Tris-hydroxymethylaminomethane (THAM): A novel organocatalyst for a environmentally benign synthesis of medicinally important tetrahydrobenzo[b]pyrans and pyran-annulated heterocycles

Article abstract of DOI:10.1039/c4nj02346c

A simple, efficient and environmentally benign protocol has been developed for the one-pot, multicomponent synthesis of medicinally important tetrahydrobenzo[b]pyrans and pyran-annulated heterocycles using a commercially available, inexpensive, non-toxic, and biodegradable tris-hydroxymethylaminomethane (THAM) as a novel organocatalyst. Ambient reaction conditions, wide scope, avoidance of conventional isolation as well as purification techniques and the reusability of the catalyst for five consecutive runs have improved the practical utility of this multicomponent reaction protocol manifold.

Full text of DOI:10.1039/c4nj02346c

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Tris-hydroxymethylaminomethane (THAM): a
novel organocatalyst for a environmentally
benign synthesis of medicinally important
tetrahydrobenzo[b]pyrans and pyran-annulated
heterocycles†
Cite this:DOI: 10.1039/c4nj02346c
Kapil S. Pandit,a Pramod V. Chavan,a Uday V. Desai,*a Makarand A. Kulkarnia and
Prakash P. Wadgaonkarb
A simple, efficient and environmentally benign protocol has been developed for the one-pot, multicomponent
synthesis of medicinally important tetrahydrobenzo[b]pyrans and pyran-annulated heterocycles using a
commercially available, inexpensive, non-toxic, and biodegradable tris-hydroxymethylaminomethane (THAM)
as a novel organocatalyst. Ambient reaction conditions, wide scope, avoidance of conventional isolation as
well as purification techniques and the reusability of the catalyst for five consecutive runs have improved the
practical utility of this multicomponent reaction protocol manifold.
Received (in Montpellier, France)
18th December 2014,
Accepted 18th March 2015
DOI: 10.1039/c4nj02346c
www.rsc.org/njc
a novel catalyst in the environmentally benign synthesis of com-
pounds with biological and pharmaceutical importance is a con-
Introduction
The first multicomponent reaction was reported by Strecker in stant endeavour.
1853 for the synthesis of a-amino acids.1 Since then, for more
A literature survey within the framework of organic com-
than a century or so, the field of multicomponent synthesis pounds with pharmaceutical importance revealed that 2-amino-
appeared dormant, but more recently the last two decades have 4H-chromenes with amino and nitrile functions at the 2 and
witnessed spectacular developments in this field.2,3 These develop- 3 positions, respectively (A, Fig. 1) are known to possess diverse
ments were mainly aimed either at the design of new multi- pharmaceutical properties, such as cytotoxic, myorelaxant, anti-
component reactions or towards making improvements in oxidant, anti-bacterial, anti-proliferative, anti-microbial, anti-HIV,
existing methodologies for known multicomponent reactions. anti-rheumatic, anti-cancer activities, etc. (Fig. 1).6a–h Many
With today’s growing concern over environmental protection compounds containing 2-amino-3-cyano-4H-chromene as the
and with the knowledge that the multicomponent reactions can structural unit also find application as cognitive enhancers in
provide an easy access to the library synthesis of structurally the treatment of neurodegenerative diseases like Alzheimer’s as
related drug like molecules, interest in the development of well as for Parkinson’s disease.7 Apart from their medicinal
environmentally benign and diversity oriented multicomponent importance, compounds belonging to this class are customarily
synthesis has become the focal point of much present day used in the field of cosmetics8 and agrochemicals,9 as well as
research.4,5 In this context, the selection of an alternate reaction with dyes.10 Owing to there being such a wide range of applica-
medium, energy source and the catalyst is known to play a very tions, the development of an efficient protocol for the synthesis
significant role. Although the choice of reaction medium, as well of compounds containing 2-amino-3-cyano-4H-chromene as the
as the energy source has some limitations, there are no boundaries structural motif is highly desirable.
on the selection of the catalyst. Thus, a wide variety of homo-
It is well known that the synthesis of 2-amino-3-cyano-4H-
geneous as well as heterogeneous catalysts have been successfully chromenes involves a one-pot, three-component condensation
used in many multicomponent reactions. However, the search for between aldehyde, malononitrile and an enolizable C–H acid,
such as dimedone, barbituric acid, naphthol (a and b), 4-hydroxy
coumarin, resorcinol, 2-hydroxy-1,4-naphthoquinone, Kojic acid,
a Department of Chemistry, Shivaji University, Kolhapur - 416004, India.
etc., and, furthermore, it is known to proceed via a Knoevenagel-
E-mail: uvdchem2011@gmail.com
b Polymer Science and Engineering Division, CSIR, National Chemical Laboratory,
carba-Michael–Thorpe–Ziegler type cascade pathway.3d As
Knoevenagel–Michael cascade reactions can be effectively carried
Pune – 411008, India
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nj02346c out using basic catalysts, a variety of bases, such as Et3N,
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Scheme 1 Diversity oriented synthesis of 2-amino-4H-chromenes using
THAM as the catalyst.
tris-hydroxymethylaminomethane (THAM) (Fig. 2B), which con-
tains an amino and three alcoholic groups, is structurally related to
meglumine and, like meglumine, it is physiologically inert, bio-
degradable, non-corrosive, and is available commercially at
extremely low cost.16 Customarily, it is used as an excipient in
pharmaceutical preparations17a or in the analysis of pharma-
ceuticals,17b and when dissolved in water it generates a basic
reaction medium.17a All these features associated with THAM
and our continued interest in the development of green synthetic
methodologies18 prompted us to examine the potential of THAM
as a basic catalyst. As an outcome of this philosophy, herein, we
describe the use of tris-hydroxymethylaminomethane (THAM) as
a novel organocatalyst in a diversity-oriented synthesis of a few
medicinally important 2-amino-4H-chromenes at ambient tem-
perature (Scheme 1).
Fig. 1 Selected, medicinally important 2-amino-3-cyano-4H-chromenes.
piperidine, K2CO3, K3PO4, (NH3)2HPO4, Mg–Al hydrotalcite,
DBU, KF–Al2O3, chitosan, basic ionic liquids, hexamethylene-
tetramine, electro generated bases,11a–l etc., have been reported
for their synthesis. In addition, their synthesis has also been
reported using heteropolyacids12 or Bronsted acids,13 as well as
by using surfactants as the catalysts.14a–d At this stage, it is worth
noting that most of these catalysts have been demonstrated to
be useful in the synthesis of a particular type of 2-amino-4H-
chromene. On the other hand, in recent years, substances like
4-dimethylaminopyridine (DMAP), urea, imidazole, potassium
phthalimide-N-oxyl, meglumine, and ethylenediammonium-
diformate, as well as clinoptilolite, have been reported as efficient
catalysts in the synthesis of structurally diverse 2-amino-4H-
chromenes.15a–g Although most of these catalysts are efficient,
we believe there certainly exists scope for the introduction of a
novel catalyst for the synthesis of medicinally significant 2-amino-
4H-chromenes.
