Palladium-catalysed direct regiospecific arylation at C5 of thiophenes bearing SO₂R substituents at C3

Abstract

The palladium catalysed direct arylation of thiophenes substituted at C3 by SO₂R subtituents was found to be fully selective in favor of carbon C5. This reaction allows the synthesis of a wide variety of 5-aryl-3-sulfonic acid derivatives using as little as 0.5–1 mol% of Pd(OAc)₂ as the catalyst in only one step.

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The functionalisation of heteroaromatics has been extensively investigated in recent decades as they exhibit useful physical or biological properties. For example, some thiophene derivatives bearing SO₂R as substituents have been described as non-steroidal anti-inflammatory drugs or anti-glaucoma agents (Fig. 1).

Fig. 1 Examples of bioactive thiophenes bearing SO₂R substituents.

The palladium-catalysed direct arylation of several heteroaromatics via C–H bond activation using aryl halides has been successful in recent years.^1,2 However, there are still limitations for these reactions in terms of regioselectivity and also heteroaromatics functional group tolerance.^3–8 We have recently reported that thiophenes substituted at C2 by SO₂R led regioselectively to the C5 arylated products.⁹ On the other hand, the regioselectivity of direct arylations of thiophene bearing SO₂R at C3 has not been reported.¹⁰ The control of the regioselectivity for direct arylation remains an essential issue due to the presence of several C–H bonds with similar reactivity on most heterocycles. In the course of the palladium-catalysed arylation of 3-substituted thiophenes, in general, the most reactive position is carbon C2;¹¹ although, arylation at C5 is also possible (Scheme 1).¹²

Scheme 1

For example, in 2003 Sharp and co-workers reported conditions that allow the regioselective arylation of methyl 3-thiophene carboxylate.^12a The use of Pd(PPh₃)₄ in toluene gave selectively the 2-arylated thiophene; whereas, Pd₂(dba)₃ in NMP gave a mixture of 2- and 5-arylated thiophenes in a 15 : 51 ratio. In 1998, Lemaire and co-workers have reported the direct 2-arylation of 3-formyl-, 3-cyano and 3-nitrothiophene with aryl iodides.^11a,b Bilodeau and co-workers have examined the regioselectivity of the arylation of 3-methylthiophene with bromobenzene using Pd[(P(t-Bu)₃]₂ as the catalyst. They obtained a mixture of the 2- and 5-phenylated thiophenes in a 3.3 : 1 ratio (30% yield of 2-phenylation and 9% yield of the 5-phenylated thiophene).^12b Recently, Fagnou and co-workers have reported the direct arylation of 3-n-hexylthiophene with 4-bromonitrobenzene.^12c A mixture of C2 and C5 arylation products was obtained in a 1.3 : 1 ratio. The direct arylation of 3-methoxythiophene has been explored by Borghese and co-workers.^11c With this reactant, the 2-arylated thiophenes were regioselectively obtained in 28–60% yields. It should be noted that, with some very specific substrates, the C5 arylated thiophenes have been obtained in quite high regioselectivities. For example, a thiophene substituted at C3 by an acetal selectively led to the C5 arylated thiophenes.^12e

If the regioselectivity of the arylation can be controlled, such a reaction appears more attractive and useful than palladium catalysed Suzuki, Stille or Negishi cross-couplings for the synthesis of arylated thiophenes. This is because no previous preparation of an organometallic derivative and its transmetallation product using B(OR)₃, XSnR₃ or ZnX₂ is required (Scheme 2).^13,14

Scheme 2

Herein, we report on the palladium-catalysed direct regiospecific arylation at C5 of thiophenes bearing SO₂R substituents at C3 with a variety of aryl bromides.

We initially examined the reactivity of both methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate 1 and thiophene-3-sulfonic acid diethylamide 2 with 4-bromobenzonitrile using KOAc as the base, DMAc as the solvent in the presence of only 0.5 mol% Pd(OAc)₂ as the catalyst (Scheme 3). From 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate 1, we expected the regioselective formation of the C5 arylated product, as we had previously observed that the use of esters as blocking groups at C2 position on a range of 3-substituted thiophenes allows control of the regioselectivity of the palladium-catalysed direct arylation at C5.^4g Under these conditions, a regiospecific arylation at C5 was observed. However, in the course of this reaction, a complete decarboxylation of the thiophene derivative occurs to give 3 in 82% yield. The progress of this reaction was monitored by GC-MS and ¹H NMR analysis. After 5 min, a ratio of 13 : 87 in 1 : 2 was observed, and 3 was formed in 39% yield. A conversion of 92% of 4-bromobenzonitrile in favor of the formation of 3 was observed after 15 min. It should be noted that both at 5 and 15 min, no trace of non-decarboxylated coupling product could be detected.

Scheme 3

This in situ decarboxylation was found to be due to the poor thermal stability of 1. The heating of 1 at 130 °C in DMAc during 16 h in the presence of KOAc without palladium catalyst produces 2 in quantitative yield (Scheme 4). Even in the absence of base, 2 was produced in 54% yield.

Scheme 4

We then employed thiophene-3-sulfonic acid diethylamide 2 as the coupling partner. A mixture of C2 and C5 arylated thiophenes might have been produced. However, again, only the C5 arylated thiophene 3 was obtained. No trace of arylation at C2 was detected. The complete regioselectivity of this arylation is certainly due to the steric hindrance of the SO₂NEt₂ substituent. Because methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate 1 is more affordable than thiophene-3-sulfonic acid diethylamide 2, it was employed as the reactant to study the scope of this reaction with other aryl bromides (Table 1).

