l-Proline Derived Secondary Aminothiourea Organocatalyst for Synthesis of Coumarin Derived Trisubstituted Methanes: Rate Enhancement by Bifunctional Catalyst over Cooperative Catalysis

Article abstract of DOI:10.1007/s10562-019-02809-4

Abstract: Although l-proline derived aminothioureas are being used as catalyst in asymmetric synthesis, their applications in multicomponent reactions are not yet reported in the literature. We report herein a l-proline derived secondary aminothiourea as

Full text of DOI:10.1007/s10562-019-02809-4

Catalysis Letters
https://doi.org/10.1007/s10562-019-02809-4
l‑Proline Derived Secondary Aminothiourea Organocatalyst
for Synthesis of Coumarin Derived Trisubstituted Methanes: Rate
Enhancement by Bifunctional Catalyst over Cooperative Catalysis
Grace Basumatary1 · Rahul Mohanta1 · Ghanashyam Bez1
Received: 8 December 2018 / Accepted: 4 May 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
Although l-proline derived aminothioureas are being used as catalyst in asymmetric synthesis, their applications in multi-
component reactions are not yet reported in the literature. We report herein a l-proline derived secondary aminothiourea as a
multifunctional catalyst in multicomponent reaction for synthesis of coumarin-based unsymmetrical trisubstituted methanes
whose prototype has been found to be acetylcholinesterase inhibitor. The method requires low catalyst loading (5 mol%), very
short reaction time (15–30 min) to give excellent yields. For the frst time, it is observed that our bifunctional catalyst signif-
cantly increases the rate of conversion in comparison to that of two cooperative organocatalysts having similar catalytic sites.
Graphical Abstract
l-Proline derived secondary aminothiourea organocatalyst in multicomponent reaction: synthesis of coumarin derived trisub-
stituted methanes
S
R
H
N
R
O
Ph
O
N
OH
O
HO
N
H
N
H
N
H
CHO
X
N
O
N
1 (5 mol%)
water, reflux, 15-30 min
(R= aryl, alkyl; X= H, Cl, Br)
X
+
O
N
O
O
NH2
O
NH2
O
2a-u (81-98%)
First L-proline derived aminothiourea organocatalyst in MCRs
Rate enhancement by bifunctional catalyst over cooperative catalysis
Excellent yields of unsymmetrical trisubstituted methanes
Low catalyst loading (5 mol%) and Very short reaction time (15-30 min)
No chromatographic purification
No use of organic solvent
Keywords l-Proline · Secondary aminothiourea · MCRs · 4-Hydroxycoumarin · 6-Aminouracil · Unsymmetrical
trisubstituted methanes
1 Introduction
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-019-02809-4) contains
Since the discovery of l-proline as a bifunctional organo-
catalyst for organic synthesis [1], many catalysts with similar
functional features have come to the fore. Despite its huge
supplementary material, which is available to authorized users.
Extended author information available on the last page of the article
Vol.:(0123456789)
1 3