Our contribution towards the introduction of a novel catalyst
is concerned with the structure, as well as the reactivity, of a
recently reported organocatalyst, namely meglumine (Fig. 2A).15e
As regards the choice of meglumine, the presence of a second-
ary amino and four hydroxyl groups have been described as
playing a significant role in the library synthesis of 2-amino-
4H-chromenes.15e Thinking along this line, we envisaged that
Results and discussion
To begin with, the one-pot synthesis of tetrahydrobenzo[b]-
pyran, 4a, was performed, whereby, to an equimolar and well-
stirred solution of anisaldehyde, malononitrile and dimedone
(1 mmol, each) in ethanol was added THAM (10 mol%). Stirring
was continued at room temperature and the progress of the
reaction was monitored by TLC. The product resulted after
two hours and was identified to be a mixture of Knoevenagel
condensation products, namely benzylidene malononitrile and
the desired 2-amino-3-cyano-4H-chromene, 4a, in nearly a 1 : 1
proportion. An increase in the stirring time did not show any
appreciable change in the proportion of the resultant products.
Taking clues from these results, we next optimized the reaction
conditions to obtain, 4a, exclusively. In this context, the effects
of catalyst loading on the course of the reaction were initially
examined. With an increase in the amount of catalyst loading,
a gradual increase in the yield of the desired product, 4a,
was noticed. However, it was not obtained as an exclusive
Fig. 2 (A) Meglumine, (B) tris-hydroxymethylaminomethane.
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Table 1 Optimization of the reaction conditions for the synthesis of 4a,
using THAM as the catalysta
protocol greener and economical, it was found that, water–
ethanol (1 : 1, v/v) as the medium gave the desired product, 4a,
in almost same yield.
Encouraged by this initial success, we next planned to
examine the generality of the reaction conditions. Accordingly,
aromatic aldehydes tethered with electron-withdrawing, as well
as electron-donating, groups and a few heteroaromatic alde-
hydes were allowed to react with malononitrile and dimedone
under the established reaction conditions. In all the cases, the
corresponding tetrahydrobenzo[b]pyran derivatives, 4b–k, were
obtained in excellent yields, as well as in high purity (TLC,
NMR) (Table 2); although, aliphatic aldehydes failed to furnish
the respective pyran derivatives in an acceptable yield. Most of
the synthesized compounds being known compounds were
characterized by comparison of their melting points with those
reported earlier, as well as by spectral methods (IR, H-NMR).
A plausible mechanism for the formation of tetrahydrobenzo-
[b]pyrans is depicted in Scheme 2.
After our initial success, based upon the plausible mecha-
nism (Scheme 2), we envisaged that 4-hydroxycoumarin, 5, and
4-hydroxyquinolin-2-one, 6, (Scheme 1) being structurally
analogous to the enolized form of dimedone (A, Scheme 2),
Sr. no. Catalyst (mol%) Reaction medium (v/v) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
—
10
10
10
20
30
30
30
30
30
30
20
10
EtOH
—
EtOH
EtOH
EtOH
EtOH
H2O
EtOH : H2O (9 : 1)
EtOH : H2O (8 : 2)
EtOH : H2O (7 : 3)
EtOH : H2O (1 : 1)
EtOH : H2O (1 : 1)
EtOH : H2O (1 : 1)
4
2
2
4
2
2
4
2
—
80c
50c
60
60
70
85d
85
87
90
91
80
70
9
2
10
11
12
13
1.5
1.5
2
1
2
a
Reaction conditions: anisaldehyde, malononitrile and dimedone
b
c
(1 mmol, each), catalyst, solvent. Isolated yield. Benzylidene malono-
nitrile. Sticky solid.
d
product (Table 1). During the studies on the effect of the replacement of the dimedone component employed in the
reaction medium, it was truly gratifying to notice an appreci- synthesis of, 4, by either, 5 or 6, could be expected to furnish
able increase in the yield of the desired product, 4a with the 2-amino-3-cyano-pyrano[3,2-c]chromen-5(4H)ones, 7, or 2-amino-3-
choice of water as the reaction medium. However, the product cyano-pyrano[3,2-c]quinolin-2-ones, 8, respectively (Scheme 1, B).
was obtained as a sticky solid. Hence, subsequent optimization
A literature survey revealed that, pyrano[3,2-c]chromenes, 7,
of the reaction conditions was confined towards the selection are known to possess anti-rheumatic activities, and a useful
of the optimum ethanol–water proportion, and during these number of protocols have been reported for their synthesis.19a–e
studies we affirmed that, with the use of a water–ethanol medium On the other hand, despite early reports on the potential of
(7: 3, v/v), the desired product, 4a, resulted as a free-flowing solid pyrano[3,2-c]quinolones, 8, as anticancer agents, reports on their
in an excellent yield (Table 1). In pursuance of making this synthesis are scanty.20 In light of these observations, we examined
Table 2 THAM catalyzed synthesis of tetrahydrobenzo[b]pyrans, 4a
Melting point (1C)
Entry
Aldehyde (1)
Product
Time (h)
Yieldb (%)
Obs.
Lit.(ref.)
1
2
3
4
5
6
7
8
4-Methoxybenzaldehyde
4-Isopropylbenzaldehyde
3-Nitrobenzaldehyde
4-Cyanobenzaldehyde
4-Methylbenzaldehyde
3,4-Dimethoxybenzaldehyde
4-Hydroxybenzaldehyde
4-Bromobenzaldehyde
3,4,5-Trimethoxybenzaldehyde
4-Allyloxybenzaldehyde
Thiophene-2-carbaldehyde
Indole-3-carbaldehyde
Cyclohexanecarbaldehyde
Piperonal
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
1.5
1.5
2.0
1.5
1.5
2.0
1.5
1.5
1.5
2.0
1.5
2.0
2.0
1.5
4.0
91
86
91
91
87
83
85
87
84
87
88
81
83
89
50
196–198
204–206
214–216
224–226
217–219
172–174
222–224
205–208
208–210
218–220
208–210
180–182
208–210
226–228
170–172
201—20315h
198–20011d
212–21415h
227–23011d
220–22215h
170–17327b
224–22615h
205–20715b
208–21015b
223–22527a
209–21115h
185–18614d
209–21111e
224–22614d
174–17615b
9
10
11
12
13
14
15
n-Butyraldehyde
a
b
Reaction conditions: aldehyde, malononitrile and dimedone (1 mmol, each), THAM (30 mol%), water–ethanol (1 : 1, v/v), RT. Yields refer to
pure isolated products. All the known compounds gave satisfactory spectral data (1H-NMR).
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performed using anisaldehyde, malononitrile and 4-hydroxy-
coumarin, 5, and anisaldehyde, malononitrile and 4-hydroxy-
N-methyl-quinolin-2-one, 6, as substrates and employing the
reaction conditions established for the synthesis of, 4. Both the
reactions proceeded smoothly (TLC), and upon completion of
the reactions, it was truly gratifying to notice the formation of
the desired products 7a and 8a in excellent yields. During the
examination of the scope of the protocol, it was experienced that,
functionally diverse aromatic, as well as heteroaromatic alde-
hydes, also furnished the corresponding pyrano[3,2-c]chromenes,
7b–k, as well as pyrano[3,2-c]quinolones, 8b–k, (Table 3) in
excellent yields and purity. On the other hand, poorly reactive
aliphatic aldehydes failed to furnish the desired products, 7/8,
in an acceptable yield.
Like the 1,3-diketones, phenols, naphthols as well as resorcinol
are known to serve as enolizable C–H acids. The literature
survey on the use of these compounds as C–H acids revealed
that, although there are many reports on the use of naphthols in
the multicomponent synthesis of tetrahydrobenzo[b]pyrans,15,21
Scheme 2 Plausible mechanism for the formation of 2-amino-4H-
chromenes.
the scope of THAM as a catalyst in the synthesis of 7, as well as reports on the choice of 3-dimethylaminophenol, 9, as the C–H acid
in the synthesis of 8. Accordingly, two model reactions were are scarce.22 Our interest in the selection of 3-dimethylaminophenol
Table 3 THAM-catalyzed synthesis of pyrano[3,2-c]chromenes, 7 and pyrano[3,2-c]quinolones, 8a
Melting point (1C)
Entry
Aldehyde (1)
Product
Time (h)
Yieldb (%)
Obs.