Table 1 Palladium catalysed coupling of methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate with aryl halides (Scheme 5)

Entry	Aryl halide	Product	Yield (%)^a
a Conditions: Pd(OAc)2 (0.005 mmol), methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (1.5 mmol), aryl halide (1 mmol), KOAc (2 mmol), DMAc, 130 °C, 16 h, isolated yields. b 4-chloropropiophenone as aryl halide. c 4-chloronitrobenzene as aryl halide. d 4-iodoanisole as aryl halide.
1		4	84
2		5	77
3		6	86
4			0^b
5		7	83
6			26^c
7		8	90
8		9	63
9		10	78
10		11	80
11			28^d
12		12	77
13		13	91
14		14	80
15		15	89
16		16	68

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4-Bromoacetophenone, 4-bromobenzaldehyde, 4-bromopropiophenone, 4-bromonitrobenzene or 4-trifluoromethylbromobenzene reacted with methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate 1 gave the products 4–8 in 77–90% yields (Scheme 5, Table 1, entries 1–3, 5 and 7). Again, in all cases, a regiospecific arylation at C5 and a complete decarboxylation was observed. A lower yield of 63% of 9 was obtained using 4-bromofluorobenzene, due to a partial conversion of this aryl bromide (Table 1, entry 8). It should be noted that even 4-chlorobromobenzene could be employed to give 10 in 78% yield (Table 1, entry 9). In the course of this reaction, no cleavage of the C–Cl bond was observed, allowing further transformations. The electron-rich aryl halides, 4-bromoanisole and 4-iodoanisole were then employed. In both cases, 11 was produced. However, a high yield of 80% was obtained from 4-bromoanisole; whereas, from 4-iodoanisole a large amount of this reactant was recovered unreacted (Table 1, entries 10 and 11).

Scheme 5

The meta-substituted aryl bromide, 3-bromoacetophenone gave product 12 in 77% yield (Table 1, entry 12). Even the ortho-substituted aryl bromides, 2-bromobenzonitrile and 1-bromonaphthalene gave the desired coupling products 13 and 14 in good yields (Table 1, entries 13 and 14). Pyridines are probably the most common heterocyclic motif found in pharmaceutically active compounds. We observed that 3- or 4-bromopyridines are also suitable reactants (Table 1, entries 15 and 16). It should be noted that regiospecific arylations at C5 of 1 with complete decarboxylation were observed in all cases. Two electron-deficient aryl chlorides were also employed as the coupling partners. From 4-chloropropiophenone, no formation of 6 was detected; whereas the use of 4-chloronitrobenzene allowed the formation of 7 in a low yield of 26% (Table 1, entries 4 and 6).

Methyl 3-(morpholinosulfamoyl)thiophene-2-carboxylate 17 reacted with 2- or 4-bromobenzonitriles or 1-bromonaphthalene also gave the 5-arylated thiophenes 18–20 in high yields with complete decarboxylation (Scheme 5, Table 2). From 5-bromopyridine, 21 was only obtained in moderate yield due to formation of side-products.

Table 2 Palladium catalysed coupling of methyl 3-(morpholinosulfamoyl)thiophene-2-carboxylate with aryl bromides (Scheme 5)^a

Entry	Aryl bromide	Product	Yield (%)^a
a Conditions: Pd(OAc)2 (0.005 mmol), methyl 3-(morpholinosulfamoyl)thiophene-2-carboxylate (2 mmol), aryl bromide (1 mmol), KOAc (2 mmol), DMAc, 150 °C, 16 h, isolated yields.
1		18	72
2		19	77
3		20	80
4		21	45

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The reaction is not limited to the use of sulfonic acid dialkylamides. Methyl 3-(N-butyl-N-phenylsulfamoyl)thiophene-2-carboxylate 22 was also successfully employed as a coupling partner (Scheme 5, Table 3). A similar reactivity to methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate was observed. From 2- or 4-bromobenzonitriles, 3-bromonitrobenzene, 1-bromonaphthalene or 3-bromoisoquinoline 23 and 25–28 were obtained in 75–82% yields. Again, in all cases, a regiospecific arylation at C5 and a complete decarboxylation was observed.

Table 3 Palladium catalysed coupling of methyl 3-(N-butyl-N-phenylsulfamoyl)thiophene-2-carboxylate with aryl bromides (Scheme 5)^a

Entry	Aryl bromide	Product	Yield (%)^a
a Conditions: Pd(OAc)2 (0.01 mmol), methyl 3-(N-butyl-N-phenylsulfamoyl)thiophene-2-carboxylate (1.5 mmol), aryl bromide (1 mmol), KOAc (2 mmol), DMAc, 150 °C, 16 h, isolated yields.
1		23	78
2		24	54
3		25	77
4		26	79
5		27	75
6		28	82

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On the other hand, thiophene-3-sulfonic acid benzylamide 29 was found to be unreactive. Using similar reaction conditions, no formation of the desired product 30 was detected (Scheme 6). The presence of a free NH on this reactant certainly poisons the catalyst.

Scheme 6

Finally, the reactivity of methyl 3-phenoxysulfonylthiophene-2-carboxylate was studied (Scheme 7, Table 4). In the presence of 4-bromobenzonitrile, product 31 was obtained in 80% yield with again a regiospecific 5-arylation with complete decarboxylation of the thiophene derivative (Table 4, entry 1). No formation of the C2 arylated product was detected. The use of other aryl bromides such as methyl 4-bromobenzoate, 3-chlorobromobenzene, 2-bromobenzonitrile or 3-bromopyridine gave 32–39 in 58–83% yields.

Scheme 7

Table 4 Palladium catalysed coupling of methyl 3-phenoxysulfonylthiophene-2-carboxylate with aryl bromides (Scheme 7)^a

Entry	Aryl bromide	Product	Yield (%)^a
a Conditions: Pd(OAc)2 (0.01 mmol), methyl 3-phenoxysulfonylthiophene-2-carboxylate (1.5 mmol), aryl bromide (1 mmol), KOAc (2 mmol), DMAc, 150 °C, 16 h, isolated yields.
1		32	80
2		33	84
3		34	83
4		35	72
5		36	58
6		37	78
7		38	77
8		39	60

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In summary, we have demonstrated that thiophenes substituted at C3 by SO₂R functions can be coupled with a variety of aryl bromides, using only 0.5–1 mol% of the Pd(OAc)₂ catalyst associated with KOAc as the base. In all cases, a regiospecific arylation at C5 was observed. From both methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate 1 and thiophene-3-sulfonic acid diethylamide 2, the product 3 was obtained in similar yields due to a complete decarboxylation of 1. A similar regioselectivity was observed with other tertiary thiophene sulfonamides and also with a thiophene sulfonic acid phenyl ester. It should be noted that for these couplings a wide range of functional groups on the aryl bromide are tolerated, including formyl, acetyl, propionyl, ester, nitrile, nitro, ester, trifluoromethyl, fluoro or chloro. Such functional group tolerance should allow easy modification of structures for the preparation of important bioactive compounds. This procedure employs a relatively low loading of a commercially available air stable palladium catalyst. The major by-products are AcOH/KBr instead of metallic salts with classical coupling procedures. Moreover, no preparation of an organometallic derivative is required, reducing the number of steps in the preparation of these compounds. Despite their interest, the products prepared by this method are new, indicating a relatively limited access to such compounds using more traditional cross-coupling procedures.

