Palladium-Catalyzed Domino Heteroarylation of Thioamides: A Simple Route to Benzothieno[2,3-b]quinolones

Abstract

Domino reactions are essential for advancing organic synthesis. This study introduces novel thioamide-based precursors for a palladium-catalyzed selective domino heteroarylation process. The method efficiently produces benzothieno[2,3-b]quinolones with yields ranging from moderate to very good. By employing aryl chlorides, the efficiency of the domino hetero-annulation process is comparable to that of aryl bromides. Executing a one-pot, two-step reaction also delivered a single domino product with high selectivity. The strategy involved fine-tuning substituent reactivity, utilizing electron-rich arenes, and forming metallocycles with nucleophilic sulfur, consistently yielding a single product. The proposed mechanism is corroborated by mechanistic studies.

 

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Key words

domino reaction - benzothiophene - palladium - selective C–S and C–N bond formation

Heterocyclic compounds are integral to numerous fields due to their diverse chemical properties and biological activities.[1] They are prevalent in pharmaceuticals, agrochemicals, dyes, and materials science.[2] Specifically, dibenzo-fused heterocyclic compounds are significant as they amalgamate the properties of benzenoid rings with those of heterocycles, resulting in unique electronic and structural characteristics. These compounds are commonly found in natural products, bioactive molecules, and advanced materials such as organic light-emitting diodes (OLEDs).[3] For instance, carbazole is utilized in OLEDs and as a transporter,[4] while thiophene derivatives serve as key material molecules.[5] The development of new classes of dibenzo-fused heterocycles is crucial due to their varied applications.[6]

Domino reactions, which involve multiple bond-forming transformations in a single synthetic operation, are highly valuable in this context. These reactions streamline the synthesis process by reducing the number of steps and minimizing the need for additional reagents. A significant challenge in domino reactions is designing effective precursors and predicting their reactivity to achieve the desired target molecule. Controlling reactivity centers, particularly with transition metals such as palladium, poses substantial challenges. Nevertheless, there has been notable progress in the literature.[7]

Recently, our group has focused on the synthesis of benzo-fused heterocycles using domino reactions. We reported a nickel-catalyzed domino reaction of aroylacetonitriles with arylboronic acids, yielding 2-aryloylbenzo[b]furans in good to excellent yields.[8] Continuing our ongoing research interest in developing new domino reactions for the synthesis of benzoheterocycles, we envisioned a class of domino precursors based on thioamide 3. The proposed thioamide 3 faces challenges such as competition between two reactive sp²-halogens and three reactive heteroatoms (N, O, and S), leading to different heteroarylation products A–D (Scheme [1]). Furthermore, thioamide-directed C–H bond functionalization results in intramolecular C–S bond formation, yielding benzothiazole, followed by N-arylation, producing indolo- and quinolo-fused benzothiazoles E and F.

Scheme 1 Designed thioamide 3 for selective domino heteroarylation and potential dibenzo-fused heterocycles A–E

In this report, we present the exclusive formation of a single domino product, benzothieno[2,3-b]quinolones, from thioamides at 120 °C using 10 mol% palladium acetate and 12 mol% adamantyl phosphine over 12 hours. The process involves sequential S-arylation followed by N-arylation, resulting in the observed domino product. Additionally, a two-component reaction also leads exclusively to the same product.

The required thioamides 3 were prepared by treating the enolate of deoxybenzoin 1a with substituted isothiocyanates 2 (Table [1]). Phenyl isothiocyanate 2a yielded the corresponding thioamide 3a in 77% yield (entry 1), whereas benzyl isothiocyanate 2b gave only 36% yield of thioamide 3b due to the instability of isothiocyanate 2b under strong basic conditions (entry 2). Isopropyl isothiocyanate 2c afforded a 64% yield of 3c (entry 3). Substituted phenyl isothiocyanates 2d–i reacted with the enolate of deoxybenzoin 1a, affording the corresponding thioamides 3d–i in 53–78% yield (entries 4–9). The reaction of tetrasubstituted deoxybenzoins 1b–c with phenyl isothiocyanate yielded the corresponding thioamides 3j–k in 79–80% yield (entries 10 and 11). Additionally, the reaction of disubstituted deoxybenzoin 1d with isopropyl isocyanate afforded thioamide 3l in 72% yield (entry 12). Thioamides 3l–n, derived from dichloro-substituted deoxybenzoin 1e, were prepared in 58–68% yield (entries 13–15).

Table 1 Synthesis of Domino Thioamide Precursors 3 ^a

Entry	X	R	R1	R2	Yield of 3 (%)b
1	Br	H	H	Ph	3a (77)
2	Br	H	H	Bn	3b (36)
3	Br	H	H	i Pr	3c (64)
4	Br	H	H	4-MeOC6H4	3d (75)
5	Br	H	H	4-MeC6H4	3e (53)
6	Br	H	H	4-O2NC6H4	3f (78)
7	Br	H	H	2-MeOC6H4	3g (69)
8	Br	H	H	2-F3CC6H4	3h (56)
9	Br	H	H	3-MeOC6H4	3i (61)
10	Br	MeO	MeO	Ph	3j (80)
11	Br	-OCH2CH2O-	-OCH2CH2O-	Ph	3k (79)
12	Br	MeO	H	i Pr	3l (72)
13	Cl	H	H	Ph	3m (58)
14	Cl	H	H	Bn	3n (68)
15	Cl	H	H	4-MeOC6H4	3o (68)

^a Reaction conditions: 1 (3 mmol), 2 (3 mmol), NaH (2 equiv), DMF (10 mL), 0 °C to r.t., 2–5 h.

^b Isolated yield.

Table 2 Optimization of Domino Heteroarylation of Thioamide 3a ^a

Entry	Deviation from the standard conditions	Yield (%)b
1	none	74
2	BINAP instead of Ad2P n Bu	72
3	t BuXPhos instead of Ad2P n Bu	51
4	DPPF instead of Ad2P n Bu	50
5	PEPPSI-IPr instead of Pd(OAc)2 and Ad2P n Bu	39
6	Cs2CO3 instead of KO t Bu	41
7	dioxane instead of DMF	57
8	toluene instead of DMF	54
9	90 °C instead of 120 °C	44
10	without Ad2P n Bu	57
11	Pd(PPh3)4 instead of Pd(OAc)2 and Ad2P n Bu	70
12	room temperature instead of 120 °C	–
13	preactivation conditions	86c
14	5 mol% Pd(OAc)2 instead of 10 mol% Pd(OAc)2	70c

^a Reaction conditions: 3a (0.3 mmol), Pd(OAc)₂ (10 mol%), Ad₂P ⁿ Bu (12 mol%), KO ^t Bu (3 equiv), DMF (2 mL), 120 °C, 12 h. ^t BuXPhos = 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl; DPPF = 1,1′-ferrocenediyl-bis(diphenylphosphine); PEPPSI-IPr [1,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride.

^b Isolated yield.

^c Preactivation conditions: Pd(OAc)₂ (10 mol%), Ad₂P ⁿ Bu (12 mol%), and KO ^t Bu (3 equiv) in DMF (2 mL) were heated at 80 °C for 10 min and then added to the reaction mixture.

