Jyoti Joshia.Sukhbeer Kumaria and Anshu Dandiab

5

An Efficient and Rapid Multicomponent 1,3-Dipolar Cycloaddition of Azomethine Ylides with Dipolarophiles: a Faster Access to Spirothiapyrrolizidines

Jyoti Joshia.Sukhbeer Kumaria and Anshu Dandiab

aDepartment of Chemistry, Malaviya National Institute of Technology, Jaipur-302017

bDepartment of Chemistry, University of Rajasthan, Jaiput-302004

Email: jjoshi.chy@.mnit.ac.in

Abstract

An efficient and eco-friendly method has been developed for the synthesis of spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole] derivatives via multicomponent 1,3-dipolar cycloaddition reaction of acenaphthenequinone, 1,3-thiazoles-4-carboxylic acid and Knoevenagel adduct in trifluoroethanol as green solvent. The present approach offers several advantages such as shorter reaction times, good yields, low cost, recycling of the solvent and simple work-up. The cycloaddition was found to be highly regio- and diastereoselective.

Keywords: Cycloaddition reaction, Azomethine ylide, Knoevenagel adduct, Spiropyrrolothiazoles, Trifluoroethanol.

1. Introduction

Creation of highly functionalized molecules from simple and starting materials while combining economic and environmental aspects is highly desirable in modern organic chemistry and still remains a great challenge [1]. From this perspective, the development of multicomponent reaction methodologies, consisting of multiple bond forming reactions in one step, provides a simple and economically favourable synthesis of complex products by decreasing the number of laboratory operations required and the quantities of chemicals and solvents used [2].

A. Multicomponent 1,3-dipolar cycloaddition reactions play a key role in the synthesis of five-membered heterocyclic compounds. 1,3-dipolar cycloaddition reactions of azomethine ylides with dipolarophiles represent an important approach for the formation of pyrrolidines, pyrrolizines and thiapyrrolizidines which are prevalent in a variety of biologically active compounds.in recent years, construction of spiro compounds by 1,3-dipolar cycloaddition reactions of azomethine ylides has been well developed, and the reactions proceed with regio- and stereoselectivity [3,4]. B. Spiroheterocycles represent an important class of naturally occurring substances characterized by their highly pronounced biological activities [5]. In particular, spirothiapyrrolizidines have gained significant attention as a result of their diverse biological activities, enabling their use as hepatoprotective [6], antibiotic [7], antidiabetic [8], anticonvulsant [9], anti-inflammatory [10], antileukemic agents [11] and in treatment for Alzheimer disease [12].

In the 21st century, with increasing environmental concerns, chemists are devoted to researching new processes that are less harmful to human health and the environment. The challenge for sustainable environments calls for the use of clean procedures that avoid the use of harmful solvents [13, 14]. The use of fluorinated solvent, as chemical reaction media in place of conventional volatile organic solvents, has grown dramatically in recent years. Fluorinated alcohols possess interesting physiochemical properties, which include lower boiling points and higher melting points than their non-fluorinated counterparts, high polarity and strong hydrogen bond donating ability [15].

2. Result and discussion

As per our current efforts on the development of safe and ‘green’ protocols for synthesis of biologically active spiroheterocyclic compounds [16], herein we report the facile and efficient synthesis of spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole] derivatives (4a-j), in a highly regio- and stereoselective manner through 1,3-dipolar cycloaddition reaction of acenaphthenequinone (1), 1,3-thiazoles-4-carboxylic acid (2) and Knoevenagel adduct (3a-j) in trifluoroethanol (Scheme 1).

Scheme 1. Synthesis of spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole] derivatives.

In the first step, we prepared the Knoevenagel adduct (3a-j) via the reaction of substituted aldehydes with ethylcyanoacetate / acetamide in ethanol under ultrasound irradiation. The choice of an appropriate reaction medium plays a pivotal role in the successful synthesis of 1,3 dipolar cycloaddition reaction.

Next, we devoted our efforts to the study of the reaction of acenaphthenequinone (1), 1,3-thiazoles-4-carboxylic acid (2) and Knoevenagel adduct (3a) in various solvents such as toluene, 1,4-dioxane, tetrahydrofuran, ethanol, methanol and trifluoroethanol, under reflux conditions (Table 1). As seen from Table 1, the best results were obtained by refluxing the mixture in trifluoroethanol for 25-35 min to afford the spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole] 4a in good yield (92%) with high regioselectivity (Table 1, entry 6).

