L-Proline catalyzed multicomponent one-pot synthesis of gem-diheteroarylmethane derivatives using facile grinding operation under solvent-free conditions at room temperature

Abstract

An efficient and straightforward L-proline catalyzed one-pot synthesis of a series of biologically relevant gem-(β-dicarbonyl)arylmethanes has been developed via a three-component reaction between indoles, aldehydes and C–H activated acids by grinding them together under solvent-free conditions at room temperature. Mild reaction conditions, high atom-economy, good yields, and eco-friendliness are some of the salient features of the present protocol.

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Introduction

Both 1,1-dihomoaryl- and 1,1-diheteroaryl-methane scaffolds, particularly involving indolyl and coumarolyl moieties represent “privileged” structural motifs in pharmaceutical drugs and numerous potentially bioactive natural products.^1–5 Fig. 1 offers a glimpse of such naturally occurring pharmaceutically potent molecules: 3,3′-diindolylmethane (DIM; I; anticancer),^6,7 1,1-bis(3′-indolyl)ethane (BIE; II; antibacterial),⁸ 5-bromo-1-ethyl-3-((4-fluorophenyl)(1H-imidazol-1-yl)methyl)-1H-indole (III; aromatase inhibitor),⁹ arzanol (IV; anti-inflammatory, antibiotic, anti-oxidant),¹⁰ carbochromen (V; a potent drug for estimation of coronary dilatory capacity),¹¹ warfarin (VI; anticoagulant normally used in the prevention of thrombosis and thromboembolism)¹² and bromadiolone (VII; anticoagulant functioning as a vitamin K antagonist).¹³ In spite of their natural prevalence and wide range of biological activities, gem-diheteroarylmethanes have indeed gained little attention to the synthetic chemists; one such method is reported earlier for the synthesis of gem-(β-dicarbonyl)arylmethanes by Minassi and co-workers.¹⁴ However, this method suffers from using chlorinated solvent, long reaction time (24–72 h) and poor yields in many occasions.¹⁴ Hence, the development of a simple and high-yielding environmentally benign protocol for the one-pot synthesis of such biologically relevant gem-(β-dicarbonyl)arylmethane scaffolds is of great challenge. Inspired by successful completion of one of our recent works in developing an efficient method to synthesize 3-aminoalkylated indoles,¹⁵ we thus have been motivated to explore our vision for a more facile and environmentally benign route to the title compounds. As part of our continuing efforts to develop green synthetic methodologies for useful organic transformations,^15,16 herein we wish to report a convenient, clean and highly efficient protocol for the synthesis of gem-(β-dicarbonyl)arylmethanes via multicomponent reaction (MCR) simply by grinding the mixture of indoles, C–H activated acids (4-hydroxycoumarin, 4-hydroxy-6-methyl-2H-pyran-2-one, dimedone, N,N-dimethylbarbituric acid, Meldrum's acid) and aldehydes in the absence of solvent under L-proline catalysis at room temperature (Scheme 1).

Fig. 1 Representative examples of few bioactive gem-dihomoaryl- and diheteroarylmethanes.^6–13

Scheme 1 L-Proline catalyzed three-component one-pot synthesis of gem-(β-dicarbonyl)arylmethanes.

A striking advantage of using amino acids as organocatalysts is their amphoteric nature, possessing both amine and carboxylic acid moieties—the amino group could catalyze the reaction via electrophilic imine formation and the carboxylic group might stabilize the charge generated on the nitrogen.¹⁷ Furthermore, MCR technique is now-a-days a well accepted strategy to the synthetic chemists at large for the construction of novel and complex molecular structures due to its several benefits including shorter reaction times, high atom-economy, lower costs, and avoidance of time consuming expensive purification processes.^18,19

In addition, implementation of several transformations in a single manipulation in MCR strategy is highly compatible with the goals of sustainable and “green” chemistry.^20,21 With increasing public concern over environmental degradation, the use of environmentally benign solvents like water²² and solvent-free reactions²³ offers very powerful green chemical protocols from both the economic and synthetic point of view with several advantages like reduced pollution, lower cost, and simplicity in processing, which are beneficial to the industry as well as to the environment. In recent years, mechanochemistry, i.e. reactions conducted by grinding solid reactants together, has attracted much attention because it allows promotion of reactions under solvent-free conditions.²⁴ Mechanochemical synthesis affords many advantages, such as greater efficiency with regard to time, materials, and energy usage, as well as the discovery of new or improved reactivity and products, as an alternative approach to synthesis.^24a