Lit.(ref.)
1
2
5
6
8
9
4-Methoxybenzaldehyde
4-Methoxybenzaldehyde
4-Isopropylbenzaldehyde
4-Isopropylbenzaldehyde
3-Nitrobenzaldehyde
7a
8a
7b
8b
7c
8c
7d
8d
7e
8e
7f
2.5
2.5
2.5
3.0
2.5
2.5
2.0
2.0
3.0
3.0
3.0
2.5
3.5
2.0
2.0
2.0
2.5
2.5
3.0
2.5
2.5
4.0
4.0
2.5
2.5
2.5
3.0
3.5
3.5
91
88
82
88
90
85
90
86
81
84
79
84
80
85
89
85
84
78
82
80
86
75
83
80
87
84
81
83
80
230–232
260–263
248–250
226–228
256–258
276–278
284–286
282–284
228–230
268–270
260–262
278–280
226–228
248–250
284–286
178–180
276–278
252–254
294–296
232–234
278–280
268–270
272–274
252–254
276–278
264–266
235–238
250–252
225–228
232–23419c
267–26820e
252–25419b
—
254–25619a
274–27620b
289–29019a
—
3-Nitrobenzaldehyde
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
4-Cyanobenzaldehyde
4-Cyanobenzaldehyde
3,4,5-Trimethoxybenzaldehyde
3,4,5-Trimethoxybenzaldehyde
4-Hydroxybenzaldehyde
4-Hydroxybenzaldehyde
4-Allyloxybenzaldehyde
4-Bromobenzaldehyde
4-Bromobenzaldehyde
Piperonal
230–23219c
267–26920b
265–26619a
NR20c
8f
8g
7h
8h
7i
8i
7j
—
254–25619a
285–28620e
180–18119d
—
Piperonal
Furan-2-carbaldehyde
Furan-2-carbaldehyde
Thiophene-2-carbaldehyde
Thiophene-2-carbaldehyde
Cyclohexanecarbaldehyde
Cyclohexanecarbaldehyde
Pyridine-3-carbaldehyde
Pyridine-3-carbaldehyde
3,4-Dimethoxybenzaldehyde
2,5-Dimethylbenzaldehyde
2,6-Dimethylbenzaldehyde
4-Allyloxybenzaldehyde
252–25319d
296–29720e
228–23019c
NR20c
8j
7k
8k
7l
267–26919a
—
8l
7m
8m
8n
7n
7o
7p
255–25719c
279–28020e
—
—
—
—
a
b
Reaction conditions: aldehyde, malononitrile and 4-hydroxycoumarin/4-hydroxyquinoline-2-one (1 mmol, each), THAM (30 mol%), RT. Yields
refer to pure isolated products. All the reported as well as new compounds gave satisfactory spectral analysis (1H-NMR); NR: not reported.
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Table 4 THAM-catalyzed synthesis of 2-amino-7-(dimethylamino)-4-aryl-4H-chromene-3-carbonitriles, 10a
Melting point (1C)
Entry
Aldehyde (1)
Product
Time (h)
Yieldb (%)
Obs.
Lit.(ref.)
1
2
3
4
5
6
7
8
4-Methoxybenzaldehyde
Benzaldehyde
4-Chlorobenzaldehyde
3-Nitrobenzaldehyde
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
2.0
2.0
2.5
2.0
2.30
2.15
3.0
3.5
2.5
3.0
2.5
3.0
3.0
2.5
2.5
85
87
85
87
82
84
80
83
86
84
85
83
84
82
83
176–178
204–207
202–205
198–201
165–168
204–207
178–181
148–149
237–240
240–242
240–242
226–228
217–220
183–185
234–237
174–17622a
206–20722a
198–20022b
NR23d
3,4-Dimethoxybenzaldehyde
4-Bromobenzaldehyde
3,4,5-Trimethoxybenzaldehyde
Cyclohexanecarbaldehyde
Piperonal
Pyridine-3-carbaldehyde
4-Methylbenzaldehyde
4-Isopropylbenzaldehyde
Thiophene-2-carbaldehyde
4-Allyloxybenzaldehyde
4-Hydroxybenzaldehyde
160–16122c
202–20422b
177–18122c
148–15222a
NR23d
9
10
11
12
13
14
15
244–24622a
—
—
—
—
—
a
b
Reaction conditions: aldehyde, malononitrile and 3-dimethylaminophenol (1 mmol, each), THAM (30 mol%), RT. Yields refer to pure isolated
products. All the known compounds gave satisfactory spectral analysis; NR: not reported.
in the synthesis of 2-amino-7-(dimethylamino)-4-aryl-4H-chromene- synthesis of pyrano[3,2-c]pyrazoles, 12, involves
a three-
3-carbonitriles, 10, stems from the anti-cancer, as well as apoptosis component condensation between aldehyde, malononitrile
inducer, activities associated with the targeted compounds, 10, and 5-methyl-2,4-dihydropyrazol-3-one – as another enolizable
and a few of their structural analogues.23 Thus, employing the C–H acid.24 In light of the advantages associated with the
reaction conditions established for the synthesis of 8, a model reduction in the number of steps, in recent years, their syn-
reaction was performed between anisaldehyde, malononitrile thesis has been reported by a one-pot, four-component con-
and 3-dimethylaminophenol. As in earlier cases, the formation densation between aldehyde, malononitrile, alkyl acetoacetate and
of a free-flowing solid was noticed in about two hours. However, hydrazine hydrate in the presence of catalysts like meglumine,25a
the reaction did not go to completion. Modification of the piperidine,25b amberlyst-A-21,25c per-6-amino-b-cyclodextrin,25d
reaction conditions, such as increasing the reaction time as Fe3O4 nanoparticles,25e CTACl,25f etc.25g–n Quite recently a catalyst-
well as the catalyst loading, were not found to be useful in free synthesis of title compounds at elevated temperature has also
driving the reaction to completion (as verified by TLC). Hence, been reported.27 This particular report indirectly projects the
the resultant solid was filtered and, taking recourse to the scope for the development of a protocol that can operate at
solubility behaviour of starting materials as well as the desired ambient temperature using a catalyst that is less expensive than
product, a non-conventional, chromatography, as well as a the cost of energy required for their synthesis under a catalyst-free
crystallization-free route, was developed to obtain pure, 10a. condition. Thus, we examined the catalytic potential of THAM in
The filtered solid after drying in air was washed successively the one-pot synthesis of 12.
with a hexane–chloroform mixture (1 : 1, v/v) and then dried again.
Initially, employing the reaction conditions established for
The purified product was found to be suitable for practical as well the synthesis of 10, a three-component condensation was
as analytical purposes. Subsequently, the protocol was extended attempted using anisaldehyde, malononitrile and 5-methyl-
towards various substituted aldehydes to obtain the corresponding 2,4-dihydro-pyrazol-3-one, 11, as the substrates (Scheme 1, D).
