Pot, atom and step economic (PASE) synthesis of 5-monoalkylbarbiturates through domino aldol-Michael reaction

Article abstract of DOI:10.1016/j.tetlet.2014.12.091

A simple pot, atom and step economic (PASE) approach for the synthesis of 5-monoalkylbarbiturates by a one-pot reaction of barbituric acids, aldehydes, and ketones, involving a domino aldol-Michael reaction is described. The operational simplicity and cost effectiveness of this procedure makes it a sustainable strategy for the synthesis of 5-monoalkylbarbiturates.

Full text of DOI:10.1016/j.tetlet.2014.12.091

Accepted Manuscript
Pot, atom and step economic (PASE) synthesis of 5-monoalkylbarbiturates
through domino aldol-Michael reaction
Subarna Jyoti Kalita, Hormi Mecadon, Dibakar Chandra Deka
PII:
S0040-4039(14)02168-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.091
TETL 45615
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 November 2014
15 December 2014
16 December 2014
Please cite this article as: Jyoti Kalita, S., Mecadon, H., Chandra Deka, D., Pot, atom and step economic (PASE)
synthesis of 5-monoalkylbarbiturates through domino aldol-Michael reaction, Tetrahedron Letters (2014), doi:
http://dx.doi.org/10.1016/j.tetlet.2014.12.091
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.
Pot, atom and step economic (PASE)
synthesis of 5-monoalkylbarbiturates
through domino aldol-Michael reaction
Leave this area blank for abstract info.
Subarna Jyoti Kalita, Hormi Mecadon* and Dibakar Chandra Deka*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Pot, atom and step economic (PASE) synthesis of 5-
monoalkylbarbiturates through domino aldol-Michael reaction
Subarna Jyoti Kalita, Hormi Mecadon and Dibakar Chandra Deka
Department of Chemistry, University of Gauhati, G. B. Nagar, Guwahati-781014, Assam, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple pot, atom and step economic (PASE) approach for the synthesis of 5-
monoalkylbarbiturates by a one-pot reaction of barbituric acids, aldehydes and ketones,
involving a domino aldol-Michael reaction is described. The operational simplicity and cost
effectiveness of this procedure makes it a sustainable strategy for the synthesis of 5-
monoalkylbarbiturates.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
5-Monoalkylbarbiturates
Sodium hydroxide
PASE
Domino reaction
The synthesis of 5-alkylbarbiturates continues to be an active
area of research because of the potential of these compounds as
sedative,1 anticonvulsant,2 immunomodulating and antitumor
activities.3 Some of the recent significant pharmacological
outcomes on 5-alkylbarbiturates include their discovery as
inhibitors of bacterial DNA gyrase,4 matrix metalloproteinase
(MMP)5 and as PET tracers with diagnostic potential in
Alzheimer’s disease.6 A number of these compounds have also
been applied in non-linear optical study7 and supramolecular
chemistry.8
simple and efficient methodology for the synthesis of these
important 5-monoalkybarbiturate heterocycles.
Classically, 5-alkylbarbiturates have been synthesized by
condensation of suitable alkylated malonates and urea.9 But, the
method has been limited due to often formation of modest yields
and side reactions. Another common approach has been the direct
alkylation of unsubstituted barbituric acid.10 Although, this
strategy can serve well for 5-dialkylbarbiturates, its applicability
for selective 5-monoalkylation is narrow because of the
propensity for dialkylation associated in the process.
Figure 1. Strategies for 5-monoalkylation of barbituric acid.
Although, much effort has been reported on selective 5-
monoalkylation of barbituric acids, to the best of our knowledge,
no substantial study has ever been made on the domino-Michael
addition of barbituric acid to ,-unsaturated compounds as a
strategy for 5-monoalkylation, except for the first report by
Zalukaev and Trostyanetskaya.15 However, this procedure is
associated with limitations such as multi-step sequence, moderate
yields, long reaction time, use of methanol, and only IR
spectroscopic data are available for synthesized compounds.
