MWI-promoted preparation of 4H-thiopyran derivatives through one-pot multi-component reactions

Article abstract of DOI:10.3184/030823407X270428

One-pot reaction of aromatic aldehydes, cyanothioacetamide and malononitrile under microwave irradiation proved to be an efficient way for the synthesis of 2,6-diamino-4-aryl-4H-thiopyran-3,5-dicarbonitriles without any added catalyst.

Full text of DOI:10.3184/030823407X270428

JOURNAL OF CHEMICAL RESEARCH 2007
DECEMBER, 693–695
RESEARCH PAPER 693
MWI-promoted preparation of 4H-thiopyran derivatives through one-pot
multi-component reactions
Xuesen Fan*, Xia Wang, Xinying Zhang, Xiaoyan Li and Guirong Qu
School of Chemical and Environmental Sciences, Henan Key Laboratory for Environmental Pollution Control, Henan Normal
University, Xinxiang, Henan 453007, P.R. China
One-pot reaction of aromatic aldehydes, cyanothioacetamide and malononitrile under microwave irradiation proved
to be an efficient way for the synthesis of 2,6-diamino-4-aryl-4H-thiopyran-3,5-dicarbonitriles without any added
catalyst.
Keywords: microwave heating, thioamides, malononitrile, 4H-thiopyrans, multi-component reactions
Recentlythiopyranderivativeshavegainedincreasingattention
due to their importance as key units in medicinal chemistry
and as versatile building blocks in organic synthesis,1 for
example, thiopyrans have been used in the construction of
analogues of natural products, such as tetrahydrodicranenone
B,2 serricornin,3 thromoboxanes,4 and cyclopentanoids.5
In view of these points, a great deal of effort has been
devoted to developing new and efficient synthetic routes to
thiopyrans.6 However, many of these reported procedures are
not fully satisfactory with regard to the cost of the reagents,
using of strong basic catalyst, low isolated yield, or long
reaction times. Therefore, development of novel methods for
the preparation of the above mentioned compounds continues
to be an interesting field of research in both synthetic and
medicinal chemistry.
that enable the preparation of thiopyrans (4) from aromatic
aldehyde (1), malononitrile (2) and cyanothioacetamide (3)
under MWI without any added catalyst (Scheme 1).
Results and discussion
Initially, the reaction of benzaldehyde (1a), malononitrile (2)
and cyanothioacetamide (3) was examined.
A mixture of 1a (0.5 mmol), 2 (0.5 mmol) and 3 (0.5 mmol)
in 5 ml ethanol was put into a commercially available
single-mode microwave synthesis apparatus equipped with
a high sensitivity IR sensor for temperature control and
measurement and irradiated at 250 W (internal temperature
80°C). TLC analysis showed that the reaction thus mediated
under MWI came to a conclusion in 15 min. The solid formed
was collected by suction. Spectra data of IR, 1H NMR and 13
C
Multi-component reactions (MCRs) have recently emerged
as valuable tools in the preparation of structurally diverse
chemical libraries of drug-like heterocyclic compounds.7
In line with the increasing interest in the preparation of large
heterocyclic compound libraries, the development of new and
synthetically valuable multi-component reactions remains a
challenge for both academic and industrial research teams.8
Furthermore, the utility of microwave energy in synthetic
organic chemistry has been increasingly recognised in
recent years since microwave irradiation (MWI) promoted
reactions possess advantages such as an environmentally
friendly nature, improved selectivity, enhanced reaction
rate and cleaner products. Therefore, MWI-mediated
multi-component reactions have constituted an especially
attractive synthetic strategy for rapid and efficient library
generation.9 In the past few years we have been involved in
a program aimed at developing efficient and green synthetic
methods for the preparation of several classes of important
heterocyclic compounds from inexpensive starting materials.
During this phase of our research, we recently reported an
efficient preparative procedure for benzopyran derivatives
from chalcones and 1,3-cyclohexanedione in the presence
of InCl3.4H2O under MWI.10 We have also reported a
multi-component reaction of aldehydes, malononitrile and
1,3-diones to give pyran derivatives in ionic liquid medium
without any added catalysts.11 In continuation of our research
interests in this field, we report here results of our investigation
NMR together with MS results indicated that the product was
4a in a yield of 85%.
