Scholarly article on topic 'One pot four component sequential synthesis of hexahydroquinoline derivatives in aqueous media via enaminone intermediates: A green protocol'

One pot four component sequential synthesis of hexahydroquinoline derivatives in aqueous media via enaminone intermediates: A green protocol Academic research paper on "Chemical sciences"

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{Enaminone / "Sequential reaction" / "Hantzsch reaction" / "Crystal structure" / "Michael reaction"}

Abstract of research paper on Chemical sciences, author of scientific article — D. Patil, D. Chandam, A. Mulik, S. Jagdale, P. Patil, et al.

Abstract A convenient green chemistry method through one pot four component tandem synthesis of hexahydroquinoline via enaminone intermediate using dimedone, ammonium acetate, aryl aldehydes and malononitrile has been described in aqueous media without the use of any external catalyst. The excess of ammonium acetate used acts as a reagent as well as catalyst. The incorporation of water as solvent along with eradication of external catalyst renders the protocol to comply with the green chemistry aspects. Shorter reaction time, high atom economy, easy work up and purification of products by non-chromatographic method are the crucial features of this methodology. The crystal structure of hexahydroquinoline basically shaped by chromatographic free selective reaction was determined by single crystal X-ray diffraction analysis.

Academic research paper on topic "One pot four component sequential synthesis of hexahydroquinoline derivatives in aqueous media via enaminone intermediates: A green protocol"

Journal of Saudi Chemical Society (2014) xxx, xxx-xxx

King Saud University Journal of Saudi Chemical Society

www.ksu.edu.sa www.sciencedirect.com

ORIGINAL ARTICLE

One pot four component sequential synthesis of hexahydroquinoline derivatives in aqueous media via enaminone intermediates: A green protocol

D. Patil a, D. Chandam a, A. Mulik a, S. Jagdale a, P. Patil b, M. Deshmukh a *

a Heterocyclic Research Laboratory, Department of Chemistry, Shivaji University, Kolhapur 416 004 (MS), India b Department of Agrochemicals and Pest Management, Shivaji University, Kolhapur 416 004 (MS), India

Received 7 December 2013; revised 7 March 2014; accepted 2 April 2014

KEYWORDS

Enaminone; Sequential reaction; Hantzsch reaction; Crystal structure; Michael reaction

Abstract A convenient green chemistry method through one pot four component tandem synthesis of hexahydroquinoline via enaminone intermediate using dimedone, ammonium acetate, aryl aldehydes and malononitrile has been described in aqueous media without the use of any external catalyst. The excess of ammonium acetate used acts as a reagent as well as catalyst. The incorporation of water as solvent along with eradication of external catalyst renders the protocol to comply with the green chemistry aspects. Shorter reaction time, high atom economy, easy work up and purification of products by non-chromatographic method are the crucial features of this methodology. The crystal structure of hexahydroquinoline basically shaped by chromatographic free selective reaction was determined by single crystal X-ray diffraction analysis.

© 2014 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

1. Introduction

MCRs with their requisition of substantially simpler method and operations as compared to the conventional multistep methods of heterocycle synthesis have gained enormous interest in diversity oriented synthesis in organic, medicinal and combinatorial chemistry [3,32]. Furthermore, the MCR tactics are determined to be economical owing to their reduction in

* Corresponding author. Fax: +91 0231 2692333. E-mail address: shubhlaxmi111@gmail.com (M. Deshmukh). Peer review under responsibility of King Saud University.

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steps thereby saving synthetic time, efforts and sustained expensive purification process besides the protection and deprotections [6,30]. Recently, MCRs have become an governing tool for atom efficient and waste free synthesis of complex building blocks of'drug-like' motifs [13,14]. MCRs are tandem reactions which offer an influential approach for molecular complexity from simple preliminary materials. These reactions prevent the fall of overall steps by avoiding isolations of extremely reactive intermediates [4,10].

In recent days, aqueous mediated reactions have captured a considerable attention in organic synthesis as a result of both economic and environmental safety reasons. The consistent persuasion water as solvent for organic reaction arises due to its abundance, economical nature, high polarity, high reactivity, typical selectivity and existence of strong hydrogen

1319-6103 © 2014 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.Org/10.1016/j.jscs.2014.04.001

bonding also supplemented by convenient work up and purification carried out by simple filtration or extraction [13,14,28]. In addition to this large surface tension, high specific heat capacity and the high cohesive energy, salting in or salting out effect, variation of pH and chemo enzymatic strategies are some of the unique properties of water that can significantly impact the conversions performed in this media. In particular, reactions with negative activation volume are reported to occur faster in water than in organic solvents [7,24].

