A convenient electro-catalyzed multicomponent synthesis of 4: H -thiopyran derivatives

Article abstract of DOI:10.1039/c7nj01211j

An environmentally benign synthesis of substituted 4H-thiopyrans was carried out by the condensation of aromatic aldehydes, malononitrile, carbon disulfide and primary amines. Constant potential electro synthesis was carried out in an undivided cell at ro

Full text of DOI:10.1039/c7nj01211j

View Article Online
View Journal
NJC
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: R. Dubey, V. K.
Singh, L. K. Sharma, A. Upadhyay, N. Kumar and R. K. P. Singh, New J. Chem., 2017, DOI:
10.1039/C7NJ01211J.
This is an Accepted Manuscript, which has been through the
Volume 40 Number
1 January 2016 Pages 1–846
Royal Society of Chemistry peer review process and has been
accepted for publication.
NJC
Accepted Manuscripts are published online shortly after
New Journal of Chemistry
www.rsc.org/njc
A journal for new directions in chemistry
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
rsc.li/njc

New Journal of Chemistry
Page 1 of 5Journal Name
Dynamic Article Links►
View Article Online
DOI: 10.1039/C7NJ01211J
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
A convenient electro-catalyzed multicomponent synthesis of 4H-thiopyran
derivatives
5
Rahul Dubey, Vinay K. Singh, Laxmi Kant Sharma, Abhishek Upadhyay, Narendra Kumar, Rana
Krishna Pal Singh*
a
Electrochemical Laboratory Green of Synthesis, Department of Chemistry, University of Allahabad,211002 India. E-mail: rkp.singh@rediffmail.com,
10 (R.K.P.Singh); Tel:+91 9335179483
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
An environmentally benign synthesis of substituted 4Hꢀthiopyran was carried out by the condensation of
15 aromatic aldehyde, malononitrile, carbon disulfide and primary amine. Constant potential electro
synthesis was carried out in an undivided cell at room temperature in the presence of lithium perchlorate
as a supporting electrolyte. Clean synthesis, use of electricity instead of chemical reagents and atom
economy
are
attractive
features
of
the
present
protocol.
The construction of heterocyclic cores undoubtedly
20 represents a highly important discipline of organic synthesis. The 45 species such as radical cations, radical anions and free radicals
serves as one of the most straight forward way.10 Highly reactive
large interest in this field is attributable to the occurrence of
heterocyclic units in numerous natural products and biologically
active compounds such as hormones, antibiotics and vitamins.1
These compounds are used as multipurpose building blocks in
can be generated electrochemically at room temperature.
Electrochemical synthesis is unique technique valuable for largeꢀ
scale processes because electricity is a cheap and environmentally
benign chemical reagent and its behavior to produce initial base
25 organic molecule and are key units in biological and medicinal 50 as catalyst can be used at ambient temperature and pressure.11The
chemistry.2 A broad range of biological activities have been
reported for sulfurꢀcontaining heterocyclic compounds.3 Among
the sulfur containing heterocycles, thiopyran structure has high
significance as a versatile scaffold for the synthesis of certain
organic transformations12 have been carried out under mild
conditions. The formation of highly reactive intermediate are
achieved due to electron transfer between electrode and substrate
molecule avoiding acid and bases as reducing and oxidizing
30 natural and synthetic products.4 Thiopyrans are broadly found in 55 agents as well as by products.13
the structure of natural product analogues with numerous
NC
NH2
S
activities such as anticancer,5 antiꢀpsychiatric,6 antiꢀbacterial,7
antihyperplasia,8 analgesic and antiꢀinflammatory9 activities.
O
CN
NC
Electrolysis 1.5V
LiClO4, EtOH, r.t,
CS2
Ar
RNH2
RNCS
Ar
H
NC
CN
NC
NH2
1
3
4
5a-j
2
R= Propyl
Thiopyrans
Isothiocynate
The electrochemical multicomponent reactions
35 (EMCRs) have been used extensively to prepare bioactive
heterocyclic compounds and became an important area of
research in organic and medicinal chemistry. Onꢀdemand
synthesis are expected to be popular in the future. New trends in
chemical synthesis increases the demand for fast chemical
40 reaction. To accomplish extremely fast reactions, we often need
to activate molecules to make substrate with build in high energy
content or prepare highly reactive reagents that react very quickly
with substrates, for such purposes, organic electrochemistry
This journal is © The Royal Society of Chemistry [year]
Scheme
derivatives
1
Electrocatalytic pathway for synthesis of 4Hꢀthiopyran
60
Most of the reported procedures utilizes the similar
reactant for the synthesis of 4Hꢀthiopyran derivatives which are
multipleꢀstep reactions and accompanied with long reaction time,
costly reagents,14,15 complex synthetic pathꢀways and low yields.