Experimental

All reactions were run under argon in Schlenk tubes using vacuum lines. DMAc analytical grade was not distilled before use. Potassium acetate (99%) was used. Commercial aryl halides and methyl 3-(sulfamoylchloride)thiophene-2-carboxylate were used without purification. ¹H and ¹³C spectrum were recorded with Bruker 300 or 400 MHz spectrometer solutions. Flash chromatography was performed on silica gel (230–400 mesh).

Methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (1)¹⁵

Diethylamine (0.183 g, 2.5 mmol) and triethylamine (1.15 g, 8.0 mmol) were added to 5 mL of dry CH₂Cl₂ under an argon atmosphere at room temperature. Methyl 3-(sulfamoylchloride)thiophene-2-carboxylate (0.481 g, 2 mmol) was then added, and the reaction was stirred for 12 h. The product was extracted with CH₂Cl₂ (3 × 15 mL), washed successively with HCl 1N, water and dried over MgSO₄. The solvent was evaporated under reduced pressure. Purification by flash chromatography (diethylether/pentane: 1/9) afforded 1 as a white solid in 86% (0.476 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ: 7.77 (d, J = 5.2 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 3.91 (s, 3H), 3.45 (q, J = 7.8 Hz, 4H), 1.15 (t, J = 7.8 Hz, 6H).

Thiophene-3-sulfonic acid diethylamide (2)

Methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.692 g, 2.5 mmol) and KOAc (0.490 g, 5 mmol) was added in 5 mL of DMAc under an argon atmosphere at 150 °C. The reaction was stirred for 12 h. After evaporation of the solvent, the product was purified by flash chromatography (diethylether/pentane: 1/9) to afford 2 as a yellow solid in 81% (0.443 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ: 7.89 (dd, J = 3.0, 1.2 Hz, 1H), 7.40 (dd, J = 5.2, 3.0 Hz, 1H), 7.28 (dd, J = 5.2, 1.2 Hz, 1H), 3.24 (q, J = 7.8 Hz, 4H), 1.14 (t, J = 7.8 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ: 139.8, 131.2, 129.6, 125.8, 42.4, 14.6. Elemental analysis: calcd (%) for C₈H₁₃NO₂S₂ (219.33): C 43.81, H 5.97, found: C 43.78, H 5.87.

General procedure for coupling reactions

As a typical experiment, the reaction of the aryl bromide (1 mmol), thiophene derivative (1.5 mmol) and KOAc (0.196 g, 2 mmol) at 130 or 150 °C (see Tables) during 16 h in DMAc (4 mL) in the presence of Pd(OAc)₂ 0.5–1 mol% (see Tables) under argon affords the coupling product after evaporation of the solvent and purification on silica gel.

5-(4-Cyanophenyl)-thiophene-3-sulfonic acid diethylamide (3)

4-Bromobenzonitrile (0.182 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 3 in 82% (0.262 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.31 (d, J = 1.3 Hz, 1H), 7.99 (d, J = 1.3 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 3.22 (q, J = 7.1 Hz, 4H), 1.08 (t, J = 7.1 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ 144.2, 141.2, 137.1, 133.6, 132.0, 126.8, 123.9, 119.0, 111.2, 42.7, 14.7. Elemental analysis: calcd (%) for C₁₅H₁₆N₂O₂S₂ (320.43): C 56.22, H 5.03, found: C 56.10, H 5.14.

5-(4-Acetylphenyl)-thiophene-3-sulfonic acid diethylamide (4)

4-Bromoacetophenone (0.199 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 4 in 84% (0.283 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.27 (d, J = 1.3 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 1.3 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 3.22 (q, J = 7.1 Hz, 4H), 2.59 (s, 3H), 1.08 (t, J = 7.1 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ 197.2, 144.5, 140.6, 136.4, 136.2, 130.9, 129.1, 125.7, 122.6, 42.1, 26.7, 14.2. Elemental analysis: calcd (%) for C₁₆H₁₉NO₃S₂ (337.46): C 56.95, H 5.68, found: C 56.87, H 5.79.

5-(4-Formylphenyl)-thiophene-3-sulfonic acid diethylamide (5)

4-Bromobenzaldehyde (0.185 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 5 in 77% (0.249 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 10.01 (s, 1H), 8.31 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 1.3 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 3.22 (q, J = 7.1 Hz, 4H), 1.08 (t, J = 7.1 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ 192.4, 144.3, 140.6, 137.7, 135.6, 131.3, 130.4, 126.1, 123.1, 42.1, 14.2. Elemental analysis: calcd (%) for C₁₅H₁₇NO₃S₂ (323.43): C 55.70, H 5.30, found: C 55.62, H 5.18.

5-(4-propionylphenyl)-thiophene-3-sulfonic acid diethylamide (6)

4-Bromopropiophenone (0.213 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 6 in 86% (0.302 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.28 (d, J = 1.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 1.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 3.22 (q, J = 7.1 Hz, 4H), 3.05 (q, J = 7.1 Hz, 2H), 1.08 (t, J = 7.1 Hz, 9H). ¹³C NMR (75 MHz, DMSO-d6): δ 199.6, 144.5, 140.6, 136.3, 136.0, 130.8, 128.8, 125.7, 122.6, 42.1, 31.2, 14.2, 8.0. Elemental analysis: calcd (%) for C₁₇H₂₁NO₃S₂ (351.49): C 58.09, H 6.02, found: C 58.01, H 6.14.

5-(4-Nitrophenyl)-thiophene-3-sulfonic acid diethylamide (7)

4-Bromonitrobenzene (0.202 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 7 in 83% (0.282 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.37 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 8.0 Hz, 2H), 8.06–8.04 (m, 3H), 3.22 (q, J = 7.1 Hz, 4H), 1.09 (t, J = 7.1 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ 146.8, 143.1, 140.8, 138.5, 132.0, 126.6, 124.4, 124.0, 42.2, 14.2. Elemental analysis: calcd (%) for C₁₄H₁₆N₂O₄S₂ (340.42): C 49.39, H 4.74, found C 49.28, H 4.87.

