“On-water” catalyst-free, one-pot synthesis of quaternary centered and spiro-tetrahydrothiophene-barbiturate hybrids

Article abstract of DOI:10.1016/j.tetlet.2017.06.029

A green and efficient method have been developed for the synthesis of quaternary centered and spiro-barbiturate-tetrahydrothiophene hybrids via Knoevenagel condensation,1,4-thia-Michael and intramolecular Aldol reactions using “on water” concept under catalyst-free conditions. Systematic studies were carried out to find the role of the water and total reaction concentration (0.086?M) to promote the reaction in two steps (one-pot). The use of water as a reaction medium, catalyst-free conditions, broad substrate scope, one-pot approach for the creation of quaternary centered and spiro molecules are the advantages of this method.

Full text of DOI:10.1016/j.tetlet.2017.06.029

Accepted Manuscript
“On-water” catalyst-free, one-pot synthesis of quaternary centered and spiro-
tetrahydrothiophene-barbiturate hybrids §
Sakkani Nagaraju, Kota Sathish, Banoth Paplal, Dhurke Kashinath
PII:
S0040-4039(17)30751-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.029
TETL 49021
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 May 2017
9 June 2017
10 June 2017
Please cite this article as: Nagaraju, S., Sathish, K., Paplal, B., Kashinath, D., “On-water” catalyst-free, one-pot
synthesis of quaternary centered and spiro- tetrahydrothiophene-barbiturate hybrids § , Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.06.029
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Leave this area blank for abstract info.
"On-water" catalyst-free, one-pot
synthesis of quaternary centered and
spiro-tetrahydrothiophene-barbiturate
hybrids§
Sakkani Nagaraju, Kota Sathish, Banoth Paplal and Dhurke Kashinath*

Tetrahedron Letters
journal homepage: www.els evier.com
"On-water" catalyst-free, one-pot synthesis of quaternary centered and spiro-
tetrahydrothiophene-barbiturate hybrids§
Sakkani Nagaraju, Kota Sathish, Banoth Paplal, and Dhurke Kashinath*
Department of Chemistry, National Institute of Technology, Warangal-506 004, India
ABSTRACT
ARTICLE INFO
Article history:
Received
A green and efficient method have been developed for the synthesis of quaternary centered and
spiro-barbiturate-tetrahydrothiophene hybrids via Knoevenagel condensation,1,4-thia-Michael
and intramolecular Aldol reactions using "on water" concept under catalyst-free conditions.
Systematic studies were carried out to find the role of the water and total reaction concentration
(0.086 M) to promote the reaction in two steps (one-pot). The use of water as a reaction medium,
catalyst-free conditions, broad substrate scope, one-pot approach for the creation of quaternary
centered and spiro molecules are the advantages of this method.
Received in revised form
Accepted
Available online
Keywords:
Spiro-barbiturates,
Tetrahydrothiophene hybrids,
1,4-Thia-Micheal addition reaction,
One-pot reaction
“On-water”
Catalyst-free
Tetrahydrothiophenes (thiolanes) are found in many biologically active molecules and natural products of Salacia family,1a,b
tetronothiodin,1c breynolide,1d and biotin.1e The tetrahydrothiophene containing natural products and semi-synthetic compounds play
role in the fatty acids synthesis (biotin) and work as potent inhibitors of α-glucosidase,1a HIV, hepatitis-B,2 and antagonist for
cholecystokinin type-B (tetronothiodin),1c agonists of selective A3 adenosine receptors.3 Also, the thiolane can be used as a precursor
for functionalized thiophenes, which are useful in medicinal and materials chemistry.4 The synthesis of the functionalized (β-
hydroxy)/fully substituted tetrahydrothiophenes (present in many biologically active compounds; Figure-11) is challenging and involve
tedious protocols by conventional methods.1a,b This has been addressed recently by using 1,4-dithiane-2,5-diol with electron deficient
olefins under basic conditions.5
The α,α-dicyanoolefines are excellent synthons in organic chemistry and used for the synthesis of complex and advanced
intermediates with quaternary centers, natural products, and medicinally important molecules. Along with these, the α,α-
dicyanoolefines are used as acceptor, donors (nucleophiles) and dienophiles in Michael, vinylogous and cycloaddition reactions
respectively.6
∗ Corresponding author: Tel. +91-870- 246-2677;
FAX No. +91-870-246-9547; e-mail: kashinath@nitw.ac.in; kashinath.dhurke@gmail.com
Me
Me
HO
O
HO
O
HN
NH
H
O
H
H
Me
HOOC
O
COOH
S
S
O
Tetronothiodin
(Cholecystokinin type-B receptor antagonist)
Biotin
O
NH2
N
OH
H
O
OH
N
N
OH
NH
O
R
OH
N
N
R
NH
N
S
OSO3
H
N
O
S
O
H
HO
HO
N
O
S
H
S
S
HO
OH
HO
OH
HO
HO
Breynolide
Salacinol derivatives
(Glucosidase inhibitor)
HO
OH
(HIV and Hepatitis inhibitors)

