One-pot, Solvent-free Cascade Michael-reductive Cyclization

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One-pot, Solvent-free Cascade Michael-reductive Cyclization Reaction for the Synthesis of Ethyl 3 .... and P(OEt)3, the following mechanism is proposed for the.
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Current Microwave Chemistry, 2014, 1, 110-118

One-pot, Solvent-free Cascade Michael-reductive Cyclization Reaction for the Synthesis of Ethyl 3,5-disubstituted-1H-pyrrole-2-carboxylates Under Microwave Irradiation Rajni Khajuria and Kamal K. Kapoor* Department of Chemistry, University of Jammu, Jammu-180 006, India Abstract: An efficient, one-pot, solvent-free synthesis of ethyl 3,5-disubstituted-1H-pyrrole-2-carboxylate is achieved by a reaction of 1,3-disubstituted propen-2-one and ethylnitroacetate, in presence of diethylamine (Et2NH) and triethylphosphite (P(OEt)3) under microwave (MW) irradiation via cascade Michael-reductive cyclization. The mechanistic outcome of the reaction has also been described. This protocol establishes an easy access to disubstituted-1H-pyrrole-2carboxylates in one pot.

Keywords: 1,3-disubstituted propen-2-ones, cascade, diethylamine, ethyl 3,5-disubstituted-1H-pyrrole-2-carboxylates, ethylnitroacetate, Michael-reductive cyclization, MW irradiation, one-pot, solvent-free, triethylphosphite. 1. INTRODUCTION Pyrrole and its derivatives have attracted immense attention in the past few decades due to their undisputable importance in nature [1], as the pyrrole ring, either in its unadorned form or as the pyrrole-2-carboxylate moiety, possesses many useful biological and electronic features. Pyrroles exhibit remarkable biological and pharmacological properties such as antibacterial [2], antifungal [3], anti-inflammatory [4], antioxidative [5], antitumor [6], antitubercular [7], hypolipidemic [8], immune suppressant [9] and are able to inhibit retroviral reverse transcriptases [i.e., human immunodeficiency virus type 1 (HIV-1)] [10], poly(ADP-ribose)polymerases [11], selective mono amine oxidase type A [12] and glycogen synthase kinase-3(GSK-3) [13]. The most notable and widely recognized pyrrole-moiety containing drugs in the market these days, include atrovastatin [14], pyrrolomycin B, pyoluteorin, pyrrolnitrin [15], tolmetin and amtolmetin [16]. Pyrroles have also been accorded much attention owing to their wide spectrum utility in the preparation of porphyrins, corrins, as monomers for polymer chemistry as well as in materials science as semi conductors, chemosensors, fluorescent sensors and for image diagnosis [17]. In view of the biological and electronic importance of pyrroles, several methods for their synthesis have been reported, including the classical Hantzch procedure [18], Knorr synthesis [19], Paal Knorr synthesis [20], Piloty-Robinson Synthesis [21], Feist synthesis [22], 1,3-dipolar cycloaddition of azomethine ylides to alkynes followed by aromatization of the intermediate pyrrolines [23], Cu-assisted cycloisomerization of alkynyl imines [24], condensation of nitroolefins or esters of vicinal nitro alcohols with stabilized *Address correspondence to this author at the Department of Chemistry, University of Jammu, Jammu-180 006, India; Tel.: +91-191-2453969; Fax: +91-191-2450014/2431365; E-mails: [email protected] and [email protected] 2213-3364/14 $58.00+.00

