Download PDF
Synlett 2019; 30(15): 1791-1794
DOI: 10.1055/s-0039-1690147
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 1,3,4-Thiadiazolo[2′,3′:2,3]imidazo[4,5-b]indoles

Behzad Jafari
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
,
Sayfidin Safarov
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
b   Institute of Chemistry, Tajikistan Academy of Sciences, ul. Aini 299, Dushanbe, 734063, Tajikistan
,
Muattar Khalikova
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
b   Institute of Chemistry, Tajikistan Academy of Sciences, ul. Aini 299, Dushanbe, 734063, Tajikistan
,
Peter Ehlers
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
,
Peter Langer∗
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
c   Leibniz Institut für Katalyse an der Universität Rostock e.V. (LIKAT), Albert-Einstein-Str. 29a, 18059 Rostock, Germany
› Author Affiliations
Further Information

Publication History

Received: 24 June 2017

Accepted after revision: 22 July 2019

Publication Date:
09 August 2019 (online)

 
 PDF Download Permissions and Reprints All articles of this category


Abstract

Hitherto unknown thiadiazolo[2′,3′:2,3]imidazo[4,5-b]indoles were synthesized for the first time by base-mediated cyclocondensation, bromination, and subsequent cyclization by two-fold Buchwald–Hartwig reactions.


#

Key words

Buchwald–Hartwig reaction - cyclizations - imidazothiazoles - palladium

Imidazothiadiazoles are known for their biological activities against various diseases. In fact, it has been reported that they exhibit antibacterial,[1] antifungal,[2] antitubercular,[1b] [3] anti-inflammatory and analgesic,[4] and anticancer activity (Figure [1]).[5] 2,6-Difunctionalized imidazothiazoles were reported as inhibitors of Fer and FerT which lead selectively to diminished cellular ATP levels of malignant cells.[5a] Other derivatives show PAR4 inhibition in nanomolar range and are employed in phase I clinical trials as platelet agents.[6]

Because of their biological properties, several methodologies exist for the synthesis and functionalisation of imidazothiadiazole derivatives.[7] However, Pd-catalysed reactions have only rarely been reported in this field. Pioneering work has been reported by the group of Routier focussing on Suzuki–Miyaura reaction and Buchwald–Hartwig reactions.[5d] [8]

Zoom Image
Figure 1 Imidazothiadiazole with anticancer properties

In recent years, we have studied the synthesis of various heterocyclic ring systems based on Pd-catalysed C–C and C–N cross-coupling reactions.[9] Due to the biological properties of fused thiadiazoles,[10] we were interested in developing a new synthetic approach to such molecules based on Pd-catalysed coupling reactions. Herein, we wish to report, to the best of our knowledge, the first synthesis of thiadiazolo[2′,3′:2,3]imidazo[4,5-b]indoles as a new heterocyclic core structure which has, surprisingly, not been reported in the literature so far. The synthetic strategy is straightforward and high-yielding and relies on base-mediated cyclisations and subsequent bromination and cyclisation by twofold Buchwald–Hartwig reaction.

Imidazo[2,1-b]-1,3,4-thiadiazole (3), containing an o-bromophenyl group, was synthesised, by analogy with the protocol of a related reaction,[11] by cyclocondensation of 2,2′-dibromoacetophenone (2) with commercially available 2-aminothiadiazole (1, Scheme [1]).[12] [13] Subsequent bromination of 3 gave product 4.[14] [15]

Zoom Image
Scheme 1 Synthesis of imidazo[2,1-b]-1,3,4-thiadiazole (4)

The synthesis of thiadiazolo[2′,3′:2,3]-imidazo[4,5-b]indole (5a) by cyclization of 4 with p-toluidine, based on a twofold Buchwald–Hartwig reaction, was next studied (Table [1]). During the optimisation of the conditions, the phosphine ligands played an important role (Figure [2]). Employment of bidendate ligand Xanthphos, using Pd2(dba)3 as the Pd source and xylene as the solvent, resulted in formation of the desired product in 84% yield (Table [1], entry 2). In contrast, XPhos, dppf, or DPEPhos did not provide the desired product (formation of complex mixtures). When Pd(PPh3)4 was used instead of Pd2(dba)3 as the Pd(0) source, the product could be isolated, albeit in only moderate yields.

