Transition-Metal-Catalyzed Rapid Synthesis of Imidazo[2,1-b]thiazoles: Access to Aza-Fused Heterocycles via Aerobic Oxidative Coupling of 2-Aminothiazoles and Acetophenones

Dedicated to Professor Hiriyakkanavar Ila on the occasion of her 80^th birthday.

Abstract

We report an efficient synthesis of 6-substituted imidazo[2,1-b]thiazoles from 2-aminothiazoles and acetophenones through intramolecular cyclization of in situ generated thiazolium ylides. This one-pot cascade process efficiently forms two C–N bonds and is facilitated by both Cu(OTf)₂/KI and FeCl₃/ZnI₂ systems. The method utilizes commercially available starting materials and features mild reaction conditions, tolerance to different functional groups, and ease of operation. The synthetic applicability has further been demonstrated through post-modification of imidazo[2,1-b]thiazole analogues.

Naturally occurring aza-fused heterocycles have found widespread clinical use. Their exceptional potential to function as reactive pharmacophores and biomimetics has greatly contributed to their distinctive value as conventional essential components of many medicines. Imidazo[2,1-b]thiazoles are an important class of aza-fused heterocycles comprising a fused imidazole unit embedded with a thiophene unit. Numerous naturally occurring substances and physiologically active compounds with imidazo[2,1-b]thiazole moieties have been identified and synthesized.[1] These moieties exhibit various biological activities, including antibacterial, antifungal, anthelmintic, anti-inflammatory, antitumor, RAF kinase inhibitory, RSK2 kinase inhibitory, and tubulin inhibitory properties.[1b] [2] Some medicinally active imidazo[2,1-b]thiazole moieties are the anthelmintic tetramisole A,[3] 5,6-diarylimidazo[2,1-b]thiazoles B,[4] ¹¹C-labeled imidazo[2,1-b]benzothiazole C [5], and sirtuin-1 analogue D [6] (Figure [1]).

Developing unique and adaptable synthetic strategies for accessing these molecules is of paramount importance in both academia and the pharmaceutical sector. Consequently, various synthetic methods for imidazo[2,1-b]thiazole moieties have been documented. One of the classical approaches is the condensation of 2-aminothiazole with α-halo ketones.[7] However, this technique is limited by the stability, lachrymatory qualities, and limited commercial availability of α-halo carbonyl compounds. Alternative pathways include the use of α-tosyloxy ketone or α-diazo ketone[8] instead of α-halo carbonyl compounds, base-mediated reaction of propargyl tosylate with 2-mercaptoimidazole,[9] copper-catalyzed A³ coupling,[10] aminothiolation of α-bromocinnamaldehydes,[11] and visible-light-promoted cyclization of chalcones with 2-mercaptoimidazole (Scheme [1]).[12] The synthesis of benzoimidazothiazole derivatives via the aerobic oxidative cyclization of 2-aminobenzothiazole with ketones/chalcones using an FeCl₃/ZnI₂ catalytic system has been reported (Scheme [1]).[13]

In this context, we planned to employ a transition-metal-catalyzed C–H bond activation protocol to synthesize imidazo[2,1-b]thiazoles. Transition-metal-catalyzed C–H bond activation is a powerful and efficient method in organic synthesis, enabling the formation of new C–C and C–N bonds from readily available starting materials.[14] As part of our ongoing interest in the development of C–H functionalization in organic transformations[15] and our keen focus on heterocyclic compounds,[16] we envisioned the synthesis of imidazo[2,1-b]thiazoles from 2-aminothiazoles and acetophenones. The rationale behind this choice lies in the greater availability of methyl ketones compared to α-halo ketones and α-tosyloxy ketones, which have been previously used as precursors to synthesize this class of compounds. In this study, we present the synthesis of imidazo[2,1-b]thiazole derivatives from ketones using transition metal-catalyzed oxidative C–H functionalization under aerobic conditions.

We initiated our studies by employing 2-aminothiazole (1a) and acetophenone (2a) as the model substrates to optimize the reaction conditions. The desired product 6-phenylimidazo[2,1-b]thiazole (3aa) was obtained in 78% yield using the Lewis acid catalyst Cu(OTf)₂ and the iodine source KI in DMF at 90 °C (Table [1], entry 5). No product was generated in the absence of either KI or Cu(OTf)₂ (Table [1], entries 3 and 4), indicating that both Cu(OTf)₂ and KI are essential for the reaction to proceed. As the catalyst and iodine additive loading were decreased, the product yield also decreased (Table [1], entries 1 and 2). We also explored the catalytic activity of other Lewis acid catalysts, such as Sc(OTf)₃, Yb(OTf)₃, and AlCl₃. When Sc(OTf)₃, Yb(OTf)₃, or AlCl₃ catalyst was used, no product was obtained (Table [1], entries 6–8). Furthermore, after examining several iodine sources (I₂, NaI, and ZnI₂), it was found that KI was more effective as compared to the other iodine sources (Table [1], entries 9–11).

Table 1 Optimization of Reaction Conditions^a

Entry	Lewis acid (mol%)	Iodine source (mol%)	Solvent	Temp (°C)	Time (h)	Yield (%)b
1	Cu(OTf)2 (10)	KI (20)	DMF	90	12	37
2	Cu(OTf)2 (5)	KI (10)	DMF	90	12	21
3	–	KI (30)	DMF	90	12	NR
4	Cu(OTf)2 (20)	–	DMF	90	12	NR
5	Cu(OTf)2 (20)	KI (30)	DMF	90	12	78
6	Sc(OTf)3 (20)	KI (30)	DMF	90	12	NR
7	Yb(OTf)3 (20)	KI (30)	DMF	90	12	NR
8	AlCl3 (20)	KI (30)	DMF	90	12	NR
9	Cu(OTf)2 (20)	ZnI2 (30)	DMF	90	12	40
10	Cu(OTf)2 (20)	I2 (30)	DMF	90	12	34
11	Cu(OTf)2 (20)	NaI (30)	DMF	90	12	42
12	Cu(OTf)2 (20)	KI (30)	DCB	90	12	trace
13	Cu(OTf)2 (20)	KI (30)	DCE	90	12	32
14	Cu(OTf)2 (20)	KI (30)	1,4-dioxane	90	12	40
15	Cu(OTf)2 (20)	KI (30)	CH3CN	90	12	NR
16	Cu(OTf)2 (20)	KI (30)	THF	90	12	NR
17	Cu(OTf)2 (20)	KI (30)	toluene	90	12	NR
18	Cu(OTf)2 (20)	KI (30)	DMF	rt	12	NR
19	Cu(OTf)2 (20)	KI (30)	DMF	90	3	28
20	Cu(OTf)2 (20)	KI (30)	DMF	90	6	42
21	FeCl3 (20)	KI (30)	DMF	90	12	42
22	FeCl3 (20)	ZnI2 (30)	DMF	90	12	67

^a Reaction conditions: 2-aminothiazole (1a, 4 mmol), acetophenone (2a, 4.8 mmol), Lewis acid catalyst (mol%), iodine source (mol%), solvent (5 mL).

^b Isolated yield based on column chromatography; NR = no reaction.

We next screened other reaction parameters like the solvent and temperature to achieve a more optimal and feasible methodology. Other common solvents like DCE, 1,2-dichlorobenzene (DCB), toluene, CH₃CN, THF, and 1,4-dioxane were screened (Table [1], entries 12–17). Product was not obtained in CH₃CN, THF, and toluene solvents (Table [1], entries 15–17). A trace amount of product 3aa was detected in DCB, while the product was obtained in a 32% yield in DCE solvent and a 40% yield in 1,4-dioxane (Table [1], entries 12–14). The product was not formed when the temperature was lowered from 90 °C to room temperature, indicating that the reaction requires elevated temperatures for successful completion (Table [1], entry 18). Shorter reaction times resulted in poorer yields (Table [1], entries 19 and 20). Intriguingly, the desired product, 6-phenylimidazo[2,1-b]thiazole (3aa), was obtained in 67% yield using 20 mol% FeCl₃ as the Lewis acid catalyst and 30 mol% ZnI₂ in DMF at 90 °C (Conditions B) (Table [1], entry 22).[13] However, the product yield decreased to 42% in the presence of FeCl₃ (20 mol%)/KI (30 mol%) (Table [1], entry 21). Thus, the optimization studies revealed that using 2-aminothiazole (1a, 1 equiv.) and acetophenone (2a, 0.8 equiv.) with Cu(OTf)₂ (20 mol%) and KI (30 mol%) in DMF at 90 °C for 12 hours (Conditions A) provided the desired product 3aa in 78% yield (Table [1], entry 5).