α-isocyano anions [25], reductive cyclization of 2-aryl succinonitriles [26] and various other cycloaddition and transition metal-catalysed cyclization methods. Ethyl 3,5-disubstituted1H-pyrrole-2-carboxylates have been earlier prepared from ethyl 2-nitro-5-oxo-3,5-disubstituted pentanoates by heating with reducing systems such as a combination of tributylphosphine and diphenyldisulphide [27], formamidine sulfinic acid (thiourea-S,S-dioxide) [28]. However, these methods suffer from the drawbacks of multistep laborious protocols, use of expensive reagents, harsh reaction conditions, tedious work-up procedures and generation of toxic by-products. P(OEt)3 is the most commonly used deoxygenating reagent and solvent. The reduction of nitro compounds by P(OEt)3 has been recognised as a versatile route to a wide variety of nitrogen containing heterocycles including indoles, indazoles, carbazoles, benz[a]carbazoles and other related compounds [29]. In our recent paper [30], we reported the synthesis of ethyl 3,5-disubstituted-1H-pyrrole-2-carboxylates via P(OEt)3 promoted reductive cyclization of ethyl 2nitro-5-oxo-3,5-disubstituted pentanoates (Scheme 1). The progress in the field of MW-assisted, solvent-free reactions is gaining significance because of their high efficiency, operational simplicity and environmentally benign nature [31]. Microwave-assisted organic synthesis (MAOS) offers simple, clean, fast, efficient, safe and economic synthesis of a large number of organic molecules as the conventional methods need longer heating time, tedious apparatus setup and the excessive use of solvents/reagents [32]. MW irradiation is proving quite successful in the formation of a variety of carbon-heteroatom bonds [33]. The application of MAOS in the synthesis of biologically important scaffolds such as indoles [34], quinoxalines [35], 1,2,4-triazoles [36], porphyrins [37], pyrazolo[4,3-d]pyrimidinones [38], 1,2,4oxadiazoles [39], azepinonaphthoquinones [40] etc. has been well demonstrated. For this reason, MW-enhanced chemistry is witnessing an exponential increase in its usage in the or© 2014 Bentham Science Publishers

One-pot, Solvent-free Cascade Michael-reductive Cyclization Reaction

Current Microwave Chemistry, 2014, Vol. 1, No. 2

111

R2 O

O R1

R2 +

O

O2N O

1a-g

Et2NH, EtOH Reflux

O

O2N

R1

EtO

P

O

OEt

MW, 80 W

R2

O

OEt R1

N H

O

3a-g

2a-g

Scheme 1. P(OEt)3 mediated synthesis of ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates 3a-g. O

O (1.0 mmol) Et2NH (1.2 mmol) MW, 90 °C, 80 W

1a

O2N O

O

EtO

P

OEt OEt

O2N

O

MW, 90 °C, 80 W

+ O

(3.0 mmol)

Step 2

Step 1

N H

O

2a

O

94% yield

(1.0 mmol)

Scheme 2. Solvent-free cascade synthesis of ethyl 3,5-diphenyl-1H-pyrrole-2-carboxylate 2a.

ganic synthesis [32, 41]. One pot reaction is much desired by the chemists because it avoids the lengthy separation processes for purification of the chemical intermediates and therefore saves time and resources coupled with increase in the overall yield. In continuation to our interest in the development of newer methodologies for organic syntheses [42], herein, we report a one-pot, solvent-free cascade synthesis of ethyl 3,5disubstituted-1H-pyrrole-2-carboxylates, using 1,3disubstituted propen-2-ones as starting materials, under MW irradiation. 2. RESULTS AND DISCUSSION One-pot reaction of 1,3-diphenylpropen-2-one 1a, ethylnitroacetate, Et2NH and P(OEt)3 was scrutinized as a model reaction to establish the feasibility of the strategy and the optimization of the reaction conditions (Scheme 2). Towards this direction, a mixture of 1,3-diphenylpropen-2-one (0.208 g, 1.0 mmol), ethylnitroacetate (0.133 g, 1.0 mmol) and Et2NH (0.088 g, 1.2 mmol) in a capped vial was irradiated in a MW synthesizer (CEM Discover) at 90°C (80 W) for 10 minutes to realise the complete formation of ethyl 2-nitro-5oxo-3,5-diphenylpentanoate (TLC). At this point, P(OEt) 3 (0.498 g, 3.0 mmol) was added and the reaction was submitted to the same conditions (MW, 90°C, 80 W) for the another 15 minutes when the completion (TLC) of reaction was observed. The reaction mixture was cooled to room temperature, transferred to a 10 mL round-bottomed flask to remove volatiles under vacuum at 70°C and the dark brown residue obtained was dissolved in ethyl acetate (30 mL). The ethyl acetate solution was washed with water (3 × 15 mL), brine (1 × 15 mL), dried (anhydrous Na2SO4) and concentrated on rotary evaporator. The resultant after column chromatography over silica (60-120 mesh) using a gradient of a mixture of petroleum ether and ethyl acetate yielded crystalline ethyl 3,5-diphenyl-1H-pyrrole-2-carboxylate 2a [30] (0.274 g, 94%). It is pertinent to mention here that in our earlier re-