Thioamide 3a was chosen as a model substrate for the domino heteroarylation reaction. After screening various reaction conditions, 3a was treated with 10 mol% of Pd(OAc)₂ and 12 mol% of Ad₂P ⁿ Bu in DMF at 120 °C for 12 h, yielding 4a as the sole product in 74% yield (Table [2]). The product 4a was characterized as benzothieno[2,3-b]quinolone. During this process, sequential C–S bond formation followed by C–N bond formation occurred, giving the observed domino product 4a. No trace amounts of other possible compounds (B–F) were isolated or detected. The standard conditions were modified by changing various parameters to obtain other possible products (B–F). Instead of Ad₂P ⁿ Bu, other ligands such as BINAP, ^t BuXPhos, DPPF, and PEPPSI-IPr were screened, delivering the product 4a in varying yields from 39 to 72% (entries 2–5); no other products were observed. The use of Cs₂CO₃ as a base gave 4a in 41% yield (entry 6). Dioxane and toluene were also screened, delivering 4a in 54–57% yield (entries 7–8). Lowering the temperature to 90 °C drastically reduced the yield of product 4a to 44% (entry 9). Interestingly, the domino heteroarylation of thioamide 3a proceeded without a ligand, yielding 4a in 57% yield (entry 10). A Pd(0) complex was also effective, yielding the product in 70% (entry 11). However, the reaction performed at room temperature afforded multiple products that could not be identified. Under pre-activated catalyst conditions, the yield of 4a increased to 86% in 12 hours (entry 13). Lowering the catalyst loading to 5 mol% reduced the yield of 4a to 70% (entry 14).

Based on the optimized reaction conditions, we studied the electronic effects of N-substituted thioamides in the domino heteroarylation reaction of 3. N-Benzyl thioamide 3b was subjected to the optimized conditions, yielding 4b in 85% within 8 hours (Table [3]). Isopropyl thioamide 3c yielded 50% of benzothieno[2,3-b]quinolone 4c in 10 h. N-4-Substituted phenyl derivatives 3d–f effectively underwent the domino heteroarylation reaction, yielding the corresponding benzothieno-fused quinolones 4d–f in 61–73% yield, respectively. 2-Methoxyphenyl- and 2-trifluoromethylphenyl-substituted thioamide derivatives 3g,h were studied under the optimized conditions. The 2-methoxyphenyl derivative yielded the product 4g in 74% within 8 h, whereas the 2-trifluoromethylphenyl derivative required 20 h for conversion, yielding 4h in 68%. The reaction was effective with 3-methoxyphenyl thioamide 3i, yielding benzothieno[2,3-b]quinolone 4i in 68% within 9 h. Tetra-methoxy- and dimethylenedioxy-substituted thioamides 3j,k were studied for their reactivity in domino reactions. Under the optimized conditions, 3j,k were transformed into the corresponding oxygenated benzothieno[2,3-b]quinolones 4j,k in moderate yields (44–57%). Interestingly, when unsymmetrical dibromo-substituted thioamide 3l was treated under the optimized conditions, we observed exclusively one domino product 4l in 56% yield after 16 h. This reaction clearly shows that the domino process is highly selective under standard conditions. We extended the scope of this reaction to dichlorosubstituted thioamides. Dichlorosubstituted thioamide 3m was effectively transformed into benzothiophene quinolone 4a in 88% yield, with slightly higher time and comparable yields. Similarly, other dichloro thioamide derivatives 3n,o were transformed into products 4b and 4d in 69–75% yields within 16 h.

Table 3 Substrate Scope of the Domino Heteroarylation of 3 ^a,b

^a Reaction conditions: 3 (0.5 mmol), Pd(OAc)₂ (10 mol%), Ad₂P ⁿ Bu (12 mol%), KO ^t Bu (3 equiv), DMF (3 mL), 120 °C, 8–20 h.

^b Isolated yield.

After successfully developing selective domino heteroarylation of thioamides, we studied a one-pot, two-step reaction. Deoxybenzoin 1a and phenyl isothiocyanate 2a were reacted with 1.5 equivalents of KO ^t Bu at room temperature for 1 h, then the precatalyst was added to the reaction mixture and heated at 120 °C for 16 h. After the starting material was consumed, the reaction mixture was purified, affording a single product, 4a, in 54% yield (Table [4]). To test this one-pot reaction, bromo deoxybenzoin 1a and isothiocyanates 2c and 2p were examined under the same conditions. Isopropyl-substituted benzothieno[2,3-b]quinolone 4c was obtained in a 40% yield, whereas the ethyl derivative 4p was produced in 56%. The tetra-methoxy-substituted benzothieno[2,3-b]quinolone 4j was achieved in a 54% yield. Dichloro deoxybenzoin 1e was reacted with 2-methoxyphenyl, 3-methoxy, and 3-methyl-substituted isothiocyanates, affording the corresponding domino products 4g, 4i, and 4q in 59–67% yields. One of the derivatives, 4g, was confirmed by X-ray crystal structure analysis (Table [4]). The reaction proceeded smoothly with cyclopropyl and cyclohexanyl isothiocyanates, resulting in domino products 4r–s in 45–60% yields.

Table 4 Substrate Scope One-Pot Two-Step Domino Heteroarylation of Deoxybenzoin 1 and Isothiocyanate 2 ^a,b

^a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), Pd(OAc)₂ (10 mol%), Ad₂P ⁿ Bu (12 mol%), KO ^t Bu (4.5 equiv), DMF (3 mL), 120 °C, 9–24 h.

^b Isolated yield.

Our previous studies showed that the first step of the reaction involves oxidative addition with electron-rich aryl bromide, followed by reductive elimination to produce 2-anilinobenzo[b]thiophene 5a (S-arylation).[9] To understand whether the second step proceeds through the oxidative addition pathway or the S_NAr pathway, we reacted 5a in the presence of KO ^t Bu in DMF at 120 °C, which yielded 4a in 80% within 1 h (Scheme [2]). These results clearly demonstrate that the second step follows the S_NAr pathway.

Scheme 2 Control experiment

Based on previous studies[9] [10] and control experiments, a plausible mechanism for the domino heteroarylation is depicted in Scheme [3]. The high chemoselectivity of the domino process is due to two key steps. Initially, Pd(0) is generated in situ by reacting Pd(OAc)₂ and Ad₂P ⁿ Bu, which then undergoes oxidative addition with an electron-rich arene to form complex A. This complex A undergoes ligand exchange with a more nucleophilic sulfur center, forming metallocycle B, a crucial step for selectivity. Metallocycle B undergoes reductive elimination to afford intermediate C, which tautomerizes to yield 2-aminobenzo[b]thiophene 5. This compound 5 then undergoes an S_NAr reaction through intermediates E and F to deliver benzothieno[2,3-b]quinolone 4. Despite the potential for multiple products (Scheme [1]), these steps ensure the exclusive formation of benzothieno[2,3-b]quinolone 4, highlighting the selectivity of the domino process.

Scheme 3 A plausible mechanism for the domino heteroarylation reaction of 3

In summary, we developed a new domino precursor based on thioamides and demonstrated that palladium-mediated selective domino heteroarylation yields various benzothieno[2,3-b]quinolones in moderate to very good yields. Aryl chlorides effectively undergo oxidative addition to produce domino products. Additionally, a one-pot, two-step reaction yields the same products without compromising selectivity. By tuning the reactivity of the substituents, specifically by utilizing electron-rich arenes for initial oxidative addition and forming metallocycles with more nucleophilic sulfur, followed by subsequent transformation, we consistently achieved a single product. This finding is supported by mechanistic studies.