Breslow, in 1980 rediscovered the use of water as solvent in organic reaction which proved that hydrophobic effects might strongly increase the rate of organic reaction [1]. Consequently the use of water as an environmentally benign solvent for chemical transformation has developed into the demand of the present day researchers.

Quinoline and their derivatives performing as a core unit in several natural products and drugs attributing to their diverse applications in the pharmaceutical industries uphold a remarkable place among the heterocyclic compounds [12]. Quinolines having 1,4-DHP nucleus have been reported as significant compounds due to their therapeutic and pharmacological properties such as vasodilator, antitumor, bronchodilator, geroprotective, antimalarial, anti-inflammatory, antiasthemat-ic, and antibacterial activities [17,29].

In particular, now days 1, 4-DHP nucleus containing drugs nimodipine, lacidipine posses improved calcium channel antagonist activity [18,21] (Fig. 1) and the cardiovascular agents such as nifedipine, nicardipine, and amlodipine are effective against treatment of hypertension [16].

Hantzsch and Liebigs reported the synthesis of 1,4-dihyro-pyridine by traditional method which involved cyclocondensation of aldehyde with ethyl acetoacetate and ammonia reflux in alcohol or in acetic acid for a prolonged time [8].

A brief review on the literature reveals that the synthesis of quinoline derivatives can be achieved by using organocatalysts [15], CAN [25], ionic liquids [11], Sc(OTf)3 [5], iodotrimethylsi-lane (ITMS) [26], microwave irradiation [19,28,31], Yb(OTf)3 [33], L-proline [9], Bi(NO3)3 5H2O [20] etc.

Nevertheless, most of the reported methods still suffer from several drawbacks, such as the long reaction time, unsatisfactory yields, drastic reaction condition, use of organic solvents as well as expensive catalysts and tedious work up procedures. Hence there emerges a through need to develop an ecological and efficient methodology for the synthesis of hexahydroquin-oline derivatives.

In prolongation of our efforts for the development of synthetic methodologies for the synthesis of heterocyclic

Scheme 1 Synthesis of hexahydroquinoline derivatives from tandem reaction.

compounds [23], we report herein an eco-friendly, expedient, atom economic and highly efficient protocol for the tandem synthesis of hexahydroquinoline derivatives via four component condensation of dimedone, aryl aldehydes, malononitrile and excess of ammonium acetate as a reagent and neutral catalyst in aqueous media (Scheme 1).

2. Experimental

2.1. General

All reagents were purchased from Thomas Baker and S.D. fine chemicals. Melting points were measured by a Labstar melting apparatus and were uncorrected. Monitoring the progress of all reactions was carried out by the thin layer chromatography (TLC). Infrared spectra were recorded on a Perkin-Elmer, FTIR-1600 spectrophotometer in KBr with absorption in cm _1. 1H NMR and 13C NMR spectra were determined on a Bruker Avance (300 and 75 MHz) spectrometer as DMSO-d6 solutions, using tetramethylsilane (TMS) as the internal standard. Chemical shifts (d) are expressed in ppm and Coupling constants J are given in Hz. Mass spectra were recorded on a Performa spectrometer.

2.2. X-ray structure analysis

X-ray diffraction data of compound 5m was collected at T = 298 K on a Bruker APEXII CCD diffractometer with graphite monochromated Mo Ka (k = 0.71073 A) radiation. Table 4 shows the unit cell parameters and other crystallo-graphic details. The determination of cell refinement and data reduction were performed with program SAINT [2]. The

structure was solved using direct methods of program SHEL-XS97 and refined anisotropically by full-matrix least-square on F2 carried out with the program SHELXL97 [27].

2.3. General procedure for the synthesis of substituted hexahydroquinoline (5a-5q)

In a 50 ml round bottom flask 5,5-dimethylcyclohexane-1,3-dione (1 mmol) and excess of ammonium acetate (3.3 mmol) in water (10 ml) were added. Then the reaction mixture was stirred at 100 0C for approximately 35-40 min. Afterward, malononitrile (1 mmol), and aryl aldehyde (1 mmol) were charged, and the mixture was stirred at 100 0C for 30 min. After completion of reaction [monitored by TLC, ethyl acetate: n-hexane (3:7)], the reaction mixture was stirred at RT. The generated solid was filtered off and recrystallized from ethanol to afford pure product.