2-amino-7-(dimethylamino)-4-aryl-4H-chromene-3-carbonitriles, As expected, the desired pyrano[3,2-c]pyrazole, 12a, was obtained
10b–o (Table 4). Among the synthesized compounds, 10d, 10e in good yield (76%). At this stage, it is worth noting that the
and 10i have already been reported as apoptosis-inducer agents. resultant pyrano[3,2-c]pyrazole may exist in two tautomeric forms,
After establishing a general route for the synthesis of tetra- namely 2,4-dihydropyrano[3,2-c]pyrazole, 12, and 1,4-dihydro-
hydrobenzo[b]pyrans, 4, as well as pyran-annulated heterocycles, pyrano[3,2-c]pyrazole, 13 (Fig. 3). However, Gogoi et al.25j and
7, 8 and 10, we turned our attention towards the synthesis of Vasuki et al.25b through X-ray crystallographic studies and
another important class of pyran-annulated heterocycles, namely Al-Matar et al.25n through NOE studies showed that, the resultant
pyrano[3,2-c]pyrazoles, 12 (Scheme 1, D). This is because; the product stays as 2,4-dihydropyrano[3,2-c]pyrazole. The observed
compounds belonging to this class hold a position of promi- physical as well as spectral data of 12a was in complete agreement
nence due to their human chk1 inhibitor activity. The classical with that reported earlier for the 2,4-dihydropyrano[3,2-c] pyrazole
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Finally, we turned our attention towards the reusability of
the catalyst. In this context, we surmised that, with the catalyst
used being completely soluble in the reaction medium, it’s isola-
tion for possible reuse would be tedious, as well as expensive.
Hence, we checked reusability of the reaction medium. Accord-
ingly, the synthesis of 8a was performed on a 10 mmol scale. The
resultant product was isolated by filtration, and the filtrate
obtained was reused for the synthesis of 8a. Only a slight decrease
in the yield of the desired product, 8a, was noticed (88% - 85%).
Fig. 3 Tautomers of pyrano[3,2-c]pyrazole, 12.
tautomer.25k,l Encouraged by this initial success, a four- Hence, this process was repeated three more times. In three
component reaction was then performed between anisaldehyde, consecutive runs, a progressive decrease in the yield was noticed
malononitrile, ethyl acetoacetate and hydrazine hydrate employ- (Fig. 4). In short, the protocol developed is scalable and the catalyst
ing the same reaction conditions. Interestingly, an appreciable can be reused for at least three consecutive runs.
increase in the yield of the desired product, 12a was noticed
Finally, a comparison was made between the protocols
(76% - 91%). Next, we examined the scope of the protocol. Thus, reported earlier and the protocol developed by us for the
the four-component condensation route was extended towards synthesis of 8a, 10a and 12a, as model compounds. The results
other aromatic aldehydes bearing electron-withdrawing as well as summarized in Table 6 reveal that the protocol developed by us
electron-donating groups, as well as towards a few heteroaromatic would be the protocol of choice for the synthesis of 8a and 10a.
aldehydes. In all the cases, the corresponding pyrano[3,2-c]- On the other hand, based upon the parameters of cost, as well
pyrazole, 12b–k, was obtained in an excellent yield (Table 5).
After establishing a general protocol for the synthesis of
various medicinally important pyrans, as well as for pyran-
annulated heterocycles, we checked the economic as well as
environmental compatibility of the developed protocol. In this
context, scalability of the protocol and reusability of the catalyst
were examined. So as to check the scalability of the protocol,
under the established reaction conditions, the synthesis of
pyrano[3,2-c]chromene, 7a, as well as pyrano[3,2-c]quinolone,
8a, were carried out on a 10 mmol scale. In both cases, the
desired products, 7a and 8a, were obtained in an excellent yield
(89% and 86%, respectively).
Fig. 4 Reusability of the catalyst.
Table 5 THAM-catalyzed four-component synthesis of pyrano[3,2-c]pyrazoles, 12a
Melting point (1C)
Entry
Aldehyde
Product
Time (h)
Yield (%)
Obs.
Lit.(ref.)
1
2
3
4
5
6
7
8
4-Methoxybenzaldehyde
4-Bromobenzaldehyde
4-Isopropylbenzaldehyde
3-Nitrobenzaldehyde
12a
12b
12c
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
2.0
2.0
2.5
2.0
2.0
2.0
2.5
3.0
2.5
2.0
3.0
3.0
2.5
2.5
2.5
91
89
84
90
90
87
81
83
85
89
79
84
81
82
83
208–210
181–183
181–184
213–215
196–198
201–203
192–194
170–172
226–228
204–207
300–302
181–184
211–214
192–194
210–213
211–21325k
179–18025k
180–18125d
214–21625k
196–19825l
204–20625k
192–19425k
172–17325d
221–22325m
202–20525c
295–29826
—
4-Cyanobenzaldehyde
4-Methylbenzaldehyde
3,4-Dimethoxybenzaldehyde
Cyclohexanecarbaldehyde
Thiophene-2-carbaldehyde
Piperonal
9
10
11
12
13
14
15
Pterphthaldehydeb
4-Allyloxybenzaldehyde
3,5-Dimethylbenzaldehyde
5-Methylfurfural
—
—
—
3-Methylthiophene-2-carbaldehyde
a
Reaction conditions: aldehyde, malononitrile, ethyl acetoacetate and hydrazine hydrate (1 mmol, each), THAM (30 mol%), water–ethanol (4 mL,
b
1 : 1, v/v), RT. Aldehyde (1 mmol), malononitrile, ethyl acetoacetate and hydrazine hydrate (2 mmol, each), THAM (30 mol%), water–ethanol
(4 mL, 1 : 1, v/v).
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Table 6 Comparison between the THAM-catalyzed protocol with earlier reported protocols for the synthesis of 8a, 10a and 12a
Entry
Catalyst (mol%/mg)
Product
Solvent
Temp. (1C)
Time (min)
Yield (%)[ref.]
1
2
3
4
Triethylamine (50/50)
Electricity
Clinoptilolite (/10 mg)
THAM (30/35 mg)
8a
8a
8a
8a
EtOH
EtOH
H2O
EtOH–H2O
Reflux
70
Reflux
RT
50
3
7820b
8620e
8815g
88b
15
2.5c
5
6
7
Piperidine (30/27)
Triethylamine (30/30)
THAM (30/35)
10a
10a
10a
EtOH
EtOH
EtOH–H2O
RT
Reflux
RT
120
30
2c
8023a
7022c
85b
8
9
PACDa (0.008 mmol)
Meglumine (10/20)
Piperidine (5/5)
Urea (10/6)
Amberlyst A-21 (15/30)
HDBAC (30/120)
Iodine (5/7)
12a
12a
12a
12a
12a
12a
12a
12a
12a
EtOH
EtOH–H2O
H2O
EtOH–H2O
H2O
PTC
H2O
H2O
EtOH–H2O
RT
RT
RT
RT
RT
RT
RT
RT
RT
1
9925d
9125a
8525b
8615b
9425c
7925i
8825h
9525e
91b
15
10
8c
35
60
7
10
11
12
13
14
15
16
Fe3O4 NPs (6/15)
THAM (30/30)
2
2c
Reaction conditions: aldehyde, malononitrile and C–H acid (1 mmol, each), THAM (30 mol%,), EtOH–H2O (1 : 1, 4 mL), RT.a Per-6-amino-b-
b
c
cyclodextrin. Present work. Time in hours.
as the non-toxic nature of the catalyst, the developed protocol General experimental procedure
could serve as a useful alternative towards the synthesis of 12a.