Results and discussion

Preliminary studies were mainly focused on optimization of the reaction conditions, and for this purpose a series of trial reactions of indole (1a), 5-bromoindole (1b) and 5-fluoroindole (1c) with benzaldehyde (2a) and 4-hydroxycoumarin (3a) were performed in 1 mmol scale in the absence and presence of different catalysts at room temperature (Table 1), and also checked the effects of varying amounts of catalyst-loading and solvents (Table 2). It was much astonishing to observe that the reaction pathway is directed towards the formation of bis-indole derivatives 5a–5c rather than the desired products 4aa, 4af and 4ah in presence of all the Lewis acid catalysts and the ionic liquid except sodium formate and L-proline, whereas the latter exhibited better performance. It was also observed that although simple indole 1a underwent the reaction affording the desired product 4aa with moderately good yield of 63% under catalyst- and solvent-free conditions, the substituted indoles 1b and 1c gave the corresponding desired product 4af and 4ah with poor yields (36% and 31%, respectively) under the same reaction conditions (Table 1; entry 11). To our delight that use of catalytic amount of L-proline was sufficient enough to enhance the reaction rate remarkably for these reactions (Table 1; entry 9). A variety of solvent systems and proportion of aldehydes were also screened for this particular reaction using L-proline as catalyst (Table 2); however, the best result was obtained when the reaction was carried out using 1.2 equivalent of aldehyde, by grinding the reactants together under solvent-free conditions (Table 2; entry 3).

Table 1 Screening of catalyst for one-pot synthesis of gem-(β-dicarbonyl)arylmethanes^a

Entry	Catalyst	Loading (mol%)	Indole (R = H)			5-Bromoindole (R = Br)			5-Fluoroindole (R = F)
			Time (h)	% Yield^b (4aa)	% Yield^b (5a)	Time (h)	% Yield^b (4af)	% Yield^b (5b)	Time (h)	% Yield^b (4ah)	% Yield^b (5c)
a Experimental conditions: 4-hydroxycoumarin (3a; 1 mmol), benzaldehyde (2a; 1.2 mmol), indole (1a; 1 mmol)/5-bromoindole (1b; 1 mmol)/5-fluoroindole (1c; 1 mmol) and catalyst on grinding under solvent-free conditions at room temperature.b Isolated yield.c Not done.
1	Anhyd·AlCl3	10	0.25	20	67	2	Trace	74	1	Trace	77
2	ZrOCl2·8H2O	10	0.33	27	60	2	Trace	72		nd^c
3	Bi(NO3)3·5H2O	10	0.33	25	58	2	Trace	69		nd^c
4	[HMIM][HSO4] (IL)	10	0.33	30	59	2	Trace	71	1.5	Trace	63
5	Sodium formate	5	1	58	Trace	4	38	21		nd^c
6	Sodium formate	10	1	61	Trace	4	38	23	2.5	41	29
7	Sodium formate	20	1	61	Trace	4	40	23	2.5	45	31
8	L-Proline	5	1	68	Trace	4	45	20		nd^c
9	L-Proline	10	1	75	Trace	4	53	24	2	61	20
10	L-Proline	20	1	78	Trace	4	53	24	2	62	20
11	No catalyst	–	1	63	Trace	8	36	51	5	31	57

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Table 2 Screening of the reactants-ratio and checking of solvent system for one-pot synthesis of gem-(β-dicarbonyl)arylmethanes^a

Entry	Condition	Reactants (in equiv.) (1a : 2a : 3a)	Time (h)	% Yield^b
a Experimental conditions: indole (1a), benzaldehyde (2a), 4-hydroxycoumarin (3a), and L-proline (10 mol%) under various conditions at room temperature.b Isolated yields.
1	Grinding	1 : 1 : 1	1	67
2	Grinding	1 : 1.1 : 1	1	69
3	Grinding	1 : 1.2 : 1	1	75
4	Grinding	1 : 1.3 : 1	1	75
5	Stirred in EtOH	1 : 1.2 : 1	24	39
6	Stirred in H2O	1 : 1.2 : 1	24	Trace
7	Stirred in THF	1 : 1.2 : 1	24	Trace

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To explore the scope and generality of the present MCR protocol for the synthesis of gem-(β-dicarbonyl)arylmethanes under the optimized conditions, a variety of aromatic aldehydes (2) containing electron donating or electron withdrawing substituents in the aromatic ring such as –Me, –OCH₂O–, –F, –Cl, and –NO₂ were reacted with 4-hydroxycoumarin (3a) and substituted indoles 1 (1H-indole, 5-bromo-1H-indole, 5-fluoro-1H-indole, and 2-methyl-1H-indole) to furnish diverse gem-(β-dicarbonyl)arylmethanes; butyraldehyde, an aliphatic aldehyde, was also found to undergo the reaction giving rise to the desired products 4ad and 4bd (Table 3) in 65% and 44% yields, respectively.

Table 3 L-Proline catalyzed one-pot synthesis of gem-(β-dicarbonyl)arylmethanes via three-component reaction^a

a Experimental conditions: C–H activated acid (1 mmol), aldehyde (1.2 mmol), indole (1 mmol) and L-proline (10 mol%) by grinding under solvent free conditions at room temperature.