2
Figure-1: Biological active compounds with thiolane moiety
The barbituric acid derivatives (including spirocycles) are well-known in medicinal chemistry.7 Some of the recent reports indicate
that these molecule can be used as inhibitors of α-glucosidase,8 anticonvulsant,9 antitumor,10 antiepileptic,11 anesthetic and sedative,12
anti-Cancer,13 anti-AIDS,14 hypnotic,15 TNF alpha converting enzyme inhibitors,16 and MMP-13,17 agents (Figure-2). One of the best
methods to synthesize spiro- barbituric acid derivatives is using barbiturate olefins which can be easily obtained by the condensation
reaction between barbituric acid and corresponding carbonyl derivatives (aldehydes and ketones). These intermediates can also be used
as acceptor, donors (nucleophiles) and dienophiles in Michael, cycloaddition reactions similar to α,α-dicyanoolefines and can be used
for the synthesis of three, five and six member rings.18
Figure-2: Biological active compounds with barbituric acid
moiety
Most of the biochemical processes in living organisms are based on the water because of its unique properties. Whereas, in synthetic
organic chemistry, water was a least preferred solvent because of its reactivity with some of the functional groups and the solubility
problem of organic molecules. But after pioneering findings of “on water” concept by Sharpless and Breslow groups,19 the use of water
is increasing in organic synthesis by using “in water” and “on water” concepts. Also, the mechanistic and kinetics studies supporting the
role of water in acceleration of the reaction, bringing the reactants together and stabilization of activated transition state by hydrogen
bond formation is well documented in the literature.20 The natural abundance makes water as a cheap and green solvent for the organic
transformations. Also, in most of the water-mediated organic reactions, the product formed is a solid which is easily isolated from the
reaction by simple filtration or washing with common organic solvents (when required). Because of these, there is a drastic increase in
the water-mediated reactions in past couple of years. Still, there is a demand to develop the green and environmentally friendly
approaches for medicinal chemistry programs and industry applications.
Consecutive/one-pot reactions are the chemical processes in which two or more consecutive reactions and multiple bonds formation
occurs in a sequential manner where the process of each step depends on the compounds/intermediates that are formed in the earlier
step. These reactions are one of the best methods in synthetic organic chemistry to prepare complex and diversified molecules with a
simple set of starting materials, avoiding the isolation and purification of the intermediates and reducing the chemical waste. Because of
these advantages, consecutive/one-pot reactions got much attention and extensively used in the methodology development, total
synthesis, process research, heterocyclic, medicinal (library generation) and industrial chemistry using green chemistry aspects such as
atom economy and sustainability.20,21
The generation of a new quaternary center with all carbons substitution is a difficult task under conventional methods, which may be
due to the reactivity of the starting materials, steric effects and also non-availability of suitable reactive partners to generate quaternary
center.22 Many of these methods involve the use of catalysts and organic solvents.23 However, the use of aqueous medium under
catalyst-free conditions has not been explored for these type of reactions where all-carbon quaternary centers are generated.24 Also to
the best of our knowledge, there is no report for the synthesis of tetrahydrothiophenes using barbiturate olefins and α,α-di-cyanoolefins
with 1,4-dithiane-2,5-diol and also for the “on-water" concept under catalyst-free conditions for the synthesis of spiro and quaternary
centered tetrahydrothiophenes using 1,4-dithiane-2,5-diol.
Keeping in view of above all, considering the medicinal importance of the spiro-barbiturates, tetrahydrothiophenes and quaternary
centered molecules, and in continuation of our interest in environmental friendly green synthetic methods,5c,25 we herein report a simple,
straight forward and catalyst-free method using one-pot reactions of aldehydes with barbituric acid/malononitrile and 1,4-dithiane-2,5-
diol to give a new family of quaternary centered and spiro-barbituric acid-tetrahydrothiophene hybrids and functionalized
tetrahydrothiophene derivatives in one-pot sequence under green conditions using “on water” concept.
To achieve this, initially, the unsaturated system (3a) was generated by the reaction of 4-nitrobenzaldehyde (1) and barbituric acid
(2), and reacted with 1,4-dithiane-2,5-diol (4) in presence of piperidine (30 mol%)5c to give the spiro-barbiturate-thiolane hybrid (5a) in
90% yield (two step sequence) (Scheme 1). The formation of the desired product was confirmed by 1H, 13C-NMR and mass spectral
data.