5-(4-Trifluoromethylphenyl)-thiophene-3-sulfonic acid diethylamide (8)

4-Trifluoromethylbromobenzene (0.225 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 8 in 90% (0.327 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.31 (d, J = 1.4 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 1.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 3.22 (q, J = 7.1 Hz, 4H), 1.09 (t, J = 7.1 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ 143.9, 140.6, 136.2, 131.0, 128.5 (q, J = 32.0 Hz), 126.4, 126.0 (q, J = 3.8 Hz), 123.0 (q, J = 272.0 Hz), 122.9, 42.1, 14.2. Elemental analysis: calcd (%) for C₁₅H₁₆F₃NO₂S₂ (363.42): C 49.57, H 4.44, found C 49.67, H 4.58.

5-(4-Fluorophenyl)-thiophene-3-sulfonic acid diethylamide (9)

4-Bromofluorobenzene (0.175 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 9 in 63% (0.197 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.18 (d, J = 1.3 Hz, 1H), 7.81 (dd, J = 8.8, 5.3 Hz, 2H), 7.73 (d, J = 1.3 Hz, 1H), 7.29 (t, J = 8.8 Hz, 2H), 3.20 (q, J = 7.1 Hz, 4H), 1.08 (t, J = 7.1 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ 162.1 (d, J = 246.2 Hz), 144.7, 140.3, 129.6, 129.1 (d, J = 3.2 Hz), 127.9 (d, J = 8.4 Hz), 121.1, 116.1 (d, J = 21.9 Hz), 42.1, 14.2. Elemental analysis: calcd (%) for C₁₄H₁₆FNO₂S₂ (313.41): C 53.65, H 5.15, found C 53.57, H 5.21.

5-(4-Chlorophenyl)-thiophene-3-sulfonic acid diethylamide (10)

4-Bromochlorobenzene (0.191 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 10 in 78% (0.257 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.21 (d, J = 1.3 Hz, 1H), 7.80 (d, J = 1.3 Hz, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 3.20 (q, J = 7.1 Hz, 4H), 1.08 (t, J = 7.1 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ 144.7, 140.6, 133.3, 131.5, 130.2, 129.4, 127.7, 121.9, 42.3, 14.4. Elemental analysis: calcd (%) for C₁₄H₁₆ClNO₂S₂ (329.87): C 50.98, H 4.89, found C 50.81, H 4.79.

5-(4-Methoxyphenyl)-thiophene-3-sulfonic acid diethylamide (11)

4-Bromoanisole (0.187 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 11 in 80% (0.260 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.09 (d, J = 1.3 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 1.3 Hz, 1H), 7.00 (d, J = 8.5 Hz, 2H), 3.80 (s, 3H), 3.20 (q, J = 7.1 Hz, 4H), 1.08 (t, J = 7.1 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ 159.6, 145.9, 140.1, 128.4, 127.1, 124.9, 119.6, 114.5, 55.2, 42.1, 14.2. Elemental analysis: calcd (%) for C₁₅H₁₉NO₃S₂ (325.45): C 55.36, H 5.88, found C 55.47, H 5.99.

5-(3-Acetylphenyl)-thiophene-3-sulfonic acid diethylamide (12)

3-Bromoacetophenone (0.199 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 12 in 77% (0.260 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.24 (d, J = 1.3 Hz, 1H), 8.22 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 1.3 Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 3.21 (q, J = 7.1 Hz, 4H), 2.65 (s, 3H), 1.09 (t, J = 7.1 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ 198.2, 145.3, 140.9, 138.1, 133.3, 130.7, 130.6, 130.2, 128.6, 125.5, 122.5, 42.7, 27.4, 14.8. Elemental analysis: calcd (%) for C₁₆H₁₉NO₃S₂ (337.46): C 56.95, H 5.68, found: C 56.99, H 5.81.

5-(2-Cyanophenyl)-thiophene-3-sulfonic acid diethylamide (13)

2-Bromobenzonitrile (0.182 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 13 in 91% (0.291 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.41 (d, J = 1.4 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.83–7.77 (m, 3H), 7.65–7.59 (m, 1H), 3.22 (q, J = 7.1 Hz, 4H), 1.09 (t, J = 7.1 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ 141.2, 140.0, 135.1, 134.5, 133.9, 132.0, 129.9, 129.3, 125.2, 118.1, 109.5, 42.0, 14.1. Elemental analysis: calcd (%) for C₁₅H₁₆N₂O₂S₂ (320.43): C 56.22, H 5.03, found: C 56.31, H 5.18.

5-Naphthalen-1-ylthiophene-3-sulfonic acid diethylamide (14)

1-Bromonaphthalene (0.207 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 14 in 80% (0.276 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.36 (d, J = 1.5 Hz, 1H), 8.05–8.01 (m, 3H), 7.63–7.54 (m, 4H), 7.55 (d, J = 1.5 Hz, 1H), 3.24 (q, J = 7.1 Hz, 4H), 1.09 (t, J = 6.9 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ 143.4, 139.7, 133.4, 130.8, 130.7, 130.0, 129.3, 128.6, 128.5, 127.2, 126.4, 125.4, 124.9, 124.4, 42.1, 14.1. Elemental analysis: calcd (%) for C₁₈H₁₉NO₂S₂ (345.48): C 62.58, H 5.54, found C 62.47, H 5.47.

5-Pyridin-3-ylthiophene-3-sulfonic acid diethylamide (15)

3-Bromopyridine (0.158 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 15 in 89% (0.263 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.57 (d, J = 4.9 Hz, 1H), 8.28 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.92 (s, 1H), 7.48 (dd, J = 7.9, 3.0 Hz, 1H), 3.20 (q, J = 7.1 Hz, 4H), 1.08 (t, J = 6.9 Hz, 6H). ₁₃C NMR (75 MHz, DMSO-d6): δ 149.4, 146.4, 142.2, 140.5, 133.1, 130.6, 128.4, 124.0, 122.4, 42.2, 14.3. Elemental analysis: calcd (%) for C₁₃H₁₆N₂O₂S₂ (296.41): C 52.68, H 5.44, found C 52.41, H 5.31.

