Synthesis of polysubstituted 3-aminothiophenes ... - ACS Publications

Entries 2–4). It was found that TBAI was the most efficient catalyst in this reaction (Table 1,. Entry 2). Moreover, other oxidants were evaluated a...
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Synthesis of Polysubstituted 3‑Aminothiophenes from Thioamides and Allenes via Tandem Thio-Michael Addition/Oxidative Annulation and 1,2-Sulfur Migration Teng Han, Yu Wang, Hong-Liang Li, Xiaoyan Luo,* and Wei-Ping Deng* School of Pharmacy and Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China S Supporting Information *

ABSTRACT: A facile synthetic method for the construction of 3-aminothiophenes from readily available thioamides and alllenes in the presence of a TBAI/TBHP catalyst system was developed. This protocol represents an efficient and straightforward way to access highly functionalized thiophenes in moderate to excellent yields under mild conditions, via a tandem thio-Michael addition, oxidative annulation, and 1,2-sulfur migration pathway.

T

hiophene is a core structure found in a variety of pharmaceutical molecules, natural products, and functional materials.1 It also serves as valuable building blocks in synthetic chemistry.2 Therefore, considerable efforts have been devoted to developing highly efficient and straightforward synthetic methods to access this privileged heterocyclic core.3 According to the literature, the synthetic methods can be classified to two general strategies, one is the direct functionalization of simple thiophenes,4 the other is the cyclization of the suitable sulfur-containing fragments.5,6 Recently, sulfur-containing compounds β-ketothioamides, due to its versatile reactivity properties,7 have been extensively employed for the synthesis of 2-aminothiophene derivatives.8 We also demonstrated two novel protocols for the synthesis of polysubstituted 2-aminothiophene by treating different electrophiles DDQ and 2-ynals with β-ketothioamides.9 However, the present methods, to the best of our knowledge, were mainly centered on the synthesis of 2-aminothiophenes. Therefore, the development of a convenient and straightforward methodology for the synthesis of 3-aminothiophenes, in view of their biological activities of 3-aminothiophenes (Figure. 1), is still highly desired. On the other hand, allene derivatives are important and versatile building blocks in synthetic chemistry, and they have been widely used for constructing structurally diverse heterocycles.10,11 We recently described a direct α,β-double electrophilic reaction by the treatment of allene-1,3-dicarboxylic esters with 1,3-dicarbonyl compounds or enamines under a mild KI/ tert-butyl hydroperoxide (TBHP) reaction system to construct the multisubstituted furans and pyrroles, respectively (Scheme 1a).12 With the continuing interests in developing novel method for the synthesis of structurally diverse and potentially biological active heterocycles,9,12 we further envisaged whether a new combination of allene-1,3-dicarboxylic ester and thioamide would generate polysubstituted thiophene skeleton via the similar α,β-double electrophilic reaction mode as our © 2017 American Chemical Society

Figure 1. Selected pharmaceutical molecules and bioactive structure bearing highly substituted thiophene.

previous reports show. Herein, we would like to demonstrate an efficient synthetic protocol for the construction of 3aminothiophene skeleton by the reaction of allenes with βketothioamides in the presence of a TBAI/TBHP system through an unexpected 1,2-sulfur migration pathway (Scheme 1b). Our investigation began with the reaction of N,N-dimethyl-3oxobutanethioamide (1a) and dimethyl penta-2,3-dienedioate (2a) in the presence of KI and TBHP in 1,4-dioxane at room temperature. To our delight, the reaction proceeded smoothly, however affording a 3-aminothiophene product 3aa in 71% yield instead of the desired 2-aminothiophene product (Table 1, entry 1). This unexpected result may suggest a novel Received: October 15, 2017 Published: December 28, 2017 1538

DOI: 10.1021/acs.joc.7b02616 J. Org. Chem. 2018, 83, 1538−1542

Note

The Journal of Organic Chemistry

3aa in 85% yield (Table 1, entries 13−14). Therefore, the combination of 1a (1.0 equiv) and 2a (1.5 equiv) in the presence of 20 mol% TBAI and 2 equiv TBHP in 1,4-dioxane at room temperature was determined as the optimal reaction conditions, providing 3aa in 85% yield (Table 1, entry 13). Under the optimal conditions, substrate scope of this synthetic protocol was investigated (Scheme 2). First, the

Scheme 1. Strategies for Synthesis of Structurally Diverse Heterocycles

Scheme 2. Scope of Thioamidesa

Table 1. Optimization of Reaction Conditionsa

entry

cat.

[O]

solvent

yield [%]b

1 2 3 4 5 6 7 8 9 10 11 12 13c 14d

KI TBAI I2 NaI TBAI TBAI TBAI TBAI TBAI TBAI TBAI TBAI TBAI TBAI

TBHP TBHP TBHP TBHP TBPB DTBP H2O2 TBHP TBHP TBHP TBHP TBHP TBHP TBHP

1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane THF EtOAc CH3CN diethyl ether EtOH 1,4-dioxane 1,4-dioxane

71 84 72 72 36 29 40 82 79 61 54 72 85 82

a

Reaction conditions: 1 (0.2 mmol), 2a, 2b (0.3 mmol), TBAI (0.04 mmol), TBHP (0.4 mmol), 1,4-dioxane (1 mL). Isolated yield, 6 h.

