Recently, the use of liquid-assisted grinding techniques for controlling or accelerating organic transformation has become one of the current interests of synthetic organic chemistry in the move towards green or sustainable synthesis. In line with this, along with establishing the standard reaction condition for the synthesis of 2-amino-3-cyano-4H-chromene derivatives 4a-n, we choose the initial multicomponent reaction of benzaldehyde 1a, malononitrile 2, and 5,5-dimethylcyclohexane-1,3-dione 3a as the representative example (Scheme 2) that was being executed in different catalytic as well as non-catalytic systems under different reaction conditions (Table 1). An immediate analysis of the data presented in Table 1 for the preparation of our desired product 4a revealed that the reaction performed without using any catalyst failed to yield any product even after 24 hours under grinding conditions (Table 1, Entry 1). Similarly, with K2CO3, and Na2CO3; no product formation was noticed after a long reaction time (Table 1, Entry 2–3). Alternatively, switching the catalytic system from inorganic bases to organic bases including Et3N, DABCO, DBU, and DMAP in grinding conditions leads to the corresponding products in poor to moderate yields with slightly reduced reaction times (Table 1, Entry 3–6). The excellent yield of the product was achieved when the reaction was executed by grinding the reactants, benzaldehyde 1a, malononitrile 2, and 5,5-dimethylcyclohexane-1,3-dione 3a in a mortar and pestle in presence of 10 mol% of Brønsted acid TsOH.H2O as the organocatalyst using water (ⴄ = 0.35 µL/mg) as the liquid assisted grinding solvents (LAGs) at ambient temperature within 5 minutes. The effects of different energy inputs on the model reaction in presence of TsOH.H2O were also investigated among which grinding proven to be efficient compared to others (stirring or reflux) as they required prolonged times and the yield of the product was not satisfactory (Table 1, Entry 7). With the aid of TFA, the corresponding product 4a was achieved in 78% yield within 36 minutes under grinding conditions (Table 1, Entry 8). In the meantime, the model reaction under ultrasound irradiation was found to slightly proceed in presence of NH2SO3H as the organocatalyst to deliver the desired product 4a in 70% yield where using grinding only 65% of the product was isolated after 2 hours (Table 1, Entry 9). The applicability of taurine as a green bio-based catalyst under grinding as well as reflux conditions were also demonstrated. But no improvements in the rate of the reaction and complete conversion were observed (Table 1, Entry 10). The synergic combination of the features of TsOH.H2O as operationally simple, inexpensive, and readily available metal-free organocatalyst along with the efficiency associated to the use of water as a safe, eco-friendly green liquid assisted grinding solvent prompted us to consider water-assisted grinding of benzaldehyde, malononitrile, and 5,5-dimethylcyclohexane-1,3-dione with the aid of a simple mortar and pestle by employing 10 mol% of TsOH.H2O as the optimum reaction condition for the synthesis of 2-amino-3-cyano-4H-chromene at ambient temperature.
Table 1
Screening of catalytic system for the synthesis of 2-amino-3-cyano-4H-chromenesa
Entry
|
Catalyst (loading)
|
Condition
|
Timeb
|
Yield (%)c
|
1
|
Catalyst-free
|
Grinding
|
24 h
|
NR
|
2
|
K2CO3 (10 mol %)
|
Grinding
|
1 h
|
NR
|
3
|
Na2CO3
|
Grinding
|
2 h
|
NR
|
3
|
Et3N (10 mol %)
|
Grinding
|
1.5 h
|
58
|
4
|
DABCO (10 mol %)
|
Grinding
|
0.5 h
|
45
|
5
|
DBU (10 mol %)
|
Grinding
|
40 min
|
50
|
6
|
DMAP (10 mol %)
|
Grinding
|
1 h
|
38
|
7
|
TsOH.H2O
(10 mol %)
|
Grinding
Stirring
Reflux
|
5 min
2 h
3 h
|
96
80d
76d
|
8
|
TFA (10 mol %)
|
Grinding
|
25 min
|
78
|
9
|
NH2SO3H
(10 mol %)
|
Grinding
USe
|
2 h
36 min
|
65
70f
|
10
|
Taurine (10 mol %)
|
Reflux
Grinding
|
78 min
55 min
|
42d
65g
|
a Reaction condition: Benzaldehyde 1 (1.0 mmol), malononitrile 2 (1.0 mmol), and 5,5-dimethylcyclohexane-1,3-dione 3a (1.0 mmol) in the presence or absence of catalyst(s) in H2O (ⴄ = 0.35 µL/mg) as LAGs [η = V (liquid; µL)/m (reagents; mg)] at ambient temperature. b Progress of the reaction was scrutinized by TLC. c Yields of the isolated products. d Reaction was carried out with 3 mL of water as the solvent. e Ultrasound irradiation. f Sonication was performed using an ultrasonic bath (model: SB-3200DT) with an operating frequency of 40 kHz and nominal power of 180 W. g Using 20 mol% of taurine. NR- No Reaction |
The effect of different LAGs and the amount of catalyst on the model reaction was further examined (Fig. 2). The preliminary used EtOH, IPA, DMF, DCM as LAGs (ⴄ = 0.35 µL/mg) and neat grinding under the influences of TsOH.H2O reduces the yield of the products even after increasing the amount of the catalyst from 2 mol% to 15 mol%. To our delight, the best results were accomplished while performing the reaction with water by employing 10 mol% of catalyst at ambient conditions. Further, increases or decreases in the catalyst loading had no suspicious significance in the rate of the reaction.