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The present protocol was successfully extended for the other four C–H activated acids viz. 4-hydroxy-6-methyl-2H-pyran-2-one (3b), dimedone (3c), N,N-dimethylbarbituric acid (3d), and Meldrum's acid (3e) for which the desired gem-(β-dicarbonyl)-arylmethanes (4ba–4ed; Table 3) were obtained in moderate to good yields. In case of 2-methylindole, the isolated yield of the product 4ce is only 40%; it is supposed that the introduction of the electron-donating methyl group into the indole nucleus enhances its reactivity prior to the C–H activated acids leading to the rapid formation of bis-indole derivative. The overall results are summarized in Table 3. In this connection it is to be mentioned that the products 4 are non-racemic in nature as expected from the use of L-proline as a catalyst. All the entries were found to exhibit optical rotations with a varying degree of [α]_D; however, enantiomeric ratio (er) of the isomers for the respective products 4 are not reported in this present communication. It is also to note that the products 4da–4dc and 4ea–4ed arising out of the reaction of N,N-dimethylbarbituric acid (3d) and Meldrum's acid (3e), respectively are expected to be of diastereoisomeric mixtures (syn and anti with respect to the α-H), and this has been observed in case of 4ea–4ed, whereas 4da–4dc were obtained with complete syn-diastereoselectivity.

We suggest herein a plausible mechanism for the L-proline catalyzed synthesis of the gem-(β-dicarbonyl)arylmethanes 4 (Scheme 2). It is well-reported in literature that L-proline can effectively participate in the formation of iminium salt¹⁷ and also can act as an efficient catalyst both in Mannich^17b,25 and Michael^17a,b,26 reactions. Thus the initially formed iminium salt (5) arising out of the reaction between aldehyde (2) and L-proline, undergoes Mannich reaction with C–H activated acid (3) to generate intermediate 7 which immediately takes part in Michael addition with the indole moiety (1) affording the desired product 4. L-Proline releases out for the next cycle.

Scheme 2 Plausible mechanism for the L-proline catalyzed multicomponent synthesis of the gem-(β-dicarbonyl)arylmethanes (4).

Conclusions

In conclusion, we have developed a green and efficient organo-catalysed multicomponent reaction of C–H activated acids, aldehydes, and indoles for the synthesis of a series of biologically interesting gem-(β-dicarbonyl)arylmethane derivatives under solvent-free conditions at room temperature. L-Proline is a very useful and environmentally friendly organo-catalyst to validate this useful transformation in a facile manner. In addition to other notable outcomes such as mild and solvent-free reaction conditions, operational simplicity and good yields, the major advantage of our present protocol is an improved conditions for the synthesis of gem-(β-dicarbonyl)-arylmethane derivatives instead of the formation of usual bis-indoles. It is to be mentioned herein that all the synthesized entries are non-racemic in nature; the effect of L-proline on imparting the degree of stereoselectivity of this reaction is under study.

Experimental

General

Infrared spectra were recorded using a Shimadzu (FT-IR 8400S) FT-IR spectrophotometer using KBr disc. ¹H and ¹³C nuclear magnetic resonance (NMR) spectra were obtained at 400 and 100 MHz, respectively, using Bruker DRX spectrometer (Bruker Instruments, Billerica, MA, USA) and DMSO-d₆ as the solvent. Mass spectra (TOF-MS) were measured on a QtofMicro™ mass spectrometer. Elemental analyses were performed with an Elementar Vario EL III Carlo Erba 1108 micro-analyzer instrument (Carlo Erba Reagenti SpA, Rodano, Italy), and optical rotation was measured on a polarimeter manufactured by Bellingham Stanley Ltd. (Model ADP410). Melting points were recorded on a Chemiline CL725 melting point apparatus and are uncorrected. Column chromatography was carried out over silica gel (Merck 60–120 mesh) and TLC was performed using silica gel 60 F₂₅₄ (Merck) plates.

General procedure for preparation of gem-diheteroaryl methane derivatives (4aa–4ed)

In an oven-dried watch-glass, C–H activated acid (4-hydroxycoumarine 3a or 4-hydroxy-6-methyl-2H-pyran-2-one 3b or dimedone 3c or N,N-dimethylbarbituric acid 3d or Meldrum’s acid 3e; 1 mmol), aldehyde (2; 1.2 mmol), indole (1; 1 mmol), and L-proline (10 mol%) were taken together, and instantly started to grind the mixture by a spatula. After few minutes of scratching/grinding, when the solid reaction mixture liquefied followed by semi-solidification, it was left for stipulated time (Table 3) with occasional grinding till it solidified again. After completion of the reaction (as monitored by TLC), the solid reaction mixture was subjected to column chromatography using silica gel (60–120 mesh) and petrol ether-ethyl acetate mixture to furnish the pure products (4aa–4ed), characterized by conventional spectroscopic methods and elemental analyses. It was also possible to isolate pure products of 4aa–4af and 4da–4dc without using column chromatographic resolution just by washing the crude products in ethanol—however, with ∼5–7% lower yields in comparison to the generalized method, possibly due to partial solubility of these compounds in ethanol.

