Sequential coupling/desilylation-coupling/cyclization in a single pot under Pd/C-Cu catalysis: Synthesis of 2-(hetero)aryl indoles

Article abstract of DOI:10.1039/c0ob01161d

A new one-pot synthesis of 2-(hetero)aryl indoles via sequential C-C coupling followed by C-Si bond cleavage and a subsequent tandem C-C/C-N bond forming reaction is described. A variety of functionalized indole derivatives were prepared by conducting thi

Full text of DOI:10.1039/c0ob01161d

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PAPER
Sequential coupling/desilylation–coupling/cyclization in a single pot under
Pd/C–Cu catalysis: Synthesis of 2-(hetero)aryl indoles†‡
R. Mohan Rao, Upendar Reddy CH, Alinakhi, Naveen Mulakayala, Mallika Alvala, M. K. Arunasree,
Rajamohan R. Poondra, Javed Iqbal* and Manojit Pal*
Received 13th December 2010, Accepted 22nd February 2011
DOI: 10.1039/c0ob01161d
A new one-pot synthesis of 2-(hetero)aryl indoles via sequential C–C coupling followed by C–Si bond
cleavage and a subsequent tandem C–C/C–N bond forming reaction is described. A variety of
functionalized indole derivatives were prepared by conducting this four step reaction under Pd/C–Cu
catalysis. The methodology involved coupling of (trimethylsilyl)acetylene with iodoarenes in the
presence of 10% Pd/C–CuI–PPh3 and triethylamine in MeOH, followed by treating the reaction
mixture with K2CO3 in aqueous MeOH, and finally coupling with o-iodoanilides. The single crystal
X-ray data of a synthesized indole derivative is presented. Application of the methodology, in vitro
pharmacological properties of the synthesized compound, along with a docking study is described.
Introduction
2-substituted indole is one of the key structural frameworks
found in many naturally occurring alkaloids, bioactive compounds
and drugs.1–4 Many synthetic methods including transition metal
catalyzed reactions have been reported for the construction of an
indole ring.5 One of the commonly used methods for the synthesis
of 2-substituted indoles involves two steps e.g. Sonogashira
coupling of 2-aminoaryl halide with a terminal alkyne followed
by cyclization of the resulting 2-alkynylanilines. The cyclization
step can be carried out in the presence of a range of catalysts
or promoters such as Cu(I)salt,6 metal alkoxide,7 fluorides,8 Lewis
acids,9 gold(III),10 and iodine.11 Alternatively, 2-substituted indoles
Scheme 1 Strategy to synthesize 2-aryl indoles in a single pot.
can be prepared directly via a single step method using Pd/C–
substituted indoles (Scheme 1) via sequential (i) C–C coupling
followed by (ii) C–Si bond cleavage and subsequent (iii) C–C
and (iv) C–N bond forming reactions in a single pot. To the
Cu mediated coupling-cyclization of o-iodoanilides with terminal
alkynes.12 However, to obtain an indole derivative possessing a
specific aryl group at the C-2 position, the use of an appropriate
best of our knowledge there is no precedence of preparing 2-aryl
terminal alkyne containing the corresponding aryl moiety was
indole derivatives using four steps in a single pot under Pd/C–Cu
necessary in all of these cases. Moreover, many arylalkynes are
catalysis.
either expensive or commercially not available, or their preparation
requires cumbersome methods.13–14 Their isolation in the pure
form is also sometimes problematic as these compounds are
prone to undergo rapid dimerization. Thus a more effective
Results and discussions
Synthesis
method was necessary to prepare 2-aryl substituted indoles of our
interest. Herein we report Pd/C–Cu mediated synthesis of 2-aryl
Based on the idea that desilylation of 2-aryl substituted
trimethylsilyl alkynes could be achieved easily by using K2CO3 in
MeOH–H2O we planned to generate a range of terminal alkynes
of our choice in situ. We anticipated that once generated these
alkynes could undergo a further Pd-mediated coupling reaction
with an appropriate o-substituted arylhalide in the same pot. To
this end, we assessed the reaction sequence involving the use of 1-
iodo-4-methyl benzene 1a, (trimethylsilyl)acetylene (TMSA) and
o-iodoanilide 2a under various reaction conditions (Table 1).
Institute of Life Sciences, University of Hyderabad Campus, Gachi-
bowli, Hyderabad, 500 046, Andhra Pradesh, India. E-mail: manojitpal@
rediffmail.com; Fax: +91 40 6657 1581; Tel: +91 40 6657 1500
† Dedicated to Prof. Nitya G. Kundu on the occassion of his 75th birthday.
‡ Electronic supplementary information (ESI) available: Crystallographic
data (CIF) for compound 3a and copies of spectra of selected compounds.
CCDC reference number 784742. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0ob01161d
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Table 1 The reaction of 1a, TMSA and 2a under various reaction
conditionsa
Entry
Catalysts
Base
Timeb (h)
% Yieldc
Fig. 1 X-ray crystal structure of 3a (ORTEP diagram). Displacement
ellipsoids are drawn at 50% probability level for non-hydrogen atoms.
1
2
3
4
5
6
Pd(PPh3)2Cl2
10% Pd/C–PPh3
10% Pd/C–PPh3
10% Pd/C
PPh3
10% Pd/C–PPh3
K2CO3
K2CO3
KOH
K2CO3
K2CO3
K2CO3
4
6
6
6
8
8
78
80
75
12
55
43
d
a All of the reactions were carried out using iodide 1a (2.137 mmol),
TMSA (4.274 mmol), Pd catalyst (0.02137 mmol), CuI (0.02137 mmol),
[PPh3 (0.04274 mmol)] and Et3N (0.5 mL) in MeOH (5.0 mL), then a
base (4.274 mmol) in water (0.5 mL) and MeOH (1.5 mL) and finally
o-iodoanilides (2a). b After adding 2a. c Isolated yield. d The reaction was
carried out without CuI.
We performed Sonogashira coupling15 of 1a with TMSA using
a Pd catalyst, CuI and Et3N in methanol at refluxing temperature.
The resulting crude reaction mixture was then directly treated
with a solution of an inorganic base in MeOH/H2O (3 : 1). After
stirring this mixture at the refluxing temperature for 0.5 h, o-
iodoanilides, 2a, were added and the mixture was stirred at the
refluxing temperature. Initially, we used (PPh3)2PdCl2 as a catalyst
and K2CO3 as a base (for the desilylation step) when the desired
product, 3a, was isolated in a good yield (entry 1, Table 1).