Table 1 Optimisation of the Buchwald–Hartwig Reactiona

Catalyst

Ligand

Yield (%)b

1

Pd2(dba)3

XPhos

 0

2

Pd2(dba)3

Xantphos

84

3

Pd2(dba)3

DPEPhos

 0

4

Pd2(dba)3

Dppf

 0

5

Pd(PPh3)4

Xantphos

42

a Reaction conditions: 4, aniline derivative (1.06 equiv), catalyst (9 mol%), ligand (27 mol%), xylene, 150 °C, 24 h.

b Isolated yields.

Zoom Image
Figure 2 Ligands employed during optimisation

The scope of the reaction, employing various anilines, was next studied (Table [2]). All tested anilines worked well giving good to very good yields. Methyl- and tert-butyl-substituted anilines worked best and gave over 80% yield of the desired products, while 4-(methylthio)aniline gave the lowest yield of 61%. In general, para-substituted anilines gave higher yields than their meta-substituted analogues (cf. 5a and 5b or 5f and 5g).

Table 2 Synthesis of 5-Aryl-thiadiazoloimidazo[4,5-b]indolesa,b

a Reaction conditions: 4, aniline (1.06 equiv), Pd2(dba)3 (9 mol%), Xanthphos (27 mol%), NaOt-Bu, xylene, 150 °C, 24 h.

b Yields of isolated products.

In conclusion, thiadiazolo[2′,3′:2,3]imidazo[4,5-b]indoles have been synthesized for the first time by cyclocondensation and subsequent palladium-catalysed two-fold Buchwald–Hartwig reactions.[16] [17] The reactions proceed in good to very good yields and with high selectivity.


#

Acknowledgment

We are grateful to the DAAD (scholarships for B. J., S. S. and M. K.) and to the State of Mecklenburg-Vorpommern.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0039-1690147.
  • Supporting Information

