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One-pot access to a library of dispiro oxindole-pyrrolidine/pyrrolothiazolethiochromane hybrids via three-component 1,3-dipolar cycloaddition reactions Gandhi Uma Rani, Sundaravel Vivek Kumar, Chelliah Bharkavi, J. Carlos Menéndez, and Subbu Perumal ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.6b00011 • Publication Date (Web): 13 Apr 2016 Downloaded from http://pubs.acs.org on April 16, 2016

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ACS Combinatorial Science

One-pot access to a library of dispiro oxindolepyrrolidine/pyrrolothiazole-thiochromane hybrids via three-component 1,3-dipolar cycloaddition reactions Gandhi Uma Rani,‡1 Sundaravel Vivek Kumar,‡1 Chelliah Bharkavi,1 J. Carlos Menéndez*2 and Subbu Perumal*1. ‡These authors contributed equally. 1

Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,

Madurai – 625021, Tamil Nadu, India. 2

Departmento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad

Complutense, 28040 Madrid, Spain

KEYWORDS: 1,3-dipolar cycloaddition; 3-arylidenethiochroman-4-ones; dispiro-oxindolopyrrolidine-thiochroman-4-one; dispiro-oxindole-pyrrolothiazole-thiochroman-4-one; azomethineylides.

ACS Paragon Plus Environment

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ABSTRACT:

A

library

of

novel

dispiro

compounds

Page 2 of 23

containing

oxindole

pyrrolidine/oxindolopyrrolothiazole-thiochroman-4-one hybrid frameworks has been synthesised in a fully regio- and stereoselective fashion by the three-component 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the condensation of isatins and secondary amino acids (sarcosine/L-thioproline) with 3-arylidenethiochroman-4-ones. This experimentally simple protocol provides good yields of structurally complex, biologically relevant heterocycles in a single operation.

INTRODUCTION Spirocyclanes1 display interesting biological activities, ascribable to their intrinsic rigid structure. Compounds containing spiro centres are frequently encountered in natural products and they possess diverse pharmacological activities.2 In particular, spirooxindole-pyrrolidine is an ubiquitous core in many alkaloids such as horsfiline,3 coerulescine,4 elacomine5 (Figure 1), pteropodine, isopteropodine,6 formosanine,7 rychnophyilline,8 strychnofoline,9 alstonisine,10 spirotryprostatins A and B,11 etc. These spirooxindole-pyrrolidine derivatives show important biological activities such as acetylcholinesterase inhibition12 and anticancer,13 antimicrobial,14 (including antimycobacterial15) and local anaesthetic16 activities. Pyrrolothiazoles also display a wide range of biological activities, including hepatoprotective,17 antibiotic,18 antidiabetic,19 anticonvulsant20 and

acetylcholinesterase inhibitory properties.21 Finally, thiochromane and

thiochromanone derivatives are known to display antiviral,22 anticancer,23 human steroid sulfatase inhibition,24 non steroidal estrogen downregulation,25 α-adrenergic antagonism,26 antifungal27 and antiparasitic activities.28


2

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Figure 1: Biologically relevant thiochroman derivatives and naturally occurring oxindolo pyrrolidines and our spirooxindole-pyrrolidine/pyrrolothiazole-thiochromane hybrids.

The aforementioned biological importance of spirooxindole-pyrrolidine/pyrrolothiazole and thiochroman sub-structures and our interest in the construction of novel heterocycles employing multi-component, domino, 1,3-dipolar cycloadditions and green transformations29 have led us now

to

report

the

assembly

of

hybrid

heterocycles

comprising

spirooxinole-

pyrrolidine/pyrrolothiazole and thiochroman-4-ones employing 1,3-dipolar cycloaddition reactions (Scheme 1) from 3-arylidenethiochroman-4-ones (figure 2), isatins (figure 3) and secondary amino acids (figure 4) . The development of multiple bond-forming transformations, which include multicomponent reactions and cycloadditions, is currently recognized as key for the generation of molecular diversity and complexity in the search for new methods for the generation of lead compounds in the pharmaceutical and agrochemical industries.30


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RESULTS AND DISCUSSION The plan for the synthesis of our target compounds is summarized in Scheme 1 and involves a three-component process having as the key step the 1,3-dipolar cycloaddition between 3arylmethylenethiochroman-4-ones 1 and the dipole generated from isatin derivatives 2 and Nsubstituted α-aminoacids 3. Thus, the diversity points in our library are the aromatic substituent in compounds 1, the substituent in the isatin ring of compounds 2 and the nature of the amino acid 3 (sarcosine, thioproline). The structural diversity of these reagents is summarized in Figures 2-4.