G. Basumatary et al.
Scheme 1 Synthesis of coumarin based trisubstituted methanes
catalytic applications, numerous eforts are being made to
derivatize l-proline to address its solubility issues by keep-
ing its stereochemical features, the bifunctional character
and overall catalytic efciency intact [2–11]. In recent years,
aminothioureas have found immense applications as bifunc-
tional catalysts for carbon-carbon bond forming reactions
after the success of chincona alkaloid derived organothio-
ureas [12, 13]. Although some l-proline derived thiourea
organocatalysts are reported in the literature for stereoselec-
tive synthesis [14–17], there are hardly any report on use of
l-proline derived aminothioureas to catalyze multicompo-
nent reactions (MCRs). Since l-proline is used extensively
for MCRs [18], we proposed to study simple, easily acces-
sible and cost-efective l-proline derived aminothioureas to
improve upon its catalytic efciency in MCRs. Given the
recent emphasis on using green solvents [19], we aimed to
carry out the reaction preferably in water so that the purifca-
tion can be done by simple fltration and recrystallization.
Coumarin is a privileged structural motif that exist in
numerous pharmacophore derived from natural and syn-
thetic sources [20]. In recent years, coumarins have been
found to slow down the progression of alzheimer disease
(AD) by inhibiting acetylcholinesterase (AChE). The
AChE terminates the impulse transmission through rapid
hydrolysis of the neurotransmitter acetylcholine (ACh), the
progressive decline of which leads to pathogenesis of AD
[21–23]. While various coumarin derivatives are reported
for acetylcholinesterase inhibition, we have very recently
observed that coumarin-based unsymmetrical trisubsti-
tuted methane (uTRSM), 3-(6-amino-1,3-dimethyluracilyl)
benzyl-4-hydroxycoumarins (2a, Table 2) acts as a potent
AChE inhibitor with IC50 value at 48.49 5.6 nM which
a tertiary aminothiourea [26]. In both the cases, the reac-
tion took high catalyst loading (20 mol%) and long reac-
tion time (3–12 h) at refux temperature. Since most of the
tertiary aminothiourea catalyzed reactions involve activa-
tion of unactivated ketones [13], we hardly saw any reason
to employ the tertiary amine group for activation of highly
acidic 4-hydroxy coumarin (pKa 5.3) in the said reaction.
We were curious to know if simpler organothiourea would
be enough to accomplish the reaction without needing the
amine altogether. Our study led to development of a new
secondary aminothiourea catalysed method for synthesis of
coumarin-based uTRSMs (Scheme 1).
2 Experimental Section
2.1 Materials and Instruments
The chemicals and reagents were available commercially
and that were used without further purifcation. (S)-2-[[3,5-
Bis(trifluoromethyl)phenyl]thioureido]-N-benzyl-N,3,3-
trimethyl-butanamide was purchased from Sigma Aldrich.
The products were characterized by IR, 1H NMR, 13C NMR,
Mass spectroscopy and elemental analysis. The IR spectra
1
were recorded on a Perkin Elmer spectrophotometer. H
NMR (400 MHz) and 13C NMR (100 MHz) spectra were
obtained on a Bruker AC-400 using CDCl3 as solvent and
TMS as internal standard, unless otherwise stated. The mass
spectra were obtained from Waters ZQ 4000 mass spectrom-
eter by the ESI method, and the elemental analyses of the
complexes were performed on a Perkin–Elmer-2400 CHN/S
analyzer. HPLC analysis was carried out on an Waters M515
equipped with Chiracel OD-H and Chiralcel AD-H columns
using n-hexane and 2-propanol as mobile phase at room
temperature.
is much better than the reference drug donepezil (IC50
=
74.13 8.3 nM) [24]. In contrast, the corresponding bis-
coumarin, 3,3′-methylene-bis(4-hydroxy coumarin), MHC
showed relatively inferior inhibition (80.16 7.1 nM).
Encouraged by the fndings, we planned to synthesize a
series of coumarin based uTRSMs by MCR which could be
screened for inhibition of AChE.
2.2 Synthesis of 2‑(3‑Phenylthioureido)ethyl
prolinamide, 1
There are two reports for synthesis of 3-(6-amino-
1,3-dimethyluracilyl)benzyl-4-hydroxycoumarins derived
from multicomponent reaction of 4-hydroxy coumarin, aryl
aldehydes and 6-aminouracil employing l-proline [25] and
To a stirred solution of Boc- l-proline (3 g, 13.95 mmol)
in anhydrous CH2Cl2 at − 5 °C, triethyl amine (1.94 mL,
13.95 mmol) and ethyl chloroformate (1.46 mL, 15.34 mmol)
were added dropwise. After 20 min of stirring, the reaction
1 3