Table 1. Optimization of the reaction condition for synthesis of compound 4a.

Entry / Solvent / Temperature / Time (h) / Yielda (%)
1 / Toluene / Reflux / 10 / 53
2 / 1,4-dioxane / Reflux / 8 / 62
3 / Tetrahydrofuran / Reflux / 6.5 / 65
4 / Ethanol / Reflux / 2 / 70
5 / Methanol / Reflux / 1.5 / 75
6 / Trifluoroethanol / Reflux / 25-35 min / 94

a Isolated yield after recrystallization.

To investigate the scope of this procedure, we reacted compounds acenaphthenequinone (1), 1,3-thiazoles-4-carboxylic acid (2) with Knoevenagel adduct (3a-j) to give the derivatives 4a-j in good yields (Table 2).

Table 2. Synthetic results of spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole] derivatives 4a-j.

Entry / Product / R / R′ / Time (min) / Yielda (%) / Mp (oC)
1 / 4a / H / COOEt / 20 / 94 / 190-192
2 / 4b / 4-CH3 / COOEt / 25 / 93 / 206-208
3 / 4c / 4-F / COOEt / 22 / 90 / 202-204
4 / 4d / 2,4-diCl / COOEt / 28 / 91 / 209-211
5 / 4e / 4-NO2 / COOEt / 30 / 89 / 214-216
6 / 4f / H / CONH2 / 20 / 92 / 200-202
7 / 4g / 4-CH3 / CONH2 / 23 / 94 / 204-206
8 / 4h / 4-F / CONH2 / 30 / 91 / 198-200
9 / 4i / 2,4-diCl / CONH2 / 25 / 87 / 158-160
10 / 4j / 4-NO2 / CONH2 / 30 / 91 / 172-174

a Isolated yield

The structure of novel spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole] derivatives 4a by 1,3-dipolar cycloaddition of azomethine ylides was elucidated with the help of IR, 1H NMR, 13C NMR and mass data as illustrated for compound 4a. In the IR spectrum, the sharp peak appeared at 1730 cm-1 and 1748 corresponds to C=O stretching for acenaphthenequinone and ester carbonyls respectively and the peak at 2245 cm-1 corresponds to C≡N stretching of the product 4a. In the 1H NMR, peaks in the range of δ 7.15–8.24 ppm show aromatic protons. The multiplate at δ 2.12-2.48 corresponding to CH2 group (–SCH2); multiplate at δ 3.08-3.30 and doublet at δ 3.45 (J = 8.8 Hz) corresponding to CH2 group (–SCH2N–); doublet at δ 3.85 (J = 9.6 Hz) corresponding to CH group (benzylic proton); multiplate at δ 4.26–4.33 ppm corresponding to CH group; In the 13C NMR, the peaks at δ 78.32 ppm corresponds to one spiro carbons and the peaks at δ 163.15 and 200.30 ppm show the presence of two carbonyl carbon. A peak observed at m/z: 468 in the mass spectrum for [M+] ion further conforms the product 4a.

2.1. Plausible mechanism

A proposed reaction mechanism for the formation of the spirothiapyrrolizidines derivatives are shown in Scheme 2.

Scheme 2. Mechanism of for the synthesis of spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole] derivatives.

The mechanism involves, TFE act as Bronsted acid (pKa = 12.4 for TFE) and enhance the electophilic character of the carbonyl groups is by high hydrogen bond donating ability of the trifluoroethanol (CF3CH2OH), which facilated the formation of an azomethine ylide, formed via decarboxylative condensation of acenaphthenequinone and 1,3-thiazoles-4-carboxylic acid, which then undergoes 1,3-dipolar cycloaddition with substrate Knoevenagel adduct to produce the cycloadduct 4.