Under the optimized conditions (Conditions A), the substrate scope was expanded by including 2-aminothiazole derivatives 1a–c and various ketones 2a–ab (Scheme [2]). Initially, a series of acetophenones 2a–ab with electron-donating and electron-withdrawing groups were explored for the reaction with 2-aminothiazole (1a). An electron-donating group (Me, OMe) at the para position of acetophenone, 2b, 2c, resulted in the corresponding products 3ab, 3ac in good yields (82–84%). Acetophenones 2d–g having a halogen group (F, Cl, Br, I) at the para position furnished the desired products 3ad–ag in moderate to good yields (55–86%).

The structure of 3af was confirmed by X-ray crystallographic analysis (Figure [2], CCDC 2359527).[17] It crystallized in the monoclinic system, space group P2₁/n, containing two molecules per unit cell. The molecule is stabilized by π···π stacking interactions with distances of 3.65–3.67 Å between the six-membered and five-membered rings.

Acetophenones 2h, 2i with an electron-withdrawing group (NO₂, CF₃) at the para position gave the desired products 3ah, 3ai with decreased yields (57–60%). Acetophenones 2j, 2k with a butyl or phenoxy group at the para position resulted in the corresponding products 3aj, 3ak with good yields (70–73%). meta-Substituted acetophenones 2l–o were also well tolerated under the optimized reaction conditions to afford the targeted products 3al–ao in moderate to good yields (61–73%). ortho-Substituted acetophenones successfully led to the desired products 3ap–as (63–78%).

This reaction was effective in synthesizing 6-(3-chloro-4-fluorophenyl)imidazo[2,1-b]thiazole (3at) and 6-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)imidazo[2,1-b]thiazole (3au) in good yields (68–72%). 1-Acetylnaphthalene (2v) and 2-acetylnaphthalene (2w) successfully afforded the corresponding products 3av, 3aw in moderate to good yields (61–67%). 2-Acetylfuran (2x) and 2-acetylthiophene (2y) were compatible with the optimized reaction conditions and converted into the desired products 3ax, 3ay in moderate to good yields (59–70%). To demonstrate the generality of the reaction, aliphatic ketones 2z, 2ab were employed instead of acetophenone analogues 2a–y. Though methyl isopropyl ketone (2z) and methyl isobutyl ketone (2ab) underwent C–H functionalization, relatively low yields of the corresponding products 3az, 3aab were obtained (53–59%). To our delight, 2-amino-4-methylthiazole (1b) and 2-amino-4-phenylthiazole (1c) were also tolerated, broadening the substrate scope, yielding 3bb, 3ca (61–65%). However, acetophenones containing an OH, NH₂, or CN group did not form any product, which may be attributed to the strong resonance effect (+R/–R) of these groups, which could perturb the electronic environment of the carbonyl group in the acetophenones. These reactions were also performed using Condition B [FeCl₃ (20 mol%) and ZnI₂ (30 mol%)]. The corresponding products were obtained in slightly lower yields compared to those obtained under Condition A, which employed 20 mol% Cu(OTf)₂ and 30 mol% KI (Scheme [2]).

The synthetic utility of our developed method was further demonstrated by the post-modification of 6-phenylimidazo[2,1-b]thiazole analogues 3 (Scheme [3]). For instance, 6-(4-methoxyphenyl)imidazo[2,1-b]thiazole (3ac) was transformed into 4-(imidazo[2,1-b]thiazol-6-yl)phenol (3aac) using BBr₃ (1 M in DCM) in 72% yield. Palladium-catalyzed Sonogashira coupling of 3ag with phenylacetylene proceeded smoothly, affording the corresponding product 3aad in 68% yield, and Suzuki–Miyaura coupling of 3af with phenylboronic acid furnished the desired product 3aae in 64% yield.

To gain insights into the reaction mechanism, we performed various control reactions under the optimized conditions. Initially, to ascertain the role of the catalyst, the reaction was performed without the Cu(OTf)₂ catalyst (Scheme [4]A) and failed to give the desired product 3aa, implying that Cu(OTf)₂ acts as an initiator of the reaction. In addition, the reaction was carried out in the absence of KI, and no desired product 3aa was obtained (Scheme [4]A). This demonstrated that not only Cu(OTf)₂ but also KI plays a pivotal role in the overall transformation process. Next, competition experiments were conducted. We found that electron-rich acetophenone is more reactive than electron-deficient acetophenone (4-Me/4-NO₂ = 65%:31%) (Scheme [4]B). Furthermore, aromatic ketones are more reactive than aliphatic ketones (4-methylacetophenone/methyl isobutyl ketone = 60%:21%) (Scheme [4]C). Under an argon atmosphere, only a trace amount of the desired product 3aa was produced (Scheme [4]D), indicating that oxygen is necessary for the reaction to be completed. The yield was substantially decreased to 16% when the reaction was conducted in the presence of AgOAc (Scheme [4]E). This observation suggests that the iodine produced in situ from the KI source acts as an additive for this process. Furthermore, to ascertain the formation of a radical intermediate, the reaction was performed in the presence of TEMPO radical scavenger (Scheme [4]F). It was found that the reaction between 2-aminothiazole (1a) and acetophenone (2a) was not quenched by the TEMPO radical scavenger, which indicates that the reaction does not proceed through a radical pathway.

Based on the control experiments, a plausible reaction mechanism is proposed and depicted in Scheme [5]. The process of producing iodine begins with oxidation of the iodide anion with aerobic oxygen in the presence of Cu(OTf)₂. In the next step, the iodoform reaction of acetophenone (2a) with in situ generated I₂ takes place, leading to the formation of α-iodo ketone B′. Subsequently, 2-aminothiazole (1a) reacts with α-iodo ketone B′ to furnish intermediate C′. Finally, intermediate C′ undergoes intramolecular cyclization to provide the desired product, 6-phenylimidazo[2,1-b]thiazole (3aa). Similar mechanism related to synthesis of 6-phenylimidazo[2,1-b]-thiazole 3aa from 2-aminothiazole 1a and acetophenonenone 2a by using FeCl₃/ZnI₂ catalytic system was mentioned in ref.[13].

In summary, we have developed a facile protocol for generating 6-substituted imidazo[2,1-b]thiazoles from commercially available 2-aminothiazole analogues 1 and acetophenone analogues 2 in the presence of Lewis acid catalyst Cu(OTf)₂ and iodide source KI via aerobic oxidative addition. This approach utilizes the generation of 2-iodoacetophenone, which subsequently undergoes reaction with 2-aminothiazole and intramolecular cyclization, forming two C–N bonds in the process. Mechanistic investigations have been conducted to establish the mechanism. The key features of this newly developed protocol include its applicability to a broad substrate scope and successful late-stage modifications. Given the importance of imidazo[2,1-b]thiazole analogues in medicine, the method may find promising and cost-effective applications in the synthesis of pharmaceuticals and biologically active compounds.

All solvents and reagents were purified by standard techniques or used as supplied from commercial sources (Sigma-Aldrich unless stated otherwise). All reactions were generally carried out under open-air conditions unless otherwise noted. TLC was performed on Merck Kieselgel 60 F254 plates, and spots were visualized under UV light. Products were purified by column chromatography on silica gel (100–200 mesh, Merck). ¹H and ¹³C NMR spectra were recorded on either Bruker AVANCE 600 (600 MHz and 151 MHz), Bruker AVANCE 400 (400 MHz and 101 MHz), Bruker AVANCE 500 (500 MHz and 126 MHz) or Bruker AVANCE 300 (300 MHz and 76 MHz) instruments using deuterated solvents as detailed and at ambient probe temperature (300 K). Chemical shifts are reported in parts per million (ppm) relative to the residual solvent peak (chloroform-d, 7.26 ppm for ¹H NMR, 77.2 ppm for ¹³C{¹H} NMR; DMSO-d ₆, 2.50 ppm for ¹H NMR, 39.6 ppm for ¹³C{¹H} NMR). The following notations are used: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m). Coupling constants are quoted in hertz and are denoted as J. Mass spectra were recorded on a Micromass^® Q-Tof (ESI) spectrometer. Single crystal XRD was recorded on a Bruker D8 VENTURE micro-focus diffractometer equipped with a PHOTON II detector.

