Scandium triflate-catalyzed one-pot multi-component synthesis of 2-amino-6-thiopyridine-3,5-dicarbonitriles

Article abstract of DOI:10.1515/hc-2012-0103

Scandium triflate efficiently promotes a one-pot, three-component condensation of aldehydes, malononitrile, and thiophenols to produce highly substituted pyridines in good yields. This reaction does not involve any hazardous organic solvent and toxic cata

Full text of DOI:10.1515/hc-2012-0103

ꢁꢁꢁꢂ
DOI 10.1515/hc-2012-0103ꢀ ꢀHeterocycl. Commun. 2012; 18(5-6): 249–252
SShcrinaivnasdS.iKuomttawtarr,iSfhlaapitAe. S-icddaiqtuai alnydzSueddhakoarnR.eB-hupsaoret*
multi-component synthesis of 2-amino-6-
thiopyridine-3,5-dicarbonitriles
Abstract: Scandium triflate efficiently promotes a one-pot, openers for treatment of urinary incontinence (Harada et
three-component condensation of aldehydes, malono- al., 2002). Several of these compounds are used as highly
nitrile, and thiophenols to produce highly substituted selective ligands for adenosine receptors (Beukers et al.,
pyridines in good yields. This reaction does not involve 2004), which are recently recognized as potential targets
any hazardous organic solvent and toxic catalyst.
for the development of new drugs for the treatment of Par-
kinson’s disease, asthma, epilepsy, cancer, kidney disease,
Keywords: aldehydes; 2-amino-6-thiopyridine-3,5-dicar- and hypoxia (Fredholm et al., 2001).
bonitrile; malononitrile; multi-component reaction; scan-
dium triflate; thiophenol.
Thus, the synthesis of highly substituted pyridines
has attracted much attention and a number of procedures
have been developed (Anabha et al., 2007). Among these,
one of the convenient approaches that attracted our atten-
tion is the three-component condensation of aldehyde,
malononitrile, and thiol to the highly substituted pyridines
developed by Evdokimov et al. (2006). Recently, a modifi-
cation to this method was reported by making use of basic
ionic liquid (Ranu et al., 2007). Conversely, the synthesis
of 2-amino-6-thiopyridine-3,5-dicarbonitrile derivatives
in the presence of Lewis acid ZnCl2 in moderate to good
yield has been reported (Sridhar et al., 2009). Syntheses
of 2-amino-6-thiopyridine-3,5-dicarbonitrile derivatives via
MCRs using catalysts KF/alumina (Singh and Singh, 2009),
*Corresponding author: Sudhakar R. Bhusare, Department of
Chemistry, Dnyanopasak College, Parbhani-431401, India,
e-mail: bhusare71@yahoo.com
Shrinivas S. Kottawar: Department of Chemistry, Dnyanopasak
College, Parbhani-431401, India
Shapi A. Siddiqui: Department of Chemistry, Dnyanopasak College,
Parbhani-431401, India
Introduction
The rapid assembly of molecular diversity is an important NAP-MgO (Kantam et al., 2010), and o-iodoxybenzoic acid
goal of synthetic organic chemistry and one of the key para- (Takale et al., 2012) have also been reported.
digms of modern drug discovery. One approach to address
As part of our continuing program on scandium(III)
this challenge involves the development of multi-compo- triflate (Kottawar et al., 2009), herein we describe a mild and
nent reactions (MCRs), in which three or more reactants are efficient method for the synthesis of 2-amino-6-thiopyridine-
combined together in a single reaction flask to generate a 3,5-dicarbonitrile derivatives using scandium(III) triflate as
product incorporating most of the atoms contained in the a Lewis acid catalyst (Scheme 1). This method is not only an
starting materials (Orru and de Greef, 2003). In addition to excellent complement to the other reported methods but is
the intrinsic atom economy and selectivity underlying such also eco-friendly in that it avoids the use of hazardous acids
reactions, simpler procedures and equipment, time and or bases and harsh reaction conditions. The advantages of
energy savings, as well as environmental friendliness have this method are inexpensive reagents, mild reaction con-
all led to a sizable effort to design and implement MCRs in ditions, experimental operational ease, and good yields of
both academia and industry (Ramo’n and Miguel, 2005). pyridine products in the range of 65–85%.