All reactions were performed using standard vial techniques with rubber septa. All solids were weighed in air. Chemicals were purchased from Aldrich, Spectrochem, Alfa Aesar, and TCI, and were used as received. Solvents were dried according to standard protocols. Flash chromatography was performed using Merck silica gel (230−400 mesh). Fractions were monitored by thin-layer chromatography (TLC) on pre-coated silica gel ⁶⁰F₂₅₄ plates (Merck & Co.) and were visualized using UV light. Nuclear magnetic resonance (NMR) spectroscopic data were recorded with Bruker ARX 400 and 700 spectrometers. ¹³C and ¹H NMR spectra were recorded in CDCl₃ and DMSO-d ₆, referenced to the signal of the deuterated solvent. Electrospray ionization high-resolution mass spectrometry (ESI HR-MS) measurements were performed with a Bruker micrOTOF-Q II mass spectrometer and a Waters Xevo-G2-XS QTof.

Deoxybenzoins were prepared by reported procedures.[9] [10] Isothiocyanates were purchased from Aldrich.

 

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X-ray Spectroscopic Analysis of 4g

X-ray quality crystals for compound 4g were grown by slow diffusion of n-hexane over a CH₂Cl₂ solution. Single-crystal X-ray diffraction data were collected with a Rigaku SuperNova fine-focused dual diffractometer, with Cu K_α radiation (λ = 1.54178 Å) or Mo-K_α radiation (0.71073 Å), equipped with a PILATUS200K detector. CCDC 2359492 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.

 

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Synthesis of β-Ketothioamides 3: General Procedure

To a stirred suspension of NaH (60% suspension in mineral oil, 2 equiv) in DMF (5.0 mL) at 0 °C, the corresponding deoxybenzoin 1 (3.0 mmol) in DMF (3.0 mL) was added dropwise. After stirring for 1 h at r.t., a solution of isothiocyanate 2 (3.0 mmol) in DMF (2.0 mL) was added to the reaction mixture at 0 °C, followed by further stirring at r.t. for 2–5 h. After complete consumption of the starting materials (monitored by TLC), the reaction mixture was quenched with sat. NH₄Cl and extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with water (3 × 50 mL) and brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude products were purified by flash chromatography.

 

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2,3-Bis(2-bromophenyl)-3-oxo-N-phenylpropanethioamide (3a)

Reaction time: 4.5 h; R_f = 0.35 (20% EtOAc/hexane).

Yield: 77% (1.13 g); pale-yellow solid; mp 168–170 °C.

IR (KBr): 3444, 3322, 2370, 2345, 1572, 1498, 1466, 1309, 1229, 1190, 1087, 1024, 924, 797, 752, 695 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.55 (s, 1 H), 7.75 (s, 1 H), 7.56 (dd, J = 8.0, 1.1 Hz, 1 H), 7.46–7.44 (m, 2 H), 7.42–7.36 (m, 4 H), 7.31–7.25 (m, 2 H), 7.16 (td, J = 7.5, 1.2 Hz, 1 H), 7.10–7.01 (m, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 191.2, 171.0, 137.8, 137.5, 136.2, 133.7, 133.4, 132.7, 130.6, 130.3, 129.1, 128.6, 127.7, 127.2, 127.0, 126.2, 126.1, 121.3, 113.8.

HR-MS (ESI): m/z [M + H] calcd for C₂₁H₁₅Br₂NOS: 487.9314 and 491.9273; found: 487.9297 and 491.9258.

 

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N-Benzyl-2,3-bis(2-bromophenyl)-3-oxopropanethioamide (3b)

Reaction time: 4 h; R_f = 0.38 (10% EtOAc/hexane).

Yield: 36% (0.544 g); white solid; mp 92–94 °C.

IR (KBr): 3450, 3356, 3054, 3028, 2918, 1603, 1571, 1509, 1472, 1454, 1425, 1400, 1308, 1269, 1185, 1104, 1047, 1024, 911, 890, 806, 757, 735 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.32 (s, 1 H), 7.48 (d, J = 7.9 Hz, 1 H), 7.43 (d, J = 8.2 Hz, 1 H), 7.35 (d, J = 7.4 Hz, 1 H), 7.32–7.22 (m, 6 H), 7.10 (d, J = 7.3 Hz, 1 H), 7.07–6.98 (m, 3 H), 6.57 (s, 1 H), 4.98 (dd, J = 15.4, 5.7 Hz, 1 H), 4.66 (dd, J = 15.4, 4.8 Hz, 1 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 190.8, 169.3, 137.7, 136.1, 136.0, 133.5, 133.2, 132.6, 130.5, 130.2, 128.9, 128.5, 128.4, 128.0, 127.8, 127.1, 126.9, 121.3, 113.2, 48.4.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₇Br₂NOS: 501.9470 and 505.9430; found: 501.9461 and found: 505.9417.

 

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2,3-Bis(2-bromophenyl)-N-isopropyl-3-oxopropanethioamide (3c)

Reaction time: 4 h; R_f = 0.38 (10% EtOAc/hexane).

Yield: 64% (0.874 g); white solid; mp 128–130 °C.

IR (KBr): 3454, 3346, 3050, 2975, 2927, 2870, 1608, 1578, 1523, 1459, 1419, 1355, 1255, 1202, 1159, 1045, 1024, 963, 913, 767, 751 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.36 (s, 1 H), 7.52 (dd, J = 7.9, 0.9 Hz, 1 H), 7.42 (dd, J = 7.5, 1.4 Hz, 1 H), 7.33–7.31 (m, 1 H), 7.20 (dd, J = 7.2, 2.0 Hz, 1 H), 7.13–7.10 (m, 1 H), 7.07–6.98 (m, 3 H), 6.08 (d, J = 6.1 Hz, 1 H), 4.73–4.61 (m, 1 H), 1.19 (d, J = 6.5 Hz, 3 H), 1.10 (d, J = 6.5 Hz, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 188.9, 169.0, 137.9, 136.2, 133.7, 133.2, 132.6, 130.4, 130.1, 128.5, 128.4, 127.0, 126.9, 121.4, 113.0, 45.6, 21.6, 21.2.

HR-MS (ESI): Calcd. for C₁₈H₁₇Br₂NOS (M + Na): 475.9290 and 479.9249; found: 475.930 and 479.9263.

 

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2,3-Bis(2-bromophenyl)-N-(4-methoxyphenyl)-3-oxopropanethioamide (3d)

Reaction time: 5 h; R_f 0.30 (25% EtOAc/hexane).

Yield: 75% (1.168 g); yellow solid; mp 148–150 °C.

