Tris-hydroxymethylaminomethane (THAM): An efficient organocatalyst in diversity-oriented and environmentally benign synthesis of spirochromenes

Article abstract of DOI:10.1016/j.crci.2018.05.005

Tris-hydroxymethylaminomethane has been demonstrated to be an efficient organocatalyst in diversity-oriented synthesis of medicinally prevalent spirochromenes by one-pot, three-component reactions between isatins, malononitrile, and enolizable C–H acids l

Full text of DOI:10.1016/j.crci.2018.05.005

C. R. Chimie xxx (2018) 1e8
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Preliminary communication/Communication
Tris-hydroxymethylaminomethane (THAM): An efficient
organocatalyst in diversity-oriented and environmentally
benign synthesis of spirochromenes
,
*
Supriya S. Khot a, Prashant V. Anbhule a, Uday V. Desai a
,
Prakash P. Wadgaonkar b
a Department of Chemistry, Shivaji University, Kolhapur 416004, India
b Polymer Science and Engineering Division, CSIR, National Chemical Laboratory, Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Tris-hydroxymethylaminomethane has been demonstrated to be an efficient organo-
catalyst in diversity-oriented synthesis of medicinally prevalent spirochromenes by one-
pot, three-component reactions between isatins, malononitrile, and enolizable CeH
acids like dimedone, 4-hydroxycoumarin, 4-hydroxy-N-methylquinolin-2-one, or in situ
generated 2-methylpyrazolon-2-one. Biodegradability and extremely low cost of the
catalyst are the noteworthy features of this chromatography-free protocol.
Received 2 April 2018
Accepted 15 May 2018
Available online xxxx
Keywords:
Multicomponent synthesis
Tris-hydroxymethylaminomethane
Organocatalysis
© 2018 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Spirochromenes
Green chemistry
1. Introduction
choice of heterogeneous catalysts; however, in the past few
years use of organocatalysts with their well-documented
It is well known that multicomponent reactions
constitute a precise synthetic tool for an easy access to
multifunctionalized and structurally related drug-like
molecules [1,2]. On the other hand, green chemistry prin-
ciples are playing very dominating role in today's organic
synthesis [3]. Consequently, the use of multicomponent
reactions in library synthesis of biologically important
molecules obeying the demands of green chemistry has
become the focal point of current day research [4]. Three
main variations involved in green multicomponent syn-
thesis of target molecules are the reaction medium, the
energy source, and the catalyst. Compared to reaction
medium and energy sources, catalyst can play a very
important role in green organic synthesis. Most of the early
developments in the field of catalysis were focused on the
advantages such as ready availability, low cost, low
toxicity, and lack of sensitivity toward moisture as well as
oxygen is considered as one of the possible solutions to
green organic synthesis [5]. A few of the nontoxic organo-
catalysts practiced in today's organic synthesis are Baker's
yeast [6],
b-cyclodextrin [7], proline [8], chitosan [9],
meglumine [10], thiourea dioxide [11], and so forth. At the
same time, search for a new organocatalyst is a constant
endeavor.
Indole is the most ubiquitous heterocyclic moiety pre-
sent in a large number of bioactive natural products [12]. It
is known that sharing of indole-3-carbon atom in the for-
mation of spiroindolines and the presence of carbonyl
group at C-2 in spiroindolines generate spiro-2-oxindoles
(spirooxindoles), which occupy a special place in organic
and medicinal chemistry. Several compounds containing
spirooxindole as the structural unit of natural and synthetic
origin are known to exhibit antimicrobial, antioxidant,
* Corresponding author.
E-mail address: uvdchem2011@gmail.com (U.V. Desai).
https://doi.org/10.1016/j.crci.2018.05.005
1631-0748/© 2018 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: S.S. Khot, et al., Tris-hydroxymethylaminomethane (THAM): An efficient organocatalyst in
diversity-oriented and environmentally benign synthesis of spirochromenes, Comptes Rendus Chimie (2018), https://doi.org/
10.1016/j.crci.2018.05.005

2
S.S. Khot et al. / C. R. Chimie xxx (2018) 1e8
antitubercular, anticancer, anti-HIV and anti-inflammatory
activities (Fig. 1) [13]. Sharing of C-3 in spirooxindoles with
pyran ring generates pyran annulated spirooxindoles (spi-
ropyrans or spirochromenes), which are also known to
exhibit useful properties like anticoagulant, spasmolytic,
diuretic, anticancer, and antianaphylactic activities [14].