The pyridine nucleus is of considerable interest as this ring
is the key constituent in a range of bioactive compounds,
both naturally occurring and synthetic, and often of con- Results and discussion
siderable complexity. 2-Amino-6-thiopyridine-3,5-dicar-
bonitrile derivatives show diverse pharmacological activi- Scandium triflate is a new type of Lewis acid, differing
ties such as anticancer (Cocco et al., 2005), antihepatitis from typical Lewis acids such as AlCl3, BF3, and SnCl4. It
B virus (Chen et al., 2005), antiprion (Perrier et al., 2000), does not undergo decomposition or deactivation in the
antibacterial (Levy et al., 2005), and are potassium channel presence of water and works as a catalyst where other
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ꢀS.S. Kottawar et al.: Synthesis of 2-amino-6-thiopyridine-3,5-dicarbonitriles
R1
R2
SH
CHO
+
NC
S
CN
CN
Sc(OTf)3
+
R2
R3
EtOH/reflux
CN
R3
N
4a-s
NH2
R1
3
1
2
4j:
4a:
R1 = 2-Cl
R
1 = H
1 = H
1 = H
R2 = 4-F
R2 = 6-Cl
R3 = H
R3 = H
R3 = H
4k:
4l:
R1 = 2-F
4b:
R
R2 = 4-OCH3
R2 = H
R2 = 6-F
R3 = H
R
1 = H
1 = H
4c:
4d:
4e:
4f:
R2 = H
R
R3 = 4-Br
R
3 = H
R
4m:
4n:
4o:
4p:
4q:
4r:
R2 = 4-OCH3
R2 = 4-OCH3
R2 = H
R2 = 4-Cl
R2 = 4-Br
R1 = H
R
3 = 4-Br
3 = 4-Br
R3 = H
R1 = 3-OCH3
R1 = H
R
1 = H
R
R
3 = H
R
R
R
2 = 3-Br
R
1 = 2-OCH3
R3 = 4-NH2
R3 = 4-NH2
R3 = 4-NH2
R3 = 2-NH2
R3 = 2-NH2
R3 = H
R3 = H
R1 = H
R2 = 4-OCH3
R2 = 4-OCH3
R2 = H
2 = H
4g: R1 = 3-Br
R
1 = 3-OCH3
2 = 4-OCH3
4h: R1 = 3-OCH3
R3 = H
3 = H
R1 = H
1 = 3-OCH3
R2 = 6-F
R1 = 2-Cl
4i:
R
R
R2 = 4-OCH3
4s:
Scheme 1ꢀ
progress of reaction. Column chromatography was carried out using
silica gel (80–120 mesh). Melting points were determined in open
Lewis acids are required in a stoichiometric amount.
Moreover, many nitrogen containing compounds can be
activated in the presence of a catalytic amount of Sc(OTf)3
in both organic and aqueous solvents (George et al., 1993).
Scandium triflate is used as catalyst in a variety of reac-
tions (Cho et al., 2006). Scandium triflate can be recovered
almost quantitatively after the reaction is completed and
can be recycled for the subsequent uses without any loss
of activity. The reactions described herein were conducted
in ethanol and were completed after 2 h. Using other sol-
vents such as toluene, dimethyl sulfoxide, N,N-dimethyl-
formamide, methanol, and 1,2-dichloroethane afforded
products 4 in lower yields ranging from 17% to 75% after a
much longer period of time up to 12 h.
It was observed that the process tolerates both elec-
tron donating and electron withdrawing substituent on
the aldehyde. Good yields of the products were obtained
after purification by column chromatography. All the com-
pounds were characterized by melting point, 1H NMR, 13C
NMR, and HR-MS.
1
capillaries and are uncorrected. H NMR spectra (400 MHz) and 13C
NMR spectra (100 MHz) were recorded on a Bruker 400 spectrometer
in DMSO-d6.
General procedure for synthesis of 2-amino-
6-thiopyridine-3,5-dicarbonitriles 4a–s
A mixture of a benzaldehyde (1, 10 mmol), malononitrile (2, 20
mmol) scandium triflate (5 mol %), a thiophenol (3, 10 mmol), and
ethanol (10 mL) in a round bottom flask was heated under reflux for
2 h. The progress of reaction was monitored by thin layer chromatog-
raphy eluting with petroleum ether/ethyl acetate, 8:2. Afer comple-
tion of reaction ethanol was evaporated under reduced pressure, and
the residue was extracted in ethyl acetate. The extract was washed
with water, dried over anhydrous magnesium sulfate, and concen-
trated under reduced pressure. The crude product 4a–s was purified
by silica gel (100–200 mesh) column chromatography eluting with
ethyl acetate/hexane, 1:9.