Scheme-1. Sulfa-1,4-Michael followed by intramolecular Aldol reaction of barbituric acid olefin (two-step sequence)5c
After confirmation of the product, above reaction (II step) was performed without catalyst (piperidine) using different solvents
[from non-polar to polar and aprotic to protic solvents] and the results are depicted in Table-1. From these experiments, it was observed
that the polar protic solvents (MeOH, EtOH, and H2O) are giving the desired product (5a) in 60-85% yield. Further, to find better
reaction conditions, experiments were conducted by using water as solvent/promoter (catalyst-free conditions) with variation in the
reaction concentration (from 5 mL to 2 mL; Scheme 2). It is noteworthy to mention that the reaction is working well at 0.086 M total
reaction concentrations with 98% yield. The reactivity of water at particular concentrations could be attributed to its capacity to bring
the reactant molecules by inducing the hydrogen bonding along with the hydrophobic behavior of organic molecules which may be
helping to promote the reaction. This argument is well supported by the experiments using water:MeOH (1:1) and water: EtOH in (1:1),
D2O, brine, Ethylene glycol and PEG-400 as reaction medium (all at 0.086 M total reaction concentrations) where there is a possibility
for partial hydrogen bonding or no hydrogen bonding (entries 16-21; Table-1).
Scheme-2: Reaction of barbiturate olefin (3a) with 1,4-dithiane-2,5-diol (4) under catalyst-free conditions
Table-1: Optimization of the reaction conditions under catalyst-free conditions
S. No.
1
Solvent
Reaction time (h)
Isolated yields (%)a
Tetrahydrofuran
Dioxane
24
24
24
ND
ND
ND
ND
ND
ND
ND
ND
60
2
3
Dimethylsulfoxide
4
N, N-Dimethylformamide
Acetonitrile
24
24
24
24
24
10
10
5
5
6
Chloroform
7
Dichloromethane
8
1,2-Dichloroethane
MeOH (0.086 M)
EtOH (0.086 M)
9
10
11
12
13
14
15
16
17
18
19
20
21
65
Water (0.0345 M)
Water (0.0432 M)
Water (0.086 M)
Water (0.172 M)
85
5
90
1
98
5
95
Water (0.345 M)
5
90
Water:MeOH (1:1; 0.086 M)
Water:EtOH (1:1; 0.086 M)
D2O (0.086 M)
4
75
3
75
24
24
24
24
Trace
60
Brine (0.086 M)
Ethylene glycol (0.086 M)
PEG-400 (0.086 M)
30
40
a
Table-1. Optimization of reaction conditions for Sulfa-1,4-Michael/intramolecular aldol reaction; All the reactions were performed at
0.320 mmoles of barbiturate olefin (3)