6-Substituted Imidazo[2,1-b]thiazoles; General Procedure

Conditions A: To a clean, oven-dried, screw cap, 20-mL reaction tube, 2-aminothiazole analogues 1 (4 mmol, 1 equiv.), acetophenone analogues 2 (4.8 mmol, 1.2 equiv.), Cu(OTf)₂ (20 mol%) and KI (30 mol%) in DMF (5 mL) were added in an open-air environment. The solution was stirred at 90 °C in an oil bath for 12 h under open-air conditions. Product formation was confirmed by conducting TLC analysis and solvent was removed under vacuum. The concentrated reaction mixture was diluted with cold aq. Na₂S₂O₃ solution and extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine (1 × 15 mL) and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure. The resulting crude mixture was purified via column chromatography on silica gel (hexane/EtOAc) to yield the corresponding product 6-substituted imidazo[2,1-b]thiazole analogues 3 as solids/liquids. (CAUTION: maintain rotary vacuum water bath temperature at 40 °C.)

Conditions B: To a clean, oven-dried, screw cap, 20-mL reaction tube, 2-aminothiazole analogues 1 (4 mmol, 1 equiv.), acetophenone analogues 2 (4.8 mmol, 1.2 equiv.), FeCl₃ (20 mol%) and ZnI₂ (30 mol%) in DMF (5 mL) were added in an open-air environment. The solution was stirred at 90 °C in an oil bath for 12 h under open-air conditions. Product formation was confirmed by conducting TLC analysis and solvent was removed under vacuum. The concentrated reaction mixture was diluted with cold aq. Na₂S₂O₃ solution and extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine (1 × 15 mL) and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure. The resulting crude mixture was purified via column chromatography on silica gel (hexane/EtOAc) to yield the corresponding product 6-substituted imidazo[2,1-b]thiazole analogues 3 as solids/liquids. (CAUTION: maintain rotary vacuum water bath temperature at 40 °C.)

6-Phenylimidazo[2,1-b]thiazole (3aa)[8c]

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), acetophenone (2a; 561 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 75:25) provided compound 3aa (625 mg, 78%) as a white solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), acetophenone (2a; 561 μL, 3.2 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 75:25) provided compound 3aa (537 mg, 67%) as a white solid.

Mp 145–146 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.82 (d, J = 7.3 Hz, 2 H), 7.73 (s, 1 H), 7.43–7.37 (m, 3 H), 7.29 (d, J = 7.4 Hz, 1 H), 6.80 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 150.2, 147.9, 134.1, 128.7, 127.4, 125.2, 118.5, 112.5, 108.0.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₉N₂S: 201.0486; found: 201.0487.

6-(p-Tolyl)imidazo[2,1-b]thiazole (3ab)[8c]

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-methylacetophenone (2b; 644 mg, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 73:27) provided compound 3ab (702 mg, 82%) as a yellow solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-methylacetophenone (2b; 644 mg, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 73:27) provided compound 3ab (591 mg, 69%) as a yellow solid.

Mp 156–158 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.71 (d, J = 9.7 Hz, 3 H), 7.41 (d, J = 4.4 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 2 H), 6.80 (d, J = 4.4 Hz, 1 H), 2.37 (s, 3 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 150.2, 148.2, 137.3, 131.5, 129.5, 125.3, 118.6, 112.4, 107.7, 21.4.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₁₁N₂S: 215.0643; found: 215.0644.

6-(4-Methoxyphenyl)imidazo[2,1-b]thiazole (3ac)[8c]

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-methoxyacetophenone (2c; 721 mg, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3ac (774 mg, 84%) as a yellow solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-methoxyacetophenone (2c; 721 mg, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in dry DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3ac (599 mg, 65%) as a yellow solid.

Mp 158–160 °C.

¹H NMR (300 MHz, CDCl₃): δ = 7.75 (d, J = 8.9 Hz, 2 H), 7.65 (s, 1 H), 7.41 (d, J = 4.5 Hz, 1 H), 6.94 (d, J = 8.9 Hz, 2 H), 6.80 (d, J = 4.5 Hz, 1 H), 3.84 (s, 3 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 159.3, 150.2, 148.0, 127.1, 126.6, 118.6, 114.3, 112.2, 107.1, 55.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₁₁N₂OS: 231.0592; found: 231.0594.

6-(4-Fluorophenyl)imidazo[2,1-b]thiazole (3ad)[8c]

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-fluoroacetophenone (2d; 663 mg, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 76:24) provided compound 3ad (480 mg, 55%) as a white solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-fluoroacetophenone (2d; 663 mg, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 76:24) provided compound 3ad (445 mg, 51%) as a white solid.

Mp 126–128 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.80–7.76 (m, 2 H), 7.67 (s, 1 H), 7.41 (d, J = 4.5 Hz, 1 H), 7.08 (t, J = 8.7 Hz, 2 H), 6.81 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 162.4 (d, J _C-F = 245.9 Hz), 150.4, 147.2, 130.5 (d, J _C-F = 3.2 Hz), 127.0 (d, J _C-F = 7.7 Hz), 118.6, 115.7 (d, J _C-F = 21.6 Hz), 112.6, 107.7.

¹⁹F{¹H} NMR (565 MHz, CDCl₃): δ = –114.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₈FN₂S: 219.0392; found: 219.0393.

6-(4-Chlorophenyl)imidazo[2,1-b]thiazole (3ae)[8c]

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-chloroacetophenone (2e; 743 mg, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 74:26) provided compound 3ae (664 mg, 71%) as a white solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-chloroacetophenone (2e; 743 mg, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in dry DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 74:26) provided compound 3ae (608 mg, 65%) as a white solid.

Mp 167–169 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.74 (d, J = 8.5 Hz, 2 H), 7.71 (s, 1 H), 7.41 (d, J = 4.5 Hz, 1 H), 7.36 (d, J = 8.5 Hz, 2 H), 6.82 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 150.5, 146.9, 133.1, 132.8, 129.0, 126.6, 118.6, 112.9, 108.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₈ClN₂S: 235.0097; found: 235.0099.

6-(4-Bromophenyl)imidazo[2,1-b]thiazole (3af)[8c]

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-bromoacetophenone (2f; 956 mg, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 78:22) provided compound 3af (904 mg, 81%) as a white solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-bromoacetophenone (2f; 956 mg, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 78:22) provided compound 3af (815 mg, 73%) as a white solid.

Mp 179–180 °C.

¹H NMR (600 MHz, CDCl₃): δ = 7.73 (s, 1 H), 7.69 (d, J = 8.5 Hz, 2 H), 7.51 (d, J = 8.5 Hz, 2 H), 7.43 (d, J = 4.5 Hz, 1 H), 6.84 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 150.5, 147.0, 133.2, 131.9, 126.9, 121.3, 118.6, 112.9, 108.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₈BrN₂S: 278.9592; found: 278.9593.

6-(4-Iodophenyl)imidazo[2,1-b]thiazole (3ag)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-iodoacetophenone (2g; 1.2 g, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 78:22) provided compound 3ag (1.1 g, 86%) as a yellow solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-iodoacetophenone (2g; 1.2 g, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 78:22) provided compound 3ag (1.04 g, 80%) as a yellow solid.

Mp 199–201 °C.

¹H NMR (300 MHz, CDCl₃): δ = 7.73–7.69 (m, 3 H), 7.58–7.53 (m, 2 H), 7.41 (d, J = 4.5 Hz, 1 H), 6.83 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 150.5, 146.9, 137.9, 133.8, 127.1, 118.6, 113.0, 108.3, 92.7.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₈IN₂S: 326.9453; found: 326.9455.

6-(4-Nitrophenyl)imidazo[2,1-b]thiazole (3ah)[8c]

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-nitroacetophenone (2h; 792 mg, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 120 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 60:40) provided compound 3ah (559 mg, 57%) as a yellow solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-nitroacetophenone (2h; 792 mg, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in dry DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 60:40) provided compound 3ah (471 mg, 48%) as a yellow solid.

Mp 280–282 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.49 (s, 1 H), 8.25 (d, J = 8.9 Hz, 2 H), 8.08 (d, J = 8.9 Hz, 2 H), 7.99 (d, J = 4.5 Hz, 1 H), 7.33 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (151 MHz, DMSO-d ₆): δ = 150.3, 145.9, 144.1, 140.8, 125.4, 124.2, 120.1, 114.4, 112.3.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₈N₃O₂S: 246.0337; found: 246.0339.

