation I has
been formed immediately aer mixing reactants as an inter-
mediate and not through the hydrolysis of product 3c. Further,
we checked the stability9 of representative products 3h and 4a
in LCMS mobile phase (0.1% formic acid in water; and
Fig. 3 Thiophenylmethylation of isatins. Reagents and conditions:
thiol 5 (1.0 mmol), formaldehyde 6 (3.0 mmol), isatin 9 (1.2 mmol), 0.1%
TFA in water, 80 ꢀC, 15 min.
Fig.
5 The 3CC reaction of thiophenol with formaldehyde and
styrene. Reagents and conditions: thiophenol 5c (1.0 mmol), formal-
dehyde 6 (3.0 mmol), styrene 10 (1.2 mmol) and 50 mol% silica–HClO4
in ACN was heated at 80 ꢀC for 4 h. Similar results were observed when
0.1% TFA in water was used instead of silica–HClO4 in ACN.
Fig. 4 The molecular conformation of 4e in crystals.
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acetonitrile) as well as in biological uids (PBS, SGF and SIF)
and both compounds were found to be stable aer incubation
ꢀ
at 37 C for 30 min (see Section S8 of ESI‡).
Based on the literature precedence on anticancer potential
for this class of compounds,4b all synthesized compounds were
screened for cytotoxicity against a panel of cancer cell lines
(results shown in ESI: Table S1‡). Analog 3e displayed cytotox-
icity against MCF-7 cells with IC50 value of 8 mM. The mecha-
nistic investigation of compound 3e for cell cycle phase
distribution, mitochondrial membrane potential (MMP) loss,
and effect on apoptotic body formation in MCF-7 cells, revealed
that the compound exhibits antiproliferative activity via MMP
loss and induction of apoptosis in MCF-7 cells (see, ESI:
Section S5‡).
Fig. 6 Thiophenylmethylation of phenols. Reagents and conditions:
thiophenol 5 (1.0 mmol) and formaldehyde 6 (3.0 mmol), o-cresol 13
(1.2 mmol), 0.1% TFA in water, 80 ꢀC, 4 h.
Fig. 7 LC-ESIMS analysis to investigate the mechanism for thiophenylmethylation of lactam. (a) TIC chromatogram of crude reaction mixture
recorded after 2 min of reaction time (insets: HPLC chromatogram of reaction mixture recorded at 2 and 30 min, respectively; UV 240 nm). (b)
Scheme depicting various formation of various intermediates and products (c–h) MS spectrum of peaks eluted at tR 3.8, 11.5, 13.3, 15.7, 20.9 and
21.5 min.
14084 | RSC Adv., 2014, 4, 14081–14088
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ESIMS: m/z 236.1 [M + H]; HR-ESIMS: m/z 236.1102 calcd for
C
Conclusion
13H17NOS + H+ (236.1103).
1-((p-Tolylthio)methyl)azepan-2-one (3b). Yield: 82%; light
In summary, results presented here indicated that phenols and
thiophenols react differently via different intermediates and
gives different types of products. The simple and efficient TFA-
catalyzed protocol for thiophenylmethylation and thio-
alkylmethylation of lactams and phenols in aqueous medium
has been described. The developed protocol has several
advantages such as metal-free conditions, aqueous medium
and broad substrate scope. Further, the LCMS-based mecha-
nistic studies suggested that reaction proceeds through thio-
phenylmethylium cation intermediate. The naphthyl analog 3e
displayed promising cytotoxic activity and induced apoptosis in
breast cancer MCF-7 cells.
yellow oil; 1H NMR (CDCl3, 400 MHz): d 7.33 (d, J ¼ 8.0 Hz, 2H),
7.08 (d, J ¼ 8.0 Hz, 2H), 4.83 (s, 2H), 3.34 (t, J ¼ 8.0 Hz, 2H), 2.44
(t, J ¼ 4.0 Hz, 2H), 2.28 (s, 3H), 1.62–1.53 (m, 6H); 13C NMR
(CDCl3, 125 MHz): d 175.8, 137.0, 131.5, 130.3, 129.7, 52.3, 48.8,
37.1, 29.8, 28.4, 23.2, 21.0; IR (CHCl3): nmax 3435, 2927, 2855,
1649, 1492, 1476, 1442, 1419, 1351, 1336, 1256, 1228, 1191,
1138, 1089, 1042 cmꢂ1; ESI-MS: m/z 249.0 [M ꢂ H]ꢂ; HR-ESIMS:
m/z 250.1264 calcd for C14H19NOS + H+ (250.1260).