To a well-stirred solution of an aldehyde (1 mmol), malononitrile
(1 mmol) and an appropriate C–H acid 3, 5, 6, 9 or 11 (1 mmol) in
ethanol : water (1: 1, 4 mL) was added tris-hydroxymethylamino-
methane (30 mol%), and stirring was continued at ambient
temperature. Upon completion of the reaction (as verified by
TLC), water (5 mL) was added and stirring was continued until a
free-flowing solid resulted in the reaction mixture. The resultant
solid was filtered, washed with water and then dried. The dried solid
was successively washed using a mixture of hexane : chloroform
(70 : 30, v/v), and then dried. All the resulted products were pure
(verified by TLC, NMR).
Conclusion
In conclusion, we demonstrated for the first time the use of a
commercially available, non-toxic, inexpensive, bio-degradable
and easy to handle tris-hydroxymethylaminomethane as a novel
organocatalyst in the library synthesis of medicinally important
tetrahydrobenzo[b]pyrans, as well as pyran-annulated hetero-
cycles. Ambient reaction conditions, high to excellent yields,
reusability of the catalyst for five consecutive runs, easy isola-
tion of the products and the avoidance of conventional work-
up, as well as facile purification procedures, are the key features
of this multicomponent protocol. Keeping in view the advan-
tages offered by the catalyst, the present protocol would be
useful in the large-scale synthesis of pyran-annulated hetero-
cycles, and this novel catalyst may find application in
Knoevenagel-initiated domino reactions for the synthesis of
heterocyclic frameworks.
The NMR spectra provided in the ESI† are of the as-isolated
products.
Spectral data of the new compounds
2-Amino-4,5-dihydro-4-(2,5-dimethylphenyl)-5-oxopyrano[3,2-c]-
chromene-3-carbonitrile, 7n. Solid; M.P.: 235–238 1C; IR (KBr):
1
3121, 2233, 1733, 1675, 1476, 1399, 1255, 1090 cmÀ1; H-NMR
(300 MHz, DMSO-d6): d 2.15 (s, 3H), 2.43 (s, 3H), 4.72 (s, 1H),
6.82 (s, 1H), 6.91 (d, 1H, J = 7.4 Hz), 7.03 (d, 1H, J = 7.4 Hz), 7.35
(s, 2H), 7.47 (d, 1H, J = 7.7 Hz), 7.52 (d, 1H, J = 7.8 Hz), 7.72
(t, 1H, J = 7.7 Hz), 7.92 (d, 1H, J = 7.7 Hz); 13C-NMR: (75 MHz,
DMSO-d6): d 19.14, 21.08, 32.90, 58.47, 105.05, 113.44, 117.07,
Experimental
General
All aldehydes, 3-dimethylaminophenol and 4-hydroxy coumarin 119.74, 122.91, 125.16, 128.03, 128.05, 130.49, 132.67, 133.32,
(Aldrich), malononitrile, dimedone, hydrazine hydrate, and 135.98, 142.42, 152.54, 153.93, 158.15, 160.08; HRMS: mass
ethyl acetoacetate (SD fine chemicals) were used as received. calculated for [C21H16N2O3]: 367.1059 [M + Na]+; obs. mass
N-Methyl quinoline-2-one was received as a gift sample from 367.1053 [M + Na]+.
M/S Bravil Chemicals, Kolhapur, India. All the melting points
2-Amino-4,5-dihydro-4-(2,6-dimethylphenyl)-5-oxopyrano[3,2-c]-
were recorded using Kumar melting point apparatus. The IR chromene-3-carbonitrile, 7o. Solid; M.P.: 250–252 1C; IR (KBr):
spectra were recorded using a Perkin Elmer Spectrum 1 spectro- 3099, 1731, 1600, 1454, 1312, 1278, 887 cmÀ1; 1H-NMR: (300 MHz,
1
meter. H and 13C NMR spectra were recorded using a Bruker DMSO-d6): d 2.05 (s, 3H), 2.53 (s, 3H), 5.10 (s, 1H), 6.92 (d, 1H,
Avance-II spectrometer. High resolution mass spectra (HRMS) J = 6.10 Hz), 7.00–7.07 (m, 2H), 7.38 (s, 2H), 7.46 (d, 1H, J =
were recorded using a Thermo Scientific Q – Exactive, Accela 8.2 Hz), 7.50 (d, 1H, J = 7.7 Hz), 7.71 (t, 1H, J = 7.5 Hz), 7.88
1250 pump, instrument.
(d, 1H, J = 7.9 Hz); 13C-NMR: (75 MHz, DMSO-d6): d 18.75, 21.43,
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31.89, 55.59, 56.50, 103.40, 112.95, 117.05, 119.35, 122.75, 125.19, d 3.54 (s, 3H), 4.47 (s, 1H), 4.51 (d, 2H, J = 5.2 Hz), 5.22 (dd, 1H,
127.32, 128.88, 130.90, 133.41, 136.65, 137.73, 137.84, 152.60, J = 10.4 & 1.4 Hz), 5.37 (dd, 1H, J = 17.3 & 1.6 Hz), 5.95–6.00
153.96, 158.44, 159.83; HRMS: mass calculated for [C21H16N2O3]: (m, 1H), 6.85 (d, 2H, J = 8.7 Hz), 7.12 (d, 2H, J = 8.6 Hz), 7.39
367.1059 [M + Na]+; obs. mass: 367.1053 [M + Na]+.
(t, 1H, J = 7.7 Hz), 7.56 (d, 1H, J = 8.6 Hz), 7.70 (t, 1H, J = 8 Hz),
4-(4-(Allyloxy)phenyl)-2-amino-4,5-dihydro-5-oxopyrano[3,2-c]- 8.02 (d, 1H, J = 8.1 Hz); 13C-NMR (75 MHz, DMSO-d6): d 29.76,
chromene-3-carbonitrile, 7p. Solid; M.P.: 225–228 1C; IR (KBr): 36.97, 58.55, 68.63, 109.77, 113.18, 114.93, 115.44, 117.80,
3111, 1739, 1653, 1453, 1401, 1252, 1043 cmÀ1 1H-NMR: 120.32, 122.65, 129.01, 132.06, 134.27, 137.00, 139.04, 150.37,
;
(300 MHz, DMSO-d6): d 4.39 (s, 1H), 4.52 (d, 2H, J = 5.1 Hz), 157.50, 159.30, 160.28, 160.89 ppm; HRMS: mass calculated for
5.23 (dd, 1H, J = 1.2 & 9.3 Hz), 5.37 (dd, 1H, J = 1.5 & 17.28 Hz), [C23H19N3O3]: 386.1499 [M + H]+; obs. mass: 386.1505 [M + H]+.
5.96–6.08 (m, 1H), 6.88 (d, 2H, J = 8.6 Hz), 7.16 (d, 2H, J =
2-Amino-4-(1,3-benzodioxol-5-yl)-6-methyl-5-oxo-5,6-dihydro-
8.5 Hz), 7.38 (s, 2H), 7.46 (d, 1H, J = 8.2 Hz), 7.50 (d, 1H, J = 4H-pyrano[3,2-c]quinoline-3-carbonitrile, 8i. Off-white solid;
7.6 Hz), 7.71 (t, 1H, J = 7.2 Hz), 7.89 (d, 1H, J = 6.8 Hz); 13C-NMR: M.P.: 276–278 1C; IR (KBr): 3394, 3340, 3180, 2209, 1648,
(75 MHz, DMSO-d6): d 36.62, 58.63, 68.63, 104.72, 113.47, 1260, 1140, 790 cmÀ1 1H-NMR (300 MHz, DMSO-d6): d 3.56
;
115.04, 117.02, 117.85, 119.77, 122.92, 125.13, 129.21, 133.34, (s, 3H), 4.47 (s, 1H), 5.96 (s, 2H), 6.69 (s, 1H), 6.75 (s, 1H), 6.80
134.22, 136.00, 152.55, 153.58, 157.74, 158.39, 160.01; HRMS: (s, 1H), 7.27 (s, 2H), 7.40 (s, 1H), 7.59 (s, 1H), 7.71 (s, 1H), 8.03
mass calculated for [C22H16N2O4]: 395.1008 [M + Na]+; obs. (s, 1H); 13C-NMR (75 MHz, DMSO-d6): d 29.78, 37.45, 58.47,
mass 395.1002 [M + Na]+.