The biological potential of spirochromenes has always been
the driving force for the chemists to develop efficient
protocols for their synthesis.
Classical synthesis of spirochromenes involve one-pot,
three-component condensation between isatin, malono-
nitrile, and enolizable CeH acids like dimedone, barbituric
acid, naphthols, 4-hydroxycoumarin, and so forth, and the
literature is enumerated with several protocols for their
to develop an enviroeconomic and diversity-oriented pro-
tocol for the synthesis of spirochromenes.
2. Results and discussion
Tris-hydroxymethylaminomethane (THAM) (Scheme 1)
is a biodegradable, noncorrosive, physiologically inert, and
thermally stable compound available commercially at
extremely low cost [20a]. It contains an amino and three
primary alcoholic groups and when dissolved in water or
watereethanol medium, it generates basic reaction me-
dium [20b]. In the recent past, we have reported its use as
an efficient organocatalyst in the diversity-oriented syn-
thesis of 2-amino-4H-chromenes by multicomponent
condensation between aldehydes and two different CeH
acids [19b]. In continuation of the same, we report herein
the use of THAM in the diversity-oriented synthesis of
spirochromenes by three-component reaction between
isatins, malononitrile, and dimedone, 4-hydroxycoumarin,
4-hydroxy-N-methylquinolone, and in situ generated 2-
methylpyrazolon-2-one (Scheme 1).
We began our studies with optimization of the reaction
conditions for the synthesis of spiro[indoletetrahy-
drochromene], 4a, as a model spirochromene (Scheme 1).
Accordingly, to an equimolar and well-stirred solution of
isatin, 1a, malononitrile, 2, and dimedone, 3a, (1 mmol
each) in ethanol (95%, 4 mL) was added THAM (30 mol %) as
the catalyst. Stirring was continued at room temperature
and progress of the reaction was monitored by thin layer
chromatography (TLC). Upon completion of the reaction
(4 h), water (5 mL) was added and the resultant solid
product was isolated by simple filtration. On the basis of
physical and spectral studies, resultant product was iden-
tified to be the desired spirochromene, 4a. In pursuance to
make this protocol greener, the model reaction was
synthesis.
A focused literature survey toward envir-
oeconomic protocols developed for the synthesis of spi-
rochromenes revealed that a few catalyst-free protocols
have been reported earlier [15]. Notably all the catalyst-free
protocols developed for the synthesis of spirochromenes
require thermal or electrochemical activation. These re-
ports indirectly project the necessity of a catalyst, an
alternate energy source, or the reaction medium for the
synthesis of spirochromenes at ambient temperature.
During our search on protocols operable at ambient tem-
perature it was noticed that a range of catalysts and reac-
tion media have been reported for their synthesis [16e18].
Each of the reported method has its own merits, whereas a
few of the reported protocols suffer from the drawbacks as
regards the use of expensive or difficult to prepare catalyst
or the reaction medium, and to the best of our knowledge
there are only a few protocols wherein the problems of
economics and environmental protection have been
addressed successfully [18aec]. With our continued inter-
est in the development of organocatalyzed protocols for the
synthesis of chromene-based heterocycles [19], we set out
Fig. 1. Representative structures of biologically active spirooxindoles.
Please cite this article in press as: S.S. Khot, et al., Tris-hydroxymethylaminomethane (THAM): An efficient organocatalyst in
diversity-oriented and environmentally benign synthesis of spirochromenes, Comptes Rendus Chimie (2018), https://doi.org/
10.1016/j.crci.2018.05.005

S.S. Khot et al. / C. R. Chimie xxx (2018) 1e8
3
Scheme 1. Diversity-oriented synthesis of spirochromenes using THAM as the catalyst.
repeated using water and watereethanol (1:1, v/v) as the
reaction media. However, the desired product, 4a, was
obtained in slightly lower yields (76% and 82%, respec-
tively). Further optimization of the reaction conditions
with respect to catalyst loading revealed that with the use
of less than 30 mol % of the catalyst the reaction does not go
to completion. In short, use of THAM (30 mol %) as the
catalyst and ethanol (95%) as the reaction medium was
observed to be the best suited reaction conditions for the
optimum yield of the desired product, 4a. To check the
scope of the reaction conditions, another reaction was
performed by replacing the dimedone component from the
model reaction with 5-methylcyclohexane-1,3-dione, 3b. In
this case too the expected spirochromene, 4g, resulted in
excellent yield. To examine the generality of the reaction
conditions, various substituted isatins were then allowed to
undergo reaction with malononitrile and dimedone 3a as
well as 3b. In all the cases, corresponding spirochromenes,
4bei, were obtained in excellent yield following simple
workup procedure. Most gratifyingly, they were noticed to
be pure for all analytical purposes.