1-((4-Methoxyphenylthio)methyl)azepan-2-one (3c). Yield:
88%; colorless oil; 1H NMR (CDCl3, 400 MHz): d 7.41 (d, J ¼ 8.0 Hz,
2H), 6.84 (d, J ¼ 12.0 Hz, 2H), 4.79 (s, 2H), 3.77 (s, 3H), 3.35 (t, J ¼
4.0 Hz, 2H), 2.45 (t, J ¼ 4.0 Hz, 2H), 1.65–1.56 (m, 6H); 13C NMR
(CDCl3, 125 MHz): d 175.9, 159.4, 134.3, 124.2, 114.6, 55.2, 53.4,
49.1, 37.1, 29.8, 28.4, 23.3; IR (CHCl3): nmax 3849, 3740, 3684, 3665,
3308, 2927, 2854, 1726, 1648, 1591, 1493, 1442, 1419, 1284, 1244,
1191, 1029 cmꢂ1; ESI-MS: m/z 266.0 [M + H]+, 288.0 [M + Na]+; HR-
ESIMS: m/z 266.1209 calcd for C14H19NO2S + H+ (266.1209).
1-((4-Chlorophenylthio)methyl)azepan-2-one (3d). Yield:
78%; light yellow oil; 1H NMR (CDCl3, 400 MHz): d 7.32 (d, J ¼
8.0 Hz, 2H), 7.19 (d, J ¼ 8.0 Hz, 2H), 4.82 (s, 2H), 3.32 (t, J ¼ 4.0
Hz, 2H), 2.41 (t, J ¼ 4.0 Hz, 2H), 1.58–1.48 (m, 6H); 13C NMR
(CDCl3, 125 MHz): d 176.0, 133.0, 132.5, 132.0, 129.3, 51.6, 48.7,
37.2, 29.8, 28.4, 23.3; IR (CHCl3): nmax 3434, 2929, 2854, 1649,
1477, 1442, 1419, 1352, 1256, 1229, 1191, 1138, 1094, 1042, 1011
cmꢂ1; ESI-MS: m/z 270.0 [M + H]+; HR-ESIMS: m/z 270.071 calcd
for C13H16ClNOS + H+ (270.0713).
1-((Naphthalen-6-ylthio)methyl)azepan-2-one (3e). Yield:
90%; brown oil; 1H NMR (CDCl3, 400 MHz): d 7.91 (s, 1H), 7.79
(m, 3H), 7.53–7.43 (m, 3H), 5.01 (s, 2H), 3.40 (t, J ¼ 4.0 Hz, 2H),
2.48 (t, J ¼ 4.0 Hz, 2H), 1.61–1.52 (m, 6H); 13C NMR (CDCl3, 100
MHz): d 176.0, 133.7, 132.1, 131.6, 129.1, 128.5, 128.1, 127.7,
127.4, 126.5, 126.0, 51.5, 48.8, 37.2, 29.8, 28.4, 23.2; IR (CHCl3):
nmax 3308, 3049, 2927, 2853, 1726, 1647, 1500, 1478, 1442, 1418,
1351, 1257, 1132, 1073, 1041 cmꢂ1; ESI-MS: m/z 286.1 [M + H]+,
308.1 [M + Na]+; HR-ESIMS: m/z 286.1248 calcd for C17H19NOS +
Experimental section
General information
All chemicals were obtained from Sigma-Aldrich Company and
used as received. 1H, 13C and DEPT NMR spectra were recorded
on Brucker-Avance DPX FT-NMR 500 and 400 MHz instruments.
Chemical data for protons are reported in parts per million
(ppm) downeld from tetramethylsilane and are referenced to
the residual proton in the NMR solvent (CDCl3, 7.26 ppm).
Carbon nuclear magnetic resonance spectra (13C NMR) were
recorded at 125 MHz or 100 MHz: chemical data for carbons are
reported in parts per million (ppm, d scale) downeld from
tetramethylsilane and are referenced to the carbon resonance of
the solvent (CDCl3, 77 ppm). ESIMS and HRMS spectra were
recorded on Agilent 1100 LC-Q-TOF and HRMS-6540-UHD
machines. IR spectra were recorded on Perkin-Elmer IR spec-
trophotometer. Melting points were recorded on digital melting
point apparatus. LC-ESIMS analysis was carried out on Triple-
Quad LC-MS/MS system (model 6410).
General procedure for thiophenyl/thioalkyl methylation of
lactams and isatins
To the solution of substituted thiol (5a, 300 mg) in 0.1% TFA in H+ (286.1260).
water (5 mL) were added formaldehyde (6, 3 equiv.) and lactam
1-((Phenylthio)methyl)piperidin-2-one (3f). Yield: 80%;
(8, 1.2 mmol)/N-vinyl lactam (7, 1.2 mmol)/isatins (9, 1.2 mmol). brown oil; 1H NMR (CDCl3, 400 MHz): d 7.47 (d, J ¼ 8.0 Hz, 2H),
The resulting reaction mixture was then reuxed at 80 ꢀC for 15– 7.28–7.20 (m, 3H), 4.86 (s, 2H), 3.29 (t, J ¼ 4.0 Hz, 2H), 2.28 (t,
60 min. Completion of the reaction was monitored by TLC (20% J ¼ 4.0 Hz, 2H), 1.70–1.65 (m, 4H); 13C NMR (CDCl3, 125 MHz): d
EtOAc in n-hexane). Reaction mixture was cooled to room 169.6, 134.0, 131.3, 128.7, 127.0, 50.7, 46.7, 32.1, 22.7, 20.9; IR
temperature and was neutralized with saturated NaHCO3 solu- (CHCl3): nmax 3793, 3700, 3308, 2945, 2865, 1726, 1644, 1485,
tion and extracted with with EtOAc (50 mL ꢃ 2). Combined 1463, 1439, 1414, 1348, 1330, 1245, 1172, 1087, 1024 cmꢂ1; ESI-
organic layers were dried over anhydrous sodium sulphate and MS: m/z 222.0 [M + H]+; HR-ESIMS: m/z 222.0948 calcd for
evaporated on vacuo rotavapor to get crude product. Crude
products were puried by silica gel column chromatography
using EtOAc: hexane to get amido alkylated products.