4
After successful optimization of the reaction conditions (catalyst-free; II step), attempts were made for one-pot, catalyst-free
synthesis of title compounds from corresponding aldehydes. Towards this, the reaction of p-nitrobenzaldehyde (1) and barbituric acid
(2) at room temperature gave the intermediate (3a) in 4 h which was further converted into spiro thiolane (5a) in 30 min with 85%
o
overall yield. To reduce the overall reaction time, the reactants in the first step were heated to 50 C to give the intermediate (30 min,
99%) which was reacted with 1,4-dithiane-2,5-diol (4) at same temperature and stirred for 30 min to give the desired product in 95%
yield (Scheme 3). Later, different substituted aldehydes with electron donating and withdrawing groups were reacted with barbituric
acid (2) to give corresponding intermediates which on reaction with 1,4-dithiane-2,5-diol (4) gave the spiro-barbiturate-thiolane
hybrids (5b-5s) in good yield. The Figure-3 indicate that the aldehydes with electron donating groups require more time (over all
reaction time) compare to the substrates with electron withdrawing groups for completion of the reaction. All the products were
characterized using complementary spectral data (See ESI for 1H-, 13C-NMR and mass spectra).26
Scheme-3: One-pot Knoevenagel condensation followed by sulfa-1,4-Michael / intramolecular Aldol reaction of barbiturate
olefins (optimized conditions)
Figure-3. Spiro-barbiturate-tetrahydrothiophene derivatives (5b-5s)
After successful synthesis of a library of spiro-barbiturates, attention was shifted towards the synthesis of functionalized
tetrahydrothiophenes with quaternary centers with geminal functional groups (electron withdrawing). To achieve this, various
o
aldehydes were treated with malononitrile (6a)/ethyl cyanoacetate (6b) in water (2 mL) at 50 C to give the olefinic system
which was reacted with 1,4-ditiane-2,5-diol (4) to give the desired products (8a-8r) in 80-95% yields (Scheme 4; Figure-4). In
this case, also the substrate dependent reactivity was observed for the aldehydes with electron donating and withdrawing groups
as discussed earlier.

Scheme-4: One-pot Knoevenagel condensation followed by sulfa-1,4-Michael/intramolecular Aldol reaction of benzylidene
malononitriles (7a and 7b) under optimized conditions.
Figure-4: Functionalized quaternary centered tetrahydrothiophene derivatives (8c-8r) and ORTEP diagram of 8k (CCDC
1545995).
From the transition states proposed, we assume that the insoluble starting materials are aggregating because of their hydrophobic
interactions with hydrogen-bonded water network. These non-covalent interactions are helping in bringing reactive partners together to
give Knoevenagel condensation product which will again react with the in situ generated monomeric mercaptaldehyde (4) by forming
active transition state which is facilitating the sulfa-1,4-Michael followed by intramolecular Aldol reactions to give the final thiolanes as
shown in Figure 5.