However, due to our long term interest in the Pd/C-mediated
alkynylation reaction16 we conducted the present reaction using
10% Pd/C–PPh3 as the catalyst system. Additionally, Pd/C is
cheaper, more stable, easier to handle, separable from the product
and has the potential to be recycled. To our satisfaction the
reaction proceeded well, affording 3a in a good yield (entry 2,
Table 1). Though the use of KOH was found to be equally effective
for the desilylation step (entry 3, Table 1) we however preferred
milder base K2CO3. Omission of any component of the catalyst
10% Pd/C–PPh3–CuI decreased the product yield (entries 4, 5 and
6, Table 1). The indole, 3a, was characterized by spectral data and
this was supported by the molecular structure, being confirmed by
X-ray analysis (Fig. 1).17
With the optimized reaction condition in hand we then decided
to expand the generality and scope of this methodology via
employing other iodoarenes and the results of this study are
summarized in Table 2. The present four-step reaction in a
single pot proceeded well with a number of iodoarenes affording
a variety of indoles in good yields. Both electron donating
groups such as Me (1a), OMe (1b), OH (1d), NH2 (1e and 1f)
or electron withdrawing groups such as CF3 (1c) and CO2Et
(1g) present on the iodoarene ring were well tolerated. A fur-
ther application of this methodology was demonstrated in the
preparation of 2-heteroaryl indoles 5a–c from 2-iodothiophene
derivative 4 (Scheme 2). The iodo compound 4 was prepared
Scheme 2 One pot synthesis of 2-heteroaryl indoles.
Scheme 3 Preparation of iodo compound 4.
from an appropriate cyclic ketone according to Scheme 3.18 Thus
condensation of the cyclic ketone with an a-cyanoester in the
presence of elemental sulfur, under Gewald reaction conditions,
provided a 2-aminothiophene derivative which was converted to
the 2-iodo derivative, 4, under Sandmeyer conditions. The reaction
of 4 with TMSA and subsequently with o-iodoanilide (2b, 2c or
2d) under the optimized conditions (entry 2, Table 1) provided
the desired 2-heteroaryl indoles (5a–c) in 60–64% yield. Notably,
N-demesylation, as well as trans-esterification, was observed
during the preparation of indole 5c in the same pot. Overall,
the present four-step method does not require the addition of
any additional amounts of the Pd/Cu-catalyst to facilitate the
final coupling–cyclization step. Due to our continued interest
in bioactive molecules19 some of the indoles synthesized were
converted to compounds of potential pharmacological interest
(Scheme 3 and 4). For example, indole 3b was converted to a
2-aryl-3-benzoylindole derivative (7) via TFAA-H3PO4 mediated
benzoylation,20a,b followed by deprotection of the resulting N-
mesyl product (6) (Scheme 4). Compound 3e was converted to an
indole-based quinaxoline derivative (8) (Scheme 5) via the reaction
with quinoxaline-2-carboxylic acid in the presence of coupling
reagents e.g. 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hy-
drochloride (EDCI.HCl) and 1-hydroxy-benzotriazole (HOBt)
under mild conditions. Notably, a quinaxoline derivative, SIRT
1720, has been reported as a potent activator of human SIRT 1.21
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Table 2 One pot synthesis of 2-aryl indolesa
Entry
1
ArI (1; Ar =)
2; R¢ =
Product (3)
Timeb (h)
6
% Yieldc
80
1a; C6H4CH3-p
2a; CH3
2
3
4
5
1b; C6H4OCH3-p
1c; C6H4CF3-m
2a
2a
2a
2a
5
5
8
4
85
78
65
69
1d; C6H4OH-p
1e; C6H3NH2(o)Cl(m)
6
7
8
1a
1c
1c
2b; F
2b
4
5
8
60d
83
68
2b
9
1d
1f
2b
2b
8
68
63
10
11
11
12
1a
2c; Cl
6
5
84d
70
1g;C6H4CO2Et-p
2b
a All the reactions were carried out using iodide 1 (2.137 mmol), TMSA (4.274 mmol), 10% Pd/C (0.02137 mmol), CuI (0.02137 mmol), PPh3
(0.04274 mmol) and Et3N (0.5 mL) in MeOH (5.0 mL), then K2CO3 (4.274 mmol) in water (0.5 mL) and MeOH (1.5 mL), and finally o-iodoanilides (2).
b After adding 2. c Isolated yield. d Known compound (see ref. 12a).
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Scheme 4 Synthesis of 2-aryl-3-aroylindole.
Fig. 2 SIRT 1 activation and docking study of indole 7.
1 indicates that it binds well with this NAD+-dependent protein
deacytylase. The key interacting amino acids were found to be
Pro2, Leu3, Glu20, Asp5 and ILE27.
Scheme 5 Synthesis of quinaxoline derivative.
Indole 3l was converted to an a-amino acid derivative, 10, via the
corresponding acid, 9 (Scheme 6). Thus, hydrolysis of 3l, followed
by the reaction of the resultant acid 9 with the methyl ester of
glycine in the presence of coupling reagents, afforded the desired
compound, 10.
Conclusions
In conclusion, we have demonstrated a new Pd/C-mediated
one-pot synthesis of 2-(hetero)aryl indoles via sequential C–
C coupling, followed by C–Si bond cleavage and subsequent
tandem C–C/C–N bond forming reactions. A variety of indole
derivatives were prepared using this methodology. Its application
has been demonstrated in preparing compounds of potential
pharmacological interest, preparation of which may be tedious
via other methods. The methodology does not involve the use of
any expensive reagents, catalysts or solvents. As far as we know,
in spite of a number of reports on efficient palladium-mediated
syntheses of 2-(hetero)aryl indoles, no successful examples of
indole synthesis using four steps in a single pot under Pd/C–
Cu catalysis have been reported. Due to the operational simplicity
and potential for introducing complexity into an indole framework
the present methodology could become a useful alternative to the
previously reported methods. The methodology therefore would
find wide application in generating a diversity based library of
indoles of potential medicinal value.
Scheme 6 Synthesis of an a-amino acid analogue of indole 3l.