Scheme 1. Synthetic plan


4

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Figure 2. Diversity of dipolarophiles 1{1,16}

Figure 3. Diversity of isatins 2{1,3}

Figure 4. Diversity of secondary amino acids 3{1,2}


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We started our investigation with the optimization of a model reaction by refluxing a mixture of 3-(4-chlorobenzylidene)thiochroman-4-one 1{2} (1 mmol), isatin 2{1} (1 mmol), sarcosine 3{1} (1 mmol) in EtOH for 7 h, which afforded 4'-(4-chlorophenyl)-1'-methyldispiro[indoline-3,2'pyrrolidine-3',3''-thiochromane]-2,4''-dione 4{2,1,1} in 75% yield, as a single diastereomer (Table 1, entry 1). The model reaction was also examined in other solvents such as MeOH, i

PrOH, 1,4-dioxane, CH3CN and toluene under heating to reflux (Table 1, entries 2–6). From the

data listed in Table 1, methanol (Table 1, entry 2) emerges as the solvent of choice, furnishing the highest yield (81 %) of the target compound.

Table 1. Solvent screen for the synthesis of 4{2,1,1}a

1

EtOH

7

Yield of 4{2,1,1} b (%) 75

2

MeOH

5

81

3

i

PrOH

8

34

4

1,4-Dioxane

10

58

5

CH3CN

8

62

6

Toluene

10

trace

Entry

a

Solvent

Reaction time (h)

Reactions performed under heating at reflux; bIsolated yield after purification by

column

chromatography.


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With these results in hand, all subsequent reactions were performed by heating an equimolar mixture of 3-arylidinethiochroman-4-one, isatin and sarcosine in MeOH under reflux for 5 – 6 h. After completion of the reaction as evident from TLC, the solvent was removed and the crude product

was

purified

by

column

chromatography

to

obtain

pure

4'-(aryl)-1'-

methyldispiro[indoline-3,2'-pyrrolidine-3',3''-thiochromane]-2,4''-diones 4. We next explored the scope and generality of this three-component cycloaddition reaction with substrates having (i) aryl rings bearing a series of electron-withdrawing and electron-releasing substituents and (ii) heteroaryl rings at the arylidene side chain. Moreover, the thiochroman-4one core was either unsubstituted or substituted with electron-releasing (methyl) or electronwithdrawing (Cl) groups. These structurally and electronically varied starting materials reacted efficiently with differently substituted, isatins and amino acids, like L-thioproline, affording the corresponding cycloadducts 5 in good yields under the same set of reaction conditions in all cases.

Scheme 2. Synthesis of spirooxindole-pyrrolidine/pyrrolothiazole-thiochroman-4-one hybrids 4 and 5.


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Table 2. Synthesis of spirooxindole-pyrrolidine/pyrrolothiazole-thiochroman-4-one hybrids 4 and 5. Entry

Comp.

Yield (%)a

Reaction time

mp oC

1

4{1,1,1}

82

5

156-157

2

4{2,1,1}

81

5

188-189

3

4{3,1,1}

84

5

217-218

4

4{4,1,1}

79

6

214-213

5

4{5,1,1}

80

5

220-221

6

4{7,1,1}

73

5

239-240

7

4{8,1,1}

84

5

204-205

8

4{9,1,1}

82

5

200-201

9

4{12,1,1}

75

5

219-220

10

4{13,1,1}

77

5

237-238

11

4{14,1,1}

70

5

235-236

12

4{2,2,1}

82

5

223-224

13

4{2,3,1}

80

5

211-212

14

5{1,1,2}

85

5

236-237

15

5{2,1,2}

80

5

228-229

16

5{3,1,2}

82

5

225-226

17

5{4,1,2}

78

5

231-232

18

5{5,1,2}

81

5

243-244

19

5{6,1,2}

74

6

227-228

20

5{7,1,2}

78

5

209-210

21

5{8,1,2}

83

5

214-215

22

5{9,1,2}

82

5

206-207

23

5{10,1,2}

78

5

230-231

24

5{11,1,2}

72

6

218-219

25

5{12,1,2}

74

5

207-208

26

5{13,1,2}

76

5

232-233

27

5{15,1,2}

84

5

233-234

28

5{16,1,2}

82

5

228-229


8

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a

29

5{2,2,2}

80

5

210-211

30

5{2,3,2}

84

5

198-199

Isolated yield after purification.