[indole-pyrano[3,2-c]chromene], 6a, and spiro[indole-pyr-
ano[3,2-c]quinolone], 8a, respectively. The salient objective
to undertake this extension was associated with the anti-
rheumatic and anticancer activity associated with the
compounds containing pyrano[3,2-c]chromene and pyrano
[3,2-c]quinolone as the structural units [21].
Using reaction conditions established for the synthesis
of 4a, two model reactions were performed using isatin,
malononitrile, and 5, or 7, as the substrates (Scheme 1).
Most gratifyingly, both the reactions proceeded smoothly
(TLC) and the desired spirochromene, 6a, and spiroquino-
line, 8a, were obtained in decent yields. Under the same
reaction conditions, various substituted isatins were also
reacted with malononitrile and 4-hydroxycoumarin as well
as 4-hydroxy-N-methylquinolin-2-one when correspond-
ing spirooxindole derivatives, 6bef and 8beg, were ob-
tained in good to excellent yields (Table 1).
Similar to pyrano[3,2-c]chromene and pyrano[3,2-c]
quinolone, dihydropyrano[2,3-c]pyrazole represents an
interesting template in medicinal chemistry and several
compounds containing dihydropyrano[2,3-c]pyrazole as
the structural motif are known to possess antimicrobial
[22a], anti-inflammatory [22b], and molluscicidal activity
[22c]. Our earlier success in the synthesis of spiro[indole-
pyrano[3,2-c]chromenes], 6, and spiro[indole-pyrano[3,2-
c]quinolones], 8, prompted us to extend our studies toward
the synthesis of spiro[indoline-3,40-pyrano[2,3-c]pyrazol]-
2-ones, 10. A literature pursuance revealed that there are
few early reports on the synthesis of title compounds,
10, involving the reaction between isatin, malononitrile,
From the plausible mechanism (Scheme 2), it is
apparent that the enolic form of cyclic-1,3-dione is actually
involved in the generation of
a pyran ring in spi-
rochromenes. On the basis of this hypothesis we surmised
that 4-hydroxycoumarin, 5, and 4-hydroxy-N-methyl-
quinolin-2-one,
7 (Scheme 1), being enolic forms of
coumarin-2,4-dione and N-methylquinolin-2,4-dione,
respectively, the replacement of dimedone component
used in the synthesis of 4a by 5 and 7 would furnish spiro
Please cite this article in press as: S.S. Khot, et al., Tris-hydroxymethylaminomethane (THAM): An efficient organocatalyst in
diversity-oriented and environmentally benign synthesis of spirochromenes, Comptes Rendus Chimie (2018), https://doi.org/
10.1016/j.crci.2018.05.005

4
S.S. Khot et al. / C. R. Chimie xxx (2018) 1e8
Scheme 2. Plausible mechanism for the formation of spirochromenes.
and 2-methylpyrazolon-2-one [23]. In all these methods,
necessary 2-methylpyrazolon-2-one was generated in situ
at ambient temperature by the reaction between a b-keto
protocol is superior to most of the earlier reported pro-
tocols in terms of operational simplicity, yield, cost, easy
availability, and environmental compatibility of the catalyst
used.
ester and hydrazine hydrate under catalyst-free condition.
Taking recourse to these reports, a pseudo four-component
reaction was carried out between isatin, malononitrile,
ethyl acetoacetate, and hydrazine hydrate (1 mmol, each),
using the reaction conditions established for the synthesis
of spirochromenes, 4 (Scheme 1). The reaction proceeded
smoothly and upon its completion, desired spiro[indoline-
3,40-pyrano-[2,3-c]pyrazol]-2-one, 10a, was obtained in
decent yield. Subsequent reactions of substituted isatins
with malononitrile and in situ generated 2-
methylpyrazolon-2-one, 9, also furnished expected spiro
[indoline-3,40-pyrano[2,3-c]pyrazol]-2-ones, 10bee, in
decent yields (Table 1). Noteworthy feature of the protocol
developed for the synthesis of spirochromenes 4, 6, 8, and
10 is that all the products were isolated by a simple pro-
cedure and none of them required chromatographic
purification.