6-(4-(Trifluoromethyl)phenyl)imidazo[2,1-b]thiazole (3ai)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-(trifluoromethyl)acetophenone (2i; 903 mg, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 62:38) provided compound 3ai (644 mg, 60%) as a yellow solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-(trifluoromethyl)acetophenone (2i; 903 mg, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 62:38) provided compound 3ai (558 mg, 52%) as a yellow solid.

Mp 165–175 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.90 (d, J = 8.1 Hz, 2 H), 7.77 (s, 1 H), 7.62 (d, J = 8.2 Hz, 2 H), 7.41 (d, J = 4.5 Hz, 1 H), 6.83 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 150.8, 146.5, 137.7, 129.2 (q, J _C-F = 32.3 Hz), 125.8 (q, J _C-F = 3.4 Hz), 125.3, 125.3 (q, J _C-F = 271.8 Hz), 118.6, 113.3, 109.1.

¹⁹F{¹H} NMR (565 MHz, CDCl₃): δ = –62.4.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₈F₃N₂S: 269.0360; found: 269.0361.

6-(4-Butylphenyl)imidazo[2,1-b]thiazole (3aj)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-butylacetophenone (2j; 846 mg, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 78:22) provided compound 3aj (720 mg, 70%) as a yellow solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-butylacetophenone (2j; 846 mg, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 78:22) provided compound 3aj (648 mg, 63%) as a yellow solid.

Mp 140–142 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.73 (d, J = 8.1 Hz, 2 H), 7.68 (s, 1 H), 7.38 (d, J = 4.5 Hz, 1 H), 7.21 (d, J = 8.1 Hz, 2 H), 6.77 (d, J = 4.5 Hz, 1 H), 2.63 (t, J = 8 Hz, 2 H), 1.62 (p, J = 7.5 Hz, 2 H), 1.42–1.33 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 150.1, 148.2, 142.3, 131.6, 128.8, 125.2, 118.6, 112.3, 107.6, 35.5, 33.7, 22.5, 14.1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₅H₁₇N₂S: 257.1112; found: 275.1114.

6-(4-Phenoxyphenyl)imidazo[2,1-b]thiazole (3ak)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-phenoxyacetophenone (2k; 1.1 g, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 69:31) provided compound 3ak (856 mg, 73%) as a white solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 4-phenoxyacetophenone (2k; 1.1 g, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 69:31) provided compound 3ak (762 mg, 65%) as a white solid.

Mp 192–194 °C.

¹H NMR (300 MHz, CDCl₃): δ = 7.81–7.76 (m, 2 H), 7.67 (s, 1 H), 7.41 (d, J = 4.5 Hz, 1 H), 7.38–7.31 (m, 2 H), 7.11 (t, J = 7.4 Hz, 1 H), 7.05 (d, J = 8.8 Hz, 4 H), 6.80 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 157.4, 156.7, 150.3, 147.6, 129.9, 129.6, 126.8, 123.4, 119.2, 119.0, 118.6, 112.4, 107.6.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₇H₁₃N₂OS: 293.0749; found: 293.0752.

6-(3-Fluorophenyl)imidazo[2,1-b]thiazole (3al)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 3-fluoroacetophenone (2l; 884 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3al (533 mg, 61%) as a red liquid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 3-fluoroacetophenone (2l; 884 μL, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3al (463 mg, 53%) as a red liquid.

¹H NMR (300 MHz, CDCl₃): δ = 7.72 (s, 1 H), 7.57 (dt, J = 7.7, 1.2 Hz, 1 H), 7.56–7.50 (m, 1 H), 7.40 (d, J = 4.5 Hz, 1 H), 7.33 (td, J = 8.0, 6.0 Hz, 1 H), 6.95 (tdd, J = 8.4, 2.6, 0.9 Hz, 1 H), 6.81 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 163.4 (d, J _C-F = 244.9 Hz), 150.4, 146.8, 136.5 (d, J _C-F = 8.4 Hz), 130.3 (d, J _C-F = 8.1 Hz), 120.8 (d, J _C-F = 2.9 Hz), 118.6, 114.2 (d, J _C-F = 20.9 Hz), 112.9, 112.2 (d, J _C-F = 22.9 Hz), 108.6.

¹⁹F{¹H} NMR (565 MHz, CDCl₃): δ = –113.3.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₈FN₂S: 219.0392; found: 219.0393.

6-(3-Methoxyphenyl)imidazo[2,1-b]thiazole (3am)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 3-methoxyacetophenone (2m; 659 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3am (626 mg, 68%) as a red liquid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 3-methoxyacetophenone (2m; 659 μL, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3am (543 mg, 59%) as a red liquid.

¹H NMR (300 MHz, CDCl₃): δ = 7.75 (s, 1 H), 7.44 (d, J = 4.5 Hz, 1 H), 7.43–7.41 (m, 1 H), 7.38 (dt, J = 7.6, 1.3 Hz, 1 H), 7.30 (t, J = 7.8 Hz, 1 H), 6.86 (dd, J = 2.6, 1.2 Hz, 1 H), 6.84 (d, J = 4.5 Hz, 1 H), 3.87 (s, 3 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 160.2, 150.2, 147.7, 135.4, 129.9, 118.7, 117.8, 113.8, 112.9, 110.5, 108.4, 55.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₁₁N₂OS: 231.0592; found: 231.0595.

6-(3-Iodophenyl)imidazo[2,1-b]thiazole (3an)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 3-iodoacetophenone (2n; 1.2 g, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3an (900 mg, 69%) as a red liquid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 3-iodoacetophenone (2n; 1.2 g, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3an (783 mg, 60%) as a red liquid.

¹H NMR (500 MHz, CDCl₃): δ = 8.18 (s, 1 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.68 (s, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.38 (d, J = 4.5 Hz, 1 H), 7.09 (t, J = 7.8 Hz, 1 H), 6.80 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 150.4, 146.2, 136.3, 134.1, 130.4, 124.4, 118.6, 112.9, 108.5, 94.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₈IN₂S: 326.9453; found: 326.9456.

6-(m-Tolyl)imidazo[2,1-b]thiazole (3ao)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 3-methylacetophenone (2o; 647 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 74:26) provided compound 3ao (626 mg, 73%) as a white solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 3-methylacetophenone (2o; 647 μL, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in dry DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 74:26) provided compound 3ao (533 mg, 62%) as a white solid.

Mp 157–158 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.71 (s, 1 H), 7.69 (s, 1 H), 7.59 (d, J = 7.7 Hz, 1 H), 7.40 (d, J = 4.5 Hz, 1 H), 7.28 (t, J = 8.2 Hz, 1 H), 7.10 (d, J = 7.5 Hz, 1 H), 6.80 (d, J = 4.5 Hz, 1 H), 2.40 (s, 3 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 150.2, 148.1, 138.5, 134.1, 128.7, 128.3, 126.1, 122.4, 118.6, 112.5, 108.0, 21.6.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₁₁N₂S: 215.0643; found: 215.0645.

6-(2-Methoxyphenyl)imidazo[2,1-b]thiazole (3ap)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-methoxyacetophenone (2p; 662 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3ap (580 mg, 63%) as a yellow liquid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-methoxyacetophenone (2p; 662 μL, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3ap (525 mg, 57%) as a yellow liquid.

¹H NMR (400 MHz, CDCl₃): δ = 8.25 (d, J = 7.7 Hz, 1 H), 8.08 (s, 1 H), 7.44 (d, J = 4.5 Hz, 1 H), 7.28 (t, J = 6.9 Hz, 1 H), 7.09 (d, J = 7.5 Hz, 1 H), 6.99 (d, J = 8.2 Hz, 1 H), 6.80 (d, J = 4.5 Hz, 1 H), 3.98 (s, 3 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 156.1, 149.0, 143.0, 132.0, 129.9, 128.0, 121.0, 118.6, 112.5, 112.3, 110.8, 55.4.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₁₁N₂OS: 231.0592; found: 231.0594.

6-(2-Chlorophenyl)imidazo[2,1-b]thiazole (3aq)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-chloroacetophenone (2q; 662 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 75:25) provided compound 3aq (666 mg, 71%) as a yellow solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-chloroacetophenone (2q; 662 μL, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 75:25) provided compound 3aq (563 mg, 60%) as a yellow solid.

Mp 165–167 °C.