Characterization data of selected entries

3-((4-Fluorophenyl)(1H-indol-3-yl)methyl)-4-hydroxy-2H-chromen-2-one (4ab). Pinkish white solid (0.312 g, 81%); mp 195–197 °C; [α]²⁵_D = +31.5 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 6.11 (s, 1H, –CH), 6.92 (t, J = 7.2 Hz, 1H, ArH), 7.06 (t, 3H, J = 8.8, 8.4 Hz, ArH), 7.13 (s, 1H, ArH), 7.36 (t, J = 7.6, 10.4 Hz, 6H, ArH), 7.60 (t, J = 7.6, 7.2 Hz, 1H, ArH), 8.04 (d, J = 7.6 Hz, 1H, ArH), 10.95 (s, 1H, –NH), 11.69 (s, 1H, –OH). ¹³C NMR (100 MHz, DMSO-d₆): δ 36.94, 108.82, 111.96, 114.52, 114.66, 114.87, 116.66, 116.71, 118.83, 118.91, 121.33, 123.95, 124.26, 124.74, 127.57, 130.38, 130.46, 132.38, 136.50, 139.24, 152.66, 159.79, 160.81, 162.20. IR ν_max (KBr): 3437, 3317, 3284, 3095, 3043, 2901, 2850, 1687, 1612, 1534, 1497, 1336, 1159, 1099, 1036, 945, 854, 758 cm⁻¹. TOF-MS: calcd for C₂₄H₁₆FNO₃Na [M + Na]⁺: 408.1012; found: 408.1015. Anal. calcd for C₂₄H₁₆FNO₃: C, 74.80; H, 4.18; N, 3.63; found: C, 74.82; H, 4.16; N, 3.66.

3-(1-(1H-Indol-3-yl)butyl)-4-hydroxy-2H-chromen-2-one (4ad). White solid (0.217 g, 65%); mp 139–140 °C; [α]²⁵_D = +42.3 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 0.95 (s, 3H, –CH₃), 1.35 (s, 2H, –CH₂), 2.09 (br s, 1H, –CH), 2.40 (br s, 1H, –CH) 4.73 (s, 1H, –CH), 6.90 (s, 1H, ArH), 7.00 (s, 1H, ArH), 7.30 (d, J = 4 Hz, 4H, ArH), 7.53 (d, J = 5.6 Hz, 2H, ArH), 8.03 (d, J = 5.2 Hz, 1H, ArH), 10.79 (s, 1H, –NH), 11.40 (br s, 1H, –OH). ¹³C NMR (100 MHz, DMSO-d₆): δ 14.14, 20.87, 31.21, 33.40, 108.27, 111.29, 116.03, 116.16, 116.21, 118.08, 118.31, 120.56, 122.87, 123.28, 123.66, 127.11, 131.50, 135.82, 152.01, 159.65, 161.35. IR ν_max (KBr): 3412, 3217, 3176, 3149, 2955, 2930, 2858, 1677, 1612, 1564, 1497, 1448, 1340, 1207, 1157, 1105, 1040, 879, 752 cm⁻¹. TOF-MS: calcd for C₂₁H₁₉NO₃Na [M + Na]⁺: 356.1263; found: 356.1269. Anal. calcd for C₂₁H₁₉NO₃: C, 75.66; H, 5.74; N, 4.20; found: C, 75.69; H, 5.73; N, 4.21.

3-(Benzo[d][1,3]dioxol-5-yl(1H-indol-3-yl)methyl)-4-hydroxy-2H-chromen-2-one (4ae). Brownish white solid (0.313 g, 76%); mp 242–244 °C; [α]²⁵_D = −33.2 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 5.95 (s, 2H, –CH₂), 6.26 (s, 1H, –CH), 6.62 (d, J = 8 Hz, 1H, ArH), 6.71 (s, 1H, ArH), 6.76 (d, J = 8.4, 1H, ArH), 7.31–7.37 (m, 5H, ArH), 7.59 (t, J = 7.2, 8 Hz, 2H, ArH), 7.91 (d, J = 7.6 Hz, 2H, ArH), 10.81 (s {weak}, 1H, –NH), 10.89 (s {weak}, 1H, –OH). ¹³C NMR (100 MHz, DMSO-d₆): δ 35.79, 100.68, 104.33, 107.50, 107.72, 115.93 (2C), 118.00, 119.49 (2C), 123.68 (2C), 123.89 (2C), 128.66, 131.57, 131.83 (2C), 133.91, 145.16, 147.27, 152.23 (2C), 164.70, 165.29. IR ν_max (KBr): 3409, 3295, 3119, 3084, 3049, 2893, 1655, 1636, 1607, 1560, 1491, 1232, 1184, 1040, 933, 764 cm⁻¹. TOF-MS: calcd for C₂₅H₁₇NO₅Na [M + Na]⁺: 434.1004; found: 434.1001. Anal. calcd for C₂₅H₁₇NO₅: C, 72.99; H, 4.16; N, 3.40; found: C, 72.95; H, 4.16; N, 3.39.