  • References and Notes

  • 2 Alwan WS, Karpoormath R, Palkar MB, Patel HM, Rane RA, Shaikh MS, Kajee A, Mlisana KP. Eur. J. Med. Chem. 2015; 95: 514
    CrossrefPubMedSearch in Google Scholar
  • 7 Khazi IA. M, Gadad AK, Lamani RS, Bhongade BA. Tetrahedron 2011; 67: 3289 ; and references cited therein
    CrossrefSearch in Google Scholar
    • 8a Copin C, Henry N, Buron F, Routier S. Eur. J. Org. Chem. 2012; 3079
    • 8b Copin C, Massip S, Léger J.-M, Jarry C, Buron F, Routier S. Eur. J. Org. Chem. 2015; 6932
    • 8c Copin C, Buron F, Routier S. Eur. J. Org. Chem. 2016; 1958
    • 8d Copin C, Henry N, Buron F, Routier S. Synlett 2016; 27: 1091
      Thieme ConnectSearch in Google Scholar
    • 10a Jafari B, Rashid F, Safarov S, Ospanov M, Yelibayeva N, Abilov ZA, Turmukhanova MZ, Kalugin SN, Ehlers P, Umar MI, Zaib S, Iqbal J, Langer P. ChemistrySelect 2018; 3: 12213
      CrossrefSearch in Google Scholar
    • 10b Jafari B, Ospanov M, Yelibayeva N, Ejaz SA, Khan SU, Amjad ST, Safarov S, Abilov ZA, Turmukhanova MZ, Kalugin SN, Ehlers P, Lecka J, Sévigny J, Iqbal J, Langer P. Eur. J. Med. Chem. 2018; 144: 116
      CrossrefPubMedSearch in Google Scholar
    • 10c Jafari B, Yelibayeva N, Ospanov M, Ejaz SA, Afzal S, Khan SU, Abilov ZA, Turmukhanova MZ, Kalugin SN, Safarov S, Lecka J, Sévigny J, Raman Q, Ehlers P, Iqbal J, Langer P. RSC Adv. 2016; 6: 107556
      CrossrefSearch in Google Scholar
    • 10d Jafari B, Jalil S, Zaib S, Safarov S, Khalikova M, Ospanov M, Yelibayeva N, Abilov ZA, Turmukhanova MZ, Kalugin SN, Ehlers P, Iqbal J, Langer P. ChemistrySelect 2019; 4: 7284
      CrossrefSearch in Google Scholar
  • 11 Safarov S, Rahmon R, Kukaniev MA, Schollmeyer D, Karpuk E, Meier H. J. Heterocycl. Chem. 2008; 45: 299
    CrossrefSearch in Google Scholar
  • 12 General Procedure A for the Synthesis of 6-(2-Bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (3) 2-Amino-5-ethyl-1,3,4-thiadiazole (1.70 g, 13 mmol) and 2,2′-dibromoacetophenone (1.88 g, 6.8 mmol) were dissolved in n-butanol (50 mL). Afterwards, the reaction mixture was heated to reflux for 8 h. After cooling to room temperature, the crude compound was purified by flash column chromatography on silica gel (ethyl acetate/heptane).
  • 13 6-(2-Bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (3) According to procedure A, product 3 (1.76 g, 84%) was isolated as a brownish solid; mp 110–112 °C. IR (ATR): ν = 3140 (w), 3069 (w), 2962 (w), 2869 (w), 1688 (m), 1608 (m), 1520 (s), 1445 (m), 1376 (m), 1261 (m), 1182 (s), 1015 (s), 938 (w), 853 (s), 759 (s) cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.39 (s, 1 H, CHAr), 8.01 (dd, 3 J = 7.9 Hz, 4 J = 1.9 Hz, 1 H, CHAr), 7.63 (dd, 3 J = 7.9 Hz, 4 J = 1.5 Hz, 1 H, CHAr), 7.34–7.39 (m, 1 H, CHAr), 7.10–7.16 (m, 1 H, CHAr), 3.01 (q, 3 J = 7.45 Hz, 2 H, CH2), 1.43 (t, 3 J = 7.53 Hz, 3 H, CH3). 13C NMR (75 MHz, CDCl3): δ = 166.3 (CAr), 144.6 (CAr), 143.3 (CAr), 134.5 (CAr), 133.9 (CHAr), 130.9 (CHAr), 128.7 (CHAr), 127.7 (CHAr), 121.0 (CAr), 113.4 (CHAr), 25.9 (CH2), 13.1 (CH3). MS (EI, 70 ev): m/z = 309 (77) [M]+, 307 (77) [M]+, 227 (29), 277 (40), 225 (28), 183 (32), 181 (32), 173 (52), 146 (100), 120 (5), 114 (7), 102 (41). HRMS: m/z calcd for C12H10N3 81BrS: 308.97529; found: 308.97518. HRMS: m/z calcd for C12H10N3BrS: 306.97773; found: 306.97720.
