An efficient desulfitative C–C cross coupling of fused thiazolidine-2-thione with boronic acids and boronic acid pinacol esters: formation of fused thiazoles

Abstract

An efficient Pd(0)-catalyzed Cu(I)-mediated desulfitative C–C cross-coupling of benzo-fused thiazolidine-2-thione with boronic acids under neutral Liebeskind–Srogl conditions is described. The desulfitative cross coupling of boronic acid pinacol esters has also been demonstrated with fused thiazolidine-2-thione under basic conditions to afford fused thiazoles with good to excellent yields.

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Introduction

Desulfitative cross-coupling reactions involving alkyl thioethers, sulfones, and sulfonyls with organometallic reagents have been widely employed toward the synthesis of diverse molecules including important heterocyclic compounds.¹ In this connection, palladium metal catalyzed – Cu(I) carboxylate mediated – Csp²–Csp² cross coupling of boronic acids and various thioorganic compounds have been explored extensively under non-basic conditions for the construction of diverse cyclic and acyclic motifs.^1,2 In this Liebeskind–Srogl cross coupling reaction, the soft Cu(I) carboxylate cofactor has high thiophilicity accelerating the desulfitative C–C cross couplings selectively.^1f,3 The non-basic Liebeskind–Srogl cross coupling reaction has also gained attention, making considerable progress.^1g,2c,4,5 The desulfitative cross-coupling of Sonogashira–Hagihara, Stille, and Suzuki–Miyaura as well as Mizoroki–Heck couplings of sulfonyl chlorides have been explored by Vogel and co-workers.⁶ Because of their stability, low toxicity, easy handling, and easy removal of degradable boron derived byproducts, “green” boronic acids⁷ are much superior to boronic esters as reactants.⁸ Currently, we are focusing on the development of methods for the synthesis of some functionalized heterocyclic compounds.⁹ In continuation, herein we report the Pd/Cu(I) mediated desulfitative carbon–carbon cross coupling for the synthesis of fused thiazole derivatives. Over the years, a variety of protocols have been developed for the rapid construction of benzo-fused or heteroaryl-fused thiazoles from prefunctionalized substrates.¹⁰ These highly functionalized thiazoles are found in many pharmaceutical agents¹¹ and in some diverse materials with potential applications.¹² The synthesis of substituted benzothiazoles has been achieved under Pd mediated Suzuki biaryl coupling of arylboronic acids with 2-halobenzothiazoles,¹³ while direct coupling of aryl bromides with benzothiazole¹⁴ is also known. Direct C–H arylation of heteroarenes via a denitrogenative and desulfitative mode of action has also been described.^15,16 Gosmini and co-workers¹⁷ have elaborated the Co(II)-catalyzed synthesis of benzothiazole derivatives through coupling of aryl or benzylzinc reagents with methylsulfanyl-N-heteroarenes. It is pertinent to note that only very few reports are available towards the construction of heteroaryl fused thiazoles and that is the motive to undertake the present investigation.

The starting materials for the present study, fused thiazolidine-2-thiones 1, have been prepared from cheap and readily available 2-haloanilines and highly reactive potassium ethyl xanthate.¹⁸ At first, the traditional Liebeskind–Srogl coupling reaction of 1 with arylboronic acid 2 with an effective thiophilic reagent – copper(I) thiophene-2-carboxylate (CuTC) and various palladium sources in the presence of phosphine ligands has been investigated (Scheme 1).

Scheme 1 Plan for the synthesis of aryl thiazoles.

Results and discussion

The screening experiments have been started using a stoichiometric amount of 4-methoxyphenylboronic acid, Pd(dba)₂ and PPh₃ in the presence of a stoichiometric amount of CuTC. The temperature range studied was 50–100 °C, and the solvent tried was dioxane under a nitrogen atmosphere. This resulted in fused thiazoles as the desired product, but the conversion (22–42%) was not effective (Table 1, entries 1–3). Satisfactory results were obtained with Pd₂(dba)₃. When a combination of Pd(OAc)₂ (10 mol%)–PPh₃ (10 mol%)–RB(OH)₂ (1.5 equiv.)–CuTC (2 equiv.) was tested at 100 °C with dioxane as the solvent, the reaction was complete in an hour under nitrogen giving the best result (89%) (Table 1, entry 8). Running the experiment with increased catalyst loading (20 mol%) or lowering the reaction temperature did not increase the yield. The effective conversion has been improved (64–89%, Table 1, entries 9–12) by a sacrificial increment of CuTC as well as arylboronic acid. This can be explained by the low thiophilicity of boron in the organoboron compounds and relatively low nucleophilic reactivity compared to CuTC.^4c,19 The oxidation of Cu(I) cofactor has been avoided under the inert atmosphere, promoting the product yield.^1c,2a,20 Phosphine free conditions (Table 1, entry 20) or extending the reaction time do not provide an encouraging result.