3-((5-Bromo-1H-indol-3-yl)(phenyl)methyl)-4-hydroxy-2H-chromen-2-one (4af). Brownish white solid (0.237 g, 53%); mp 138–140 °C; [α]²⁵_D = +12.8 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 6.09 (s, 1H, –CH), 7.15–7.19 (m, 2H, ArH), 7.23–7.29 (m, 5H, ArH), 7.35–7.38 (m, 3H, ArH), 7.48 (d, J = 1.6 Hz, 1H, ArH), 7.59–7.63 (m, 1H, ArH), 8.05 (dd, J = 1.6, 0.8, 8.2 Hz, 1H, ArH), 11.17 (d, J = 1.2 Hz, 1H, –NH), 11.75 (br s, 1H, –OH). ¹³C NMR (100 MHz, DMSO-d₆): δ 37.18, 108.63, 111.45, 114.00, 114.38, 116.67, 121.16, 123.37, 123.69, 123.99, 124.29, 126.23, 126.68, 128.24 (2C), 128.46 (2C), 129.59, 132.41, 135.08, 142.80, 152.65, 160.82, 162.15. IR ν_max (KBr): 3398, 3265, 3242, 3074, 3022, 2895, 2860, 1687, 1616, 1566, 1489, 1452, 1415, 1326, 1248, 1169, 1105, 1041, 939, 887, 758 cm⁻¹. TOF-MS: calcd for C₂₄H₁₆BrNO₃Na [M + Na]⁺: 468.0211; found: 468.0218. Anal. calcd for C₂₄H₁₆BrNO₃: C, 64.59; H, 3.61; N, 3.14; found: C, 64.63; H, 3.60; N, 3.17.

3-((5-Fluoro-1H-indol-3-yl)(phenyl)methyl)-4-hydroxy-2H-chromen-2-one (4ah). Reddish white solid (0.235 g, 61%); mp 178–179 °C; [α]²⁵_D = +23.2 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 6.06 (s, 1H, –CH), 6.88–6.92 (m, 1H, ArH), 7.01 (d, J = 10 Hz, 1H, ArH), 7.15–7.18 (m, 1H, ArH), 7.23–7.29 (m, 5H, ArH), 7.34–7.38 (m, 3H, ArH), 7.61 (t, J = 8, 7.6 Hz, 1H, ArH), 8.03 (d, J = 7.6 Hz, 1H, ArH), 11.06 (s, 1H, –NH), 11.80 (br s, 1H, –OH). ¹³C NMR (100 MHz, DMSO-d₆): δ 37.34, 103.42, 103.65, 108.62, 109.22, 109.47, 112.85, 112.95, 114.79, 116.67, 123.95, 124.30, 126.21, 127.03, 127.86, 127.95, 128.24, 128.48, 132.41, 133.05, 142.77, 152.63, 160.84, 162.17. IR ν_max (KBr): 3480, 3328, 3278, 3107, 1686, 1614, 1564, 1494, 1219, 1161, 1061, 897, 847, 760 cm⁻¹. TOF-MS: calcd for C₂₄H₁₆FNO₃Na [M + Na]⁺: 408.1012; found: 408.1015. Anal. calcd for C₂₄H₁₆FNO₃: C, 74.80; H, 4.18; N, 3.63; found: C, 74.88; H, 4.15; N, 3.61.

3-((4-Chlorophenyl)(1H-indol-3-yl)methyl)-4-hydroxy-6-methyl-2H-pyran-2-one (4bb). Brown solid (0.209 g, 57%); mp 107–109 °C; [α]²⁵_D = +23.6 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 2.15 (s, 3H, –CH₃), 5.78 (s, 1H, –CH), 6.02 (s, 1H, –CH), 6.90 (t, J = 7.6 Hz, 1H, ArH), 7.03–7.06 (m, 2H, ArH), 7.22–7.27 (m, 5H, ArH), 7.35 (d, J = 8 Hz, 1H, ArH), 10.86 (s, 1H, –NH), 11.51 (br s, 1H, –OH). ¹³C NMR (100 MHz, DMSO-d₆): δ 19.35, 35.63, 100.02, 103.78, 111.49, 114.23, 118.38, 120.86 (2C), 124.13, 127.11, 127.57 (2C), 130.06 (2C), 130.10, 136.03, 142.26, 161.03, 163.90, 165.52. IR ν_max (KBr): 3402, 3261, 3042, 2945, 2920, 1670, 1634, 1576, 1489, 1444, 1404, 1279, 1094, 968, 831, 742 cm⁻¹. TOF-MS: calcd for C₂₁H₁₆ClNO₃Na [M + Na]⁺: 388.0716; found: 388.0721. Anal. calcd for C₂₁H₁₆ClNO₃: C, 68.95; H, 4.41; N, 3.83; found: C, 68.97; H, 4.39; N, 3.85.

3-((5-Bromo-1H-indol-3-yl)(phenyl)methyl)-4-hydroxy-6-methyl-2H-pyran-2-one (4bc). Deep brown solid (0.246 g, 60%); mp 110–112 °C; [α]²⁵_D = +35.3 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 2.15 (s, 3H, –CH₃), 5.76 (s, 1H, –CH), 6.03 (s, 1H, –CH), 7.09 (d, J = 2 Hz, 1H, ArH), 7.12–7.15 (m, 2H, ArH), 7.23–7.24 (m, 4H, ArH), 7.32 (s, 1H, ArH), 7.34–7.37 (m, 1H, ArH), 11.07 (s, 1H, –NH), 11.46 (s, 1H, –OH). ¹³C NMR (100 MHz, DMSO-d₆): δ 19.28, 35.91, 101.55, 103.65, 110.84, 113.46, 114.64, 120.56, 123.10, 125.65, 125.90, 126.53, 127.70, 127.96, 128.06, 129.04, 134.62, 142.63, 163.75, 165.38, 166.32. IR ν_max (KBr): 3398, 3362, 3317, 3076, 3006, 2922, 2851, 1668, 1570, 1556, 1447, 1275, 1099, 1033, 987, 878, 702 cm⁻¹. TOF-MS: calcd for C₂₁H₁₆BrNO₃Na [M + Na]⁺: 432.0211; found: 432.0218. Anal. calcd for C₂₁H₁₆BrNO₃: C, 61.48; H, 3.93; N, 3.41; found: C, 61.46; H, 3.95; N, 3.43.