Pharmacology
As part of our ongoing program on the identification of activators
of SIRT 1 (Silent information regulator 1),22 we screened some of
the compounds synthesized for their SIRT 1 activation properties
in vitro. SIRT 1 activators have been reported to be beneficial
for the potential treatment of type 2 diabetes via their anti-aging
effect.23 The in vitro activity was determined by using a SIRT
1 fluorescence activity assay kit from Cyclex Inc according to a
known method.21 Thus bacterially purified human SIRT 1 enzyme
was incubated with the fluorophore-labelled substrate peptide
(25 mM) and cofactor, NAD+ (25 mM), in the presence or absence
of compounds. Suramin, a known inhibitor of SIRT 1 was also
used in this assay. Among all the compounds tested, 2-aryl-3-
benzoylindole derivative, 7, was found to be an activator of human
SIRT 1 when tested at 10 mM in vitro whereas suramin showed
significant inhibition (Fig. 2). No significant activation of SIRT
1 was observed when 2-arylindole derivatives (3) were used at the
same concentration. In order to understand its interaction with
SIRT 1, the indole, 7, was docked into the active site of SIRT 1
(Fig. 2). Indeed, the binding energy (i.e. -5.81 Kcal mol-1) of the
interaction of compound 7 with the activator domain of hSIRT
Experimental
Chemistry
General methods. Unless stated otherwise, reactions were
monitored by thin layer chromatography (TLC) on silica gel
plates (60 F254), visualizing with ultraviolet light or iodine spray.
Column chromatography was performed on silica gel (60–120
1
mesh) using distilled petroleum ether and ethyl acetate. H and
13C NMR spectra were determined in CDCl3 solution using 400
and 100 MHz spectrometers, respectively. Proton chemical shifts
(d) are relative to tetramethylsilane (TMS, d = 0.0) as the internal
standard and expressed in parts per million. Spin multiplicities
are given as s (singlet), d (doublet), t (triplet), and m (multiplet)
as well as b (broad). Coupling constants (J) are given in hertz.
Infrared spectra were recorded on a FT-IR spectrometer. Melting
points were determined by using a Buchi melting point B-540
apparatus and are uncorrected. MS spectra were obtained on a
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mass spectrometer. HR-MS was determined using waters LCT
premier XETOF ARE-047 apparatus. Elemental analyses were
performed using a Perkin Elmer 240 C analyzer.
Analysis found C, 57.54; H, 3.97; N, 4.19; C17H14F3NO2S requires
C, 57.78; H, 3.99; N, 3.96.
4-(5-methyl-1-(methylsulfonyl)-1H-indol-2-yl)phenol
(3d).
white solid; yield 0.42 g (65%); mp 190–192 ◦C; Rf = 0.4 (10%
General procedure for the preparation of 2-aryl indoles (3a–
l). To a solution of aryl iodide (1, 2.137 mmol), 10% Pd/C
(0.003 g, 0.0214 mmol), CuI (0.004 g, 0.02137 mmol), and PPh3
(0.012 g, 0.04274 mmol) in methanol (5.0 mL), were added
triethylamine (0.5 mL, 1.26 mmol) and (trimethylsilyl)acetylene
(0.42 g, 4.274 mmol) at room temperature with stirring. The
mixture was stirred at the refluxing temperature for 3 h (the
reaction was monitored by TLC) and a solution of K2CO3
(0.59 g, 4.274 mmol), dissolved in water (0.5 mL) and methanol
(1.5 mL), was added at the same temperature. The mixture was
stirred at the refluxing temperature for an additional 0.5 h and
o-iodoanilide (2, 2.137 mmol) was added. The stirring continued
for an additional 4–11 h (the reaction was monitored by TLC)
at the same temperature. After completion the reaction mixture
was quenched with saturated NH4Cl solution (60 mL) and
extracted with CH2Cl2 (3 ¥ 50 mL). The organic layers were
collected, combined, washed with 2.0 N HCl (50 mL) followed
by water (50 mL) and saturated NaCl solution (50 mL), dried over
anhydrous Na2SO4 and concentrated under vacuum. The residue
was purified by flash chromatography (EtOAc/n-Hexane) to give
the desired product.
1
EtOAc-n-Hexane); H NMR (400 MHz, CDCl3) d: 2.30 (s, 3H),
2.56 (s, 3H), 6.8 (s, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.12–7.20 (m,
2H), 7.5 (d, J = 8.0 Hz, 1H) 7.90 (d, J = 8.8 Hz, 2H). 13C NMR
(100 MHz, CDCl3) d: 21.2, 39.8, 114.1, 115.5, 121.9, 125.8 (2C),
125.3, 126.6, 130.4, 132.8, 133.5, 134.6, 136.4 (2C), 162.5; MS (ES
mass): m/z 302.3 (M + 1, 50%). HR-MS: calcd for C16H16NO3S
(M + H): 302.0851, found: 302.0875; Elemental Analysis found:
C, 63.56; H, 5.05; N, 4.79; C16H15NO3S requires C, 63.77; H, 5.02;
N, 4.65.
4-chloro-2-(5-methyl-1-(methylsulfonyl)-1H-indol-2-yl)aniline
(3e). yield 0.49 g (69%); light brown solid; mp 171–173 ◦C; Rf =
0.4 (20% EtOAc-n-Hexane); 1H NMR (400 MHz, CDCl3) d 2.46
(s, 3H), 2.88 (s, 3H), 3.90 (bs, 2H), 6.63 (s, 1H), 6.68 (d, J = 8.0,
1H), 7.16–7.25 (m, 3H), 7.4 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 21.2, 39.8, 113.1, 114.9, 116.6,
119.5, 121.1, 122.4, 126.7, 130.2, 130.3, 133, 134.1, 135.6, 136.9,
144.9; MS (ES mass): m/z 335.3 (M + 1, 100%); HR-MS: calcd
for C16H16N2O2SCl (M + H): 335.0621, found 335.0639; Elemental
Analysis found: C, 57.57; H, 4.50; N, 8.29; C16H15ClN2O2S requires
C, 57.40; H, 4.52; N, 8.37.