With the above result in hand, we then began the search for
the scope of the aldehyde substrate (Scheme 1). The results
shown in Table 1 indicated that aromatic aldehydes bearing
either electron-donating or electron-withdrawing functional
groups such as nitro, chloro, fluoro, bromo, hydroxyl or
methoxy groups were able to take part in the reactions
forming compounds 4. At the same time, the electronic
property and the position of the substituents on the aromatic
ring of the aldehydes have obvious effects on the outcome of
the condensation process. In general, shorter reaction times
were needed and higher yields were obtained with substrates
bearing electron-withdrawing groups on the para- or meta-
position of the aromatic rings (Table 1, entries 2, 4, 7 and
9). On the other hand, while substrates bearing electron-
donating groups or groups on the ortho-position can afford
the corresponding products with good yields, a longer reaction
period was necessary to complete the reaction (Table 1, entries
3, 6, 8 and 10) and the yields are somewhat lower. Aliphatic
aldehydes including valeraldehyde and hexanal were also
tried as substrates. However, the reactions were complicated
and gave unidentified mixtures of products.
Although there are several reports of the preparation of
this kind of compound, they are usually via the reaction of
arylidenemalononitrile with 2-cyanothioacetamide in the
presence of N-methylmorpholine or other basic promoters
Ar
CN
NC
MWI
ethanol
NH2
+
NC
Ar-CHO
+
CN
NC
NH2
S
3
H2N
S
4
1
2
Scheme 1
* Correspondent. E-mail: xuesen.fan@yahoo.com
PAPER: 07/4839

694 JOURNAL OF CHEMICAL RESEARCH 2007
Table 1 Preparation of thiopyrans under MWI
Entry
Ar
Reaction time/min)
Product
Yield/%a
M.p./°C
1
2
C6H5
15
5
10
8
12
16
10
16
12
15
18
4a
4b
4c
4d
4e
4f
4g
4h
4i
85
91
82
90
82
75
85
76
88
78
70
185–186 (181–183)12
198–200 (202–204)13
164–165
p-NO2C6H4
o-NO2C6H4
m-NO2C6H4
p-ClC6H4
3
4
210–211
5
188–189 (189–190)12
168–170
6
o-ClC6H4
7
p-BrC6H4
o-BrC6H4
p-FC6H4
187–188 (183) 12
174–174.5
8
9
172–172.5 (166–167)12
181–183 (163–165)14
170–171
10
11
o-FC6H4
4-OH-3-CH3OC6H3
4j
4k
aIsolated yields based on aldehyde.
MS (ESI): m/z 322 [M + Na]+. Anal. Calcd for C13H9N5O2S: C 52.17,
H 3.03, N 23.40; found: C 52.20, H 3.18, N 23.29%.
with reaction times of several hours. It is to say that not
only are tedious preparative procedures unavoidable in that
arylidenemalononitriles need to be prepared in advance from
aldehydes and malononitrile, but also undesired products
may be formed since the strongly basic conditions employed
may be incompatible with functionalities embedded in the
substrates. In contrast, with our method, thiopyrans were
prepared from commercially available materials and the
preparative procedure is usually complete in 5–18 minutes
without any added catalysts.
In conclusion, we have developed an efficient MWI-
promoted one-pot preparation of thiopyrans from aromatic
aldehydes, malononitrile and cyanothioacetamide. The
method has the advantages of high efficiency and preparative
simplicity. Further efforts to find more applications of MWI-
mediated multicomponent reactions are currently in progress
in our laboratory.
2,6-Diamino-4-(3-nitrophenyl)-4H-thiopyran-3,5-dicarbonitrile
(4d): IR: νmax 3440, 3325, 2200 cm-1. NMR (DMSO-d6): δH 4.55
(s,1H,CH), 7.06 (br s, 4H, 2 NH2), 7.65–7.70 (m, 2H, ArH), 8.04 (s,
1H, ArH), 8.10–8.13 (m, 2H, ArH); δC 152.05, 148.1, 145.8, 133.6,
130.5, 122.3, 121.1, 118.6, 71.05, 42.5. MS (ESI): m/z 322 [M + Na]+.