l-Proline Derived Secondary Aminothiourea Organocatalyst for Synthesis of Coumarin Derived…
Table 1 Screening of the catalyst for the model reaction
Entry Catalyst
t (h:min) % Yielda
mixture was washed successively with a cold solution of
citric acid (5% aqueous, 20 mL), a solution of sodium bicar-
bonate (10%, 20 mL) and water (20 mL). The organic layer
was dried over Na2SO4, fltered, and diluted with CH2Cl2
to a volume of 200 mL. This solution was added dropwise
(30–60 min) to a vigorously stirred solution of ethylenedi-
amine (4.66 mL, 69.77 mmol, 5 equiv.) in CH2Cl2 (200 mL)
previously cooled to −78 °C. When the addition was com-
pleted, the mixture was stirred for 10 min at that temperature
and then warmed to room temperature and stirred overnight.
The reaction mixture was concentrated in vacuo to a vol-
ume of about 50 mL, and extracted with 1 M aqueous HCl
solution (2×20 mL). The aqueous layer was basifed with
concentrated ammonia and it was thoroughly extracted with
CHCl3 (10 × 25 mL). The organic phases were combined,
dried over Na2SO4, fltered, and the solvent was evaporated
in vacuo to give the product 1a as colourless oil (3.15 g,
87%). Part of the crude product (1a) (2.056 g, 8 mmol) was
dissolved in anhydrous CH2Cl2 (20 mL) and phenyl isothio-
cyanate (0.96 mL, 8 mmol) was added dropwise at 0 °C with
continuous stirring. The reaction was allowed to stir for 1 h
at room temperature for complete conversion (part of the
crude product was purifed by column chromatography to get
the 2-(3-phenylthioureido)ethyl-N-Boc-prolinamide as white
solid). The remaining solution was cooled to 0 °C and TFA
(2 mL) was added with stirring. After the consumption of
the starting material, as indicated by TLC analysis, the reac-
tion mixture was diluted with H2O (10 mL) and the resulting
solution was neutralized with aqueous NaHCO3 solution.
The reaction mixture was extracted with CH2Cl2 (2×20 mL)
and the combined organic layer was washed with brine, dried
over Na2SO4, fltered and the solvent was removed in vacuo.
The solid crude product was recrystallized from methanol
to get the pure product 1 as white solid in 77% overall yield
(2.079 g, 7.12 mmol). M.p. 110–112 °C; IR (KBr): ν 3435,
2923, 1650, 1525, 1104 cm−1; 1H NMR (400 MHz, CDCl3,
δ ppm): 1.65–2.09 (m, 6H, 2-CH2, 2NH), 2.90–3.00 (m, 2H,
–CH2), 3.47–3.77 (m, 5H, 2-CH2, –CH), 6.81 (m, 1H, ArH),
7.22–7.43 (m, 4H, ArH), 7.87 (s, 1H, –NH), 7.99 (s, 1H,
–NH); 13C NMR (100 MHz, CDCl3, δ ppm): 25.67, 31.99,
38.58, 45.18, 46.90, 60.20, 122.71, 125.03, 126.72, 128.32,
129.63 136.70, 173.25, 181.16; ESI-MS (m/z): 292.12 (M+).
1
2
3
4
5
6
7
N,N′-Diphenyl thiourea
2:00
2:00
1:30
2:30
1:30
1:30
1:00
80
82
89
86
90
90
89
N-Benzyl-N′-phenyl thiourea
N,N′-Diphenyl thiourea, pyrrolidine
N,N′-Diphenyl thiourea, piperidine
N,N′-Diphenyl thiourea, l-proline
l-Proline
NHPh
N
S
H
O
NHPh
N
,
PhHN
NHPh
8
0:40
1:30
0:20
88
76
93
H
O
S
NHPh
N
,
PhHN
NHPh
9
n
B
O
10
S
H
N
NHPh
N
H
N
H
1
O
Reaction conditions: 3-Nitrobenzaldehyde (1 mmol), 4-hydroxy cou-
marin (1 mmol), 6-amino-1,3-dimethyluracil (1 mmol) was heated to
refux in water (1 mL) with the specifed catalyst (0.05 mmol)
aYield of the purifed product
that precipitated out of the solution was fltered of, washed
with water and then with ethanol twice to remove any unre-
acted starting materials and trace of catalyst present. The
solid crude product was then dissolved in ethanol and kept
overnight to get the pure recrystallized product.
3 Results and Discussion
Initially, we optimized the reaction conditions for a model
reaction of an equimolar mixture of 6-amino-1,3-dimethylu-
racil, m-nitrobenzaldehyde and 4-hydroxycoumarin (1 mmol
each). When the model reaction was carried out in 1 mL of
water in the presence of 10 mol% of N,N′-diphenylthiourea
at refux temperature (Table 1, entry 1), it was completed
in 2 h to give 80% isolated yield. Catalysis of the model
reaction by N-Benzyl-N′-phenyl thiourea also took similar
reaction time with no appreciable diference in yield. The
observations revealed that organothiourea alone can cata-
lyze the reaction in the absence of an amine source and the
role of the tertiary amine group is very nominal in the reac-
tion reported by Parvin et al. [26]. This might be due to
the fact that the tertiary amine groups in organothioureas
basically acts a base to catalyze the reaction via enolization
2.3 General Procedure for the Synthesis of uTRSMs
To an equimolar solution of 6-amino-1,3-dimethyluracil
(0.155 g, 1 mmol), aldehyde (1 mmol) and 4-hydroxycou-
marin (0.162 g, 1 mmol) in 1 mL of water, 5 mol% of thio-
urea catalyst was added and the solution was stirred under
refux condition. In about 5 min, the product started form-
ing (as evident from TLC). The stirring was continued until
completion of the reaction (monitored by TLC). The result-
ing mixture was cooled to room temperature and the solid
1 3