With this in mind, we have recently developed a domino strategy
for some 5-monoalkylbarbiturates but, through an indirect
approach, by FeCl3.6H2O catalyzed in situ conversion of 6-
aminouracils to barbituric acid, followed by Michael addition
The synthesis of 5-monoalkylbarbiturates has been rather
difficult until, Jursic and co-workers11 first reported platinum and
palladium catalyzed efficient reductive alkylation procedure.
Susequently, some methods viz Ir(III) catalyzed reaction of
barbituric acid and alcohols,12 ring opening strategy of
spiro[2.5]barbiturates13 were developed and, recently, the first
multi-component approach by involving carbodiimides,
malonates and halides was also reported.14 However, the
involvement of expensive catalysts and complex reaction
conditions in these alkylation processes are often the concern in
their applicability. Hence, it is still highly challenging to develop
———
 Corresponding author. Tel.: +91-9864075111; fax: +91-0361-2700311; e-mail: dcdeka@rediffmail.com
 Corresponding author. Tel.: +91-9436175136; e-mail: hmecadon@gmail.com

2
Tetrahedron Letters
Table: 1 Model reaction and optimization under various conditions.a
Temp ( oC)
Time (min)
60
40
40
40
40
40
40
40
40
40
40
1440
720
Yield (%)c
70
85
85
85
80
45
70
57
Trace
Trace
Trace
15
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
Catalyst
5 % NaOH
10 % NaOH
15 % NaOH
10 % NaOH
10 % NaOH
10 % NaOH
10% LiOH
10 % Na2CO3
15 mol% FeCl3.6H2O
15 mol% FeSO4.7H2O
15 mol% CuCl2.2H2O
10 % NaOH
Solventb
EtOH
EtOH
EtOH
EtOH/ H2O (2:3)
EtOH/ H2O (1:4)
H2O
EtOH/ H2O (2:3)
EtOH/ H2O (2:3)
EtOH/ H2O (2:3)
EtOH/ H2O (2:3)
EtOH/ H2O (2:3)
EtOH/ H2O (2:3)
EtOH/ H2O (2:3)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
RTd
----------------
Reflux
Trace
aReaction scale: 1 mmol of each 1a, 2a and 3a. b 5mL. cIsolated yield. dRT ≈ 25 oC.
to,-unsaturated ketones (Fig. 1, A).16 Now, we wish to report
here a simpler procedure for 5-monoalkylbarbiturates through
NaOH catalyzed one-pot condensation of barbituric acid,
aldehydes and ketones in EtOH/Water as the solvent (Fig. 1, B).
The reaction proceeded through an in situ generation of ,-
unsaturated ketones followed by Michael addition with barbituric
acids.
In significance this work describes as an example of pot,
atom and step economic (PASE)17 synthesis which is currently a
relevant strategy for greener chemical processes. Furthermore,
NaOH is a cheap and easily accessible shelf catalyst. The high
yields of this procedure and the operational simplicity further
augment the applicability of this protocol, while the use of
solvent medium EtOH/H2O merits over the potential cost and
toxicity from employing organic solvents.
Table 2. Scope of the PASE synthesis of 5-monoalkylbarbiturates.a
4aa (85%)b; 40 min
4af (93%) b; 55 min
4ak (81%) b; 50 min
4bc (85%) b,c,d; 65 min
4ab (85%) b; 50 min
4ag (87%) b; 50 min
4al (78%) b; 50 min
4ca (87%) b,c; 90 min
4ac (87%) b; 55 min
4ah (80%) b; 50 min
4am (70%) b; 65 min
4cb (86%) b,c; 90 min
4ad (82%) b; 60min
4ae (71%) b; 70 min
4ai (87%) b; 55 min
4aj (90%) b; 55 min
4ba (86%) b,c,d; 70 min 4bb (88%) b,c,d; 60 min
4cc (88%) b,c; 80 min
4cd (80) b,c; 80 min
aReaction scale: 1 mmol of each of 1, 2 and 3. bIsolated yield. cPurified by column chromatography. dCombined diastereomeric yield.