Table 1 Optimization of the reaction conditions^ad

Entry	2 (equiv.)/CuTC (equiv.)	Catalyst (mol%)/ligand (mol%)	Solvent	Time (h)	Temp (°C)	Yield^b (%) 3aa
a Experiments were performed in dioxane/THF (5 mL) under N2 atm.b Isolated yield.c No reaction.d L1 = PPh3; L2 = XPhos.
1	1/1	Pd(dba)2 (10)/L1 (5)	Dioxane	16	50	22
2	1/1	Pd(dba)2 (20)/L1 (10)	Dioxane	12	50	34
3	1/1	Pd(dba)2 (10)/XPhos (10)	Dioxane	8	100	42
4	1.2/1	Pd2(dba)3 CHCl3 (10)/L1 (10)	Dioxane	5	80	55
5	1.5/2	Pd2(dba)3 CHCl3 (10)/L1 (10)	Dioxane	5	100	68
6	1.5/1	Pd2(dba)3 CHCl3 (10)/L2 (10)	Dioxane	3	100	52
7	1.5/2	PdCl2 (10)/L2 (10)	Dioxane	8	100	22
8	1.5/2	Pd(OAc)2 (10)/L1 (10)	Dioxane	1	100	89
9	1.5/2	Pd(OAc)2 (10)/L1 (10)	THF	1	100	72
10	1.5/2	Pd(OAc)2 (20)/L1 (10)	Dioxane	1	100	65
11	2/2	Pd(OAc)2 (10)/L1 (5)	Dioxane	1	100	64
12	2/3	Pd(OAc)2 (10)/L1 (10)	Dioxane	1	100	82
13	1.5/2	Pd(OAc)2 (10)/L1 (10)	Dioxane	1	130	32
14	1.5/2	Pd(OAc)2 (5)/L1 (10)	THF	1	100	52
15	1.2/1	Pd(TFA)2 (10)/L1 (10)	Dioxane	5	100	58
16	1.5/2	Pd(TFA)2 (20)/L2 (10)	Dioxane	5	100	66
17	1.5/2	Pd(OAc)2 (10)/L1 (10)	Dioxane	24	rt	—^c
18	1/2	Pd(MeCN)2Cl2 (10)/L1 (10)	Dioxane	12	100	42
19	2/2	Pd(MeCN)2Cl2 (10)/L2 (10)	Dioxane	8	100	53
20	1.5/2	Pd(OAc)2 (10 mol%)	Dioxane	18	100	^c
21	1.5/2	Pd(PPh3)4 (10 mol%)	Dioxane	8	100	61

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Encouraged by this optimised condition, the substrate scope of the reaction has been explored by coupling a range of arylboronic acids and (E)-β-styrylboronic acids with 1 to obtain 3 in good yields and the derivatives synthesized are shown in Table 2.

Table 2 Synthesis of aryl thiazoles 3aa–3ap^a

a Reaction conditions: thiazolidine-2-thione 1 (0.10 mmol), R–B(OH)₂ 2 (0.15 mmol), CuTC (0.20 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%) and PPh₃ (0.01 mmol, 10 mol%) in dioxane (5 mL) were heated at 100 °C for 1–2 h under N₂ atm.

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The homocoupling of boronic acids cannot be avoided resulting in biaryls due to the efficiency of the copper salt,²¹ though the conversion achieved is quite satisfactory. With sterically hindered arylboronic acids or some functionalized boronic acids or alkylboronic acids, the transformation was not successful under the optimized conditions. All the synthesized compounds have been characterized by NMR studies and further confirmed by single crystal X-ray analysis of 3ah (ref. 22) as shown in Fig. 1.

Fig. 1 X-ray crystal structures of 3ah and 3aw. Thermal ellipsoids are shown at the 50% probability level.

Having successfully effected the coupling with boronic acid, we wanted to test the efficacy of this protocol with organoboron pinacol esters. However, the neutral Liebeskind–Srogl desulfitative coupling reaction conditions are apparently not suitable in the case of organoboron pinacol esters, even with 3–5 equivalent of CuTC in the Pd(OAc)₂/PPh₃ system. The base is essential for the cross-coupling with organoboron pinacol esters. Earlier, Yu and Liebeskind^8b have explored Pd(0)-catalyzed, Cu(I) carboxylate-mediated cross-coupling of thiol esters and B-alkyl-9-BBN under basic conditions. We started with oxygen bases such as Na₂CO₃, K₂CO₃, Cs₂CO₃ and K₃PO₄ to accelerate the activation of the organoboron pinacol ester in dioxane at 100 °C under a nitrogen atmosphere, which resulted in a poor yield with undesired side products. Fortunately, clean transformation has been achieved in the presence of a stoichiometric amount of KF with moderate yield, though switching over to CsF (2.0 equiv.) ended with the desired product in moderate to excellent yield (Table 3).

