InCl3-Catalyzed, Three-Component Reactions for the Synthesis of Some Novel Functionalized/Annulated Barbituric Acids

Article abstract of DOI:10.1080/00397911.2015.1045081

Some novel 5-aminoalkylbarbituric acids and corresponding chromene derivatives were synthesized via a one-pot, three-component Mannich reaction starting from 1,3-dimethylbarbituric acid, arylaldehydes, and amines.

Full text of DOI:10.1080/00397911.2015.1045081

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InCl3-Catalyzed, Three-Component Reactions for the
Synthesis of Some Novel Functionalized/Annulated
Barbituric Acids
Meenakshi Sharmaa, Pallabi Boraha & Pulak J. Bhuyana
a Medicinal Chemistry Division, CSIR-North East Institute of Science & Technology, Jorhat,
Assam, India
Accepted author version posted online: 05 May 2015.
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To cite this article: Meenakshi Sharma, Pallabi Borah & Pulak J. Bhuyan (2015): InCl3-Catalyzed, Three-Component Reactions
for the Synthesis of Some Novel Functionalized/Annulated Barbituric Acids, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1045081
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InCl3-Catalyzed, Three-Component Reactions for the Synthesis of Some Novel
Functionalized/Annulated Barbituric Acids
Meenakshi Sharma1, Pallabi Borah1, Pulak J. Bhuyan1
1Medicinal Chemistry Division, CSIR-North East Institute of Science & Technology,
Jorhat, Assam, India
Corresponding author: Meenakshi Sharma, Email: meenakshi.aka@gmail.com
Abstract
Some novel 5-aminoalkylbarbituric acids and corresponding chromene derivatives were
synthesized via one-pot three component Mannich reaction starting from 1,3-
dimethylbarbituric acid, arylaldehydes and amines.
KEYWORDS: 5-aminoalkylbarbituric acids; Chromene; One pot three component
reaction; Mannich reaction.
INTRODUCTION
6-Hydroxy-uracils (barbituric acids) represent a large number of compounds of biological
importance which have wide application as drugs and pharmaceuticals. 5-Alkylated
barbituric acids are one class of such compounds with diverse biological activity such as
anti-convulsant,1 sedative-hypnotic,2 anticancer, HIV-1 and HIV-2 protease inhibitors3
etc. Barbiturates, a class of 5-alkylatedbarbituric acids, are widely being used in the
treatment of anxiety, insomnia, seizure disorders, migraine headaches and as
anaesthetics.4 Reports of barbituric acid derivatives which display anticancer, analeptic,
anti-AIDS activity are also present.6 Positive Allosteric Modulators (PAM, Fig I) has
1

anticonvulsant5 properties, thiopentone (Fig I) shows intravenous anaesthetic6 behaviour
whereas bucolome (Fig I) acts as an analgesic.6 Biologically viable list of substituted
barbituric acid is very long and its applications have increased with time.7
Chromenes are an important class of naturally occurring compounds. They are found to
have wide range of biological properties such as anticonvulsant,8 antimicrobial,9
antitumor,10 diuretic, spasmolytic, and antinaphylactic activities.11Literature reports show
using of harsh conditions for preparation of chromene derivatives.12a,b Recently,
Marugan12c et al. have reported the synthesis as well as biological activity of molecules
(I, II, Fig I)) as antagonists for neuropeptide S receptor (NPSR).
Awareness has emerged worldwide to use more of renewable resources and step
economy protocol for organic synthesis.13 One-pot multicomponent reactions (MCRs) is
an efficient as well as environmentally benign synthetic methodology. It widely abides
the needs for economy of steps, minimal usage of hazardous solvents, and reduction of
waste and provides combinatorial libraries of medicinal scaffolds. Recently, imine based
MCRs14a are being widely used due to its immense versatility. Mannich reaction falls
under this category which results in the formation of β-amino carbonyl compounds which
finds wide application as precursors in many pharmaceuticals.14b
In continuation of our interest on synthesizing diverse heterocyclic compounds of
biological significance,15 we report here the synthesis of some novel 5-
aminoalkylbarbituric acids 4/ chromene derivatives 6 from an one-pot three component
2