Spectral data of 2-aryl indoles (3a–k)
5-fluoro-1-(methylsulfonyl)-2-p-tolyl-1◦H-indole12a (3f). yield
5-methyl-1-(methylsulfonyl)-2-p-tolyl-1H-indole
(3a). yield
◦
0.39 g (60%); white solid; mp 203–205 C ( 209–210 C12a); Rf =
0.51 g (80%); off white solid; mp 178–180 ◦C; Rf = 0.71 (20%
◦
1
0.47 (10% EtOAc-n-Hexane); White solid, mp 190 C; H NMR
(400 MHz, CDCl3) d: 2.41 (s, 3H), 2.74 (s, 3H), 6.6 (s, 1H), 7.16 (s,
1H), 7.30 (d, J = 2 Hz, 2H), 7.32 (d, J = 1.6 Hz, 1H), 7.44 (d, J =
7.6 Hz, 2H), 7.55 (d, J = 2 Hz, 1H), 8.07–8.09 (m, 1H); 13C NMR
(100 MHz, CDCl3) d: 21.4, 39.9, 111.7, 116.9 (2C), 120.4, 125.0,
128.5, 129.1 (2C), 130.1, 131.5, 134.2, 136.2, 139.3, 143.5; IR
(cm-1): 3139,1272, 1360; MS (ES mass): m/z 304.6 (M + 1, 100%);
HR-MS: calcd for C16H15FNO2S: 304.2546, found 304.2462.
1
EtOAc-n-Hexane); H NMR (400 MHz, CDCl3) d: 2.40 (s, 3H),
2.45 (s, 3H), 2.66 (s, 3H), 6.6 (s, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.21
(d, J = 7.6 Hz, 2H), 7.36 (s, 1H), 7.44 (d, J = 8 Hz, 2H), 7.97 (d,
J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d: 21.2, 21.4, 38.9,
112.6 (2C), 115.6, 120.8 (2C), 126.2, 128.4, 129.1, 129.91, 130.6,
134.2, 136.2, 138.7, 142.2; MS (ES mass): m/z 300.3 (M + 1,
40%); HR-MS: calcd for C17H18NO2S (M + H): 300.1058, found
300.1056; Elemental Analysis found C, 68.43; H, 5.70; N, 4.44;
C17H17NO2S requires C, 68.20; H, 5.72; N, 4.68
5-fluoro-2-(4-methoxyphenyl)-1-(methylsulfonyl)-1H -indole
(3g). yield 0.56 g (83%); off white solid; mp 198–200 ◦C; Rf = 0.55
(10% EtOAc-n-Hexane); 1H NMR (400 MHz, CDCl3) d: 2.72 (s,
3H), 3.86 (s, 3H), 6.59 (s, 1H), 6.95 (d, J = 8.4 Hz, 2H), 7.29 (d, J =
2 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 1.6 Hz, 1H), 8.04 (d,
J = 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d: 39.8, 55.3, 111.5,
113.3, 116.9 (2C), 120.3, 123.5, 124.9, 130.2 (2C), 131.5, 131.6,
136.2, 143.3, 160.4; MS (ES mass): m/z 320.3 (M + 1, 10%); HR-
MS: calcd for C16H15FNO3S: 320.0757, found 320.0746; Elemental
Analysis found C, 60.04; H, 4.40; N, 4.47; C16H14FNO3S requires
C, 60.18; H, 4.42; N, 4.39.
2-(4-methoxyphenyl)-5-methyl-1-(methylsulfonyl)-1H -indole
(3b). yield 0.57 g (85%); pale yellow solid; mp 184–186 ◦C; Rf =
0.57 (20% EtOAc-n-Hexane); 1H NMR (400 MHz, CDCl3) d: 2.45
(s, 3H), 2.67 (s, 3H), 3.85 (s, 3H), 6.58 (s, 1H), 6.94 (d, J = 8.4 Hz,
2H), 7.16 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.49 (d, J = 8.8 Hz,
2H), 7.97 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d:
21.4, 39.1, 55.4, 112.4 (2C), 113.3, 115.8, 120.8, 124.4, 126.3, 130.8,
131.5, 134.3, 136.3 (2C), 142.2, 160.2; MS (ES mass): m/z 316.4
(M + 1, 70%); HR-MS: calcd, for C17H18NO3S (M + H): 316.1007,
found: 316.0995; Elemental Analysis found: C, 64.97; H, 5.42; N,
4.32; C17H17NO3S requires C, 64.74; H, 5.43; N, 4.44
5-fluoro-1-(methylsulfonyl)-2-(3-(trifluoromethyl)phenyl)-1H -
indole (3h). yield 0.52 g (68%); off white solid; mp 121–123 ◦C;
5-methyl-1-(methylsulfonyl)-2-(3-(trifluoromethyl)phenyl) -1H-
◦
1
indole (3c). yield 0.59 g (78%); white solid; mp > 150 C; Rf =
Rf = 0.35 (10% EtOAc-n-Hexane); H NMR (400 MHz, CDCl3)
0.37 (10% EtOAc-n-Hexane); 1H NMR (400 MHz, CDCl3) d: 2.47
(s, 3H), 2.68 (s, 3H), 6.72 (s, 1H), 7.22 (dd, J1 = 1.2 Hz, J2 = 1.2 Hz,
d: 2.72 (s, 3H), 6.83 (s, 1H), 7.17 (dd, J1 = 1.6 Hz, J2 = 2.0 Hz,
2H), 7.51–7.87 (m, 5H); 13C NMR (100 MHz, CDCl3) d: 39.1,
112.1, 121.8, 122.6, 123.3, 124.5, 125.3, 126.2, 128.3, 129.6, 130.1,
131.4, 132.7, 135.4, 137.6, 142.2; MS (ES mass): m/z 358.9
(M + 1, 10%); HR-MS: calcd for C16H12F4NO2S: 358.0525, found
358.0536; Elemental Analysis found C, 53.55; H, 3.08; N, 4.05;
C16H11F4NO2S requires C, 53.78; H, 3.10; N, 3.92.