101.36, 108.46, 108.52, 109.52, 113.20, 115.46, 120.20, 121.09,
2-Amino-6-methyl-5-oxo-4-[4-(propan-2-yl)phenyl]-5,6-dihydro- 122.65, 122.69, 132.10, 138.86, 139.11, 146.48, 147.62, 150.48,
4H-pyrano[3,2-c]quinoline-3-carbonitrile, 8b. Off-white solid; 159.30, 160.29 ppm; HRMS: mass calculated for [C21H15N3O4]:
M.P.: 226–228 1C; IR (KBr): 3390, 3315, 2947, 2201, 1640, 374.1141 [M + H]+ and 396.0960 [M + Na]+; obs. mass: 374.1135
1605, 860, 765 cmÀ1
;
1H-NMR (300 MHz, DMSO-d6): d 1.14 [M + H]+ and 396.0955 [M + Na]+.
(s, 3H), 1.17 (s, 3H), 2.84 (m, 1H), 3.55 (s, 3H), 4.50 (s, 1H), 6.90
2-Amino-5,6-dihydro-6-methyl-5-oxo-4-(thiophen-2-yl)-4H-
(s, 2H), 7.06 (d, 2H, J = 8 Hz), 7.12 (d, 2H, J = 8 Hz), 7.28 (t, 1H, pyrano[3,2-c]quinoline-3-carbonitrile, 8k. Yellow solid; M.P.:
J = 7.5 Hz), 7.41 (d, 1H, 8.6 Hz), 7.59 (t, 1H, J = 8 Hz), 8.1 (d, 1H, 278–280 1C; IR (KBr): 3350, 3144, 2189, 1650, 1610, 1475,
J = 7.8 Hz); 13C-NMR (75 MHz, DMSO-d6): d 24.18, 29.59, 33.60, 1410, 1060, 847 cmÀ1 1H-NMR (300 MHz, DMSO-d6): d 3.61
;
37.23, 58.87, 109.82, 113.47, 114.57, 120.15, 122.23, 122.90, (s, 3H), 4.90 (s, 1H), 6.85 (s, 1H), 6.98 (s, 1H), 7.04 (s, 2H), 7.10
126.45, 127.69, 131.51, 138.99, 141.83, 147.04, 150.67, 159.38, (s, 1H), 7.27 (t, 1H, J = 7.4 Hz), 7.41 (d, 1H, J = 7.4 Hz), 7.59
160.46 ppm; HRMS: mass calculated for [C23H21N3O2]: 394.1531 (t, 1H, J = 7.3 Hz), 7.99 (d, 1H, J = 7.6 Hz); 13C-NMR (75 MHz,
[M + H]+; obs. mass: 394.1526 [M + H]+.
DMSO-d6): d 29.60, 32.43, 58.91, 109.63, 113.49, 114.27, 122.20,
2-Amino-4-(4-cyanophenyl)-6-methyl-5-oxo-5,6-dihydro-4H- 123.02, 124.12, 124.79, 126.77, 131.48, 138.96, 148.38, 150.43,
pyrano[3,2-c]quinoline-3-carbonitrile, 8d. Pale yellow solid; 159.76, 160.47 ppm; HRMS: mass calculated for [C18H14N3O2S]:
M.P.: 282–284 1C; IR (KBr): 3385, 3300, 3058, 2926, 2215, 336.0807 [M + H]+; obs. mass: 355.0795 [M + H]+.
1672, 1610, 854, 765 cmÀ1
;
1H-NMR (300 MHz, DMSO-d6): d
2-Amino-4-cyclohexyl-6-methyl-5-oxo-5,6-dihydro-4H-pyrano-
3.54 (s, 3H), 4.62 (s, 1H), 7.15 (s, 2H), 7.30 (t, 1H, J = 7.6 Hz), [3,2-c]quinoline-3-carbonitrile, 8l. Off-white solid; M.P.: 272–
7.59–7.65 (m, 3H), 8.03 (d, 1H, J = 7.6 Hz), 7.39 (s, 1H), 7.42 274 1C; IR (KBr): 3390, 3327, 2940, 2190, 1640, 1590, 1470, 1280,
(s, 1H), 7.45 (s, 1H); 13C-NMR (75 MHz, DMSO-d6): d 29.61, 880, 789 cmÀ1 1H-NMR (300 MHz, DMSO-d6): d 0.93–1.03
;
37.90, 57.31, 66.84, 108.31, 110.36, 113.21, 114.77, 118.83, (m, 3H), 1.13–1.25 (m, 1H), 1.35–1.43 (m, 1H), 1.60–1.75 (m, 6H),
119.67, 122.41, 123.00, 128.97, 131.92, 132.36, 139.18, 149.86, 3.40 (s, 1H), 3.64 (s, 3H), 7.21 (s, 2H), 7.35 (t, 1H, J = 7.4 Hz), 7.58
151.03, 159.40, 160.28 ppm; HRMS: mass calculated for (d, 1H, J = 8.6 Hz), 7.69 (t, 1H, J = 7.4 Hz), 7.93 (d, 1H, J = 7.9 Hz);
[C21H14N4O2]: 355.1195 [M + H]+; obs. mass: 355.1195 [M + H]+. 13C-NMR (75 MHz, DMSO-d6): d 26.03, 26.45, 26.68, 27.32, 29.92,
2-Amino-5,6-dihydro-4-(4-hydroxyphenyl)-6-methyl-5-oxo-4H- 31.08, 37.51, 43.64, 52.83, 110.04, 113.22, 115.45, 121.72, 122.33,
pyrano[3,2-c]quinoline-3-carbonitrile, 8f. Off-white solid; M.P.: 122.60, 131.84, 138.90, 151.81, 160.63, 161.86 ppm; HRMS: mass
278–280 1C; IR (KBr): 3440, 3387, 3292, 3070, 2922, 2209, 1672, calculated for [C20H21N3O2]: 336.1712 [M + H]+ and 358.1531
1610, 854, 765 cmÀ1
(s, 3H), 4.41 (s, 1H), 6.65 (d, 2H, J = 6.9 Hz), 7.00 (d, 2H, J =
;
1H-NMR (300 MHz, DMSO-d6): d 3.54 [M + Na]+; obs. mass: 336.1697 [M + H]+ and 358.1526 [M + Na]+.