G. Basumatary et al.
from N,N′-diphenylthiourea. We reasoned that the thiourea
group in N,N′-diphenylthiourea and the carboxylate group in
l-proline might have engaged in H-bonding interaction lead-
ing to partial functional deactivation of the thiourea group
[28]. Similar observation was made when the model reac-
tion was carried out with phenyl prolinamide as catalyst, but
signifcant reduction of reaction time (1 h) was noted. The
same catalyst completed the reaction within 40 min in the
presence of 10 mol% N,N′-diphenylthiourea as co-catalyst.
These observations confrmed that the presence of both
functionalities may be critical to achieve faster completion
of the reaction. But when the reaction was carried out with
N-benzyl-N′-phenyl prolinamide with N,N′-diphenylthiourea
as co-catalyst (entry 8), the reaction took almost the same
time as that of N,N′-diphenylthiourea as the sole catalyst
(entry 1). It shows that the presence of the secondary amine
in pyrrolidine accelerated the reaction much faster than that
of the tertiary amine (entry 9) in the presence of thiourea
unit. In order to see if a bifunctional catalyst having the
same catalytic sites could be a better catalyst than coopera-
tive catalysis by separate pyrrolidine moiety and thiourea,
we decided to synthesize a secondary aminothiourea 1 from
l-proline (Scheme 2). The catalyst (1) was synthesized by
Fig. 1 2°/3°—aminothiourea catalysed C–C bond forming reaction
Scheme 2 Synthesis of the catalyst
of unactivated ketone (Fig. 1). In this case, the 4-hydroxy
coumarin is naturally an enol and hardly requires any base
catalyst for activation to undergo addition reaction at refux
temperature. The fact that a secondary amine can work both
as base and nucleophile, we proposed to add a pyrrolidine
source along with organothiourea as catalysts to accelerate
the rate of the reaction between 4-hydroxy coumarin and the
aldehyde (via iminium salt formation) further.
converting Boc-protected l-proline to the amide derivative
(A) followed by treatment with phenyl isothiocyanide in
methylene chloride and then TFA in three simple steps [29].
With the secondary aminothiourea in hand, we carried
out the model reaction with 10 mol% of the catalyst 1 in
1 mL of water by heating at refux temperature. Gratifyingly,
we observed complete conversion of the starting aldehyde
within 20 min to obviate the desired product with an excel-
lent isolated yield of 93%. It was interesting to observe that
the reaction with the catalyst 1 took much lesser time than
those where equimolar mixture of pyrrolidine and thiourea
were used. This proves for the frst time that catalytic ef-
ciency of bifunctional catalyst is better than cooperative
catalysis by two monofunctional catalysts.
We planned to study whether an equimolar mixture of
secondary amine and thiourea can positively affect the
model reaction. To that efect, we treated the reaction mix-
ture with N,N′-diphenylthiourea (10 mol%) and pyrrolidine
(10 mol%) in water (Table 1, entry 3). The reaction time
was reduced (1.5 h) slightly to generate the desired product
in 87% yield. The fact that nucleophilicity of l-proline in
water is slightly higher than pyrrolidine [27], the reaction
mixture was refuxed in water with l-proline (10 mol%) as
well. The reaction took similar time (1.5 h) to obviate 90%
isolated yield of the desired product, but it was comparable
to l-proline (Table 1, entry 6) with no visible contribution
In order to see the efect of solvents on efcacy of the reac-
tion, we frst screened the solvents like ethanol, methanol,
water, ethanol-water (1:1), CH3CN, THF, CHCl3, and DCM
at various reaction temperatures (Table 1S in supplementary
materials). The best result was obtained in water where the
1 3