3. Materials and methods

Analytical grade solvents and commercially available reagents were used without further purification. The melting points of all compounds were determined on a Toshniwal apparatus in capillary and uncorrected. The purity of compounds was checked on thin layers of silica Gel-G coated glass plates and benzene:ethylacetate (8:2) as eluent. IR spectra were recorded on a Shimadzu FT IR-8400S spectrophotometer using KBr pellets. 1H and 13C NMR spectra were recorded in dimethyl sulfoxide (DMSO-d6) as a solvent on a Bruker Avance spectrophotometer at 400 and 100 MHz, respectively. Chemical shifts are expressed in parts per million (ppm) using tetramethylsilane (TMS) as an internal standard. The abbreviations were used to explain the multiplicities: s=singlet, d = doublet, t = triplet, m = multiplet. The mass spectra of representative compounds were obtained using Shimadzu GC-MS-QP-2010 spectrometer at 70 eV.

3.1. General procedure for the synthesis of spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole] derivatives 4: An equimolar appropriate mixture of acenaphthenequinone 1 (1 mmol), 1,3-thiazoles-4-carboxylic acid 2 (1 mmol) and Knoevenagel adduct 3a-j (1 mmol) in 2,2,2-trifluoroethanol (2–3 mL) was refluxed for the appropriate time (25–35 min). After completion of the reaction as indicated by (TLC), the solid precipitates were filtered and washed with TFE to furnish pure spirothiapyrrolizidine derivatives. The TFE was distilled off (to recover for the next run). All the synthesized compounds were well characterized by 1H NMR, 13C NMR and Mass.

(4a) Ethyl 6′-cyano-7′-phenyl-2-oxo-3′,6′,7′,7a′-tetrahydro-1′H,2H-spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole]-6′-carboxylate: IR (KBr, νmax, cm-1): 2245 (C≡N), 1748 (C=O), 1730 (C=O). 1H NMR (400 MHz, DMSO-d6) δ: 1.28 (t, J = 7.2 Hz, 3H, CH3), 2.12-2.48 (m, 2H, CH2), 3.08-3.30 (m, 1H, CH), 3.45 (d, J = 8.8 Hz, 1H, CH), 3.63-3.68 (m, 2H, OCH2), 3.85 (d, J = 9.6 Hz, 1H, CH2), 4.26-4.33 (m, 1H, CH), 7.15-8.24 (m, 11H, ArH); 13C NMR (100 MHz, DMSO-d6) δ: 13.50, 36.60, 51.20, 54.26, 62.85, 66.11, 71.23, 73.15, 78.32 (spiro C), 114.85, 121.47, 126.50, 127.18, 127.88, 128.20, 128.42, 128.63, 129.84, 130.07, 130.55, 131.44, 132.66, 133.10, 134.40, 140.72, 163.15 (C=O), 200.30 (C=O); MS m/z: 454 [M]+ for C27H22N2O3S.

(4b)Ethyl 6′-cyano-7′-(4-methylphenyl)-2-oxo-3′,6′,7′,7a′-tetrahydro-1′H,2H-spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole]-6′-carboxylate IR (KBr, νmax, cm-1): 2242 (C≡N), 1745 (C=O), 1734 (C=O). 1H NMR (400 MHz, DMSO-d6) δ: 1.17 (s, 3H, CH3), 1.32 (t, J = 8.0 Hz, 3H, CH3), 2.04-2.27 (m, 2H, CH2), 2.98-3.21 (m, 1H, CH), 3.36 (d, J = 8.4 Hz, 1H, CH), 3.47-3.59 (m, 2H, OCH2), 3.78 (d, J = 9.6 Hz, 1H, CH2), 4.19-4.28 (m, 1H, CH), 7.03-8.11 (m, 10H, ArH); 13C NMR (100 MHz, DMSO-d6) δ: 12.09, 21.35, 35.40, 52.18, 54.30, 61.37, 66.45, 72.58, 73.09, 79.20 (spiro C), 115.30, 121.32, 126.35, 127.39, 127.57, 127.94, 128.15, 128.50, 129.07, 130.24, 131.25, 131.74, 132.52, 133.18, 135.02, 141.42, 164.26 (C=O), 199.32 (C=O); MS m/z: 468 [M]+ for C28H24N2O3S.