ported two-step methodology [30], the overall yield of 2a from 1a was about 76% since the pure Michael product ethyl 2-nitro-5-oxo-3,5-diphenylpentanoate was obtained in 84% yield. It reveals that the present methodology has advantages over the earlier methodology in terms of time, labour and yield. In another set of experiment, a mixture of 1,3diphenylpropen-2-one 1a, ethylnitroacetate, Et2NH and P(OEt)3 in 1:1:1.2:3 ratio in a capped vial was irradiated (MW, 90°C, 80 W) (Scheme 3). TLC monitoring of this tandem reaction revealed that the reaction was completed in 40 minutes and the desired product ethyl 3,5-diphenyl-1Hpyrrole-2-carboxylate 2a was obtained in only 72% yield. In view of better yield and faster reaction, cascade reaction (Scheme 4) was chosen for future experiments to establish the substrate scope as depicted in Table 1. To expand the scope of this reaction, different 1,3disubstituted propen-2-ones (Table 1, entries 1b-1m) were examined. The desired products were obtained in good to excellent yields (Scheme 4, Table 1, 84-95%). In light of our earlier proposed mechanism [30] for the preparation of ethyl 3,5-disubstituted-1H-pyrrole-2-carboxylates from ethyl 2-nitro-5-oxo-3,5-disubstituted pentanoates and P(OEt)3, the following mechanism is proposed for the present reaction (Scheme 5). A reaction with (2E,2'E)-3,3'-(1,4-phenylene)bis(1phenylpropen-2-one) 1n [49], under similar reaction conditions, interestingly, yielded 1,4-bis(2-carboethoxy-5phenylpyrrol-3-yl)benzene 2n as a brown solid in 63% overall yield (Scheme 6). It is pertinent to mention here that bispyrrolylbenzenes are interesting structural units having applications in the generation of supramolecular host conjugated macrocycles [50], heterojunction organic-inorganic semiconductor nanowire arrays [51] and conductive electrochromic polymers [52].

112 Current Microwave Chemistry, 2014, Vol. 1, No. 2

Khajuria and Kapoor

O

Et2NH

(1.0 mmol)

(1.2 mmol)

O

MW, 90 °C, 80 W

1a + EtO

OEt

O

O2N

N H

OEt

P

2a

(3.0 mmol)

O

O

72% yield

(1.0 mmol)

Scheme 3. One-pot, solvent-free tandem synthesis of ethyl 3,5-diphenyl-1H-pyrrole-2-carboxylate 2a. O R1

R2

(1.0 mmol)

O

Et2NH (1.2 mmol) MW, 90 °C, 80 W

1a-m + O2N

O

R1

Step 1

O

EtO

O2N O

P

R2

OEt

(3.0 mmol)

OEt

O

MW, 90 °C, 80 W

N H

R1

O

R2 Step 2

2a-m

O (1.0 mmol)

Scheme 4. One-pot, solvent-free cascade synthesis of ethyl 3,5-disubstituted-1H-pyrrole-2-carboxylates 2a-m. O O2N

C2H5

O

C2H5

NH C2H5

O R1

H O

C2H5

O

NH

-

O

R1

R2

C2H5

O

O2N

NH

O2N O

C2H5

R2

O

R1

R2

OEt EtO EtO

P

O OEt

O

EtO

O

N

R1

O _ EtO

O

O

R2

O

N

O

EtO

O

O

EtO

O

P

R1

P

OEt

EtO

P

OEt

O

O N

O

O

OEt

R2

R1

R2

OEt EtO

P

EtO

O

P

OEt OEt

O

O O

NH O

_ HO 2

R1

R2

O

H N

O

H H

R2

H migration

O

H

R1

R2

O

O

N

H

H N

HO

_ EtO O

R1

R1

O

O

N

O

R2

Scheme 5. General mechanism for the formation of ethyl 3,5-disubstituted-1H-pyrrole-2-carboxylates.

R1

O H R2

One-pot, Solvent-free Cascade Michael-reductive Cyclization Reaction

Table 1. Entry

1

Current Microwave Chemistry, 2014, Vol. 1, No. 2

113

One-pot, solvent-free cascade synthesis of ethyl 3,5-disubstituted-1H-pyrrole-2-carboxylates (Scheme 4). 1,3-Disubstituted Propen-2-ones R1

R2

C6H5

C6H5

Producta

O N H

Time b (min)

Yieldc (%)

Mpd (lit. mp °C)

25 (10, 15)

94

137-138 (139-140) [43]

50 (20, 30)

88

133-135 (135) [44]

40 (20, 20)

84

206-208 (205-206) [45]

50 (15, 35)

93

148-149 (149-150) [45]

55 (25, 30)

95

181-183 (185) [44]

45 (15, 30)

92

167-168 (168170) [46]