IR (KBr): 3338, 2967, 2935, 2840, 1606, 1573, 1510, 1487, 1461, 1442, 1428, 1408, 1333, 1309, 1292, 1249, 1192, 1166, 1119, 1104, 1088, 1046, 1026, 951, 909, 892, 832, 809, 796, 767, 759, 739 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.54 (s, 1 H), 7.69 (s, 1 H), 7.56 (dd, J = 8.0, 1.2 Hz, 1 H), 7.47–7.43 (m, 2 H), 7.27–7.25 (m, 3 H), 7.16 (td, J = 7.5, 1.3 Hz, 1 H), 7.10–7.01 (m, 3 H), 6.93–6.89 (m, 2 H), 3.81 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 191.4, 170.6, 158.9, 137.8, 136.3, 133.7, 133.4, 132.7, 130.6, 130.24 (2C), 130.19, 128.5, 127.7, 127.2, 127.0, 121.3, 114.4, 113.6, 55.6.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₇Br₂NO₂S: 517.9420 and 521.9379; found: 517.9440 and 521.9402.

 

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2,3-Bis(2-bromophenyl)-3-oxo-N-(p-tolyl)propanethioamide (3e)

Reaction time: 3.5 h; R_f = 0.30 (10% EtOAc/hexane).

Yield: 53% (0.800 g); yellow solid; mp 180–182 °C.

IR (KBr): 3446, 3341, 3054, 3024, 2925, 2852, 1603, 1572, 1512, 1485, 1464, 1430, 1411, 1334, 1305, 1255, 1194, 1090, 1047, 1023, 909, 798, 767, 757, 746 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.54 (s, 1 H), 7.70 (s, 1 H), 7.56 (dd, J = 7.9, 1.2 Hz, 1 H), 7.46–7.43 (m, 2 H), 7.27–7.25 (m, 2 H), 7.23–7.18 (m, 3 H), 7.15 (dd, J = 7.5, 1.2 Hz, 1 H), 7.09–7.02 (m, 3 H), 2.35 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 191.1, 170.7, 137.8, 137.7, 136.2, 134.8, 133.73, 133.70, 133.3, 132.6, 130.6, 130.2, 129.7, 128.5, 127.2, 127.0, 126.1, 121.3, 113.6, 21.3.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₇Br₂NOS: 501.9470 and 505.9430; found: 501.9410 and 505.9399.

 

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2,3-Bis(2-bromophenyl)-N-(4-nitrophenyl)-3-oxopropanethioamide (3f)

Reaction time: 4 h; R_f = 0.31 (25% EtOAc/hexane).

Yield: 78% (1.250 g); yellow solid; mp 180–182 °C.

IR (KBr): 3446, 3332, 3076, 2931, 2852, 1559, 1535, 1509, 1467, 1389, 1337, 1305, 1288, 1185, 1111, 1084, 1023, 853, 755 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.46 (s, 1 H), 8.23 (d, J = 9.0 Hz, 2 H), 7.85 (s, 1 H), 7.63 (d, J = 9.0 Hz, 2 H), 7.59 (dd, J = 8.1, 1.0 Hz, 1 H), 7.50–7.40 (m, 2 H), 7.25–7.20 (m, 1 H), 7.18 (dd, J = 7.5, 1.1 Hz, 1 H), 7.15–7.02 (m, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 191.2, 172.5, 145.7, 143.2, 137.4, 135.6, 133.7, 133.5, 132.7, 131.0, 130.5, 128.7, 128.3, 127.0, 125.6 (2C), 124.5, 121.0, 114.4.

HR-MS (ESI): m/z [M + H] calcd. for C₂₁H₁₄Br₂N₂O₃S: 532.9165 and 536.9124; found: 532.9105 and 536.9049.

 

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2,3-Bis(2-bromophenyl)-N-(2-methoxyphenyl)-3-oxopropanethioamide (3g)

Reaction time: 3.5 h; R_f = 0.38 (20% EtOAc/hexane)

Yield: 69% (1.075 g); yellow solid; mp 176–178 °C.

IR (KBr): 3446, 3322, 3046, 3021, 2935, 2838, 1605, 1570, 1522, 1463, 1432, 1410, 1351, 1319, 1289, 1249, 1191, 1162, 1113, 1083, 1047, 1027, 951, 908, 800, 769, 747 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.51 (s, 1 H), 8.68 (d, J = 8.0 Hz, 1 H), 8.45 (s, 1 H), 7.57 (d, J = 7.9 Hz, 1 H), 7.46 (t, J = 6.7 Hz, 2 H), 7.34 (d, J = 7.0 Hz, 1 H), 7.20–6.97 (m, 6 H), 6.81 (d, J = 8.2 Hz, 1 H), 3.59 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 188.4, 169.9, 150.6, 137.9, 136.4, 133.7, 133.1, 132.6, 130.3, 130.2, 128.5, 128.2, 127.7, 127.5, 126.9, 126.8, 123.0, 121.3, 120.4, 114.9, 110.7, 55.9.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₇Br₂NO₂S: 517.9420 and 521.9379; found: 517.9402 and 521.9383.

 

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2,3-Bis(2-bromophenyl)-3-oxo-N-((2-trifluoromethyl)phenyl)propanethioamide (3h)

Reaction time: 4 h; R_f = 0.32 (10% EtOAc/hexane).

Yield: 56% (0.936 g); pale-yellow solid; mp 150–152 °C.

IR (KBr): 3450, 3343, 3068, 2923, 2848, 1604, 1572, 1500, 1465, 1407, 1315, 1294, 1169, 1136, 1059, 1031, 952, 919, 813, 759 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.46 (s, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.74 (s, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.61 (d, J = 7.9 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.50 (d, J = 7.2 Hz, 1 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.41 (d, J = 7.7 Hz, 1 H), 7.38 (d, J = 6.1 Hz, 1 H), 7.20 (t, J = 7.5 Hz, 1 H), 7.13–7.01 (m, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 192.3, 171.4, 137.5, 135.6, 135.47, 135.46, 133.5, 133.3, 132.7, 132.3, 130.7, 130.4, 130.1, 128.4, 127.7, 127.4, 126.9, 126.6 (q, J = 5.1 Hz), 123.2 (q, J=272 Hz), 125.6 (q, J = 30.2 Hz), 121.2, 114.2.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₄Br₂F₃NOS: 555.9188 and 559.9147; found: 555.9202 and 559.9156.

 

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2,3-Bis(2-bromophenyl)-N-(3-methoxyphenyl)-3-oxopropanethioamide (3i)

Reaction time: 3.5 h; R_f = 0.37 (20% EtOAc/hexane); Yield: 61% (0.950 g); pale-yellow solid; mp 121–123 °C.

IR (KBr): 3450, 3341, 3068, 3015, 2935, 2835, 1603, 1588, 1572, 1495, 1463, 1430, 1408, 1299, 1283, 1256, 1193, 1153, 1089, 1045, 1025, 947, 918, 868, 758, 744, 705 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.53 (s, 1 H), 7.68 (s, 1 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.42–7.40 (m, 2 H), 7.24 (s, 1 H), 7.23–7.20 (m, 1 H), 7.12 (t, J = 7.2 Hz, 1 H), 7.06–6.97 (m, 4 H), 6.85 (d, J = 7.8 Hz, 1 H), 6.79 (dd, J = 8.3, 2.1 Hz, 1 H), 3.76 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 191.0, 171.0, 160.1, 138.5, 137.8, 136.2, 133.7, 133.4, 132.7, 130.7, 130.3, 129.8, 128.6, 128.5, 127.2, 127.0, 121.3, 118.1, 113.8, 113.4, 111.8, 55.6.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₇Br₂NO₂S: 517.9420 and 521.9379; found: 517.9397 and 521.9420.