  • 14 General Procedure B for the Synthesis of 5-Bromo-6-(2-bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (4) 6-(2-Bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (3; 1.40 g, 3.6 mmol) dissolved in acetic acid (15 mL) and bromine (0.26 mL) dissolved in acetic acid (1.5 mL) were added dropwise at ambient temperature over 15 min. The reaction was vigorously stirred for 75 min. A saturated aqueous solution of NaOAc (410 mg, 5 mmol) was slowly added with cooling, the precipitate formed was collected by filtration, and the crude compound was purified by flash column chromatography on silica gel (ethyl acetate/heptane).
  • 15 5-Bromo-6-(2-bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (4) According to procedure B, product 4 (1.35 g, 76%) was isolated as a yellow solid; mp 109–110 °C. IR (ATR): ν = 2979 (w), 2934 (w), 2915 (w), 1594 (w), 1524 (m), 1467 (s), 1426 (m), 1322 (m), 1284 (w), 1106 (s), 1044 (s), 977 (s), 754 (s), 724 (s), 669 (m), 638 (s) cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.69 (d, 3 J = 8.1 Hz, 1 H, CHAr), 7.47 (d, 3 J = 7.5 Hz, 1 H, CHAr), 7.38 (d, 3 J = 7.3 Hz, 1 H, CHAr), 7.28 (d, 3 J = 7.7 Hz, 1 H, CHAr), 3.09 (q, 3 J = 7.5 Hz, 2 H, CH2), 1.46 (t, 3 J = 7.8 Hz, 3 H, CH3). 13C NMR (62 MHz, DMSO): δ = 168.0 (CAr), 143.4 (CAr), 142.2 (CAr), 133.7 (CAr), 132.8 (CHAr), 132.4 (CHAr), 130.6 (CHAr), 127.5 (CHAr), 123.1 (CAr), 94.8 (CAr), 25.0 (CH2), 12.8 (CH3). MS (EI, 70 ev): m/z = 389 (35) [M]+, 387 (66) [M]+, 385 (33) [M]+, 253 (100), 251 (98), 226 (9), 201 (6), 172 (16), 151 (15), 149 (14), 146 (15), 128 (16), 120 (28), 102 (17). HRMS: m/z calcd for C12H9N3Br2S: 384.88784; found: 384.88737. HRMS: m/z calcd for C12H9N3Br81BrS: 386.88580; found: 386.88539. HRMS: m/z calcd for C12H9N3 81Br2S: 384.88375; found: 388.88329.
  • 16 General Procedure C for the Synthesis of 2-Ethyl-5-(substituted)-5H-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-b]indole 5a–g 5-Bromo-6-(2-bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (4, 100 mg, 0.275 mmol), aniline derivative (0.412 mmol), Pd2(dba)3 (0.025 mmol), XantPhos (0.0750 mmol), NaOt-Bu (0.750 mmol) were heated in dry xylene (2 mL) at 150 °C for 24 h. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The crude compound was purified by flash column chromatography on silica gel (ethyl acetate/heptane).
  • 17 2-Ethyl-5-(p-tolyl)-5H-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-b]indole (5a) According to procedure C, using p-toluidine, product 5a (73 mg, 84%) was isolated as a brown solid; mp 187–188 °C. IR (ATR): ν = 3034 (w), 2980 (w), 2939 (w), 2872 (w), 1606 (m), 1537 (m), 1513 (s), 1436 (m), 1380 (m), 1259 (s), 1186 (m), 1081 (w), 970 (w), 888 (w), 797 (s), 749 (m), 736 (s) cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.96–8.01 (m, 1 H, CHAr), 7.60–7.63 (m, 1 H, CHAr), 7.55 (d, 3 J = 8.4 Hz, 2 H, CHAr), 7.38 (d, 3 J = 8.5 Hz, 2 H, CHAr), 7.26–7.30 (m, 2 H, CHAr), 3.01 (q, 3 J = 7.6 Hz, 2 H, CH2), 2.47 (s, 3 H, CH3), 1.41 (t, 3 J = 7.6 Hz, 3 H, CH3). 13C NMR (75 MHz, CDCl3): δ = 164.5 (CAr), 144.0 (CAr), 138.7 (CAr), 136.9 (CAr), 134.1 (CAr), 131.3 (CAr), 130.3 (CHAr), 125.0 (CHAr), 122.8 (CHAr), 121.3 (CHAr), 120.3 (CAr), 119.3 (CAr), 118.6 (CHAr), 111.4 (CHAr), 26.0 (CH2), 21.4 (CH3), 13.3 (CH3). MS (EI, 70 ev): m/z = 332 (93) [M]+, 278 (10), 277 (40), 276 (100), 263 (9), 262 (50), 250 (5), 219 (36), 166 (8), 138 (26), 102 (12). HRMS: m/z calcd for C19H16N4S: 332.10902; found: 332.10875.