5-Pyridin-4-ylthiophene-3-sulfonic acid diethylamide (16)

4-Bromopyridine hydrochloride (0.194 g, 1 mmol) and methyl 3-(N,N-diethylsulfamoyl)thiophene-2-carboxylate (0.416 g, 1.5 mmol) affords 16 in 68% (0.201 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.62 (bs, 2H), 8.36 (s, 1H), 8.08 (s, 1H), 7.77 (d, J = 4.3 Hz, 2H), 3.21 (q, J = 7.3 Hz, 4H), 1.08 (t, J = 7.1 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d6): δ 150.4, 142.7, 140.6, 139.2, 131.7, 123.8, 119.7, 42.1, 14.2. Elemental analysis: calcd (%) for C₁₃H₁₆N₂O₂S₂ (296.41): C 52.68, H 5.44, found C 52.72, H 5.24.

Methyl 3-(morpholinosulfamoyl)thiophene-2-carboxylate (17)

Morpholine (0.522 g, 6 mmol), and triethylamine (1.15 g, 8 mmol) were added to 5 mL of dry CH₂Cl₂ under argon atmosphere at room temperature. Methyl 3-(sulfamoylchloride)thiophene-2-carboxylate (0.481 g, 2 mmol) was then added, and the reaction was stirred for 12 h. The product was extracted with CH₂Cl₂ (3 × 15 mL), washed successively with HCl 1N, water and dried over MgSO₄. The solvent was evaporated under reduced pressure. Purification by flash chromatography (diethylether/pentane: 3/7) afforded 17 as a white solid in 91% (0.530 g) yield.

¹H NMR (400 MHz, DMSO-d6): 8.02 (d, J = 5.2 Hz, 1H), 7.44 (d, J = 5.2 Hz, 1H), 3.84 (s, 3H), 3.65–3.60 (m, 4H), 3.20–3.10 (m, 4H).

¹³C NMR (100 MHz, DMSO-d6): δ: 160.0, 138.1, 134.3, 131.3, 130.1, 65.6, 53.1, 45.8. Elemental analysis: calcd (%) for C₁₀H₁₃NO₅S₂ (291.35): C 41.22, H 4.50, found: C 41.34, H 4.64.

4-[4-(Morpholine-4-sulfonyl)-thiophen-2-yl]-benzonitrile (18)

4-Bromobenzonitrile (0.182 g, 1 mmol) and methyl 3-(morpholinosulfamoyl)thiophene-2-carboxylate (0.436 g, 1.5 mmol) affords 18 in 72% (0.241 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.38 (d, J = 1.3 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 1.3 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 3.66 (t, J = 4.5 Hz, 4H), 2.96 (t, J = 4.5 Hz, 4H). ¹³C NMR (75 MHz, DMSO-d6): δ 143.8, 136.5, 135.7, 133.3, 133.1, 126.5, 123.8, 118.5, 110.8, 65.2, 45.8. Elemental analysis: calcd (%) for C₁₅H₁₄N₂O₃S₂ (334.42): C 53.87, H 4.22, found: C 54.04, H 4.14.

2-[4-(Morpholine-4-sulfonyl)-thiophen-2-yl]-benzonitrile (19)

2-Bromobenzonitrile (0.182 g, 1 mmol) and methyl 3-(morpholinosulfamoyl)thiophene-2-carboxylate (0.436 g, 1.5 mmol) affords 19 in 77% (0.257 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.45 (d, J = 1.5 Hz, 1H), 8.00 (d, J = 6.9 Hz, 1H), 7.82–7.80 (m, 2H), 7.75 (d, J = 1.5 Hz, 1H), 7.66–7.60 (m, 1H), 3.66 (t, J = 4.5 Hz, 4H), 2.96 (t, J = 4.5 Hz, 4H). ¹³C NMR (75 MHz, DMSO-d6): δ 141.4, 135.0, 134.9, 134.4, 133.9, 133.8, 130.1, 129.4, 125.7, 118.2, 109.7, 65.2, 45.8. Elemental analysis: calcd (%) for C₁₅H₁₄N₂O₃S₂ (334.42): C 53.87, H 4.22, found: C 54.01, H 4.30.

4-(5-Naphthalen-1-ylthiophene-3-sulfonyl)-morpholine (20)

1-Bromonaphthalene (0.207 g, 1 mmol) and methyl 3-(morpholinosulfamoyl)thiophene-2-carboxylate (0.436 g, 1.5 mmol) affords 20 in 80% (0.287 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.42 (d, J = 1.3 Hz, 1H), 8.09–8.00 (m, 3H), 7.65–7.53 (m, 4H), 7.49 (d, J = 1.3 Hz, 1H), 3.67 (t, J = 4.5 Hz, 4H), 3.00 (t, J = 4.5 Hz, 4H). ¹³C NMR (75 MHz, DMSO-d6): δ 143.5, 134.6, 133.3, 132.6, 130.6, 129.8, 129.4, 128.6, 128.5, 127.3, 126.4, 125.5, 125.4, 124.4, 65.2, 45.8. Elemental analysis: calcd (%) for C₁₈H₁₇NO₃S₂ (359.46): C 60.14, H 4.77, found: C 60.31, H 4.64.

4-(5-Pyrimidin-5-ylthiophene-3-sulfonyl)-morpholine (21)

5-Bromopyrimidine (0.158 g, 1 mmol) and methyl 3-(morpholinosulfamoyl)thiophene-2-carboxylate (0.436 g, 1.5 mmol) affords 21 in 45% (0.140 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 9.23 (s, 2H), 9.18 (s, 1H), 8.42 (d, J = 1.5 Hz, 1H), 8.00 (d, J = 1.5 Hz, 1H), 3.66 (t, J = 4.5 Hz, 4H), 2.96 (t, J = 4.5 Hz, 4H). ¹³C NMR (75 MHz, DMSO-d6): δ 157.8, 153.8, 138.7, 135.6, 133.5, 126.8, 124.2, 65.2, 45.8. Elemental analysis: calcd (%) for C₁₂H₁₃N₃O₃S₂ (311.38): C 46.29, H 4.21, found: C 46.20, H 4.14.