¹H NMR (500 MHz, CDCl₃): δ = 8.22 (s, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.49 (d, J = 4.4 Hz, 1 H), 7.40 (d, J = 7.5 Hz, 1 H), 7.16 (t, J = 7.7 Hz, 1 H), 6.87 (d, J = 4.3 Hz, 1 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 149.4, 145.2, 134.6, 133.8, 131.2, 128.6, 127.6, 120.9, 118.7, 113.0, 112.3.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₈ClN₂S: 235.0097; found: 235.0098.

6-(o-Tolyl)imidazo[2,1-b]thiazole (3ar)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-methylacetophenone (2r; 629 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 76:24) provided compound 3ar (643 mg, 75%) as a yellow liquid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-methylacetophenone (2r; 629 μL, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 76:24) provided compound 3ar (549 mg, 64%) as a yellow liquid.

¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 7.4 Hz, 1 H), 7.60 (s, 1 H), 7.47 (d, J = 4.5 Hz, 1 H), 7.29–7.25 (m, 3 H), 6.85 (d, J = 4.5 Hz, 1 H), 2.55 (s, 3 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 149.4, 147.4, 135.4, 133.6, 131.0, 129.2, 127.5, 126.1, 118.5, 112.4, 110.8, 21.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₁₁N₂S: 215.0643; found: 215.0644.

6-(2-Bromophenyl)imidazo[2,1-b]thiazole (3as)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-bromoacetophenone (2s; 648 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 78:22) provided compound 3as (870 mg, 78%) as a white solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-bromoacetophenone (2s; 648 μL, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 78:22) provided compound 3as (770 mg, 69%) as a white solid.

Mp 176–178 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.19 (s, 1 H), 8.07 (d, J = 7.9 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 1 H), 7.44 (d, J = 4.5 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.13 (td, J = 7.7, 1.4 Hz, 1 H), 6.83 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 149.4, 145.1, 134.6, 133.8, 131.2, 128.5, 127.6, 120.9, 118.7, 112.9, 112.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₈BrN₂S: 278.9592; found: 278.9594.

6-(3-Chloro-4-fluorophenyl)imidazo[2,1-b]thiazole (3at)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 3-chloro-4-fluoroacetophenone (2t; 828 mg, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 73:27) provided compound 3at (688 mg, 68%) as a white solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 3-chloro-4-fluoroacetophenone (2t; 828 mg, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 73:27) provided compound 3at (637 mg, 63%) as a white solid.

Mp 142–144 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.87 (dd, J = 7.1, 2.1 Hz, 1 H), 7.69 (s, 1 H), 7.66 (ddd, J = 8.5, 4.6, 2.2 Hz, 1 H), 7.43 (d, J = 4.5 Hz, 1 H), 7.15 (t, J = 8.7 Hz, 1 H), 6.85 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 157.6 (d, J _C-F = 249.2 Hz), 150.6, 145.9, 131.6 (d, J _C-F = 3.4 Hz), 127.5, 124.9 (d, J _C-F = 7.4 Hz), 121.4 (d, J _C-F = 18.3 Hz), 118.6, 116.9 (d, J _C-F = 21.4 Hz), 113.0, 108.2.

¹⁹F{¹H} NMR (565 MHz, CDCl₃): δ = –117.6.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₇ClFN₂S: 253.0003; found: 253.0006.

6-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)imidazo[2,1-b]thiazole (3au)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)ethan-1-one (2u; 855 mg, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 69:31) provided compound 3au (744 mg, 72%) as a yellow solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)ethan-1-one (2u; 855 mg, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 69:31) provided compound 3au (703 mg, 68%) as a yellow solid.

Mp 172–173 °C.

¹H NMR (300 MHz, DMSO-d ₆): δ = 8.06 (s, 1 H), 7.85 (d, J = 4.4 Hz, 1 H), 7.27 (s, 1 H), 7.24 (d, J = 2.1 Hz, 1 H), 7.19 (d, J = 4.4 Hz, 1 H), 6.82 (d, J = 7.9 Hz, 1 H), 4.22 (s, 4 H).

¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 148.9, 146.0, 143.5, 142.6, 127.8, 120.0, 117.9, 117.2, 113.3, 112.7, 108.6, 64.1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₁N₂O₂S: 259.0541; found: 259.0543.

6-(Naphthalen-1-yl)imidazo[2,1-b]thiazole (3av)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 1-acetylnaphthalene (2v; 729 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 69:31) provided compound 3av (611 mg, 61%) as a yellow solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 1-acetylnaphthalene (2v; 729 μL, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 69:31) provided compound 3av (551 mg, 55%) as a yellow solid.

Mp 172–173 °C.

¹H NMR (300 MHz, CDCl₃): δ = 8.60 (d, J = 9.8 Hz, 1 H), 7.91–7.84 (m, 2 H), 7.75 (dd, J = 7.1, 1.2 Hz, 1 H), 7.70 (s, 1 H), 7.52 (ddd, J = 7.0, 5.7, 2.7 Hz, 3 H), 7.45 (d, J = 4.5 Hz, 1 H), 6.83 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 149.8, 147.2, 134.1, 132.0, 131.4, 128.4, 128.3, 127.2, 126.4, 126.1, 125.8, 125.5, 118.6, 112.5, 111.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₅H₁₁N₂S: 251.0643; found: 251.0644.

6-(Naphthalen-2-yl)imidazo[2,1-b]thiazole (3aw)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-acetylnaphthalene (2w; 818 mg, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3aw (671 mg, 67%) as a white solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-acetylnaphthalene (2w; 818 mg, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3aw (601 mg, 60%) as a white solid.

Mp 174–176 °C.

¹H NMR (300 MHz, CDCl₃): δ = 8.37 (s, 1 H), 7.92–7.81 (m, 5 H), 7.48–7.44 (m, 3 H), 6.83 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 150.6, 148.1, 133.9, 133.0, 131.6, 128.4, 128.3, 127.8, 126.4, 125.8, 123.8, 123.7, 118.6, 112.7, 108.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₅H₁₁N₂S: 251.0643; found: 251.0646.

6-(Furan-2-yl)imidazo[2,1-b]thiazole (3ax)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-acetylfuran (2x; 482 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 68:32) provided compound 3ax (448 mg, 59%) as a yellow liquid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-acetylfuran (2x; 482 μL, 4.8 mmol), FeCl_3­ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 68:32) provided compound 3ax (418 mg, 55%) as a yellow liquid.

¹H NMR (300 MHz, CDCl₃): δ = 7.65 (s, 1 H), 7.41–7.40 (m, 2 H), 6.81 (d, J = 4.5 Hz, 1 H), 6.71 (d, J = 3.8 Hz, 1 H), 6.46 (dd, J = 3.3, 1.8 Hz, 1 H).

¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 150.5, 149.7, 141.5, 140.1, 118.6, 112.8, 111.5, 107.9, 105.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₉H₇N₂OS: 191.0279; found: 191.0281.

6-(Thiophen-2-yl)imidazo[2,1-b]thiazole (3ay)[8c]

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-acetylthiophene (2y; 519 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3ay (578 mg, 70%) as a yellow solid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), 2-acetylthiophene (2y; 519 μL, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 70:30) provided compound 3ay (512 mg, 62%) as a yellow solid.

Mp 130–131 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.06 (s, 1 H), 7.87 (d, J = 4.4 Hz, 1 H), 7.38 (d, J = 5.0 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 7.22 (d, J = 4.4 Hz, 1 H), 7.03 (t, J = 4 Hz, 1 H).

¹³C{¹H} NMR (75 MHz, DMSO-d ₆): δ = 149.0, 141.4, 137.9, 127.8, 124.3, 122.3, 120.0, 113.3, 108.6.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₉H₇N₂S₂: 207.0051; found: 207.0050.

6-Isopropylimidazo[2,1-b]thiazole (3az)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), methyl isopropyl ketone (2z; 515 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 66:34) provided compound 3az (353 mg, 53%) as a reddish liquid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), methyl isopropyl ketone (2z; 515 μL, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 66:34) provided compound 3az (313 mg, 47%) as a reddish liquid.

¹H NMR (300 MHz, CDCl₃): δ = 7.32 (d, J = 4.5 Hz, 1 H), 7.17 (s, 1 H), 6.72 (d, J = 4.5 Hz, 1 H), 3.04–2.94 (m, 1 H), 1.30 (d, J = 6.9 Hz, 6 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 156.1, 149.2, 118.5, 111.4, 107.2, 28.9, 22.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₈H₁₁N₂S: 167.0643; found: 167.0644.