With the optimum conditions in hand, the general feasibility of the present protocol was demonstrated by treating a diverse set of aryl aldehydes 1b-o with malononitrile 2, and 5,5-dimethylcyclohexane-1,3-dione 3a in presence of 10 mol% of TsOH.H2O in water (ⴄ = 0.35 µL/mg) using liquid assisted mechanical grinding conditions (Scheme 3, Table 2). Surprisingly, the corresponding 2-amino-3-cyano-4H-chromene products 4a-t were obtained in good to excellent yield in all the cases within 5–10 minutes. Aldehydes possessing electron-donating groups including methyl and –OMe afforded the desired products 4b and 4c in 88% and 86% yield respectively at 8 minutes (Table 2). While substitution by different halogen groups like F, Cl, Br on C-4 and C-3 positions of the phenyl ring of the aldehyde was found to be efficiently delivered the products 4d, 4e, 4f, 4j, 4l in excellent yields. Strong electron-withdrawing groups like NO2 and CN attached to the benzaldehyde ring proceeded smoothly under the standard condition. The reaction was also found to be well worked for heteroaryl aldehydes, getting the respective products 4m, 4n, and 4o in 90%, 92%, and 93% yields correspondingly. Similarly, using cyclohexane-1,3-dione 3b instead of 5,5-dimethylcyclohexane-1,3-dione 3a, the three-component reaction with various aryl as well as heteroaryl aldehydes and malononitrile under the standard reaction conditions afforded the desired products 4p-t in good to excellent yield (86–97% yield) within 6 to 10 minutes (Table 2).
Enlightened by these results, we extended this domino three-component reaction of malononitrile 2, 5,5- dimethylcyclohexane-1,3-dione 3a with isatins 5a by replacing aryl/heteroaryl aldehydes 3a-o in presence of 10 mol% of TsOH.H2O with water as LAGs under mechanochemical grinding at ambient temperature for 5 minutes (Scheme 4, Table 3). To our delight, the corresponding 2-amino-7,7-dimethyl-2',5-dioxo-5,6,7,8- tetrahydrospiro[chromene-4,3'-indoline]-3-carbonitrile 6a was obtained in 96% yield only at 5 minutes. Then we carried out a total of eleven reactions with different types of isatin derivatives such as 5-chloro isatin 5b/5-chloro isatin 5b/5-nitro isatin 5c/ N-methyl isatin 5d/ N-propyl isatin 5e/ N-benzyl isatin 5f with malononitrile 2 and 5,5-dimethylcyclohexane-1,3-dione 3a/ cyclohexane-1,3-dione 3b under the standard conditions to furnished the respective products 2-amino-3-cyano-tetrahydro-spiro[chromene-4,3'-indoline] 6b-l in 90–97% yields at 4 to 8 minutes (Table 3). Isatins having substitutions like chloro, bromo, nitro are well suited for this reaction, delivering the products 6b, 6c, 6d, and 6i in good to excellent yield. Similarly, N-unsubstituted isatins (R3 = H) (5a-d) as well as N-substituted isatins (R3 = Me, propyl, benzyl) (5e-g), were efficiently tolerated by this reaction.