Methyl 3-(N-butyl-N-phenylsulfamoyl)thiophene-2-carboxylate (22)

N-butylaniline (0.447 g, 3 mmol) and triethylamine (1.15 g, 8 mmol) were added to 5 mL of dry CH₂Cl₂ under argon atmosphere at room temperature. Methyl 3-(sulfamoylchloride)thiophene-2-carboxylate (0.481 g, 2 mmol) was then added, and the reaction was stirred for 12 h. The product was extracted with CH₂Cl₂ (3 × 15 mL), washed successively with HCl 1N, water and dried over MgSO₄. The solvent was evaporated under reduced pressure. Purification by flash chromatography (diethylether/pentane: 4/6) afforded 22 as a white solid in 79% (0.558 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 7.87 (d, J = 5.2 Hz, 1H), 7.40–7.28 (m, 3H), 7.18 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 5.2 Hz, 1H), 3.80–3.75 (m, 5H), 1.32–1.28 (m, 4H), 0.85–0.80 (m, 3H). ¹³C NMR (75 MHz, DMSO-d6): δ 160.0, 140.2, 138.2, 133.4, 130.9, 130.4, 129.1, 128.5, 127.8, 53.0, 50.5, 30.0, 18.9, 13.4. Elemental analysis: calcd (%) for C₁₆H₁₉NO₄S₂ (353.46): C 54.37, H 5.42, found: C 54.40, H 5.51.

5-(4-Cyanophenyl)-thiophene-3-sulfonic acid nbutylphenyl-amide (23)

4-Bromobenzonitrile (0.182 g, 1 mmol) and methyl 3-(N-butyl-N-phenylsulfamoyl)thiophene-2-carboxylate (0.530 g, 1.5 mmol) affords 23 in 78% (0.309 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.11 (d, J = 0.9 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 0.9 Hz, 1H), 7.40–7.31 (m, 3H), 7.13 (d, J = 7.3 Hz, 2H), 3.65 (t, J = 7.0 Hz, 2H), 1.32–1.27 (m, 4H), 0.83 (t, J = 7.0 Hz, 3H). ¹³C NMR (75 MHz, DMSO-d6): δ 143.6, 138.7, 138.5, 136.5, 133.1, 132.6, 129.1, 128.4, 127.9, 126.3, 123.4, 118.5, 110.7, 49.7, 29.7, 18.8, 13.3. Elemental analysis: calcd (%) for C₂₁H₂₀ N₂O₂S₂ (396.53): C 63.61, H 5.08, found: C 63.54, H 5.20.

5-(4-Formylphenyl)-thiophene-3-sulfonic acid nbutylphenyl-amide (24)

4-Bromobenzaldehyde (0.185 g, 1 mmol) and methyl 3-(N-butyl-N-phenylsulfamoyl)thiophene-2-carboxylate (0.530 g, 1.5 mmol) affords 24 in 54% (0.215 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 10.03 (s, 1H), 8.11 (m, 1H), 7.99–7.96 (m, 4H), 7.80 (m, 1H), 7.41–7.33 (m, 3H), 7.14 (d, J = 7.2 Hz, 2H), 3.66 (t, J = 7.0 Hz, 2H), 1.32–1.30 (m, 4H), 0.83 (t, J = 7.0 Hz, 3H). ¹³C NMR (75 MHz, DMSO-d6): δ 192.4, 144.2, 138.7, 138.5, 137.6, 135.6, 131.4, 130.3, 129.1, 128.5, 127.9, 126.2, 123.1, 49.6, 29.7, 18.8, 13.3. Elemental analysis: calcd (%) for C₂₁H₂₁NO₃S₂ (399.53): C 63.13, H 5.30, found: C 63.23, H 5.11.

5-(3-Nitrophenyl)-thiophene-3-sulfonic acid nbutylphenyl-amide (25)

3-Bromonitrobenzene (0.202 g, 1 mmol) and methyl 3-(N-butyl-N-phenylsulfamoyl)thiophene-2-carboxylate (0.530 g, 1.5 mmol) affords 25 in 77% (0.320 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.51 (d, J = 1.7 Hz, 1H), 8.20 (td, J = 7.9, 1.7 Hz, 2H), 8.09 (d, J = 1.3 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.44–7.32 (m, 3H), 7.14 (d, J = 7.9 Hz, 2H), 3.67 (t, J = 7.0 Hz, 2H), 1.35–1.28 (m, 4H), 0.83 (t, J = 7.0 Hz, 3H). ¹³C NMR (75 MHz, DMSO-d6): δ 148.4, 143.0, 138.6, 138.6, 133.8, 132.1, 132.1, 130.8, 129.1, 128.5, 127.9, 123.3, 123.0, 120.1, 49.6, 29.7, 18.8, 13.3. Elemental analysis: calcd (%) for C₂₀H₂₀N₂O₄S₂ (416.52): C 57.67, H 4.84, found: C 57.60, H 4.81.

5-(2-Cyanophenyl)-thiophene-3-sulfonic acid nbutylphenyl-amide (26)

2-Bromobenzonitrile (0.182 g, 1 mmol) and methyl 3-(N-butyl-N-phenylsulfamoyl)thiophene-2-carboxylate (0.530 g, 1.5 mmol) affords 26 in 79% (0.313 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.19 (d, J = 1.5 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.83–7.78 (m, 2H), 7.70–7.61 (m, 2H), 7.41–7.30 (m, 3H), 7.15 (d, J = 7.7 Hz, 2H), 3.65 (t, J = 7.0 Hz, 2H), 1.31–1.29 (m, 4H), 0.82 (t, J = 7.0 Hz, 3H). ¹³C NMR (75 MHz, DMSO-d6): δ 141.2, 138.5, 138.0, 135.1, 134.3, 133.8, 133.3, 130.0, 129.3, 129.1, 128.5, 127.9, 125.1, 118.1, 109.6, 49.7, 29.7, 18.8, 13.3. Elemental analysis: calcd (%) for C₂₁H₂₀N₂O₂S₂ (396.53): C 63.61, H 5.08, found: C 63.62, H 5.31.

