Mol Divers DOI 10.1007/s11030-014-9505-y
FULL-LENGTH PAPER
A green, multicomponent, regio- and stereo-selective 1,3-dipolar cycloaddition of azides and azomethine ylides generated in situ with bifunctional dipolarophiles using PEG-400 Jayant Sindhu · Harjinder Singh · J. M. Khurana
Received: 13 September 2013 / Accepted: 13 January 2014 © Springer International Publishing Switzerland 2014
Abstract A series of novel dispiropyrrolidine-linked 1,2,3triazole derivatives have been prepared by one-pot, fourcomponent protocol that employed 5-arylidene-3-(prop-2ynyl)thiazolidine-2,4-dione, isatin, sarcosine and substituted azides using Cu(I) generated in situ as catalyst in PEG-400 as a highly efficient and green media. This is the first report of a four-component reaction involving a classical Huisgen reaction, in which the two dipolar moieties (substituted azides and in situ generated azomethine ylides) react with acetylenic and olefinic dipolarophiles, respectively. The 1,3dipolar cycloaddition proceeds in a highly regio- and stereoselective manner. This methodology can be an ideal tool for the preparation of biologically important five-membered heterocyclic compounds in one pot. Keywords Spiro compounds · Dipolar cycloaddition · Azomethine ylides · Multicomponent reactions (MCRs) · Pyrrolidines · Thiazolidin-2,4-dione · 1,2,3-Triazoles · PEG-400
Introduction Design of highly efficient reaction methodologies for the synthesis of compounds having structural complexity and diversity with promising biological properties is a major challenge for the organic and medicinal chemists [1]. This Electronic supplementary material The online version of this article (doi:10.1007/s11030-014-9505-y) contains supplementary material, which is available to authorized users. J. Sindhu · H. Singh · J. M. Khurana (B) Department of Chemistry, University of Delhi, Delhi 110007, India e-mail: [email protected]
can be overcome by using multicomponent reactions (MCR) which involve formation of two and more bonds in a single reaction step and generate highly diverse molecules from readily available starting molecules. Continuous efforts have been devoted to the synthesis of compounds containing different nitrogen-containing heterocyclic units because of their broad applications in medicinal chemistry [2]. Spiropyrrolidine-oxindoles structural units form the core of many alkaloids and natural products exhibiting important biological activities [3]. They display a fascinating array of biological applications such as antidiabetic [4], antimycobacterial [5], antimicrobial [6], anticholinesterase [7], anticancer [8], etc. Five-membered [1,2,3]-triazoles display biological activities such as neuroprotective agents [9], anticancer [10], antitubercular [11] and antimicrobial [12]. Due to the wide range of biological activities of 1,2,3-triazoles and spiropyrrolidine-oxindoles and the ease of their synthesis, both [1,2,3]-triazoles and spiropyrrolidine-oxindoles have been incorporated into a variety of heterocyclic compounds [13,14]. 2,4-Thiazolidinediones (TZDs) also exhibit numerous biological activities, such as antihyperglycemic [15], euglycemic [16], anti-inflammatory [17], antimalarial [18], antioxidant [19], cytotoxic [20], antiproliferative [21], PPAR γ agonist [22], antitumor [23], antibacterial [24] and antiviral effect [25]. 1,3-Dipolar cycloaddition reaction is an efficient tool for the construction of five-membered nitrogen-containing heterocyclic units in a highly regio- and stereo-selective manner. Azomethine ylides and azides serve as expedient precursors for the construction of biologically important fivemembered nitrogen heterocycles [26,27]. The multicomponent reaction involving intermolecular [3 + 2] cycloaddition reaction of azomethine ylides with various alkenes represents an efficient and convergent method for the synthesis of spiropyrrolidine and pyrrolizidine units [28].
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Mol Divers Table 1 Synthesis of (Z )-5-arylidene-3-(prop-2-ynyl)thiazolidine2,4-diones (1a–1e) S.No
Ar
Yield (%)
M.p.(◦ C)
1a
4-BrC6 H4
92
217–220
1b
4-MeC6 H4
94
159–161
1c
4-(NO2 )C6 H4
90
155–157
1d
C7 H5 O2 (Piperonal)
92
170–171
1e
4-MeOC6 H4
96
177–178
The in situ generation of azomethine ylides would be an added advantage, as it reduces overall steps and increases the efficiency of the reaction for the synthesis of spiropyrrolidine linked 1,2,3-triazoles. The biological importance of spiro[pyrrolidine-3,3 -oxindole], 1,2,3-triazoles and TZDs sub-structures led us to investigate the synthesis of hybrid heterocycles comprising spiro[pyrrolidine-3,3 oxindole], 1,2,3-triazoles and TZDs. In conjunction with our interest in the synthesis of novel heterocycles employing domino [29] and 1,3-dipolar cycloaddition reactions [30,31], we decided to explore the synthesis of some novel hybrids of spiro[pyrrolidine-3,3 -oxindole], 1,2,3-triazoles and TZDs by a one-pot four-component reaction. Such a strategy would provide a rapid synthesis of new hybrid molecules containing spiro[pyrrolidine-3,3 -oxindole], 1,2,3-triazoles and TZDs which are otherwise accessible through multistep synthesis.
Scheme 1 Synthesis of (Z )-5-arylidene-3-(prop-2ynyl)thiazolidine-2,4-dione (1a–1e)
Results and discussion The present manuscript reports the synthesis of targeted 1(N-methyl)-spiro[2.3 ]oxindole- spiro[3.5 ]-3 -N-((1-(aryl) -1H -1,2,3-triazol-4-yl) methyl)thiazolidine-2 ,4 -dione-4(aryl)-pyrrolidines (5a–5n), by a multicomponent approach. The synthesis of functionalized dipolarophile viz. (Z)-5-(4bromobenzylidene) -3-(prop-2-ynyl) thiazolidine-2,4-dione (1a) which is one of the components of the MCR was carried out by a two-step one-pot reaction of 2,4-thiazolidinedione (1.0 eq) and 4-bromobenzaldehyde (1.0 eq) in the presence of piperidine (1.0 eq) in PEG-400 at 100 ◦ C until reaction completion as indicated by TLC (ethyl acetate: petroleum ether, 30:70, v/v). The resultant (Z)-5-(4-bromobenzylidene)thiazolidine-2,4-dione on reaction with propargyl bromide (1.0 eq) yielded 5-(4-bromobenzylidene)-3-(prop-2-ynyl)thiazolidine-2,4-dione(1a) in 92 % (entry 1, Table 1). The generality of this protocol was checked by carrying out the reactions using different aromatic aldehydes containing both electron withdrawing and electron donating substituents yielded the corresponding thiazolidine-2,4-dione derivatives 1b–1e (Scheme 1) in high yields as shown in Table 1. All the synthesized dipolarophiles (1a–1e) are novel compounds, and their structures were confirmed by 1 H, 13 C NMR, IR spectra and HRMS. The Z -configuration of the double bond was confirmed by 1 H NMR and single crystal X-ray crystallographic of 1a (Fig. 1).
Ar S O O
N H
ArCHO Piperidine, PEG-400 100oC, 3-4 h
S O O
N H i
S N
H H
O
H 7.85, s, 1H 133.2 4.91, d, 2H, J=2.8 Hz 30.7 2.26, t, 1H, J=2.8 Hz 75.8
H
1a Fig. 1 Characteristic 1 H,
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13 C
NMR signals and single crystal X-ray structure of 1a
N O
1a-1e
Br
O
Br 100oC, 20 min 92% yield
Ar
S
O
1a
Mol Divers
tion (entries 1–8, Table 2). The four-component reaction was then explored at higher temperatures, under ultrasonic irradiation and also in presence of bases in PEG-400 (entries 9–16, Table 2). It was observed that when cycloaddition reaction of (Z )-5-(4bromobenzylidene)-3-(prop-2-ynyl)thiazolidine-2,4-dione (1.0 mmol) (1a), isatin (1.0 mmol) (2), 1-azido-4-fluorobenzene (1.0 mmol) (3a), sarcosine (1.00 mmol) (4), was performed in PEG-400 using aq. CuSO4 .5H2 O (10 mol%) followed by aq. sodium ascorbate (20 mol%) as catalyst at 130 ◦ C, it resulted in the formation of 1-N-methylspiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4-fluorophenyl)-1 H -1,2,3-triazol-4-yl) methyl)thiazolidine-2 ,4 -dione-4-(4bromophenyl)-pyrrolidine (5a) in 82 % yield in 12 h (Scheme 2). The structure of 5a was elucidated using one and twodimensional NMR spectroscopic data, IR and HRMS spectra. The HMBC and COSY correlations are useful in the signal assignments of 5a, and various characteristic signals are shown in Fig. 2. The 1 H NMR spectrum of 5a revealed one sharp singlet at δ 1.99 due to the N-methyl protons. The benzylic proton on C4 carbon of pyrrolidine ring exhibits a multiplet at δ 4.46–4.42. Two protons of C5 carbon of pyrrolidine exhibit a multiplet at δ 3.82–3.77 and 3.49–3.45. Two protons of N-CH2 appear as multiplet at δ 4.68–4.60. The disappearance of triplet at δ 2.26 for acetylenic C–H in (Z )-5-(4-bromobenzylidene)-3-(prop2-ynyl)thiazolidine-2,4-dione (1a) and appearance of singlet at δ 8.12 for proton at C-5 carbon of triazole ring confirm the formation of triazole ring. This higher value of δ justifies the substitution of aryl group on N − 1. Aromatic protons appeared as a multiplet in the region of δ 7.90–6.46, and there was one singlet at δ 10.74 for the NH proton of oxindole. Also disappearance of proton peak from δ 7.85 for C=C–H also confirms the disappearance of exocyclic double bond. The regiochemistry of the product formed in the reaction can be confirmed by 1 H NMR. The regioisomer 5a would show a multiplet for the benzylic proton on C4 carbon of pyrrolidine ring, whereas the regioisomer 7 (see Fig. 4) would show a singlet. 1 H NMR of the product showed a multiplet at δ 4.46–4.42 rather than a singlet thus suggesting the formation of 5a. Further, the off-resonance decoupled 13 C NMR of
Table 2 Optimization of reaction conditions for the synthesis 1-Nmethyl-spiro[2.3 ] oxindole-spiro [3.5 ]-3 -N-((1-(4-fluorophenyl)1H -1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-bromo phenyl)-pyrrolidine (5a) Entry Solvent
Base
Temp (◦ C) Time (h) Yield (%)a