2-Amino-4-(4-fluorophenyl)-6-(phenylthio)pyridine-3,5-dicar-
bonitrile (4a)ꢀColorless solid; yield 65%; mp 217–219°C; lit mp 218–
220°C (Singh and Singh, 2009); reaction time 1.8 h.
Conclusion
2-Amino-4-(4-methoxyphenyl)-6-(phenylthio)pyridine-3,5-
dicarbonitrile (4b)ꢀColorless solid; yield 75%; mp 237–239°C; lit
mp 239–241°C (Singh and Singh, 2009); reaction time 2.0 h.
A mild and efficient method for the synthesis of 2-amino-
6-thiopyridine-3,5-dicarbonitriles 4 by using scandium(III)
triflate as a Lewis acid catalyst is described. This general
synthesis does not require the use of hazardous acids or
bases and is conducted under mild conditions.
2-Amino-4-phenyl-6-(phenylthio)pyridine-3,5-dicarbonitrile
(4c)ꢀColorless solid; yield 85%; mp 218–220°C; lit mp 215–217°C (Sin-
gh and Singh, 2009); reaction time 2.0 h.
2-Amino-4-(4-chlorophenyl)-6-(phenylthio)pyridine-3,5-dicar-
bonitrile (4d)ꢀWhite solid; yield 65%; mp 224–226°C; lit mp 223–
225°C (Singh and Singh, 2009); reaction time 1.8 h.
Experimental
2-Amino-4-(4-bromophenyl)-6-(phenylthio)pyridine-3,5-dicar-
All solvents were used as commercial anhydrous grade without fur-
ther purification. Merck aluminum sheets 20×20 cm coated with bonitrile (4e)ꢀYellow solid; yield 65%; mp 232–237°C; lit mp 232–
silica gel 60 F254 were used for thin layer chromatography to monitor 234°C (Singh and Singh, 2009); reaction time 1.8 h.
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ꢀ251
2-Amino-4-(3-bromo-6-methoxyphenyl)-6-phenylsulfanylpyri- 2-(4-Bromophenylthio)-6-amino-4-(3,4-dimethoxyphenyl)
dine-3,5-dicarbonitrile (4f)ꢀYellow solid; yield 65%; mp 270–271°C; pyridine-3,5-dicarbonitrile (4n)ꢀYellow solid; yield 65%; mp 268–
reaction time 2.5 h; 1H NMR: δ 7.81 (br s, 2H, NH2), 7.71 (dd, J = 8.8 Hz, 270°C; reaction time 2.5 h; 1H NMR: δ 7.94 (br s, 2H), 7.62 (d, 2H), 7.52
2.4 Hz, 1H) 7.62–7.59 (m, 3H), 7.58–7.49 (m, 3H), 7.21 (d, J = 8.8 Hz, 1H), (d,4H), 7.48 (d, 3H), 7.25 (d, 4H) 3.91 (s, 6H); 13C NMR: δ 167.2, 162.1,
3.8 (s, 3H); 13C NMR: δ 165.6, 159.4, 155.2, 154.8, 134.8, 134.5, 132.0, 129.7, 158.8, 158.0, 140.1, 138.1, 133.1, 129.3, 128.3, 124.2, 123.8, 118.3, 113.2,
129.5, 126.9, 124.6, 114.9, 114.6, 114.4, 111.8, 94.1, 88.0, 56.2. HRMS. Calcd 111.0, 95.2, 89.2, 58.4. HRMS. Calcd for C21H15N4O2S [M+]: m/z 466.6574.
for C20H13BrN4OS [M+]: m/z 435.9993. Found: m/z 435.9992.
Found: m/z 466.6580.