2-Amino-4-(3,4-dimethoxyphenyl)-6-methyl-5-oxo-5,6-dihydro-
7.1 Hz), 7.22 (s, 2H), 7.39 (t, 1H, J = 7.8 Hz), 7.56 (d, 1H, J = 4H-pyrano[3,2-c]quinoline-3-carbonitrile, 8n. Off-white solid; M.P.:
7.6 Hz), 7.70 (t, 1H, J = 7.1 Hz), 8.01 (d, 1H, J = 7.1 Hz), 9.29 264–266 1C; IR (KBr): 3379, 3318, 3186, 3043, 2945, 2187, 1662, 1599,
1
(s, 1H); 13C-NMR (75 MHz, DMSO-d6): d 29.75, 36.94, 58.78, 1464, 1384, 848, 755 cmÀ1; H-NMR (300 MHz, DMSO-d6): d 3.55
110.03, 113.22, 115.41, 115.50, 120.39, 122.61, 128.97, 131.98, (s, 3H), 3.70 (s, 6H) 4.48 (s, 1H), 6.67 (d, 1H, J = 8 Hz), 6.85
135.16, 139.00, 150.26, 156.65, 159.28, 160.30 ppm; HRMS: mass (d, 2H), 7.24 (s, 2H), 7.39 (t, 1H, J = 7.5 Hz), 7.56 (d, 1H, J =
calculated for [C20H15N3O3]: 346.1192 [M + H]+ and 368.1011 8.6 Hz), 7.71 (t, 1H, J = 8.0 Hz), 8.02 (d, 1H, J = 7.8 Hz); 13C-NMR
[M + Na]+; obs. mass: 346.1179 [M + H]+ and 368.1006 [M + Na]+. (75 MHz, DMSO-d6): d 29.79, 37.30, 56.00, 58.48, 109.69, 112.23,
2-Amino-6-methyl-5-oxo-4-[4-(prop-2-en-1-yloxy)phenyl]-5,6- 112.44, 113.20, 115.46, 119.84, 120.32, 122.66, 132.07, 137.37,
dihydro-4H-pyrano[3,2-c]quinoline-3-carbonitrile, 8g. White solid; 139.07, 145.72, 148.20, 148.85, 150.40, 159.34, 160.35 ppm; HRMS:
M.P.: 226–228 1C; IR (KBr): 3379, 3313, 2939, 2189, 1665, 1599, mass calculated for [C22H19N3O4]: 412.1273 [M + Na]+; obs. mass:
1384, 1257, 1125, 832, 751 cmÀ1; 1H-NMR (300 MHz, DMSO-d6): 412.1258 [M + Na]+.
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2-Amino-7-(dimethylamino)-4-(3-nitrophenyl)-4H-chromene-
Paper
2-Amino-7-(dimethylamino)-4-[4-(prop-2-en-1-yloxy)phenyl]-
3-carbonitrile, 10d. White solid; M.P.: 198–201 1C; IR (KBr): 4H-chromene-3-carbonitrile, 10n. Yellowish solid; M.P.: 183–
3414, 3325, 3170, 2958, 2215, 1640, 1580, 1360, 1220, 1125, 185 1C; IR (KBr): 3427, 3321, 3190, 2930, 2195, 1634, 1540, 1398,
780 cmÀ1 1H-NMR (300 MHz, DMSO-d6): d 2.88 (s, 6H), 4.71 1238, 1116, 1011, 818, 786 cmÀ1; 1H-NMR (300 MHz, DMSO-d6):
;
(s, 1H), 6.26–6.37 (m, 3H), 6.36 (d, 1H, J = 8.6 Hz), 6.68 (d, 1H, d 2.84 (s, 6H), 4.44 (s, 1H), 4.46 (s, 1H), 4.47 (s, 1H), 5.20 (dd,
J = 8 Hz), 7.46 (t, 1H, J = 7.9 Hz), 7.53 (d, 1H, J = 7.8 Hz), 7.93 J = 1H, 10.1 & 1.3 Hz), 5.33 (dd, 1H, J = 16.6 & 1.5 Hz), 5.90–6.10
(s, 1H), 7.99 (d, 1H, J = 8 Hz); 13C-NMR (75 MHz, DMSO-d6): d (m, 1H), 6.19 (d, 1H, J = 2.3 Hz), 6.33–6.36 (m, 3H), 6.71 (d, 1H,
40.32, 57.11, 99.27, 108.93, 109.63, 120.48, 121.82, 122.45, J = 8.5 Hz), 6.76 (d, 2H, J = 8.6 Hz), 7.02 (d, 2H, J = 8.6 Hz);
129.47, 129.66, 134.16, 148.43, 148.47, 149.46, 150.62, 160.59 13C-NMR (75 MHz, DMSO-d6): d 39.60, 40.43, 57.27, 68.66,
ppm; HRMS: mass calculated for [C18H16N4O3]: 337.1301 98.99, 109.87, 111.31, 115.10, 117.77, 121.28, 128.83, 129.90,
[M + H]+ and 359.1120 [M + Na]+; obs. mass: 337.1295 [M + H]+ 134.31, 139.35, 149.41, 150.64, 157.35, 160.72 ppm; HRMS:
and 359.1115 [M + Na]+.
mass calculated for [C21H21N3O2]: 348.1712 [M + H]+; obs. mass:
2-Amino-4-(benzo[d][1,3]dioxol-6-yl)-7-(dimethylamino)-4H- 348.1707 [M + H]+.
chromene-3-carbonitrile, 10i. Yellowish solid; M.P.: 237–240 1C;
2-Amino-7-(dimethylamino)-4-(4-hydroxyphenyl)-4H-chromene-
IR (KBr): 3375, 3387, 3310, 3092, 2927, 2195, 1662, 1599, 840, 3-carbonitrile, 10o. White solid; M.P.: 234–237 1C; IR (KBr): 3440,
755 cmÀ1 1H-NMR (300 MHz, DMSO-d6): d 2.87 (s, 6H), 4.45 3385, 3315, 3165, 2210, 1685, 1595, 1340, 1160, 1085, 845, 780
;
(s, 1H), 5.88 (d, 2H, J = 5.1 Hz), 6.14 (s, 1H), 6.20 (d, 1H, J = cmÀ1; 1H-NMR (300 MHz, DMSO-d6): d 2.85 (s, 6H), 4.47 (s, 1H),
2.1 Hz), 6.37 (m, 2H), 6.53 (s, 1H), 6.64–6.73 (m, 3H); 13C-NMR 6.21 (s, 1H), 6.45 (d, 1H, J = 8.7 Hz), 6.66–6.77 (m, 5H), 6.95
(75 MHz, DMSO-d6): d 40.41, 57.74, 99.08, 101.00, 107.98, (d, 2H, J = 8.1 Hz), 9.24 (brs, 1H); 13C-NMR (75 MHz, DMSO-d6):
108.03, 109.53, 110.70, 120.76, 129.64, 140.65, 146.37, 147.91, d 40.44, 57.41, 98.96, 109.83, 111.58, 115.63, 12.35, 128.80,
149.37, 150.40, 160.46 ppm; HRMS: mass calculated for 129.91, 137.49, 149.37, 150.55, 156.44, 160.64 ppm; HRMS:
[C19H17N3O3]: 336.1348 [M + H]+ and 358.1168 [M + Na]+; obs. mass calculated for [C18H17N3O2]: 308.1399 [M + H]+ and
mass: 336.1341 [M + H]+ and 358.1158 [M + Na]+.
330.1218 [M + Na]+; obs. mass: 306.1237 [M + H]+ and 328.1056
2-Amino-7-(dimethylamino)-4-(4-methylphenyl)-4H-chromene- [M + Na]+.