2-((1H-Indol-3-yl)(phenyl)methyl)-3-hydroxy-5,5-dimethylcyclohex-2-enone (4ca). Brownish white solid (0.242 g, 70%); mp 164–168 °C; [α]²⁵_D = +22.7 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 1.01 (s, 6H, 2CH₃), 2.28 (s, 4H, 2CH₂), 5.83 (s, 1H, –CH), 6.86–6.92 (m, 2H, ArH), 7.02 (t, J = 7.6, 7.2 Hz, 1H, ArH), 7.08 (d, J = 4 Hz, 1H, ArH), 7.17–7.22 (m, 5H, ArH), 7.34 (d, J = 8 Hz, 1H, ArH), 10.37 (br s, 1H, –NH), 10.73 (s, 1H, –OH). ¹³C NMR (100 MHz, DMSO-d₆): δ 28.42 (2C), 32.07, 35.42, 46.50, 49.38, 111.69, 116.39, 117.15, 118.41, 119.04, 120.96, 124.54, 125.32, 127.77, 127.94 (2C), 128.61 (2C), 136.43, 145.14, 165.41, 195.54. IR ν_max (KBr): 3443, 3394, 3325, 3269, 3240, 3045, 2949, 2862, 1676, 1601, 1581, 1564, 1495, 1448, 1265, 1225, 1148, 1105, 1016, 863, 949, 741 cm⁻¹. TOF-MS: calcd for C₂₃H₂₃NO₂Na [M + Na]⁺: 368.1626; found: 368.1630. Anal. calcd for C₂₃H₂₃NO₂: C, 79.97; H, 6.71; N, 4.05; found: C, 79.95; H, 6.69; N, 4.09.

2-((1H-Indol-3-yl)(p-tolyl)methyl)-3-hydroxy-5,5-dimethylcyclohex-2-enone (4cb). Reddish white solid (0.223 g, 62%); mp 88–92 °C; [α]²⁵_D = +23.8 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 1.00 (s, 6H, 2CH₃), 2.16 (d, J = 8 Hz, 2H, –CH₂), 2.21 (s, 3H, CH₃), 2.37–2.39 (m, 2H, –CH₂), 5.78 (s, 1H, –CH), 6.85–6.90 (m, 2H, ArH), 6.96–7.07 (m, 5H, ArH), 7.19 (d, J = 7.6 Hz, 1H, ArH), 7.33 (d, J = 8 Hz, 1H, ArH), 10.30 (s, 1H, –NH), 10.71 (s, 1H, –OH). ¹³C NMR (100 MHz, DMSO-d₆): δ 20.60, 27.97, 31.63 (2C), 34.62, 43.32, 50.45, 111.23, 116.07, 116.86, 117.94, 118.64, 120.49, 124.03, 127.49, 127.95 (2C), 128.11 (2C), 133.60, 136.01, 141.62, 170.29, 196.05. IR ν_max (KBr): 3406, 3396, 3317, 3108, 2951, 2920, 2856, 1650, 1602, 1591, 1573, 1454, 1255, 1225, 1094, 1012, 742 cm⁻¹. TOF-MS: calcd for C₂₄H₂₅NO₂Na [M + Na]⁺: 382.1783; found: 382.1788. Anal. calcd for C₂₄H₂₅NO₂: C, 80.19; H, 7.01; N, 3.90; found: C, 80.21; H, 6.99; N, 3.91.

2-((4-Fluorophenyl)(1H-indol-3-yl)methyl)-3-hydroxy-5,5-dimethylcyclohex-2-enone (4cc). Reddish brown white solid (0.244 g, 67%); mp 105–107 °C; [α]²⁵_D = +35.1 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 1.00 (s, 6H, 2CH₃), 2.17 (br s, 2H, –CH₂), 2.40 (br s, 2H, –CH₂), 5.80 (s, 1H, –CH), 6.88 (dd, J = 7.6, 8 Hz, 2H, ArH), 6.96–7.04 (m, 3H, ArH), 7.15–7.20 (m, 3H, ArH), 7.34 (d, J = 8 Hz, 1H, ArH), 10.44 (s, 1H, –NH), 10.75 (s, 1H, –OH). ¹³C NMR (100 MHz, DMSO-d₆): δ 28.39 (2C), 32.06, 34.84, 43.65, 50.84, 111.73, 114.23, 114.44, 116.21, 117.01, 118.48, 118.98, 121.02, 124.48, 127.75, 130.17, 130.25, 136.48, 141.17, 159.34, 161.73, 196.45. IR ν_max (KBr): 3398, 3278, 3052, 2947, 2864, 1709, 1585, 1500, 1223, 1149, 1085, 1014, 746 cm⁻¹. TOF-MS: calcd for C₂₃H₂₂FNO₂Na [M + Na]⁺: 386.1532; found: 386.1537. Anal. calcd for C₂₃H₂₂FNO₂: C, 76.01; H, 6.10; N, 3.85; found: C, 76.05; H, 6.11; N, 3.83.