Table 3 Optimization of the reaction conditions^a

Entry	2′ (equiv.)/CuTC (equiv.)	Pd(OAc)2 (mol%)/PPh3 (mol%)	Base (equiv.)	Time (h)	Temp (°C)	Yield^b (%) 3ai
a Experiments were performed in dioxane (5 mL) under N2 atm.b Isolated yield.c No reaction.
1	1.5/3	10/10	Nil	18	100	—^c
2	1.5/5	10/10	Nil	18	100	—^c
3	1.5/2	10/10	Na2CO3 (1.0)	18	100	Trace
4	1.5/2	10/10	K2CO3 (1.0)	12	100	12
5	1.5/2	10/10	K3PO4 (2.0)	8	100	28
6	1.5/2	10/10	Cs2CO3 (1.0)	8	100	42
7	1.5/2	10/10	KF (2.0)	5	100	61
8	1.5/2	10/10	CsF (2.0)	2	100	78
9	1.5/1	10/10	CsF (2.0)	8	100	34
10	1.5/2	10/10	CsF (2.0)	24	rt	—^c
11	1.5/2	10/5	CsF (2.0)	2	100	58
12	1.5/2	Pd(PPh3)4 (10)	CsF (2.0)	4	100	43
13	1.5/2	Pd(OAc)2 (10)	CsF (2.0)	24	100	—^c

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No reaction occurred in the absence of the ligand. The additional compounds added to the library of fused thiazole analogues through this protocol are shown in Table 4. It can be noted that under the optimized conditions, the coupling of thiazolidine-2-thione with the heteroaryl organoboron pinacol ester system seems to be more facile compared to arylboron pinacol esters. Interestingly, homocoupling is not a problem with boronic acid pinacolate ester.

Table 4 Synthesis of aryl thiazoles 3aq–3bb^a

a Reaction conditions: thiazolidine-2-thione 1 (0.10 mmol), R–BPin 2′ (0.15 mmol), CuTC (0.20 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.01 mmol, 10 mol%) and CsF (0.20 mmol) in dioxane (5 mL) heated at 100 °C for 2–3 h under N₂ atm.

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The synthesized compounds were characterized by NMR studies and further confirmed by single crystal X-ray analysis of 3aw (ref. 26) as shown in Fig. 1.

Based on the anticipated interaction between organosulfur and organoboron (thiophilic/borophilic) in the presence of Cu cofactors,^{1,2a,8b,23,24} a mechanism for the formation of 3 has been illustrated in Scheme 2. The proposed mechanism for the formation of 3 by the boranepinacol ester strategy starts with the Cu(I) thiolate species 5 obtained by the thione–thiol tautomerization,²⁵ which undergoes oxidative addition with the Pd(0) catalyst and with an additional equivalent of CuTC cofactor to form an intermediate 6. In the transmetalation step, the fluoride accelerates the pinacolate deprotection from 2′ to yield 8 with extrusion of 7 and Cu₂S. The subsequent reductive elimination results in the cross-coupled product 3.

Scheme 2 Mechanism for the formation of fused thiazole 3.

To support the proposed mechanism, some control experiments have been performed (Scheme 3). In the first experiment, a mixture of thiazolidine-2-thione and 4-methoxyphenylboronic acid (2 equiv.) (or boronic ester with CsF) was heated under aerobic conditions^1g at 100 °C for 2 h in the presence of Cu(II) acetate (1.5 equiv.) and 1,10-phenanthroline (2 equiv.) in dioxane, which resulted in the carbon-sulfur cross-coupled product 4a. This reaction does not proceed under nitrogen atmosphere indicating that the reaction may go via disulfide formation. Under the optimized conditions, Suzuki active bromo substituted thiazolidine-2-thione and 4-methoxyphenylboronic acid (2 equiv.), again yielded the anticipated thiazole derivative without traces of the traditional Suzuki coupled product (Table 2), while with boronic acid pinacol esters, a complex mixture was observed with the bromo substituted thiazolidine-2-thione system. Finally, the reaction of N-deuterium substituted aryl thiazolidine-2-thione and 4-methoxyphenylboronic acid under the same conditions furnished the benzothiazole with no deuterium incorporation, proving no hydrogen exchange occurs in the mechanism. From the above observations, a chemoselective desulfitative coupling occurred at C=S and in no case was the C–S–C was affected to yield fused hetero benzothiazoles.

Scheme 3 Control experiments.

In addition, under the optimized conditions the same strategy has also been tested with a controlled amount of water and under normal conditions in the absence of CuTC as well, but the desired product was not achieved (Table S1 see ESI†).