Therefore, the introduction of ecofriendly methods, accompanied
65 with higher yields, are in demand. As a part of our ongoing effort
towards the electro synthesis of multicomponent reaction.16, 17We
[journal], [year], [vol], 00–00 |1

New Journal of Chemistry
Page 2 of 5
View Article Online
DOI: 10.1039/C7NJ01211J
report the electrosynthesis of 4Hꢀthiopyran derivatives via direct
addition of aromatic aldehydes, malononitrile, primary amine and
carbon disulfide without any additive catalyst.
propylamine, afforded good yields (Table 2, entry 3, 4, 5).
Aromatic primary amine albeit in a poor yield (Table 2, entry 1,
7). For example, aniline gave a 50% yield of 5a. The standard
conditions could also be applied to aromatic amines, such as
45 aniline and oꢀchloroaniline, poor yields of compounds 5a were
obtained.
In present work we report
a catalyst free four
5
component reaction using aromatic aldehyde (1 mmol),
malononitrile (2 mmol), primary amine (1 mmol) and carbon
disulfide (1 mmol), lithium perchlorate(0.5 M) was used as an
electrolyte and ethanol (30 mL) as solvent. The electrochemical
synthesis was carried out in an undivided cell equipped with
Table 2 Effect of primary amine in preparation of 5a
10 platinum electrode working as well as the counter electrode at
room temperature under constant potential. The progress of the
reaction was monitored by TLC using hexane/ethyl acetate
mixture.
Entry Primary amine Solvent Potential Time Current Yield
(V)
1.5
(min) (mA) (%)
1
2
3
4
5
6
7
Aniline
EtOH
40
30
26
24
22
30
40
24
12
12
10
15
12
24
40
82
88
86
92
82
40
Cyclohexylamine EtOH
1.5
1.5
1.5
1.5
1.5
1.5
Different potentials were applied under the mentioned
15 conditions for conversions of the starting materials into product.
It was observed that when potential of the reaction was 1.5 V, Pt
electrodes surface (1cm2) was found to be optimal for the
electrochemically induced chain process and attributed to the
highest yield of 5a using EtOH as solvent and Lithium
20 perchlorate as electrolyte (Table 1, entry 6).
Butylamine
Ethylamine
Propylamine
Benzylamine
EtOH
EtOH
EtOH
EtOH
Table
nitrophenyl)ꢀ4Hꢀdicarbonitrile (5a)
1
aOptimization for the synthesis of 2,6ꢀdiaminoꢀ4ꢀ(3ꢀ
o-Chloroaniline EtOH
50
55
60
65
70
75
A mechanistic rationalization for the reaction is
16, 18, 19
proposed in (Scheme 2). The plausible mechanism11,
shows that the deprotonation of an alcohol at the cathode leads to
formation of alkoxide anion, its subsequent reaction in solution
with malononitrile gives rise to malononitrile anion.
Entry
Solvent
Potential (V) Time (min) Current (mA) Yieldb (%)
1
MeCN
1.5
1.5
1.5
1.0
1.2
1.5
35
30
30
28
25
22
10
10
12
10
12
15
70
75
75
80
84
92
2C2H5OH
2e
H2
At Cthode
In Solution
2C2H5
O
2
3
4
5
6
nꢀPrOH
MeOH
EtOH
CH2(CN)2
2
C2H5OH
C2H5
O
CH(CN)2
O
OH
CH(CN)2
O
H
CH(CN)2
Ar CH
C(CN)2
Ar
Ar
CH(CN)2
Ar
6
1
CH(CN)2
N
C
NC
Ar
S
EtOH
C
S
S
H2
N
R
HS
C
HN R
CN
CN
3
4
B
EtOH
A
25 aOptimize conditions: 3ꢀnitrobenzaldehyde 1 (1 mmol), malononitrile 2 (2
mmol), carbon disulfide 3 (1 mmol), propyl amine 4 (1 mmol), LiClO4
(0.5 M), EtOH solvent (30 mL), Pt electrode at r.t.