l-Proline Derived Secondary Aminothiourea Organocatalyst for Synthesis of Coumarin Derived…
Table 2 Synthesis of coumarin based Trisubstituted methanes via Scheme 1
Entry
Aldehyde
Product
Time
(min)
%Yielda
mp (oC)
Reported
Found
O
O
O
HO
1
20
15
15
85
218
220
230
–
–
–
220
221
232
220
NA
NA
–222 [2]
N
N
O
O
N
N
O
O
NH2
2a
O
NO2
HO
NO2
2
3
98
93
O
O
NH2
2b
NO2
O
O
HO
O
N
NO2
O
N
O
NH2
2c
NO2
O
4
5
15
15
95
95
205
246
–
–
207
248
NA
O
HO
O
N
O
N
NO2
O
NH2
2d
F
O
248–250 [3]
227–228 [3]
O
HO
N
F
O
N
O
NH2
2e
O
O
O
Cl
O
HO
Cl
6
7
15
15
97
95
227
219
–
–
229
220
N
O
N
O
NH2
2f
Cl
O
218
NA
–220 [2]
O
HO
N
Cl
O
N
O
O
O
NH2
2g
O
Br
O
Br
HO
O
8
15
96
210
–
212
N
O
N
NH2
2h
1 3

G. Basumatary et al.
Table 2 (continued)
Entry
Aldehyde
Product
Time
(min)
%Yielda
95
mp (oC)
Reported
Found
Br
O
9
15
236
–
238
237–238 [3]
221–223 [3]
NA
O
HO
N
Br
O
N
O
O
NH2
2i
CN
O
10
15
95
221
–
222
O
HO
N
N
CN
O
N
N
O
O
O
NH2
2j
O
O
O
O
HO
O
11
12
20
20
90
90
200
180
–
–
202
181
O
NH2
2k
O
O
178
NA
–180 [2]
O
O
HO
O
N
N
O
N
N
O
O
O
NH2
2l
O
13
20
92
202
–
204
HO
O
O
NH2
2m
Cl
O
NO2
14
15
20
20
98
91
230–231
228–230
NA
NA
O
HO
NO2
N
Cl
O
N
O
NH2
2n
O
O
O
Cl
O
HO
Cl
N
O
O
N
O
NH2
2o
O
1 3

l-Proline Derived Secondary Aminothiourea Organocatalyst for Synthesis of Coumarin Derived…
Table 2 (continued)
Entry
Aldehyde
Product
Time
(min)
%Yielda
mp (oC)
Reported
Found
O
O
O
O
O
16
15
91
239–240
NA
O
O
HO
O
N
N
O
O
N
N
O
O
NH2
2p
N
O
HO
17
18
20
92
223–225
NA
N
O
NH2
2q
O
O
O
HO
O
O
O
30
88
195–197
NA
O
N
N
O
O
N
O
O
O
NH2
2r
HO
O
19
30
15
81
93
110–111
265–267
NA
NA
N
O
NH2
2s
NO2
O
20b
O
HO
O
Br
NO2
N
O
N
O
O
NH2
2t
NO2
O
21c
15
95
243–245
NA
O
HO
O
Cl
NO2
N
O
N
NH2
2u
Reaction conditions: Stoichiometric mixture of 6-amino-1,3-dimethyluracil, aldehyde and 4-hydroxycoumarin in 1 mL water (solvent) with
5 mol% of the catalyst 1 at refux temperature
aIsolated yield
b6-Bromo-4-hydroxycoumarin was employed
c6-Chloro-4-hydroxycoumarin was employed
NA not available
1 3