2-((5-Fluoro-1H-indol-3-yl)(phenyl)methyl)-3-hydroxy-5,5-dimethylcyclohex-2-enone (4cf). Brownish white solid (0.236 g, 65%); mp 169–171 °C; [α]²⁵_D = +44.3 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 0.92 (s, 6H, 2CH₃), 2.20 (br s, 4H, 2CH₂), 5.68 (s, 1H, –CH), 6.77–6.80 (m, 2H, ArH), 6.92 (s, 1H, ArH), 7.01–7.03 (m, 1H, ArH), 7.09–7.13 (m, 4H, ArH), 7.25 (q, J = 4.4, 4.8, 9.4 Hz, 1H, ArH), 10.49 (br s, 1H, –NH), 10.79 (s, 1H, –OH). ¹³C NMR (100 MHz, DMSO-d₆): δ 28.37 (2C), 32.08 (2C), 35.38, 44.61, 103.45, 103.68, 108.86, 109.12, 112.57, 112.67, 116.70, 125.45, 126.71, 127.87, 127.99, 128.53, 135.06, 144.63, 155.68, 157.97, 195.23. IR ν_max (KBr): 3487, 3366, 2949, 1682, 1548, 1473, 1253, 1163, 1084, 1024, 842, 783 cm⁻¹. TOF-MS: Calcd for C₂₃H₂₂FNO₂Na [M + Na]⁺: 386.1532; found: 386.1529. Anal. calcd for C₂₃H₂₂FNO₂: C, 76.01; H, 6.10; N, 3.85; found: C, 76.03; H, 6.08; N, 3.87.

5-((1H-Indol-3-yl)(phenyl)methyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4da). White solid (0.329 g, 91%); mp 172–174 °C; [α]²⁵_D = +34.8 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 2.76 (s, 3H, –CH₃), 2.89 (s, 3H, –CH₃), 4.89 (d, J = 2.8 Hz, 1H, –CH), 4.96 (d, J = 2.8 Hz, 1H, –CH), 6.81 (t, J = 7.2, 7.6 Hz, 1H, ArH), 6.97 (t, J = 7.2, 7.6 Hz, 1H, ArH), 7.05 (d, J = 8 Hz, 1H, ArH), 7.09–7.20 (m, 5H, ArH), 7.29 (d, J = 8 Hz, 1H, ArH), 7.40 (br s, 1H, ArH), 10.98 (s, 1H, –NH). ¹³C NMR (100 MHz, DMSO-d₆): δ 28.19, 28.32, 47.19, 55.11, 112.00, 118.80, 118.97, 121.64, 124.85 (2C), 126.75 (2C), 127.59 (2C), 128.52 (2C), 136.47, 139.96, 151.51, 168.35, 169.15. IR ν_max (KBr): 3144, 3063, 3034, 2955, 1738, 1680, 1672, 1444, 1286, 1136, 1107, 1008, 927, 837, 762 cm⁻¹. TOF-MS: calcd for C₂₁H₁₉N₃O₃Na [M + Na]⁺: 384.1324; found: 384.1328. Anal. calcd for C₂₁H₁₉N₃O₃: C, 69.79; H, 5.30; N, 11.63; found: C, 69.82; H, 5.28; N, 11.59.

5-((5-Fluoro-1H-indol-3-yl)(phenyl)methyl)-1,3-dimethyl pyrimidine-2,4,6(1H,3H,5H)-trione (4dc). White solid (0.353 g, 93%); mp 174–176 °C; [α]²⁵_D = +31.9 (acetone, c 1.0); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): δ 2.84 (s, 3H, –CH₃), 2.96 (s, 3H, –CH₃), 4.38 (d, J = 3.2 Hz, 1H, –CH), 5.00 (d, J = 2.8 Hz, 1H, –CH), 6.79–6.92 (m, 2H, ArH), 7.20–7.28 (m, 5H, ArH), 7.36 (q, J = 4.4 Hz, 1H, ArH), 7.58 (s, 1H, ArH), 11.18 (s, 1H, –NH). ¹³C NMR (100 MHz, DMSO-d₆): δ 28.20, 28.31, 46.91, 54.93, 103.45, 103.68, 109.63, 109.89, 112.97, 113.07, 113.45, 127.00, 127.64, 128.54, 133.12, 139.73, 151.51, 155.83, 158.13, 168.32, 169.04. IR ν_max (KBr): 3388, 3122, 2951, 1747, 1668, 1467, 1288, 1170, 1105, 925, 806, 761 cm⁻¹. TOF-MS: calcd for C₂₁H₁₈FN₃O₃Na [M + Na]⁺: 402.1230; found: 402.1233. Anal. calcd for C₂₁H₁₈FN₃O₃: C, 66.48; H, 4.78; N, 11.08; found: C, 66.46; H, 4.75; N, 11.03.