2.4. Characterization data of some novel representative compounds

Table 1 Optimization of the catalyst for one-pot tandem synthesis of hexahydroquinolines.a

Entry Catalyst (loading) Condition Time (h) Yield (%)b

1 - RT 12 c

2 - 70 9

3 - 80 6

4 - Reflux 7 30

5 AcONH4 (0.5 mmol) Reflux 4 45

6 AcONH4 (l mmol) Reflux 3.5 55

7 AcONH4 (l.5 mmol) Reflux 2 67

8 AcONH4 (2 mmol) Reflux 1 89b,79d

9 AcONH4 (2.5 mmol) Reflux 1 88

a Reaction condition: 5,5-dimethyl 1,3-cyclohexadione (1 mmol), ammonium acetate (1.3 mmol), 3-trifluoro methyl benzaldehyde (1 mmol), and malononitrile (1 mmol) in water (10 ml). b Isolated yield. c No reaction occurred.

d % Atom economy = (MW of desired product/^] of all reactants) x 100 = 79%.

2.4.1. 2-Amino-4-[4-(nitro) phenyl]-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline (5i)

Yellow solid; m.p. 290-292 0C; IR (KBr, cm"1): 3487, 3393, 3325, 3222, 2959, 2177, 1654, 1603, 1517, 1479; *H NMR (300 MHz, DMSO-d6): d 0.88 (s, 3H, CH3), 1.0 (s, 3H, CH3), 1.95-2.19 (dd, 2H, J = 16.2 Hz, CH2), 2.29-2.46 (dd, 2H, J = 17.1 Hz, CH2), 4.45 (s, 1H, CH), 5.95 (s, 2H, NH2), 7.36-7.39 (d, 2H, J = 8.7 Hz, Ar-H), 8.11-8.14(d, 2H, J = 8.7 Hz, Ar-H), 9.0 (br s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d 27.1, 29.2, 32.5, 38.0, 50.4, 57.8, 108.19, 121.6, 124.0, 128.5, 146.3, 150.8, 150.9, 158.1, 194.4; ESI-MS (m/z): 339.2 (M + H+); Anal. Calcd. for C18H18N4O3 (338.360): C, 63.89; H, 5.36; N, 16.56%. Found: C, 63.86; H, 5.31; N, 16.60%.

2.4.2. 2-Amino-4-[3-(fluoro) phenyl]-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline( 5j)

Yellow solid; m.p. 262-265 0C; IR (KBr, cm"1): 3418, 3326, 3236, 2960, 2181, 1639, 1599, 1477; *H NMR (300 MHz, DMSO-d6): d 0.89 (s, 3H, CH3), 1.00 (s, 3H, CH3), 1.97-2.19 (dd, 2H, J = 15 Hz, CH2), 2.29-2.43 (dd, 2H, J = 17.1 Hz, CH2), 4.33 (s, 1H, CH), 5.83 (s, 2H, NH2), 6.83-6.97 (m, 3H, Ar-H), 7.24-7.31(m, 1H, Ar-H), 8.84 (br s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d 27.0, 29.2, 32.4, 37.4,

50.4, 58.5, 108.7, 121.8, 123.3, 130.4, 150.4, 161.0, 164.2, 194.4; ESI-MS (m/z): 312.2 (M + H+); Anal. Calcd. for C18-H18FN3O (311.353): C, 69.44; H, 5.83; N, 13.50%. Found: C, 69.39; H, 5.79; N, 13.54%.

2.4.3. 2-Amino-4-[3-(trifluoromethyl) phenyl]-3-cyano-7,7-dimethyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline (5k)

Light yellow solid; m.p. 285-287 0C; IR (KBr, cm"1): 3392, 3335, 3225, 2922, 2180, 1657, 1605, 1478: *H NMR (300 MHz, DMSO-d6): d 0.87 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.15-2.34 (dd, 2H, J = 18 Hz, CH2), 2.42-2.49 (dd, 2H, J = 17.4 Hz, CH2), 4.42 (s, 1H, CH), 5.89 (s, 2H, NH2), 7.38-7.55 (m, 4H, Ar-H), 9.09 (br s, 1H,NH); 13C NMR (75 MHz, DMSO-d6): d 26.6, 29.4, 32.4, 37.7, 50.4, 58.4, 108.5, 121.7, 122.9, 123.3, 123.5, 126.5, 129.0, 129.5, 129.7,

131.4, 148.9, 150.7, 150.8, 194.5; ESI-MS (m/z): 362.2 (M + H + ); Anal. Calcd. for C19H18F3N3O (361.360): C, 63.15; H, 5.02; N, 11.63%. Found: C, 63.12; H, 4.97; N, 11.67%.