C
12H15NOS + H+ (222.0947).
1-((p-Tolylthio)methyl)piperidin-2-one (3g). Yield: 82%; light
yellow oil; 1H NMR (CDCl3, 400 MHz): d 7.37 (d, J ¼ 8.0 Hz, 2H),
1-((Phenylthio)methyl)azepan-2-one (3a). Yield: 80%; light 7.10 (d, J ¼ 8.0 Hz, 2H), 4.82 (s, 2H), 3.33 (t, J ¼ 4.0 Hz, 2H), 2.30
yellow oil; 1H NMR (CDCl3, 400 MHz): d 7.47 (d, J ¼ 8.0 Hz, 2H), (m, 5H), 1.73 (m, 4H); 13C NMR (CDCl3, 125 MHz): d 176.0,
7.32 (dd, J ¼ 8.8 Hz, 2H), 7.24 (dd, J ¼ 4, 4 Hz, 1H), 4.93 (s, 2H), 137.5, 132.2, 130.2, 129.7, 51.6, 46.9, 32.2, 22.9, 21.14, 21.10; IR
3.40 (t, J ¼ 4.0 Hz, 2H), 2.49 (t, J ¼ 4.0 Hz, 2H), 1.66–1.56 (m, 6H); (CHCl3): nmax 3435, 2944, 2866, 1647, 1488, 1462, 1443, 1415,
13C NMR (CDCl3, 125 MHz): d 176.0, 134.0, 130.8, 128.9, 126.9, 1348, 1330, 1282, 1245, 1171, 1089, 1043 cmꢂ1; ESI-MS: m/z
51.6, 48.7, 37.2, 29.8, 28.3, 23.2; IR (CHCl3): nmax 3308, 2927, 236.1 [M + H]+; HR-ESIMS: m/z 236.1109 calcd for C13H17NOS +
2854, 1726, 1648, 1478, 1439, 1419, 1257, 1083, 1025 cmꢂ1
;
H+ (236.1103).
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8.0 Hz, 2H), 7.25 (d, J ¼ 8.0 Hz, 2H), 4.73 (s, 2H), 3.44 (t, J ¼ 4.0
Hz, 2H), 2.31 (t, J ¼ 4.0 Hz, 2H), 1.98 (m, 2H); 13C NMR (CDCl3,
100 MHz): d 175.0, 133.1, 132.15, 132.1, 129.1, 46.7, 46.6, 30.7,
17.5; IR (CHCl3): nmax 3434, 2920, 1687, 1477, 1460, 1419, 1289,
1251, 1158, 1094, 1011 cmꢂ1; ESI-MS: m/z 264.0 [M + Na]+; HR-
ESIMS: m/z 264.0217 calcd for C11H12ClNOS + Na+ (264.0220).
1-((Naphthalen-3-ylthio)methyl)pyrrolidin-2-one(3o). Yield:
88%; light yellow oil; 1H NMR (CDCl3, 400 MHz): d 7.90 (s, 1H),
7.77 (m, 3H), 7.50–7.42 (m, 3H), 4.85 (s, 2H), 3.42 (t, J ¼ 4.0 Hz,
2H), 2.26 (t, J ¼ 4.0 Hz, 2H), 1.92 (m, 2H); 13C NMR (CDCl3, 100
MHz): d 175.0, 133.7, 132.2, 131.1, 129.2, 128.6, 128.0, 127.7,
127.4, 126.6, 126.1, 46.5, 46.0, 30.8, 17.5; IR (CHCl3): nmax 3860,
3789, 3308, 3052, 2920, 1726, 1687, 1624, 1588, 1490, 1459,
1418, 1289, 1253, 1157, 1132, 1071, 1042 cmꢂ1; ESI-MS: m/z
258.0 [M + H]+, 280.0 [M + Na]+; HR-ESIMS: m/z 258.0941 calcd
for C15H15NOS + H+ (258.0947).
1-((Benzylthio)methyl)azepan-2-one (3p). Yield: 70%; light
yellow oil; 1H NMR (CDCl3, 400 MHz): d 7.38–7.23 (m, 5H), 4.57
(s, 2H), 3.78 (s, 2H), 3.34 (t, J ¼ 4.0 Hz, 2H), 2.48 (t, J ¼ 4.0 Hz,
2H), 1.70–1.6 (m, 6H); 13C NMR (CDCl3, 100 MHz): d 175.4,
137.8, 127.9, 127.5, 126.0, 48.7, 47.5, 36.3, 34.6, 28.9, 27.5, 22.4;
IR (CHCl3): nmax 3435, 3060, 3027, 2926, 2853, 1645, 1494, 1478,
1453, 1442, 1420, 1352, 1337, 1229, 1190, 1137, 1082, 1071, 1029
cmꢂ1; ESI-MS: m/z 250.1 [M + H]+, 272.1 [M + Na]+; HR-ESIMS:
m/z 250.1259 calcd for C14H19NOS + H+ (250.1260).