1H), 7.40 (s, 1H), 7.51–7.81 (m, 4H), 7.98 (d, J = 8.4 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) d: 21.2, 39.8, 114.2, 115.5, 121.2, 125.3,
125.3, 126.1, 126.6, 128.0, 129.9, 130.4, 132.8, 133.9, 134.6, 136.4,
140.4; MS (ES mass): m/z 354.1 (M + 1, 50%); HR-MS: calcd
for C17H15F3NO2S (M + H): 354.0776, found 354.0746; Elemental
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4-(5-fluoro-1-(methylsulfonyl)-1H-indol-2-yl)phenol (3i). yield
0.44 g (68%); white solid; mp >150 ◦C; Rf = 0.42 (20% EtOAc-n-
Hexane) 1H NMR (400 MHz, CDCl3) d: 2.57 (s, 3H), 6.79 (s, 1H),
6.93 (d, J = 8.4 Hz, 2H), 7.20–7.79 (m, 3H), 7.88 (d, J = 8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3) d: 40.3, 112.4, 113.3, 114.9
(2C), 120.8, 123.5, 128.7, 129.8 (2C), 131.9, 132.6, 136.3, 138.5,
161.8; MS (ES mass): m/z 306.3 (M + 1, 10%); HR-MS: calcd
for C15H13FNO3S (M + H): 306.0600, found 306.0623; Elemental
Analysis found: C, 59.19; H, 3.95; N, 4.45; C15H12FNO3S requires
C, 59.01; H, 3.96; N, 4.59.
aqueous NH4Cl and extracted with ethyl acetate (3 ¥ 25 mL). The
organic layers were collected, combined, dried over anhydrous
Na2SO4, filtered and concentrated. The residue was purified by
silica gel column chromatography using n-Hexane/EtOAc (7 : 3)
to give the desired product as a white soli◦d (yield: 0.16 g, 64%); Rf =
0.4 (20% EtOAc-n-Hexane); mp >200 C; IR (KBr, cm-1) 2930,
1718, 1274; 1H NMR (400 MHz, CDCl3) d: 1.09 (t, J = 7.3 Hz, 3H),
1.87–1.89 (m, 4H), 2.78–2.79 (m, 2H), 2.88–2.89 (m, 2H), 3.09 (s,
3H), 4.12–4.17 (m, 2H), 6.63 (s, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.61
(s, 1H), 8.02 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d: 14.1, 22.4, 22.8, 25.2, 26.3, 29.6, 40.9, 60.5, 113.3, 116.5, 126.7,
129.7, 133.2, 134.6, 135.7, 136.5, 137.0, 138.2, 148.7, 168.5; MS (ES
mass): m/z 420.1 (M-1, 100%); HR-MS: calcd for C20H21FNO4S2
(M + H): 422.0896, found 422.0892; Elemental analysis found C,
56.78; H, 4.77; N, 3.41; C20H20FNO4S2 requires C, 56.99; H, 4.78;
N, 3.32.
4-(5-fluoro-1-(methylsulfonyl)-1H-indol-2-yl)aniline (3j). yield
◦
0.41 g (63%); light brown solid; mp 133–135 C; Rf = 0.45 (20%
1
EtOAc-n-Hexane); H NMR (400 MHz, CDCl3) d: 2.72 (s, 3H),
4.10 (bs, 2H), 6.55 (s, 1H), 6.71 (d, J = 8.4 Hz, 2H), 7.29 (d,
J = 2.4 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 1.6 Hz,
1H), 8.03 (d, J = 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d:
40.3, 112.4, 113.3, 115.7 (2C), 120.8, 123.5, 128.7, 129.8 (2C),
131.9, 132.6, 136.3, 138.5, 146.8; MS (ES mass): m/z 305.6 (M +
1, 10%); HR-MS: calcd for C15H14FN2O2S (M + H): 305.0760,
found 305.0778; Elemental Analysis found: C, 59.43; H, 4.30; N,
9.02; C15H13FN2O2S requires C, 59.20; H, 4.31; N, 9.20.
Ethyl-2-(5-chloro-1-(methylsulfonyl)-1H -indol-2-yl)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (5b). A mixture of
ethyl 2-iodo-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (4a,
0.2 g, 0.593 mmol), 10% Pd/C (0.003 g, 0.023 mmol), PPh3, (0.01 g,
0.041 mmol), CuI (0.008 g, 0.041 mmol) and triethylamine (0.09 g,
0.13 mL, 0.890 mmol) was stirred in MeOH (3 mL) at room
temperature for 15 min. Then (trimethylsilyl)acetylene (0.058 g,
0.084 mL, 0.593 mmol) was added and the mixture was refluxed
for 1 h. After the starting material was consumed, K2CO3 (0.082 g,
0.593 mmol) dissolved in 2 : 1 MeOH–H2O (3 mL) was added and
the mixture was refluxed for another 1 h. Then N-(4-chloro-2-
iodophenyl)methanesulfonamide (2c, 0.203 g, 0.593 mmol), was
added and the mixture was heated to reflux for 2 h. Upon
completion of the reaction, the reaction mixture was diluted
with saturated aqueous NH4Cl and extracted with ethyl acetate
(3 ¥ 25 mL). The organic layers were collected, combined,
dried over anhydrous Na2SO4, filtered and concentrated. The
residue was purified by silica gel column chromatography using
n-Hexane/EtOAc (7 : 3) to give the desired product as an off white
5-chloro-1-(methylsulfonyl)-2-p-tolyl-1H-indole12a (3k). yield
◦
0.57 g (84%); white solid, mp 206–208 ◦C (207–209 C12a); Rf =
0.65 (20% EtOAc-n-Hexane); Brown solid, mp 145 ◦C; 1H NMR
(400 MHz, CDCl3) d: 2.41 (s, 3H), 2.73 (s, 3H), 6.61 (s, 1H),
7.24 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 1.6 Hz, 1H), 7.43 (d, J =
8 Hz, 2H), 7.55 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) d: 21.4, 39.8, 111.7, 115.7 (2C), 120.4,
125.0, 128.5, 128.9 (2C), 130.1, 131.5, 134.2, 136.2, 139.3, 143.5; IR
(cm-1): 3258, 1434, 1634; MS (ES mass): m/z 320.1 (M + 1, 10%);
HR-MS: calcd for C16H15ClNO2S: 320.0210, found 320.0064.
Ethyl 4-(5-fluoro-1-(methylsulfonyl)-1H-indol-2-yl)benzoate(3l).
yield 0.54 g (70%); white solid, mp 155 ◦C; Rf = 0.65 (20% EtOAc-n-
Hexane); 1H NMR (400 MHz, CDCl3) d: 1.37–1.49 (t, J = 6.9 Hz,
3H), 2.72 (s, 3H), 4.41–4.44 (q, J = 6.9 Hz, 2H), 6.76 (s, 1H), 7.13
(t, J = 9.7 Hz, 1H), 7.27 (d, J = 7.9 Hz, 2H), 7.63–7.64 (d, J =
7.9 Hz, 2H), 8.16–8.04 (m, 3H); 13C NMR (100 MHz, CDCl3) d:
14.3, 39.3, 61.1, 107.0, 113.2 (2C), 113.7, 117.2, 129.4 (2C), 130.9,
131.2, 134.5, 135.8, 142.7, 159.2, 161.6, 166.1; IR (cm-1): 3016,
1719, 1609, 1481; MS (ES mass): m/z 362.1 (M + 1)+, (100%);
HR-MS: calcd for C18H17FNO4S: 362.1019, found 362.1012.