40 (15, 25)

86

136-137 (135-137) [43]

OEt

2a OMe

2

C6H5

4-OMe-C6H4 O N H

OEt

2b OH

3

C6H5

4-OH-C6H4 O N H

OEt

2c F

4

4-F- C6H 4

4-F-C6H 4 O

F

N H

OEt

2d

5

4-Cl-C6H4

C6H5

O

Cl

N H

OEt

2e

6

4-Me-C6H4

C6H5

O

Me

N H

OEt

2f Me N Me

7

C6H5

4-N(Me)2- C6H4 O N H

2g

OEt

114 Current Microwave Chemistry, 2014, Vol. 1, No. 2

Khajuria and Kapoor

Table 1. Contd…… Entry

1,3-Disubstituted Propen-2-ones R1

Producta

R2

Time b (min)

Yieldc (%)

Mpd (lit. mp °C)

30 (10, 20)

90

182-184 (187) [47]

50 (10, 40)

91

140

80 (30, 50)

88

119-122

50 (15, 35)

90

158-160

30 (10, 20)

86

114-115 (115) [48]

45 (20, 25)

93

205-208

Cl

8

C6H5

4-Cl-C6H4

O N H

OEt

2h MeO

OMe OMe

9

C6H5

3,4,5-(OMe)3C6H2

O N H

OEt

2i

S

10

C6H5

2-Thienyl

O N H

OEt

2j

11

C6H5

2-Styryl O N H

OEt

2k Me

12

C6H5

O

Me

N H

OEt

2l Cl

13

4-Me-C6H4

2-Cl-C6H4

O

Me

N H

OEt

2m a

All the products were characterized by their physical and spectral data. Total reaction time (the time of completion of step 1, the time of completion of step 2). Isolated yield. d Literature reference of melting point. b c

3. CONCLUSION In summary, we have successfully developed a novel, efficient, economical method for the synthesis of a series of pyrrole-2-carboxylates via a cascade reaction. This procedure offers a new direct, solvent-free, high to excellent yield-

ing procedure for the preparation of ethyl 3,5-disubstituted1H-pyrrole-2-carboxylates 2a-n. To the best of our knowledge, this will be the first report on the one-pot synthesis of ethyl 3,5-disubstituted-1H-pyrrole-2-carboxylates from 1,3disubstituted propen-2-ones.

One-pot, Solvent-free Cascade Michael-reductive Cyclization Reaction

O

O2N O

O

+

Et2NH (2.4 mmol) MW, 90 °C, 80 W Step 1

(2.0 mmol)

Current Microwave Chemistry, 2014, Vol. 1, No. 2

EtO O

O

O2N

O NO2

O

O

O

P

OEt OEt

(6.0 mmol)

HN

O

MW, 90 °C, 80 W O Step 2

O

115

O

NH

O 2n 1n

63% Yield

(1.0 mmol)

Scheme 6. One-pot, solvent-free cascade synthesis of 1,4-bis(2-carboethoxy-5-phenylpyrrol-3-yl)benzene 2n.

4. EXPERIMENTAL SECTION

4.2.1. Ethyl 3,5-diphenyl-1H-pyrrole-2-carboxylate 2a

4.1. General

White crystalline solid, yield: 94%, Mp. 137-138°C (lit. m.p. 139-140°C) [43]; 1H NMR (CDCl3, 400MHz): δ (ppm) 9.45 (br s, 1H, exchangeable with D2O), 7.64-7.60 (m, 4H), 7.50-7.34 (m, 6H), 6.65 (d, J = 3.2 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 161.26, 135.38, 135.10, 133.46, 131.06, 129.59, 129.09, 128.35, 127.95, 127.63, 127.14, 124.69, 118.62, 109.93, 60.43, 14.20; IR (KBr) (υmax, cm-1): 3313, 1662; Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81%. Found: C, 78.38; H, 5.82; N, 4.73%. MS(ESI) (m/z): 292 (M+H) +.