The structure of compounds 4 and 5 was deduced from one- and two-dimensional NMR spectroscopic data, as detailed for 4{3,1,1} as a representative example (vide supporting information). Finally, the complete stereochemistry of the product was unambiguously assigned by X-ray diffraction study31 of a single crystal of 4{8,1,1} (Figure 5).

Figure 5. Single crystal XRD analysis for 4{8,1,1}.

In our structural assignment, we have assumed that all the molecules have the same connectivity and that the relative stereochemistry is the same as that shown by the X-ray in all cases. Some diagnostic NMR signals are common to all compounds 4 and 5 and support this assumption. As an example, the chemical shifts of the C-2” diastereotopic protons, which are in the same range for all compounds, are summarized in Table 3. Moreover the stereochemistry of the 7a’ stereocenter in compounds 5 is in accordance with our earlier reports on related compounds.32


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Table 3. Chemical shifts of the C-2” diastereotopic protons of compounds 4 and 5

Entry

Compound

1

4{1,1,1}

2.59 (d, J = 14.4 Hz, 1H), 3.33 (d, J = 14.4 Hz, 1H)

2

4{2,1,1}

2.61 (d, J = 14.1 Hz, 1H), 3.33 (d, J = 14.4 Hz, 1H),

3

4{3,1,1}

2.61 (d, J = 14.1 Hz, 1H), 3.32 (d, J = 14.4 Hz, 1H)

4

4{4,1,1}

2.62 (d, J = 14.1 Hz, 1H), 3.37‒3.47 (m, 1H) merged

5

4{5,1,1}

2.63 (d, J = 14.4 Hz, 1H), 3.38 (d, J = 14.4 Hz, 1H)

6

4{7,1,1}

2.70 (d, J = 14.1 Hz, 1H), 3.09 (d, J = 14.1 Hz, 1H),

7

4{8,1,1}

2.65 (d, J = 14.1 Hz, 1H), 3.37 (d, J = 14.4 Hz, 1H)

8

4{9,1,1}

2.64 (d, J = 14.4 Hz, 1H), 3.35 (d, J = 14.1 Hz, 1H)

9

4{12,1,1}

2.48 (d, J = 14.1 Hz, 1H),3.48‒3.57 (m, 1H) merged

10

4{13,1,1}

2.57 (d, J = 14.4 Hz, 1H), 3.31 (d, J = 14.4 Hz, 1H)

11

4{14,1,1}

2.59 (d, J = 14.4 Hz, 1H), 3.33‒3.43 (m, 1H) merged

12

4{2,2,1}

2.60 (d, J = 14.1 Hz, 1H), 3.28 (d, J = 14.4 Hz, 1H)

13

4{2,3,1}

2.60 (d, J = 14.4 Hz, 1H), 3.27 (d, J = 14.4 Hz, 1H)

14

5{1,1,2}

2.60 (d, J = 14.1 Hz, 1H), 3.39‒3.53 (m, 1H) merged

15

5{2,1,2}

2.61 (d, J = 14.1 Hz, 1H),3.39‒3.52 (m, 1H) merged

16

5{3,1,2}

2.61 (d, J = 14.1 Hz, 1H), 3.38‒3.51 (m, 1H) merged

17

5{4,1,2}

2.62 (d, J = 14.1 Hz, 1H), 3.40‒3.56 (m, 1H) merged

Chemical shift of the C-2” protons


10

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18

5{5,1,2}

2.63 (d, J = 14.4 Hz, 1H), 3.39‒3.55 (m, 1H) merged

19

5{6,1,2}

2.63 (d, J = 14.4 Hz, 1H), 3.39‒3.54 (m, 1H) merged

20

5{7,1,2}

2.67 (d, J = 14.1 Hz, 1H), 3.23 (d, J = 14.1 Hz, 1H)

21

5{8,1,2}

2.65 (d, J = 14.1 Hz, 1H), 3.47‒3.56 (m, 1H) merged

22

5{9,1,2}

2.64 (d, J = 14.1 Hz, 1H), 3.38‒3.54 (m, 1H) merged

23

5{10,1,2}

2.65 (d, J = 14.1 Hz, 1H), 3.20 (d, J = 14.1 Hz, 1H)

