an efficient one -pot three component protocol for … · the one -pot three component domino...

AN EFFICIENT ONE-POT THREE COMPONENT PROTOCOL FOR THE SYNTHESIS

OF BIOLOGICAL IMPORTANT DIHYDROBENZOTHIOPHENE DERIVATIVES

V.JEYACHANDRAN1,MADASAMYKUMAR

2D.MANIKANDAN

3

1,3Associate Professor,

2Assistant Professor, Department of Chemistry,

BIST, BIHER, Bharath University,Chennai-73 [email protected]

ABSTRACT

A library of novel dihydrobenzo[b]thiophene have been synthesized regioselectively in good yields through

the one-pot three component domino reactions of 5-aryldihydro-3(2H)-thiophenones, β-nitrostyrene and

malononitrile in the presence of morpholine. This transformation presumably involves Knoevenagel

condensation–Michael addition–intramolecular Thorpe-Ziegler cyclization–Tautomerization–Elimination

sequence of reactions.

Designing new multicomponent reactions (MCRs) as well as improving known MCRs

constitute a research area of immense interest in contemporary organic synthesis.1 In contrast to

classical multistep linear synthetic protocols, MCRs enable expedient and efficient assembly of

molecules of structural complexity and diversity in one-pot operations with facile execution, high

atom-economy and selectivity.1b,1c,2,3

These reactions obviate the isolation and purification of

intermediates and diminish waste generation[1-6], thereby enhance the greenness of the

transformations. Consequently, MCRs have emerged as a powerful tool for delivering molecular

libraries needed in combinatorial approaches for the assembly and lead identification of bioactive

compounds.4

2-Arylbenzo[b]thiophene derivatives are found within the structural core of several

biologically active compounds.1–4

For example, Raloxifene® (Evista®) 1,2 a selective estrogen

receptor modulator (SERM) for the treatment and prevention of osteoporosis in postmenopausal

women; an anti-tubulin agent 2 being investigated as a human cancer cell growth inhibitor;3 and

recently described ERβ agonists for central nervous system disorders,4 contain 2-

arylbenzo[b]thiophene moiety. Benzo[b]thiophene derivatives currently in pharmaceutical use or

International Journal of Pure and Applied MathematicsVolume 119 No. 12 2018, 5335-5348ISSN: 1314-3395 (on-line version)url: http://www.ijpam.euSpecial Issue ijpam.eu

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development include estrogen receptor antagonists,5 antimitotic agents,

6 modulators of multidrug

resistance,7 angiogenesis inhibitors,

8 cognition enhancers,

9 and antifungal

10 and antiinflammatory

11

agents[7-9].

Figure 1. Dihydrobenzo[b]thiophene derivatives synthesized in the present work

The methods of synthesis of 2,3-dihydro-1-benzothiophene-4-carbonitriles reported in the literature span a

variety of approaches.12–14,15-18

The key step in these syntheses involves formation of the benzothiophene ring

via the domino domino Knoevenagel condensation-Michael addition-intramolecular Thorpe–Ziegler

cyclization-elimination sequence or creation of benzene ring (Scheme 1)[10-15].

S

O

ArAr'

+ + CNNC

S

Ar

CN

NH2

NO2

Ar'

Morpholine

EtOH, MW

NO2

1 2 3

4

It was proposed to investigate the synthesis of dihydrobenzothiophene4 as given in Scheme 1[31-45]. This

synthesis commences from the reaction of 5-p-tolyldihydrothiophen-3(2H)-one 1, malanonitrile 3 and (E)-1-

methyl-4-(2-nitrovinyl)benzene 2 in EtOH in presence of morpholine under reflux condition for 5 h affording

70 % yield of 4[22-29]. This transformation presumably occurs via a domino Knoevenagel condensation-

Michael addition-intramolecular Thorpe–Ziegler cyclization-elimination sequence. As shown in Scheme 2,

the three-component reactions presumably proceed through a domino mechanism initiated by the

condensation of the starting 5-p-tolyldihydrothiophen-3(2H)-one 1with malononitrile 3 yielding an α,β-

unsaturated nitrile which then undergoes a Michael addition to the (E)-1-methyl-4-(2-nitrovinyl)benzene 2to

furnish anion. This intermediate affords 9via an intramolecular Thorpe-Ziegler cyclisation-tautomerization.

Finally, 9 is aromatized by elimination of HCN to afford compounds 6[16-21].

International Journal of Pure and Applied Mathematics Special Issue

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Scheme 2. Proposed mechanism for formation of4

Figure 2. The regioisomer of 4’not formed in the reaction

Figure 3. Selected H,H-COSY and HMBC correlations


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4a

4b

4c

4d

Figure 4. Synthesized compounds

CONCLUSIONS

The present investigation reports a one-pot three component protocol for the regioselective synthesis

of novel dihydrobenzo[b]thiophene through Knoevenagel condensation–Michael addition–intramolecular

Thorpe-Ziegler cyclization–Tautomerization–Elimination sequence. This reaction results in the formation of

four new C–C bonds in a single operation. The structure of all the dihydrobenzo[b]thiophenes was elucidated

with NMR technique.