1
Ethanol
–
Reflux
24
50
2
Methanol
–
Reflux
24
45
3
H2 O
–
Reflux
24
20
4
Acetonitrile –
Reflux
24
35
5
THF
–
Reflux
24
55
6
DMF
–
90
20
65
7
PEG-400
–
90
18
72
8
PEG-600
–
90
19
68
9
PEG-400
–
30
6
50b
10
PEG-400
–
40
8
62b
11
PEG-400
–
100
16
75
12
PEG-400
–
120
14
78
13
PEG-400
–
130
12
82
14
PEG-400
–
140
12
80
15
PEG-400
Piperidine 140
12
76
16
PEG-400
Et 3 N
12
78
a b
140
Yield after column chromatography Reaction performed under ultrasonic irradiation
Dipolarophiles 1 possess two dipolar functional groups (C=C and C≡C) which make them diverse synthons for the synthesis of five-membered heterocycles particularly triazoles and pyrrolidines. Therefore, the study of the regio- and stereoselectivity of the products formed is of considerable interest. Using a series of dipolarophiles (1a–1e), we initiated our investigation on the four-component [3+2] cycloaddition reaction of 1 with isatin (2), substituted azides (3) and sarcosine (4). Initially, the cycloaddition reaction of an equimolar mixture of a (Z )-5-(4-bromobenzylidene)-3(prop-2-ynyl)thiazolidine-2,4-dione (1a), isatin (2), 1-azido4-fluorobenzene (3a) and sarcosine (4), was performed in ethanol using aqueous solution of CuSO4 . 5H2 O (10 mol%) followed by aqueous solution of sodium ascorbate (20 mol%) as catalyst under reflux. The reaction was incomplete even after 24 h as observed by TLC(ethyl acetate: petroleum ether, 40:60, v/v) and resulted in formation of 5a (50 %). The yield of 5a depends on the solvents employed for reacScheme 2 Synthesis of 1-Nmethyl-spiro[2.3 ]oxindolespiro[3.5 ]-3 -N-((1-(4fluorophenyl)-1H -1,2,3-triazol4-yl)methyl)thiazolidine-2 ,4 dione-4-(4-bromophenyl)pyrrolidine using multicomponent approach
CH3 N
Br H S
S
O
+
N O 1a
O+ N H 2
NH
N3
O
+ F 3
N H
COOH
CuSO4.5H2O (10 mol %), Br Sodium ascorbate(20 mol%), PEG-400, 12h, 130oC
4
N O N
F
O O
N
N
5a
123
Mol Divers Fig. 2 HMBC and COSY correlations useful in the signal assignments of 5a and various characteristic 1 H and 13 C NMR peaks
F N N
H H N
N
O
H H OO N
S
F 8.28 (s, 1H, Ar-H), 122.9 4.68-4.60 (m, 2H, N-CH2)
N
Br
H
H
H
10.74 (s, 1H, -NH)
H-H COSY
H N
F N N
N O
Br
O
H H N
78.9 1.99 (s, 3H, N-CH3), 36.3
N H
H
H
N N
O
N 176.8
H H OO N
S
N
174.2
3.82-3.77 (m, 1H, C-H), 57.3 3.49-3.45 (m, 1H, C-H), 57.3
HMBC
S
N 72.1 H
H
H
O 168.9
Br
4.46-4.42 (m, 1H, C-H), 50.8
Fig. 3 Single crystal X-ray structure and crystal packing of 5a showing two molecules present in a crystal lattice (labels are omitted for clarity)
the product exhibited signals at δ 72.1 and 78.9 ppm which corresponds to the spiro carbon C3 and C2 of the pyrrolidine ring of 5a. The signals at δ 176.8 ppm and δ 168.9 ppm of the product 5a are due to the keto carbonyls of thiazolidi2,4-dione ring. The resonance at δ 174.7 ppm is due to the oxindole carbonyl carbon. Signal at δ 36.9 ppm is due to N-CH3 and peaks at δ 50.8 and 57.3 are due to C4 and C5 carbon of pyrrolidine ring. The mass spectrum of 5a showed a molecular ion peak at m/z 633.0673 (M+ +1). The formation of only one regioisomer i.e. 5a was also confirmed by the single crystal X-ray structural analysis (Fig. 3). In view of the successful formation of the desired 5a in high yields, the generality of the above protocol of four component reaction was checked by carrying out the
123
reactions of different substituted aryl azides (3) containing both electron withdrawing and electron releasing substituent with (Z )-5-(arylidene)-3-(prop-2-ynyl)thiazolidine2,4-diones (1), isatin (2) and sarcosine (4) under the optimized conditions (Scheme 3). All the reactions proceeded successfully and yielded the corresponding products 5a–5n in excellent yields as depicted in Table 3. The proposed pathway for the formation of 5 is given in Fig. 4. The proposed pathway consists of two parts. The first part involves formation of intermediate 6 by Cu(I) catalysed [3+2] azide-alkyne cycloaddition. The Cu(I) is generated in situ by well-known reduction of Cu(II) to Cu(I) by sodium ascorbate [32]. In the second part, intermediate 6 undergoes subsequent [3 + 2] cycloaddition reaction with in situ gener-
Mol Divers Scheme 3 Synthesis of 1-Nmethyl-spiro[2.3 ]oxindolespiro[3.5 ]-3 -N-((1-(4-aryl)1H -1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4aryl)-pyrrolidines using multicomponent approach
CH3 N Ar
S
O
+
N O 1
N3
O
+ R2
O+ N H 2
H CuSO4.5H2O (10 mol %), Sodium ascorbate(20 mol%), N H
COOH
N
N
4
N R2
S.no
Ar
R1
R2
Time (h)
Yield (%)
M.p. (◦ C)
5a
4-BrC6 H4
F
H
11
82
252
5b
4-MeC6 H4
Me
H
10.5
92
207
5c
4-MeC6 H4
H
Cl
10.5
90
209
5d
4-BrC6 H4
OMe
H
11
88
239
5e
4-BrC6 H4
Me
H
11
86
240
5f
4-BrC6 H4
H
Cl
11
86
236
5g
4-BrC6 H4
Br
H
11
84
250
5h
4-MeC6 H4
Br
H
10.5
88
253
5i
4-(NO2 )C6 H4
F
Cl
10
94
244
5j
4-(NO2 )C6 H4
Br
H
10
92
245
5k
C7 H5 O2
F
Cl
10
94
253
5l
4-(NO2 )C6 H4
OMe
H
10
96
236
5m
4-OMeC6 H4
F
Cl
12
86
230
5n
4-OMeC6 H4
F
H
12
84
237
O O
O
R1
Table 3 Synthesis of 1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 N-((1-(aryl)-1H -1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione4-(aryl)-pyrrolidines (5a–5n)
S
PEG-400, 10-12h, 130oC
R1 3
NH
Ar
N
5a-5n
Conclusion We have reported an efficient and green methodology for the synthesis of biologically important 1-N-methylspiro[2.3 ] oxindole-spiro [3.5 ]-3 -N-((1-(aryl)-1H -1,2,3 -triazol-4-yl)methyl)thiazolidine-2 ,4 -dione-4-(aryl)-pyrrolidine by reaction of 5-(arylidene)-3-(prop-2-ynyl)thiazolidine-2,4-dione (1), isatin (2), substituted azides (3) and sarcosine (4) using Cu(I) as catalyst in PEG-400 at 130 ◦ C. This protocol offers the multicomponent synthesis of dispirooxindolopyrrolidine/ thiazolidin-2,4-dione/ 1,2,3triazoles hybrids which are otherwise accessible only through multistep synthesis and thus offers advantages in terms of atom economy, easy workup, green reaction media and high yields.
Experimental Chemistry
ated azomethine ylide to yield the desired products 5 (Path b). Formation of 6a during the four-component condensation was confirmed by CO-TLC with an authentic sample of 6a. The intermediacy of 6a was further confirmed by an independent reaction of 6a with isatin and sarcosine in PEG-400 which led to the formation of 5a and hence the intermediacy of 6 in general in the four-component condensation. The role of Cu(I) in catalysing only the first part of the pathway was also confirmed by an independent reaction of 6a with isatin and sarcosine. The reaction was attempted both in presence and absence of CuSO4 · 5H2 O (10 mol%) and sodium ascorbate (20 mol%). The reactions resulted in the formation of 5a in 80 and 81 % yield, respectively, in 12 h, which suggests that Cu(I) is catalysing only the azide-alkyne cycloaddition reaction and has no effect on dipolar cycloaddition reaction of azomethine ylide and double bond. The formation of regioisomer 7, as shown in Fig. 4, has already been ruled out based on 1 H NMR, 2D NMR and X-ray structure. PEG-400 is a superior solvent because of high solubility of intermediate 6.
Compounds structures were confirmed by their spectral data. Silica gel 60 F254 (Precoated aluminium plates) from Merck was used to monitor reaction progress. Melting points were determined on Buchi melting point 545 apparatus and are uncorrected. IR (KBr) spectra were recorded on Perkin Elmer FTIR spectrophotometer, and the values are expressed as ν maxcm−1 . The 1 H and 13 C spectra were recorded on Jeol JNM ECX-400P at 400 MHz and 100 MHz, respectively. Mass spectra were recorded at Bruker Micro TOF Q – II. Chemical shift values are recorded on δ scale, and the coupling constants (J) are in Hertz. Abbreviations used for 1 H NMR signals are: s=singlet, d=doublet, t=triplet, m=multiplet, etc. The aryl azides used in the synthesis of compounds 5a–5m were prepared from aromatic amines as reported in the literature [33]. General procedure for the synthesis of(Z)-5-arylidene-3(prop-2-ynyl)thiazolidine-2,4-dione (1a–1e) An equimolar mixture of thiazolidine-2,4-dione (3.0 mmol) and substituted aldehydes (3.0 mmol) was dissolved in 5
123
Mol Divers R1
O
N N N H R2
O H
N CuLn CuSO4.5H2O
S
CuLn O
H
N N N
Ar O
Ar
S
O
N
Ar
R1
+ [LnCu]
H
R2
Sodium ascorbate O
R2
H Ar
N
S
N
O
N CuLn N N
R1
O
S H
O
N
1 R2
S
Ar
O
R1
O H N Ar
N N N
S
N
O N N H
O
COOH
N H
O
O N H
6 6a; Ar=4-BrC6H4, R1=F, R2=H
Path a
N H
Path b
COOH O O N H
O N H
R2
R2
O
R1 N N N
N
O N
R1 N
Ar
Ar
S
O
O
H
H
S N
O
N N N
O
NH NH
R2 R1 H N
O
H
H N
R2 Ar S
N
R1 H3C
N
N N
O
N N
O
O
O
N
S
N
N
O
H Ar
N
Formed (5)
Not formed (7)
Fig. 4 Plausible mechanism for the regio- and stereo-selective formation of 1-N-methylspiro [2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(aryl)-1H -1,2,3triazol-4-yl)methyl)thiazolidine-2 ,4 -dione-4-(aryl)-pyrrolidine (5a–5n)
mL of PEG-400 in a 50 mL round-bottomed flask. Piperidine (3.0 mmol) was then added to the above reaction mixture. The reaction mixture was magnetically stirred in an oil-bath maintained at 100 ◦ C for 3–4 h. The progress of the reaction was monitored by TLC (eluent: ethyl acetate: petroleum ether, 30:70 v/v). After completion of the reaction, equimolar amount of propargyl bromide (3.0 mmol) was then added to the above reaction mixture, and the mixture was further stirred at 100 ◦ C. The reaction was found to be complete after 20 min as evident from TLC (eluent: ethyl acetate: petroleum ether, 30:70 v/v). After completion of the reaction, the reaction mixture was allowed to cool at room temperature and was quenched with water (∼ 5mL). The precipitate formed was collected by filtration at pump and washed with water. The crude material was recrystallized from ethanol to afford pure product. All the productsare novel compounds and
123
were characterized by IR, 1 H NMR, spectra.