(4c) Ethyl 6′-cyano-7′-(4-fluorophenyl)-2-oxo-3′,6′,7′,7a′-tetrahydro-1′H,2H-spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole]-6′-carboxylate IR (KBr, νmax, cm-1): 2240 (C≡N), 1725 (C=O), 1720 (C=O). 1H NMR (400 MHz, DMSO-d6) δ: 1.30 (t, J = 7.6 Hz, 3H, CH3), 3.02-3.12 (m, 2H, CH2), 3.25-3.38 (m, 1H, CH2), 3.48 (d, J = 10.0 Hz, 1H, CH2), 3.56-3.62 (m, 2H, OCH2), 4.01 (d, J = 10.8 Hz, 2H, CH), 4.47 (d, J = 8.4 Hz, 1H, CH), 7.23-8.11 (m, 10H, ArH); 13C NMR (100 MHz, DMSO-d6) δ: 11.20, 36.12, 51.40, 55.09, 57.50, 58.30, 60.42, 66.57, 68.28, 68.87, 79.50 (spiro C), 114.24, 118.30, 125.54, 126.35, 129.25, 130.56, 132.50, 132.74, 133.87, 134.44, 135.60, 137.29, 142.46, 146.22, 169.55 (C=O), 199.05 (C=O); MS m/z: 472 [M]+ for C27H21FN2O3S.

(4d) Ethyl 6′-cyano-7′-(2,4-dichlorophenyl)-2-oxo-3′,6′,7′,7a′-tetrahydro-1′H,2H-spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole]-6′-carboxylate: IR (KBr, νmax, cm-1): 2235 (C≡N), 1750 (C=O), 1735 (C=O); 1H NMR (400 MHz, DMSO-d6) δ: 1.21 (t, J = 8.4 Hz, 3H, CH3), 3.02-3.11 (m, 2H, CH2), 3.17-3.29 (m, 1H, CH2), 3.38 (d, J = 8.4 Hz, 1H, CH2), 3.49 (s, 3H, OCH3), 3.55-3.63 (m, 2H, OCH2) 3.78 (d, J = 10.8 Hz, 1H, CH), 4.49 (d, J = 10.4 Hz, 1H, CH), 7.19-8.33 (m, 9H, ArH); 13C NMR (100 MHz, DMSO-d6) δ: 12.50, 36.24, 52.43, 53.70, 57.04, 62.93, 63.55, 70.29, 79.35 (spiro C), 114.52, 122.28, 126.54, 127.45, 127.74, 128.22, 128.39, 128.61, 129.05, 130.16, 130.27, 132.64, 133.56, 140.66, 164.08 (C=O), 199.31 (C=O); MS m/z: 522 [M]+ for C27H20Cl2N2O3S.

(4e) Ethyl6′-cyano-7′-(4-nitrophenyl)-2-oxo-3′,6′,7′,7a′-tetrahydro-1′H,2H spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole]-6′-carboxylate: IR (KBr, νmax, cm-1): 2238 (C≡N), 1754 (C=O), 1736 (C=O). 1H NMR (400 MHz, DMSO-d6) δ: 1.23 (t, J = 8.0 Hz, 3H, CH3), 2.92-3.04 (m, 2H, CH2), 3.18-3.25 (m, 2H, CH2), 3.34-3.42 (m, 2H, OCH2), 3.91 (d, J = 10.8 Hz, 1H, N–CH2), 4.28 (d, J = 10.4 Hz, 2H, CH), 4.72 (d, J = 8.0 Hz, 1H, CH), 7.20-8.48 (m, 10H, ArH); MS m/z: 499 [M]+ for C27H21N3O5S.

(4f)6′-cyano-7′-phenyl-2-oxo-3′,6′,7′,7a′-tetrahydro-1′H,2H-spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole]-6′-carboxamide: IR (KBr, νmax, cm-1): 2254 (C≡N), 1715 (C=O), 1684 (C=O); 1H NMR (400 MHz, DMSO-d6) δ: 2.74-2.80 (m, 1H, CH2), 2.95-3.04 (m, 1H, CH2), 3.11-3.23 (m, 1H, CH2), 3.48 (d, J = 10.4 Hz, 1H, CH), 4.05 (d, J = 10.4 Hz, 1H, CH), 4.17-4.33 (m, 1H, CH), 6.94-7.87 (m, 11H, ArH & 2H, NH2); 13C NMR (100 MHz, DMSO-d6) δ: 33.24, 52.45, 53.40, 63.08, 71.24, 79.62 (spiro C), 114.60, 122.57, 126.73, 127.34, 127.75, 128.15, 128.61, 129.17, 129.40, 130.19, 131.25, 131.76, 135.48, 143.50, 164.84 (C=O), 200.07 (C=O); MS m/z: 425 [M]+ for C25H19N3O2S.