6-Isobutylimidazo[2,1-b]thiazole (3aab)

Using the general procedure (Conditions A), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), methyl isobutyl ketone (2ab; 600 μL, 4.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 66:34) provided compound 3aab (426 mg, 59%) as a reddish liquid.

Using the general procedure (Conditions B), a mixture of 2-aminothiazole (1a; 400 mg, 4 mmol), methyl isobutyl ketone (2ab; 600 μL, 4.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 66:34) provided compound 3aab (361 mg, 50%) as a reddish liquid.

¹H NMR (500 MHz, CDCl₃): δ = 7.30 (d, J = 4.5 Hz, 1 H), 7.15 (s, 1 H), 6.69 (d, J = 4.5 Hz, 1 H), 2.49 (d, J = 7.4 Hz, 2 H), 2.00 (dt, J = 13.5, 6.8 Hz, 1 H), 0.92 (d, J = 6.7 Hz, 6 H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 148.9, 148.5, 118.3, 111.2, 109.4, 38.5, 28.6, 22.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₉H₁₃N₂S: 181.0799; found: 181.0798.

3-Methyl-6-(p-tolyl)imidazo[2,1-b]thiazole (3bb)

Using the general procedure (Conditions A), a mixture of 2-amino-4-methylthiazole (1b; 400 mg, 3.5 mmol), 4-methylacetophenone (2b; 564 μL, 4.2 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 76:24) provided compound 3bb (557 mg, 61%) as a reddish liquid.

Using the general procedure (Conditions B), a mixture of 2-amino-4-methylthiazole (1b; 400 mg, 3.5 mmol), 4-methylacetophenone (2b; 564 μL, 4.2 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 76:24) provided compound 3bb (484 mg, 53%) as a reddish liquid.

¹H NMR (500 MHz, CDCl₃): δ = 7.73 (d, J = 8.0 Hz, 2 H), 7.59 (s, 1 H), 7.21 (d, J = 7.9 Hz, 2 H), 6.40 (s, 1 H), 2.42 (s, 3 H), 2.37 (s, 3 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 149.8, 148.0, 137.2, 131.6, 129.5, 127.8, 125.2, 106.7, 105.7, 21.4, 13.6.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₃N₂S: 229.0799; found: 229.0801.

3,6-Diphenylimidazo[2,1-b]thiazole (3ca)

Using the general procedure (Conditions A), a mixture of 2-amino-4-phenylthiazole (1c; 400 mg, 2.3 mmol), acetophenone (2a; 327 µl, 2.8 mmol), Cu(OTf)₂ (20 mol%), KI (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 74:26) provided compound 3ca (414 mg, 65%) as a yellow solid.

Using the general procedure (Conditions B), a mixture of 2-amino-4-phenylthiazole (1c; 400 mg, 2.3 mmol), acetophenone (2a; 327 µl, 2.8 mmol), FeCl₃ (20 mol%), ZnI₂ (30 mol%) in DMF (5 mL) was stirred for 12 h at 90 °C in an oil bath. Purification by column chromatography (hexane/EtOAc, 74:26) provided compound 3ca (369 mg, 58%) as a yellow solid.

Mp 189–190 °C.

¹H NMR (300 MHz, CDCl₃): δ = 7.85–7.77 (m, 2 H), 7.69 (s, 1 H), 7.43 (d, J = 4.5 Hz, 1 H), 7.41–7.32 (m, 2 H), 7.13 (t, J = 7.4 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 4 H), 6.82 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 157.5, 156.9, 150.4, 147.7, 130.0, 129.7, 126.9, 123.5, 119.4, 119.1, 118.7, 112.6, 107.7.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₇H₁₃N₂S: 277.0799; found: 277.0798.

4-(Imidazo[2,1-b]thiazol-6-yl)phenol (3aac)

6-(4-Methoxyphenyl)imidazo[2,1-b]thiazole (3ac; 78 mg, 0.3 mmol) was dissolved in dry DCM (10 mL), and the resulting solution was cooled to 0 °C. BBr₃ (1 M in DCM, 0.6 mL, 0.6 mmol) was then added dropwise to the solution, and the reaction was stirred at room temperature for 12 h under an argon atmosphere. The formation of product was confirmed by TLC analysis. The reaction mixture was quenched with NaHCO₃ solution and extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine (1 × 15 mL) and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure. The resulting crude mixture was purified via column chromatography on silica gel (hexane/EtOAc, 65:35) to yield the corresponding product 3aac (47 mg, 72%) as a liquid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.43 (s, 1 H), 8.01 (s, 1 H), 7.88 (d, J = 4.4 Hz, 1 H), 7.62 (d, J = 8.5 Hz, 2 H), 7.20 (d, J = 4.4 Hz, 1 H), 6.77 (d, J = 8.5 Hz, 2 H).

¹³C{¹H} NMR (151 MHz, DMSO-d ₆): δ = 156.7, 148.8, 146.8, 126.1, 120.0, 115.4, 112.4, 107.7.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₉N₂OS: 217.0436; found: 217.0435.

6-(4-(Phenylethynyl)phenyl)imidazo[2,1-b]thiazole (3aad)

6-(4-Iodophenyl)imidazo[2,1-b]thiazole (3ag; 100 mg, 0.3 mmol, 1 equiv.) was dissolved in dry THF (10 mL). Subsequently, Et₃N (84 μL, 0.6 mmol, 2 equiv.), Pd(PPh₃)₂Cl₂ (6 mg, 2.5 mol%) and CuI (1 mg, 0.5 mol%) were added. The reaction mixture was stirred at room temperature for 10 min and then phenylacetylene (40 μL, 0.36 mmol, 1.2 equiv.) was added. Next, the reaction mixture was stirred for 12 h at room temperature under an argon atmosphere. Product formation was confirmed by TLC analysis, and the solvent was removed under vacuum. The concentrated reaction mixture was diluted with cold aq. NH₄Cl solution and extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine (1 × 10 mL) and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure. The resulting crude mixture was purified via column chromatography on silica gel (hexane/EtOAc, 72:28) to yield the corresponding product 3aad (61 mg, 68%) as a white solid.

Mp 194–196 °C.

¹H NMR (300 MHz, CDCl₃): δ = 7.82 (d, J = 8.5 Hz, 2 H), 7.77 (s, 1 H), 7.59–7.52 (m, 4 H), 7.43 (d, J = 4.5 Hz, 1 H), 7.38–7.33 (m, 3 H), 6.83 (d, J = 4.5 Hz, 1 H).

¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 150.6, 147.4, 134.1, 132.1, 131.7, 128.5, 128.3, 125.2, 123.5, 122.2, 118.6, 112.9, 108.6, 90.0, 89.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₉H₁₃N₂S: 301.0799; found: 301.0801.

6-([1,1′-Biphenyl]-4-yl)imidazo[2,1-b]thiazole (3aae)

To a solution of 6-(4-bromophenyl)imidazo[2,1-b]thiazole (3af; 33 mg, 0.1 mmol, 1 equiv.) in THF (10 mL), a solution of phenylboronic acid (132 mg, 1.1 mmol, 9 equiv.) in EtOH (3 mL) and a solution of Na₂CO₃ (165 mg, 1.6 mmol, 13 equiv.) (5 mL) were added under an argon atmosphere. Then, Pd(PPh₃)₄ (3 mg, 2 mol%) was added. The mixture was refluxed for 12 h. Product formation was confirmed by TLC. After completion of the reaction, solvent was removed. Then, EtOAc and H₂O were added to the reaction mixture. The solution was extracted with EtOAc (3 × 15 mL). The combined organic layer was dried over Na₂SO₄. The solvent was removed under reduced pressure. The resulting crude mixture was purified via column chromatography on silica gel (hexane/EtOAc, 76:24) to yield the corresponding product 3aae (22 mg, 64%) as a yellow solid.

Mp 191–193 °C.

¹H NMR (500 MHz, CDCl₃): δ = 8.12 (d, J = 7.8 Hz, 1 H), 7.44 (t, J = 8.1 Hz, 1 H), 7.36 (dd, J = 14.4, 8.4 Hz, 6 H), 7.27 (s, 1 H), 7.15 (d, J = 4.5 Hz, 1 H), 6.71 (d, J = 4.5 Hz, 1 H), 6.42 (s, 1 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 148.9, 146.3, 142.7, 140.0, 132.6, 130.6, 129.5, 129.0, 128.5, 127.8, 127.2 (2 C), 118.6, 112.2, 111.4.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₇H₁₃N₂S: 277.0799; found: 277.0801.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Dr. Urmila Saha for helping with the single crystal X-ray analysis. We also thank TRC IACS for the instrument facility.