3
Initially, stirring a mixture of benzaldehyde (2a, 1mmol) and
acetophenone (3a, 1 mmol) in 5mL of 5% NaOH in EtOH at
room temperature until the generation of -unsaturated ketone,
followed by addition of barbituric acid (1a, 1 mmol) and
refluxing afforded 5-(3-oxo-1,3-diphenylpropyl)pyrimidine-
2,4,6(1H,3H,5H)-trione (4aa) in 70% yield in 60 minutes (Table
1, entry 1). The progress of the reaction was gradually monitored
by TLC. On further examination of the reaction conditions 10%
NaOH in ethanol gave the highest yield of 4aa with 85% yield in
40 minutes (Table 1, entry 2). The effect of solvent was then
examined by executing the reaction in either ethanol and water
mixture or water alone (Table 1, entries 4-6). It was found that
the use of EtOH/H2O (2:3) gave yield similar to when ethanol
alone was used, while reaction performed in water alone gave
lower yield. So, from environment and economic perspective,
EtOH/H2O (2:3) system was chosen as the optimized medium for
all further reactions. Some potential catalysts were also tried to
study the best catalytic efficacy in the EtOH/H2O (2:3) solvent
condition. It was observed that, although catalysts such as LiOH
or Na2CO3 led to the desired product, the yields obtained were
lower than when NaOH was used (Table 1, entries 7 & 8). On the
other hand, Lewis acids such as FeCl3.6H2O, FeSO4.7H2O and
CuCl2.2H2O were not effective to give the desired product (Table
1, entries 9-11). Furthermore, the NaOH catalyzed reaction
carried out by stirring at room temperature for 1440 minutes gave
4aa with only 15% yield, while uncatalyzed reaction but under
refluxing condition was found to be ineffective (Table 1, entries
12-13).
All the synthesized compounds were characterized through
1H-, 13C-NMR, IR, mass spectral and elemental analyses.
Mechanistically, the reaction is believed to involve an initial
NaOH-catalyzed aldol condensation between aldehde and ketone
to give,-unsaturated ketones which is followed by Michael
addition by barbituric acid (Scheme 1).
In summary, we have described a simplified procedure for the
synthesis of 5-monoalkylbarbiturates through the application of
pot, atom and step economic (PASE) synthetic approach
involving in situ generation of ,-unsaturated ketones and
subsequent Michael addition with barbituric acids. The protocol
with the facets of green chemistry provides an alternative but a
more cost-effective method to efficiently prepare 5-
monoalkylbarbiturates in an operationally simple and
environment-friendly reaction conditions.
Acknowledgments
H. M. and S. J. K. Acknowledge DST-INSPIRE, DST, Govt.
of India for the financial assistance. The authors also thank SAIF,
GU, NEHU, and IIT-Guwahati for sample analysis. We are
thankful to the referees for their valuable comments and
suggestions.
References and notes
1. (a) López-Muñoz, F.; Ucha-Udabe, R.; Alamo, C. Neropyschiatr. Dis.
Treat. 2005, 4, 329-343; (b) Morgan, W. W. Adv. Alcohol Subst. Abuse
1990, 9, 67-82; (c) McMillan, D. E.; Wenger, G. R. J. Exp. Anal. Behav.
1983, 40, 133-142.
2. (a) Andrews, P. R.; Mark, L. C.; Winkler, D. A. Jones, G. P. J. Med.
Chem. 1983, 26, 1223-1229; (b) Andrews, P. R.; Jones, G. P.; Poulton,
D. B. Eur. J. Pharmacol. 1982, 79, 61-65; (c) Mcdonald, R. L. Barker, J.
L. Neurology 1979, 4, 432-437.
3. (a) Maquoi, E.; Sounni, N. E.; Devy, L.; Olivier, F.; Frankenne, F.; Krell,
H.-W.; Grams, F.; Foidart, J.-M.; Nöel, A. Clin. Cancer Res. 2004, 10,
4038-4047; (b) Gomez, G. G.; Hutchison, R. B.; Kruse, C. A. Cancer
Treat. Rev. 2001, 27, 375-402.