G. Basumatary et al.
Table 3 Efect of catalyst and reaction conditions on stereoselectivity of the model reaction
Entry
1
Catalyst
Temp.
t (h:min)
% Yielda
%eeb
1 (5 mol%)
RT
10 °C
RT
12:00
48:00
12:00
70
–
67
nil
–
nil
2
3
RT
RT
12:00
77
28
nil
nil
4
12:00
Reaction conditions: 3-nitrobenzaldehyde (0.1 mmol), 4-hydroxy coumarin (0.1 mmol), 6-amino-1,3-dimethyluracil (0.1 mmol) was in water
(0.2 mL) with the specifed catalysts
aYield of the purifed product
b%ee was determined by HPLC using Chiralcel AD-H column
reaction was completed within 20 min of heating at refux tem-
perature to obviate the desired product in 93% isolated yield.
Then we went on to optimize the catalyst loading (Table 2S
in the supplementary materials) for the reaction. Under
catalyst-free condition, only a trace amount of product was
obtained upon stirring for 12 h. The same reaction when car-
ried out employing 1 mol% of the catalyst resulted in 70% yield
of the desired product within 1 h of stirring under refux. But, a
signifcant increase in reaction rate was observed upon increas-
ing the catalyst loading to 5 mol% to obtain the desired product
with 93% yield within 20 min. However, further enhancement
of catalyst loading to 10–15 mol% did not reduce the reaction
time appreciably and gave almost similar yields.
aliphatic aldehyde (entry 19) producing the desired products
in good to excellent yields. When the reaction was expanded
to the substituted 4-hydroxy coumarins, we noted excellent
conversion under the optimised conditions (Entries 20–21).
3.2 Study of Asymmetric Induction
Although this l-proline derived bifunctional amidothiourea
catalyst is asymmetric in nature, it did not give any stere-
oselectivity probably due to the high reaction temperature.
In our bid to achieve enantiomeric induction by conducting
the reaction at room temperature, we observed the reaction
for 12 h to get 70% yield and no enantioselectivity (Table 3,
entry 1). The reaction at 10 °C did not give the desired
product at all within 48 h. Interestingly, the reaction failed
to show any enantioselective induction when the reaction
was catalysed by N-phenyl l-prolinamide in the presence
of a chiral thiourea catalyst, (S)-2-[[3,5-bis(trifuoromethyl)
phenyl]thioureido]-N-benzyl-N,3,3-trimethylbutanamide at
room temperature (Table 3, entry 3–4).
3.1 Substrate Scope
Having achieved the optimum reaction conditions, we
expanded the scope of our protocol by varying the alde-
hyde in the model reaction. The results are summarized in
Table 2. The reaction worked extremely well with almost
all the aldehydes. Aromatic aldehydes having electron-with-
drawing substituents (entries 2–10) as well as the ones con-
taining electron-donating substituents (entries 11–13) gave
very good to excellent yields. Thus the nature and position
of the substituents did not have much of an efect on the
reaction rate. The reaction also worked well with a heteroaro-
matic aldehyde (entry 17), ethyl glyoxalate (entry 18) and an
3.3 Mechanistic Perspective
While trying to unfold the mechanism of the reaction, we
carried out two control experiments by reacting m-nitroben-
zaldehyde with 4-hydroxycoumarin and 6-amino-1,3-di-
methyluracil separately under the optimized reaction
1 3

l-Proline Derived Secondary Aminothiourea Organocatalyst for Synthesis of Coumarin Derived…
Scheme 3 Control experiments
Fig. 2 Plausible reaction
mechanism
conditions. The formation of symmetrical trisubstituted
methanes (3) from the reaction of 4-hydroxycoumarin
took only 30 min for complete conversion, while the reac-
tion of 6-amino-1,3-dimethyluracil with the same aldehyde
under similar reaction conditions took almost double the
reaction time (1 h) for complete conversion to the corre-
sponding symmetrical TRSM, 4 (Scheme 3). On the other
hand, the reaction with other coumarin derivatives such as
1 3