After establishing a general protocol for the diversity-
oriented synthesis of spirochromenes from environmental
point of view, it was quite logical to check the possibility of
reuse of the catalyst. However, the catalyst, THAM, being
soluble in water, it was surmised that making this nontoxic
and biodegradable catalyst reusable would certainly be
more expensive than the cost of the catalyst itself. Thus, no
attempts were made to check reusability of the catalyst.
Finally, a comparison was made between the present pro-
tocol and many other protocols reported earlier for the
synthesis of 4a as a model compound. From the results
summarized in Table 2, it is evident that the developed
3. Conclusion
We have demonstrated for the first time the use of a
commercially available and biodegradable THAM as an
efficient organocatalyst in diversity-oriented synthesis of
spirochromenes. The protocol mainly exhibits remarkable
versatility on various substrates to afford the desired
products in good to excellent yields. Ambient reaction
conditions, simple workup procedure, and avoidance of
conventional purification methods have improved the
practical utility of the protocol manifold.
4. Experimental section
4.1. General procedure for the synthesis of spirooxindoles, 4,
6, 8 and 10
To a well-stirred solution of isatin and malononitrile
(1 mmol each) in ethanol (95%, 4 mL) was added dimedone,
4-hydroxycoumarin, 4-hydroxy-N-methylquinolin-2-one,
or 2-methyl-pyrazol-2-one [generated in situ from ethyl
acetoacetate and hydrazine hydrate, 1 mmol each]. To this
solution was added THAM (30 mol %) and stirring was
continued at ambient temperature. Upon completion of the
reaction (TLC), water (5 mL) was added and stirring was
continued for 10 min more. Resultant solid product was
filtered, washed repeatedly with water, and dried. The
Please cite this article in press as: S.S. Khot, et al., Tris-hydroxymethylaminomethane (THAM): An efficient organocatalyst in
diversity-oriented and environmentally benign synthesis of spirochromenes, Comptes Rendus Chimie (2018), https://doi.org/
10.1016/j.crci.2018.05.005

S.S. Khot et al. / C. R. Chimie xxx (2018) 1e8
5
Table 1
THAM catalyzed diversity-oriented synthesis of spirochromenes.a
Entry
Isatin (1)
CeH acid (3)
Product
Time (h)
Yield (%)
Reference
R
R1
R2
1
2
3
4
5
6
7
8
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
Me
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
H
Cl
Br
H
H
H
H
H
H
Cl
Br
H
H
H
H
H
3a
3a
3a
3a
3a
3a
3b
3b
3b
3c
3c
3c
3c
3c
3c
3c
3c
3d
3d
3d
3d
3d
3d
3d
3e
3e
3e
3e
3e
4a
4b
4c
4d
4e
4f
4g
4h
4i
6a
6b
6c
6d
6e
6f
6g
6h
8a
8b
8c
8d
8e
8f
8g
10a
10b
10c
10d
10e
4
4
3.5
4
3
3.5
3
3.5
3
4
4
4
5
3
4
3
4
4
4
4.5
4
3
4
3.5
4
4
5
3
4
94
84
86
82
92
89
92
83
95
87
90
85
80
94
91
93
89
86
90
87
84
92
90
87
84
87
83
92
86
[18c]
[17b]
[18c]
[18c]
[17g]
e
F
NO2
Br
H
Cl
NO2
H
Cl
Me
F
NO2
H
Br
Br
H
Cl
Me
F
NO2
H
Br
H
H
Cl
Br
NO2
e
e
9
e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
[18c]
[18c]
[16f]
[17a]
[18c]
e
e
[18c]
[16d]
e
e
e
e
e
e
[18c]
[17g]
[17g]
[16f]
[17g]
All the products gave satisfactory spectral data.
a
Reaction conditions: isatin, malononitrile, and enolizable CeH acid (1 mmol each), THAM (30 mol %), ethanol (95%, 4 mL), rt.
dried solid was washed thrice with hexaneechloroform
mixture (1:1, v/v) and dried again. Resultant product did
not require any further purification.