Conclusions

In summary, we have demonstrated a Pd(0)/Cu(I)-mediated desulfitative C–C cross-coupling of boronic acids with fused thiazolidine-2-thione under neutral conditions. We have also performed desulfitative coupling under basic conditions with thiazolidine-2-thione and organoboron pinacol esters resulting in C–C bond formation. This strategy involves mild reaction conditions towards the synthesis of diversely substituted benzo-fused thiazoles in good to excellent yields.

Experimental section

General remarks

Nuclear magnetic resonance (¹H and ¹³C NMR) spectra were recorded on a 300 MHz spectrometer in CDCl₃ using TMS as an internal standard. Chemical shifts are reported in parts per million (δ), coupling constants (J values) are reported in Hertz (Hz) and spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet), m (multiplet). ¹³C NMR spectra were routinely run with broadband decoupling. Pre coated silica gel on aluminium plates (Merck) were used for TLC analysis with a mixture of petroleum ether (60–80 °C) and ethyl acetate as eluent. Elemental analyses were performed on a Perkin Elmer 2400 Series II Elemental CHNS analyser. Mass spectra were recorded in an LCQ Fleet mass spectrometer, Thermo Fisher Instruments Limited, US. Electrospray ionisation mass spectrometry (ESI-MS) analysis was performed in the positive ion and negative ion mode on a liquid chromatography ion trap.

General procedure

A typical procedure for the synthesis of fused aryl thiazoles 3.
Neutral conditions. To a stirred solution of thiazolidine-2-thione 1 (0.10 mmol) in dioxane (5 mL), R–B(OH)₂ 2 (0.15 mmol), CuTC (0.20 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%) and PPh₃ (0.01 mmol, 10 mol%) were added in a reaction vessel, and the reaction mixture heated at 100 °C for 1 h under N₂ atm. The completion of the reaction was monitored by TLC. After cooling to room temperature, the reaction mixture was filtered through Celite. Then, the filtrate was washed with a saturated solution of NH₄Cl (3 × 10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried with anhydrous Na₂SO₄ and concentrated in vacuo. The residue was then purified by column chromatography on silica gel (hexane–ethyl acetate 9 : 1) to yield arylthiazole 3.
Basic conditions. To a stirred solution of thiazolidine-2-thione 1 (0.10 mmol) in dioxane (5 mL), R–BPin 2′ (0.15 mmol), CuTC (0.20 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.01 mmol, 10 mol%) and CsF (0.20 mmol) were added in a reaction vessel, and the reaction mixture heated at 100 °C for 2 h under N₂ atm. The completion of the reaction was monitored by TLC. After cooling to room temperature, the reaction mixture was filtered through Celite. Then, the filtrate was washed with a saturated solution of NH₄Cl (3 × 10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried with anhydrous Na₂SO₄ and concentrated in vacuo. The residue was then purified by column chromatography on silica gel (hexane–ethyl acetate 9 : 1) to yield aryl thiazole 3a.

2-(4-Methoxyphenyl)thiazolo[5,4-b]pyridine (3aa). Isolated as white solid; mp: 120–123 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.53 (dd, J = 4.6, 1.2 Hz, 1H), 8.23 (dd, J = 8.2, 1.3 Hz, 1H), 8.05 (d, J = 8.8 Hz, 2H), 7.42 (dd, J = 8.2, 4.7 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 168.1, 162.2, 158.2, 147.2, 146.3, 129.2, 129.0, 125.9, 121.1, 114.3, 55.3. Anal. calcd for C₁₃H₁₀N₂OS: C, 64.44; H, 4.16; N, 11.56%. Found: C, 64.46; H, 4.11; N, 11.59%.

2-(m-Tolyl)thiazolo[5,4-b]pyridine (3ab). Isolated as white solid; mp: 84–86 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.56 (dd, J = 4.6, 1.4 Hz, 1H), 8.27 (dd, J = 8.2, 1.5 Hz, 1H), 7.94–7.82 (m, 2H), 7.45–7.32 (m, 3H), 2.45 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 168.7, 158.2, 147.0, 146.7, 138.8, 133.1, 132.2, 129.7, 128.8, 127.8, 124.7, 121.2, 21.2. Anal. calcd for C₁₃H₁₀N₂S: C, 69.00; H, 4.45; N, 12.38%. Found: C, 69.04; H, 4.41; N, 12.33%.

2-(3,5-Dichlorophenyl)thiazolo[5,4-b]pyridine (3ac). Isolated as off-white solid; mp: 172–174 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.65–8.60 (m, 1H), 8.31 (dd, J = 8.2, 1.4 Hz, 1H), 8.03–7.95 (m, 2H), 7.52–7.47 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 165.2, 163.9, 158.2, 147.7, 146.9, 135.9, 131.1, 130.5, 125.7, 121.8. Anal. calcd for C₁₂H₆Cl₂N₂S: C, 51.26; H, 2.15; N, 9.96%. Found: C, 51.31; H, 2.17; N, 9.92%.