13 C
NMR and Mass
Spectral data (Z)-5-(4-Bromobenzylidene)-3-(prop-2-ynyl)thiazolidine-2, 4-dione(1a) White solid; M.p.: 217–220 ◦ C; Yield 90 % NMR (400 MHz, CDCl3 ) δH : 7.85 (s, 1H, C=C–H), 7.61–7.58 (m, 2H, Ar-H), 7.36–7.33 (m, 2H, Ar-H), 4.49 (d, 2H, N-CH2 , J = 2.8 Hz), 2.26–2.25 (t, 1H, C≡C–H, J = 2.8 Hz); 13 C NMR (100 MHz, CDCl3 ) δ 166.3, 164.9, 133.2, 132.5, 131.9, 131.4, 125.3, 121.6, 75.8, 72.3, 30.7; IR (KBr, cm−1 ): νmax = 3264, 1732, 1683, 1605, 1489, 1407, 1380, 1335, 1156, 1072. MS (ESI) m/z calcd. for:, C13 H8 BrNO2 S: 320.9459 HRMS(ESI): 321.9480 [M+ + 1]. 1H
Mol Divers
(Z)-5-(4-Methylbenzylidene)-3-(prop-2-ynyl)thiazolidine-2, 4-dione (1b) White solid; M.p.: 159–161 ◦ C; Yield 94 % 1 H NMR (400 MHz, CDCl ) δH : 7.89 (s, 1H, C=C–H), 3 7.39–7.37 (m, 2H, Ar-H), 7.27–7.25 (m, 2H, Ar-H), 4.47 (d, 2H, N-CH2 , J = 2.8Hz), 2.38 (s, 3H, Ar − CH3 ), 2.25– 2.24 (t, 1H, C≡C–H, J = 2.8Hz); 13 C NMR (100 MHz, CDCl3 ) δ 167.3, 165.5, 142.0, 135.2, 130.7, 130.3, 119.9, 76.4, 72.5, 30.9, 21.9; IR (KBr, cm−1 ): νmax = 3281, 2983, 1737, 1675, 1613, 1600, 1511, 1422, 1377, 1315, 1154, 1090, MS (ESI) m/z calcd. for:, C14 H11 NO2 S: 257.0510 HRMS(ESI):258.0560 [M+ + 1]. (Z)-5-(4-Nitrobenzylidene)-3-(prop-2-ynyl)thiazolidine-2, 4-dione(1c) Yellow solid; M.p.: 155–157 ◦ C; Yield 90 % NMR (400 MHz, CDCl3 ) δH : 8.31–8.29 (m, 2H, ArH), 7.93 (s, 1H, C=C–H), 7.65–7.36 (m, 2H, Ar-H), 4.50 (d, 2H, N-CH2 , J = 2.8 Hz), 2.28–2.27 (t, 1H, C≡C–H, J = 2.8 Hz); 13 C NMR (100 MHz, CDCl3 ) δ 165.6, 164.4, 148.1, 138.9, 131.2, 130.6, 125.5, 124.3, 75.6, 72.5, 30.9; IR (KBr, cm−1 ): νmax = 3285, 1745, 1681, 1610, 1592, 1514, 1421, 1385, 1319, 1151, 1083. MS (ESI) m/z calcd. for:, C13 H8 N2 O4 S: 288.0204 HRMS(ESI):289.0250 [M+ + 1]. 1H
(Z)-5-((Benzo[d][1,3]dioxol-5-yl)methylene)-3-(prop-2 -ynyl)thiazolidine-2,4-dione(1d) Off White solid; M.p.: 170–171 ◦ C; Yield 91 % 1 H NMR (400 MHz, DMSO) δH : 7.86 (s, 1H, C=C–H), 7.17– 7.12 (m, 2H, Ar-H), 7.07–7.05 (m, 1H, Ar-H), 6.10 (s, 2H,O– CH2 –O), 4.38 (d, 2H, N-CH2 , J = 2.8 Hz), 3.29–3.28 (t, 1H, C≡C–H, J = 2.8 Hz); 13 C NMR (100 MHz, DMSO) δ 166.4, 164.5, 149.6, 149.2, 133.9, 126.9, 126.3, 118.0, 109.3, 109.2, 102.1, 77.2, 74.5, 30.5; IR (KBr, cm−1 ): νmax = 3285, 2907, 1733, 1675, 1627, 1587, 1500, 1383, 1252, 1158, 1039. MS (ESI) m/z calcd. for:, C14 H9 NO4 S: 287.0252 HRMS(ESI): 288.0265 [M+ + 1]. (Z)-5-(4-Methoxybenzylidene)-3-(prop-2-ynyl)thiazolidine -2,4-dione(1e) White solid; M.p.: 177–178 ◦ C; Yield 92 % NMR (400 MHz, CDCl3 ) δH : 7.87 (s, 1H, C=C–H), 7.45–7.43 (m, 2H, Ar-H), 6.98–6.96 (m, 2H, Ar-H), 4.48 (d, 2H, N-CH2 , J = 2.8 Hz), 3.85 (s, 3H, Ar-OMe), 2.25 (t, 1H, C≡C–H, J = 2.8 Hz); 13 C NMR (100 MHz, CDCl3 ) δ 167.6, 165.1, 162.3, 135.1, 132.6, 126.0, 118.4, 114.6, 76.5, 72.3, 1H
55.9, 31.0; IR (KBr, cm−1 ): νmax = 3251, 2949, 1731, 1673, 1591, 1510, 1411, 1387, 1262, 1181, 1153, 1028. MS (ESI) m/z calcd. for:, C14 H11 NO3 S: 273.0459 HRMS(ESI): 274.0470 [M+ + 1]. General procedure for the synthesis of1-N-methyl-spiro[2.3 ] oxindole-spiro[3.5 ]-3 -N-((1-(aryl)-1H-1,2,3-triazol-4-yl) methyl)thiazolidine-2 ,4 -dione-4-(aryl)-pyrrolidines (5a–5n) An equimolar mixture of 5-(arylidene)-3-(prop-2-ynyl)thiazolidine-2,4-dione (1) (3.0 mmol), isatin (2) (3.0 mmol), substituted azides (3) (3.0 mmol) and sarcosine (4) (3.0 mmol) was dissolved in 5 mL of PEG-400 in a 50 mL round-bottomed flask. Aqueous solution of CuSO4 .5H2 O (10 mol%) and aqueous solution of sodium ascorbate (20 mol%) were then added to the reaction mixture. The reaction contents were stirred magnetically in an oil-bath maintained at 130 ◦ C for 10–12 h. The progress of the reaction was monitored by TLC (eluent: ethyl acetate: petroleum ether, 40:60 v/v). After completion of the reaction, the reaction mixture was allowed to cool at room temperature and was quenched with water (∼5 mL). The precipitate formed was collected by filtration at pump and washed with water. The crude material was purified by Flash Chromatography over silica gel (230–400 mesh) to afford pure products. The products were characterized by IR, 1 H NMR, 13 C NMR and Mass spectra. Spectral data 1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 , 4 -dione-4-(4-bromophenyl)-pyrrolidine (5a) White solid; M.p.: 252 ◦ C; Yield 82 % 1 H NMR (400 MHz, DMSO) δH : 10.74 (s, 1H, –NH), 8.28 (s, 1H, Ar-H), 7.91–7.87 (m, 2H, Ar-H), 7.53–7.51 (m, 2H, Ar-H), 7.45–7.41 (m, 2H, Ar-H), 7.38–7.36 (m, 2H, Ar-H), 6.90–6.85 (m, 2H, Ar-H), 6.70–6.68 (m, 1H, Ar-H), 6.46– 6.42 (m, 1H, Ar-H), 4.68–4.60 (m, 2H, N-CH2 ), 4.46–4.42 (m, 1H, C–H), 3.82–3.77 (m, 1H, C–H), 3.49–3.45 (m, 1H, C–H), 1.99 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 174.2, 168.5, 162.8, 160.4, 141.7, 132.3, 131.4, 122.4, 122.3, 121.8, 116.8, 116.6, 109.9, 78.9, 71.5, 57.3, 50.8, 36.3, 34.5; IR (KBr, cm−1 ): νmax = 3246, 3156, 1715, 1686, 1515, 1378, 1322, 1232, 1149. MS (ESI) m/z calcd. for:, C29 H22 BrFN6 O3 S: 632.0642 HRMS(ESI): 633.0673 [M+ + 1].
123
Mol Divers
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4methylphenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-methylphenyl)-pyrrolidine (5b) White solid; M.p.: 207 ◦ C; Yield 92 % δH : 10.74 (s, 1H, –NH), 8.24 (s, 1H, Ar-H), 7.73–7.71 (m, 2H, Ar-H), 7.40–7.38 (m, 2H, ArH), 7.27–7.25 (m, 2H, Ar-H), 7.13–7.11 (m, 2H, Ar-H), 6.95– 6.90 (m, 2H, Ar-H), 6.71–6.69 (m, 1H, Ar-H), 6.51–6.47 (m, 1H, Ar-H), 4.67–4.59 (m, 2H, N-CH2 ), 4.45–4.40 (m, 1H, C– H), 3.88–3.83 (m, 1H, C–H), 3.46–3.42 (m, 1H, C–H), 2.37 (s, 3H, CH3 ), 2.26 (s, 3H, CH3 ), 2.02 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ 176.2, 174.4, 168.8, 143.4,141.6, 138.3, 136.9, 134.7, 134.2, 130.2, 130.1, 129.8, 129.1, 126.2, 122.6, 121.6, 121.4, 119.9, 78.9, 72.1, 57.3, 51.2, 36.2, 34.6, 20.6, 20.6; IR (KBr, cm−1 ): νmax = 3275, 1717, 1676, 1393, 1325, 1150, 1042. MS (ESI) m/z calcd. for:, C31 H28 N6 O3 S: 564.1944 HRMS(ESI): 565.1944 [M+ + 1].
1 H NMR (400 MHz, DMSO)
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(3chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-methylphenyl)-pyrrolidine (5c) White solid; M.p.: 209 ◦ C; Yield 90 % NMR (400 MHz, DMSO) δH : 10.76 (s, 1H, –NH), 8.42 (s, 1H, Ar-H), 8.01(m, 1H, Ar-H), 7.91–7.89 (m, 1H, Ar-H), 7.65–7.63 (m, 1H, Ar-H), 7.61–7.58 (m, 1H, Ar-H), 7.29– 7.27 (m, 2H, Ar-H), 7.15–7.13 (m, 2H, Ar-H), 6.94–6.92 (m, 1H, Ar-H), 6.89–6.85 (m, 1H, Ar-H), 6.17–6.70 (m, 2H, ArH), 6.49–6.45 (m, 1H, Ar-H), 4.70–4.62 (m, 2H, N-CH2 ), 4.46–4.41 (m, 1H, C–H), 3.88–3.84 (m, 1H, C–H), 3.46– 3.42 (m, 1H, C–H), 2.27 (s, 3H, CH3 ), 2.02 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) 176.3, 174.5, 168.7, 143.7, δ 141.8, 137.4, 136.9, 134.7, 134.2, 131.6, 129.9, 129.8, 129.1, 128.5, 126.2, 122.7, 121.8, 121.5, 119.8, 118.5, 109.8, 78.9, 72.2, 57.3, 51.3, 36.2, 34.6, 20.6; IR (KBr, cm−1 ): νmax = 3422, 2948, 1718, 1689, 1593, 1470, 1384, 1321, 1146, 1042. MS (ESI) m/z calcd. for:, C30 H25 ClN6 O3 S: 584.1397 HRMS(ESI): 585.1467 [M+ + 1]. 1H
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-bromophenyl)-pyrrolidine (5d) White solid; M.p.: 239 ◦ C; Yield 88 % 1 H NMR (400 MHz, CDCl ) 3 δH : 7.72 (s, 1H, Ar-H), 7.52– 7.50 (m, 2H, Ar-H), 7.46–7.44 (m, 2H, Ar-H), 7.36 (s, 1H, Ar-H), 7.32–7.30 (m, 2H, Ar-H), 7.11–7.09 (m, 2H, Ar-H),
123
6.88–6.84 (m, 1H, Ar-H), 6.66–6.61(m, 2H, Ar-H), 4.87– 4.66 (m, 2H, N-CH2 ), 4.58–4.54 (m, 1H, C–H), 4.01–3.96 (m, 1H, C–H), 3.86 (s, 3H, -OME), 3.58–3.54 (m, 1H, C– H), 2.18 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, CDCl3 ) δ 176.4, 174.7, 169.5, 159.8, 142.1, 141.9, 137.0, 136.6, 131.9, 131.9, 130.2, 130.1, 127.0, 125.9, 122.9, 122.7, 122.1, 121.9, 120.7, 114.7, 109.7, 79.7, 72.4, 58.3, 55.6, 51.4, 36.8, 35.1; IR (KBr, cm−1 ): νmax = 3232, 1686, 1516, 1376, 1250, 1147, 1044. MS (ESI) m/z calcd. for:, C30 H25 BrN6 O4 S: 644.0841 HRMS(ESI): 645.0896 [M+ + 1]. 1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4methylphenyl))-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-bromophenyl)-pyrrolidine (5e) White solid; M.p.: 240 ◦ C; Yield 86 % NMR (400 MHz, CDCl3 ) δH : 7.52–7.41 (m, 5H, Ar-H), 7.33–7.27 (m, 3H, Ar-H), 7.11–7.09 (m, 1H, Ar-H), 6.86– 6.82 (m, 1H, Ar-H), 7.36 (s, 1H, Ar-H), 7.32–7.30 (m, 2H, Ar-H), 7.11–7.09 (m, 2H, Ar-H), 6.88–6.84 (m, 1H, ArH), 6.65–6.59 (m, 2H, Ar-H), 4.88–4.66 (m, 2H, N-CH2 ), 4.59–4.54 (m, 1H, C–H), 4.01–3.96 (m, 1H, C–H), 3.59– 3.55 (m, 1H, C–H), 2.42 (s, 3H,–CH3 ) 2.18 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) 176.3, 174.2, 168.5, 143.5, δ 141.5, 138.3, 137.3, 134.2, 132.4, 131.4, 130.2, 126.1, 122.4, 122.6, 121.4, 121.0, 119.9, 109.9, 78.9, 71.5, 57.3, 50.8, 36.4, 34.6, 20.6.; IR (KBr, cm−1 ): νmax = 3246, 1712, 1686, 1473, 1378, 1322, 1149, 1050. MS (ESI) m/z calcd. for:, C30 H25 BrN6 O3 S: 628.0892 HRMS(ESI): 629.0892 [M+ + 1]. 1H