24

5{11,1,2}

2.34 (d, J = 14.1 Hz, 1H), 3.42‒3.50 (m, 1H), merged

25

5{12,1,2}

2.87‒2.91 (m, 1H) merged, 3.66 (d, J = 14.1 Hz, 1H)

26

5{13,1,2}

2.58 (d, J = 14.1 Hz, 1H), 3.39‒3.50 (m, 1H) merged

27

5{15,1,2}

2.55 (d, J = 14.4 Hz, 1H), 3.38-3.53 (m, 1H) merged

28

5{16,1,2}

2.60 (d, J = 14.1 Hz, 1H), 3.39‒3.57 (m, 1H) merged

29

5{2,2,2}

2.61 (d, J = 14.1 Hz, 1H), 3.36-3.50 (m, 1H) merged

30

5{2,3,2}

2.60 (d, J = 14.4 Hz, 1H), 3.36‒3.50 (m, 1H) merged

The mechanism for the formation of the cycloadducts presumably proceeds through the generation of azomethine ylide 6 from the reaction between isatins and sarcosine/thioproline, comprising the initial formation of an iminium species which would then evolve by decarboxylation. The subsequent reaction of 6 with dipolarophile 1 would give the cycloadducts 4 and 5 (Scheme 3). Despite the presence of three or four stereocenters in the cycloadducts 4 and 5, respectively, it is remarkable to find the selective formation of only one of the possible diastereomers, since the electron-rich carbon of the dipole adds to the electron-deficient β-carbon of the α,β-unsaturated system of 1 in path ‘a’ rather than path ‘b’ (Scheme 4). Presumably the


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Page 12 of 23

cycloaddition occurs in such a way that (i) the carbonyl of the thiochroman-4-one ring system and the aryl ring of the pyrrolidine ring are trans to each other to avoid steric interaction and (ii) the two carbonyls of the products are trans to each other to minimize electrostatic repulsion. The other two possible disasteromeric pairs of compounds are not obtained.

Scheme 3. Plausible mechanism for the formation of spirooxindole-pyrrolidine/pyrrolo-thiazolethiochroman-4-one hybrids 4 and 5


12

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Scheme 4. Proposed approach of 1,3-dipole to dipolarophile, explaining the regio- and diastereoselective formation of spirooxindole-pyrrolidine/pyrrolothiazole-thiochroman-4-one hybrids CONCLUSION In conclusion, we disclose a facile, three-component 1,3-dipolar cycloaddition reaction for the regio-

and

stereoselective

synthesis

of

biologically

relevant

novel

spirooxindole-

pyrrolidine/pyrrolothiazole-thiochroman-4-one hybrids in good yields from simple, readily available starting materials. This transformation occurs with the formation of two C-C and one C-N bonds and the generation of three contiguous stereocenters in a one-pot operation that proceeds with a very high atom economy and has water and carbon dioxide as the only side products. EXPERIMENTAL PROCEDURES General procedure for the synthesis of dispirooxindole-pyrrolidine/pyrrolothiazole– thiochroman-4-one heterocyclic hybrids: A mixture of the suitable 3-arylidinethiocroman-4one (1 mmol), isatin (1 mmol) and sarcosine/L-thioproline (1 mmol) in MeOH (5 ml) was heated under reflux for 6-7 h. After completion of the reaction as evident from TLC, the solvent was removed and the crude product was purified by column chromatography eluting with a 4:1 (v/v) petroleum ether–ethyl acetate mixture to afford the desired products. Characterization data for representative compounds follow; for the full set of data, see the Supporting Information. 4'-(4-Fluorophenyl)-1'-methyldispiro[indoline-3,2'-pyrrolidine-3',3''-thiochromane]-2,4''dione 4{1,1,1}: White solid. Yield: 82%; mp = 156-157 °C (AcOEt-petroleum ether); IR (KBr)


13


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Page 14 of 23

υmax: 3209, 3063, 2954, 2845, 1696, 1672, 1617, 1587, 1511, 1470 cm-1; 1H NMR (300 MHz, CDCl3) δH: 2.09 (s, 3H), 2.59 (d, J = 14.4 Hz, 1H), 3.33 (d, J = 14.4 Hz, 1H), 3.44 (t, J = 8.4 Hz, 1H), 3.92 (t, J = 9.9 Hz, 1H), 5.16 (dd, J = 10.5, 7.8 Hz, 1H), 6.57 (t, J = 7.5 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 6.75 (t, J = 6.4 Hz, 2H), 6.95 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 7.047.09 (m, 2H), 7.49 (t, J = 6.6 Hz, 2H), 7.69 (br s, 1H), 8.16 (dd, J = 8.1, 1.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δC: 34.0, 34.1, 46.5, 56.9, 59.9, 74.9, 109.3, 115.3 (2JC, F = 20.9 Hz), 122.0, 124.5, 126.0, 126.3, 127.2, 129.0, 130.7, 130.9, 132.1 (3JC, 142.0, 162.0 (1JC,