2-(3-(Trifluoromethyl)phenyl)thiazolo[5,4-b]pyridine (3ad). Isolated as white solid; mp: 101–103 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.62 (dd, J = 4.6, 1.3 Hz, 1H), 8.40 (s, 1H), 8.33 (dd, J = 8.2, 1.5 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.49 (dd, J = 8.2, 4.7 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 166.5, 158.2, 147.5, 146.9, 134.1, 130.7, 130.3, 129.6, 127.8, 125.4, 124.1 (¹J_C–F = 272.2), 121.8, 121.6. Anal. calcd for C₁₃H₇F₃N₂S: C, 55.71; H, 2.52; N, 10.00. Found: C, 55.76; H, 2.53; N, 10.04%.

2-(3-Bromophenyl)thiazolo[5,4-b]pyridine (3ae)²⁷. Isolated as white solid; mp: 121–122 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.60 (dd, J = 4.6, 1.3 Hz, 1H), 8.33–8.28 (m, 2H), 8.00 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.66 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.47 (dd, J = 8.2, 4.7 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 166.6, 158.3, 147.3, 146.9, 135.1, 134.3, 130.5, 130.2, 130.1, 126.2, 123.2, 121.6.

2-(4-Fluoro-2-isopropoxyphenyl)thiazolo[5,4-b]pyridine (3af). Isolated as colorless solid; mp: 119–120 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.54 (d, J = 4.6 Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.87 (dd, J = 11.8, 2.1 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.43 (dd, J = 8.2, 4.7 Hz, 1H), 7.06 (t, J = 8.4 Hz, 1H), 4.75–4.61 (m, 1H), 1.43 (d, J = 6.1 Hz, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 166.7, 158.1, 154.6 (¹J_C–F = 245.2), 151.3, 148.6 (³J_C–F = 10.5), 146.5, 129.4, 126.1, 123.8 (⁴J_C–F = 3.0), 121.2, 115.9 (²J_C–F = 21.0), 114.9, 71.9, 21.7. Anal. calcd for C₁₅H₁₃FN₂OS: C, 62.48; H, 4.54; N, 9.72%. Found: C, 62.50; H, 4.51; N, 9.77%.

2-(Benzo[b]thiophen-2-yl)thiazolo[4,5-c]quinoline (3ag). Isolated as white solid; mp: 213–214 °C; ¹H NMR (300 MHz, CDCl₃) δ 9.54 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.01 (dd, J = 15.8, 7.7 Hz, 2H), 7.94–7.83 (m, 2H), 7.77 (t, J = 7.7 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.60–7.50 (m, 1H), 7.45–7.42 (m, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 161.9, 148.1, 145.9, 144.2, 140.9, 140.4, 139.3, 136.2, 130.5, 129.1, 127.7, 127.6, 126.5, 125.8, 125.1, 124.8, 124.7, 122.6. ESI-MS m/z calcd for C₁₈H₁₀N₂S₂: [M + H]⁺ 318.03; found: 319.02. Anal. calcd for C₁₈H₁₀N₂S₂: C, 67.90; H, 3.17; N, 8.80%. Found: C, 67.95; H, 3.12; N, 8.84%.

2-(Benzo[b]thiophen-3-yl)benzo[d]thiazole (3ah). Isolated as off-white solid; mp: 79–81 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.97 (dd, J = 4.9, 3.9 Hz, 1H), 8.17–8.12 (m, 1H), 8.10 (s, 1H), 7.91 (dd, J = 8.0, 0.7 Hz, 2H), 7.56–7.41 (m, 4H). ¹³C NMR (75 MHz, CDCl₃) δ 162.1, 153.9, 140.4, 136.1, 134.1, 130.2, 129.9, 126.2, 125.3, 125.3, 125.1, 124.9, 123.3, 122.5, 121.2. ESI-MS m/z calcd for C₁₅H₉NS₂: [M + H]⁺ 267.02; found: 268.11. Anal. calcd for C₁₅H₉NS₂: C, 67.38; H, 3.39; N, 5.24%. Found: C, 67.33; H, 3.37; N, 5.27%.

2-(Naphthalen-1-yl)benzo[d]thiazole (3ai)²⁸. Isolated as white solid; mp: 124–125 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.95 (d, J = 8.3 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 8.02–7.92 (m, 4H), 7.66–7.55 (m, 4H), 7.49–7.43 (m, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 167.4, 153.9, 135.2, 133.8, 130.8, 130.5, 130.4, 129.2, 128.2, 127.4, 126.3, 126.0, 125.7, 125.0, 124.7, 123.3, 121.2. ESI-MS m/z calcd for C₁₇H₁₁NS: [M + H]⁺ 261.06; found: 261.99.