To further explore the applicability of the present approach, we investigated a series of trial reactions between 1 equivalent of benzaldehyde 1a with 2 equivalent of 5,5-dimethylcyclohexane-1,3-dione 3a under different reaction conditions (Scheme 5). Initial execution of the reaction in the absence of any catalyst as well as any solvents or in presence of EtOH either in stirring, grinding, or reflux conditions, formation of the desired product 2,2'-(phenylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) 7a was not detected (Table 4, Entry 1–3). Grinding the reactants under catalyst-free conditions in water furnished the desired product in a 40% yield (Table 4, Entry 2). Then we employed 2 mol% of TsOH.H2O as the easily accessible catalyst in the model reaction in solvent-free stirring or grinding conditions, but no improvements in the rate of the reaction were observed (Table 4, Entry 5–6). Surprisingly, switching the neat grinding to liquid assisted grinding by employing ethanol, and water as the liquid assisted grinding solvents (LAGs), an increase in the yield of the product was observed (Table 4, Entry 7–8). With water as the LAGs, the desired product 7a was achieved in 87% yield in only 8 minutes under the influences of 2 mol% of the catalyst (Table 4, Entry 8). By increasing the loading of the catalyst from 2 to 5 mol%, the yield of the product was found to be increased up to 95% in only 3 minutes (Table 4, Entry 9). However, there was no change in the product yield with increased loading of the catalyst from 5 to 10 mol% (Table 4, Entry 10). In the meantime, the reaction rate was found to be slow when we changed the reaction condition with 5 mol% of TsOH.H2O in EtOH, ACN as LAGs under mechanical grinding (Table 4, Entry 11–12). On the other hand, the unusual requirements of long reaction time and low yield of the product for the reaction conducted in reflux or ultrasonication with 5 mol% of TsOH.H2O using water as the solvent system suggest the mechanochemical grinding as the best method of choice for this three-component reaction (Table 4, Entry 13–14). Furthermore, the yield of the product was also decreased when employing 5 mol% of secondary amine catalyst L-proline in water under grinding or reflux conditions (Table 4, Entry 15–16).
Table 4
Optimization of reaction conditions for the synthesis of 2,2'-aryl/heteroaryl-methylene-bis(3-hydroxy-cyclohex-2-enone) derivatives
Entry
|
Catalyst
|
Loading
|
Solvent
|
Condition
|
Time (min)b
|
Yield (%)c
|
1
|
-
|
-
|
Neat
|
Stirring
|
180
|
NR
|
2
|
-
|
-
|
Neat
|
Grinding
|
70
|
NR
|
3d
|
-
|
-
|
EtOH
|
Reflux
|
120
|
NR
|
4e
|
-
|
-
|
H2O
|
Grinding
|
30
|
40
|
5
|
TsOH.H2O
|
2 mol%
|
Neat
|
Stirring
|
90
|
NR
|
6
|
TsOH.H2O
|
2 mol%
|
Neat
|
Grinding
|
40
|
38
|
7e
|
TsOH.H2O
|
2 mol%
|
EtOH
|
Grinding
|
25
|
53
|
8e
|
TsOH.H2O
|
2 mol%
|
H2O
|
Grinding
|
8
|
87
|
9e
|
TsOH.H2O
|
5 mol%
|
H2O
|
Grinding
|
3
|
95
|
10e
|
TsOH.H2O
|
10 mol%
|
H2O
|
Grinding
|
3
|
96
|
11e
|
TsOH.H2O
|
5 mol%
|
EtOH
|
Grinding
|
15
|
69
|
12e
|
TsOH.H2O
|
5 mol%
|
ACN
|
Grinding
|
60
|
20
|
13f
|
TsOH.H2O
|
5 mol%
|
H2O
|
Ultrasound
|
90
|
55
|
14d
|
TsOH.H2O
|
5 mol%
|
H2O
|
Reflux
|
150
|
68
|
15e
|
L-proline
|
5 mol%
|
H2O
|
Grinding
|
20
|
45
|
16d
|
L-proline
|
5 mol%
|
H2O
|
Reflux
|
90
|
28
|
aReaction condition: Benzaldehyde 1a (1.0 mmol), 5,5-dimethylcyclohexane-1,3-dione 3a (2.0 mmol) in the presence or absence of catalyst(s) in different solvent system as well as neat conditions. b The progress of the reaction was scrutinized by TLC. c Yields of the isolated products. d Reaction was carried out in stirring or reflux conditions by using 3 mL of solvent. e All the starting materials were ground in a mortar and pestle using different LAGs (ⴄ = 0.25 µL/mg) where [η = V (liquid; µL)/m (reagents; mg)]. f Sonication was performed using an ultrasonic bath (model: SB-3200DT) with an operating frequency of 40 kHz and nominal power of 180 W. NR- No Reaction |
After ascertaining the optimal reaction conditions and to broadening the scopes of the reaction, a series of different types of aldehydes possessing electron-rich as well as electron-deficient substituents were treated with 5,5-dimethyl cyclohexane-1,3-dione 3a/ cyclohexane-1,3-dione 3b (Scheme 6). The reaction condition was proven to be very efficient for all the substrates and as represented in Table 5, the respective 2,2'-aryl/heteroaryl-methylene-bis(3-hydroxy-cyclohex-2-enone) products 7a-p were formed in good to excellent yields within 3 to 8 minutes without resulting in any side products. This operationally simple and highly beneficial approach efficiently tolerates different halogenated groups such as fluoro, chloro, bromo as well as other functional groups like nitro, hydroxyl present in the different positions of the aryl ring of aldehydes with both 5,5-dimethyl cyclohexane-1,3-dione 3a or cyclohexane-1,3-dione 3b and furnished the product 7b, 7c, 7d, 7f, 7g, 7j, 7k, 7l, 7m, and 7n in 98%, 96%, 93%, 95%, 94%, 95%, 93%, 87%, 96% and 95% yield respectively. Similarly, methoxy substituted aldehydes are well documented for this reaction. The reaction condition was found to be limited to aliphatic aldehydes.