2-Amino-4-(3-bromophenyl)-6-phenylthiopyridine-3,5-dicar- 2-Amino-4-phenyl-6-(4-aminophenylthio)pyridine-3,5-dicarbo-
bonitrile (4g)ꢀColorless solid; yield 69%; mp 254–256°C; lit mp nitrile (4o)ꢀYellow solid; yield 69%; mp 219–221°C; reaction time
1
1
255–257°C (Singh and Singh, 2009); reaction time 2.0 h; H NMR: δ 2.0 h; H NMR: δ 7.70 (br s, 2H, NH2), 7.55–7.52 (m, 5H), 7.17 (d, J =
7.86 (br s, 2H, NH2), 7.81–7.77 (m, 3H), 7.60–7.48 (m, 6H); 13C NMR: δ 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 5.58 (br s, 2H, NH2); 13C NMR: δ
166.0, 159.5, 156.9, 136.1, 134.7, 133.1, 131.0, 130.8, 129.6, 129.4, 127.5, 168.6, 159.6, 158.4, 150.6, 136.7, 134.0, 130.2, 128.6, 128.4, 115.4, 115.1,
127.0, 121.7, 115.1, 114.8, 93.3, 87.1. HRMS. Calcd for C19H11BrN4S [M+]: 114.5, 109.5, 92.5, 86.4. HRMS. Calcd for C19H13N5S [M+]: m/z 343.0892.
m/z 405.9888. Found: m/z 405.9883.
Found: m/z 343.0884.
2-Amino-4-(3,4-dimethoxyphenyl)-6-phenylthiopyridine-3,5- 2-(4-Aminophenylthio)-6-amino-4-(4-methoxyphenyl)pyri-
dicarbonitrile (4h)ꢀYellow solid; yield 68%; mp 227–229°C; lit mp dine-3,5-dicarbonitrile (4p)ꢀYellow solid; yield 70%; mp 275–
229–230°C (Takale et al., 2012); reaction time 2.5 h; 1H NMR: δ 7.75 (br 277°C; reaction time 2.5 h; 1H NMR: δ 8.30 (d, 2H), 7.98–7.90 (m, 3H),
s, 2H, NH2), 7.60–7.58 (m, 2H), 7.49–7.47 (m, 3H), 7.20 (m, 1H), 7.13–7.10 7.78 (br s, 2H), 7.60–7.51 (m, 3H), 7.26–7.17 (m, 5H), 5.92 (s, 2H), 3.86 (s,
(m, 2H), 3.83 (s, 3H), 3.79 (s, 3H); 13C NMR: δ 166.1, 159.7, 158.3, 150.4, 3H); 13C NMR: δ 169.2, 163.1, 159.7, 158.9, 136.3, 134.5, 132.5, 131.0, 131.3,
148.3, 134.8, 129.6, 129.4, 127, 125.8, 121.5, 115.6, 115.3, 112.3, 111.5, 93.4, 129.2, 127.7, 127.0, 126.2, 124.3, 124.0, 117.3, 115.8, 114.6, 94.2, 88.1, 55.4.
87.0, 55.7, 55.5 cm-1. HRMS. Calcd for C21H16N4O2S [M+]: m/z 388.0994. HRMS. Calcd for C20H15N5OS [M+]: m/z 373.1322. Found: m/z 373.1132.
Found: m/z 388.0990.
2-(4-Aminophenylthio)-6-amino-4-(3,4-dimethoxyphenyl)pyri-
2-Amino-4-(2-chloro-6-fluorophenyl)-6-(phenylthio)pyri- dine-3,5-dicarbonitrile (4q)ꢀYellow solid; yield 68%; mp 280–
dine-3,5-dicarbonitrile (4i)ꢀYellow solid; yield 69%; mp 146– 282°C; reaction time 1.8 h; 1H NMR: δ 8.38 (d, 2H), 8.02–7.98 (m, 3H),
1
148°C; reaction time 1.8 h; H NMR: δ 8.11 (br s, 2H NH2), 7.70–7.68 7.70 (br s, 2H), 7.65–7.58 (m, 3H), 7.19–7.10 (m, 5H), 5.88 (s, 2H), 3.91
(m, 2H), 7.67–7.61 (m, 4H), 7.56–7.49 (m, 4H); 13C NMR: δ 166.6, 159.8, (s, 6H); 13C NMR: δ 169.2, 163.1, 159.7, 158.9, 136.3, 134.5, 132.5, 131.0,
159.3, 157.3, 150.6, 135.0, 133.6, 133.5, 132.4, 129.9, 129.5, 126.4, 126.2, 131.3, 129.2, 127.7, 127.0, 126.2, 124.3, 124.0, 117.3, 115.8, 114.6, 94.2, 88.1,
126.3, 121.1, 120.9, 115.4, 115.1, 114.0, 113.7, 93.4, 87.7. HRMS. Calcd for 55.4. HRMS. Calcd for C21H17N5O2S [M+]: m/z 403.1042. Found: m/z
C19H10ClFN4S [M+]: m/z 380.0299. Found: m/z 380.0291.
403.1043.