2-(4-(Methylthio)phenyl)benzo[d]thiazole (3aj)²⁹. Isolated as white solid; mp: 142–144 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.06–8.02 (m, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.90–7.84 (m, 1H), 7.51–7.44 (m, 1H), 7.39–7.33 (m, 1H), 7.30 (d, J = 8.6 Hz, 2H), 2.52 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 167.5, 154.0, 142.7, 134.7, 129.9, 127.6, 126.2, 125.8, 124.9, 122.9, 121.5, 14.9. ESI-MS m/z calcd for C₁₄H₁₁NS₂: [M + H]⁺ 257.03; found: 258.12.

5-Nitro-2-(3-(trifluoromethyl)phenyl)benzo[d]thiazole (3ak). Isolated as pale yellow solid; mp: 124–126 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.92 (d, J = 2.1 Hz, 1H), 8.37 (s, 1H), 8.32–8.26 (m, 2H), 8.06 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.68 (t, J = 7.9 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 169.4, 153.5, 146.9, 141.3, 133.1, 131.6 (²J_C–F = 33.0), 130.7, 129.8, 128.2 (³J_C–F = 3.7), 124.2 (³J_C–F = 3.0), 123.5 (¹J_C–F = 271.5), 122.1, 119.9, 118.6. Anal. calcd for C₁₄H₇F₃N₂O₂S: C, 51.85; H, 2.18; N, 8.64%. Found: C, 51.88; H, 2.14; N, 8.69%.

5-Bromo-2-(4-methoxyphenyl)-7-methylbenzo[d]thiazole (3al). Isolated as white solid; mp: 145–147 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, J = 8.8 Hz, 2H), 7.82 (s, 1H), 7.38 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H), 2.75 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 166.7, 161.9, 152.5, 136.1, 134.4, 129.9, 129.0, 126.3, 121.3, 117.9, 114.3, 55.42, 18.20. ESI-MS m/z calcd for C₁₅H₁₂BrNOS: [M + H]⁺ 334.98; found: 334.00. Anal. calcd for C₁₅H₁₂BrNOS: C, 53.90; H, 3.62; N, 4.19%. Found: C, 53.94; H, 3.64; N, 4.13%.

2-(4-Chlorophenyl)-6-methoxybenzo[d]thiazole (3am). Isolated as white solid; mp: 129–131 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.96–7.91 (m, 3H), 7.43 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 2.5 Hz, 1H), 7.09 (dd, J = 9.0, 2.5 Hz, 1H), 3.87 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 163.9, 157.8, 148.5, 136.4, 132.3, 132.1, 129.1, 128.2, 123.7, 115.7, 104.0, 55.7. Anal. calcd for C₁₄H₁₀ClNOS: C, 60.98; H, 3.66; N, 5.08%. Found: C, 60.94; H, 3.69; N, 5.03%.

(E)-2-(4-Chlorostyryl)thiazolo[5,4-b]pyridine (3an). Isolated as white solid; mp: 172–174 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.56 (d, J = 3.5 Hz, 1H), 8.21 (d, J = 8.1 Hz, 1H), 7.55–7.50 (m, 3H), 7.43–7.37 (m, 4H). ¹³C NMR (75 MHz, CDCl₃)* δ 167.2, 157.9, 147.2, 137.4, 135.7, 133.7, 129.7, 129.3*, 128.7, 122.8, 121.5. Anal. calcd for C₁₄H₉ClN₂S: C, 61.65; H, 3.33; N, 10.27%. Found: C, 61.68; H, 3.31; N, 10.23%. *Two carbons are merged.

(E)-2-(4-(Trifluoromethyl)styryl)benzo[d]thiazole (3ao). Isolated as white solid; mp: 161–163 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.03 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.67 (s, 4H), 7.51 (d, J = 8.3 Hz, 2H), 7.50–7.38 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 165.9, 153.7, 138.6, 135.5, 134.4, 130.7 (²J_C–F = 32.2), 127.3, 126.4, 125.8, 125.7 (³J_C–F = 3.7), 124.3 (¹J_C–F = 270.6), 123.1, 122.1, 121.5. Anal. calcd for C₁₆H₁₀F₃NS: C, 62.94; H, 3.30; N, 4.59%. Found: C, 62.97; H, 3.35; N, 4.53%.

(E)-2-(2-([1,1′-Biphenyl]-4-yl)vinyl)benzo[d]thiazole (3ap). Isolated as white solid; mp: 192–193 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.01 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 10.5 Hz, 6H), 7.54 (s, 1H), 7.52–7.33 (m, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 166.9, 153.8, 141.9, 140.1, 137.0, 134.3, 134.2, 128.8, 127.8, 127.6, 127.4, 126.9, 126.2, 125.2, 122.8, 121.9, 121.4. ESI-MS m/z calcd for C₂₁H₁₅NS: [M + H]⁺ 313.09; found: 314.14. Anal. calcd for C₂₁H₁₅NS: C, 80.48; H, 4.82; N, 4.47%. Found: C, 80.45; H, 4.88; N, 4.43%.