2-Amino-20,5-dioxo-7-methyl-5,6,7,8-tetrahydrospiro
[chromene-4,30-indoline]-3-carbonitrile, 4g: white solid; mp
> 280 ꢀC; IR (KBr): 3364, 2192, 1721 cmꢁ1; 1H NMR (DMSO-
d6, 300 MHz):
d
1.01 (d, 3H, J ¼ 5.1 Hz), 2.05 (m, 1H), 2.24 (t,
2H, J ¼ 15 Hz), 2.64 (t, 2H, J ¼ 18.3 Hz), 6.78 (d, 1H, J ¼
7.2 Hz), 6.88 (d, 1H, J ¼ 7.3 Hz), 6.94 (m, 1H), 7.12 (t, 1H, J ¼
7.5 Hz), 7.19 (br s, 2H), 10.40 (s, 1H); 13C NMR (DMSO-d6,
4.2. Spectral data of new compounds
2-Amino-50,70-dibromo-8,8-dimethyl-20,5-dioxo-5,6,7,8-
tetrahydrospiro[chromene-4,30-indoline]-3-carbonitrile, 4f:
75 MHz):d 20.50, 27.81, 34.68, 34.92, 44.78, 47.31, 58.92,
109.61, 111.86, 112.07, 117.75, 122.02, 123.45, 123.57, 128.51,
134.93, 142.47, 159.14, 165.24, 165.79, 178.6, 195.3 ppm.
2-Amino-20,5-dioxo-70-chloro-7-methyl-5,6,7,8-tetrahydro-
spiro[chromene-4,30-indoline]-3-carbonitrile, 4h:ꢁw1hite solid;
white solid; mp > 280 ꢀC; IR (KBr): 3357, 2197, 1732 cmꢁ1
;
1H NMR (DMSO-d6, 300 MHz):
d
1.03 (d, 6H, J ¼ 2.4 Hz), 2.14
(s, 2H), 2.52 (d, 2H, J ¼ 7.2 Hz), 6.78 (d, 1H, J ¼ 8.1 Hz), 6.95
(s, 1H), 7.09 (br s, 2H), 10.47 (s, 1H); 13C NMR (DMSO-d6,
mp > 280 ꢀC; IR (KBr): 3342, 2202, 1736 cm
;
1H NMR
75 MHz):
d 27.89, 28.04, 32.32, 47.57, 50.54, 57.48, 110.86,
(DMSO-d6, 300 MHz):
1H), 2.24e2.36 (m, 2H), 2.26 (d, 2H, J ¼ Hz), 6.76 (d, 1H, J ¼
d
1.03 (d, 3H, J ¼ 6 Hz), 2.01e2.08 (m,
110.96, 117.43, 123.49, 126.38, 128.31, 136.57, 141.35, 159.30,
164.68, 178.23, 195.08 ppm.
Please cite this article in press as: S.S. Khot, et al., Tris-hydroxymethylaminomethane (THAM): An efficient organocatalyst in
diversity-oriented and environmentally benign synthesis of spirochromenes, Comptes Rendus Chimie (2018), https://doi.org/
10.1016/j.crci.2018.05.005

6
S.S. Khot et al. / C. R. Chimie xxx (2018) 1e8
Table 2
Comparison of THAM catalyzed synthesis of 4a with earlier reported protocols.
Entry
Catalyst
Solvent
Time
Yield (%)
Reference
1
2
3
4
5
6
7
8
Fe3O4@APTPOSS MNPs
Sulfated choline-based heteropolyanion
Fe2O3 NPs@SiO2@vitB1-Npa
EDDFb in PEG 600
Cesium fluoride
Nickel oxide nanoparticles
[Bmim]OH
e
45 h
45 h
10 h
12 h
5 h
5 h
10 h
7 h
10 h
1 min
2 h
5 h
3 h
2.5 h
10 h
8 min
18 min
15 min
4 h
88
91
98
91
82
98
96
91
96
84
92
98
94
97
95
98
96
95
94
[17a]
[16a]
[17b]
[16b]
[17c]
[17e]
[16f]
Ethanol
)))), water
SF
Ethanol
Water
[Bmim]OH
Water
Water
SF
WatereEtOH
SF
SF
EtOH
Water
EtOH
Amino-appended
b-cyclodextrin
[17h]
[17f]
9
(DABCO)@mesoporous silica SBA-15
ZrO2 nanoparticles
Trisodium citrate trihydrate
Protic guanidinium ionic liquid
[Bmim]BF4
(Silica-bonded DBU) Cl
FeN3@SiO2 nanoparticles
CuO nanoparticles
10
11
12
13
14
15
16
17
18
18
[17g]
[18c]
[16c]
[16d]
[17j]
[17d]
[16e]
[18a]
[18b]
This work
Meglumine
EtOH
EtOH
EtOH
Sodium acetatec
THAM
a
Ultrasound.
EDDF: ethylenediammonium diformate.