1-((Butylthio)methyl)azepan-2-one (3q). Yield: 68%; light
yellow oil; 1H NMR (CDCl3, 400 MHz): d 4.55 (s, 2H), 3.45 (t, J ¼
4.0 Hz, 2H), 2.56 (m, 4H), 1.73–1.67 (m, 6H), 1.61–1.57 (m, 2H),
1.42–1.38 (m, 2H), 0.92 (t, 4.0 Hz, 3H); 13C NMR (CDCl3, 125
MHz): d 176.1, 49.0, 48.3, 37.3, 31.7, 30.3, 29.9, 28.6, 23.5, 21.9,
13.7; IR (CHCl3): nmax 3789, 3682, 3435, 2928, 2856, 1648, 1442,
1420, 1352, 1257, 1228, 1190, 1138, 1082 cmꢂ1; ESI-MS: m/z
216.14 [M + H]+, 238.12 [M + Na]+; HR-ESIMS: m/z 216.1421
calcd for C11H21NOS + H+ (216.1417).
1-((Pentylthio)methyl)azepan-2-one (3r). Yield: 68%; light
yellow oil; 1H NMR (CDCl3, 400 MHz): d 4.55 (s, 2H), 3.45 (t, J ¼
4.0 Hz, 2H), 2.56–2.52 (m, 4H), 1.73–1.61 (m, 8H), 1.35 (m, 2H),
0.91 (t, J ¼ 4.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d 176.3, 49.2,
48.4, 37.3, 31.0, 30.7, 29.9, 29.4, 28.5, 23.5, 22.3, 14.0; IR
(CHCl3): nmax 3435, 2927, 2855, 1648, 1476, 1442, 1420, 1383,
1352, 1256, 1228, 1190, 1138, 1082, 1041 cmꢂ1; ESI-MS: m/z
230.15 [M + H]+; HR-ESIMS: m/z 230.1578 calcd for C12H23NOS +
H+ (230.1573).
1-((4-Methoxyphenylthio)methyl)piperidin-2-one (3h). Yield:
84%; light brown oil; 1H NMR (CDCl3, 400 MHz): d 7.42 (d, J ¼
8.0 Hz, 2H), 6.84 (d, J ¼ 8.0 Hz, 2H), 4.75 (s, 2H), 3.78 (s, 3H),
3.33 (t, J ¼ 4.0 Hz, 2H), 2.29 (t, J ¼ 4.0 Hz, 2H), 1.74 (m, 4H); 13
C
NMR (CDCl3, 125 MHz): d 169.8, 159.6, 135.0, 124.1, 114.5, 55.2,
52.4, 47.0, 32.2, 22.9, 21.1; IR (CHCl3): nmax 3790, 3435, 2943,
2868, 1726, 1644, 1591, 1570, 1493, 1463, 1443, 1415, 1349,
1331, 1285, 1244, 1171, 1092, 1028 cmꢂ1; ESI-MS: m/z 252.1 [M +
H]+; HR-ESIMS: m/z 252.1057 calcd for C13 H17NO2S + H+
(252.1052).
1-((4-Chlorophenylthio)methyl)piperidin-2-one (3i). Yield:
82%; light yellow oil; 1H NMR (CDCl3, 400 MHz): d 7.33 (d, J ¼
8.0 Hz, 2H), 7.16 (d, J ¼ 8.0 Hz, 2H), 4.78 (s, 2H), 3.26 (t, J ¼ 4.0
Hz, 2H), 2.22 (t, J ¼ 4.0 Hz, 2H), 1.67 (m, 4H); 13C NMR (CDCl3,
125 MHz): d 179.8, 133.1, 132.8, 132.5, 128.9, 50.8, 46.8, 32.2,
22.8, 21.1; IR (CHCl3): nmax 3435, 2946, 2867, 2345, 1729, 1646,
1572, 1477, 1463, 1443, 1414, 1388, 1348, 1331, 1283, 1245,
1172, 1157, 1093, 1011 cmꢂ1; ESI-MS: m/z 256.0 [M + H]+; HR-
ESIMS: m/z 256.0557 calcd for C12H15ClNOS + H+ (256.0557).
1-((Naphthalen-3-ylthio)methyl)piperidin-2-one (3j). Yield:
89%; brown oil; 1H NMR (CDCl3, 400 MHz): d 7.93 (s, 1H), 7.76
(m, 3H), 7.53–7.41 (m, 3H), 4.95 (s, 2H), 3.28 (t, J ¼ 4.0 Hz, 2H),
2.27 (t, J ¼ 4.0 Hz, 2H), 1.65 (m, 4H); 13C NMR (CDCl3, 125 MHz):
d 170.0, 133.6, 132.2, 131.5, 130.0, 128.8, 128.5, 127.7, 127.4,
126.6, 126.1, 50.8, 47.0, 32.3, 22.9, 21.1; IR (CHCl3): nmax 3435,
3051, 2945, 2866, 1644, 1588, 1485, 1462, 1414, 1348, 1330,
1281, 1246, 1172, 1132, 1090, 1071 cmꢂ1; ESI-MS: m/z 272.1 [M +
H]+; HRMS: m/z 272.1110 calcd for C16H17NOS + H+ (272.1103).