2.4.4. 2-Amino-4-[3, 4-(dimethyl) phenyl]-3-cyano-7,7-dimethyl-5-oxo-l, 4, 5, 6,7,8-hexahydroquinoline (5l)

Yellow solid; m.p. >300 0C; IR (KBr, cm"1): 3394, 3332, 3226, 2964, 2192, 1661, 1603, 1476; *H NMR (300 MHz,

Table 2 Screening of solvents using 2 mmol of NH4OAc catalyst for tandem synthesis of hexahydroquinolines.a

Entry Solvent Temperature °C Time (h) Yield (%)b

1 Water 100 1 89

2 Water:EtOH (1:1) 85 2 75

3 EtOH 78 4 55

4 MeOH 65 5 47

5 IPA 85 5.5 45

6 DMF 110 7 c

7 DMSO 100 5 40

a Reaction condition: 5,5-dimethyl 1,3-cyclohexadione (1 mmol), ammonium acetate (1.3 mmol),3-trifluoro methyl benzaldehyde (1 mmol),

malononitrile (1 mmol).

b Isolated yield.

c No reaction occurred.

Table 3 Synthesis of hexahydroquinoline derivatives (5a-5q) from tandem reaction with different aryl aldehydes.a

Entry Aldehyde (R) 4 Product 5

Time (min) Yield (%)b Atom economy (%)c M.P. °C (observed) M.P. °C (Lit.)R

293-296

294-295e

Table 3 (continued)

Entry Aldehyde (R) 4 Product 5

Time (min) Yield (%)b Atom economy (%)c M.P. °C (observed) M.P. °C (Lit.)R

288-290

297-299

290-292

262-265

285-287

290-291d

295-296d

(continued on next page)

Table 3 (continued)

Entry Aldehyde (R) 4 Product 5

Time (min) Yield (%)b Atom economy (%)c M.P. °C (observed) M.P. °C (Lit.)R

84 79.04

H,C CH,

272-275

269-270d

a Reaction condition: 5,5-dimethyl 1,3-cyclohexadione (1 mmol), ammonium acetate (1.3mmol), aryl aldehyde (1 mmol), malononitrile (1 mmol) and excess of NH4OAc (2 mmol) as a catalyst in 10 ml water. b Isolated yield.

c % Atom economy = (MW of desired product/^] of all reactants) x 100. d Litvic et al. [19]. e Tu et al. [31].

DMSO-d6): d 0.94 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.93-2.17 (dd, 2H, J = 16.2 Hz, CH2), 2.26-2.43 (dd, 2H, J = 17.4 Hz, CH2), 2.13 (s, 3H, Ar-CH3), 2.15 (s, 3H, Ar-CH3), 4.20 (s, 1H, CH), 5.71 (s, 2H, NH2), 6.80-6.85 (m, 2H, Ar-H), 6.956.98 (m, 1H, Ar-H), 8.90 (br s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d 19.3, 20.0, 27.0, 29.4, 32.4, 37.2, 50.6, 59.5, 109.4, 122.1, 124.7, 128.5, 129.6, 134.0, 135.0, 145.2, 149.8, 150.5, 194.3; ESI-MS (m/z): 322.2 (M + H+); Anal. Calcd. for C20H23N3O (321.416): C, 74.74; H, 7.21; N, 13.07%. Found: C, 74.70; H, 7.18; N, 13.11%.