  • References and Notes

  • 2 Alwan WS, Karpoormath R, Palkar MB, Patel HM, Rane RA, Shaikh MS, Kajee A, Mlisana KP. Eur. J. Med. Chem. 2015; 95: 514
    CrossrefPubMedSearch in Google Scholar
  • 7 Khazi IA. M, Gadad AK, Lamani RS, Bhongade BA. Tetrahedron 2011; 67: 3289 ; and references cited therein
    CrossrefSearch in Google Scholar
    • 8a Copin C, Henry N, Buron F, Routier S. Eur. J. Org. Chem. 2012; 3079
    • 8b Copin C, Massip S, Léger J.-M, Jarry C, Buron F, Routier S. Eur. J. Org. Chem. 2015; 6932
    • 8c Copin C, Buron F, Routier S. Eur. J. Org. Chem. 2016; 1958
    • 8d Copin C, Henry N, Buron F, Routier S. Synlett 2016; 27: 1091
      Thieme ConnectSearch in Google Scholar
    • 10a Jafari B, Rashid F, Safarov S, Ospanov M, Yelibayeva N, Abilov ZA, Turmukhanova MZ, Kalugin SN, Ehlers P, Umar MI, Zaib S, Iqbal J, Langer P. ChemistrySelect 2018; 3: 12213
      CrossrefSearch in Google Scholar
    • 10b Jafari B, Ospanov M, Yelibayeva N, Ejaz SA, Khan SU, Amjad ST, Safarov S, Abilov ZA, Turmukhanova MZ, Kalugin SN, Ehlers P, Lecka J, Sévigny J, Iqbal J, Langer P. Eur. J. Med. Chem. 2018; 144: 116
      CrossrefPubMedSearch in Google Scholar
    • 10c Jafari B, Yelibayeva N, Ospanov M, Ejaz SA, Afzal S, Khan SU, Abilov ZA, Turmukhanova MZ, Kalugin SN, Safarov S, Lecka J, Sévigny J, Raman Q, Ehlers P, Iqbal J, Langer P. RSC Adv. 2016; 6: 107556
      CrossrefSearch in Google Scholar
    • 10d Jafari B, Jalil S, Zaib S, Safarov S, Khalikova M, Ospanov M, Yelibayeva N, Abilov ZA, Turmukhanova MZ, Kalugin SN, Ehlers P, Iqbal J, Langer P. ChemistrySelect 2019; 4: 7284
      CrossrefSearch in Google Scholar
  • 11 Safarov S, Rahmon R, Kukaniev MA, Schollmeyer D, Karpuk E, Meier H. J. Heterocycl. Chem. 2008; 45: 299
    CrossrefSearch in Google Scholar
  • 12 General Procedure A for the Synthesis of 6-(2-Bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (3) 2-Amino-5-ethyl-1,3,4-thiadiazole (1.70 g, 13 mmol) and 2,2′-dibromoacetophenone (1.88 g, 6.8 mmol) were dissolved in n-butanol (50 mL). Afterwards, the reaction mixture was heated to reflux for 8 h. After cooling to room temperature, the crude compound was purified by flash column chromatography on silica gel (ethyl acetate/heptane).
  • 13 6-(2-Bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (3) According to procedure A, product 3 (1.76 g, 84%) was isolated as a brownish solid; mp 110–112 °C. IR (ATR): ν = 3140 (w), 3069 (w), 2962 (w), 2869 (w), 1688 (m), 1608 (m), 1520 (s), 1445 (m), 1376 (m), 1261 (m), 1182 (s), 1015 (s), 938 (w), 853 (s), 759 (s) cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.39 (s, 1 H, CHAr), 8.01 (dd, 3 J = 7.9 Hz, 4 J = 1.9 Hz, 1 H, CHAr), 7.63 (dd, 3 J = 7.9 Hz, 4 J = 1.5 Hz, 1 H, CHAr), 7.34–7.39 (m, 1 H, CHAr), 7.10–7.16 (m, 1 H, CHAr), 3.01 (q, 3 J = 7.45 Hz, 2 H, CH2), 1.43 (t, 3 J = 7.53 Hz, 3 H, CH3). 13C NMR (75 MHz, CDCl3): δ = 166.3 (CAr), 144.6 (CAr), 143.3 (CAr), 134.5 (CAr), 133.9 (CHAr), 130.9 (CHAr), 128.7 (CHAr), 127.7 (CHAr), 121.0 (CAr), 113.4 (CHAr), 25.9 (CH2), 13.1 (CH3). MS (EI, 70 ev): m/z = 309 (77) [M]+, 307 (77) [M]+, 227 (29), 277 (40), 225 (28), 183 (32), 181 (32), 173 (52), 146 (100), 120 (5), 114 (7), 102 (41). HRMS: m/z calcd for C12H10N3 81BrS: 308.97529; found: 308.97518. HRMS: m/z calcd for C12H10N3BrS: 306.97773; found: 306.97720.