5-Naphthalen-1-yl-thiophene-3-sulfonic acid nbutylphenylamide (27)

1-Bromonaphthalene (0.207 g, 1 mmol) and methyl 3-(N-butyl-N-phenylsulfamoyl)thiophene-2-carboxylate (0.207 g, 1.5 mmol) affords 27 in 75% (0.316 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.29 (d, J = 0.9 Hz, 1H), 8.03–7.93 (m, 3H), 7.63–7.55 (m, 4H), 7.45–7.35 (m, 3H), 7.22 (d, J = 7.3 Hz, 2H), 7.12 (s, 1H), 3.66 (t, J = 7.0 Hz, 2H), 1.31–1.29 (m, 4H), 0.83 (t, J = 7.0 Hz, 3H). ¹³C NMR (75 MHz, DMSO-d6): δ 143.1, 138.6, 137.4, 133.3, 131.7, 130.5, 129.8, 129.3, 129.0, 128.5, 128.4, 127.8, 127.1, 126.4, 125.4, 125.2, 124.4, 49.4, 29.7, 18.9, 13.3. Elemental analysis: calcd (%) for C₂₄H₂₃NO₂S₂ (421.58): C 68.38, H 5.50, found: C 68.47, H 5.61.

5-Quinolin-3-ylthiophene-3-sulfonic acid nbutylphenylamide (28)

3-Bromoquinoline (0.208 g, 1 mmol) and methyl 3-(N-butyl-N-phenylsulfamoyl)thiophene-2-carboxylate (0.207 g, 1.5 mmol) affords 28 in 82% (0.346 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 9.30 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 2.2 Hz, 1H), 8.12–8.03 (m, 3H), 7.90 (d, J = 1.5 Hz, 1H), 7.79 (td, J = 7.2, 1.5 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 7.42–7.31 (m, 3H), 7.16 (d, J = 6.7 Hz, 2H), 3.68 (t, J = 7.0 Hz, 2H), 1.33–1.31 (m, 4H), 0.82 (t, J = 7.0 Hz, 3H). ¹³C NMR (75 MHz, DMSO-d6): δ 147.9, 147.0, 142.4, 138.6, 138.5, 131.9, 131.8, 130.0, 129.1, 128.7, 128.5, 128.3, 127.9, 127.5, 127.3, 125.6, 122.7, 49.7, 29.7, 18.8, 13.4. Elemental analysis: calcd (%) for C₂₃H₂₂N₂O₂S₂ (422.57): C 65.37, H 5.25, found: C 65.41, H 5.14.

Methyl 3-benzylsulfamoylthiophene-2-carboxylate (29)¹⁶

Benzylamine (0.321 g, 3 mmol) and pyridine (1.0 ml, 13 mmol) were added to 5 mL of dry CH₂Cl₂ under argon atmosphere at room temperature. Methyl 3-(sulfamoylchloride)thiophene-2-carboxylate (0.481 g, 2 mmol) was then added, and the reaction was stirred for 12 h. The product was extracted with CH₂Cl₂ (3 × 15 mL), washed successively with HCl 1N, water and dried over MgSO₄. The solvent was evaporated under reduced pressure. Purification by flash chromatography (diethylether/pentane: 6/4) afforded 29 as a white solid in 70% (0.435 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 7.89 (d, J = 5.2 Hz, 1H), 7.75 (bs, 1H), 7.37 (d, J = 5.2 Hz, 1H), 7.20–7.15 (m, 5H), 4.15 (s, 2H), 3.84 (s, 3H).

Methyl 3-phenoxysulfonylthiophene-2-carboxylate (31)

Phenol (0.235 g, 2.5 mmol) and triethylamine (1.15 g, 8 mmol) were added to 5 mL of dry CH₂Cl₂ under an argon atmosphere at room temperature. Methyl 3-(sulfamoylchloride)thiophene-2-carboxylate (0.481 g, 2 mmol) was then added, and the reaction was stirred for 12 h. The product was extracted with CH₂Cl₂ (3 × 15 mL), washed successively with HCl 1N, water and dried over MgSO₄. The solvent was evaporated under reduced pressure. Purification by flash chromatography (diethylether/pentane: 3/7) afforded 31 as a white solid in 89% (0.530 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ: 8.04 (d, J = 5.2 Hz, 1H), 7.48–7.30 (m, 4H), 7.15 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H). ¹³C NMR (75 MHz, DMSO-d6): δ: 159.0, 148.8, 135.9, 135.6, 132.7, 130.8, 127.6, 121.9, 53.3. Elemental analysis: calcd (%) for C₁₂H₁₀O₅S₂ (298.34): C 48.31, H 3.38, found: C 48.42, H 3.21.

5-(4-Cyanophenyl)-thiophene-3-sulfonic acid phenyl ester (32)

4-Bromobenzonitrile (0.182 g, 1 mmol) and methyl 3-phenoxysulfonylthiophene-2-carboxylate (0.446 g, 1.5 mmol) affords 32 in 80% (0.273 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.50 (d, J = 1.3 Hz, 1H), 8.17 (d, J = 1.3 Hz, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 8.8 Hz, 2H), 7.42 (t, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 7.1 Hz, 2H). ¹³C NMR (75 MHz, DMSO-d6): δ 149.0, 144.7, 136.2, 136.0, 134.3, 133.1, 130.1, 127.6, 126.5, 123.6, 122.0, 118.4, 111.1. Elemental analysis: calcd (%) for C₁₇H₁₁NO₃S₂ (341.41): C 59.81, H 3.25, found: C 59.78, H 3.14.

4-(4-Phenoxysulfonylthiophen-2-yl)-benzoic acid methyl ester (33)

Methyl 4-bromobenzoate (0.215 g, 1 mmol) and methyl 3-phenoxysulfonylthiophene-2-carboxylate (0.446 g, 1.5 mmol) affords 33 in 84% (0.314 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.48 (d, J = 1.3 Hz, 1H), 8.11 (d, J = 1.3 Hz, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 7.42 (t, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 7.9 Hz, 2H), 3.88 (s, 3H). ¹³C NMR (75 MHz, DMSO-d6): δ 165.6, 149.0, 145.3, 136.0, 135.7, 134.2, 130.1, 130.0, 129.5, 127.6, 126.0, 122.9, 122.0, 52.2. Elemental analysis: calcd (%) for C₁₈H₁₄O₅S₂ (374.43): C 57.74, H 3.77, found: C 57.61, H 3.64.