◦
solid (yield 0.16 g, 62%); mp >200 C; Rf = 0.3 (20% EtOAc-n-
hexane); IR (KBr, cm-1): 2926, 1714, 1333; 1H NMR (400 MHz,
CDCl3) d: 1.07 (t, J = 7.3 Hz, 3H), 1.84–1.85 (m, 4H), 2.77–2.79
(m, 2H), 2.86–2.87 (m, 2H), 3.07 (s, 3H), 4.10–4.16 (m, 2H), 6.60
(s, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.56 (s, 1H), 7.97 (d, J = 2.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) d: 13.9, 22.4, 22.8, 25.2, 26.2,
29.7, 40.6, 60.4, 112.2, 115.5, 120.6, 125.3, 129.6, 130.3, 132.4,
133.9, 135.1, 136.1, 138.7, 163.4; MS (ES mass): m/z 438.1 (M +
1, 100%); HR-MS: calcd for C20H21NO4S2Cl (M + H): 438.0601,
found 438.0596; Elemental analysis found C, 54.99; H, 4.58; N,
3.02; C20H20NO4S2Cl requires C, 54.85; H, 4.60; N, 3.20.
Preparation of 2-heteroaryl indoles (5)
Ethyl-2-(5-fluoro-1-(methylsulfonyl)-1H -indol-2-yl)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (5a). A mixture of
ethyl 2-iodo-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (4a,
0.2 g, 0.593 mmol), 10% Pd/C (0.003 g, 0.023 mmol), PPh3
(0.01 g, 0.041 mmol), CuI (0.008 g, 0.041 mmol) and triethylamine
(0.09 g, 0.13 mL, 0.890 mmol) was stirred in MeOH (3 mL)
at room temperature for 15 min. Then trimethylsilylacetylene
(0.058 g, 0.084 mL, 0.593 mmol) was added and refluxed for
1 h. After the starting material was consumed, K2CO3 (0.082 g,
0.593 mmol) dissolved in 2 : 1 MeOH–H2O (3 mL) was added
and the mixture was refluxed for another 1 h. Then N-(4-fluoro-
2-iodophenyl)methane sulfonamide (2b, 0.187 g, 0.593 mmol),
was added and the mixture was allowed to reflux for 2 h. Upon
completion of the reaction, the mixture was diluted with saturated
Methyl
2-(5-cyano-1H-indol-2-yl)-5,6,7,8-tetrahydro-4H-
cyclohepta[b]thiophene-3-carboxylate (5c). A mixture of ethyl 2-
iodo-5,6,7,8-tetrahydr-4H-cyclohepta[b] thiophene-3-carboxylate
(4b, 0.1 g, 0.2857 mmol), 10% Pd/C (0.002 g, 0.011 mmol), PPh3
(0.005 g, 0.019 mmol), CuI (0.004 g, 0.019 mmol), triethylamine
(0.044 g, 0.07 mL, 0.428 mmol), were stirred in MeOH (3 mL)
at room temperature for 15 min. Then trimethylsilylacetylene
(0.027 g, 0.04 mL, 0.2857 mmol) was added and the mixture was
heated to reflux for 1 h. After the starting material was consumed,
K2CO3 (0.02 g, 0.2857 mmol) dissolved in 2 : 1 MeOH–H2O
(3 mL) was added and the mixture was stirred at refluxing
temperature for another 1 h. Then N-(4-cyano-2-iodophenyl)
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methanesulfonamide (2d, 0.092 g, 0.2857 mmol), was added
and stirring continued for 2 h at refluxing temperature. Upon
completion of the reaction, the mixture was diluted with saturated
aqueous NH4Cl and the product was extracted with ethyl acetate
(3 ¥ 15 mL). The organic layers were collected, combined, dried
over anhydrous Na2SO4, filtered and concentrated. The residue
was purified by silica gel column chromatography using 7 : 3
n-hexane: EtOAc to give the desired product as an off white solid
(yield 0.06 g, 60%); mp 150–152 ◦C; Rf = 0.3 (20% EtOAc-n-
hexane); IR (KBr, cm-1): 3316, 2921, 2847, 1694, 1439; 1H NMR
(400 MHz, CDCl3) d: 1.68–1.66 (m, 4H), 1.89–1.88 (m, 2H),
2.82–2.80 (m, 4H), 3.9 (s, 3H), 6.78 (s, 1H), 7.44 (d, J = 3.5 Hz,
2H), 7.91 (d, J = 3.5 Hz, 1H), 10.6 (s, 1H); 13C NMR (100 MHz,
CDCl3) d: 27.1, 27.6, 29.2, 29.5, 32.2, 52.6, 102.9, 103.1, 112.2,
120.8, 125.2, 125.8, 127.8, 129.1, 133.4, 133.6, 137.7, 141.3, 141.6,
167.7; MS (ES mass): m/z 348.9 (M-1, 100%); HR-MS: calcd
for C20H19N2O2S (M + H): 351.1146, found 351.1154; Elemental
analysis found C, 68.39; H, 5.20; N, 7.78; C20H18N2O2S requires
C, 68.55; H, 5.18; N, 7.99.
21.3, 55.2, 112.9, 114.2 (2C), 120.8, 121.8, 122.6, 127.1 (2C), 127.4
(2C), 128.9 (2C), 130.5, 132.6, 133.1, 134.9, 135.1, 137.5, 142.4,
160.5, 193.4; MS (ES mass): m/z 342.1 (M + 1, 100%); HR-MS:
calcd for C23H20NO2 (M + H) 342.1494 found 342.1479; Elemental
analysis found C, 80.78; H, 5.60; N, 4.24; C23H19NO2 requires C,
80.92; H, 5.61; N, 4.10.
Preparation of N-(4-chloro-2-(5-methyl-1-(methylsulfonyl)-1H-
indol-2-yl)phenyl) quinoxaline-2-carboxamide (8). To a mixture
of 2-quinoxaline carboxylic acid (11 mg, 0.06 mmol) and com-
pound 3e (20 mg, 0.06 mmol) in CH2Cl2 (5 mL) was added
EDCI.HCl (13.5 mg, 0.071 mmol), HOBT (10 mg, 0.071 mmol)
and DIPEA (16 mg, 0.119 mmol) under a nitrogen atmosphere.