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(3chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-bromophenyl)-pyrrolidine (5f) White solid; M.p.: 236 ◦ C; Yield 86 % NMR (400 MHz, DMSO) δH : 10.80 (s, 1H, -NH), 8.42 (s, 1H, Ar-H), 8.00 (m, 1H, Ar-H), 7.91–7.89 (m, 1H, Ar-H), 7.63–7.53 (m, 4H, Ar-H), 7.40–7.38 (m, 2H, Ar-H), 6.92– 6.84 (m, 2H, Ar-H), 6.72–6.70 (m, 1H, Ar-H), 6.46–6.42 (m, 1H, Ar-H), 4.71–4.63 (m, 2H, N-CH2 ), 4.48–4.44 (m, 1H, C–H), 3.84–3.80 (m, 1H, C–H), 3.51–3.47 (m, 1H, C– H), 2.02 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 174.1, 168.5, 143.5, 141.9, 137.4, 137.3, 134.2, 132.3, 131.6, 131.4, 130.0, 128.5, 126.2, 122.4, 121.8, 121.5, 121.0, 119.8, 118.5, 109.9, 78.9, 71.5, 57.3, 50.8, 36.3, 34.5; IR (KBr, cm−1 ): νmax = 3229, 1718, 1686, 1471, 1335, 1222, 1149, 1051. MS (ESI) m/z calcd. for:, C29 H22 BrClN6 O3 S: 648.0346 HRMS(ESI): 649.0398 [M+ + 1]. 1H
Mol Divers
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4bromophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-bromophenyl)-pyrrolidine (5g) White solid; M.p.: 250 ◦ C; Yield 84 % NMR (400 MHz, DMSO) δH : 10.70 (s, 1H, -NH), 8.36 (s, 1H, Ar-H), 7.86–7.79 (m, 4H, Ar-H), 7.56–7.54 (m, 2H, Ar-H), 7.41–7.38 (m, 2H, Ar-H), 6.91–6.87 (m, 2H, Ar-H), 6.72–6.70 (m, 1H, Ar-H), 6.46–6.42 (m, 1H, Ar-H), 4.70– 4.62 (m, 2H, N-CH2 ), 4.48–4.44 (m, 1H, C–H), 3.84–3.79 (m, 1H, C–H), 3.52–3.48 (m, 1H, C–H), 2.02 (s, 3H, NCH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 174.1, 168.5, 143.5, 141.9, 137.3, 135.6, 132.7, 132.3, 131.4, 130.1, 126.1, 126.2, 122.4, 121.9, 121.6, 121.5, 121.3, 121.0, 109.9, 78.9, 71.5, 57.3, 50.7, 36.3, 34.5; IR (KBr, cm−1 ): νmax = 3252, 2861, 1715, 1685, 1492, 1335, 1223, 1149, 1051. MS (ESI) m/z calcd. for:, C29 H22 Br 2 N6 O3 S: 691.9841 HRMS(ESI): 692.9889 [M+ + 1]. 1H
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4bromophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-methylphenyl)-pyrrolidine (5h) White solid; M.p.: 253 ◦ C; Yield 88 % NMR (400 MHz, DMSO) δH : 10.83 (s, 1H, -NH), 8.31 (s, 1H, Ar-H), 8.22–8.20 (m, 2H, Ar-H), 7.93–7.90 (m, 2H, Ar-H), 7.76–7.73 (m, 2H, Ar-H), 7.48–7.43 (m, 2H, Ar-H), 6.92–6.88 (m, 2H, Ar-H), 6.73–6.70 (m, 1H, Ar-H), 6.47–6.44 (m, 1H, Ar-H), 4.72–4.65 (m, 2H, NCH2 ), 4.65–4.61 (m, 1H, C–H), 3.91–3.86 (m, 1H, C–H), 3.58–3.54 (m, 1H, C–H), 2.03 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 173.9, 168.3, 162.6, 146.9, 145.6, 143.5, 141.6, 132.9, 131.6, 130.2, 126.2, 123.4, 122.4, 122.3, 122.2, 121.8, 121.6, 116.8, 116.6, 110.0, 78.9, 71.0, 57.2, 50.8, 36.4, 34.6; IR (KBr, cm−1 ): νmax = 3209, 2872, 1717, 1683, 1516, 1468, 1338, 1235, 1187, 1044. MS (ESI) m/z calcd. for:, C30 H25 BrN6 O3 S: 628.0892 HRMS(ESI): 629.0873 [M+ + 1]. 1H
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(3chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-nitrophenyl)-pyrrolidine (5i) White solid; M.p.: 244 ◦ C; Yield 94 % 1 H NMR (400 MHz, DMSO) δH : 10.82 (s, 1H, -NH), 8.37 (s, 1H, Ar-H), 8.20–8.15 (m, 3H, Ar-H), 7.94–7.91 (m, 1H, Ar-H), 7.73–7.71 (m, 2H, Ar-H), 7.67–7.63 (m, 1H, Ar-H), 6.88–6.84 (m, 2H, Ar-H), 6.71–6.69 (m, 1H, Ar-H), 6.43– 6.39 (m, 1H, Ar-H), 4.70–4.63 (m, 2H, N-CH2 ), 4.63–4.59
(m, 1H, C–H), 3.89–3.84 (m, 1H, C–H), 3.56–3.51 (m, 1H, C–H), 2.01 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 173.9, 168.3, 158.1, 155.5, 146.9, 145.7, 143.5, 141.9, 131.6, 130.1, 126.2, 123.5, 122.2, 122.0, 121.6, 118.2, 118.0, 110.0, 79.0, 71.0, 57.2, 50.8, 36.3, 34.5; IR (KBr, cm−1 ): νmax = 3087, 2872, 1715, 1682, 1506, 1467, 1339, 1242, 1152, 1042. MS (ESI) m/z calcd. for:, C29 H21 ClFN7 O5 S: 633.0997 HRMS(ESI): 634.1004 [M+ + 1]. 1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4bromophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-nitrophenyl)-pyrrolidine (5j) White solid; M.p.: 245 ◦ C; Yield 92 % 1 H NMR (400 MHz, DMSO) δH : 10.84 (s, 1H, -NH), 8.37 (s, 1H, Ar-H), 8.22–8.20 (m, 2H, Ar-H), 7.87–7.84 (m, 2H, Ar-H), 7.81–7.79 (m, 2H, Ar-H), 7.76–7.74 (m, 2H, Ar-H), 7.67–7.63 (m, 1H, Ar-H), 6.91–6.87 (m, 2H, Ar-H), 6.73– 6.71 (m, 1H, Ar-H), 6.44–6.43 (m, 1H, Ar-H), 4.72–4.66 (m, 2H, N-CH2 ), 4.66–4.61 (m, 1H, C–H), 3.91–3.86 (m, 1H, C–H), 3.58–3.54 (m, 1H, C–H), 2.04 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) 176.3, 173.9, 168.3, 146.9, δ 145.6, 143.5, 141.8, 135.6, 132.7, 131.6, 130.2, 126.1, 123.4, 122.2, 121.9, 121.7, 121.6, 121.3, 110.0, 79.0, 71.0, 57.2, 50.8, 36.4, 34.6; IR (KBr, cm−1 ): νmax = 3074, 2867, 1752, 1715, 1685, 1516, 1465, 1340, 1239, 1153, 1044. MS (ESI) m/z calcd. for:, C29 H22 BrN7 O5 S: 659.0587 HRMS(ESI): 660.0644 [M+ + 1]. 1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(3chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-((benzo[d][1,3]dioxol-6-yl)) -pyrrolidine(5k) White solid; M.p.: 253 ◦ C; Yield 94 % 1 H NMR (400 MHz, DMSO) δH : 10.87 (s, 1H, -NH), 8.35 (s, 1H, Ar-H), 8.16–8.14 (m, 1H, Ar-H), 7.94–7.90 (m, 1H, Ar-H), 7.67–7.62 (m, 1H, Ar-H), 7.04 (s, 1H, Ar-H), 6.88–6.82 (m, 4H, Ar-H), 6.69–6.67 (m, 1H, Ar-H), 6.44– 6.40 (m, 1H, Ar-H), 5.99–5.97 (m, 2H, O − CH2 -O), 4.68– 4.59 (m, 2H, N-CH2 ), 4.40–4.35 (m, 1H, C–H), 3.77–3.73 (m, 1H, C–H), 3.47–3.41 (m, 1H, C–H), 1.98 (s, 3H, NCH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 174.3, 168.8, 158.1, 155.6, 147.4, 146.6, 143.5, 142.0, 133.3, 131.6, 130.0, 126.1, 123.6, 122.6, 122.2, 121.9, 121.5, 120.8, 120.7, 118.2, 118.0, 109.9, 108.1, 101.0, 78.8, 72.2, 57.6, 51.2, 36.2, 34.5; IR (KBr, cm−1 ): νmax = 3060, 2881, 1748, 1718, 1683, 1502, 1468, 1336, 1248, 1149, 1040. MS (ESI) m/z calcd. for:, C30 H22 ClFN6 O5 S: 632.1045 HRMS(ESI): 633.0642 [M+ + 1].
123
Mol Divers
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-nitrophenyl)-pyrrolidine (5l) White solid; M.p.: 236 ◦ C; Yield 96 % 1 H NMR (400 MHz, DMSO) δH : 10.83 (s, 1H, –NH), 8.22– 8.20 (m, 3H, Ar-H), 7.67–7.62 (m, 1H, Ar-H), 7.77–7.73 (m, 4H, Ar-H), 7.14–7.12 (m, 2H, Ar-H), 6.93–6.91 (m, 2H, Ar-H), 6.73–6.72 (m, 1H, Ar-H), 6.50–6.46 (m, 1H, Ar-H), 4.71–4.61 (m, 3H, N-CH2 & C–H), 3.91–3.86 (m, 1H, C–H), 3.83 (s, 3H, -OMe), 3.58–3.54 (m, 1H, C–H), 2.04 (s, 3H, NCH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 174.0, 168.3, 159.2, 146.9, 145.6, 143.4, 141.3, 131.6, 130.2, 129.8, 126.2, 123.4, 122.2, 121.6, 121.5, 114.8, 110.0, 79.0, 71.0, 57.2, 55.5, 50.8, 36.5, 34.6; IR (KBr, cm−1 ): νmax = 3074, 2859, 1750, 1714, 1677, 1518, 1470, 1351, 1257, 1150, 1041. MS (ESI) m/z calcd. for:, C30 H25 N7 O6 S: 611.1587 HRMS(ESI): 612.1659 [M+ + 1]. 1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(3chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-methoxyphenyl)-pyrrolidine (5m) White solid; M.p.: 230 ◦ C; Yield 86 % NMR (400 MHz, DMSO) δH : 10.75 (s, 1H, –NH), 8.37 (s,1H, Ar-H), 8.19–8.17 (m, 1H, Ar-H), 7.96–7.92 (m, 1H, Ar-H), 7.69–7.65 (m, 1H, Ar-H), 7.38–7.31 (m, 2H, Ar-H), 6.92–6.85 (m, 4H, Ar-H), 6.71–6.69 (m, 1H, Ar-H), 6.48– 6.44 (m, 1H, Ar-H), 4.69–4.61 (m, 2H, N-CH2 ), 4.44–4.40 (m, 1H, C–H), 3.85–3.80 (m, 1H, C–H), 3.72 (s, 3H, –OMe), 3.46–3.42 (m, 1H, C–H), 2.01 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 174.4, 168.8, 158.6, 155.6, 143.5, 142.0, 133.3, 131.1, 129.9, 129.7, 126.2, 122.7, 122.2, 121.9, 121.4, 120.8, 120.7, 120.6, 118.2, 118.0, 113.8, 109.8, 78.9, 72.4, 57.5, 55.0, 50.9, 36.1, 34.5; IR (KBr, cm−1 ): νmax = 3064, 2869, 1755, 1714, 1687, 1520, 1470, 1348, 1257, 1150, 1041. MS (ESI) m/z calcd. for:, C30 H24 ClFN6 O4 S: 618.1252 HRMS(ESI):619.1342 [M+ + 1]. 1H
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-methoxyphenyl)-pyrrolidine (5n) White solid; M.p.: 237 ◦ C; Yield 84 % 1 H NMR (400 MHz, DMSO) δH : 10.74 (s, 1H, -NH), 8.26 (s,1H, Ar-H), 7.90–7.87 (m, 2H, Ar-H), 7.45–7.41 (m, 2H, Ar-H), 7.31–7.29 (m, 2H, Ar-H), 6.92–6.85 (m, 4H, Ar-H), 6.69–6.67 (m, 1H, Ar-H), 6.47–6.44 (m, 1H, Ar-H), 4.67– 4.59 (m, 2H, N-CH2 ), 4.42–4.38 (m, 1H, C–H), 3.83–3.78 (m, 1H, C–H), 3.70 (s, 3H, −OMe), 3.44–3.40 (m, 1H, C– H), 1.99 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ
123
176.3, 174.5, 168.8, 158.7, 155.6, 143.5, 141.8, 133.0, 131.1, 130.0, 129.7, 126.2, 122.7, 122.4, 122.3, 121.8, 121.5, 116.8, 116.6, 113.9, 109.9, 78.9, 72.4, 57.5, 55.0, 50.9, 36.2, 34.6; IR (KBr, cm−1 ): νmax = 3084, 2879, 1750, 1717, 1687, 1518, 1470, 1351, 1257, 1150, 1041. MS (ESI) m/z calcd. for:, C30 H25 FN6 O4 S: 584.1642 HRMS(ESI): 585.1718 [M+ +1]. Single crystal X-ray structure determination X-ray intensity data for compounds 1a and 5a were collected on Oxford Diffraction Xcalibur CCD diffractometer with graphite monochromatic MoKα radiation (λ = 0.71073A◦ ) at temperature 298 K. Computations were carried out using WinGX-32 graphical user interface. The structure was solved by direct methods using SIR97. Data were refined and extended using SHELX-97 software. Non-hydrogen atoms were refined anisotropically. Carbon-bound hydrogen atoms were included in idealized positions and refined using a riding model. Crystallographic data (excluding structure factors) for the structure have been deposited with the Cambridge Crystallographic Data Center with CCDC no. 955802 for 1a and CCDC no. 956317 for 5a. These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_ request/cif. Acknowledgments JS and HS thank UGC, New Delhi, India for the grant of Junior Research Fellowships.