Grinding.
b
c
8.1 Hz), 6.95 (d,1H, J ¼ 4.5Hz), 7.08(s,1H), 7.12 (brs,2H),10.46
(s, 1H); 13C NMR (DMSO-d6, 75 MHz):
20.51, 20.66, 27.71,
d 29.69, 48.65, 57.75, 106.97, 109.68, 112.76, 115.50, 117.89,
d
122.15, 122.87, 123.88, 128.77, 132.72, 134.74, 139.14, 142.97,
151.96, 159.22, 159.36,178.29 ppm.
27.89, 44.87, 47.60, 58.92, 110.89, 111.48, 123.50, 123.62,
126.46, 128.25, 141.17, 159.21, 165.50, 178.31, 195.08 ppm.
2-Amino-20,5-dioxo-7-methyl-70-nitro-5,6,7,8-tetrahydro-
spiro[chromene-4,30-indoline]-3-carbonitrile, 4i:ꢁw1hite solid;
2-Amino-6-methyl-50-chloro-20,5-dioxo-5,6-dihydro-
spiro[pyrano[3,2-c]quinoline-4,30-indoline]-3-carbonitrile,
8b: brown color solid; mp > 280 ꢀC; IR (KBr):3417, 2192,
mp > 280 ꢀC; IR (KBr): 3365, 2199, 1726 cm
;
1H NMR
1717, 1670 cmꢁ1 1H NMR (DMSO-d6, 300 MHz):
; d 3.49 (s,
(DMSO-d6, 300 MHz):
(m, 4H), 6.71e7.18 (m, 5H), 10.44 (s, 1H); 13C NMR (DMSO-
d6, 75 MHz): 20.55, 27.90, 35.15, 58.92, 111.42, 114, 126.31,
d
1.02 (s, 3H), 2.00 (s, 1H), 2.24e2.56
3H), 6.80e6.84 (m, 1H), 7.00e7.05 (m, 1H), 7.41e7.46 (m,
1H), 7.53e7.60 (m, 3H), 7.37e7.8 (m, 1H), 8.04 (d, 1H, J ¼
d
7.8 Hz), 10.56 (s, 1H); 13C NMR (DMSO-d6, 75 MHz):
d 29.72,
131.10, 159.17, 165.80, 178.24, 195.32 ppm.
49.17, 57.19, 106.41, 110.21, 110.32, 111.71, 112.82, 115.09,
115.51, 117.81, 122.89, 122.94, 132.77, 136.38, 136.48, 139.20,
152.17, 159.28, 159.46, 178.38 ppm.
20-Amino-7-chloro-2,50-dioxo-50H-spiro[indoline-3,40-
pyrano[3,2-c]chromene]-30-carbonitrile, 6f: off-white solid;
mp > 280 ꢀC; IR (KBr): 3361, 2197,1737 cmꢁ1
;
1H NMR
2-Amino-6-methyl-50-methyl-20,5-dioxo-5,6-dihydro-
spiro[pyrano[3,2-c]quinoline-4,30-indoline]-3-carbonitrile,
8c: off-white solid; mp > 280 ꢀC; IR (KBr):3420, 2192,
(DMSO-d6, 300 MHz):
¼ 9.3 Hz), 7.54 (q, 2H, J ¼ 8.4 Hz), 7.77 (s, 3H), 7.95 (d,1H, J ¼
6.9 Hz), 11.15 (s, 1H); 13C NMR (DMSO-d6, 75 MHz):
19.00,
d
6.97 (t, 1H, J ¼ 7.8 Hz), 7.26 (q, 2H, J
d
1721,1660 cmꢁ1 1H NMR (DMSO-d6, 300 MHz):
; d 3.19 (s,
48.95, 56.50, 56.97, 101.40, 112.89, 114.20, 117.19, 117.28,
123.21, 123.40, 123.85, 125.54, 129.48, 134.28, 135.21,
140.43, 152.56, 155.73, 158.87, 158.99, 177.66 ppm.