6
Figure-5: Possible transition states for sulfa-1,4-Michael /
intramolecular aldol reactions of 1,4-dithiane-2,5-diol and 2-benzylidenemalononitrile and barbiturate olefins.
In conclusion, we have demonstrated successful synthesis of the spiro-barbiturate-thiolane hybrids and quaternary centered
tetrahydrothiophene derivatives under green and catalyst free conditions. The aqueous conditions, one-pot approach, high yields, broad
substrate scope are advantages of this method. Further synthetic applications and biological studies are in progress and will be published
elsewhere. Further functionalization of the resulting products is in progress in our laboratory.
Acknowledgments
SN thanks, UGC-New Delhi for the fellowship. KS thanks DST for the INSPIRE fellowship. BP thanks MHRD-NITW for
fellowship. DK thanks, DST (SERB), New Delhi for the financial support (SB/FT/CS-136/2012 and SB/EMEQ-103/2014).
§Supporting information available
References and notes
1. (a) Mohan S, Eskandari R, Pinto BM. Acc Chem Res. 2014;47:211; (b) Benetti S, Risi CD, Pollini PG, Zanirato V. Chem Rev. 2012;112:2129; (c)
Toshikazu K, Tsutomu K, Hiromi N, Mari T, Atsuko N, Tatsuo O, Yoshizaki H, Arisawa M. Eur J Pharmacol. 1992;221:99 (d) Amos B, Smith III,
Empfield R J, Rivero AR, Vaccaro AH, Duan WJJ, Sulikowski MM. J Am Chem. Soc.1992;114:9419; (e) De Clercq PJ. Chem Rev. 1997;97:1755.
2. Almond M, Cleary D, Liotta DC, Painter GR, Soria, J. WO 2000009494 A1:2000.
3. Jeong LS, Choe SA, Gunaga P Kim H. O, Lee H W, Lee SK, Tosh DK, Patel A, Palaniappan K K, Gao Z G, Jacobson K A, Moon H R. J Med Chem.
2007;50:159.
4. (a) Gramec D, Mašič LP, Dolenc MS. Chem Res Toxicol. 2014;27:1344 and references cited here in; (b) Barbarella V, in Thiophene in Materials
Chemistry, World Scienti Publishing Company Pvt. Limited,2012.
5. (a) Connor CJO, Roydhouse MD, Przybyz AM, Wall MD, Southern JM, J Org Chem. 2010;75:2534; (b) Zhang Y, Vongvilai P, Sakulsombat M,
Fischer A, Ramström O. Adv Synth Catal. 2014;356:987; (c) Nagaraju S, Satyanarayana N, Paplal B, Vasu A K. Kanvah S, Sridhar B, Prabhakar S,
Kashinath D. RSC Adv. 2015;5;94474.
6. Kaur J, Chauhan P, Chimni SS, Org Biomol Chem. 2016;14:7832.
7. a) Bojarski JT, Mokrosz JL, Barton HJ, Paluchowska MH, Adv. Heterocycl. Chem. 1985;38:229; b) Abraham DJ, Rotella DP, Burgers Medicinal
Chemistry, Drug Discovery and Development, Wiley-Blackwell, Hoboken,2010; c) López-Muñoz F, Ucha-Udabe R, Cecilio. “History of barbiturates
a century after their clinical introduction”. Alamo Neuropsychiatr Dis Treat. 2005;1:329.
8. Barakat A, Islam MS, Al-Majid AM, Ghabbour HA, Fun HK, Javed K, Imad R, Yousuf S, Choudhary MI, Wadood A. Bioorg Med Chem. 2015;23:
6740.
9. Sudha S, Lakshmana MK, Pradhan N, Pharmacol Biochem Behav. 1996;54:633.
10. Oliva A, De Cillis G, Grams F, Livi V, Zimmerman G, Menta E, Krell HW, US Pat., 6,335,332, B1,2002.
11. Lyons KE, Pahwa R. CNS Drugs. 2008;22:1037.
12. Sriram D, Bal TR, Yogeeswari PJ. Pharm Pharm Sci.2005;8:565.
13. Maquoi E, Sounni NE, Devy L, Olivier F, Frankenne F, Krell HW, Grams F, Foidart JM, Noël A. Clini Cancer Res. 2004;10: 4038.
14. Naguib FNM, Levesque DL, Wang EC, Panzica PP, El Kouni MH, Biochem Pharmacol. 1993;46:1273.
15. Girgis AS, Farag H, Ismail SMN, George RF. Eur J Med Chem. 2011;46:4964.
16. Duan J, Jiang B, Chen L, Lu Z, Barbosa J, Pitts W J. US Pat. Appl. 2003,0229084.
17. Kim SH, Pudzianowski AT, Leavitt KJ, Barbosa J, McDonnell PA, Metzler WJ, Rankin BM, Liu R, Vaccaro W, Pitts W. Bioorg Med Chem
Lett.2005;15:1101.
18. (a) Dorofeeva EO, Elinson MN, Vereshchagin AN, Stepanov NO, Bushmarinov IS, Belyakov PA, Sokolova OO, Nikishin GI. RSC Adv.2012;2:4444;
(b) Soleimani E, Yazdani H, Saei P, Tetrahedron Lett. 2015;56:1635; (c) Zhao HW, Tian T, Li B, Yang Z, Pang H-L, Meng W, Song XQ, Chen XQ.
J Org Chem. 2015;80:10380; (d) Liu H, Liu Y, Yuan C, Liu H, Liu Y, Yuan C, Wang GP, Zhu SF, Wu Y, Wang B, Sun Z, Xiao Y, Zhou QL, Guo H.
Org Lett. 2016;18:1302; (e) Liu Y, Yang W, Wu Y, Liu Y, Yang W, Wu Y, Mao B, Gao X, Liu H, Sun Z, Xiao Y, Guo H. Adv Synth Catal.
2016;358:2867.
19. (a) Breslow R. Acc. Chem. Res.2004;37:471; (b) Narayan S, Muldoon J, Finn MG, Fokin VV, Kolb HC, Sharpless KB. Angew Chem Int Ed.
2005;44:3275.
20. Gawande MB, Bonifácio VDB, Luque R, Branco PS, Varma RS. Chem Soc Rev. 2013;42:5522.
21. (a) Tietze LF, Beifuss U. Angew Chem Int Ed Engl. 1993;32:131; (b) Herrera RP, Marqués-Lopez E, In Multicomponent Reactions: Concepts and
Applications for Design and Synthesis; John Wiley & Sons,2015; (c) Touré BB, Hall DG. Chem. Rev. 2009;109:4439; (d) Biggs-Houck JE, Younai