2.4.5. 2-Amino-4-[3-(chloro) phenyl]-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline (5m)

Yellow solid; m.p. >300 0C; IR (KBr, cm"1): 3355, 3199, 2967, 2185, 1657, 1602, 1487, 1368; *H NMR (300 MHz, DMSO-d6): d 0.90(s, 3H, CH3), 1.01(s, 3H, CH3), 1.98-2.21 (dd, 2H, J = 15 Hz, CH2), 2.36-2.50 (dd, 2H, J = 18 Hz, CH2), 4.35 (s,1H,CH), 5.85 (s, 2H, NH2), 7.10-7.12 (d, 2H, J = 6 Hz, Ar-H) 7.18-7.21 (d, 1H, J = 9 Hz, Ar-H), 7.267.31 (m, 1H, Ar-H), 8.96 (br s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d 27.3, 29.3, 32.5, 37.6, 50.4, 58.6,

108.7, 121.8, 126.1, 126.5, 127.0, 130.5, 133.2, 150.0, 150.4,

150.8, 194.4; ESI-MS (m/z): 350.2 (M + Na+); Anal. Calcd. for C18H18ClN3O (327.808): C, 65.95; H, 5.53; N, 12.82%. Found: C, 65.91; H, 5.46; N, 12.86%.

3. Results and discussion

Herein we have reported a one pot tandem reaction and a new synthetic strategy for selectively substituted hexahydroquinoline derivatives using dimedone, malononitrile, aryl aldehydes and ammonium acetate via enaminone intermediate. To study this latest method, we explored the reaction of dimedone and excess of ammonium acetate in water at reflux condition which afforded the expected enamine adduct intermediates. Further the sequential addition of malononitrile and aldehyde successfully gave hexahydroquinoline derivatives in excellent yields as well as good atom economy (Scheme 1).

Initially, we engaged dimedone (1 mmol), ammonium acetate (1.3mmol), 3-trifluoro methyl benzaldehyde (1 mmol) and malononitrile (1 mmol) as model substrates for the optimization of reaction conditions. In the beginning we tried to establish a protocol for the above model reaction without any catalytic assistance in aqueous media varying the temperature criteria from room temperature to reflux condition, however the reaction failed to proceed even after prolonged stirring at RT to 80 0C (Table 1, Entries 1-3), although trace amount (30%) of desired product was afforded at reflux condition after 7h (Table 1, Entry 4). Moreover the same reaction was employed incorporating excess addition of NH4OAc as a catalyst from 0.5 to 2.5 mmol under reflux condition (Table 1, Entries 5-9), then we got the desired product hexahydroquino-line in excellent yield (89%) at 2 mmol of excess addition of NH4OAc and the time of reaction completion becomes only 1 h (Table 1, Entry 8).

Interestingly we found that the reaction using water as solvent (Table 2, Entry 1) resulted in excellent yield (89%) of desired product than any other solvents (Table 2, Entries 27). Our optimization studies revealed that the yield increased with catalyst loading up to 2 mmol and then remained with

no improvement in the yield with 2.5 mmol of catalyst loading (Table 1, Entry 9).

With the standard optimized parameter, we next concentrated on the scope of this reaction which was investigated by synthesizing a library of hexahydroquinoline derivatives

Table 4 Crystal data and structure refinement for 5m.

Identification code 5m

Empirical formula CigHigClNsO

Formula weight 327.80

Temperature 298(2) K

Wavelength 0.71073 A

Crystal system, space group Triclinic, P-1

Unit cell dimensions a = 7.5314(3) A a = 103.039(2)0

b = 9.3764(4) À b = 94.004(2)°

c = 12.3556(5) À c = 99.177(2)0

Volume 834.05(6) A3

Z, Calculated density 2, 1.305 mg/m3

Absorption coefficient 0.237 mm"1

F(000) 344

Crystal size 0.20 x 0.15 x 0.11mm

Theta range for data collection 2.27-25.000

Limiting indices -8 6 h 6 8, -11 6 k 6 11,

-14 6 l 6 14

Reflections collected/unique 8471/2756 [R(int) = 0.0275]

Completeness to theta 25.00 94.0%

Absorption correction Multi-scan 0.9744 and 0.9542

Max. and min. transmission

Refinement method Full-matrix least-squares on F2

Data/restraints/parameters 2756/0/210

Goodness-of-fit on F2 1.035

Final R indices [I > 2r(I)] R1 = 0.0739, wR2 = 0.1231

R indices (all data) R1 = 0.0739, wR2 = 0.1231

Largest diff. peak and hole 0.278 and -0.442 e A-3

CCDC number CCDC 960507

Table 5 Intramolecular hydrogen bonds for 5m.

D-H.. .A D-H (A) H.. .A (A) D.. .A (A) [D-H.. .A(o)]

N3-H3.. .O1#1 0.86 2.13 2.912 150.5

N2-H2B.. .O1#1 0.86 2.18 2.958 150.5

N2-H2A.. .N1#2 0.86 2.26 3.089 161.0

Symmetry code: #1 x + 1,y,z. #2 — x + 2, — y— 1, —z.