Xanthenes and their derivatives on the other hand recently gained tremendous interest in medicinal chemistry and material sciences due to their remarkable therapeutic potential and optoelectronic properties allowed by their attractive structural features.88,89 They are commonly encountered in agricultural,90 laser technology91 and found in diverse pharmacological applications92–94 such as antiestrogenic, antibacterial, antimicrobial as well as hypoglycaemic activities, neuropeptide YY5 receptor antagonist, etc.
Consequently, a vast array of catalytic systems such as sulfamic acid,95 diethylamine,96 2,4,6-trichloro-1,3,5-triazine,97 p-TSA,98 and catalyst-free99 conditions have been discovered. Although the reported methodology offers several advantages, some of them suffer disadvantages like harsh reaction conditions, prolonged reaction time, high energy inputs, utilization of volatile organic solvents, non-recyclable catalytic system, low yield, and narrow substrate scopes.
Recognizing all these limitations and encouraged by our aforementioned results, as well as our ongoing interest in the multicomponent synthesis of medicinally privileged heterocycles,100–103 we performed a domino three-component reaction between 1 equivalent of salicylaldehyde 8a and 2 equivalent of 5,5-dimethyl cyclohexane-1,3-dione 3a by employing water (ⴄ = 0.25 µL/mg) as the liquid assisted additives in presence of 5 mol% of TsOH.H2O as the organocatalyst under mechanochemical grinding conditions. To our delight, the reaction afforded the corresponding 9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one, 9a in 96% yield within 8 minutes. Enlightened by this successful result, we attempted a series of reactions between different derivatives of salicylaldehydes 8 and 5,5-dimethyl cyclohexane-1,3-dione 3a/ cyclohexane-1,3-dione 3b under the standard conditions (Scheme 7, Table 6). Salicylaldehydes with halogenated substrates (R = Br) and electron releasing substrates (R = 4-OMe, 6-OMe) all were found to be very suitable for this reaction and furnished the desired products in excellent yield. On the other hand, heteroaryl substituted salicylaldehyde like 2-hydroxy naphthaldehyde also worked well in these reaction conditions (Table 6).
All of the synthesized compounds were isolated pure just by filtering off the precipitate along with continuous washing by water followed by recrystallization from ethanol. Notably, the approach does not necessitate the use of time-consuming column chromatographic techniques. The structure of the synthesized compounds has been determined based on spectroscopic analysis such as 1H NMR, 13C NMR, and HRMS (see supporting information).
To further validate the potentiality of the present one-pot three-component domino work, three preparative scales up reaction for the synthesis of 4d, 6b, 7b, and 9b on a 10 mmol scale (Scheme 8). With the help of 10 mol% of TsOH.H2O, the mechanochemical water-assisted grinding of 4-flurobenzaldehyde 1d, malononitrile 2, and 5,5-dimethyl cyclohexane-1,3-dione 3a smoothly afforded 2.94 gm (94% yield) of the desired product 4d after 10 minutes at ambient conditions (Scheme 8a). Similarly, the three-component reaction between 1.47 gm of 5-chloro isatin, 0.66 gm of malononitrile, and 1.42 gm of 5,5-dimethylcyclohexane-1,3-dione 3a efficiently proceeded at 8 minutes of grinding using 10 mol% of the TsOH.H2O in presence of water as LAGs to deliver 3.51 gm of the product 6b (95% yield) (Scheme 8b). Alternatively, we were also successful in the construction of 3.59 gm of the product 7b (93% yield) from1.24 gm of 3-flurobenzaldehyde 1i, 0.66 gm of malononitrile 2, and 2.84 gm of 3a (Scheme 8c). Similarly, by employing 5 mol% of TsOH.H2O with the aid of water-assisted mechanochemical grinding via a mortar and pestle, we synthesized the products 9b in 4.22 gm (95% yield) (Scheme 8d). Although all the four reactions took place in a slightly longer reaction time when using 10 mmol scales as compared to 1 mmol scales, the yield of the products was accomplished in the almost same quantity.