3H), 3.46 (s, 3H), 6.93e7.09 (m, 3H), 7.08 (s,1H), 7.28 (t,1H, J
¼ 7.5 Hz), 7.45 (t, 1H, J ¼ 7.5 Hz), 7.52 (s, 2H), 7.58 (d, 1H, J ¼
8.7 Hz), 7.76 (t, 1H, J ¼ 7.2 Hz), 8.08 (d, 1H, J ¼ 7.5 Hz); 13
C
20-Amino-5,7-dibromo-2,50-dioxo-50H-spiro[indoline-3,40-
pyrano[3,2-c]chromene]-30-carbonitrile, 6g: white solid;
NMR (DMSO-d6, 75 MHz): d 26.94, 29.73, 48.26, 57.33,
106.85, 108.60, 112.74, 115.56, 117.77, 122.90, 123.65, 129.01,
132.08, 133.86, 139.15, 144.45, 151.99, 159.17, 159.47,
176.84 ppm.
mp > 280 ꢀC; IR (KBr): 3361, 2205, 1734 cmꢁ1 1H NMR
;
(DMSO-d6, 300 MHz):
¼ 10.8 Hz), 7.78 (d,1H, J ¼ 7.5 Hz), 7.83 (s, 2H), 7.94 (d,1H, J ¼
7.8 Hz), 11.19 (s, 1H); 13C NMR (DMSO-d6, 75 MHz):
19.00,
d
7.54 (q, 2H, J ¼ 8.4 Hz), 7.65 (d, 2H, J
2-Amino-6-methyl-50-fluoro-20,5-dioxo-5,6-dihydro-spiro
d
[pyrano[3,2-c]quinoline-4,30-indoline]-3-carbonitrile,
8d:
off-white solid; mp > 280 ꢀC; IR (KBr): 3416, 2197, 1721,
1670 cmꢁ1 1H NMR (DMSO-d6, 300 MHz):
3.49 (s, 3H),
49.40, 56.49, 100.86, 103.07, 113.04, 114.77, 117.19, 117.24,
123.27, 125.52, 127.11, 143.09, 134.29, 136.84, 141.74, 152.60,
156.04, 159.05, 159.09, 177.37 ppm.
;
d
6.85 (d, 1H, J ¼ 7.8 Hz), 7.21 (d, 2H, J ¼ 7.8 Hz), 7.44 (t,1H, J ¼
7.5 Hz), 7.58 (t, 3H, J ¼ 9.9 Hz), 7.76 (t,1H, J ¼ 7.5 Hz), 8.06 (d,
1H, J ¼ 7.8 Hz), 10.67 (s, 1H); 13C NMR (DMSO-d6, 75 MHz):
2-Amino-6-methyl-20,5-dioxo-5,6-dihydro-spiro[pyrano
[3,2-c]quinoline-4,30-indoline]-3-carbonitrile, 8a: yellowꢁis1h
ꢀ
solid; mp > 280 C; IR (KBr): 3420, 2199, 1721, 1675 cm
;
d 29.75, 48.94, 57.02, 106.27, 111.03, 112.86, 115.53, 117.81,
1H NMR (DMSO-d6, 300 MHz):
d
3.48 (s, 3H), 6.84e7.00 (m,
122.91, 122.97, 124.21, 126.16, 128.66, 132.78,136.78, 139.21,
141.93, 152.25, 159.30, 159.49, 178.14 ppm.
2H), 7.02 (d, 1H, J ¼ 7.2 Hz), 7.17 (t, 1H, J ¼ 7.4 Hz), 7.46 (s,
3H), 7.59 (d, 1H, J ¼ 8.7 Hz), 7.76 (t, 1H, J ¼ 4.5 Hz), 8.06 (d,
1H, J ¼ 7.8 Hz), 10.52 (S, 1H); 13C NMR (DMSO-d6, 75 MHz):
2-Amino-6-methyl-50-nitro-20,5-dioxo-5,6-dihydro-spiro
[pyrano[3,2-c]quinoline-4,30-indoline]-3-carbonitrile,
8e:
Please cite this article in press as: S.S. Khot, et al., Tris-hydroxymethylaminomethane (THAM): An efficient organocatalyst in
diversity-oriented and environmentally benign synthesis of spirochromenes, Comptes Rendus Chimie (2018), https://doi.org/
10.1016/j.crci.2018.05.005

S.S. Khot et al. / C. R. Chimie xxx (2018) 1e8
7
off-white solid; mp > 280 ꢀC; IR (KBr): 3430, 2192, 1730,
1665, 1520, 1337 cmꢁ1 1H NMR (DMSO-d6, 300 MHz):
(c) G. Brahmachari (Ed.), Green Synthetic Approaches for Biologi-
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402860;
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(b) S. Servi, Synthesis 1 (1990) 1e25.