F

F

= 7.9 Hz), 132.3, 133.4, 141.6,

= 244.3 Hz), 177.1, 193.5; ESI-MS: m/z. Calcd: 444.13; Found: 445.13

(M+1); Anal. Calcd for C26H21FN2O2S: C, 70.25; H, 4.76; N, 6.30; %. Found C, 69.95; H, 4.69; N, 6.22 %. 7'-(4-Fluorophenyl)-7',7a'-dihydro-1'H,3'H-dispiro[indoline-3,5'-pyrrolo[1,2-c]thiazole6',3''-thiochromane]-2,4''-dione 5{1,1,2}: White solid. Yield: 85%; mp = 236‒237°C (AcOEtpetroleum ether); IR (KBr) υmax: 3135, 2934, 2815, 1694, 1672, 1620, 1588, 1473 cm-1; 1H NMR (300 MHz, CDCl3) δH: 2.60 (d, J = 14.1 Hz, 1H), 2.82 (t, J = 8.7 Hz, 1H), 2.95 (dd, J = 9.1, 5.2 Hz, 1H), 3.39‒3.53 (m, 3H), 4.73-4.81 (m, 1H), 4.87 (d, J = 9.9 Hz, 1H), 6.58‒6.64 (m, 1H), 6.66 (d, J = 7.5 Hz, 1H), (6.76, dd, J = 7.9, 1.0 Hz, 1H), (6.86, d, J = 7.8 Hz, 1H), 6.94‒7.00 (m, 2H), 7.01‒7.10 (m, 3H), 7.44 (dd, J = 8.1, 5.4 Hz, 2H), 7.88 (br s, 1H), 8.06 (dd, J = 8.1, 1.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δC: 31.1, 32.8, 44.2, 48.8, 63.9, 67.2, 68.9, 108.9, 114.5 (2JC, F = 21.1 Hz), 120.2, 123.5, 123.9, 125.2, 125.7, 128.2, 129.6 (2JC, F = 20.4 Hz), 130.03 (3JC, F = 7.7 Hz), 131.5, 131.6, 140.7, 141.5, 161.0 (1JC, F = 244.3 Hz), 175.5, 191.5; ESI-MS: m/z. Calcd: 488.10; Found: 487.14 (M-1); Anal. Calcd for C27H21FN2O2S2: C, 66.37; H, 4.33; N, 5.73; %. Found C, 65.99; H, 4.49; N, 5.68 %.


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ASSOCIATED CONTENT Further details on the experimental and isolation procedures, spectral data, and copies of 1H and 13

C NMR spectra for all synthesized compounds. This material is available free of charge via the

Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author e-mail: [email protected] and [email protected] Author Contributions ‡These authors contributed equally. ACKNOWLEDGMENTS SP thanks UGC New Delhi for the award of BSR Faculty Fellowship. JCM thanks MINECO for financial support through grants CTQ2012-33272-BQU and CTQ2015-68380-R. ABBREVIATIONS AChE, Acetylcholinesterase; TLC, thin layer chromatography. REFERENCES 1. Moss, G. P. Extension and revision of the nomenclature for spiro compounds. Pure Appl. Chem. 1999, 71, 531-558. 2. a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. in The Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1986; Vol. 4, 2–147; b) Cordell, G. A., Ed. The Alkaloids: Chemistry and Biology, Vol. 51; Academic Press: San Diego,


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31. Crystallographic data (excluding structure factors) for compound 4{8,1,1} have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1411532. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223336033 or e-mail:[email protected]]. 32. (a) Prasanna, P.; Balamurugan, K.; Perumal, S.; Yogeeswari, P.; Sriram, D. A regio- and stereoselective

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Graphical Abstract

A library of novel dispiro compounds containing oxindole-pyrrolidine/oxindolopyrrolothiazolethiochroman-4-one hybrid frameworks has been synthesized via three-component 1,3-dipolar cycloaddition reactions.


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One-Pot Access to a Library of Dispiro Oxindole ... - ACS Publications

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