All the commercially available reagents were purchased from Aldrich and were used without further purification. The reactions were performed with a Discover™ single mode cavity MW synthesizer (CEM Corporation). Melting points (°C) were measured in open glass capillaries using Perfit melting point apparatus and are uncorrected. The progress of the reaction and the purity of the final products were monitored by thin layer chromatography (TLC) using silica gel pre-coated aluminium sheets (60 F254, Merck). Visualization of spots was effected by exposure to ultraviolet light (UV) at 254 nm, iodine vapours, 2% 2,4-dinitrophenylhydrazine in methanol containing few drops of H2SO4, draggendroff reagent and anisaldehyde reagent. Column chromatography was performed on silica gel (60-120 mesh). IR spectra (ν, cm-1) were recorded on Perkin-Elmer FTIR spectrophotometer using KBr discs. 1H NMR and 13C NMR spectra in CDCl3, DMSO-d6 as solvents were recorded on Burker AC-400 spectrometer operating at 400 MHz for 1H and 100 MHz for 13C, with tetramethylsilane (TMS) as internal standard. Electron impact mass spectra (EIMS) were recorded on Micro Mass VG-7070 H mass spectrometer at 70ev. Elemental analysis were performed on Leco CHNS-932 analyzer. 4.2. General Procedure for the Synthesis of ethyl 3,5disubstituted-1H-pyrrole-2-carboxylates, 2a-m A mixture of 1,3-disubstituted propen-2-one (1.0 mmol), ethylnitroacetate (0.133 g, 1.0 mmol) and Et2NH (0.088 g, 1.2 mmol) in a capped vial was irradiated in a MW synthesizer (CEM Discover) at 90°C (80 W) till the time (Table 1), the complete formation of ethyl 2-nitro-5-oxo-3,5disubstituted pentanoate (TLC) was noticed. At this point, P(OEt)3 (0.498 g, 3.0 mmol) was added and the reaction was submitted to the same conditions (MW, 90°C, 80 W) to realise the complete formation of product (TLC, Table 1). The reaction mixture was cooled to room temperature, transferred to a 10mL round-bottomed flask and volatiles were removed under vacuum at 70°C. The residue thus obtained, was dissolved in ethyl acetate (30 mL) and washed with water (3 × 15 mL), brine (1 × 15 mL), dried (anhydrous Na2SO4) and concentrated on rotary evaporator. The resultant after column chromatography over silica (60-120 mesh) using a gradient of a mixture of petroleum ether and ethyl acetate yielded ethyl 3,5-disubstituted-1H-pyrrole-2-carboxylate (2a-m, 84-95% yield).

4.2.2. Ethyl 3-(4-methoxyphenyl)-5-phenyl-1H-pyrrole-2carboxylate 2b Blue solid, Yield: 88%, Mp. 133-135°C (lit. mp. 135°C) [44]; 1H NMR (CDCl3, 400MHz): δ (ppm) 9.25 (br s, 1H, exchangeable with D2O), 7.58 (d, J = 7.4 Hz, 2H), 7.53-7.39 (m, 4H), 7.34 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 8.2 Hz, 2H), 6.56 (d, J = 2.9 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 161.14, 159.12, 135.57, 133.53, 131.42, 130.79, 130.18, 129.38, 128.14, 127.17, 125.07, 118.56, 113.14, 110.09, 60.53, 55.02, 14.61; IR (KBr) (υmax, cm-1): 3338, 1667; Anal. Calcd for C20H19NO3: C, 74.75; H, 5.96; N, 4.36%. Found: C, 74.81; H, 5.89; N, 4.46%. MS(ESI) (m/z): 322 (M+H) +. 4.2.3. Ethyl 3-(4-hydroxyphenyl)-5-phenyl-1H-pyrrole-2carboxylate 2c Voilet solid, Yield: 84%, Mp. 206-208°C (lit. mp. 205206°C) [45]; 1H NMR (CDCl3, 400MHz): δ (ppm) 10.39 (br s, 1H, exchangeable with D2O), 8.70 (s, 1H), 7.79-7.74 (m, 2H), 7.47-7.39 (m, 4H), 7.31 (t, J = 7.3 Hz, 1H), 6.78 (d, J = 8.1 Hz, 2H), 6.60 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 160.49, 156.12, 135.27, 133.51, 131.08, 130.72, 130.51, 128.40, 127.12, 126.40, 124.82, 118.00, 114.52, 114.14, 109.22, 59.60, 14.02; IR (KBr) (υmax, cm-1): 3361, 1662; Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56%. Found: C, 74.34; H, 5.52; N, 4.49%. MS(ESI) (m/z): 308 (M+H) +. 4.2.4. Ethyl 3,5-bis(4-fluorophenyl)-1H-pyrrole-2-carboxylate 2d Shiny green solid, Yield: 93%, Mp. 148-149°C (lit. mp. 149-150°C) [45]; 1H NMR (CDCl3, 400MHz): δ (ppm) 9.41