(4g) 6′-cyano-7′-(4-methylphenyl)-2-oxo-3′,6′,7′,7a′-tetrahydro-1′H,2H-spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole]-6′-carboxamide: IR (KBr, νmax, cm-1): 2252 (C≡N), 1735 (C=O), 1700 (C=O). 1H NMR (400 MHz, DMSO-d6) δ: 2.18 (s, 3H, CH3), 2.92-3.08 (m, 1H, CH2), 3.20-3.34 (m, 1H, CH2), 3.28-3.44 (m, 1H, CH2), 3.79 (d, J = 10.4 Hz, 1H, CH2), 4.52 (d, J = 10.4 Hz, 1H, CH), 4.65-4.72 (m, 1H, CH), 7.15-8.40 (m, 10H, ArH & 2H, NH2); 13C NMR (100 MHz, DMSO-d6) δ: 18.30, 34.62, 52.60, 53.20, 64.13, 69.56, 79.04 (spiro C), 115.40, 121.48, 126.50, 127.15, 127.78, 120.10, 128.45, 129.55, 129.86, 130.40, 130.67, 131.54, 132.08, 142.28, 163.37 (C=O), 198.74 (C=O); MS m/z: 439 [M]+ for C26H21N3O2S.

(4h) 6′-cyano-7′-(4-fluorophenyl)-2-oxo-3′,6′,7′,7a′-tetrahydro-1′H,2H-spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole]-6′-carboxamide: IR (KBr, νmax, cm-1): 2256 (C≡N), 1718 (C=O), 1680 (C=O); 1H NMR (400 MHz, DMSO-d6) δ: 2.68-2.79 (m, 1H, CH2), 2.99-3.11 (m, 1H, CH2), 3.15-3.28 (m, 1H, CH2), 3.55 (d, J = 10.6 Hz, 1H, CH), 4.11 (d, J = 10.4 Hz, 1H, CH), 4.29-4.40 (m, 1H, CH), 6.99-8.03 (m, 10H, ArH & 2H, NH2); 13C NMR (100 MHz, DMSO-d6) δ: 34.50, 52.30, 53.23, 64.12, 70.50, 79.40 (spiro C), 115.04, 121.10, 125.40, 127.60, 127.88, 128.08, 128.48, 129.11, 129.34, 130.24, 130.65, 131.36, 134.15, 142.80, 164.25 (C=O), 199.20 (C=O); MS m/z: 443 [M]+ for C25H18FN3O2S.

(4i) 6′-cyano-7′-(2,4-dichlorophenyl)-2-oxo-3′,6′,7′,7a′-tetrahydro-1′H,2H-spiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole]-6′-carboxamide: IR (KBr, νmax, cm-1): 2245 (C≡N), 1728 (C=O), 1690 (C=O); 1H NMR (400 MHz, DMSO-d6) δ: 2.94-3.07 (m, 1H, CH2), 3.15-3.21 (m, 1H, CH2), 3.26-3.33 (m, 1H, CH2), 3.50 (s, 3H, OCH3), 3.72 (d, J = 10.0 Hz, 1H, CH), 4.41 (d, J = 10.0 Hz, 1H, CH), 4.57-4.65 (m, 1H, CH), 7.09-8.40 (m, 9H, ArH & 2H, NH2); 13C NMR (100 MHz, DMSO-d6) δ: 30.59, 35.57, 52.50, 53.06, 56.09, 64.77, 70.67, 79.08 (spiro C), 114.87, 115.08, 116.16, 122.17, 126.39, 127.69, 128.13, 129.91, 130.22, 130.60, 130.63, 130.74, 131.74, 131.82, 132.29, 141.68, 148.30, 164.06 (C=O), 199.70 (C=O); MS m/z: 493 [M]+ for C25H17Cl2N3O2S.