4. (a) Ruble, J. C.; Hurd, A. R.; Johnson, T. A.; Sherry, D. A.; Barbachyn,
M. R.; Toogood, P. L.; Bundy, G. L.; Graber, D. R.; Kamilar, G. M. J.
Am. Chem. Soc. 2009, 131, 3991-3997; (b) Miller, A. A.; Bundy, G. L.;
Mott, J. E.; Skepner, J. E.; Boyle, T. P.; Harris, D. W.; Hromockyj, A. E.;
Marotti, K. R.; Zurenko, G. E.; Munzner, J. B.; Sweeney, M. T.;
Bammert, G. F.; Hamel, J. C.; Ford, C. W.; Zhong, W.-Z.; Graber, D. R.;
Martin, G. E.; Han, F.; Dolak, L. A.; Seest, E. P.; Ruble, J. C.; Kamilar,
G. M.; Palmer, J. R.; Banitt, L. S.; Hurd, A. R.; Barbachyn, M. R.
Antimicrob. Agents Chemother. 2008, 52, 2806-2812.
5. For examples see (a) Wang, J.; O’Sullivan, S.; Harmon, S.; Keaveny, R.;
Radomski, M. W.; Medina, C.; Gilmer, J. F. J. Med. Chem. 2012, 55,
2154-2162; (b) Fisher, J. F.; Mobashery, S. Cancer Metastasis Rev.
2006, 25, 115-136; (c) Fridman, R. Cancer Metastasis Rev. 2006, 25, 7-
8; (d) Breyholz, H.-J.; Schäfers, M.; Wagner, S.; Höltke, C.; Faust, A.;
Rabeneck, H.; Levkau, B.; Schober, O.; Kopka, K. J. Med. Chem. 2005,
48, 3400-3409.
6. Calamai, E.; Dall’Angelo, S.; Koss, D.; Domarkas, J.; McCarthy, T. J.;
Mingarelli, M.; Riedel, G.; Schweiger, L. F.; Welch, A.; Platt, B.; Zanda,
M. Chem. Commun. 2013, 49, 792-794.
Under the optimized conditions, the scope of the reaction was
explored first by reacting unsubstituted barbituric acid (1a) with
various aldehydes (2) and acetophenones (3). As shown in Table
2, aromatic and heteroaromatic aldehydes reacted efficiently with
1a
and
3
and their corresponding
5-(3-oxo-1,3-
diarylpropyl)pyrimidine-2,4,6(1H,3H,5H)-triones
(4aa-4ad)
were obtained in high yields. Aliphatic aldehydes such as
valeraldehyde also satisfactorily gave its resultant 5-(1-oxo-1-
phenylheptan-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (Table 2,
4ae) in 71% yield. Similar results were obtained when acetone,
instead of acetophenone, was reacted with 1a and various
aromatic and aliphatic aldehydes (Table 2, 4af-4am). The
generality of the reaction was further investigated where 1-
methylbarbituric acid (1b) and 1,3-dimethylbarbituric acid (1c)
were used and reacted with various aldehydes and ketones.
Gratifyingly, all the corresponding 5-monoalkylbarbiturates were
successfully obtained in good yields (Table 2, 4ba-4cd).
However, the reactions involving 1b and 1c were found to be
slower and sluggish than when 1a was used, which could be
probably due to the presence of electron releasing methyl group/s
that reduced the substrate’s nucleophilicity. The reactivity of
barbiuturic acids in this synthesis was found to be of the order
1a>1b>1c. Also, the 5-monoalkylbarbiturates 4ba-4bc (Table 2),
from using 1b, were obtained as diastereomers, as indicated by
their NMR spectral data.
7. Ivanova, B. B.; Spiteller, M. Cryst. Growth Des. 2010, 10, 2470-2474;
(b) Andreu, R.; Garín, J.; Orduna, J.; Alcalá, R.; Villacampa, B. Org.
Lett. 2003, 5, 3143-3146.