116 Current Microwave Chemistry, 2014, Vol. 1, No. 2

(br s, 1H, exchangeable with D2O), 7.61-7.50 (m, 4H), 7.417.37 (m, 2H), 7.08 (s, 2H), 6.52 (s, 1H), 4.31 (q, J = 6.9 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 164.00, 161.17, 135.00, 132.89, 131.15, 131.04, 130.03, 127.89, 127.28, 127.01, 126.50, 116.67, 115.60, 110.22, 60.19, 14.16; IR (KBr) (υmax, cm-1): 3320, 1673; Anal. Calcd for C19H15F2NO2: C, 69.72; H, 4.62; N, 4.28%. Found: C, 69.64; H, 4.69; N, 4.37%. MS(ESI) (m/z): 328, 329 (M+H) +. 4.2.5. Ethyl 5-(4-chlorophenyl)-3-phenyl-1H-pyrrole-2-carboxylate 2e Pale yellow solid, Yield: 95%, Mp. 181-183°C (lit. mp. 185°C) [44]; 1H NMR (CDCl3, 400MHz): δ (ppm) 9.81 (br s, 1H, exchangeable with D2O), 7.60-7.53 (m, 4H), 7.41-7.33 (m, 5H), 6.57 (d, J = 2.8 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 160.51, 135.03, 134.74, 133.46, 133.05, 129.26, 129.00, 128.91, 127.27, 127.02, 126.71, 119.06, 110.03, 60.16, 14.41; IR (KBr) (υmax, cm-1): 3319, 1673; Anal. Calcd for C19H16ClNO2: C, 70.05; H, 4.95; N, 4.30%. Found: C, 69.97; H, 4.89; N, 4.39%. MS(ESI) (m/z): 326, 328 (M+H)+. 4.2.6. Ethyl 5-(4-methylphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 2f Pale yellow solid, Yield: 92%, Mp. 167-168°C (lit. mp. 168-170°C) [46]; 1H NMR (CDCl3, 400MHz): δ (ppm) 9.63 (br s, 1H, exchangeable with D2O), 7.59-7.54 (m, 3H), 7.457.42 (d, J = 8.2 Hz, 2H), 7.36-7.29 (m, 4H), 6.89 (s, 1H), 4.32 (q, J = 7.1, 2H), 2.00 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (CDCl3, 100 MHz): δ (ppm) 164.44, 138.62, 136.13, 133.44, 132.48, 129.03, 128.87, 128.63, 128.01, 127.77, 126.48, 126.01, 123.91, 111.08, 61.56, 21.51, 14.07; IR (KBr) (υmax, cm-1): 3328, 1669; Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59%. Found: C, 78.73; H, 6.34; N, 4.52%. MS(ESI) (m/z): 306 (M+H)+. 4.2.7. Ethyl 3-(4-(dimethylamino)phenyl)-5-phenyl-1H-pyrrole-2-carboxylate 2g White crystalline solid, Yield: 86%, Mp. 136-137°C (lit. mp. 135-137°C) [43]; 1H NMR (CDCl3, 400MHz): δ (ppm) 9.34 (br s, 1H, exchangeable with D2O), 7.61-7.53 (m, 4H), 7.43-7.39 (m, 2H), 7.33-7.28 (m, 1H), 6.78-6.75(m, 2H), 6.59 (d, J = 3.1 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 2.98 (s, 6H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 161.6, 150.1, 135.5, 134.2, 131.6, 130.5, 129.2, 128.0, 125.0, 123.4, 118.3, 112.1, 109.8, 60.4, 40.9, 14.6; IR (KBr) (υmax, cm-1): 3342, 1664; Anal. Calcd for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38%. Found: C, 75.47; H, 6.54; N, 8.45%. MS(ESI) (m/z): 335 (M+H)+. 4.2.8. Ethyl 3-(4-chlorophenyl)-5-phenyl-1H-pyrrole-2-carboxylate 2h Shiny yellow solid, Yield: 90%, Mp. 182-184°C (lit. mp. 187°C) [47]; 1H NMR (CDCl3, 400MHz): δ (ppm) 9.50 (br s, 1H, exchangeable with D2O), 7.62-7.57 (m, 4H), 7.44-7.36 (m, 5H), 6.64 (s, 1H), 4.31 (br s, 2H), 1.29 (br s, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 161.27, 134.91, 134.23, 133.70, 133.51, 129.62, 129.54, 129.28, 127.70, 127.23, 126.02, 118.98, 110.25, 60.56, 14.21; IR (KBr) (υmax, cm-1): 3327, 1675; Anal. Calcd for C19H16ClNO2: C, 70.05; H,