1-((Phenylthio)methyl)pyrrolidin-2-one (3k). Yield: 72%;
light yellow oil; 1H NMR (CDCl3, 400 MHz): d 7.44 (d, J ¼ 8.0 Hz,
2H), 7.29–7.21 (m, 3H), 4.74 (s, 2H), 3.42 (t, J ¼ 4.0 Hz, 2H), 2.28
(t, J ¼ 4.0 Hz, 2H), 1.95 (m, 2H); 13C NMR (CDCl3, 125 MHz): d
174.8, 133.6, 130.8, 129.0, 127.1, 46.6, 45.8, 30.7, 17.5; IR
(CHCl3): nmax 3435, 3055, 2920, 1686, 1582, 1482, 1460, 1437,
1419, 1289, 1252, 1157, 1024 cmꢂ1; ESI-MS: m/z 208.0 [M + H]+,
230.0 [M + Na]+; HR-ESIMS: m/z 208.0791 calcd for C11H13NOS +
H+ (208.0790).
1-((p-Tolylthio)methyl)pyrrolidin-2-one (3l). Yield: 76%; light
yellow oil; 1H NMR (CDCl3, 400 MHz): d 7.34 (d, J ¼ 8.0 Hz, 2H),
7.10 (d, J ¼ 8.0 Hz, 2H), 4.70 (s, 2H), 3.44 (t, J ¼ 4.0 Hz, 2H), 2.32
(s, 3H), 2.31–2.25 (m, 2H), 1.96 (m, 2H); 13C NMR (CDCl3, 125
MHz): d 174.8, 137.5, 131.7, 129.8, 47.3, 45.9, 30.8, 29.7, 21.1,
17.6; IR (CHCl3): nmax 3308, 2920, 2851, 1690, 1492, 1460, 1418,
1289, 1252, 1157, 1090, 1040 cmꢂ1; ESI-MS: m/z 222.0 [M + H]+;
HR-ESIMS: m/z 222.0948 calcd for C12H15NOS + H+ (222.0947).
1-((Hexylthio)methyl)azepan-2-one (3s). Yield: 64%; light
yellow oil; 1H NMR (CDCl3, 400 MHz): d 4.55 (s, 2H), 3.45 (t, J ¼
4.0 Hz, 2H), 2.56 (m, 4H), 1.73–1.60 (m, 8H), 1.29–1.26 (m, 8H),
0.90 (t, J ¼ 4.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d 176.2, 49.1,
48.3, 37.2, 31.3, 30.7, 29.9, 29.6, 28.5, 23.5, 22.5, 14.0; IR
(CHCl3): nmax 3435, 2926, 2855, 1648, 1468, 1442, 1420, 1352,
1256, 1228, 1190, 1138, 1082, 1040 cmꢂ1; ESI-MS: m/z 230.15 [M
+ H]+, 266.15 [M + Na]+; HR-ESIMS: m/z 244.1723 calcd for
1-((4-Methoxyphenylthio)methyl)pyrrolidin-2-one
(3m).
Yield: 80%; brown oil; 1H NMR (CDCl3, 400 MHz): d 7.40 (d, J ¼
8.0 Hz, 2H), 6.84 (d, J ¼ 8.0 Hz, 2H), 4.63 (s, 2H), 3.78 (s, 3H),
3.45 (t, J ¼ 4.0 Hz, 2H), 2.28 (t, J ¼ 4.0 Hz, 2H), 1.97 (m, 2H); 13
C
NMR (CDCl3, 100 MHz): d 174.8, 159.6, 134.5, 123.6, 114.6, 55.2,
48.2, 45.9, 30.8, 17.6; IR (CHCl3): nmax 3435, 2924, 2837, 1688,
1591, 1570, 1494, 1460, 1420, 1325, 1286, 1245, 1174, 1104, 1028
cmꢂ1; ESI-MS: m/z 238.0 [M + H]+; HR-ESIMS: m/z 238.0892
calcd for C12H15NO2S + H+ (238.0896).
C
13H25NOS + H+ (244.1730).
1-(((4-Methoxyphenyl)thio)methyl)indoline-2,3-dione (4a).