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FULL-LENGTH PAPER
A green, multicomponent, regio- and stereo-selective 1,3-dipolar cycloaddition of azides and azomethine ylides generated in situ with bifunctional dipolarophiles using PEG-400 Jayant Sindhu · Harjinder Singh · J. M. Khurana
Received: 13 September 2013 / Accepted: 13 January 2014 © Springer International Publishing Switzerland 2014
Abstract A series of novel dispiropyrrolidine-linked 1,2,3triazole derivatives have been prepared by one-pot, fourcomponent protocol that employed 5-arylidene-3-(prop-2ynyl)thiazolidine-2,4-dione, isatin, sarcosine and substituted azides using Cu(I) generated in situ as catalyst in PEG-400 as a highly efficient and green media. This is the first report of a four-component reaction involving a classical Huisgen reaction, in which the two dipolar moieties (substituted azides and in situ generated azomethine ylides) react with acetylenic and olefinic dipolarophiles, respectively. The 1,3dipolar cycloaddition proceeds in a highly regio- and stereoselective manner. This methodology can be an ideal tool for the preparation of biologically important five-membered heterocyclic compounds in one pot. Keywords Spiro compounds · Dipolar cycloaddition · Azomethine ylides · Multicomponent reactions (MCRs) · Pyrrolidines · Thiazolidin-2,4-dione · 1,2,3-Triazoles · PEG-400
Introduction Design of highly efficient reaction methodologies for the synthesis of compounds having structural complexity and diversity with promising biological properties is a major challenge for the organic and medicinal chemists [1]. This Electronic supplementary material The online version of this article (doi:10.1007/s11030-014-9505-y) contains supplementary material, which is available to authorized users. J. Sindhu · H. Singh · J. M. Khurana (B) Department of Chemistry, University of Delhi, Delhi 110007, India e-mail: [email protected]
can be overcome by using multicomponent reactions (MCR) which involve formation of two and more bonds in a single reaction step and generate highly diverse molecules from readily available starting molecules. Continuous efforts have been devoted to the synthesis of compounds containing different nitrogen-containing heterocyclic units because of their broad applications in medicinal chemistry [2]. Spiropyrrolidine-oxindoles structural units form the core of many alkaloids and natural products exhibiting important biological activities [3]. They display a fascinating array of biological applications such as antidiabetic [4], antimycobacterial [5], antimicrobial [6], anticholinesterase [7], anticancer [8], etc. Five-membered [1,2,3]-triazoles display biological activities such as neuroprotective agents [9], anticancer [10], antitubercular [11] and antimicrobial [12]. Due to the wide range of biological activities of 1,2,3-triazoles and spiropyrrolidine-oxindoles and the ease of their synthesis, both [1,2,3]-triazoles and spiropyrrolidine-oxindoles have been incorporated into a variety of heterocyclic compounds [13,14]. 2,4-Thiazolidinediones (TZDs) also exhibit numerous biological activities, such as antihyperglycemic [15], euglycemic [16], anti-inflammatory [17], antimalarial [18], antioxidant [19], cytotoxic [20], antiproliferative [21], PPAR γ agonist [22], antitumor [23], antibacterial [24] and antiviral effect [25]. 1,3-Dipolar cycloaddition reaction is an efficient tool for the construction of five-membered nitrogen-containing heterocyclic units in a highly regio- and stereo-selective manner. Azomethine ylides and azides serve as expedient precursors for the construction of biologically important fivemembered nitrogen heterocycles [26,27]. The multicomponent reaction involving intermolecular [3 + 2] cycloaddition reaction of azomethine ylides with various alkenes represents an efficient and convergent method for the synthesis of spiropyrrolidine and pyrrolizidine units [28].
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Mol Divers Table 1 Synthesis of (Z )-5-arylidene-3-(prop-2-ynyl)thiazolidine2,4-diones (1a–1e) S.No
Ar
Yield (%)
M.p.(◦ C)
1a
4-BrC6 H4
92
217–220
1b
4-MeC6 H4
94
159–161
1c
4-(NO2 )C6 H4
90
155–157
1d
C7 H5 O2 (Piperonal)
92
170–171
1e
4-MeOC6 H4
96
177–178
The in situ generation of azomethine ylides would be an added advantage, as it reduces overall steps and increases the efficiency of the reaction for the synthesis of spiropyrrolidine linked 1,2,3-triazoles. The biological importance of spiro[pyrrolidine-3,3 -oxindole], 1,2,3-triazoles and TZDs sub-structures led us to investigate the synthesis of hybrid heterocycles comprising spiro[pyrrolidine-3,3 oxindole], 1,2,3-triazoles and TZDs. In conjunction with our interest in the synthesis of novel heterocycles employing domino [29] and 1,3-dipolar cycloaddition reactions [30,31], we decided to explore the synthesis of some novel hybrids of spiro[pyrrolidine-3,3 -oxindole], 1,2,3-triazoles and TZDs by a one-pot four-component reaction. Such a strategy would provide a rapid synthesis of new hybrid molecules containing spiro[pyrrolidine-3,3 -oxindole], 1,2,3-triazoles and TZDs which are otherwise accessible through multistep synthesis.
Scheme 1 Synthesis of (Z )-5-arylidene-3-(prop-2ynyl)thiazolidine-2,4-dione (1a–1e)
Results and discussion The present manuscript reports the synthesis of targeted 1(N-methyl)-spiro[2.3 ]oxindole- spiro[3.5 ]-3 -N-((1-(aryl) -1H -1,2,3-triazol-4-yl) methyl)thiazolidine-2 ,4 -dione-4(aryl)-pyrrolidines (5a–5n), by a multicomponent approach. The synthesis of functionalized dipolarophile viz. (Z)-5-(4bromobenzylidene) -3-(prop-2-ynyl) thiazolidine-2,4-dione (1a) which is one of the components of the MCR was carried out by a two-step one-pot reaction of 2,4-thiazolidinedione (1.0 eq) and 4-bromobenzaldehyde (1.0 eq) in the presence of piperidine (1.0 eq) in PEG-400 at 100 ◦ C until reaction completion as indicated by TLC (ethyl acetate: petroleum ether, 30:70, v/v). The resultant (Z)-5-(4-bromobenzylidene)thiazolidine-2,4-dione on reaction with propargyl bromide (1.0 eq) yielded 5-(4-bromobenzylidene)-3-(prop-2-ynyl)thiazolidine-2,4-dione(1a) in 92 % (entry 1, Table 1). The generality of this protocol was checked by carrying out the reactions using different aromatic aldehydes containing both electron withdrawing and electron donating substituents yielded the corresponding thiazolidine-2,4-dione derivatives 1b–1e (Scheme 1) in high yields as shown in Table 1. All the synthesized dipolarophiles (1a–1e) are novel compounds, and their structures were confirmed by 1 H, 13 C NMR, IR spectra and HRMS. The Z -configuration of the double bond was confirmed by 1 H NMR and single crystal X-ray crystallographic of 1a (Fig. 1).
Ar S O O
N H
ArCHO Piperidine, PEG-400 100oC, 3-4 h
S O O
N H i
S N
H H
O
H 7.85, s, 1H 133.2 4.91, d, 2H, J=2.8 Hz 30.7 2.26, t, 1H, J=2.8 Hz 75.8
H
1a Fig. 1 Characteristic 1 H,
123
13 C
NMR signals and single crystal X-ray structure of 1a
N O
1a-1e
Br
O
Br 100oC, 20 min 92% yield
Ar
S
O
1a
Mol Divers
tion (entries 1–8, Table 2). The four-component reaction was then explored at higher temperatures, under ultrasonic irradiation and also in presence of bases in PEG-400 (entries 9–16, Table 2). It was observed that when cycloaddition reaction of (Z )-5-(4bromobenzylidene)-3-(prop-2-ynyl)thiazolidine-2,4-dione (1.0 mmol) (1a), isatin (1.0 mmol) (2), 1-azido-4-fluorobenzene (1.0 mmol) (3a), sarcosine (1.00 mmol) (4), was performed in PEG-400 using aq. CuSO4 .5H2 O (10 mol%) followed by aq. sodium ascorbate (20 mol%) as catalyst at 130 ◦ C, it resulted in the formation of 1-N-methylspiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4-fluorophenyl)-1 H -1,2,3-triazol-4-yl) methyl)thiazolidine-2 ,4 -dione-4-(4bromophenyl)-pyrrolidine (5a) in 82 % yield in 12 h (Scheme 2). The structure of 5a was elucidated using one and twodimensional NMR spectroscopic data, IR and HRMS spectra. The HMBC and COSY correlations are useful in the signal assignments of 5a, and various characteristic signals are shown in Fig. 2. The 1 H NMR spectrum of 5a revealed one sharp singlet at δ 1.99 due to the N-methyl protons. The benzylic proton on C4 carbon of pyrrolidine ring exhibits a multiplet at δ 4.46–4.42. Two protons of C5 carbon of pyrrolidine exhibit a multiplet at δ 3.82–3.77 and 3.49–3.45. Two protons of N-CH2 appear as multiplet at δ 4.68–4.60. The disappearance of triplet at δ 2.26 for acetylenic C–H in (Z )-5-(4-bromobenzylidene)-3-(prop2-ynyl)thiazolidine-2,4-dione (1a) and appearance of singlet at δ 8.12 for proton at C-5 carbon of triazole ring confirm the formation of triazole ring. This higher value of δ justifies the substitution of aryl group on N − 1. Aromatic protons appeared as a multiplet in the region of δ 7.90–6.46, and there was one singlet at δ 10.74 for the NH proton of oxindole. Also disappearance of proton peak from δ 7.85 for C=C–H also confirms the disappearance of exocyclic double bond. The regiochemistry of the product formed in the reaction can be confirmed by 1 H NMR. The regioisomer 5a would show a multiplet for the benzylic proton on C4 carbon of pyrrolidine ring, whereas the regioisomer 7 (see Fig. 4) would show a singlet. 1 H NMR of the product showed a multiplet at δ 4.46–4.42 rather than a singlet thus suggesting the formation of 5a. Further, the off-resonance decoupled 13 C NMR of
Table 2 Optimization of reaction conditions for the synthesis 1-Nmethyl-spiro[2.3 ] oxindole-spiro [3.5 ]-3 -N-((1-(4-fluorophenyl)1H -1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-bromo phenyl)-pyrrolidine (5a) Entry Solvent
Base
Temp (◦ C) Time (h) Yield (%)a
1
Ethanol
–
Reflux
24
50
2
Methanol
–
Reflux