  • 14 General Procedure B for the Synthesis of 5-Bromo-6-(2-bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (4) 6-(2-Bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (3; 1.40 g, 3.6 mmol) dissolved in acetic acid (15 mL) and bromine (0.26 mL) dissolved in acetic acid (1.5 mL) were added dropwise at ambient temperature over 15 min. The reaction was vigorously stirred for 75 min. A saturated aqueous solution of NaOAc (410 mg, 5 mmol) was slowly added with cooling, the precipitate formed was collected by filtration, and the crude compound was purified by flash column chromatography on silica gel (ethyl acetate/heptane).
  • 15 5-Bromo-6-(2-bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (4) According to procedure B, product 4 (1.35 g, 76%) was isolated as a yellow solid; mp 109–110 °C. IR (ATR): ν = 2979 (w), 2934 (w), 2915 (w), 1594 (w), 1524 (m), 1467 (s), 1426 (m), 1322 (m), 1284 (w), 1106 (s), 1044 (s), 977 (s), 754 (s), 724 (s), 669 (m), 638 (s) cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.69 (d, 3 J = 8.1 Hz, 1 H, CHAr), 7.47 (d, 3 J = 7.5 Hz, 1 H, CHAr), 7.38 (d, 3 J = 7.3 Hz, 1 H, CHAr), 7.28 (d, 3 J = 7.7 Hz, 1 H, CHAr), 3.09 (q, 3 J = 7.5 Hz, 2 H, CH2), 1.46 (t, 3 J = 7.8 Hz, 3 H, CH3). 13C NMR (62 MHz, DMSO): δ = 168.0 (CAr), 143.4 (CAr), 142.2 (CAr), 133.7 (CAr), 132.8 (CHAr), 132.4 (CHAr), 130.6 (CHAr), 127.5 (CHAr), 123.1 (CAr), 94.8 (CAr), 25.0 (CH2), 12.8 (CH3). MS (EI, 70 ev): m/z = 389 (35) [M]+, 387 (66) [M]+, 385 (33) [M]+, 253 (100), 251 (98), 226 (9), 201 (6), 172 (16), 151 (15), 149 (14), 146 (15), 128 (16), 120 (28), 102 (17). HRMS: m/z calcd for C12H9N3Br2S: 384.88784; found: 384.88737. HRMS: m/z calcd for C12H9N3Br81BrS: 386.88580; found: 386.88539. HRMS: m/z calcd for C12H9N3 81Br2S: 384.88375; found: 388.88329.
  • 16 General Procedure C for the Synthesis of 2-Ethyl-5-(substituted)-5H-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-b]indole 5a–g 5-Bromo-6-(2-bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (4, 100 mg, 0.275 mmol), aniline derivative (0.412 mmol), Pd2(dba)3 (0.025 mmol), XantPhos (0.0750 mmol), NaOt-Bu (0.750 mmol) were heated in dry xylene (2 mL) at 150 °C for 24 h. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The crude compound was purified by flash column chromatography on silica gel (ethyl acetate/heptane).
  • 17 2-Ethyl-5-(p-tolyl)-5H-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-b]indole (5a) According to procedure C, using p-toluidine, product 5a (73 mg, 84%) was isolated as a brown solid; mp 187–188 °C. IR (ATR): ν = 3034 (w), 2980 (w), 2939 (w), 2872 (w), 1606 (m), 1537 (m), 1513 (s), 1436 (m), 1380 (m), 1259 (s), 1186 (m), 1081 (w), 970 (w), 888 (w), 797 (s), 749 (m), 736 (s) cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.96–8.01 (m, 1 H, CHAr), 7.60–7.63 (m, 1 H, CHAr), 7.55 (d, 3 J = 8.4 Hz, 2 H, CHAr), 7.38 (d, 3 J = 8.5 Hz, 2 H, CHAr), 7.26–7.30 (m, 2 H, CHAr), 3.01 (q, 3 J = 7.6 Hz, 2 H, CH2), 2.47 (s, 3 H, CH3), 1.41 (t, 3 J = 7.6 Hz, 3 H, CH3). 13C NMR (75 MHz, CDCl3): δ = 164.5 (CAr), 144.0 (CAr), 138.7 (CAr), 136.9 (CAr), 134.1 (CAr), 131.3 (CAr), 130.3 (CHAr), 125.0 (CHAr), 122.8 (CHAr), 121.3 (CHAr), 120.3 (CAr), 119.3 (CAr), 118.6 (CHAr), 111.4 (CHAr), 26.0 (CH2), 21.4 (CH3), 13.3 (CH3). MS (EI, 70 ev): m/z = 332 (93) [M]+, 278 (10), 277 (40), 276 (100), 263 (9), 262 (50), 250 (5), 219 (36), 166 (8), 138 (26), 102 (12). HRMS: m/z calcd for C19H16N4S: 332.10902; found: 332.10875.

   Permissions and Reprints All articles of this category
Zoom Image
Figure 1 Imidazothiadiazole with anticancer properties
Zoom Image
Scheme 1 Synthesis of imidazo[2,1-b]-1,3,4-thiadiazole (4)
Zoom Image
Figure 2 Ligands employed during optimisation