 

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2,3-Bis(2-bromo-4,5-dimethoxyphenyl)-3-oxo-N-phenylpropanethioamide (3j)

Reaction time: 4 h; R_f = 0.45 (33% EtOAc/hexane).

Yield: 80% (1.462 g); pale-yellow solid; mp 210–212 °C.

IR (KBr): 3449, 3273, 3076, 3050, 3016, 2958, 2932, 2838, 1607, 1582, 1560, 1499, 1459, 1439, 1420, 1371, 1324, 1298, 1255, 1216, 1190, 1166, 1099, 1048, 1033, 988, 872, 839, 779, 755 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.48 (s, 1 H), 7.95 (s, 1 H), 7.40–7.39 (m, 4 H), 7.32–7.27 (m, 1 H), 6.97 (s, 1 H), 6.94 (s, 1 H), 6.88 (s, 1 H), 6.83 (s, 1 H), 3.82 (s, 3 H), 3.81 (s, 3 H), 3.77 (s, 3 H), 3.74 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 190.8, 171.4, 150.0, 149.6, 149.04, 147.9, 137.5, 130.4, 129.1 (2C), 128.1, 127.6, 126.0, 116.9, 115.7, 115.2, 114.9, 113.8, 111.3, 56.2, 56.18, 56.16, 56.10.

HR-MS (ESI): m/z [M + H] calcd. for C₂₅H₂₃Br₂NO₅S: 607.9736 and 611.9697; found: 607.9772 and 611.9746.

 

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2,3-Bis(6-bromobenzo[d][1,3]dioxol-5-yl)-3-oxo-N-phenylpropanethioamide (3k)

Reaction time: 5 h; R_f = 0.30 (20% EtOAc/hexane).

Yield: 79% (1.368); yellow solid; mp 163–165 °C.

IR (KBr): 3339, 2900, 1578, 1499, 1474, 1448, 1328, 1298, 1236, 1116, 1036, 932, 878, 758, 695 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.46 (s, 1 H), 7.86 (s, 1 H), 7.42–7.36 (m, 4 H), 7.32–7.27 (m, 1 H), 7.03 (s, 1 H), 6.95 (s, 1 H), 6.93 (s, 1 H), 6.81 (s, 1 H), 5.98 (d, J = 0.9 Hz, 1 H), 5.96 (d, J = 0.9 Hz, 1 H), 5.95 (d, J = 1.1 Hz, 1 H), 5.92 (d, J = 1.1 Hz, 1 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 191.2, 170.7, 149.1, 148.7, 148.2, 146.9, 137.4, 131.1, 129.1, 128.7, 127.7, 126.2, 118.0, 113.5, 113.2, 112.8, 112.5, 112.3, 108.1, 102.4, 102.1.

LR-MS (ESI): m/z [M + Na] calcd. for C₂₃H₁₅Br₂NO₅S: 597.8930 and 601.8890; found: 597.8911 and 601.8895.

 

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3-(2-Bromo-4,5-dimethoxyphenyl)-2-(2-bromophenyl)-N-isopropyl-3-oxopropanethioamide (3l)

Reaction time: 4 h; R_f = 0.32 (25% EtOAc/hexane).

Yield: 72% (1.113 g); white solid; mp 141–143 °C.

IR (KBr): 3345, 2971, 2835, 1601, 1585, 1381, 1252, 1160, 1020, 941, 888, 855, 792, 772 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.33 (s, 1 H), 7.52 (dd, J = 8.0, 0.8 Hz, 1 H), 7.28 (dd, J = 7.6, 1.6 Hz, 1 H), 7.14 (td, J = 7.5, 1.1 Hz, 1 H), 7.07 (td, J = 7.6, 1.0 Hz, 1 H), 6.86 (s, 1 H), 6.74 (s, 1 H), 6.06 (d, J = 7.6 Hz, 1 H), 4.70–4.61 (m, 1 H), 3.76 (s, 3 H), 3.67 (s, 3 H), 1.18 (d, J = 6.4 Hz, 3 H), 1.09 (d, J = 6.4 Hz, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 188.8, 169.1, 149.4, 147.7, 136.6, 133.9, 133.0, 130.5, 130.2, 128.6, 126.9, 115.1, 113.2, 111.7, 111.3, 56.1, 56.0, 45.6, 21.6, 21.2.

HR-MS (ESI): m/z [M + H] calcd. for C₂₀H₂₁Br₂NO₃S: 513.9682 and 517.9641; found: 513.9668 and 517.9629.

 

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2,3-Bis(2-chlorophenyl)-3-oxo-N-phenylpropanethioamide (3m)

Reaction time: 6 h; R_f = 0.35 (20% EtOAc/hexane).

Yield: 58% (0.697 g); pale-yellow solid; mp 168–170 °C.

IR (KBr): 3463, 3337, 3060, 3028, 2927, 2738, 1605, 1594, 1577, 1498, 1466, 1432, 1413, 1332, 1308, 1255, 1231, 1193, 1156, 1123, 1094, 1056, 947, 923, 889, 799, 755, 743, 709 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.57 (s, 1 H), 7.77 (s, 1 H), 7.42–7.35 (m, 6 H), 7.30 (d, J = 6.7 Hz, 1 H), 7.27 (d, J = 6.0 Hz, 1 H), 7.23 (d, J = 7.5 Hz, 1 H), 7.18 (t, J = 7.6 Hz, 1 H), 7.12 (t, J = 7.2 Hz, 2 H), 7.03 (t, J = 7.4 Hz, 1 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 191.1, 170.3, 137.4, 136.1, 135.8, 134.1, 133.6, 131.8, 130.6, 130.2, 130.1, 129.4, 129.1, 128.5, 127.8, 127.7, 126.4, 126.1, 112.1.

HR-MS (ESI): m/z [M + H] calcd. for C₂₁H₁₅Cl₂NOS: 400.0324; found: 400.0360.

 

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N-Benzyl-2,3-bis(2-chlorophenyl)-3-oxopropanethioamide (3n)

Reaction time: 4 h; R_f = 0.38 (10% EtOAc/hexane).

Yield: 68% (0.843 g); white solid; mp 124–126 °C.

IR (KBr): 3371, 3063, 3028, 2922, 1605, 1577, 1513, 1469, 1310, 1255, 1188, 1057, 1033, 912, 759, 740 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.35 (s, 1 H), 7.34–7.27 (m, 5 H), 7.24–7.20 (m, 4 H), 7.11 (t, J = 7.1 Hz, 2 H), 7.07–7.00 (m, 2 H), 6.61 (s, 1 H), 4.99 (dd, J = 15.5, 5.7 Hz, 1 H), 4.68 (dd, J = 15.5, 4.8 Hz, 1 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 190.8, 168.7, 136.1, 136.0, 135.7, 133.9, 133.5, 131.9, 130.4, 130.1, 129.9, 129.4, 128.9, 127.9 (2C), 127.7, 127.6, 126.3, 111.5, 48.2.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₇Cl₂NOS: 414.0481; found: 414.0441.

 

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2,3-Bis(2-chlorophenyl)-N-(4-methoxyphenyl)-3-oxopropanethioamide (3o)

Reaction time: 4 h; R_f = 0.43 (20% EtOAc/hexane).