The mixture was stirred at room temperature for 5 h. After
completion of the reaction (monitored by TLC), the mixture was
poured into cold water (10 mL) and extracted with CH2Cl2 (3 ¥
20 mL). The organic layers were collected, combined, dried over
anhydrous Na2SO4 and concentrated. The residue was purified
by column chromatography using EtOAc/n-hexane to give the
desired product as a gummy mass (yield 0.016 g, 55%); Rf = 0.22
(20% EtOAc/n-hexane); IR (KBr, cm-1): 3327, 2924, 1690, 1677,
Preparation of (2-(4-methoxyphenyl)-5-methyl-1-(methylsulfo-
nyl)-1H-indol-3-yl) (phenyl) methanone (6). A mixture of TFAA
(270 mg, 12.83 mmol) and benzoic acid (360 mg, 3.2 mmol) was
stirred for 20 min until all the solids were dissolved. After being
stirred for additional 20 min, the indole, 3b (1.10 g, 3.52 mmol),
was added in one portion. To this mixture was added 85% H3PO4
(58 mg, 0.59 mmol) drop wise for a duration of 20 min. The
mixture was then stirred for 4 h (monitored by TLC) and the
excess of TFA/TFAA was distilled out at atmospheric pressure.
The remaining liquid was partitioned between CHCl3 (40 mL) and
H2O (20 mL). The organic layer was separated and washed with
5% NaOH (10 mL) and then brine (10 mL). The mixture was dried
over anhydrous Na2SO4, filtered and concentrated under vacuum.
The residue was purified by column chromatography using EtOAc-
n-hexane to give the desired product as pale yellow solid (yield
1.03 g, 70%); mp 90–92 ◦C; Rf = 0.69 (20% EtOAc-n-hexane); IR
1
1367, 1173; H NMR (400 MHz, CDCl3) d: 2.48 (s, 3H), 2.83
(s, 3H), 6.69 (s, 1H), 7.25 (s, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.27
(d, J = 8.8 Hz, 1H), 7.31 (bs, 1H), 7.38–7.41 (m, 2H), 7.43–7.45
(m, 2H), 7.98 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 8.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) d: 22.6, 40.3, 113.9, 114.4, 114.4,
115.4, 117.4, 118.2, 121.7, 122.1, 122.7, 123.4, 125.4, 128.5, 129.0,
131.9, 132.0, 132.1, 132.4, 134.1, 137.8, 138.3, 138.5, 140.9, 161.6;
MS (ES mass): m/z 491.1 (M + 1, 100%); HR-MS: calcd for
C25H20N4ClO3S (M + H): 491.0945 found 491.0952; Elemental
analysis found C, 61.27; H, 3.88; N, 11.24; C25H19N4ClO3S requires
C, 61.16; H, 3.90; N, 11.41.
Preparation
of
4-(5-fluoro-1-(methylsulfonyl)-1H-indol-2-
yl)benzoic acid (9). To the solution of 3l (0.16 g, 0.44 mmol) in
THF and water (5 ml) (3 : 1), NaOH (0.04 g, 0.968 mmol) was
added and refluxed for 3 h. The progress of the reaction was
checked by TLC. After completion of the reaction the reaction
mixture was neutralized by 1 N HCl, extracted with ethyl acetate,
washed with water and brine solution, and dried over anhydrous
sodium sulfate. The reaction mixture was concentrated under
reduced pressure. Crude was purified by washing with hexane
to get the product white solid (yield: 0.01 g, 70%); mp 266 ◦C;
1H NMR (400 MHz, acetone-d6) d: 2.91 (s, 3H), 6.98–6.85 (m,
1H), 7.25–7.16 (m, 1H), 7.49–7.36 (m, 1H), 7.77–7.62 (m, 2H),
8.20–8.01 (m, 3H), 10.95 (s, 1H). 13C NMR (100 MHz, acetone-d6)
d: 40.9, 107.0, 107.3, 113.1,113.3, 117.1 (2C), 125.2, 129.0, 130.2,
131.2 (2C), 134.2, 142.8, 158.6, 161.0; IR (cm-1): 3430, 3014, 1691,
1608. MS (ES mass): m/z 331.9 (M - 1)+, 100%); HR-MS: calcd
for C16H13FNO4S is 334.1100 found 334.1102.
1
(KBr, cm-1): 2923, 1727, 1377, 1253, 1177; H NMR (400 MHz,
CDCl3) d: 2.44 (s, 3H), 2.78 (s, 3H), 3.71 (s, 3H), 6.68 (d, J = 8.8 Hz,
2H), 7.19–7.37 (m, 6H), 7.52 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 8.06
(d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d: 21.3, 40.4,
55.2, 112.9, 115.3 (2C), 120.8, 121.8, 122.6, 127.3 (2C), 128.0 (2C),
129.4 (2C), 130.5, 132.6, 133.1, 134.9, 135.1, 137.5, 142.4, 160.5,
193.4; MS (ES mass): m/z 420.2 (M + 1, 100%); HR-MS: calcd
for C24H22NO4S (M + H): 420.1270, found 420.1291; Elemental
analysis found C, 68.69; H, 5.12; N, 3.51; C24H21NO4S requires C,
68.72; H, 5.05; N, 3.34.