24
45
3
H2 O
–
Reflux
24
20
4
Acetonitrile –
Reflux
24
35
5
THF
–
Reflux
24
55
6
DMF
–
90
20
65
7
PEG-400
–
90
18
72
8
PEG-600
–
90
19
68
9
PEG-400
–
30
6
50b
10
PEG-400
–
40
8
62b
11
PEG-400
–
100
16
75
12
PEG-400
–
120
14
78
13
PEG-400
–
130
12
82
14
PEG-400
–
140
12
80
15
PEG-400
Piperidine 140
12
76
16
PEG-400
Et 3 N
12
78
a b
140
Yield after column chromatography Reaction performed under ultrasonic irradiation
Dipolarophiles 1 possess two dipolar functional groups (C=C and C≡C) which make them diverse synthons for the synthesis of five-membered heterocycles particularly triazoles and pyrrolidines. Therefore, the study of the regio- and stereoselectivity of the products formed is of considerable interest. Using a series of dipolarophiles (1a–1e), we initiated our investigation on the four-component [3+2] cycloaddition reaction of 1 with isatin (2), substituted azides (3) and sarcosine (4). Initially, the cycloaddition reaction of an equimolar mixture of a (Z )-5-(4-bromobenzylidene)-3(prop-2-ynyl)thiazolidine-2,4-dione (1a), isatin (2), 1-azido4-fluorobenzene (3a) and sarcosine (4), was performed in ethanol using aqueous solution of CuSO4 . 5H2 O (10 mol%) followed by aqueous solution of sodium ascorbate (20 mol%) as catalyst under reflux. The reaction was incomplete even after 24 h as observed by TLC(ethyl acetate: petroleum ether, 40:60, v/v) and resulted in formation of 5a (50 %). The yield of 5a depends on the solvents employed for reacScheme 2 Synthesis of 1-Nmethyl-spiro[2.3 ]oxindolespiro[3.5 ]-3 -N-((1-(4fluorophenyl)-1H -1,2,3-triazol4-yl)methyl)thiazolidine-2 ,4 dione-4-(4-bromophenyl)pyrrolidine using multicomponent approach
CH3 N
Br H S
S
O
+
N O 1a
O+ N H 2
NH
N3
O
+ F 3
N H
COOH
CuSO4.5H2O (10 mol %), Br Sodium ascorbate(20 mol%), PEG-400, 12h, 130oC
4
N O N
F
O O
N
N
5a
123
Mol Divers Fig. 2 HMBC and COSY correlations useful in the signal assignments of 5a and various characteristic 1 H and 13 C NMR peaks
F N N
H H N
N
O
H H OO N
S
F 8.28 (s, 1H, Ar-H), 122.9 4.68-4.60 (m, 2H, N-CH2)
N
Br
H
H
H
10.74 (s, 1H, -NH)
H-H COSY
H N
F N N
N O
Br
O
H H N
78.9 1.99 (s, 3H, N-CH3), 36.3
N H
H
H
N N
O
N 176.8
H H OO N
S
N
174.2
3.82-3.77 (m, 1H, C-H), 57.3 3.49-3.45 (m, 1H, C-H), 57.3
HMBC
S
N 72.1 H
H
H
O 168.9
Br
4.46-4.42 (m, 1H, C-H), 50.8
Fig. 3 Single crystal X-ray structure and crystal packing of 5a showing two molecules present in a crystal lattice (labels are omitted for clarity)
the product exhibited signals at δ 72.1 and 78.9 ppm which corresponds to the spiro carbon C3 and C2 of the pyrrolidine ring of 5a. The signals at δ 176.8 ppm and δ 168.9 ppm of the product 5a are due to the keto carbonyls of thiazolidi2,4-dione ring. The resonance at δ 174.7 ppm is due to the oxindole carbonyl carbon. Signal at δ 36.9 ppm is due to N-CH3 and peaks at δ 50.8 and 57.3 are due to C4 and C5 carbon of pyrrolidine ring. The mass spectrum of 5a showed a molecular ion peak at m/z 633.0673 (M+ +1). The formation of only one regioisomer i.e. 5a was also confirmed by the single crystal X-ray structural analysis (Fig. 3). In view of the successful formation of the desired 5a in high yields, the generality of the above protocol of four component reaction was checked by carrying out the
123
reactions of different substituted aryl azides (3) containing both electron withdrawing and electron releasing substituent with (Z )-5-(arylidene)-3-(prop-2-ynyl)thiazolidine2,4-diones (1), isatin (2) and sarcosine (4) under the optimized conditions (Scheme 3). All the reactions proceeded successfully and yielded the corresponding products 5a–5n in excellent yields as depicted in Table 3. The proposed pathway for the formation of 5 is given in Fig. 4. The proposed pathway consists of two parts. The first part involves formation of intermediate 6 by Cu(I) catalysed [3+2] azide-alkyne cycloaddition. The Cu(I) is generated in situ by well-known reduction of Cu(II) to Cu(I) by sodium ascorbate [32]. In the second part, intermediate 6 undergoes subsequent [3 + 2] cycloaddition reaction with in situ gener-
Mol Divers Scheme 3 Synthesis of 1-Nmethyl-spiro[2.3 ]oxindolespiro[3.5 ]-3 -N-((1-(4-aryl)1H -1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4aryl)-pyrrolidines using multicomponent approach
CH3 N Ar
S
O
+
N O 1
N3
O
+ R2
O+ N H 2
H CuSO4.5H2O (10 mol %), Sodium ascorbate(20 mol%), N H
COOH
N
N
4
N R2
S.no
Ar
R1
R2
Time (h)
Yield (%)
M.p. (◦ C)
5a
4-BrC6 H4
F
H
11
82
252
5b
4-MeC6 H4
Me
H
10.5
92
207
5c
4-MeC6 H4
H
Cl
10.5
90
209
5d
4-BrC6 H4
OMe
H
11
88
239
5e
4-BrC6 H4
Me
H
11
86
240
5f
4-BrC6 H4
H
Cl
11
86
236
5g
4-BrC6 H4
Br
H
11
84
250
5h
4-MeC6 H4
Br
H
10.5
88
253
5i
4-(NO2 )C6 H4
F
Cl
10
94
244
5j
4-(NO2 )C6 H4
Br
H
10
92
245
5k
C7 H5 O2
F
Cl
10
94
253
5l
4-(NO2 )C6 H4
OMe
H
10
96
236
5m
4-OMeC6 H4
F
Cl
12
86
230
5n
4-OMeC6 H4
F
H
12
84
237
O O
O
R1
Table 3 Synthesis of 1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 N-((1-(aryl)-1H -1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione4-(aryl)-pyrrolidines (5a–5n)
S
PEG-400, 10-12h, 130oC
R1 3
NH
Ar
N
5a-5n
Conclusion We have reported an efficient and green methodology for the synthesis of biologically important 1-N-methylspiro[2.3 ] oxindole-spiro [3.5 ]-3 -N-((1-(aryl)-1H -1,2,3 -triazol-4-yl)methyl)thiazolidine-2 ,4 -dione-4-(aryl)-pyrrolidine by reaction of 5-(arylidene)-3-(prop-2-ynyl)thiazolidine-2,4-dione (1), isatin (2), substituted azides (3) and sarcosine (4) using Cu(I) as catalyst in PEG-400 at 130 ◦ C. This protocol offers the multicomponent synthesis of dispirooxindolopyrrolidine/ thiazolidin-2,4-dione/ 1,2,3triazoles hybrids which are otherwise accessible only through multistep synthesis and thus offers advantages in terms of atom economy, easy workup, green reaction media and high yields.
Experimental Chemistry
ated azomethine ylide to yield the desired products 5 (Path b). Formation of 6a during the four-component condensation was confirmed by CO-TLC with an authentic sample of 6a. The intermediacy of 6a was further confirmed by an independent reaction of 6a with isatin and sarcosine in PEG-400 which led to the formation of 5a and hence the intermediacy of 6 in general in the four-component condensation. The role of Cu(I) in catalysing only the first part of the pathway was also confirmed by an independent reaction of 6a with isatin and sarcosine. The reaction was attempted both in presence and absence of CuSO4 · 5H2 O (10 mol%) and sodium ascorbate (20 mol%). The reactions resulted in the formation of 5a in 80 and 81 % yield, respectively, in 12 h, which suggests that Cu(I) is catalysing only the azide-alkyne cycloaddition reaction and has no effect on dipolar cycloaddition reaction of azomethine ylide and double bond. The formation of regioisomer 7, as shown in Fig. 4, has already been ruled out based on 1 H NMR, 2D NMR and X-ray structure. PEG-400 is a superior solvent because of high solubility of intermediate 6.
Compounds structures were confirmed by their spectral data. Silica gel 60 F254 (Precoated aluminium plates) from Merck was used to monitor reaction progress. Melting points were determined on Buchi melting point 545 apparatus and are uncorrected. IR (KBr) spectra were recorded on Perkin Elmer FTIR spectrophotometer, and the values are expressed as ν maxcm−1 . The 1 H and 13 C spectra were recorded on Jeol JNM ECX-400P at 400 MHz and 100 MHz, respectively. Mass spectra were recorded at Bruker Micro TOF Q – II. Chemical shift values are recorded on δ scale, and the coupling constants (J) are in Hertz. Abbreviations used for 1 H NMR signals are: s=singlet, d=doublet, t=triplet, m=multiplet, etc. The aryl azides used in the synthesis of compounds 5a–5m were prepared from aromatic amines as reported in the literature [33]. General procedure for the synthesis of(Z)-5-arylidene-3(prop-2-ynyl)thiazolidine-2,4-dione (1a–1e) An equimolar mixture of thiazolidine-2,4-dione (3.0 mmol) and substituted aldehydes (3.0 mmol) was dissolved in 5
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Mol Divers R1
O
N N N H R2
O H
N CuLn CuSO4.5H2O
S
CuLn O
H
N N N
Ar O
Ar
S
O
N
Ar
R1
+ [LnCu]
H
R2
Sodium ascorbate O
R2
H Ar
N
S
N
O
N CuLn N N
R1
O
S H
O
N
1 R2
S
Ar
O
R1
O H N Ar
N N N
S
N
O N N H
O
COOH
N H
O
O N H
6 6a; Ar=4-BrC6H4, R1=F, R2=H
Path a
N H
Path b
COOH O O N H
O N H
R2
R2
O
R1 N N N
N
O N
R1 N
Ar
Ar
S
O
O
H
H
S N
O
N N N
O
NH NH
R2 R1 H N
O
H
H N
R2 Ar S
N
R1 H3C
N
N N
O
N N
O
O
O
N
S
N
N
O
H Ar
N
Formed (5)
Not formed (7)
Fig. 4 Plausible mechanism for the regio- and stereo-selective formation of 1-N-methylspiro [2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(aryl)-1H -1,2,3triazol-4-yl)methyl)thiazolidine-2 ,4 -dione-4-(aryl)-pyrrolidine (5a–5n)
mL of PEG-400 in a 50 mL round-bottomed flask. Piperidine (3.0 mmol) was then added to the above reaction mixture. The reaction mixture was magnetically stirred in an oil-bath maintained at 100 ◦ C for 3–4 h. The progress of the reaction was monitored by TLC (eluent: ethyl acetate: petroleum ether, 30:70 v/v). After completion of the reaction, equimolar amount of propargyl bromide (3.0 mmol) was then added to the above reaction mixture, and the mixture was further stirred at 100 ◦ C. The reaction was found to be complete after 20 min as evident from TLC (eluent: ethyl acetate: petroleum ether, 30:70 v/v). After completion of the reaction, the reaction mixture was allowed to cool at room temperature and was quenched with water (∼ 5mL). The precipitate formed was collected by filtration at pump and washed with water. The crude material was recrystallized from ethanol to afford pure product. All the productsare novel compounds and
123
were characterized by IR, 1 H NMR, spectra.