5-(3-Chlorophenyl)-thiophene-3-sulfonic acid phenyl ester (34)

3-Bromochlorobenzene (0.191 g, 1 mmol) and methyl 3-phenoxysulfonylthiophene-2-carboxylate (0.446 g, 1.5 mmol) affords 34 in 83% (0.291 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.43 (d, J = 1.3 Hz, 1H), 8.08 (d, J = 1.3 Hz, 1H), 7.92 (s, 1H), 7.74–7.71 (m, 1H), 7.51–7.33 (m, 5H), 7.13 (d, J = 7.9 Hz, 2H). ¹³C NMR (75 MHz, DMSO-d6): δ 149.0, 145.0, 135.1, 134.1, 134.0, 133.8, 131.0, 130.0, 128.7, 127.5, 125.4, 124.5, 122.4, 122.0. Elemental analysis: calcd (%) for C₁₆H₁₁ClO₃S₂ (350.84): C 54.77, H 3.16, found: C 54.84, H 3.21.

5-(3,5-Bis-trifluoromethylphenyl)-thiophene-3-sulfonic acid phenyl ester (35)

3,5-Bis-trifluoromethylbromobenzene (0.293 g, 1 mmol) and methyl 3-phenoxysulfonylthiophene-2-carboxylate (0.446 g, 1.5 mmol) affords 35 in 72% (0.326 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.53 (d, J = 1.5 Hz, 1H), 8.48 (s, 2H), 8.46 (d, J = 1.5 Hz, 1H), 8.14 (s, 1H), 7.44 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 7.1 Hz, 2H). ¹³C NMR (75 MHz, DMSO-d6): δ 149.0, 143.2, 136.4, 134.5, 134.2, 131.2 (q, J = 32.0 Hz), 130.1, 127.6, 126.6 (m), 124.7, 123.0 (q, J = 273.3 Hz), 122.1. Elemental analysis: calcd (%) for C₁₈H₁₀F₆O₃S₂ (452.39): C 47.79, H 2.23, found: C 47.87, H 2.20.

5-(2-Cyanophenyl)-thiophene-3-sulfonic acid phenyl ester (36)

2-Bromobenzonitrile (0.182 g, 1 mmol) and methyl 3-phenoxysulfonylthiophene-2-carboxylate (0.446 g, 1.5 mmol) affords 36 in 58% (0.198 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.57 (d, J = 1.5 Hz, 1H), 8.02 (dd, J = 5.6, 0.7 Hz, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.85–7.80 (m, 2H), 7.70–7.63 (m, 1H), 7.45–7.32 (m, 3H), 7.15 (d, J = 6.9 Hz, 2H). ¹³C NMR (75 MHz, DMSO-d6): δ 148.9, 142.2, 136.9, 134.6, 134.3, 133.9, 133.5, 130.2, 130.1 129.7, 127.6, 125.4, 122.0, 118.0, 109.8. Elemental analysis: calcd (%) for C₁₇H₁₁NO₃S₂ (341.41): C 59.81, H 3.25, found: C 59.87, H 3.34.

5-Naphthalen-1-yl-thiophene-3-sulfonic acid phenyl ester (37)

1-Bromonaphthalene (0.207 g, 1 mmol) and methyl 3-phenoxysulfonylthiophene-2-carboxylate (0.446 g, 1.5 mmol) affords 37 in 78% (0.286 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 8.60 (d, J = 1.5 Hz, 1H), 8.02 (d, J = 6.0 Hz, 2H), 7.83–7.77 (m, 1H), 7.63–7.55 (m, 4H), 7.45–7.39 (m, 4H), 7.21 (d, J = 6.9 Hz, 2H). ¹³C NMR (75 MHz, DMSO-d6): δ 149.1, 144.1, 135.5, 133.3, 133.0, 130.5, 130.1, 129.6, 129.2 128.5, 127.6, 127.3, 126.5, 125.4, 125.2, 124.1, 122.1. Elemental analysis: calcd (%) for C₂₀H₁₄O₃S₂ (366.46): C 65.55, H 3.85, found: C 56.22, H 5.03.

5-Pyridin-3-ylthiophene-3-sulfonic acid phenyl ester (38)

3-Bromopyridine (0.158 g, 1 mmol) and methyl 3-phenoxysulfonylthiophene-2-carboxylate (0.446 g, 1.5 mmol) affords 38 in 77% (0.244 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.47 (d, J = 1.3 Hz, 1H), 8.20 (d, J = 6.6 Hz, 1H), 8.10 (d, J = 1.3 Hz, 1H), 7.48 (dd, J = 6.6, 4.8 Hz, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 7.7 Hz, 2H). ¹³C NMR (75 MHz, DMSO-d6): δ 149.7, 149.0, 146.6, 143.3, 135.5, 134.1, 133.3, 130.1, 128.0, 127.6, 124.1, 122.6, 122.1. Elemental analysis: calcd (%) for C₁₅H₁₁NO₃S₂ (317.38): C 56.78, H 3.49, found: C 56.87, H 3.41.

5-Isoquinolin-4-ylthiophene-3-sulfonic acid phenyl ester (39)

4-bromoisoquinoline (0.208 g, 1 mmol) and methyl 3-phenoxysulfonylthiophene-2-carboxylate (0.446 g, 1.5 mmol) affords 39 in 60% (0.220 g) yield.

¹H NMR (300 MHz, DMSO-d6): δ 9.41 (s, 1H), 8.68 (d, J = 1.3 Hz, 1H), 8.61 (s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 7.92–7.88 (m, 2H), 7.82–7.77 (m, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.50 (t, J = 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 7.7 Hz, 2H). ¹³C NMR (75 MHz, DMSO-d6): δ 153.6, 149.1, 143.6, 140.5, 136.4, 133.4, 132.8, 132.0, 130.0 128.4, 128.0, 127.8, 127.6, 126.2, 123.4, 123.2, 122.1. Elemental analysis: calcd (%) for C₁₉H₁₃NO₃S₂ (367.44): C 62.11, H 3.57, found: C 62.00, H 3.40.

Acknowledgements

This research was supported by a CEFIPRA fellowship. We thank the CNRS and “Rennes Metropole” for providing financial support.

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