Scheme 2 A plausible mechanism for the formation of hexahydroquinoline.

in the presence of 2 mmol NH4OAc at reflux condition using water as a reaction medium (Table 3).The optimized tandem methodology tolerated a wide spectrum of aldehydes with good to excellent yields of the targeted molecules. From Table 3 it is evident that the reaction proceeded smoothly for both electron rich and electron deficient aromatic aldehydes.

The crude products were further purified by recrystalliza-tion from ethanol to afford the pure substituted hexahydro-quinoline 5a-5q in good to excellent yields.

All the products were characterized by IR, 1H NMR, 13C NMR, LC-MS and by elemental analysis and well matched with literature reported compounds [19,31].The stereochemistry and structure of 2-amino-4-[3-(chloro) phenyl]-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline motif was further confirmed by single crystal X-ray analysis (Fig. 2, 5m).

The stereochemistry of structure 5m exposes that both six membered rings of the hexahydroquinoline derivative adopt half chair conformation with atoms C2 and C6 forming flaps in the each ring. The proton attached to nitrogen N3 forms a H-bond with the oxygen O1 (>C=O) such that the N3-H3...Oj distance is 2.912 A, while that of N2-H2B...Oi (>C=O) distance is 2.958 A. As well as the proton attached to nitrogen N2 forms an H-bond with nitrogen Ni (—CN) screening N2-H2A.. .N1 distance 3.089 A (Table 5).

A tentative mechanism for this transformation is proposed in Scheme 2. The reaction proceeds through three different steps. Step 1 involves the formation of enaminone 6 from dimedone and excess of ammonium acetate. The excess of

ammonium acetate act as a source of acetic acid, which can protonate carbonyl group to create a more reactive species. Enaminone contains nucleophilic character of enamine and nucleophilic character of enone [22].

In step 2 there is formation of arylidenemalononitrile 7 by Knoevenagel reaction of aldehyde and malononitrile, finally step 3 involves Michael addition reaction with intramolecular cyclization between enaminone 6 and arylidenemalononitrile 7 affording the final product hexahydroquinoline 5.

The luxuriance of the procedure was confirmed by using the percent atom economy (Fig. 3). It was observed that percent

Products

Figure 3 Percent atom economy of products.

Table 6 Results obtained using large scale synthesis of hexahydroquinoline derivatives from tandem reaction with different aryl aldehydes.

Entry Aldehydes Aldehydes amount ( mmol) Product Time (min) Yielda (%)

1 4-OCH3 C6H4 20 5b 80 88

2 СбН5 20 5c 70 89

3 4-F C6H4 20 5f 60 93

a Isolated yield.

atom economy of the reaction is good which pointed out that maximum quantity of raw materials finished in to the product and a minimum quantity of waste was formed.

To sustain this protocol, we explored the efficiency of our procedure using three representative aryl aldehydes containing in their structure hydrogen, electron-donating groups and weak electron-withdrawing groups. Reactions were performed in aqueous media at reflux temperature and the reactants were used in the same ratio as formerly determined.

Thus, a large-scale synthesis of compound 5b, 5c and 5f was carried out on 20 mmol scale (Table 6).The reaction mixture was refluxed for reported time and the desired product was obtained in 88%, 89% and 93% yield, respectively.

4. Conclusion

In conclusion we have provided an efficient and diversity oriented four component route using readily available starting materials for the tandem synthesis of a series of hexahydro-quinoline derivatives in aqueous media using ammonium acetate as an inexpensive and neutral catalyst. The experimental simplicity, excellent yields in small and large scale, shorter reaction time, simple work up procedure, no need of external catalyst, purification of products by non-chromatographic method and high atom economy are the captivating features of this protocol.

Supplementary information

Crystallographic data for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as Supplementary Publication No. CCDC 960507. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (www.ccdc.cam.a-c.uk/data_request/cif or e-mail: deposit@ccdc.cam.ac.Uk).

Acknowledgments

The authors are thankful to the Department of Chemistry, Shi-vaji University, Kolhapur for spectral measurements. D.R. Patil is grateful to the UGC New Delhi [F.No.41-211/2012 (SR)] for awarding him a Junior Research Fellowship. The authors are also grateful to the Department of Chemistry, IIT Madras, Chennai for providing single crystal analysis data of compound 5m (CCDC 960507).

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