Yield: 95%; orange red solid; m.p. 109–111 ꢀC; 1H NMR (CDCl3,
400 MHz): d 7.63 (m, 2H), 7.33 (d, J ¼ 8.0 Hz, 2H), 7.13 (m, 1H),
7.00 (d, J ¼ 8.0 Hz, 1H), 6.78 (d, J ¼ 8.0 Hz, 2H), 4.98 (s, 2H), 3.76
(s, 3H); 13C NMR (CDCl3, 100 MHz): d 182.6, 160.6, 157.2, 149.4,
1-((4-Chlorophenylthio)methyl)pyrrolidin-2-one (3n). Yield:
78%; light yellow oil; 1H NMR (CDCl3, 400 MHz): d 7.38 (d, J ¼
14086 | RSC Adv., 2014, 4, 14081–14088
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138.3, 136.2, 125.3, 124.1, 121.6, 117.7, 115.0, 112.0, 55.4, 45.8;
IR (CHCl3): nmax 3447, 2921, 1738, 1611, 1590, 1493, 1469, 1363,
1339, 1286, 1267, 1171, 1094, 1022 cmꢂ1; ESI-MS: m/z 300 [M +
H]+, 322 [M + Na]+; HR-ESIMS: m/z 300.0661 calcd for
C
C
General procedure for thiophenylmethylation of phenols
To the solution of substituted thiophenol (5a–b, 1.0 mmol) in
0.1% TFA in water (5 mL) was added formaldehyde (6, 3 equiv.).
The resulting reaction mixture was then reuxed at 80 ꢀC for 30
min. The ortho-cresol (13, 2.0 mmol) wꢀas then added and
reaction mixture was further stirred at 80 C for 4 h. The reac-
tion mixture was puried by silica gel column chromatography
using EtOAc: hexane as mobile phase to yield pair of products,
one with para-substituted o-cresols 14aa–14ba and other with
ortho-/para-disubstituted o-cresols 14ab–14bb.
16H13NO3S + H+ (300.0689) and m/z 322.0478 calcd for
16H13NO3S + Na+ (322.0508).
5-Bromo-1-(((4-methoxyphenyl)thio)methyl)indoline-2,3-
1
ꢀ
dione (4b). Yield: 86%; orange red solid; m.p. 135–137 C; H
NMR (CDCl3, 400 MHz): d 7.72 (M, 2H), 7.31 (d, J ¼ 8 Hz, 2H),
6.92 (d, J ¼ 12.0 Hz, 1H), 6.79 (d, J ¼ 8.0 Hz, 2H), 4.96 (s, 2H),
3.77 (s, 3H); 13C NMR (CDCl3, 100 MHz): d 181.4, 160.7, 156.5,
148.1, 140.4, 136.2, 128.0, 121.3, 118.8, 117.1, 115.1, 113.8, 55.3,
45.9; IR (CHCl3): nmax 3436, 2055, 1742, 1638, 1493, 1467, 1439,
1247, 1158, 1019 cmꢂ1; ESI-MS: m/z 377.9 [M + H]+, 399.9 [M +
Na]+; HR-ESIMS: m/z 377.9782 calcd for C16H12BrNO3S + H+
(377.9794).
2-Methyl-4-((phenylthio)methyl)phenol (14aa). Yield: 55%;
1
ꢀ
white solid; m.p. 68–70 C; H NMR (CDCl3, 400 MHz): d 7.31–
7.29 (m, 2H), 7.26–7.22 (m, 2H), 7.18–7.14 (m, 1H), 7.04 (s, 1H),
6.98 (d, J ¼ 8.0 Hz, 1H), 6.65 (d, J ¼ 8.0 Hz, 1H), 5.0 (s, 1H), 4.03
(s, 2H), 2.18 (s, 3H); 13C NMR (CDCl3, 100 MHz): d 153.1, 136.7,
131.7, 129.6, 129.3, 128.9, 127.6, 126.3, 124.2, 115.1, 38.5, 15.9;
IR (CHCl3): nmax 3847, 3350, 3058, 2921, 2850, 2351, 2284, 1600,
1585, 1501, 1479, 1436, 1384, 1368, 1298, 1265, 1245, 1201,
1-(((4-Methoxyphenyl)thio)methyl)-5-nitroindoline-2,3-dione
1
(4c). Yield: 85%; orange red solid; m.p. 180–181 ꢀC; H NMR
(CDCl3, 400 MHz): d 8.54 (d, J ¼ 8.0 Hz, 1H), 8.48 (s, 1H), 7.30–
7.28 (d, J ¼ 8.0 Hz, 2H), 7.14 (d, J ¼ 8.0 Hz, 1H), 6.80 (d, J ¼ 8.0
Hz, 2H), 5.04 (s, 2H), 3.80 (s, 3H); IR (CHCl3): nmax 3436, 2920,
2064, 1749, 1615, 1531, 1494, 1475, 1340, 1247, 1163, 1018
cmꢂ1; ESI-MS: m/z 345.0 [M + H]+, 367.0 [M + Na]+; HR-ESIMS:
m/z 345.0535 calcd for C16H12N2O5S + H+ (345.0540) and m/z
367.0359 calcd for C16H12N2O5S + Na+ (367.0359).
1151, 1114, 1089, 1070, 1042, 1024 cmꢂ1
.