Khajuria and Kapoor

4.95; N, 4.30%. Found: C, 69.97; H, 4.88; N, 4.37%. MS(ESI) (m/z): 326, 328 (M+H)+. 4.2.9. Ethyl 3-(3,4,5-trimethoxyphenyl)-5-phenyl-1H-pyrrole2-carboxylate 2i White crystalline solid, yield: 91%, Mp. 140°C; 1H NMR (CDCl3, 400MHz): δ (ppm) 9.38 (br s, 1H, exchangeable with D2O), 7.65-7.63(m, 2H), 7.49-7.45 (t, J = 8Hz, 2H), 7.38-7.35 (m, 1H), 6.89 (s, 2H), 6.65 (d, J = 4.0 Hz, 1H), 4.32 (q, J = 8.0 Hz, 2H), 3.93 (d, J = 4.0 Hz, 9H), 1.32 (t, J = 8.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 161.06, 152.56, 137.27, 135.30, 133.42, 130.91, 130.58, 129.15, 128.08, 124.78, 118.44, 109.86, 106.76, 60.97, 60.47, 56.14, 14.49; IR (KBr) (υmax, cm-1): 3308, 1627; Anal. Calcd for C22H23NO5: C, 69.28; H, 6.08; N, 3.67%. Found: C, 69.37; H, 5.95; N, 3.58%. MS(ESI) (m/z): 382 (M+H)+. 4.2.10. Ethyl 5-phenyl-3-(2-thienyl)-1H-pyrrole-2-carboxylate 2j Brown solid, Yield: 88%, Mp. 119-122°C; 1H NMR (CDCl3, 400MHz): δ (ppm) 9.55 (br s, 1H, exchangeable with D2O), 7.62-7.57 (m, 3H), 7.44-7.30 (m, 5H), 6.64 (s, 1H), 4.31 (br s, 2H), 1.29 (br s, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 161.30, 134.94, 134.27, 134.13, 133.70, 133.50, 129.55, 129.28, 127.71, 127.22, 127.12, 126.02, 118.97, 110.48, 60.57, 14.20; IR (KBr) (υmax, cm-1): 3318, 1649; Anal. Calcd for C17H15NO2S: C, 68.66; H, 5.08; N, 4.71%. Found: C, 68.75; H, 4.99; N, 4.79%. MS(ESI) (m/z): 298 (M+H) +. 4.2.11. Ethyl 5-phenyl-3-styryl-1H-pyrrole-2-carboxylate 2k White crystalline solid, Yield: 90%, Mp. 158-160°C; 1H NMR (CDCl3, 400MHz): δ (ppm) 9.27 (br s, 1H, exchangeable with D2O), 7.85-7.81 (m, 1H), 7.64-7.44 (m, 2H), 7.407.25 (m, 8H), 7.10-7.06 (m, 1H), 6.90 (d, J = 2.8 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 161.50, 137.73, 136.19, 131.02, 130.17, 129.50, 129.08, 128.66, 128.06, 17.42, 126.43, 124.83, 121.16, 119.99, 104.56, 60.60, 14.59; IR (KBr) (υmax, cm-1): 3138, 1609; Anal. Calcd for C21H19NO2: C, 79.47; H, 6.03; N, 4.41%. Found: C, 79.42; H, 5.95; N, 4.52%. MS(ESI) (m/z): 318 (M+H)+. 4.2.12. Ethyl 3-methyl-5-phenyl-1H-pyrrole-2-carboxylate 2l White solid, Yield: 86%, Mp. 114-115°C (lit. mp. 115°C) [48]; 1H NMR (CDCl3, 400MHz): δ (ppm) 9.27 (br s, 1H, exchangeable with D2O), 7.67-7.54 (m, 2H), 7.47-7.41 (m, 2H), 7.35 (m, 1H), 6.75 (s, 1H), 4.41 (q, j = 6.9 Hz, 2H), 1.97 (s, 3H), 1.42 (t, j = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) δ 163.62, 137.11, 133.54, 131.50, 128.94 , 128.06 , 126.69 , 107.51, 61.50, 15.41, 14.70.; IR (KBr) (υmax, cm-1): 3259, 1660; Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11%. Found: C, 73.41; H, 6.51; N, 6.19%. MS(ESI) (m/z): 230 (M+H)+. 4.2.13. Ethyl 3-(2-chlorophenyl)-5-(4-methylpheny)l-1Hpyrrole-2-carboxylate 2m Shiny green crystalline solid, Yield: 93%, Mp. 205208°C; 1H NMR (CDCl3, 400MHz): δ (ppm) 9.59 (br s, 1H, exchangeable with D2O), 7.54 (s, 2H), 7.48 (s, 1H), 7.42 (s,