Anal. Calcd for C13H9N5O2S: C 52.17, H 3.03, N 23.40; found: C
52.20, H 3.22, N 23.50%.
2,6-Diamino-4-(4-chlorophenyl)-4H-thiopyran-3,5-dicarbonitrile
(4e): IR: νmax 3460, 3320, 2200 cm-1. NMR (DMSO-d6): δH 4.28 (s,
1H, CH), 6.93 (br s, 4H, 2 NH2), 7.21 (d, 2H, J = 8.4 Hz, ArH),
7.38 (d, 2H, J = 8.4 Hz, ArH); δC 151.4, 142.5, 131.8, 128.75, 128.6,
118.7, 71.7, 42.7. MS (ESI): m/z 311 [M + Na]+.
2,6-Diamino-4-(2-chlorophenyl)-4H-thiopyran-3,5-dicarbonitrile
(4f): IR: νmax 3480, 3320, 2200 cm-1. NMR (DMSO-d6): δH 4.76 (s,
1H, CH), 6.95 (br s, 4H, 2 NH2), 7.23–7.41 (m, 4H, ArH); δC 151.4,
140.9, 131.65, 129.8, 129.7, 129.1, 128.0, 118.3, 71.0, 42.65. MS
(ESI): m/z 311 [M + Na]+. Anal. Calcd for C13H9ClN4S: C 54.07,
H 3.14, N 19.40; found: C 54.15, H 3.25, N 19.48%.
2,6-Diamino-4-(4-bromophenyl)-4H-thiopyran-3,5-dicarbonitrile
(4g): IR: νmax 3460, 3330, 2210 cm-1. NMR (DMSO-d6) δ: 4.26 (s,
1H, CH), 6.49 (br s, 4H, 2 NH2), 7.15 (d, 2H, J = 8.0 Hz, ArH), 7.52
(d, 2H, J = 8.0 Hz, ArH), 13C NMR (DMSO-d6) δ 151.4, 142.9, 131.7,
129.0, 120.3, 118.7, 71.6, 42.7. MS (ESI): m/z 355, 357 [M + Na]+.
2,6-Diamino-4-(2-bromophenyl)-4H-thiopyran-3,5-dicarbonitrile
(4h): IR: νmax 3450, 3330, 2220 cm-1. NMR (DMSO-d6): δH 4.78
(s, 1H, CH), 6.94 (br s, 4H, 2 NH2), 7.15–7.19 (m, 1H, ArH), 7.34–
7.37 (m, 2H, ArH), 7.55–7.59 (m,1H, ArH); δC 151.0, 142.9, 132.8,
129.95, 129.4, 128.7, 118.2, 71.2, 42.4. MS (ESI): m/z 355, 357 [M +
Na]+. Anal. Calcd for C13H9BrN4S: C 46.86, H 2.72, N 16.81; found:
C 46.98, H 2.65, N 16.88%.
2,6-Diamino-4-(4-fluorophenyl)-4H-thiopyran-3,5-dicarbonitrile
(4i): IR: νmax 3450, 3325, 2200 cm-1. NMR (DMSO-d6): δH 4.27 (s,
1H, CH), 6.91 (br s, 4H, 2 NH2), 7.12–7.24 (m, 4H, ArH); δC 151.3,
139.55, 128.7, 128.6, 118.75,115.6, 115.4, 72.0, 42.4. MS (ESI): m/z
295 [M + Na]+.
Experimental
Melting points were measured by a Kofler micro-melting point
apparatus. Infrared spectra were recorded on a Bruker Vector 22
spectrometer in KBr discs. H NMR spectra were determined on a
1
Bruker AC 400 spectrometer as DMSO-d6 or CD3OD solutions.
Chemical shifts are reported in ppm downfield from the internal
standard tetramethylsilane. Mass spectra were obtained in ESI mode
using a Bruker Esquire 3000 mass spectrometer. Elemental analyses
were performed on an EA-1110 instrument.
The microwave irradiations were performed in a commercially
available single-mode microwave synthesis apparatus equipped
with a high sensitivity infrared sensor for temperature control and
measurement (MAS-I, Sineo Microwave Chemical Technology Co.