Mannich reaction of 1,3-dimethyl barbituric acid 1, aryl aldehyde 2 and amines 3
(Scheme I).
DISCUSSION
First, the reaction of 1,3-dimethyl barbituric acid 1, benzaldehyde 2a and pyrrolidine 3a
was carried out in absence of catalyst and solvent (Table I, entry 1), but no reaction
occurred. Interestingly, when the reaction was carried out using ethanol as solvent (Table
I, entry 2), it gave 50 % yield of the product 4a in 6 h even in the absence of catalyst.
But, addition of InCl3 as catalyst in the reaction improved the yield of the product
considerably and reduced the reaction time. 10 mol% of InCl3 (Table I, entry 4) was
found optimum to obtain the desired product in high yield, and increase or decrease in the
amount of catalyst InCl3 (Table I, entry 4-6) did not improve the yield of the product. The
reaction did not occur when it was conducted using InCl3 (10 mol %) as catalyst under
solvent free conditions (Table I, entry 3). Subsequently, a range of catalysts were studied
on their effectiveness but no such satisfactory results were obtained (Table I, entry 7-8).
Henceforth, the protocol with one-pot three component methodology using equimolar
amounts of 1,3-dimethyl barbituric acid 1, arylaldehydes 2 and amines 3 in presence of
InCl3 (10 mol%) was followed, which resulted in an excellent yield of desired 5-
aminoalkylbarbituric acids. The experimental procedure is clean and simple:16 equimolar
mixture of 1,3-dimethyl barbituric acid 1, benzaldehyde 2a and pyrrolidine 3a and InCl3
(10 mol%) were fed in a round bottom flask and kept under stirring condition at room
temperature for a time period of 2h in ethanol. After work up, we obtained an excellent
3

yield of 5-aminoalkylbarbituric acid 4a by simple filtration and further recrystallized it
from ethanol. The structure of the compound was confirmed as 4a from the spectroscopic
data and elemental analysis. The generality of the reaction scheme was performed by
synthesizing a library of compounds 4b-k (Table II) using different cyclic secondary
amines viz pyrrolidine, piperidine and morpholine. Similar reaction with acyclic
secondary and primary aliphatic amines gave us the desired product in moderate yield. In
the same way, generality of the reaction scheme was done by synthesizing compounds 4l-
o (Table II). The synthesized compounds were characterized by spectroscopic data and
elemental analysis. It was found that on conducting the reaction using 1.1 equivalent of
amine, product obtained was identical with the one using equimolar amine. Also, using
excess amine did not improve the yield of the desired product.
Notably, instead of benzaldehyde, when we performed the same reaction utilizing
salicylaldehyde 5, 1,3-dimethyl barbituric acid 1 and pyrrolidine 3a, we obtained
chromene derivative 6a in excellent yields (Scheme I). Although it is obvious because of
the presence of two suitably located OH groups which favoured the formation of pyran
ring by eliminating water easily, but notable point is that cyclization occurred at very
mild condition. However, the reaction did not occur in case of both primary as well as
secondary aliphatic amines. Generalization of the reaction scheme was done by
synthesizing a series of chromene derivatives 6a-c (Table II).
Solvent optimization was done using various solvents namely acetonitrile,
tetrahydrofuran, DMF and toluene, but no satisfactory results were obtained. Electronic
4

effects of the substituents in the aldehydes used were studied. The electron-donating
group (EDG) at the para position of the benzaldehydes gave comparatively better yields
of the product while stronger EWG-substituted ones gave evidently less yields.
Moreover, halogenated benzaldehydes correspondingly gave very good yield as
compared to other arylaldehydes. This methodology is not applicable to aliphatic
aldehydes. However, primary aromatic amines were reluctant to the reaction and on
performing the reaction, both in three as well as two component way, only resulted the
condensed compound 8 with elimination of aniline 3f (Scheme II).
The probable mechanism supporting the formation of 4a and 6a is presented in scheme
III. Initialy, aldehyde 2a and pyrrolidine 3a reacts in presence of protic solvent ethanol to
form the intermediate [A], which thereafter undergoes nucleophilic attack by 1,3-
dimethyl barbituric acid to generate the product 4a. Similarly, salicylaldehyde 5 reacts
with pyrrolidine 3a to give intermediate [B] which then suffers nucleophilic attack by 1
and gives [C]. [C] on further elimination of water gives the desired product 6a.
In conclusion, we have reported the efficient method for the synthesis of some novel 5-
aminoalkylbarbituratic acids and corresponding chromene derivatives via simple one pot
three component Mannich reaction at room temperature. The above said reaction protocol
can be further utilized for synthesizing many more heterocyclic compounds.
5