13 C
NMR and Mass
Spectral data (Z)-5-(4-Bromobenzylidene)-3-(prop-2-ynyl)thiazolidine-2, 4-dione(1a) White solid; M.p.: 217–220 ◦ C; Yield 90 % NMR (400 MHz, CDCl3 ) δH : 7.85 (s, 1H, C=C–H), 7.61–7.58 (m, 2H, Ar-H), 7.36–7.33 (m, 2H, Ar-H), 4.49 (d, 2H, N-CH2 , J = 2.8 Hz), 2.26–2.25 (t, 1H, C≡C–H, J = 2.8 Hz); 13 C NMR (100 MHz, CDCl3 ) δ 166.3, 164.9, 133.2, 132.5, 131.9, 131.4, 125.3, 121.6, 75.8, 72.3, 30.7; IR (KBr, cm−1 ): νmax = 3264, 1732, 1683, 1605, 1489, 1407, 1380, 1335, 1156, 1072. MS (ESI) m/z calcd. for:, C13 H8 BrNO2 S: 320.9459 HRMS(ESI): 321.9480 [M+ + 1]. 1H
Mol Divers
(Z)-5-(4-Methylbenzylidene)-3-(prop-2-ynyl)thiazolidine-2, 4-dione (1b) White solid; M.p.: 159–161 ◦ C; Yield 94 % 1 H NMR (400 MHz, CDCl ) δH : 7.89 (s, 1H, C=C–H), 3 7.39–7.37 (m, 2H, Ar-H), 7.27–7.25 (m, 2H, Ar-H), 4.47 (d, 2H, N-CH2 , J = 2.8Hz), 2.38 (s, 3H, Ar − CH3 ), 2.25– 2.24 (t, 1H, C≡C–H, J = 2.8Hz); 13 C NMR (100 MHz, CDCl3 ) δ 167.3, 165.5, 142.0, 135.2, 130.7, 130.3, 119.9, 76.4, 72.5, 30.9, 21.9; IR (KBr, cm−1 ): νmax = 3281, 2983, 1737, 1675, 1613, 1600, 1511, 1422, 1377, 1315, 1154, 1090, MS (ESI) m/z calcd. for:, C14 H11 NO2 S: 257.0510 HRMS(ESI):258.0560 [M+ + 1]. (Z)-5-(4-Nitrobenzylidene)-3-(prop-2-ynyl)thiazolidine-2, 4-dione(1c) Yellow solid; M.p.: 155–157 ◦ C; Yield 90 % NMR (400 MHz, CDCl3 ) δH : 8.31–8.29 (m, 2H, ArH), 7.93 (s, 1H, C=C–H), 7.65–7.36 (m, 2H, Ar-H), 4.50 (d, 2H, N-CH2 , J = 2.8 Hz), 2.28–2.27 (t, 1H, C≡C–H, J = 2.8 Hz); 13 C NMR (100 MHz, CDCl3 ) δ 165.6, 164.4, 148.1, 138.9, 131.2, 130.6, 125.5, 124.3, 75.6, 72.5, 30.9; IR (KBr, cm−1 ): νmax = 3285, 1745, 1681, 1610, 1592, 1514, 1421, 1385, 1319, 1151, 1083. MS (ESI) m/z calcd. for:, C13 H8 N2 O4 S: 288.0204 HRMS(ESI):289.0250 [M+ + 1]. 1H
(Z)-5-((Benzo[d][1,3]dioxol-5-yl)methylene)-3-(prop-2 -ynyl)thiazolidine-2,4-dione(1d) Off White solid; M.p.: 170–171 ◦ C; Yield 91 % 1 H NMR (400 MHz, DMSO) δH : 7.86 (s, 1H, C=C–H), 7.17– 7.12 (m, 2H, Ar-H), 7.07–7.05 (m, 1H, Ar-H), 6.10 (s, 2H,O– CH2 –O), 4.38 (d, 2H, N-CH2 , J = 2.8 Hz), 3.29–3.28 (t, 1H, C≡C–H, J = 2.8 Hz); 13 C NMR (100 MHz, DMSO) δ 166.4, 164.5, 149.6, 149.2, 133.9, 126.9, 126.3, 118.0, 109.3, 109.2, 102.1, 77.2, 74.5, 30.5; IR (KBr, cm−1 ): νmax = 3285, 2907, 1733, 1675, 1627, 1587, 1500, 1383, 1252, 1158, 1039. MS (ESI) m/z calcd. for:, C14 H9 NO4 S: 287.0252 HRMS(ESI): 288.0265 [M+ + 1]. (Z)-5-(4-Methoxybenzylidene)-3-(prop-2-ynyl)thiazolidine -2,4-dione(1e) White solid; M.p.: 177–178 ◦ C; Yield 92 % NMR (400 MHz, CDCl3 ) δH : 7.87 (s, 1H, C=C–H), 7.45–7.43 (m, 2H, Ar-H), 6.98–6.96 (m, 2H, Ar-H), 4.48 (d, 2H, N-CH2 , J = 2.8 Hz), 3.85 (s, 3H, Ar-OMe), 2.25 (t, 1H, C≡C–H, J = 2.8 Hz); 13 C NMR (100 MHz, CDCl3 ) δ 167.6, 165.1, 162.3, 135.1, 132.6, 126.0, 118.4, 114.6, 76.5, 72.3, 1H
55.9, 31.0; IR (KBr, cm−1 ): νmax = 3251, 2949, 1731, 1673, 1591, 1510, 1411, 1387, 1262, 1181, 1153, 1028. MS (ESI) m/z calcd. for:, C14 H11 NO3 S: 273.0459 HRMS(ESI): 274.0470 [M+ + 1]. General procedure for the synthesis of1-N-methyl-spiro[2.3 ] oxindole-spiro[3.5 ]-3 -N-((1-(aryl)-1H-1,2,3-triazol-4-yl) methyl)thiazolidine-2 ,4 -dione-4-(aryl)-pyrrolidines (5a–5n) An equimolar mixture of 5-(arylidene)-3-(prop-2-ynyl)thiazolidine-2,4-dione (1) (3.0 mmol), isatin (2) (3.0 mmol), substituted azides (3) (3.0 mmol) and sarcosine (4) (3.0 mmol) was dissolved in 5 mL of PEG-400 in a 50 mL round-bottomed flask. Aqueous solution of CuSO4 .5H2 O (10 mol%) and aqueous solution of sodium ascorbate (20 mol%) were then added to the reaction mixture. The reaction contents were stirred magnetically in an oil-bath maintained at 130 ◦ C for 10–12 h. The progress of the reaction was monitored by TLC (eluent: ethyl acetate: petroleum ether, 40:60 v/v). After completion of the reaction, the reaction mixture was allowed to cool at room temperature and was quenched with water (∼5 mL). The precipitate formed was collected by filtration at pump and washed with water. The crude material was purified by Flash Chromatography over silica gel (230–400 mesh) to afford pure products. The products were characterized by IR, 1 H NMR, 13 C NMR and Mass spectra. Spectral data 1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 , 4 -dione-4-(4-bromophenyl)-pyrrolidine (5a) White solid; M.p.: 252 ◦ C; Yield 82 % 1 H NMR (400 MHz, DMSO) δH : 10.74 (s, 1H, –NH), 8.28 (s, 1H, Ar-H), 7.91–7.87 (m, 2H, Ar-H), 7.53–7.51 (m, 2H, Ar-H), 7.45–7.41 (m, 2H, Ar-H), 7.38–7.36 (m, 2H, Ar-H), 6.90–6.85 (m, 2H, Ar-H), 6.70–6.68 (m, 1H, Ar-H), 6.46– 6.42 (m, 1H, Ar-H), 4.68–4.60 (m, 2H, N-CH2 ), 4.46–4.42 (m, 1H, C–H), 3.82–3.77 (m, 1H, C–H), 3.49–3.45 (m, 1H, C–H), 1.99 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 174.2, 168.5, 162.8, 160.4, 141.7, 132.3, 131.4, 122.4, 122.3, 121.8, 116.8, 116.6, 109.9, 78.9, 71.5, 57.3, 50.8, 36.3, 34.5; IR (KBr, cm−1 ): νmax = 3246, 3156, 1715, 1686, 1515, 1378, 1322, 1232, 1149. MS (ESI) m/z calcd. for:, C29 H22 BrFN6 O3 S: 632.0642 HRMS(ESI): 633.0673 [M+ + 1].
123
Mol Divers
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4methylphenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-methylphenyl)-pyrrolidine (5b) White solid; M.p.: 207 ◦ C; Yield 92 % δH : 10.74 (s, 1H, –NH), 8.24 (s, 1H, Ar-H), 7.73–7.71 (m, 2H, Ar-H), 7.40–7.38 (m, 2H, ArH), 7.27–7.25 (m, 2H, Ar-H), 7.13–7.11 (m, 2H, Ar-H), 6.95– 6.90 (m, 2H, Ar-H), 6.71–6.69 (m, 1H, Ar-H), 6.51–6.47 (m, 1H, Ar-H), 4.67–4.59 (m, 2H, N-CH2 ), 4.45–4.40 (m, 1H, C– H), 3.88–3.83 (m, 1H, C–H), 3.46–3.42 (m, 1H, C–H), 2.37 (s, 3H, CH3 ), 2.26 (s, 3H, CH3 ), 2.02 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ 176.2, 174.4, 168.8, 143.4,141.6, 138.3, 136.9, 134.7, 134.2, 130.2, 130.1, 129.8, 129.1, 126.2, 122.6, 121.6, 121.4, 119.9, 78.9, 72.1, 57.3, 51.2, 36.2, 34.6, 20.6, 20.6; IR (KBr, cm−1 ): νmax = 3275, 1717, 1676, 1393, 1325, 1150, 1042. MS (ESI) m/z calcd. for:, C31 H28 N6 O3 S: 564.1944 HRMS(ESI): 565.1944 [M+ + 1].
1 H NMR (400 MHz, DMSO)
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(3chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-methylphenyl)-pyrrolidine (5c) White solid; M.p.: 209 ◦ C; Yield 90 % NMR (400 MHz, DMSO) δH : 10.76 (s, 1H, –NH), 8.42 (s, 1H, Ar-H), 8.01(m, 1H, Ar-H), 7.91–7.89 (m, 1H, Ar-H), 7.65–7.63 (m, 1H, Ar-H), 7.61–7.58 (m, 1H, Ar-H), 7.29– 7.27 (m, 2H, Ar-H), 7.15–7.13 (m, 2H, Ar-H), 6.94–6.92 (m, 1H, Ar-H), 6.89–6.85 (m, 1H, Ar-H), 6.17–6.70 (m, 2H, ArH), 6.49–6.45 (m, 1H, Ar-H), 4.70–4.62 (m, 2H, N-CH2 ), 4.46–4.41 (m, 1H, C–H), 3.88–3.84 (m, 1H, C–H), 3.46– 3.42 (m, 1H, C–H), 2.27 (s, 3H, CH3 ), 2.02 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) 176.3, 174.5, 168.7, 143.7, δ 141.8, 137.4, 136.9, 134.7, 134.2, 131.6, 129.9, 129.8, 129.1, 128.5, 126.2, 122.7, 121.8, 121.5, 119.8, 118.5, 109.8, 78.9, 72.2, 57.3, 51.3, 36.2, 34.6, 20.6; IR (KBr, cm−1 ): νmax = 3422, 2948, 1718, 1689, 1593, 1470, 1384, 1321, 1146, 1042. MS (ESI) m/z calcd. for:, C30 H25 ClN6 O3 S: 584.1397 HRMS(ESI): 585.1467 [M+ + 1]. 1H
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-bromophenyl)-pyrrolidine (5d) White solid; M.p.: 239 ◦ C; Yield 88 % 1 H NMR (400 MHz, CDCl ) 3 δH : 7.72 (s, 1H, Ar-H), 7.52– 7.50 (m, 2H, Ar-H), 7.46–7.44 (m, 2H, Ar-H), 7.36 (s, 1H, Ar-H), 7.32–7.30 (m, 2H, Ar-H), 7.11–7.09 (m, 2H, Ar-H),
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6.88–6.84 (m, 1H, Ar-H), 6.66–6.61(m, 2H, Ar-H), 4.87– 4.66 (m, 2H, N-CH2 ), 4.58–4.54 (m, 1H, C–H), 4.01–3.96 (m, 1H, C–H), 3.86 (s, 3H, -OME), 3.58–3.54 (m, 1H, C– H), 2.18 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, CDCl3 ) δ 176.4, 174.7, 169.5, 159.8, 142.1, 141.9, 137.0, 136.6, 131.9, 131.9, 130.2, 130.1, 127.0, 125.9, 122.9, 122.7, 122.1, 121.9, 120.7, 114.7, 109.7, 79.7, 72.4, 58.3, 55.6, 51.4, 36.8, 35.1; IR (KBr, cm−1 ): νmax = 3232, 1686, 1516, 1376, 1250, 1147, 1044. MS (ESI) m/z calcd. for:, C30 H25 BrN6 O4 S: 644.0841 HRMS(ESI): 645.0896 [M+ + 1]. 1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4methylphenyl))-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-bromophenyl)-pyrrolidine (5e) White solid; M.p.: 240 ◦ C; Yield 86 % NMR (400 MHz, CDCl3 ) δH : 7.52–7.41 (m, 5H, Ar-H), 7.33–7.27 (m, 3H, Ar-H), 7.11–7.09 (m, 1H, Ar-H), 6.86– 6.82 (m, 1H, Ar-H), 7.36 (s, 1H, Ar-H), 7.32–7.30 (m, 2H, Ar-H), 7.11–7.09 (m, 2H, Ar-H), 6.88–6.84 (m, 1H, ArH), 6.65–6.59 (m, 2H, Ar-H), 4.88–4.66 (m, 2H, N-CH2 ), 4.59–4.54 (m, 1H, C–H), 4.01–3.96 (m, 1H, C–H), 3.59– 3.55 (m, 1H, C–H), 2.42 (s, 3H,–CH3 ) 2.18 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) 176.3, 174.2, 168.5, 143.5, δ 141.5, 138.3, 137.3, 134.2, 132.4, 131.4, 130.2, 126.1, 122.4, 122.6, 121.4, 121.0, 119.9, 109.9, 78.9, 71.5, 57.3, 50.8, 36.4, 34.6, 20.6.; IR (KBr, cm−1 ): νmax = 3246, 1712, 1686, 1473, 1378, 1322, 1149, 1050. MS (ESI) m/z calcd. for:, C30 H25 BrN6 O3 S: 628.0892 HRMS(ESI): 629.0892 [M+ + 1]. 1H