One-pot, Solvent-free Cascade Michael-reductive Cyclization Reaction

Current Microwave Chemistry, 2014, Vol. 1, No. 2

1H), 7.30-7.27 (m, 4H), 6.58 (s, 1H), 4.21 (br s, 2H), 2.42 (s, 3H), 1.14 (br s, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 161.25, 137.84, 135.50, 135.02, 133.90, 131.88, 129.72, 129.09, 128.39, 128.31, 125.96, 124.72, 119.94, 109.83, 60.32, 21.27, 13.95; IR (KBr) (υmax, cm-1): 3208, 1612; Anal. Calcd for C20H18ClNO2: C, 70.69; H, 5.34; N, 4.12%. Found: C, 70.62; H, 5.43; N, 4.21%. MS(ESI) (m/z): 340, 342 (M+H) +.

Lit.

=

Literature

MW

=

Microwave

4.3. Procedure for the synthesis of 1,4-bis(2-carboethoxy5-phenylpyrrol-3-yl)benzene, 2n A mixture of (2E,2'E)-3,3'-(1,4-Phenylene)bis(1phenylpropen-2-one) (0.338 g, 1.0 mmol) 1n, ethylnitroacetate (0.266 g, 2.0 mmol) and Et2NH (0.176 g, 2.4 mmol) was irradiated in a capped vial (MW, 90°C , 80 W) for 30 minutes (completion indication by TLC) and P(OEt)3 (0.996 g, 6.0 mmol) was added to the reaction mixture. Further irradiation for 60 minutes resulted in the completion of reaction (TLC). The reaction mixture was cooled to room temperature, transferred to a 10mL round-bottomed flask and volatiles were removed under vacuum at 70°C. The dark brown residue thus obtained, was dissolved in ethyl acetate (30 mL) and washed with water (3 × 15 mL), brine (1 × 15 mL), dried (anhydrous Na2SO4) and concentrated on rotary evaporator. The resultant after column chromatography over silica (60120 mesh) using a gradient of a mixture of petroleum ether and ethyl acetate yielded 1,4-bis(2-carboethoxy-5phenylpyrrol-3-yl)benzene 2n as a brown solid in 63% yield. 4.3.1. 1,4-bis(2-carboethoxy-5-phenylpyrrol-3-yl)benzene 2n

MS(ESI) =

Mass spectroscopy(electron spray ionization)

Mp

=

Melting point

NMR

=

Nuclear magnetic resonance

Na2SO4

=

Sodium sulphate

P(OEt)3

=

Triethylphoshite

TLC

=

Thin layer chromatography

REFERENCES [1] [2] [3] [4] [5] [6] [7] [8]

1

Brown solid, yield: 63%, Mp. 289-291°C; H NMR (DMSO-d6, 400MHz): δ (ppm) 11.98 (br s, 2H, exchangeable with D2O), 7.95 (s, 2H), 7.53 (d, J = 53.5 Hz, 5H), 7.35 (s, 1H), 6.85 (s, 1H), 4.26 (s, 4H), 1.28 (s, 6H); 13C NMR (DMSO-d6, 100 MHz): δ (ppm)161.08, 136.20, 134.10, 132.79, 131.55, 129.15, 129.02, 127.97, 125.93, 119.03, 110.29, 60.12, 14.70; IR (KBr) (υmax, cm-1): 3311, 1660; Anal. Calcd for C32H28N2O4: C, 76.17; H, 5.59; N, 5.55%. Found: C, 76.25; H, 5.48; N, 5.64%. MS(ESI) (m/z): 505 (M+H) +.

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[11]

CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS The authors are grateful to the Department of Science and Technology, GOI, New Delhi for funding (Project No. SR/S1/OC-38/2010) and the NMR facility under PURSE. R.K. is thankful to UGC for fellowship. SUPPLEMENTARY MATERIALS Supplementary material is available on the publisher’s web site along with the published article.

[12]

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ABBREVIATIONS Et2NH

=

Diethylamine

IR

=

Infrared

117

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Received: May 01, 2014

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[43]

[44]

[45]

[46] [47] [48] [49] [50] [51] [52]

Revised: June 18, 2014

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Accepted: June 19, 2014