S
NH
N
C
N
H
R
S
CN
Ar
bIsolated yield of the product 5a
CN
7
R
N C S
30
The reaction conditions were optimized under various
solvents and potentials. In all the tested solvents such as MeCN,
nꢀPrOH, MeOH, and EtOH at constant potential (1.5 V) the yield
of 4Hꢀthiopyran 5a was good (Table 1), which indicates that the
reaction is not very sensitive to reaction media. EtOH was the
NH2
S
CN
H
NH2
S
NH2
S
CN
Ar
CN
Ar
N
Ar
NH
NH2
H
CN
CN
CN
8
5a-j
35 best solvent in terms of the reaction time, current and excellent
yield (Table 1, entry 6), hence it was used throughout the present
work. With the optimal conditions in hand, we studied the scope
and the generality of the protocol by examining reactions of 4Hꢀ
thiopyran 5a with a variety of amines 3. As shown in Table 2,
40 aliphatic primary amines, such as butylamine, ethylamine, and
80 Scheme 2 Plausible electro catalyzed pathway for synthesis of
4Hꢀthiopyran derivatives
Then Knoevenagel condensation of aldehyde with
malononitrile anion takes place in the solution with the
2
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 5
New Journal of Chemistry
View Article Online
DOI: 10.1039/C7NJ01211J
NC
NH2
S
elimination of water and formation of the corresponding 2ꢀ
arylidene malononitrile intermediate, another mole of
malononitrile anion attacks intermediate 6 via Michael addition to
form new adduct A (2ꢀarylpropaneꢀ1,1,3,3ꢀtetracarbonitrile). The
intermediate 6 was isolated. On the other hand, primary amine 3
O
H
25
87
HO
5
6
6
182ꢀ184
HO
NC
NC
NH2
5e
5f
NH2
S
5
O
H
24
23
26
24
22
N
88
87
92
170ꢀ172
188ꢀ189
181ꢀ183
N
reacts to carbon disulfide
4
to form intermediate
B
(alkylcarbamodithionic acid) it is fast exothermic reaction. Now
intermediate B, which is form in another round bottom flask was
poured into the adductA. A and B react to each other to form
10 adduct 7, here rearrangement and cleavage of carbon and sulphur
bond takes place forming intermediate 8, by removing of
isothiocyanate, intermediate 8 undergoes rearrangement and
cyclisation leads to formation of finally thiopyran derivatives 5a
The reaction took place in presence of benzaldehyde and
15 malononitrile at optimized conditions (room temperature, 1.5 V,
EtOH and LiClO4), and the intermediate 6 was formed within 5ꢀ7
min in excellent yield (96%). After completion of electrolysis
(20ꢀ26 Min), the solid mixture was filtered and solvent was
evaporated under vacuum. The residue was purified by
20 recrystallization from EtOH to furnish the desired product. In this
protocol all experiments were carried out in a conventional
electrochemical cell containing a platinum electrode working as
well as the counter electrode and a saturated calomel electrode
(SCE) as reference electrode.
NC
NC
NH2
NH2
S
O
H
Cl
7
Cl
NC
NH2
5g
Br
NC
NH2
Br
O
H
8
9
S
NC
NC
NH2
5h
NH2
S
O
H
88
185ꢀ187
198ꢀ200
NC
NC
NH2
5i
5j
NH2
S
O
O2N
O2N
10
90
H
NC
NH2
Optimized conditionsa: Aromatic aldehyde 1 (1 mmol), malononitrile 2
(2 mmol), carbon disulfide 3 (1 mmol), propyl amine 4 (1 mmol),
30 LiClO4(0.5 M), solvent (30 mL), Pt electrode at r.t.
25 Table 3 Electro catalyzed synthesis of 4Hꢀthiopyran derivative under
optimized conditionsa
bIsolated yield of the product 5a.
Under the optimized reaction conditions (room
temperature, EtOH, 1.5 V andlithium perchlorate as a supporting
35 electrolyte), we examined a variety of functionalized aldehydes to
assess the scope and generality of this reaction. The results are
summarized in Table 2. The aryl aldehydes bearing both electronꢀ
donating groups and electronꢀwithdrawing groups were subjected
to the reaction and in all cases desired products were formed.