EXPERIMENTAL
Representative Procedure For The Synthesis Of Compound 4
A mixture of aldehyde (0.105g, 1mmol), 1,3-dimethylbarbituric acid (0.155g, 1mmol)
and pyrrolidine (0.07g, 1mmol) in presence of 10 mol% of InCl3 were taken in a round
bottomed flask. To this, ethanol (5 mL) added and stirred the reaction mixture vigorously
at room temperature for 2h. After completion of reaction (monitored by TLC), solid
compound appeared was filtered off and recrystallized from ethanol. The product 4a was
obtained in 82% (0.25 g) yield. The structure of the compound was ascertained from
spectroscopic data and elemental analysis. Similarly compounds 4b-o and 6a-d were
synthesized and characterized.
4a; Yield: 82%; Mp: 175.3˚C; IR (CHCl3) νmax = 1607, 1674, 3460 cm-1; 1H NMR (300
MHz,CDCl3): 2.09 (br, 4H), 2.78 (br, 1H), 3.06 (br, 2H), 3.31(s, 6H), 3.63 (br, 1H),
5.17 (s, 1H), 7.11-7.90 (m, 5H), 9.73 (br, OH); 13C NMR (75MHz, CDCl3) 23.92,
24.37, 27.28, 28.56, 34.17, 45.25, 83.97, 126.50, 127.75, 127.84, 128.06, 128.92, 129.12,
130.08, 151.03, 152.97, 163.16; MS (ESI) 316.41 (M+H)+; Anal. Calcd for C17H21N3O3:
C,64.74; H, 6.71; N,13.32 %. Found: C, 64.81; H, 6.77; N, 13.43 %.
6a; Yield: 83%; Mp: 170.4˚C; IR (CHCl3) νmax = 1614, 1681, 3061 cm-1;1H NMR (300
MHz, CDCl3): 2.15 (br, 4H), 3.03 (br, 2H), .3.30 (s, 6H), 3.64 (s, 6H), 5.64 (s, 1H),
6.81-7.56 (m, 4H); 13C NMR (75MHz, CDCl3) 23.42, 23.96, 24.92, 27.19, 45.55.
52.22, 54.60, 84.41, 117.58, 120.55, 124.51, 127.61, 130.09, 152.59, 154.75, 161.57,
6

163.90; MS (ESI) 314.22 (M+H)+; Anal. Calcd for C17H19N3O3: C, 65.16; H, 6.11; N,
13.40 %. Found: C, 65.17; H, 6.17; N, 13.51 %.
ACKNOWLEDGMENTS
The author thanks DST and CSIR, New Delhi, for financial support. M.S thanks DST for
Inspire Fellowship.
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra of all compounds for this article can be
accessed on the publisher’s website.
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8

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9

Table I. Catalyst and solvent screening for the synthesis of compound 4a
Ent.
1
Catalyst (mol %) Solvent
T.(h) Yd.(%)
-
7
NR
50
-
2
-
EtOH
-
6
4
3
InCl3
NR
(10 mol %)
InCl3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
EtOH
4
2
4
4
5
69
82
78
69
60
(5 mol %)
InCl3
(10 mol %)
InCl3
(20 mol %)
K2CO3
(10 mol %)
L-Proline
(10 mol %)
Yd. = Yield, Ent. = Entry, T. = Time, NR. = No Reaction
10

Table II. Synthesis of 5-aminoalkylbarbituric acids 4 and chromene 6
Ent R2
R3
R4
[X]n
Pd. Time (h) Yd. (%)
1
H
-
-
[CH2]
[CH2]
[CH2]
[CH2]
[CH2]
[CH2]2
[CH2]2
[CH2]2
[CH2]2
[CH2]2
[CH2O]
-
2
82
81
80
77
83
80
82
81
76
83
80
81
80
79
75
83
82
81
4a
4b
4c
4d
4e
4f
2
CH3
OCH3
NO2
Cl
-
-
2
3
-
-
2
4
-
-
2
5
-
-
2
6
H
-
-
2.5
2.5
2.5
2
7
CH3
OCH3
NO2
Cl
-
-
4g
4h
4i
8
-
-
9
-
-
10
11
12
13
-
-
2
4j
H
-
-
2.5
3
4k
4l
H
C2H5
C2H5
H
CH(CH3)2
H
H
H
-
-
3
4m
4n
4o
6a
6b
6c
14
CH3
NO2
H
CH(CH3)2
-
3
15
16
17
18
CH(CH3)2
-
2.5
3
-
-
-
[CH2]
[CH2]2
[CH2O]
H
-
2.5
3
H
-
Ent. = Entry, Pd. = Product, Yd. = Yield
11

Figure I. Some bioactive molecules
12

Scheme I. Synthesis of 5-aminoalkylbarbituric acids 4 and chromene 6
13

Scheme II.
14

Scheme III. Plausible mechanism for the formation of 4a and 6a
15