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(3chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-bromophenyl)-pyrrolidine (5f) White solid; M.p.: 236 ◦ C; Yield 86 % NMR (400 MHz, DMSO) δH : 10.80 (s, 1H, -NH), 8.42 (s, 1H, Ar-H), 8.00 (m, 1H, Ar-H), 7.91–7.89 (m, 1H, Ar-H), 7.63–7.53 (m, 4H, Ar-H), 7.40–7.38 (m, 2H, Ar-H), 6.92– 6.84 (m, 2H, Ar-H), 6.72–6.70 (m, 1H, Ar-H), 6.46–6.42 (m, 1H, Ar-H), 4.71–4.63 (m, 2H, N-CH2 ), 4.48–4.44 (m, 1H, C–H), 3.84–3.80 (m, 1H, C–H), 3.51–3.47 (m, 1H, C– H), 2.02 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 174.1, 168.5, 143.5, 141.9, 137.4, 137.3, 134.2, 132.3, 131.6, 131.4, 130.0, 128.5, 126.2, 122.4, 121.8, 121.5, 121.0, 119.8, 118.5, 109.9, 78.9, 71.5, 57.3, 50.8, 36.3, 34.5; IR (KBr, cm−1 ): νmax = 3229, 1718, 1686, 1471, 1335, 1222, 1149, 1051. MS (ESI) m/z calcd. for:, C29 H22 BrClN6 O3 S: 648.0346 HRMS(ESI): 649.0398 [M+ + 1]. 1H
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1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4bromophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-bromophenyl)-pyrrolidine (5g) White solid; M.p.: 250 ◦ C; Yield 84 % NMR (400 MHz, DMSO) δH : 10.70 (s, 1H, -NH), 8.36 (s, 1H, Ar-H), 7.86–7.79 (m, 4H, Ar-H), 7.56–7.54 (m, 2H, Ar-H), 7.41–7.38 (m, 2H, Ar-H), 6.91–6.87 (m, 2H, Ar-H), 6.72–6.70 (m, 1H, Ar-H), 6.46–6.42 (m, 1H, Ar-H), 4.70– 4.62 (m, 2H, N-CH2 ), 4.48–4.44 (m, 1H, C–H), 3.84–3.79 (m, 1H, C–H), 3.52–3.48 (m, 1H, C–H), 2.02 (s, 3H, NCH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 174.1, 168.5, 143.5, 141.9, 137.3, 135.6, 132.7, 132.3, 131.4, 130.1, 126.1, 126.2, 122.4, 121.9, 121.6, 121.5, 121.3, 121.0, 109.9, 78.9, 71.5, 57.3, 50.7, 36.3, 34.5; IR (KBr, cm−1 ): νmax = 3252, 2861, 1715, 1685, 1492, 1335, 1223, 1149, 1051. MS (ESI) m/z calcd. for:, C29 H22 Br 2 N6 O3 S: 691.9841 HRMS(ESI): 692.9889 [M+ + 1]. 1H
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4bromophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-methylphenyl)-pyrrolidine (5h) White solid; M.p.: 253 ◦ C; Yield 88 % NMR (400 MHz, DMSO) δH : 10.83 (s, 1H, -NH), 8.31 (s, 1H, Ar-H), 8.22–8.20 (m, 2H, Ar-H), 7.93–7.90 (m, 2H, Ar-H), 7.76–7.73 (m, 2H, Ar-H), 7.48–7.43 (m, 2H, Ar-H), 6.92–6.88 (m, 2H, Ar-H), 6.73–6.70 (m, 1H, Ar-H), 6.47–6.44 (m, 1H, Ar-H), 4.72–4.65 (m, 2H, NCH2 ), 4.65–4.61 (m, 1H, C–H), 3.91–3.86 (m, 1H, C–H), 3.58–3.54 (m, 1H, C–H), 2.03 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 173.9, 168.3, 162.6, 146.9, 145.6, 143.5, 141.6, 132.9, 131.6, 130.2, 126.2, 123.4, 122.4, 122.3, 122.2, 121.8, 121.6, 116.8, 116.6, 110.0, 78.9, 71.0, 57.2, 50.8, 36.4, 34.6; IR (KBr, cm−1 ): νmax = 3209, 2872, 1717, 1683, 1516, 1468, 1338, 1235, 1187, 1044. MS (ESI) m/z calcd. for:, C30 H25 BrN6 O3 S: 628.0892 HRMS(ESI): 629.0873 [M+ + 1]. 1H
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(3chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-nitrophenyl)-pyrrolidine (5i) White solid; M.p.: 244 ◦ C; Yield 94 % 1 H NMR (400 MHz, DMSO) δH : 10.82 (s, 1H, -NH), 8.37 (s, 1H, Ar-H), 8.20–8.15 (m, 3H, Ar-H), 7.94–7.91 (m, 1H, Ar-H), 7.73–7.71 (m, 2H, Ar-H), 7.67–7.63 (m, 1H, Ar-H), 6.88–6.84 (m, 2H, Ar-H), 6.71–6.69 (m, 1H, Ar-H), 6.43– 6.39 (m, 1H, Ar-H), 4.70–4.63 (m, 2H, N-CH2 ), 4.63–4.59
(m, 1H, C–H), 3.89–3.84 (m, 1H, C–H), 3.56–3.51 (m, 1H, C–H), 2.01 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 173.9, 168.3, 158.1, 155.5, 146.9, 145.7, 143.5, 141.9, 131.6, 130.1, 126.2, 123.5, 122.2, 122.0, 121.6, 118.2, 118.0, 110.0, 79.0, 71.0, 57.2, 50.8, 36.3, 34.5; IR (KBr, cm−1 ): νmax = 3087, 2872, 1715, 1682, 1506, 1467, 1339, 1242, 1152, 1042. MS (ESI) m/z calcd. for:, C29 H21 ClFN7 O5 S: 633.0997 HRMS(ESI): 634.1004 [M+ + 1]. 1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4bromophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-nitrophenyl)-pyrrolidine (5j) White solid; M.p.: 245 ◦ C; Yield 92 % 1 H NMR (400 MHz, DMSO) δH : 10.84 (s, 1H, -NH), 8.37 (s, 1H, Ar-H), 8.22–8.20 (m, 2H, Ar-H), 7.87–7.84 (m, 2H, Ar-H), 7.81–7.79 (m, 2H, Ar-H), 7.76–7.74 (m, 2H, Ar-H), 7.67–7.63 (m, 1H, Ar-H), 6.91–6.87 (m, 2H, Ar-H), 6.73– 6.71 (m, 1H, Ar-H), 6.44–6.43 (m, 1H, Ar-H), 4.72–4.66 (m, 2H, N-CH2 ), 4.66–4.61 (m, 1H, C–H), 3.91–3.86 (m, 1H, C–H), 3.58–3.54 (m, 1H, C–H), 2.04 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) 176.3, 173.9, 168.3, 146.9, δ 145.6, 143.5, 141.8, 135.6, 132.7, 131.6, 130.2, 126.1, 123.4, 122.2, 121.9, 121.7, 121.6, 121.3, 110.0, 79.0, 71.0, 57.2, 50.8, 36.4, 34.6; IR (KBr, cm−1 ): νmax = 3074, 2867, 1752, 1715, 1685, 1516, 1465, 1340, 1239, 1153, 1044. MS (ESI) m/z calcd. for:, C29 H22 BrN7 O5 S: 659.0587 HRMS(ESI): 660.0644 [M+ + 1]. 1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(3chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-((benzo[d][1,3]dioxol-6-yl)) -pyrrolidine(5k) White solid; M.p.: 253 ◦ C; Yield 94 % 1 H NMR (400 MHz, DMSO) δH : 10.87 (s, 1H, -NH), 8.35 (s, 1H, Ar-H), 8.16–8.14 (m, 1H, Ar-H), 7.94–7.90 (m, 1H, Ar-H), 7.67–7.62 (m, 1H, Ar-H), 7.04 (s, 1H, Ar-H), 6.88–6.82 (m, 4H, Ar-H), 6.69–6.67 (m, 1H, Ar-H), 6.44– 6.40 (m, 1H, Ar-H), 5.99–5.97 (m, 2H, O − CH2 -O), 4.68– 4.59 (m, 2H, N-CH2 ), 4.40–4.35 (m, 1H, C–H), 3.77–3.73 (m, 1H, C–H), 3.47–3.41 (m, 1H, C–H), 1.98 (s, 3H, NCH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 174.3, 168.8, 158.1, 155.6, 147.4, 146.6, 143.5, 142.0, 133.3, 131.6, 130.0, 126.1, 123.6, 122.6, 122.2, 121.9, 121.5, 120.8, 120.7, 118.2, 118.0, 109.9, 108.1, 101.0, 78.8, 72.2, 57.6, 51.2, 36.2, 34.5; IR (KBr, cm−1 ): νmax = 3060, 2881, 1748, 1718, 1683, 1502, 1468, 1336, 1248, 1149, 1040. MS (ESI) m/z calcd. for:, C30 H22 ClFN6 O5 S: 632.1045 HRMS(ESI): 633.0642 [M+ + 1].
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1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-nitrophenyl)-pyrrolidine (5l) White solid; M.p.: 236 ◦ C; Yield 96 % 1 H NMR (400 MHz, DMSO) δH : 10.83 (s, 1H, –NH), 8.22– 8.20 (m, 3H, Ar-H), 7.67–7.62 (m, 1H, Ar-H), 7.77–7.73 (m, 4H, Ar-H), 7.14–7.12 (m, 2H, Ar-H), 6.93–6.91 (m, 2H, Ar-H), 6.73–6.72 (m, 1H, Ar-H), 6.50–6.46 (m, 1H, Ar-H), 4.71–4.61 (m, 3H, N-CH2 & C–H), 3.91–3.86 (m, 1H, C–H), 3.83 (s, 3H, -OMe), 3.58–3.54 (m, 1H, C–H), 2.04 (s, 3H, NCH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 174.0, 168.3, 159.2, 146.9, 145.6, 143.4, 141.3, 131.6, 130.2, 129.8, 126.2, 123.4, 122.2, 121.6, 121.5, 114.8, 110.0, 79.0, 71.0, 57.2, 55.5, 50.8, 36.5, 34.6; IR (KBr, cm−1 ): νmax = 3074, 2859, 1750, 1714, 1677, 1518, 1470, 1351, 1257, 1150, 1041. MS (ESI) m/z calcd. for:, C30 H25 N7 O6 S: 611.1587 HRMS(ESI): 612.1659 [M+ + 1]. 1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(3chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-methoxyphenyl)-pyrrolidine (5m) White solid; M.p.: 230 ◦ C; Yield 86 % NMR (400 MHz, DMSO) δH : 10.75 (s, 1H, –NH), 8.37 (s,1H, Ar-H), 8.19–8.17 (m, 1H, Ar-H), 7.96–7.92 (m, 1H, Ar-H), 7.69–7.65 (m, 1H, Ar-H), 7.38–7.31 (m, 2H, Ar-H), 6.92–6.85 (m, 4H, Ar-H), 6.71–6.69 (m, 1H, Ar-H), 6.48– 6.44 (m, 1H, Ar-H), 4.69–4.61 (m, 2H, N-CH2 ), 4.44–4.40 (m, 1H, C–H), 3.85–3.80 (m, 1H, C–H), 3.72 (s, 3H, –OMe), 3.46–3.42 (m, 1H, C–H), 2.01 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ 176.3, 174.4, 168.8, 158.6, 155.6, 143.5, 142.0, 133.3, 131.1, 129.9, 129.7, 126.2, 122.7, 122.2, 121.9, 121.4, 120.8, 120.7, 120.6, 118.2, 118.0, 113.8, 109.8, 78.9, 72.4, 57.5, 55.0, 50.9, 36.1, 34.5; IR (KBr, cm−1 ): νmax = 3064, 2869, 1755, 1714, 1687, 1520, 1470, 1348, 1257, 1150, 1041. MS (ESI) m/z calcd. for:, C30 H24 ClFN6 O4 S: 618.1252 HRMS(ESI):619.1342 [M+ + 1]. 1H
1-N-methyl-spiro[2.3 ]oxindole-spiro[3.5 ]-3 -N-((1-(4fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl) thiazolidine-2 ,4 -dione-4-(4-methoxyphenyl)-pyrrolidine (5n) White solid; M.p.: 237 ◦ C; Yield 84 % 1 H NMR (400 MHz, DMSO) δH : 10.74 (s, 1H, -NH), 8.26 (s,1H, Ar-H), 7.90–7.87 (m, 2H, Ar-H), 7.45–7.41 (m, 2H, Ar-H), 7.31–7.29 (m, 2H, Ar-H), 6.92–6.85 (m, 4H, Ar-H), 6.69–6.67 (m, 1H, Ar-H), 6.47–6.44 (m, 1H, Ar-H), 4.67– 4.59 (m, 2H, N-CH2 ), 4.42–4.38 (m, 1H, C–H), 3.83–3.78 (m, 1H, C–H), 3.70 (s, 3H, −OMe), 3.44–3.40 (m, 1H, C– H), 1.99 (s, 3H, N-CH3 ); 13 C NMR (100 MHz, DMSO) δ
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176.3, 174.5, 168.8, 158.7, 155.6, 143.5, 141.8, 133.0, 131.1, 130.0, 129.7, 126.2, 122.7, 122.4, 122.3, 121.8, 121.5, 116.8, 116.6, 113.9, 109.9, 78.9, 72.4, 57.5, 55.0, 50.9, 36.2, 34.6; IR (KBr, cm−1 ): νmax = 3084, 2879, 1750, 1717, 1687, 1518, 1470, 1351, 1257, 1150, 1041. MS (ESI) m/z calcd. for:, C30 H25 FN6 O4 S: 584.1642 HRMS(ESI): 585.1718 [M+ +1]. Single crystal X-ray structure determination X-ray intensity data for compounds 1a and 5a were collected on Oxford Diffraction Xcalibur CCD diffractometer with graphite monochromatic MoKα radiation (λ = 0.71073A◦ ) at temperature 298 K. Computations were carried out using WinGX-32 graphical user interface. The structure was solved by direct methods using SIR97. Data were refined and extended using SHELX-97 software. Non-hydrogen atoms were refined anisotropically. Carbon-bound hydrogen atoms were included in idealized positions and refined using a riding model. Crystallographic data (excluding structure factors) for the structure have been deposited with the Cambridge Crystallographic Data Center with CCDC no. 955802 for 1a and CCDC no. 956317 for 5a. These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_ request/cif. Acknowledgments JS and HS thank UGC, New Delhi, India for the grant of Junior Research Fellowships.
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