3-carbonitrile, 10k. Off-white solid; M.P.: 240–242 1C; IR (KBr):
5-Amino-7-[4-(prop-2-en-1-yloxy)phenyl]-2,7-dihydropyrano-
3390, 3324, 3181, 2959, 2203, 1695, 1604, 1384, 1176, 1053, 839, [3,2-c]pyrazole-6-carbonitrile, 12m. Off-white solid; M.P.: 181–
762 cmÀ1 1H-NMR (300 MHz, DMSO-d6): d 2.24 (s, 3H), 2.86 184 1C; IR (KBr): 3471, 3258, 2186, 1640, 1404, 1050, 741 cmÀ1
; ;
(s, 6H), 4.47 (s, 1H), 5.97 (s, 2H), 6.21 (s, 1H), 6.32 (d, 1H, J = 1H-NMR (300 MHz, DMSO-d6): d 1.78 (s, 3H), 4.53 (brs, 3H),
8 Hz), 6.67 (d, 1H, J = 8.7 Hz), 6.99 (s, 4H); 13C-NMR (75 MHz, 5.25 (d, 1H, J = 10.6 Hz), 5.40 (d, 1H, J = 17.2 Hz), 5.97–6.08
DMSO-d6): d 21.07, 40.40, 58.30, 99.17, 109.49, 110.80, 127.69, (m, 1H), 6.81 (brs, 2H), 6.88 (d, 1H, J = 8.2 Hz), 7.06 (d, 1H,
129.19, 129.65, 135.90, 143.32, 149.40, 150.29, 160.28 ppm; HRMS: J = 8.3 Hz), 12.06 (s, 1H); 13C-NMR (75 MHz, DMSO-d6): d 10.20,
mass calculated for [C19H19N3O]: 306.1606 [M + H]+ and 328.1426 35.92, 58.07, 68.63, 98.34, 114.96, 117.81, 121.27, 128.93,
[M + Na]+; obs. mass: 306.1601 [M + H]+ and 328.1420 [M + Na]+. 134.29, 135.99, 137.12, 155.23, 157.40, 161.17 ppm; HRMS:
2-Amino-7-(dimethylamino)-4-[4-(propan-2-yl)phenyl]-4H- mass calculated for [C17H16N4O2]: 309.1352 [M + H]+ and
chromene-3-carbonitrile, 10l. Off-white solid; M.P.: 226–228 1C; 331.1171 [M + Na]+; obs. mass: 309.1346 [M + H]+ and 331.1165
IR (KBr): 3429, 3310, 3181, 2957, 2197, 1633, 1525, 1394, 1233, [M + Na]+.
1114, 1032, 866, 786 cmÀ1
2.85 (s, 6H), 3.63 (s, 3H), 3.76 (s, 3H), 4.96 (s, 1H), 6.19 (brs, 3H), pyrazole-6-carbonitrile, 12n. Off-white solid; M.P.: 211–214 1C;
6.33 (d, 1H, J = 8.4 Hz), 6.48 (s, 1H), 6.63 (d, 1H, J = 8.2 Hz), IR (KBr): 3300, 3119, 2189, 1640, 1494, 1408, 1048, 760 cmÀ1
;
1H-NMR (300 MHz, DMSO-d6): d
5-Amino-7-(3,5-dimethylphenyl)-2,7-dihydropyrano[3,2-c]-
;
6.78–6.83 (m, 2H); 13C-NMR (75 MHz, DMSO-d6): d 24.33, 24.35, 1H-NMR (300 MHz, DMSO-d6): d 1.79 (s, 3H), 2.23 (s, 6H), 4.49
33.48, 40.44, 56.98, 99.00, 109. 88, 111.21, 121.37, 126.88, (s, 1H), 6.75 (s, 2H), 6.80 (s, 2H), 6.85 (s, 1H), 12.05(s, 1H);
127.65, 129.90, 144.56, 146.96, 149.44, 150.64, 160.86 ppm; 13C-NMR (75 MHz, DMSO-d6): d 10.24, 21.41, 36.65, 57.90,
HRMS: mass calculated for [C21H23N3O]: 334.1919 [M + H]+ 98.19, 121.25, 125.63, 128.71, 136.02, 137.75, 144.86, 155.23,
and 356.1739 [M + Na]+; obs. mass: 334.1914 [M + H]+ and 161.30 ppm; HRMS: mass calculated for [C16H16N4O]: 281.1402
356.1728 [M + Na]+.
[M + H]+ and 303.1222 [M + Na]+; obs. mass: 281.1397 [M + H]+
2-Amino-7-(dimethylamino)-4-(thiophen-3-yl)-4H-chromene- and 303.1216 [M + Na]+.
3-carbonitrile, 10m. Creamy solid; M.P.: 217–220 1C; IR (KBr):
5-Amino-7-(5-methylfuran-3-yl)-2,7-dihydropyrano[3,2-c]pyr-
3414, 3292, 3170, 2915, 2190, 1640, 1515, 1380, 1210, 1100, azole-6-carbonitrile, 12o. Off-white solid; M.P.: 191–194 1C; IR
1045, 840, 760 cmÀ1 1H-NMR (300 MHz, DMSO-d6): d 2.88 (KBr): 3247, 3140, 2197, 1647, 1497, 1409, 1038, 786 cmÀ1
; ;
(s, 6H), 4.88 (s, 1H), 6.20 (s, 1H), 6.42 (d, 1H, J = 8.2 Hz), 6.63 1H-NMR (300 MHz, DMSO-d6): d 2.00 (s, 3H), 2.19 (s, 3H), 4.69
(s, 2H), 6.86–6.91 (s, 3H), 7.19 (d, 1H, J = 5.6 Hz); 13C-NMR (s, 1H), 5.95 (s, 1H), 6.03 (d, 2H, J = 2.8 Hz), 6.92 (s, 2H), 12.13
(75 MHz, DMSO-d6): d 35.85, 40.37, 99.05, 109.48, 110.43, (s, 1H); 13C-NMR (75 MHz, DMSO-d6): d 10.09, 13.81, 30.39,
124.03, 124.79, 126.73, 129.61, 149.18, 150.65, 151.91, 160.79 54.64, 95.73, 106.76, 106.76, 121.07, 136.30, 151.19, 154.34,
ppm; HRMS: mass calculated for [C16H15N3OS]: 298.1014 155.26, 161.91 ppm; HRMS: mass calculated for [C13H12N4O2]:
[M + H]+ and 320.0834 [M + Na]+; obs. mass: 298.1009 [M + H]+ 257.1039 [M + H]+ and 279.0858 [M + Na]+; obs. mass: 257.1025
and 320.0750 [M + Na]+.
[M + H]+ and 279.0852 [M + Na]+.
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5-Amino-7-(4-methylthiophen-3-yl)-2,7-dihydropyrano[3,2-c]-
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pyrazole-6-carbonitrile, 12p. Off-white solid; M.P.: 210–213 1C;
IR (KBr): 3440, 3180, 2186, 1660, 1601, 1494, 1405, 1060, 840
cmÀ1; 1H-NMR (300 MHz, DMSO-d6): d 1.83 (s, 3H), 2.22 (s, 3H),
5.01 (s, 1H), 6.77 (d, 1H, J = 5.1 Hz), 6.83 (brs, 2H), 7.26 (d, 2H,
J = 5.2 Hz), 12.14 (s, 1H); 13C-NMR (75 MHz, DMSO-d6): d 10.07,
13.98, 29.67, 58.09, 98.21, 121.06, 123.83, 130.18, 133.18,
136.38, 142.87, 154.92, 160.88 ppm; HRMS: mass calculated
for [C13H12N4OS]: 273.0810 [M + H]+ and 295.0630 [M + Na]+;
obs. mass: 273.0805 [M + H]+ and 295.0624 [M + Na]+.
Acknowledgements
KSP and UVD thank UGC, New Delhi for financial assistance.
We are also thankful to B. J. Corporation, Kolhapur for the
generous gift of N-methylquinolone.
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