G. Basumatary et al.
4-methylcoumarin, and 4-methoxycoumarin did not generate
unsymmetrical TRSMs 5 and 6, but the symmetrical TRSM,
4 only.
efciency of bifunctional catalyst is better than cooperative
catalysis by two monofunctional catalysts.
Acknowledgements The analytical services provided by Sophisticated
Analytical Instrumentation Facility (SAIF), North Eastern Hill Univer-
sity, Shillong, India are acknowledged.
Above observations suggest that (i) the hydroxy group at
4-position of the coumarin is vital for the reaction, (ii) the
pyrrolidine moeity has acted as a base to activate 4-hydroxy
coumarin to form the Knoevenagel product, and (iii) the
activation of the aldehyde by the thiourea for addition of
the pyrrolidine nucleophile is true in all the cases. The base
catalyzed activation of 6-amino-1,3-dimethyluracil does not
arise at all, rather it is driven by the amino group in it. The
thiourea scafold might have also catalyzed the formation of
the iminium salt through H-bond activation of aldehyde for
nucleophilic attack by pyrrolidine moeity of the catalyst 1.
Due to greater electrophilicity of H-bond activated aldehyde,
the formation of iminium ion with proline derived pyrroli-
dine is much faster which ultimately afects overall reaction
time. It may be noted that the transformation of the carbonyl
compound into an iminium species increases the electrophi-
licity of the carbonyl compound for the subsequent attack of
nucleophiles [30]. The higher electrophilicity of the resultant
iminium ion might have facilitated easier C–C bond forming
reaction with C-3 carbon of 4-hydroxy coumarin to yield the
Knoevenagel product. Since 6-amino-1,3-dimethyluracil is
a softer nucleophile than 4-hydroxy coumarin, the former
will undergo 1,4-addition reaction preferentially with the
Knoevenagel product to give the desired product. With all
probabilities, the Michael addition of 6-aminouracil to the
Knoevenagel product may be very fast and requires no cata-
lyst. As a result, the reaction did not show any stereoselective
induction in the presence of the chiral catalysts (Table 3).The
plausible mechanim is schematically presented in the Fig. 2.
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For the frst time, we have reported the catalytic application of
l-proline derived aminothiourea 1 in a multicomponent reac-
tion. The bifunctional catalyst 1 demonstrated multiple cata-
lytic role in the multicomponent synthesis of coumarin-based
unsymmetrical trisubstituted methanes whose prototype has
been found to be acetylcholinesterase inhibitor. The secondary
aminothiourea core of the l-proline derived catalyst has shown
excellent catalytic activity in the synthesis of coumarin based
trisubstituted methanes. The better activity of the catalyst 1 is
explained to be the result of dual catalytic role of the secondary
amine group as base and nucleophile to accelerate the reaction
rate. The method requires low catalyst loading (5 mol%) and
very short reaction time (15–30 min) to give excellent yields.
The use of water as a reaction medium facilitated isolation of
the product by simple fltration and therefore chromatographic
separation employing hazardous organic solvents could be
avoided. Nevertheless, we report for the frst time that catalytic
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jurisdictional claims in published maps and institutional afliations.
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l-Proline Derived Secondary Aminothiourea Organocatalyst for Synthesis of Coumarin Derived…
Afliations
Grace Basumatary1 · Rahul Mohanta1 · Ghanashyam Bez1
1
* Ghanashyam Bez
Department of Chemistry, North Eastern Hill University,
Shillong 793022, India
ghanashyambez@yahoo.com
1 3