2-Methyl-4,6-bis((phenylthio)methyl)phenol (14ab). Yield:
28%; light brown solid; m.p. 97–99 ꢀC; 1H NMR (CDCl3, 400
MHz): d 7.34–7.31 (m, 2H), 7.27–7.17 (m, 8H), 6.97 (s, 1H), 6.84
(s, 1H), 5.95 (s, 1H), 4.11 (s, 2H), 3.96 (s, 2H), 2.21 (s, 3H); 13C
NMR (CDCl3 100 MHz): d 152.2, 136.7, 134.5, 131.0, 130.7, 129.6,
129.0, 128.9, 128.8, 128.7, 127.1, 126.2, 125.4, 122.0, 38.4, 36.0,
15.9; IR (CHCl3): nmax 3445, 2921, 2852, 1619, 1480, 1438,
4-Chloro-1-(((4-methoxyphenyl)thio)methyl)indoline-2,3-
1
ꢀ
dione (4d). Yield: 87%; orange red solid; m.p. 116–118 C; H
NMR (CDCl3, 400 MHz): d 7.54 (d, J ¼ 4.0 Hz, 1H), 7.40–7.30 (m,
2H), 7.13 (d, J ¼ 8.0 Hz, 1H), 6.86–6.77 (m, 3H), 4.94 (s, 2H), 3.77
(s, 3H); 13C NMR (CDCl3, 100 MHz): d 181.1, 160.8, 157.1, 150.4,
144.7, 136.3, 132.6, 126.2, 124.3, 115.1, 114.6, 112.7, 55.3, 46.1;
IR (CHCl3): nmax 3436, 2067, 1636, 1493, 1361, 1287, 1247, 1171,
1020 cmꢂ1; ESI-MS: m/z 334.0 [M + H]+, 355.9 [M + Na]+; HR-
ESIMS: m/z 356.0101 calcd for C16H12ClNO3S + Na+ (356.0110).
5-Fluoro-1-(((4-methoxyphenyl)thio)methyl)indoline-2,3-
1019 cmꢂ1
.
4-(((4-Chlorophenyl)thio)methyl)-2-methylphenol
(14ba).
1
ꢀ
Yield: 48%; light brown solid; m.p. 92–94 C; H NMR (CDCl3,
400 MHz): d 7.20 (m, 4H), 7.03 (s, J ¼ 8.0 Hz, 1H), 6.95 (m, 1H),
6.66 (d, J ¼ 8.0 Hz, 1H), 5.04 (s, 2H), 3.99 (s, 2H), 2.19 (s, 3H); 13
C
NMR (CDCl3, 125 MHz): d 152.3, 134.1, 131.4, 130.7, 130.3,
128.0, 126.7, 123.2, 114.1, 37.9, 14.9; IR (CHCl3): nmax 3745,
3324, 3024, 2927, 2854, 1601, 1506, 1474, 1442, 1426, 1387,
1366, 1298, 1270, 1260, 1249, 1208, 1179, 1151, 1112, 1095, 1007
cmꢂ1; ESI-MS: m/z 263.02 [M ꢂ H]ꢂ; HR-ESIMS: m/z 263.0298
calcd for C14H13ClOS–Hꢂ (263.0303).
1
ꢀ
dione (4e). Yield: 94%; orange red solid; m.p. 103–104 C; H
NMR (CDCl3, 400 MHz): d 7.35–7.29 (m, 4H), 6.99 (d, J ¼ 4.0 Hz,
1H), 6.79 (d, J ¼ 8.0 Hz, 2H), 4.98 (s, 2H), 3.77 (s, 3H); 13C NMR
(CDCl3, 100 MHz): d 182.0, 160.6, 158.5, 157.0, 145.4, 136.2,
124.8, 121.3, 118.3, 115.0, 113.4, 112.3, 55.3, 45.9; IR (CHCl3):
nmax 3436, 2918, 1745, 1621, 1484, 1247, 1019 cmꢂ1; ESI-MS: m/z
318.0 [M + H]+, 340.0 [M + Na]+; HR-ESIMS: m/z 340.0429 calcd
for C16H12FNO3S + Na (340.0414).
2,4-Bis(((4-chlorophenyl)thio)methyl)-6-methylphenol (14bb).
Yield: 28%; light yellow sticky solid; 1H NMR (CDCl3, 400 MHz): d
7.24–7.14 (m, 8H), 6.95 (s, 1H), 6.78 (s, 1H), 5.77 (s, 1H), 4.07 (s,
2H), 3.92 (s, 2H), 2.21 (s, 3H); 13C NMR (CDCl3, 100 MHz): d 152.1,
135.0, 133.3, 132.9, 132.3, 132.28, 131.1, 131.0, 129.1, 128.9,
128.7, 128.6, 38.6, 35.9, 15.8; IR (CHCl3): nmax 3446, 2922, 1619,
1476, 1387, 1219, 1095, 1016 cmꢂ1
.