8. (a) Yagai, S.; Karatsu, T.; Kitamura, A. Langmuir 2005, 21, 11048-
11052; (b) McClenaghan, N. D.; Absalon, C.; Bassani, D. M. J. Am.
Chem. Soc. 2003, 125, 13004-13005; (c) Timmerman, P.; Prins, L. J.
Eur. J. Org. Chem. 2001, 3191-3205.
9. (a) Devi, I.; Bhuyan, P. J. Tetrahedron Lett. 2005, 46, 5727-5729; (b)
Weygand-Hilgetag Preparative Organic Chemistry; Hilgetag, G.;
Martini, A. Eds.; Wiley, New York, 1972, pp 493.
10. For examples see (a) Trost, B. M.; Schroeder, G. M. J. Org. Chem. 2000,
65, 1569-1573; (b) Brunner, H.; Fürst, J. Inorg. Chim. Acta 1994, 220,
63-66; (c) Centolla, P.; Nelson, J. W.; Kollof, H. G. J. Am. Chem. Soc.
1943, 65, 2091-2092.
Scheme 1. Possible reaction mechanism.

4
Tetrahedron
11. (a) Jursic, B. S.; Steven, E. D. Tetrahedron Lett. 2003, 44, 2203-2210;
(b) Neumann, D. M.; Jursic, B. S.; Martin, K. L. Tetrahedron Lett. 2002,
43, 1603-1606.
12. Löfberg, C.; Grigg, R.; Keep, A.; Derrick, A.; Sridharan, V.; Kilner, C.
Chem. Commun. 2006, 5000-5002.
13. Singh, P.; Paul, K. J. Heterocycl. Chem. 2006, 43, 607-612.
14. (a) Volonterio, A.; Zanda, M. Org. Lett. 2007, 9, 841-844; (b)
Volonterio, A.; Zanda, M. J. Org. Chem. 2008, 73, 7486-7497.
15. Zalukaev, L. P.; Trostyanetskaya, V. L. Khim. Geterotsikl. Soedin. 1971,
6, 836-837; Chem. Heterocycl. Compd. 1971, 7, 781-782.
16. Kalita, S. J.; Mecadon, H.; Deka, D. C. RSC Adv. 2014, 4, 1402-1411.
17. For examples see (a) Clarke, P. A.; Zaytzev, A V.; Whitwood, A. C.
Tetrahedron Lett. 2007, 48, 5209-5212; (b) Clarke, P. A.; Santos, S.;
Martin, W.H. C. Green Chem. 2007, 9, 438-440; (c) Bhuyan, D.; Sarma,
R.; Dommaraju, Y.; Prajapati, D. Green Chem. 2014, 16, 1158-1162; (d)
Xiang, H.; Chen, Y.; He, Q.; Xie, Y.; Yang, C. RSC Adv. 2013, 3, 5807-
5810.
18. Experimental details: All reagents were obtained from commercial
sources and were used without further purification.
General experimental procedure for the synthesis of 5-
monoalkylbarbiturates: Ketone (3, 1 mmol) was slowly added to a
stirring solution of aldehyde (2, 1 mmol) and 10% NaOH (5 mL) in
EtOH/H2O (2:3). The reaction mixture was stirred until the starting
materials were consumed at which time barbituric acid (1a/1b/1c, 1
mmol) was added. The mixture was heated to reflux until the reaction
was complete as evidenced by TLC. The mixture was cooled, and the pH
was made neutral with dilute aqueous HCl (1M), and extracted with
EtOAc (10 mL x 3). The combined organic layers were dried (Na2SO4)
and filtered, and the solvent was removed by evaporation under reduced
pressure. The crude product was purified by recrystallization from
EtOH/DCM or by column chromatography eluting with EtOAc/Hexane
(v/v 3:2) to give the desired product.
Supplementary Material
Characterization data viz 1H-, 13C-NMR, IR and Mass spectral
data and elemental analysis data of all the compounds and copies
of 1H- and 13C-NMR spectral data of all compounds can be found
in the electronic supplementary information (ESI).