2-Phenylbenzo[d]thiazole (3aq)²⁹. Isolated as white solid; mp: 110–111 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.04–7.99 (m, 3H), 7.82 (d, J = 7.9 Hz, 1H), 7.45–7.37 (m, 4H), 7.33–7.27 (m, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 167.8, 153.9, 134.9, 133.4, 130.8, 128.8, 127.4, 126.1, 125.0, 123.0, 121.4.

2-(4-Fluorophenyl)benzo[d]thiazole (3ar)²⁸. Isolated as white solid; mp: 101–103 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.10–8.04 (m, 3H), 7.89 (d, J = 7.9 Hz, 1H), 7.52–7.46 (m, 1H), 7.41–7.35 (m, 1H), 7.21–7.14 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 166.6, 165.9, 162.6 (¹J_C–F = 250.5), 153.9, 134.9, 129.3 (³J_C–F = 8.2), 126.3, 125.1, 123.1, 121.5, 116.0 (²J_C–F = 21.7).

2-(3-(Trifluoromethoxy)phenyl)benzo[d]thiazole (3as)³⁰. Isolated as off-white solid; mp: 100–102 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.10 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 6.6 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.53 (dd, J = 11.6, 4.7 Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.35 (dd, J = 8.3, 1.0 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 165.9, 153.9, 149.7, 141.6, 135.3, 130.3, 126.5, 125.7 (¹J_C–F = 248.2), 125.4, 123.4, 122.9, 121.6, 119.3, 119.7. ESI-MS m/z calcd for C₁₄H₈F₃NOS: [M + H]⁺ 295.03; found: 295.02.

2-(4-Methoxyphenyl)benzo[d]thiazole (3at)³¹. Isolated as white solid; mp: 111–114 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, J = 8.8 Hz, 3H), 7.86 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 167.7, 161.7*, 154.1, 134.7, 128.9, 126.0, 124.6, 122.7, 121.4, 114.2, 55.2. *Two quaternary carbons are merged.

2-(3-Nitrophenyl)benzo[d]thiazole (3au)²⁸. Isolated as pale yellow solid; mp: 141–143 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.92 (s, 1H), 8.41 (d, J = 7.7 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 164.7, 153.8, 148.6, 135.1, 135.0, 132.9, 130.0, 126.7, 125.9, 125.0, 123.6, 122.1, 121.7. ESI-MS m/z calcd for C₁₃H₈N₂O₂S: [M + H]⁺ 256.03; found 257.02.

2-(4-Chlorophenyl)thiazolo[5,4-b]pyridine (3av). Isolated as white solid; mp: 157–158 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.58 (dd, J = 4.6, 1.4 Hz, 1H), 8.27 (dd, J = 8.2, 1.5 Hz, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.46–7.42 (m, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 167.0, 158.3, 147.11, 147.06, 137.6, 131.8, 129.9, 129.3, 128.6, 121.5. Anal. calcd for C₁₂H₇ClN₂S: C, 58.42; H, 2.86; N, 11.35%. Found: C, 58.46; H, 2.82; N, 11.39%.

2-(Pyridin-3-yl)thiazolo[5,4-b]pyridine (3aw). Isolated as colorless solid; mp: 168–169 °C; ¹H NMR (300 MHz, CDCl₃) δ 9.34–9.30 (m, 1H), 8.76 (dd, J = 4.8, 1.6 Hz, 1H), 8.62 (dd, J = 4.7, 1.5 Hz, 1H), 8.38 (ddd, J = 8.0, 2.2, 1.7 Hz, 1H), 8.33 (dd, J = 8.2, 1.5 Hz, 1H), 7.51–7.45 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 165.1, 158.0, 151.9, 148.4, 147.4, 146.8, 134.5, 130.2, 129.3, 123.7, 121.6. ESI-MS m/z calcd for C₁₁H₇N₃S: [M + H]⁺ 213.04; found: 214.00. Anal. calcd for C₁₁H₇N₃S: C, 61.95; H, 3.31; N, 19.70%. Found: C, 61.91; H, 3.34; N, 19.73%.