Ltd., Shanghai, P.R. China).
Preparation of thiopyran derivatives 4: general procedure
The aromatic aldehyde (1, 1 mmol), malononitrile (2, 0.066 g, 1 mmol)
cyanothioacetamide (3, 0.10 g, 1 mmol) and ethanol (5 ml) were
mixed in a flask and irradiated at 250 W (internal temperature 80°C)
for a sufficient time as required to complete the reaction (monitored
by TLC). Upon completion, the reaction mixture was allowed to cool
to room temperature and the solid product was collected by filtration
and washed with 95% ethanol to give the desired products 4 (Table 1).
All the new products were fully characterised by IR, 1H and 13C
NMR, MS and elemental analysis.
2,6-Diamino-4-phenyl-4H-thiopyran-3,5-dicarbonitrile (4a): IR:
νmax 3450, 3320, 2210 cm-1. NMR (DMSO-d6): δH 4.22 (s, 1H, CH),
6.89 (br s, 4H, 2 NH2), 7.19–7.24 (m, 3H, ArH), 7.30–7.33 (m, 2H,
ArH); δC 151.3, 143.55, 128.8, 127.2, 126.7, 118.9, 72.1, 43.4. MS
(ESI): m/z 277 [M + Na]+.
2,6-Diamino-4-(2-fluorophenyl)-4H-thiopyran-3,5-dicarbonitrile
(4j): IR: νmax 3440, 3325, 2200 cm-1. NMR (DMSO-d6): δH 4.52 (s,
1H, CH), 6.95 (br s, 4H, 2 NH2), 7.14–7.32 (m, 4H, ArH); δC 160.8,
158.4, 152.0, 129.7, 129.6, 129.4, 129.3, 129.0, 129.0, 124.8, 118.45,
115.85, 115.6, 70.7, 37.3. MS (ESI): m/z 295 [M + Na]+.
2,6-Diamino-4-(4-hydroxy-3-methoxyphenyl)-4H-thiopyran-3,5-
dicarbonitrile (4k): IR: νmax 3450, 3310, 2200 cm-1. NMR (DMSO-
d6): δH 3.70 (s, 3H, OCH3), 4.10 (s, 1H, CH), 6.58 (d, 1H, J = 8.0 Hz,
ArH), 6.68–6.74 (m, 2H, ArH), 6.80 (br s, 4H, 2 NH2), 8.91 (s,
1H, OH); δC 150.8, 147.6, 145.9, 134.5, 119.1, 118.9, 115.6, 111.2,
72.8, 55.7, 43.1. MS (ESI): m/z 323 [M + Na]+. Anal. Calcd for
C14H12N4O2S: C 55.99, H 4.03, N 18.65; found: C 56.10, H 4.05,
N 18.78%.
We are grateful to the National Natural Science Foundation of
China (Project No. 20 772 025).
2,6-Diamino-4-(4-nitrophenyl)-4H-thiopyran-3,5-dicarbonitrile
(4b): IR: νmax 3410, 3315, 2220 cm-1. NMR (CD3OD): δH 4.47 (s,
1H, CH), 7.53 (d, 2H, J = 8.0 Hz, ArH), 8.20 (d, 2H, J = 8.0 Hz,
ArH); δC 152.1, 149.5, 146.8, 127.3, 123.2, 117.5, 71.65, 43.2.
MS (ESI): m/z 322 [M + Na]+.
Received 17 September 2007; accepted 17 December 2007
Paper 07/4839
doi: 10.3184/030823407X270428
2,6-Diamino-4-(2-nitrophenyl)-4H-thiopyran-3,5-dicarbonitrile
(4c): IR: νmax 3400, 3320, 2210 cm-1. NMR (DMSO-d6): δH 4.97
(s, 1H, CH), 7.04 (br s, 4H, 2 NH2), 7.48–7.55 (m, 2H, ArH), 7.69–
7.73 (t, 1H, ArH, J = 7.6 Hz), 7.84–7.86 (d, 1H, ArH, J = 8.0 Hz);
δC 151.7, 148.3, 137.6, 133.85, 130.0, 128.8, 124.4, 118.1, 70.7, 37.9.
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