Yield: 68% (0.878 g); yellow solid; mp 62–64 °C.

IR (KBr): 3349, 3054, 2933, 2836, 1607, 1576, 1510, 1466, 1434, 1298, 1247, 1092, 1057, 1033, 830, 810, 762 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 15.55 (s, 1 H), 7.69 (s, 1 H), 7.36 (d, J = 7.7 Hz, 2 H), 7.27–7.20 (m, 4 H), 7.18 –7.15 (m, 1 H), 7.12–7.09 (m, 2 H), 7.02 (t, J = 7.5 Hz, 1 H), 6.91 (d, J = 8.8 Hz, 2 H), 3.81 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 191.4, 170.0, 158.9, 136.1, 135.8, 134.2, 133.7, 131.9, 130.5, 130.13 (2C), 130.10, 129.4, 128.6, 127.8, 127.7, 126.4, 114.3, 111.9, 55.6.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₇Cl₂NO₂S: 430.0430; found: 430.0453.

 

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Palladium-Catalyzed Domio Heteroarylation of Thioamides via the Preactivation Protocol; General Procedure

An oven-dried 8 mL reaction vial was charged with Pd(OAc)₂ (10 mol%), Ad₂P ⁿ Bu (12 mol%), and KO ^t Bu (1.5 equiv) in DMF (1.5 mL) and stirred at 90 °C for 5 min. Then it was cooled, and the respective thioenolate anion, generated from thioamide 3 (0.5 mmol) in the presence of KO ^t Bu (1.5 mmol) in DMF (1.5 mL) in another oven-dried 8 mL reaction vial, was added at r.t. The reaction mixture was stirred at 120 °C and monitored by TLC. After the starting material had been completely consumed, the reaction mixture was cooled to r.t. and purified by flash chromatography.

 

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One-Pot Two-Step Palladium-Catalyzed Domio Heteroarylation; General Procedure

An oven-dried 8 mL reaction vial was charged with deoxybenzoin 1 (0.5 mmol), isothiocyanate 2 (0.5 mmol), and KO ^t Bu (3 equiv) in DMF (1.5 mL) and stirred at r.t. for 1 hour. Another reaction vial charged with Pd(OAc)₂ (10 mol%), Ad₂P ⁿ Bu (12 mol%), and KO ^t Bu (1.5 mmol) in DMF (1.5 mL) was stirred at 90 °C for 5 minutes. This pre-catalyst was then added to the first reaction mixture at r.t. and stirred at 120 °C. The reaction mixture was monitored by TLC. After the starting material had been completely consumed, the reaction mixture was cooled to r.t. and purified by flash chromatography.

 

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6-Phenylbenzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4a)

Reaction time: 8 h; R_f = 0.32 (25% EtOAc/hexane).

Yield: 86% (0.141 g); white solid; mp 256–258 °C.

IR (KBr): 3048, 2923, 2852, 1618, 1589, 1520, 1483, 1442, 1340, 1288, 1184, 1091, 1018, 798, 760, 730, 702 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.00 (d, J = 7.6 Hz, 1 H), 8.66 (d, J = 7.6 Hz, 1 H), 7.73–7.71 (m, 3 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.54–7.49 (m, 4 H), 7.40 (t, J = 7.6 Hz, 1 H), 7.34 (t, J = 7.6 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.8, 157.8, 141.7, 139.9, 136.5, 132.1, 131.8, 131.2 (2C), 130.8, 128.8, 127.0, 126.2, 125.5, 125.0, 123.4, 121.2, 117.0, 116.4.

HR-MS (ESI): m/z [M + H] calcd. for C₂₁H₁₃NOS: 328.0791; found: 328.0792.

 

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6-Benzylbenzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4b)

Reaction time: 8 h; R_f = 0.34 (20% EtOAc/hexane).

Yield: 85% (0.145 g); brown solid; mp 214–216 °C.

IR (KBr): 3059, 2923, 1616, 1581, 1522, 1489, 1438, 1277, 1138, 1021, 758, 729 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.99 (d, J = 7.5 Hz, 1 H), 8.63 (dd, J = 8.0, 1.4 Hz, 1 H), 7.61 (d, J = 7.9 Hz, 1 H), 7.57–7.45 (m, 2 H), 7.37–7.25 (m, 6 H), 7.13 (d, J = 7.5 Hz, 2 H), 5.50 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.3, 157.1, 140.0, 136.5, 133.8, 132.2, 131.2, 129.3, 128.3, 127.2, 126.2, 126.02, 125.7, 125.03, 124.8, 123.3, 121.3, 117.0, 115.1, 55.0.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₅NOS: 342.0947; found: 342.0966.

 

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6-Isopropylbenzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4c)

Reaction time: 18 h; R_f = 0.39 (20% EtOAc/hexane).

Yield: 55% (0.081 g); white solid; mp 150–152 °C.

IR (KBr): 3063, 3015, 2971, 2931, 2865, 1618, 1592, 1517, 1497, 1331, 1258, 1166, 1127, 1083, 1018, 794, 754, 746 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.03 (d, J = 8.0 Hz, 1 H), 8.70 (dd, J = 8.0, 1.4 Hz, 1 H), 7.78 (d, J = 8.7 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.68–7.64 (m, 1 H), 7.53 (t, J = 7.6 Hz, 1 H), 7.43–7.36 (m, 2 H), 4.99 (br s, 1 H), 1.86 (d, J = 7.1 Hz, 6 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.5, 139.1, 136.7, 131.2, 131.0, 127.8, 126.8, 126.1, 124.88 (2C), 124.86 (2C), 122.9, 120.9, 116.4, 59.6, 20.5.

HR-MS (ESI): m/z [M + H] calcd. for C₁₈H₁₅NOS: 294.0947; found: 294.0974.

 

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6-(4-Methoxyphenyl)benzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4d)

Reaction time: 14 h; R_f = 0.30 (25% EtOAc/hexane).

Yield: 61% (0.109 g); white solid; mp 268–270 °C.

IR (KBr): 3050, 2953, 2927, 2835, 1618, 1594, 1515, 1479, 1406, 1285, 1252, 1024, 839, 750, 730 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.99 (d, J = 7.8 Hz, 1 H), 8.65 (d, J = 7.7 Hz, 1 H), 7.61 (d, J = 7.7 Hz, 1 H), 7.54–7.49 (m, 2 H), 7.43–7.32 (m, 4 H), 7.18 (d, J = 8.3 Hz, 2 H), 6.95 (d, J = 8.3 Hz, 1 H), 3.96 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.8, 161.1, 158.5, 142.0, 136.6, 132.5, 132.2, 131.8, 129.9, 127.0, 126.1, 125.5, 125.0, 124.9, 123.3, 121.2, 116.9, 116.4, 116.2, 55.9.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₅NO₂S: 358.0896; found: 358.0930.

 

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6-(p-Tolyl)benzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4e)

Reaction time: 9 h; R_f = 0.32 (20% EtOAc/hexane).

Yield: 70% (0.120 g); white solid; mp 250–252 °C.