• References

• 1a Budriesi R, Ioan P, Leoni A, Pedemonte N, Locatelli A, Micucci M, Chiarini A, Galietta LJ. V. J. Med. Chem. 2011; 54: 3885
  CrossrefPubMedSearch in Google Scholar
• 1b Güzeldemirci NU, Küçükbasmacı Ö. Eur. J. Med. Chem. 2010; 45: 63
  CrossrefPubMedSearch in Google Scholar
• 1c Metaye T, Millet C, Kraimps JL, Saunier B, Barbier J, Begon F. Biochem. Pharmacol. 1992; 43: 1507
  CrossrefPubMedSearch in Google Scholar
• 2a Andreani A, Granaiola M, Leoni A, Locatelli A, Morigi R, Rambaldi M, Lenaz G, Fato R, Bergamini C, Farruggia G. J. Med. Chem. 2005; 48: 3085
  CrossrefPubMedSearch in Google Scholar
• 2b Gürsoy E, Güzeldemirci NU. Eur. J. Med. Chem. 2007; 42: 320
  CrossrefPubMedSearch in Google Scholar
• 2c Burnelli S, Granaiola M, Leoni A, Locatelli A, Morigi R, Rambaldi M, Varoli L, Calonghi N, Cappadone C, Farruggia G, Zini M, Stefanelli C, Masotti L, Radin NS, Shoemaker RH, Andreani A. J. Med. Chem. 2008; 51: 809
  CrossrefPubMedSearch in Google Scholar
• 2d Park J.-H, El-Gamal MI, Lee YS, Oh C.-H. Eur. J. Med. Chem. 2011; 46: 5769
  CrossrefPubMedSearch in Google Scholar
• 2e Sbenati RM, Semreen MH, Semreen AM, Shehata MK, Alsaghir FM, El-Gamal MI. Bioorg. Med. Chem. 2021; 29: 115897
  CrossrefPubMedSearch in Google Scholar
• 3 Raeymaekers AH. M, Allewijn FT. N, Vandenberk J, Demoen PJ. A, Van Offenwert TT. T, Janssen PA. J. J. Med. Chem. 1966; 9: 545
  CrossrefPubMedSearch in Google Scholar
• 4 Scribner A, Meitz S, Fisher M, Wyvratt M, Leavitt P, Liberator P, Gurnett A, Brown C, Mathew J, Thompson D, Schmatz D, Biftu T. Bioorg. Med. Chem. Lett. 2008; 18: 5263
  CrossrefPubMedSearch in Google Scholar
• 5 Yousefi BH, Manook A, Drzezga A, v. Reutern B, Schwaiger M, Wester H.-J, Henriksen G. J. Med. Chem. 2011; 54: 949
  CrossrefPubMedSearch in Google Scholar
• 6 Lipson VV, Yaremenko FG, Vakula VM, Kovalenko SV, Kyrychenko AV, Desenko SM, Musatov VI, Borysko PO, Zozulya SO. Funct. Matter. 2023; 30: 486
  Search in Google Scholar
• 7a Herath A, Dahl R, Cosford ND. P. Org. Lett. 2010; 12: 412
  CrossrefPubMedSearch in Google Scholar
• 7b Denora N, Laquintana V, Pisu MG, Dore R, Murru L, Latrofa L, Trapani G, Sanna E. J. Med. Chem. 2008; 51: 6876
  CrossrefPubMedSearch in Google Scholar
• 7c Paudler WW, Kuder JE. J. Org. Chem. 1966; 31: 809
  CrossrefSearch in Google Scholar
• 7d Brouwer C, Sinclair K, Cuevas J, Pike VW, Cai L. Synthesis 2006; 133
• 7e Chunavala KC, Joshi G, Suresh E, Adimurthy S. Synthesis 2011; 635
• 7f Mohamadi A, Sheikhi E, Ansari S, Bijanzadeh HR, Adib M. Synlett 2010; 1606
• 8a Xie Y.-Y, Zheng Q.-G, Chen Q.-G. Synthesis 2002; 1505
• 8b Yadav JS, Subba Reddy BV, Gopal Rao Y, Srinivas M, Narsaiah AV. Tetrahedron 2007; 48: 7717
  CrossrefSearch in Google Scholar
• 8c Sumran G, Aggarwal R. Synth. Commun. 2006; 36: 875
  CrossrefSearch in Google Scholar
• 8d Mukku N, Maiti B. RSC Adv. 2020; 10: 770
  CrossrefPubMedSearch in Google Scholar
• 8e Bangade VM, Reddy BC, Thakur PB, Babu BM, Meshram HM. Tetrahedron Lett. 2013; 54: 4767
  CrossrefSearch in Google Scholar
• 9 Omar MA, Frey W, Conrad J, Beifuss U. J. Org. Chem. 2014; 79: 10367
  CrossrefPubMedSearch in Google Scholar
• 10 Rassokhina IV, Tikhonova TA, Kobylskoy SG, Babkin IY, Shirinian VZ, Gevorgyan V, Zavarzin IV, Volkova YA. J. Org. Chem. 2017; 82: 9682
  CrossrefPubMedSearch in Google Scholar
• 11 Chen Z, Jin W, Xia Y, Zhang Y, Xie M, Ma S, Liu C. Org. Lett. 2020; 22: 8261
  CrossrefPubMedSearch in Google Scholar
• 12 Chen Z, Xue F, Zhang Y, Jin W, Wang B, Xia Y, Xie M, Abdukader A, Liu C. Org. Lett. 2022; 24: 3149
  CrossrefPubMedSearch in Google Scholar
• 13 Mishra S, Monir K, Mitra S, Hajra A. Org. Lett. 2014; 16: 6084
  CrossrefPubMedSearch in Google Scholar
• 14a Louillat M.-L, Patureau FW. Chem. Soc. Rev. 2014; 43: 901
  CrossrefPubMedSearch in Google Scholar
• 14b Shi ZZ, Zhang C, Tang CH, Jiao N. Chem. Soc. Rev. 2012; 41: 3381
  CrossrefPubMedSearch in Google Scholar
• 14c Dick AR, Sanford MS. Tetrahedron 2006; 62: 2439
  CrossrefSearch in Google Scholar
• 14d Punniyamurthy T, Velusamy S, Iqbal J. Chem. Rev. 2005; 105: 2329
  CrossrefPubMedSearch in Google Scholar
• 14e Yamaguchi J, Yamaguchi AD, Itami K. Angew. Chem. Int. Ed. 2012; 51: 8960
  CrossrefPubMedSearch in Google Scholar
• 14f Campbell AN, Stahl SS. Acc. Chem. Res. 2012; 45: 851
  CrossrefPubMedSearch in Google Scholar
• 15a Midya GC, Paladhi S, Dhara K, Dash J. Chem. Commun. 2011; 47: 6698
  CrossrefPubMedSearch in Google Scholar
• 15b Maiti S, Burgula L, Chakraborti G, Dash J. Eur. J. Org. Chem. 2017; 332
  Crossref
• 15c Maiti S, Mandal T, Dash B, Dash J. J. Org. Chem. 2021; 86: 1396
  CrossrefPubMedSearch in Google Scholar
• 16a Dhara K, Mandal T, Das J, Dash J. Angew. Chem. Int. Ed. 2015; 54: 15831 ; Angew. Chem. 2015, 127, 16057
  CrossrefPubMedSearch in Google Scholar
• 16b Mandal T, Chakraborti G, Karmakar S, Dash J. Org. Lett. 2018; 20: 4759
  CrossrefPubMedSearch in Google Scholar
• 16c Mandal T, Karmakar S, Kapat A, Dash J. ACS Omega 2021; 6: 27062
  CrossrefPubMedSearch in Google Scholar
• 16d Ghosh T, Mandal I, Basak SJ, Dash J. J. Org. Chem. 2021; 86: 14695
  CrossrefPubMedSearch in Google Scholar
• 16e Basak SJ, Dash J. J. Org. Chem. 2024; 89: 233
  CrossrefPubMedSearch in Google Scholar
• 16f Basak SJ, Dash J. J. Org. Chem. 2024; 89: 3612
  CrossrefPubMedSearch in Google Scholar
• 17 CCDC 2359527 (3af) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures

Corresponding Author

Publication History

Received: 31 May 2024

Accepted after revision: 18 July 2024

Accepted Manuscript online:
18 July 2024

Article published online:
13 August 2024

© 2024. Thieme. All rights reserved

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• References

• 1a Budriesi R, Ioan P, Leoni A, Pedemonte N, Locatelli A, Micucci M, Chiarini A, Galietta LJ. V. J. Med. Chem. 2011; 54: 3885
  CrossrefPubMedSearch in Google Scholar
• 1b Güzeldemirci NU, Küçükbasmacı Ö. Eur. J. Med. Chem. 2010; 45: 63
  CrossrefPubMedSearch in Google Scholar
• 1c Metaye T, Millet C, Kraimps JL, Saunier B, Barbier J, Begon F. Biochem. Pharmacol. 1992; 43: 1507
  CrossrefPubMedSearch in Google Scholar
• 2a Andreani A, Granaiola M, Leoni A, Locatelli A, Morigi R, Rambaldi M, Lenaz G, Fato R, Bergamini C, Farruggia G. J. Med. Chem. 2005; 48: 3085
  CrossrefPubMedSearch in Google Scholar
• 2b Gürsoy E, Güzeldemirci NU. Eur. J. Med. Chem. 2007; 42: 320
  CrossrefPubMedSearch in Google Scholar
• 2c Burnelli S, Granaiola M, Leoni A, Locatelli A, Morigi R, Rambaldi M, Varoli L, Calonghi N, Cappadone C, Farruggia G, Zini M, Stefanelli C, Masotti L, Radin NS, Shoemaker RH, Andreani A. J. Med. Chem. 2008; 51: 809
  CrossrefPubMedSearch in Google Scholar
• 2d Park J.-H, El-Gamal MI, Lee YS, Oh C.-H. Eur. J. Med. Chem. 2011; 46: 5769
  CrossrefPubMedSearch in Google Scholar
• 2e Sbenati RM, Semreen MH, Semreen AM, Shehata MK, Alsaghir FM, El-Gamal MI. Bioorg. Med. Chem. 2021; 29: 115897
  CrossrefPubMedSearch in Google Scholar
• 3 Raeymaekers AH. M, Allewijn FT. N, Vandenberk J, Demoen PJ. A, Van Offenwert TT. T, Janssen PA. J. J. Med. Chem. 1966; 9: 545
  CrossrefPubMedSearch in Google Scholar
• 4 Scribner A, Meitz S, Fisher M, Wyvratt M, Leavitt P, Liberator P, Gurnett A, Brown C, Mathew J, Thompson D, Schmatz D, Biftu T. Bioorg. Med. Chem. Lett. 2008; 18: 5263
  CrossrefPubMedSearch in Google Scholar
• 5 Yousefi BH, Manook A, Drzezga A, v. Reutern B, Schwaiger M, Wester H.-J, Henriksen G. J. Med. Chem. 2011; 54: 949
  CrossrefPubMedSearch in Google Scholar
• 6 Lipson VV, Yaremenko FG, Vakula VM, Kovalenko SV, Kyrychenko AV, Desenko SM, Musatov VI, Borysko PO, Zozulya SO. Funct. Matter. 2023; 30: 486
  Search in Google Scholar
• 7a Herath A, Dahl R, Cosford ND. P. Org. Lett. 2010; 12: 412
  CrossrefPubMedSearch in Google Scholar
• 7b Denora N, Laquintana V, Pisu MG, Dore R, Murru L, Latrofa L, Trapani G, Sanna E. J. Med. Chem. 2008; 51: 6876
  CrossrefPubMedSearch in Google Scholar
• 7c Paudler WW, Kuder JE. J. Org. Chem. 1966; 31: 809
  CrossrefSearch in Google Scholar
• 7d Brouwer C, Sinclair K, Cuevas J, Pike VW, Cai L. Synthesis 2006; 133
• 7e Chunavala KC, Joshi G, Suresh E, Adimurthy S. Synthesis 2011; 635
• 7f Mohamadi A, Sheikhi E, Ansari S, Bijanzadeh HR, Adib M. Synlett 2010; 1606
• 8a Xie Y.-Y, Zheng Q.-G, Chen Q.-G. Synthesis 2002; 1505
• 8b Yadav JS, Subba Reddy BV, Gopal Rao Y, Srinivas M, Narsaiah AV. Tetrahedron 2007; 48: 7717
  CrossrefSearch in Google Scholar
• 8c Sumran G, Aggarwal R. Synth. Commun. 2006; 36: 875
  CrossrefSearch in Google Scholar
• 8d Mukku N, Maiti B. RSC Adv. 2020; 10: 770
  CrossrefPubMedSearch in Google Scholar
• 8e Bangade VM, Reddy BC, Thakur PB, Babu BM, Meshram HM. Tetrahedron Lett. 2013; 54: 4767
  CrossrefSearch in Google Scholar
• 9 Omar MA, Frey W, Conrad J, Beifuss U. J. Org. Chem. 2014; 79: 10367
  CrossrefPubMedSearch in Google Scholar
• 10 Rassokhina IV, Tikhonova TA, Kobylskoy SG, Babkin IY, Shirinian VZ, Gevorgyan V, Zavarzin IV, Volkova YA. J. Org. Chem. 2017; 82: 9682
  CrossrefPubMedSearch in Google Scholar
• 11 Chen Z, Jin W, Xia Y, Zhang Y, Xie M, Ma S, Liu C. Org. Lett. 2020; 22: 8261
  CrossrefPubMedSearch in Google Scholar
• 12 Chen Z, Xue F, Zhang Y, Jin W, Wang B, Xia Y, Xie M, Abdukader A, Liu C. Org. Lett. 2022; 24: 3149
  CrossrefPubMedSearch in Google Scholar
• 13 Mishra S, Monir K, Mitra S, Hajra A. Org. Lett. 2014; 16: 6084
  CrossrefPubMedSearch in Google Scholar
• 14a Louillat M.-L, Patureau FW. Chem. Soc. Rev. 2014; 43: 901
  CrossrefPubMedSearch in Google Scholar
• 14b Shi ZZ, Zhang C, Tang CH, Jiao N. Chem. Soc. Rev. 2012; 41: 3381
  CrossrefPubMedSearch in Google Scholar
• 14c Dick AR, Sanford MS. Tetrahedron 2006; 62: 2439
  CrossrefSearch in Google Scholar
• 14d Punniyamurthy T, Velusamy S, Iqbal J. Chem. Rev. 2005; 105: 2329
  CrossrefPubMedSearch in Google Scholar
• 14e Yamaguchi J, Yamaguchi AD, Itami K. Angew. Chem. Int. Ed. 2012; 51: 8960
  CrossrefPubMedSearch in Google Scholar
• 14f Campbell AN, Stahl SS. Acc. Chem. Res. 2012; 45: 851
  CrossrefPubMedSearch in Google Scholar
• 15a Midya GC, Paladhi S, Dhara K, Dash J. Chem. Commun. 2011; 47: 6698
  CrossrefPubMedSearch in Google Scholar
• 15b Maiti S, Burgula L, Chakraborti G, Dash J. Eur. J. Org. Chem. 2017; 332
  Crossref
• 15c Maiti S, Mandal T, Dash B, Dash J. J. Org. Chem. 2021; 86: 1396
  CrossrefPubMedSearch in Google Scholar
• 16a Dhara K, Mandal T, Das J, Dash J. Angew. Chem. Int. Ed. 2015; 54: 15831 ; Angew. Chem. 2015, 127, 16057
  CrossrefPubMedSearch in Google Scholar
• 16b Mandal T, Chakraborti G, Karmakar S, Dash J. Org. Lett. 2018; 20: 4759
  CrossrefPubMedSearch in Google Scholar
• 16c Mandal T, Karmakar S, Kapat A, Dash J. ACS Omega 2021; 6: 27062
  CrossrefPubMedSearch in Google Scholar
• 16d Ghosh T, Mandal I, Basak SJ, Dash J. J. Org. Chem. 2021; 86: 14695
  CrossrefPubMedSearch in Google Scholar
• 16e Basak SJ, Dash J. J. Org. Chem. 2024; 89: 233
  CrossrefPubMedSearch in Google Scholar
• 16f Basak SJ, Dash J. J. Org. Chem. 2024; 89: 3612
  CrossrefPubMedSearch in Google Scholar
• 17 CCDC 2359527 (3af) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures

• Supplementary Material