The preparation procedure, 1H and

13CNMR spectroscopic data of 4 are presented below:

General procedure for synthesis of 5-amino-2-(aryl)-6-nitro-7-aryl-2,3-dihydro-1-benzothiophene-4-

carbonitrile(4):


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A mixture of 5-p-tolyldihydrothiophen-3(2H)-one 1 (1 mmol), malanonitrile 2 (1 mmol), (E)-1-methyl-4-(2-

nitrovinyl)benzene 2 (1 mmol) and morpholine3 (1.5 mmol) in ethanol under microwave radiation for 20 min.

After completion of the reaction as monitored by TLC, the reaction mixture was concentrated under vacuum

and the residue subjected to column chromatography using petroleum ether: ethyl acetate mixture (4:1) as

eluent to afford the pure product 4.

5-amino-2-phenyl-6-nitro-7-phenyl-2,3-dihydro-1-benzothiophene-4-carbonitrile (4a)

Isolated as yellow solid ; Yield 72%; 1H NMR (300 MHz, CDCl3)δH 2.32(s, 3H), 2.36 (s, 3H ),3.67

(dd, 1H, J = 17.1, 9.3 Hz), 3.82 (dd, 1H, J = 17.1, 9.3 Hz), 5.03 (t, 1H, J = 9.3 Hz), 5.52 (s, 2H ,

NH2), 7.11-7.32 (m, 8H, Ar-H). 13

C NMR (75 MHz, CDCl3) δC 21.1, 21.4, 45.3, 52.9, 95.9, 114.7,

126.8, 126.9, 129.5, 129.7, 132.7, 133.4, 135.4,135.7,136.2,138.1,139.1,141.6,147.8ppm. Anal.

Calcd for C21H15N3O2S: C, 67.54; H, 4.05; N, 11.25 %. Found C, 67.51; H, 4.02; N, 11.21 %.

5-amino-2,7-bis(4-isopropylphenyl)-6-nitro-2,3-dihydrobenzo[b]thiophene-4-carbonitrile (4b)

Isolated as pale yellow solid. Yield: 80%; m.p. 139-141 oC;

1H NMR (300 MHz, CDCl3) δH: 1.25 (d,

6H, 7.2 Hz), 1.29 (d, 6H, 6.9 Hz), 2.86–2.99 (m, 2H), 3.73 (dd, 1H, J = 17.1, 7.8 Hz), 3.89 (dd, 1H,

J = 17.1, 7.8 Hz), 5.11 (t, 1H, J = 8.4 Hz), 5.18 (s, 2H, NH2), 7.21–7.48 (m, 8H, Ar-H); 13

C NMR

(75 MHz, CDCl3) δC: 23.7, 23.8, 33.8, 34.0, 45.3, 52.8, 93.7, 96.7, 114.9, 127.1, 127.3, 128.4, 131.4,

133.9, 131.1, 143.0, 148.6, 149.2, 150.3, 151.1. Anal. Calcd for C27H25N3O4S: C, 66.51; H, 5.71; N,

8.62%. Found C, 66.49; H, 5.68; N, 8.60%.

5-amino-2-(4-chlorophenyl)-6-nitro-7-(p-tolyl)-2,3-dihydrobenzo[b]thiophene-4-carbonitrile

(4c)

Isolated as pale yellow solid. Yield: 80%; m.p. 180-182oC;

1H NMR (300 MHz, CDCl3) δH: 2.42 (s,

3H), 3.76 (dd, 1H, J = 17.2, 8.3 Hz), 3.87 (dd, 1H, J = 17.2, 8.3 Hz), 5.04 (t, 1H, J = 8.3 Hz), 5.15 (s,

2H, NH2), 7.25–7.48 (m, 8H, Ar-H); 13

C NMR (75 MHz, CDCl3) δC: 21.1, 45.6, 52.8, 93.1, 97.1,

115.7, 127.5, 123.3, 129.7, 129.9, 130.9, 133.6, 134.1, 138.3, 140.7, 142.9, 147.6, 150.8. Anal.

Calcd for C23H16ClN3S: C, 62.63; H, 3.82; N, 9.96%. Found C, 62.64; H, 3.80; N, 9.93%.

5-amino-2-(4-chlorophenyl)-7-(4-methoxyphenyl)-6-nitro-2,3-dihydrobenzo[b]thiophene-4-

carbonitrile (4d)


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Isolated as pale yellow solid. Yield: 74%; m.p. 199-201 oC;

1H NMR (300 MHz, CDCl3) δH: 3.63 (dd, 1H, J =

17.1, 8.7 Hz), 3.74–3.94(m, 4H, OCH3, CH), 5.03 (t, 1H, J = 8.7 Hz), 5.07(s, 2H, NH2), 7.00–7.65 (m, 8H,

Ar-H); 13

C NMR (75 MHz, CDCl3) δC: 45.6, 52.4, 55.1, 93.6 96.9, 114.4, 115.9, 127.5, 128.8, 129.2, 129.9,

130.6, 133.9, 138.3, 143.6, 147.9, 150.6, 160.9. Anal. Calcd for C22H16ClN3O3S: C, 60.34; H, 3.68; N,

9.60%. Found C, 60.30; H, 3.67; N, 9.57%.

SPECTRUL ANALYSIS


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Figure 5. 1H NMR spectra of 4b

Figure 6. 13

C NMR spectra of 4b


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Figure 7. DEPT-90 spectra of 4b

Figure 8. DEPT-135 spectra of 4b


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Figure 9. H,H-COSY spectra of 4b

Figure 10. C,H-COSY spectra of 4b


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Figure 11. HMBC spectra of 4b

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