5-((1H-Indol-3-yl)(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (4ea). White solid (0.234 g, 67%); mp 129–131 °C; [α]²⁵_D = +41.6 (acetone, c 1.0 for syn-isomer); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): for syn isomer: δ 1.45 (s, 3H, –CH₃), 1.74 (s, 3H, –CH₃), 5.17 (d, J = 2.8 Hz, 1H, –CH), 5.35 (d, J = 2.4 Hz, 1H, –CH), 6.79–6.86 (m, 1H, ArH), 6.92–7.02 (m, 2H, ArH), 7.07–7.19 (m, 4H, ArH), 7.22–7.25 (m, 2H, ArH), 7.36 (dd, J = 1.6, 2.4, 4.8 Hz, 1H, ArH), 10.95 (s, 1H, –NH). ¹³C NMR (100 MHz, DMSO-d₆): δ 27.19, 28.14, 31.14, 52.14, 105.46, 111.90, 113.67, 119.01, 121.62, 124.38, 126.47, 126.79, 128.22, 128.42, 128.66, 129.32, 136.25, 141.66, 143.37, 165.52, 166.05. IR ν_max (KBr): 3398, 2970, 2941, 1761, 1745, 1604, 1307, 1215, 1081, 1012, 904, 829, 756 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): for anti isomer: δ 1.99 (s, 6H, 2CH₃), 4.27 (d, J = 12.4 Hz, 1H, –CH), 4.74 (d, J = 12.4 Hz, 1H, –CH), 6.79–6.86 (m, 1H, ArH), 6.92–7.02 (m, 2H, ArH), 7.07–7.19 (m, 4H, ArH), 7.30 (d, J = 8.4 Hz, 2H, ArH), 7.46 (d, J = 8 Hz, 1H, ArH), 10.82 (s, 1H, –NH). TOF-MS: calcd for C₂₁H₁₉NO₄Na [M + Na]⁺: 372.1212; found: 372.1218. Anal. calcd for C₂₁H₁₉NO₄: C, 72.19; H, 5.48; N, 4.01; found: C, 72.26; H, 5.45; N, 3.99.

5-((1H-Indol-3-yl)(p-tolyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (4eb). White solid (0.182 g, 63%); mp 128–130 °C; [α]²⁵_D = +68.2 (acetone, c 1.0 for syn-isomer); e.r. could not be evaluated at this time. ¹H NMR (400 MHz, DMSO-d₆): for syn isomer: δ 1.45 (s, 3H, –CH₃), 1.73 (s, 3H, –CH₃), 2.21 (s, 3H, –CH₃), 5.12 (s, 1H, –CH), 5.31 (s, 1H, –CH), 6.92–6.97 (m, 3H, ArH), 7.09–7.14 (m, 2H, ArH), 6.82 (q, J = 8.4, 7.6, 7.2, 15.4 Hz, 2H, ArH), 7.19–7.24 (m, 1H, ArH), 7.28–7.39 (m, 1H, ArH), 10.93 (s, 1H, –NH). ¹³C NMR (100 MHz, DMSO-d₆): δ 27.20, 28.14, 31.14, 21.02, 52.13, 105.13, 111.87, 113.88, 117.07, 118.92, 119.03, 121.57, 124.36, 127.45, 128.81, 128.98, 129.24, 135.79, 136.26, 138.55, 165.48, 166.10. IR ν_max (KBr): 3425, 3181, 2997, 2850, 1776, 1734, 1577, 1504, 1298, 1193, 1063, 902, 850, 740 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): for anti isomer: δ 2.00 (s, 6H, 2CH₃), 2.10 (s, 3H, –CH₃), 4.22 (d, J = 12 Hz, 1H, –CH), 4.69 (d, J = 12.4 Hz, 1H, –CH), 6.92–6.97 (m, 3H, ArH), 7.09–7.14 (m, 3H, ArH), 7.19–7.24 (m, 1H, ArH), 7.28–7.33 (m, 1H, ArH), 7.43 (d, J = 7.6 Hz, 1H, ArH), 10.79 (s, 1H, –NH). TOF-MS: calcd for C₂₂H₂₁NO₄Na [M + Na]⁺: 386.1368; found: 386.1372. Anal. calcd for C₂₂H₂₁NO₄: C, 72.71; H, 5.82; N, 3.85; found: C, 72.68; H, 5.80; N, 3.89.

Acknowledgements

The authors are thankful to IICB, Kolkata, CDRI (Lucknow) and Chemistry Department, Visva-Bharati University, India for spectral measurements. S.D. is grateful to the UGC, New Delhi for awarding him a Junior Research Fellowship. Financial support from CSIR, New Delhi [no. 02(0110)/12/EMR-II] is also deeply acknowledged. The authors are thankful to the reviewers for their useful comments.

References

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