Preparation of (2-(4-methoxyphenyl)-5-methyl-1H-indol-3-yl)
(phenyl) methanone (7). A mixture of compound 6 (0.993 g,
2.37 mmol) and K2CO3 (166 mg, 1.2 eq) in MeOH (5 mL) was
refluxed for 3 h. After completion, the reaction mixture was filtered
and the residue was washed with MeOH (5 mL). The methanol
filtrates were collected, combined and concentrated under reduced
pressure. The residue was purified by column chromatography
using EtOAc/n-hexane to give the desired product as an off white
Preparation of methyl 2-(4-(5-fluoro-1-(methylsulfonyl)-1H-
indol-2-yl)benzamido)acetate (10). To a mixture of compound 9
(0.1 g, 0.3 mmol) and methyl glycine ester (0.038 g, 0.3 mmol)
in THF (5 mL) was added EDCI.HCl (0.07 g, 0.36 mmol),
HOBT (0.05 g, 0.36 mmol) and DIPEA (0.78 g, 0.6 mmol)
under a nitrogen atmosphere. The mixture was stirred at room
temperature for 3 h. The progress of the reaction was checked
by TLC. After completion of reaction the mixture was poured in
cold water (10 mL) and extracted with EtOAc (3 ¥ 20 mL). The
◦
solid (yield 0.61 g, 75%); mp 160–162 C; Rf = 0.5 (20% EtOAc-
n-hexane); IR (KBr, cm-1) 2917, 1729, 1248, 1174; 1H NMR
(400 MHz, CDCl3) d: 2.44 (s, 3H), 3.74 (s, 3H), 6.71 (d, J = 8.4 Hz,
2H), 7.04–7.20 (m, 3H), 7.22–7.27 (m, 4H), 7.63 (d, J = 7.6 Hz,
2H), 7.77 (s, 1H), 8.39 (bs, 1H); 13C NMR (100 MHz, CDCl3) d:
3814 | Org. Biomol. Chem., 2011, 9, 3808–3816
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organic layers were collected, combined, dried over anhydrous
Na2SO4 and concentrated. The residue was purified by column
chromatography using EtOAc-n-hexane (6 : 4) to give the desired
product as a white solid (yield: 0.08 g, 65%); mp: 230 ◦C; 1H NMR
(400 MHz, acetone-d6) d: ppm 3.02 (s, 3H), 3.71 (s, 3H), 4.17 (t, J =
5.69 Hz, 2H), 6.92 (s, 1H), 7.23 (dd, J = 13.09, 5.35 Hz, 1H), 7.45
(d, J = 7.82 Hz, 1H), 7.71 (d, J = 7.96 Hz, 2H), 7.92 –8.03 (m, 3H),
8.07 (dd, J = 9.07, 4.37 Hz, 1H), 8.25 (s, 1H). 13C NMR (100 MHz,
acetone-d6) d: 39.5, 41.1, 51.3, 106.5, 106.7, 112.9, 113.0, 116.8,
116.9, 126.5 (2C), 130.2 (2C), 134.3, 135.1, 142.8, 161.2, 166.5,
170.2; IR (cm-1): 3072, 2951, 1739, 1341. MS (ES mass): m/z 404.7
(M + 1)+, (100%); HR-MS: calcd for C19H18FN2O5S is 405.1221
found 405.1209.
sample. Absorbance/fluorescence is directly proportional to the
enzyme activity (Fig. 2).
Docking studies
Homology Model of hSIRT 1 (144–217). The three dimen-
sional model of hSIRT 1 (uniprot code: Q96EB6, 144–217 amino
acid residues) was developed by threading method using PRIME
homology modelling program (Schro¨dinger L.L.C., USA). The
multi step Schro¨dinger’s Protein preparation tool (PPrep) has
been used for final preparation of the receptor model. Hydrogen’s
were added to the model automatically via the Maestro interface.26
PPrep neutralizes side chains and residues which are not involved
in salt bridges.27 This step is then followed by restrained minimiza-
tion using the OPLS 2005 force field to RMSD of 0.3 A0.
Single crystal x-ray diffraction (SXRD). X-ray data for the
single crystal of 3a has been collected at room temperature on a
Rigaku AFC-7S diffractometer equipped with a mercury CCD
Docking Procedure. The compound 7 was sketched using
ChemDraw and then converted to their 3D representation. The
compound 7 and protein (homology model of hSIRT 1) were
prepared for docking (i.e. adding hydrogen’s, gasteiger charge
addition, and energy minimization) by using Chimera program.
Autodock 4.0 program was used for docking.
The best model of activator domain of hSIRT 1 was developed
and validated. The receptor grid was generated with co-ordinates
X: 43.804; Y: 47.333; Z: 29.948. The best 5 poses and correspond-
ing scores have been evaluated by the Autodock 4.0 program.
˚
detector using graphite monochromated Mo-Ka (l = 0.7107 A)
radiation. Data collection, indexing, initial cell refinements, frame
integration and final cell refinements were carried out using
CrystalClear SM 1.3.6 software. The crystal structure was solved
with direct methods (SIR2004)24 and refined using least squares
procedure (CRYSTALS)25 using the CrystalStructure 3.8.1 soft-
ware. The non-hydrogen atoms were refined anisotropically. The
hydrogen atoms bonded to carbons were positioned geometrically
˚
and refined in the riding model approximation with C–H = 0.95 A,
and with U(H) set to 1.2UeqI.
Acknowledgements
Crystal data of 3a. Molecular formula = C17H17NO2S, For-
M.P. thanks DST, New Delhi, India for financial support (Grant
NO. SR/S1/OC-53/2009).
¯
˚
˚
mula weight = 299.39, Triclinic, P1, a = 5.805(4) A, b = 10.234(6) A,
3
˚
˚
c = 13.495(8) A, V = 750.8(8) A , T = 298 K, Z = 2, Dc = 1.324
Mg m-3, m(Mo-Ka) = 0.219 mm-1, 8318 reflections measured,
2988 unique reflections, 2515 observed reflections [I > 2.0s(I)],
R1_obs = 0.057, Goodness of fit = 1.089. Crystallographic data
(excluding structure factors) for 3a have been deposited with the
Cambridge Crystallographic Data Centre as CCDC 784742.‡
Notes and references
1 G. W. Gribble, Comprehensive Heterocyclic Chemistry IIA. R. Katritzky,
C. W. Rees, E. F. Scriven, ed.; Pergamon: Oxford, 1996; Vol. 2, pp 207–
257.
2 W. B. Young, A. Kolesnikov, R. Rai, P. A. Sprengeler, E. M. Leahy,
W. D. Shrader, J. Sangalang, J. Burgess-Henry, J. Spencer, K. Elrod and
L. Cregar, Bioorg. Med. Chem. Lett., 2001, 11, 2253.
3 R. L. Mackman, H. C. Hui, J. G. Breitenbucher, B. A. Katz, C. Luong,
A. Martelli, D. McGee, K. Radika, M. Sendzik, J. R. Spencer, P. A.
Sprengeler, J. Tario, E. Verner and J. Wang, Bioorg. Med. Chem. Lett.,
2002, 12, 2019.
4 W. Chai, J. G. Breitenbucher, A. Kwok, X. Li, V. Wong, N. I. Carruthers,
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of the small molecules on SIRT 1 was determined by using a SIRT
1 fluorescence activity assay kit from Cyclex Inc. according to
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also subtracted from the reading. Finally a graph is plotted
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