40 During the course of reaction we observed that when aryl
aldehydes bear electron withdrawing group, current measured
was considerably high and desired product was formed fast at
constant potential in comparison to aryl aldehyde bearing
electronꢀdonating group (Table 3, entry 1, 7, 10). Therefore, we
45 concluded that the electronic nature of the substituents on the aryl
ring was not much effect on yield of the final products.
Entry ArCHO
Product
Time YieldbMp
(min)
(%)
OC
NH2
S
NC
O2
N
O2N
O
H
1
2
92
87
212ꢀ215
20
26
NH2
NC
NC
5a
5b
NH2
S
O
H
Present work is the development of facile, simple,
efficient,catalyst free green method for the synthesis of some 4Hꢀ
thiopyran derivatives. Application of electricity as reagent, use of
50 simple solvent and supporting electrolyte are special features of
the reaction which makes it environmentally benign. The MCR
chemistry with its tremendous advantages in terms of accessible
chemical structure space, diversity and efficiency can help to
achieve more rapidly technological and scientific advancements.
55 It constitute one of the most efficient tools in modern synthetic
organic chemistry with ideal synthesis atom efficiency, quick and
simple implementation, environmentꢀfriendly and they offer a
target and diversityꢀoriented synthesis.
H3C
H3C
183ꢀ186
NC
NC
NH2
H3CO
NH2
H3CO
O
26
26
3
4
S
85
88
171ꢀ174
230ꢀ232
H
NH2
NH2
S
NC
NC
5c
O
H
NC
NH2
5d
60
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 |3

New Journal of Chemistry
Page 4 of 5
View Article Online
DOI: 10.1039/C7NJ01211J
13. M.N. Elinson, A.S. Dorofeev, S.K. Feducovich, R.F.
Nasybullin, S.V. Gorbunov, G.I. Nikishin, Electrochem.
Commun. 2006, 8, 1567.
14. (a) M. A. Bodaghifard, A. Mobinikhaledi, S. Asadbegi, Appl.
Organometal. Chem. 2017, 31, aoc.3557; (b) A.
Mobinikhaledi, M. A. Bodaghifard, S. Asadbegi,Mol. Divers.
2016, 20,461ꢀ468.
15. V.D. Dyachenko, T.A. Ryl’skaya, I.V. Dyachenko, I.N.
Kalashnik, A.V. Chernykh, Russ. J. Gen. Chem. 2015, 85,
1069–1073.
16. (a) A. Upadhyay, L. K. Sharma, V. K. Singh, R. K. P. Singh,
Tetrahedron Letters 2016, 57, 5599ꢀ5604; (b) A. Upadhyay,
L. K. Sharma, V. K. Singh, R. Dubey, N. Kumar, R. K. P.
Singh, Tetrahedron Letters 2017, 58, 1245ꢀ1249
17. (a) S. Singh, L. K. Sharma, A. Saraswat, I. R. Siddiqui, H. K.
Kehrib, R. K. P. Singh, RSC Adv., 2013, 3, 4237–4245; (b) S.
Singh, L. K. Sharma, A. Saraswat, R. K. P. Singh,
MonatshChem 2012, 143,1427–1430
18. (a) S. Yadav, M. Srivastava, P. Rai, J Singh, K. P. Tiwari, J.
Singh, New J. Chem.2015, 39, 4556ꢀ4561; (b) S. Singh, Mo.
Saquib, J. Tiwari, F. Tufail, J. Singh, J. Singh, New J.
Chem.2016, 40, 63ꢀ67.
Experimental Procedure
A solution of lithium perchlorate (0.5 mmol), aromatic
65
70
75
80
85
aldehyde (1 mmol), malononitrile (2 mmol), primary amine (1
mmol) and carbon disulfide (1 mmol), were mixed in ethanol
(30mL), The reaction mixture transferred in to electrochemical
cell equipped with platinum electrode (1cm2) as working as well
as counter electrode, constant potential (1.5 V) electrolysis was
carried out at room temperature. The progress of the reaction was
monitored by TLC using hexane/ethyl acetate mixture. After
10 completion of electrolysis (20ꢀ26 min), the solid mixture was
filtered and solvent was evaporated under vacuum. The residue
was purified by recrystallization from EtOH to furnish the desired
product.