Preparation of bis((4-methoxyphenyl)thio)methane (11).4a
X-ray crystallography of 5-uoro-1-(((4-methoxyphenyl)thio)-
methyl)indoline-2,3-dione (4e)
To the solution of thiophenol (5a, 1.0 mmol) in 0.1% TFA in
water (5 mL) was added formaldehyde (6, 3 equiv.). The result-
ing reaction mixture was then reuxed at 80 ꢀC for 6 h. The Single crystals of 5-uoro-1-(((4-methoxyphenyl)thio)methyl)-
crude reaction mixture was puried by silica gel column chro- indoline-2,3-dione 4e were obtained by slow evaporation at
matography using EtOAc: hexane as mobile phase to yield room temperature, from a mixture of methanol–water. The
product 11. Yield: 72%; white solid; m.p. 67–68 ꢀC; 1H NMR X-ray data was collected from a dry crystal mounted on an
(CDCl3, 400 MHz): d 7.30 (d, J ¼ 8.0 Hz, 2H), 6.76 (d, J ¼ 8.0 Hz, ‘Xcalibur, Sapphire3’, Oxford diffractometer. The crystal struc-
2H), 4.05 (s, 2H), 3.69 (s, 3H); 13C NMR (CDCl3, 100 MHz): d ture was solved by direct method using SHELXS-97 followed by
159.6, 134.5, 125.3, 114.6, 55.4, 44.5; IR (CHCl3): nmax 3436, full matrix anisotropic least square renement using SHELXL-
2920, 2833, 2040, 1633, 1590, 1492, 1461, 1438, 1284, 1244, 97.10 All the hydrogen atoms were located from difference
1196, 1094, 1026 cmꢂ1; ESI-MS: m/z 293.0 [M + H]+.
Fourier map and rened isotropically. All the relevant
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Paper
crystallographic data collection parameters and structure
renement details for 4e is summarized in Table S4.‡ Bond
lengths and bond angles are given in Table S5.‡
C. S. Yee and M. C. Chang, Chem. Rev., 2003, 103, 2167–
2201; (c) C. Yin, F. Huo, J. Zhang, R. Martınez-Manez,
Y. Yang, H. Lv and S. Li, Chem. Soc. Rev., 2013, 42, 6032–6059.
3 (a) A. B. Smith, Y. S. Cho and H. Ishiyama, Org. Lett., 2001, 3,
3971–3974; (b) H. Hagiwara, K. Kobayashi, S. Miya, T. Hoshi,
T. Suzuki, M. Ando, T. Okamoto, M. Kobayashi,
I. Yamamoto, S. Ohtsubo, M. Kato and H. Uda, J. Org.
Chem., 2002, 67, 5969–5976.
4 (a) H. Abdel-Ghany, A. M. El-Sayed, A. Khodairy and H. Salah,
Synth. Commun., 2001, 31, 2523–2535; (b) G. Ramachandran,
N. S. Karthikeyan, P. Giridharan and K. I. Sathiyanarayanan,
Org. Biomol. Chem., 2012, 10, 5343–5346; (c) M. Yamauchi,
S. Katayama and T. Watanabe, Synthesis, 1982, 11, 935–
936.
Crystal data for 4e: C16 H12F1N1O3S1, M ¼ 317.33, mono-
clinic, space group: P21/c, a ¼ 21.243 (5), b ¼ 5.558 (5), c ¼
ꢀ
ꢀ
ꢀ
˚
13.288 (5) A, a ¼ 90 , b ¼ 107.615 (5) , g ¼ 90 ; V ¼ 1495.3 (15)
A , Z ¼ 4, Dc ¼ 1.410 mg mꢂ3, m ¼ 0.239 mmꢂ1, q range: 3.65 to
3
˚
26.0ꢀ, 5636 reections measured, 2926 independent (Rint
¼
0.0492), 248 parameters. The structure was solved by direct
methods and rened by full-matrix least-squares on F2; nal R
indices for 1337 observed reections [I > 2s (I)]: R1 ¼ 0.0652, wR2
¼ 0.1593; maximal/minimum residual electron density: 0.199
and ꢂ0.176 e Aꢂ3.‡
˚
5 S. B. Bharate, R. Mudududdla, J. B. Bharate, N. Battini,
S. Battula, R. R. Yadav, B. Singh and R. A. Vishwakarma,
Org. Biomol. Chem., 2012, 10, 5143–5150.
6 R. Mudududdla, S. K. Jain, J. B. Bharate, A. P. Gupta,
B. Singh, R. A. Vishwakarma and S. B. Bharate, J. Org.
Chem., 2012, 77, 8821–8827.
Acknowledgements
R. M. and R. S. are thankful to CSIR and DST for the award of
Research Fellowships. SBB thanks Department of Science and
Technology (DST, Govt. of India) for nancial support under
Fast-Track Scheme (grant no. SR/FT/CS-168/2011).
7 (a) A. Chanda and V. V. Fokin, Chem. Rev., 2009, 109, 725–
748; (b) M.-O. Simon and C.-J. Li, Chem. Soc. Rev., 2012, 41,
1415–1427.
Notes and references
´
8 S. B. Bharate, R. Mudududdla, R. Sharma and
R. A. Vishwakarma, Tetrahedron Lett., 2013, 54, 2913–
2915.
9 J. E. Coughlin, R. K. Pandey, S. Padmanabhan,
K. G. O'Loughlin, J. Marquis, C. E. Green, J. C. Mirsalis
and R. P. Iyer, Drug Metab. Dispos., 2012, 40, 970–
981.
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