3,5-Dimethyl-4-(thiazolo[5,4-b]pyridin-2-yl)isoxazole (3ax). Isolated as colorless solid; mp: 154–155 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.59 (d, J = 4.5 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.47 (dd, J = 8.2, 4.7 Hz, 1H), 2.82 (s, 3H), 2.64 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 170.2, 158.6, 158.5, 157.6, 146.9, 146.1, 129.8, 121.5, 111.7, 13.3, 12.1. ESI-MS m/z calcd for C₁₁H₉N₃OS: [M + H]⁺ 231.05; found: 232.06. Anal. calcd for C₁₁H₉N₃OS: C, 57.13; H, 3.92; N, 18.17%. Found: C, 57.17; H, 3.95; N, 18.19%.

2-(4-(Trifluoromethoxy)phenyl)thiazolo[5,4-c]quinoline (3ay). Isolated as white solid; mp: 171–172 °C; ¹H NMR (300 MHz, CDCl₃) δ 9.55 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.7 Hz, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃)* δ 166.6, 153.1, 151.3, 148.5, 146.0, 144.2, 140.4, 131.4, 130.5, 129.1, 127.7, 124.8, 123.2 (¹J_C–F = 264.0), 121.3. ESI-MS m/z calcd for C₁₇H₉F₃N₂OS: [M + H]⁺ 346.04; found: 346.95. Anal. calcd for C₁₇H₉F₃N₂OS: C, 58.96; H, 2.62; N, 8.09%. Found: C, 58.98; H, 2.65; N, 8.04%. *one quaternary carbon not picked up.

3,5-Dimethyl-4-(thiazolo[5,4-c]quinolin-2-yl)isoxazole (3az). Isolated as off-white solid; mp: 242–243 °C; ¹H NMR (300 MHz, CDCl₃) δ 9.53 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 2.87 (s, 3H), 2.69 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 170.1, 158.4, 158.1, 147.8, 145.9, 144.2, 139.2, 130.5, 128.9, 127.7, 124.8, 123.1, 111.4, 13.4, 12.1. ESI-MS m/z calcd for C₁₅H₁₁N₃OS: [M + H]⁺ 281.06; found: 282.03 Anal. calcd for C₁₅H₁₁N₃OS: C, 64.04; H, 3.94; N, 14.94%. Found: C, 64.08; H, 3.96; N, 14.99%.

(E)-2-(4-Methylstyryl)benzo[d]thiazole (3ba)³². Isolated as white solid; mp: 139–140 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.99 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.77–7.67 (m, 1H), 7.50–7.44 (m, 4H), 7.39 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 2.38 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 167.2, 153.8, 139.6, 137.6, 134.2, 129.6, 128.3, 127.3, 126.2, 125.1, 122.7, 121.4, 121.0, 21.4. ESI-MS m/z calcd for C₁₆H₁₃NS: [M + H]⁺ 251.08; found: 252.09.

(E)-2-Styrylbenzo[d]thiazole (3bb)²⁸. Isolated as white solid; mp 110–112 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.00 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.58 (dd, J = 9.7, 3.1 Hz, 2H), 7.52–7.47 (m, 2H), 7.45–7.37 (m, 5H). ¹³C NMR (75 MHz, CDCl₃) δ 166.9, 153.8, 137.6, 135.3, 134.3, 129.4, 128.9, 127.3, 126.2, 125.3, 122.9, 122.0, 121.4.

2-((4-Methoxyphenyl)thio)benzo[d]thiazole (4a)³³. Isolated as off-white solid; mp: 79–81 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.86 (d, J = 7.8 Hz, 1H), 7.60–7.69 (m, 3H), 7.43–7.36 (m, 1H), 7.28–7.22 (m, 1H), 7.01 (d, J = 8.9 Hz, 2H), 3.88 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 171.8, 161.5, 154.0, 137.4, 135.2, 125.9, 123.9, 121.5, 120.6, 119.9, 115.3, 55.3. ESI-MS m/z calcd for C₁₄H₁₁NOS₂: [M + H]⁺ 273.03; found; 274.06.

4-(Benzo[d]thiazol-2-ylthio)-3,5-dimethylisoxazole (4b). Isolated as colorless solid; mp 102–104 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.74 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 2.41 (s, 3H), 2.19 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.9, 167.8, 161.7, 154.1, 134.9, 126.2, 124.3, 121.7, 120.7, 102.5, 11.5, 9.9. ESI-MS m/z calcd for C₁₂H₁₀N₂OS₂: [M + H]⁺ 262.02; found: 262.98. Anal. calcd for C₁₂H₁₀N₂OS₂: C, 54.94; H, 3.84; N, 10.68%. Found: C, 54.98; H, 3.86; N, 10.65%.

Acknowledgements

The authors thank DST, New Delhi for assistance under the IRHPA program for the NMR facility. K. R. gratefully acknowledges the award of a Junior Research Fellowship and financial support from CSIR (Grant No. 02(0061)/12/EMR-II), New Delhi.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H, ¹³C NMR & mass spectra of all the synthesized compounds. CCDC 1059158 and 1059159. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra17827d

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