5
Acknowledgements
15 We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microꢀanalyses and spectra. Authors R. Dubey is
thankful to UGC, New Delhi, for the award of Junior Research
Fellowship (JRF) and Dr. V. K. Singh for the award of a DS
Kothari postdoctoral fellowship.
19. N. M. Evdokimov, A. S. Kireev, A. A. Yakovenko, M. Yu.
Antipin, I. V. Magedov, A. Kornienko, J. Org. Chem. 2007,
72, 3443ꢀ3453.
20 Notes and references
90
1. J. J. Li, John Wiley & Sons, Hoboken 2013.
2. E. Vedejs, G. Krafft, Tetrahedron 1982, 38, 2857.
3. S. Schneller, Adv. Heterocycl. Chem. 1975, 18, 59.
25
30
35
40
45
50
55
60
4. (a) S. Lane, S. J. Quick, R. K. J. Taylor, Chem. Soc., Perkin
Trans. 1 1984, 2549–2552; (b) D. E. Ward, Chem. Commun.
2011, 11375–11393; (c) D. E. Ward, Y Gai, Y. Lai, Synlett
1996, 261–262; (d) H. Poleschner, K. Seppelt, Eur. J. Org.
Chem. 2001, 2477–2480; (e) A. B. C. Lucassen, B.
Zwanenburg, Eur. J. Org. Chem. 2004, 74–83; (f) A. Rosiak,
W. Frey, J. Christoffers, Eur. J. Org. Chem. 2006, 4044ꢀ
4054.
5. W. Wang, H. Li, J. Wang, L. Zu, J. Am. Chem. Soc. 2006,
128, 10354.
6. L. A. van Vliet, N. Rodenhuis, D. Dijkstra, H. Wikström, T.
A. Pugsley, K. A. Serpa, L. T. Meltzer, T. G. Heffner, L. D.
Wise, M. E. Lajiness, R. M. Huff, K. Svensson, S. Sundell,
M. Lundmark, J. Med. Chem. 2000, 43, 2871.
95
7. M. J. Brown, P. S. Carter, A. E. Fenwick, A. P. Fosberry, D.
W. Hamprecht, M. J. Hibbs, R. L. Jarvest, L. Mensah, P. H.
Milner, P. J. O’Hanlon, A. J. Pope, C. M. Richardson, A.
West, D. R. Witty, Bioorg. Med. Chem. Lett. 2002, 12, 3171.
8. W. Quaglia, M. Pigini, A. Piergentili, M. Giannella, F.
Gentili, G. Marucci, A. Carrieri, A. Carotti, E. Poggesi, A.
Leonardi, C. Melchiorre, J. Med. Chem. 2002, 45, 1633.
9. D. RogierJr, J. Carter, J. Talley, Dihydrobenzopyrans,
dihydrobenzothiopyrans, and tetrahydroquinolines for the
treatment of COXꢀ2ꢀmediated disorders, World Patent WO
2001049675, 2004.
10. Junꢀichi Yoshida, Chem. Commun.2005, 4509–4516 DOI:
10.1039/b508341a
11. L. Wang, J. Gao, L. Wan, Y. Wang, C. Yao, Res. Chem.
Intermed. 2015, 41, 2775–2784.
12. (a) P. T. Anastas, M. M. Kirchhoff, Acc. Chem. Res. 2002,
35, 686; (b) S. Seka, O. Burize, J. Y. Nédélec, J. Périchon,
Chem.Eur.J.2002,8, 2534ꢀ2538; (c) D. Nematollahi, A. R.
Rahchamani, J. Electroanal. Chem. 2002, 520, 145; (d) G.
Hilt, Angew. Chem., Int. Ed. 2003, 42, 1720; (e) P. Gomes,
C. Gosmini, J. Périchon, J. Org. Chem. 2003, 68, 1142; (f) Z.
Zha, A. Hui, Y. Zhou, Q. Miao, Z. Wang, H. Zhang, Org.
Lett. 2005, 7, 1903.
4
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 5
New Journal of Chemistry
View Article Online
DOI: 10.1039/C7NJ01211J
Table of Contents:
1 Sentence + 1 image (8x4 cm) in MS Word (.doc file)
Sentence:
A convenient one pot electro-synthesis of 4-H-thiopyrans by condensation of aromatic
aldehydes, malononitrile, carbon disulfide and primary amine.
Image