A, Shaw JT. Curr Opin Chem Biol. 2010;14:371; (e) Dömling A, Wang W, Wang K. Chem Rev. 2012;112:3083–3135; (f) Eds Zhu J, Wang Q, Wang
M, Multicomponent Reactions in Organic Synthesis, WILEY-VCH,2015.
22. (a) Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis; Baro A; Christoffers J; Eds.; Wiley-VCH: Weinheim, 2006; (b) Liu Y;
Han, SJ, Liu WB, Stoltz BM. Acc Chem Res. 2015;48:740. (and references cited there in;)
23. (a) Khan A, Yang L, Xu J, Yi Jin L, Zhang YJ. Angew Chem Int Ed. 2014;53:11257; (b) Ohmatsu K, Imagawa N, Ooi T. Nat Chem. 2014;6:47; (c)
Xiao H, Chai Z, Wu Zheng C, Yang YQ, Liu W, Zhang JK, Zhao G. Angew Chem Int Ed. 2010;49:4467.
24. Srinivasarao Y, Garima S, Ravikrishna D. Tetrahedron Lett. 2016;57:591.
25. a) Paplal B, Nagaraju S, Palakollu V, Kanvah S, Kumar BV, Kashinath D, RSC Adv. 2015;5:57842; b) Paplal B, Nagaraju S, Palakollu V, Sujatha K,
Kanvah S, Kumar BV, Kashinath D, RSC Adv. 2014;4:54168; c) Nagaraju S, Satyanarayana N, Paplal B, Vasu AK, Kanvah S, Kashinath D, RSC Adv.
2015;5:81768.
26. General Procedure for the One-pot synthesis of thiolanes: A mixture of aldehyde (1 Equiv) and malononitrile / barbituric acid (1 Equiv) in water (2
mL; total reaction concentration 0.086 M) was heated at 50 oC for 30 min. After the formation of intermediate (olefin), 1,4-dithiane-2,5-diol (0.75
Equiv) was added at same temperature and heating continued until the completion of the reaction (monitored by TLC). Then the reaction mixture was
extracted EtOAc (20 X 2 mL). The combined organic layers were dried using sodium sulfate and concentrated under reduced pressure to give the
crude product which was purified by column chromatography. Purification using petroleum ether-EtOAc gave the desired product. Representative
analytical data of 4-hydroxy-7,9-dimethyl-1-(4-nitrophenyl)-2-thia-7,9-diazaspiro[4.5]decane-6,8,10-trione (5a): Yield = 95% (White solid); 1H-
NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 5.33 (s, 1H), 5.25 (s, 1H), 3.76 (t, J = 9.8 Hz, 1H), 3.39 (t, J = 9.8 Hz,
1H), 3.32 (s, 3H), 2.99 (s, 3H). 13C-NMR (101 MHz, CDCl3): δ 169.03, 165.09, 149.98, 148.09, 142.48, 129.40, 123.70, 82.20, 67.44, 54.81, 36.47,
29.40, 28.33. Mass (ESI-MS): Calculated for C15H15N3O6S, m/z: 365; found: 364 (M-1) [please see the electronic supporting information for spectral
data other compounds].

8
"On-water" catalyst-free, one-pot synthesis of quaternary centered and spiro- tetrahydrothiophene-
barbiturate hybrids§
Sakkani Nagaraju, Kota Sathish, Banoth Paplal and Dhurke Kashinath*
Highlights:
1. Use of “On-water" concept for tetrahydrothiophene synthesis
2. Catalyst-free protocol for the spiro-barbiturates
3. Consecutive/one-pot sequence for Knoevenagel, thia-Michael and Aldol reactions
4. Simple procedure for the all carbon quaternary cantered molecules

"On-water" catalyst-free, one-pot synthesis of quaternary centered and spiro- tetrahydrothiophene-
barbiturate hybrids§
Sakkani Nagaraju, Kota Sathish, Banoth Paplal and Dhurke Kashinath*
27.