IR (KBr): 3041, 2918, 1617, 1595, 1481, 1406, 1284, 1184, 1029, 750, 728 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.99 (d, J = 7.9 Hz, 1 H), 8.65 (d, J = 7.9 Hz, 1 H), 7.60 (d, J = 7.9 Hz, 1 H), 7.53–7.47 (m, 4 H), 7.39–7.31 (m, 4 H), 6.93 (d, J = 8.4 Hz, 1 H), 2.55 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.8, 158.0, 141.8, 141.1, 137.3, 136.5, 132.1, 131.8, 131.7, 128.4, 126.9, 126.1, 125.5, 124.91, 124.87, 123.3, 121.2, 116.9, 116.4, 21.6.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₅NOS: 342.0947; found: 342.0947.

 

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6-(4-Nitrophenyl)benzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4f)

Reaction time: 10 h; R_f = 0.40 (33% EtOAc/hexane).

Yield: 73% (0.136 g); yellow solid; mp 304–306 °C.

IR (KBr): 3056, 3032, 2927, 2852, 1618, 1593, 1521, 1490, 1410, 1349, 1313, 1290, 1253, 1190, 1105, 977, 838, 749, 730 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.82 (d, J = 8.6 Hz, 1 H), 8.64 (d, J = 9.1 Hz, 2 H), 8.48 (d, J = 9.2 Hz, 1 H), 8.14 (d, J = 9.1 Hz, 2 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.68 (t, J = 8.4 Hz, 1 H), 7.58–7.49 (m, 2 H), 7.42 (t, J = 7.9 Hz, 1 H), 6.97 (d, J = 8.9 Hz, 1 H).

¹³C{¹H} NMR (100 MHz, DMSO): δ = 172.6, 156.7, 148.7, 144.4, 141.0, 135.7, 132.4, 131.5, 130.9, 126.6, 126.1, 126.0, 125.0, 124.6, 123.6, 123.5, 122.2, 116.5, 115.8.

HR-MS (ESI): m/z [M + H] calcd. for C₂₁H₁₂N₂O₃S: 373.0641; found: 373.0627.

 

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6-(2-Methoxyphenyl)benzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4g)

Reaction time: 8 h; R_f = 0.31 (20% EtOAc/hexane).

Yield: 74% (0.132 g); white solid; mp 234–236 °C.

IR (KBr): 2971, 2927, 2835, 1612, 1588, 1480, 1338, 1278, 1248, 1015, 757, 724 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.00 (d, J = 7.9 Hz, 1 H), 8.69 (d, J = 7.7 Hz, 1 H), 7.70–7.58 (m, 2 H), 7.52 (t, J = 7.7 Hz, 2 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.40 (t, J = 7.4 Hz, 1 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.28–7.18 (m, 2 H), 6.89 (d, J = 8.4 Hz, 1 H), 3.69 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.9, 158.3, 155.6, 141.4, 136.6, 132.4, 132.0, 131.8, 130.1, 127.7, 126.8, 125.9, 125.4, 124.8, 124.7, 123.2, 122.0, 121.2, 116.8, 115.9, 113.4, 55.9.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₅NO₂S: 358.0896; found: 358.0868.

 

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6-(2-(Trifluoromethyl)phenyl)benzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4h)

Reaction time: 20 h; R_f = 0.38 (20% EtOAc/hexane).

Yield: 68% (0.134 g); white solid; mp 224–226 °C.

IR (KBr): 3071, 3040, 3006, 2923, 2861, 1617, 1590, 1519, 1483, 1457, 1443, 1409, 1369, 1340, 1319, 1192, 1167, 1157, 1138, 1120, 1064, 1036, 884, 817, 785, 757, 729 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.99 (d, J = 8.0 Hz, 1 H), 8.65 (d, J = 7.9 Hz, 1 H), 8.04 (d, J = 7.7 Hz, 1 H), 7.94 (t, J = 7.4 Hz, 1 H), 7.86 (t, J = 7.6 Hz, 1 H), 7.67–7.56 (m, 2 H), 7.56–7.45 (m, 2 H), 7.44–7.31 (m, 2 H), 6.69 (d, J = 8.4 Hz, 1 H).

¹³C{¹H} NMR (175 MHz, CDCl₃): δ = 173.9, 157.7, 141.8, 137.0, 136.2, 135.1, 132.1, 131.9, 131.8, 131.6, 129.6 (q, J = 32.1 Hz), 129.1 (q, J = 4.7 Hz), 126.9, 126.2, 125.3, 125.0, 125.0, 123.6, 122.4 (q, J= 273 Hz), 121.2, 117.2, 116.4.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₂F₃NOS: 396.0664; found: 396.0674.

 

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6-(3-Methoxyphenyl)benzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4i)

Reaction time: 9 h; R_f = 0.30 (25% EtOAc/hexane).

Yield: 68% (0.122 g); pale-yellow solid; mp 212–214 °C.

IR (KBr): 3065, 2835, 1618, 1588, 1521, 1482, 1340, 1243, 1172, 1040, 794, 752, 728 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.98 (d, J = 8.0 Hz, 1 H), 8.64 (d, J = 7.7 Hz, 1 H), 7.63–7.59 (m, 2 H), 7.53–7.48 (m, 2 H), 7.39–7.31 (m, 2 H), 7.22 (dd, J = 8.4, 1.8 Hz, 1 H), 7.09 (d, J = 7.7 Hz, 1 H), 7.05 (s, 1 H), 6.97 (d, J = 8.5 Hz, 1 H), 3.89 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.8, 161.7, 157.6, 141.5, 140.8, 136.4, 132.1, 131.9, 131.8, 126.9, 126.1, 125.4, 124.9 (2C), 123.4, 121.2, 120.5, 116.9, 116.7, 116.4, 113.9, 55.8.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₅NO₂S: 358.0896; found: 358.0898.

 

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2,3,8,9-Tetramethoxy-6-phenylbenzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4j)

Reaction time: 14 h; R_f = 0.30 (2% MeOH/dichloromethane).

Yield: 54% (0.121 g); brown solid; mp 246–248 °C.

IR (KBr): 2920, 1586, 1498, 1416, 1310, 1274, 1210, 1175, 1053, 1035, 924, 865, 821, 756, 700 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.56 (s, 1 H), 7.95 (s, 1 H), 7.72–7.70 (m, 3 H), 7.57 (d, J = 6.0 Hz, 2 H), 7.01 (s, 1 H), 6.21 (s, 1 H), 4.04 (s, 3 H), 4.01 (s, 3 H), 3.89 (s, 3 H), 3.67 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 172.6, 155.5, 153.0, 148.6, 147.8, 146.7, 140.0, 137.3, 131.1, 130.8, 129.8, 128.7, 123.9, 118.9, 116.7, 106.9, 105.8, 103.6, 97.9, 56.3 (2C), 56.1, 55.9.

HR-MS (ESI): m/z [M + H] calcd. for C₂₅H₂₁NO₅S: 448.1213; found: 448.1247.

 

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6-Phenyl-[1,3]dioxolo[4",5":4′,5′]benzo[1′,2′:4,5]thieno[2,3-b][1,3]dioxolo[4,5-g]quinolin-12(6H)-one (4k)

Reaction time: 10 h; R_f = 0.47 (dichloromethane).

Yield: 57% (0.118 g); yellow solid; mp >340 °C.

IR (KBr): 3046, 2962, 2905, 2773, 1616, 1586, 1561, 1531, 1498, 1474, 1443, 1313, 1263, 1159, 1123, 1053, 1036, 929, 866, 831, 750 cm^–1.