;
d
3.48 (s, 3H), 7.07 (d, 1H, J ¼ 8.4 Hz), 7.46 (t, 1H, J ¼ 7.5 Hz),
7.59 (d, 1H, J ¼ 8.4 Hz), 7.67 (s, 2H), 7.77 (t, 1H, J ¼ 7.5 Hz),
8.07 (d, 2H, J ¼ 8.7 Hz), 8.17 (d, 1H, J ¼ 8.7 Hz), 11.29 (s, 1H);
13C NMR (DMSO-d6, 75 MHz):
d 29.79, 48.83, 56.19, 105.71,
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109.82, 112.91, 115.59, 117.70, 119.94, 123, 123.06, 126.33,
132.90, 135.78, 139.26, 142.98, 149.51, 152.60, 159.39,
159.74, 179 ppm.
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Green Chem. 18 (2016) 6215e6221.
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2-Amino-6-methyl-70-chloro-20,5-dioxo-5,6-dihydro-
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8f: brown colored solid; mp > 280 ꢀC; IR (KBr):3370, 2200,
1724, 1674 cmꢁ1 1H NMR (DMSO-d6, 300 MHz):
; d 3.49 (s,
3H), 6.90 (t, 1H, J ¼ 7.8 Hz), 7.03 (d, 1H, J ¼ 7.2 Hz), 7.24 (d,
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(e) B. Yu, D.Q. Yu, H.M. Liu, Eur. J. Med. Chem. 97 (2015) 673e698;
(f) B.E. Evans, K.E. Rittle, M.G. Bock, R.M. DiPardo, R.M. Freidinger,
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Eur. J. Med. Chem. 46 (2011) 1181e1188.
(DMSO-d6, 75 MHz):
d 29.75, 49.51, 57.11, 106.47, 112.71,
113.97, 115.59, 117.76, 122.66, 122.93, 123, 123.48, 128.90,
132.88, 136.46, 139.18, 140.72, 152.06, 159.26, 159.44,
178.32 ppm.
2-Amino-6-methyl-50,70-dibromo-20,5-dioxo-5,6-dihydro-
spiro[pyrano[3,2-c]quinolone-4,30-indoline]-3-carbonitrile,
8g: off-white solid; mp > 280 ꢀC; IR (KBr): 3455, 3260,
2200, 1723, 1671 cmꢁ1 1H NMR (DMSO-d6, 300 MHz):
;
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299e344;
d
3.50 (s, 3H), 7.42e7.48 (m, 2H), 7.63 (d, 4H, J ¼ 5.7 Hz),
7.77 (t, 1H, J ¼ 7.5 Hz), 8.06 (d, 1H, J ¼ 7.8 Hz), 11.03 (s, 1H);
13C NMR (DMSO-d6, 75 MHz):
29.81, 50.02, 56.50, 56.54,
(b) M.M.M. Santos, Tetrahedron 70 (2014) 9735e9757 and refer-
ences cited therein.
d
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G.I. Nikishin, Mendeleev Commun. 22 (2012) 143e144;
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Chem. 14 (2012) 1696e1704;
102.85, 105.90, 112.86, 114.38, 115.61, 117.72, 123.03, 126.29,
132.92, 133.50, 138.21, 139.25, 142.05, 152.34, 159.34,
159.57, 178.01 ppm.
(d) T. Ponpandian, S. Muthusubramanian, Synth. Commun. 44
(2014) 868e874;
(e) M.N. Elinson, A.I. Ilovaisky, A.S. Dorofeev, V.M. Merkulova,
N.O. Stepanov, F.M. Miloserdov, Y.N. Ogibin, G.I. Nikishin, Tetrahe-
dron 63 (2007) 10543e10548.
Acknowledgments
U.V.D. and S.S.K. thank UGC, New Delhi, for the financial
support [F. 43-221/2014 (SR)]. The authors are thankful to
M/s B. J. Corporation, Kolhapur, for the generous gift of 4-
hydroxy-N-methylquinolin-2-one.
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5693e5699;
Appendix A. Supplementary data
(e) L. Moradi, Z. Atei, Green Chem. Lett. Rev. 4 (2017) 380e384;
(f) S.A. Padvi, Y.A. Tayade, Y.B. Wagh, D.S. Dalal, Chin. Chem. Lett. 27
(2016) 714e720.
Supplementary data related to this article can be found
at https://doi.org/10.1016/j.crci.2018.05.005.
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diversity-oriented and environmentally benign synthesis of spirochromenes, Comptes Rendus Chimie (2018), https://doi.org/
10.1016/j.crci.2018.05.005