2-Amino-4-(2,6-dichlorophenyl)-6-phenylthiopyridine-3,5- 2-(2-Aminophenylthio)-6-amino-4-phenylpyridine-3,5-dicarbo-
dicarbonitrile (4j)ꢀYellow solid; yield 74%; mp 185–187°C; reaction nitrile (4r)ꢀYellow solid; yield 75%; mp 146–148°C; reaction time
time 2.0 h; 1H NMR: δ 8.13 (br s, 2H, NH2), 7.75 (d, J = 8.4 Hz, 2H), 7.65– 2.5 h; 1H NMR: δ 7.79 (br s, 2H), 7.62–7.56 (m, 5H), 7.21 (d, 2H), 6.68 (d,
7.62 (m, 3H), 7.51–7.50 (m, 3H); 13C NMR: δ 166.7, 159.4, 154.2, 135.0, 133.0, 2H), 5.69 (br s, 2H); 13C NMR: δ 169.2, 159.1, 158.7, 151.2, 136.9, 134.6,
132.6, 131.5, 130.0, 129.5, 128.9, 126.3, 113.9, 113.6, 92.9, 87.1. HRMS. Calcd 130.8, 128.9, 128.0, 118.4, 116.1, 115.8, 110.2, 93.5, 88.2. HRMS. Calcd for
for C19H10Cl2N4S [M+]: m/z 396.0003. Found: m/z 396.0008.
C19H13N5S [M+]: m/z 343.0892. Found: m/z 343.0884.
2-Amino-4-(2,6-difluorophenyl)-6-(phenylthio)pyridine-3,5-di- 2-(2-Aminophenylthio)-6-amino-4-(3,4-dimethoxyphenyl)
carbonitrile (4k)ꢀWhite solid; yield 75%; mp 170–172°C; reaction pyridine-3,5-dicarbonitrile (4s)ꢀYellow solid; yield 69%; mp
1
time 2 h.
146–148°C; reaction time 2.5 h; H NMR: δ 8.24 (d, 1H), 8.02–7.98 (m,
3H), 7.73 (br s, 2H), 7.62–7.51 (m, 5H), 7.13 (dd, 3H), 5.82 (s, 2H), 3.89
2-(4-Bromophenylthio)-6-amino-4-phenylpyridine-3,5-dicarbo- (s, 6H); 13C NMR: δ 166.7, 162.1, 159.2, 158.2, 135.3, 134.1, 132.8, 131.4,
nitrile (4l)ꢀWhite solid; yield 67%; mp 256–258°C; reaction time 1.8 130.1, 128.3, 127.9, 127.4, 126.9, 124.4, 124.0, 116.5, 115.2, 114.3, 93.4, 87.0,
h; 1H NMR: δ 7.90 (br s, 2H, NH2), 7.56 (d, 2H), 7.48 (d, 2H), 7.42 (d, 55.3. HRMS. Calcd for C21H17N5O2S [M+]: m/z 403.1042. Found: m/z
3H), 7.10 (d, 2H); 13C NMR: δ 163.5, 158.3, 157.6, 157.3, 139.3, 133.1, 131.4, 403.1032.
127.3, 123.9, 123.5, 118.3, 114.8, 114.2, 94.2, 89.2, 58.4. HRMS. Calcd for
C19H11N4S [M+]: m/z 407.8465. Found: m/z 435.8458.
Acknowledgments: We acknowledge Dr. P.L. More and Dr.
W.N. Jadhav, Dnyanopasak College, Parbhani, for provid-
2-Amino-4-(4-methoxyphenyl)-6-(4-bromophenylthio)pyri-
ing necessary facilities and UGC, New Delhi, for financial
dine-3,5-dicarbonitrile (4m)ꢀYellow solid; yield 75%; mp 262–
support (MRP-47–125/06).
264°C; reaction time 2.0 h; 1H NMR: δ 7.81 (br s, 2H, NH2), 7.67 (d, J =
8.4 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.11 (d, J =
8.8 Hz, 2H) 3.83 (s, 3H); 13C NMR: δ 165.5, 160.8, 159.7, 158.3, 136.8,
132.3, 130.2, 126.6, 125.7, 123.4, 115.4, 115.1, 114.0, 93.3, 87.0, 55.3. HRMS. Received July 26, 2012; accepted August 30, 2012; previously
Calcd for C21H16N4OS [M+]: m/z 435.9993. Found: m/z 435.9987. published online November 16, 2012
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