¹H NMR (400 MHz, CDCl₃ + TFA-d): δ = 8.07 (s, 1 H), 8.04 (s, 1 H), 7.84–7.83 (m, 3 H), 7.50–7.48 (m, 2 H), 7.07 (s, 1 H), 6.55 (s, 1 H), 6.19 (s, 2 H), 6.05 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃ + TFA-d): δ = 159.0, 154.9, 148.7, 148.4, 148.2, 140.0, 138.7, 132.6, 132.0, 127.0, 126.9, 126.4, 116.8, 116.4, 113.6, 105.9, 104.0, 102.4, 101.9, 100.9, 96.4.

HR-MS (ESI): m/z [M] calcd. for C₂₃H₁₃NO₅S: 415.0509; found: 415.0540.

 

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6-Isopropyl-8,9-dimethoxybenzo[4,5]thieno[2,3-b]quinolin-11 (6H)-one (4l)

Reaction time: 16 h; R_f = 0.29 (50% EtOAc/hexane).

Yield: 56% (0.099 g); white solid; mp 218–220 °C.

IR (KBr): 3058, 2969, 2934, 2848, 1624, 1590, 1502, 1458, 1442, 1376, 1324, 1271, 1238, 1203, 1154, 1116, 1084, 1026, 880, 827, 790, 777, 751, 729 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.02 (d, J = 7.6 Hz, 1 H), 8.08 (s, 1 H), 7.74 (d, J = 7.6 Hz, 1 H), 7.52 (t, J = 7.4 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.16 (s, 1 H), 4.96 (br s, 1 H), 4.04 (s, 3 H), 4.03 (s, 3 H), 1.88 (d, J = 6.8 Hz, 6 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 172.3, 155.2, 151.9, 146.0, 136.4, 134.4, 130.8, 130.7, 125.5, 124.4 (2C), 120.6, 116.3, 106.5, 98.5, 59.1, 56.0, 55.9, 20.4.

HR-MS (ESI): m/z [M + H] calcd. for C₂₀H₁₉NO₃S: 354.1164; found: 354.1176.

 

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6-Ethylbenzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4p)

Reaction time: 23 h; R_f = 0.28 (33% ethyl acetate/hexane).

Yield: 56% (0.078 g); white solid; mp 176–178 °C.

IR (KBr): 3063, 3041, 2979, 2923, 2861, 1612, 1587, 1515, 1492, 1466, 1442, 1413, 1364, 1275, 1145, 1083, 847, 799, 762, 734 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.93 (d, J = 7.9 Hz, 1 H), 8.61 (d, J = 7.8 Hz, 1 H), 7.65–7.57 (m, 2 H), 7.49 (t, J = 7.5 Hz, 1 H), 7.39 (d, J = 8.5 Hz, 1 H), 7.36–7.29 (m, 2 H), 4.30 (q, J = 7.0 Hz, 2 H), 1.48 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.1, 155.9, 139.1, 136.5, 132.0, 131.1, 127.4, 126.1, 125.7, 124.89, 124.81, 123.0, 121.2, 116.8, 114.2, 46.6, 12.6.

HR-MS (ESI): m/z [M + H] calcd. for C₁₇H₁₃NOS: 280.0791; found: 280.0798.

 

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6-(m-Tolyl)benzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4q)

Reaction time: 24 h; R_f = 0.48 (20% EtOAc/hexane).

Yield: 59% (0.100 g); white solid; mp 216–218 °C.

IR (KBr): 3048, 2918, 2852, 1619, 1594, 1516, 1489, 1441, 1337, 1292, 1168, 1091, 1019, 794, 748, 727 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.00 (d, J = 8.0 Hz, 1 H), 8.68 (d, J = 7.9 Hz, 1 H), 7.62–7.58 (m, 2 H), 7.54–7.49 (m, 3 H), 7.41 (t, J = 7.4 Hz, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), 7.31–7.30 (m, 2 H), 6.94 (d, J = 8.5 Hz, 1 H), 2.51 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.8, 157.9, 141.7, 141.6, 139.8, 136.5, 132.1, 131.8, 131.5, 130.9, 129.0, 127.0, 126.1, 125.6, 125.4, 125.0, 124.9, 123.4, 121.2, 116.9, 116.5, 21.5.

HR-MS (ESI): m/z [M + H] calcd. for C₂₂H₁₅NOS: 342.0947; found: 342.0955.

 

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6-Cyclopropylbenzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4r)

Reaction time: 11 h; R_f = 0.29 (20% EtOAc/hexane).

Yield: 60% (0.087 g); white solid; mp 206–208 °C.

IR (KBr): 3055, 2995, 2923, 2848, 1619, 1593, 1571, 1519, 1492, 1458, 1441, 1412, 1357, 1342, 1287, 1255, 1170, 1095, 1044, 944, 841, 796, 751, 729 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.97 (d, J = 8.0 Hz, 1 H), 8.62 (dd, J = 8.0, 1.6 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.69–7.65 (m, 1 H), 7.53–7.49 (m, 1 H), 7.42–7.35 (m, 2 H), 3.51–3.45 (m, 1 H), 1.54–1.49 (m, 2 H), 1.34–1.30 (m, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.6, 157.9, 141.3, 136.1, 132.1, 131.4, 127.0, 125.8, 125.7, 124.7, 124.6, 123.1, 121.0, 117.0, 116.1, 32.2, 11.3.

HR-MS (ESI): m/z [M + H] calcd. for C₁₈H₁₃NOS: 292.0791; found: 292.0792.

 

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6-Cyclohexylbenzo[4,5]thieno[2,3-b]quinolin-11(6H)-one (4s)

Reaction time: 24 h; R_f = 0.34 (33% EtOAc/hexane).

Yield: 45% (0.075 g); white solid; mp 162–164 °C.

IR (KBr): 3041, 2908, 2812, 1619, 1591, 1526, 1489, 1282, 1178, 1081, 768, 747 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.02 (d, J = 7.2 Hz, 1 H), 8.69 (d, J = 7.7 Hz, 1 H), 7.88 (s, 1 H), 7.73 (d, J = 7.7 Hz, 1 H), 7.65 (s, 1 H), 7.52 (t, J = 7.4 Hz, 1 H), 7.39 (dd, J = 16.1, 7.9 Hz, 2 H), 4.43 (br s, 1 H), 2.65 (s, 2 H), 2.07 (d, J = 11.2 Hz, 4 H), 1.87 (d, J = 12.2 Hz, 1 H), 1.57 (d, J = 12.3 Hz, 2 H), 1.40 (dd, J = 24.4, 11.9 Hz, 1 H).

¹³C{¹H} NMR (175 MHz, CDCl₃): δ = 173.4, 157.6, 139.4, 137.4, 130.9, 127.8, 126.7, 126.1, 125.1 (2C), 125.0 (2C), 123.0, 120.9, 117.3 (2C), 30.1, 26.7, 25.3.

HR-MS (ESI): m/z [M + H] calcd. for C₂₁H₁₉NOS: 334.1260; found: 334.1260.

 

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Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 07 June 2024

Accepted after revision: 04 July 2024

Accepted Manuscript online:
04 July 2024

Article published online:
29 July 2024