reaction was extended to a variety of different substituted thioamides 1. The results revealed that various alkyl or phenyl substituted thioamides 1 all reacted smoothly with allenes and gave corresponding multisubstituted 3-aminothiophene structure in moderate to good yields (Scheme 2 3aa−3da). It is worth mentioning that the thioamide 1e with electron donating phenyl group gave the product 3ea in 75% yield, while the substrate 1f with electron-withdrawing phenyl group afforded 3fa in only moderate yield (47%). Furthermore, malonatederived thioamides all reacted smoothly with dimethyl penta2,3-dienedioate (2a) to afford 3ga−3ja in good yields (74− 87%). The N,N-dimethyl thioamide motif can be replaced by other amino groups and also afford corresponding 3ka−3oa in moderate to good yields. The structure of compound 3la was determined by single-crystal X-ray diffraction analysis (see the Supporting Information). Notably, the 3-(dimethylamino)N,N-dimethyl-3-thioxopropanamide can also be transformed into the corresponding 3-aminothiophene 3pa in 78% yield. Moreover, when the ethyl ester-substituted allene was employed instead of the methyl ester, there was no significant effect on the yield of the reaction and the desired product (3gb) was obtained in 84% yield. To account for the reaction process, a hypothetic mechanism was proposed based on literature reports and our previous work

a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), cat. (0.04 mmol), oxidant (0.4 mmol), solvent (1 mL), under air atmosphere, 6 h. bIsolated yield. c1a (0.2 mmol), 2a (0.3 mmol). d1a (0.3 mmol), 2a (0.2 mmol), 6 h.

synthetic strategy for constructing 3-aminothiophene (Scheme 1b). Encouraged by this finding, we further optimized the reaction conditions. First, a variety of iodine sources, such as TBAI, I2, and NaI, were examined (Table 1, entries 2−4). It was found that TBAI was the most efficient catalyst in this reaction (Table 1, entry 2). Moreover, other oxidants were evaluated and we found that TBHP was the best choice (Table 1, entries 5−7). Additionally, the solvent effect was also investigated and 1,4-dioxane was found to be the optimal solvent (Table 1, entries 8−12). Further optimization by adjusting the molar ratio of the substrates 1a and 2a showed that 1.5 equiv of 2a was optimal to afford the desired product 1539

DOI: 10.1021/acs.joc.7b02616 J. Org. Chem. 2018, 83, 1538−1542

Note

The Journal of Organic Chemistry (Scheme 3).7b,12 Initially, β-ketothioamides 1 reacts with allenes to give thio-Michael addition product A, which is

Methyl 4-(Dimethylamino)-2-(2-methoxy-2-oxoethyl)-5-propionylthiophene-3-carboxylate (3aa). Yellow oil, 50.8 mg, 85% yield. 1 H NMR (400 MHz, CDCl3, δ) 3.91 (s, 2H), 3.88 (s, 3H), 3.73 (s, 3H), 2.87 (s, 6H), 2.53 (s, 3H). 13C NMR (100 MHz, CDCl3, δ) 189.5, 169.5, 164.5, 154.9, 145.5, 128.9, 128.3, 52.6, 52.1, 43.9, 35.8, 28.9. HRMS (EI) calcd for C13H17NO5S [M]+: 299.0822; found, 299.0828. Methyl 5-(Dimethylamino)-3-(2-methoxy-2-oxoethyl)-4-propionylthiophene-2-carboxylate (3ba). Yellow oil, 53.8 mg, 86% yield. 1 H NMR (400 MHz, CDCl3, δ) 3.90 (s, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 2.92−2.87 (m, 2H), 2.87 (s, 6H), 1.19 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ) 192.5, 169.6, 164.6, 154.7, 144.8, 128.8, 126.9, 52.6, 52.2, 43.8, 35.8, 34.6, 8.8. HRMS (EI) calcd for C14H19NO5S [M]+: 313.0978; found, 313.0982. Methyl 4-(Dimethylamino)-2-(2-methoxy-2-oxoethyl)-5-pivaloylthiophene-3-carboxylate (3ca). Yellow oil, 48.4 mg, 71% yield. 1 H NMR (400 MHz, CDCl3, δ) 3.90 (s, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 2.75 (s, 6H), 1.34 (s, 9H). 13C NMR (100 MHz, CDCl3, δ) 200.3, 169.8, 164.6, 155.9, 141.6, 127.5, 118.9, 52.6, 52.1, 44.8, 43.7, 35.5, 28.1. HRMS (EI) calcd for C16H23NO5S [M]+: 341.1291; found, 341.1296. Methyl 5-Benzoyl-4-(dimethylamino)-2-(2-methoxy-2-oxoethyl) thiophene-3-carboxylate (3da). Yellow oil, 39.7 mg, 55% yield. 1H NMR (400 MHz, CDCl3, δ) 7.79 (d, J = 7.7 Hz, 2H), 7.57−7.51 (m, 1H), 7.49−7.40 (m, 2H), 3.93−3.85 (m, 5H), 3.72 (s, 3H), 2.80 (s, 6H). 13C NMR (100 MHz, CDCl3, δ) 186.6, 169.5, 164.6, 155.8, 146.2, 140.0, 132.2, 129.0, 128.4, 126.9, 118.4, 52.6, 52.1, 43.8, 35.8. HRMS (EI) calcd for C18H19NO5S [M]+: 361.0978; found, 361.0983. Methyl 4-(Dimethylamino)-2-(2-methoxy-2-oxoethyl)-5-(4-methoxybenzoyl) thiophene-3-carboxylate (3ea). Yellow oil, 58.7 mg, 85% yield. 1H NMR (400 MHz, CDCl3, δ) 7.81 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.91−3.86 (m, 8H), 3.73 (s, 3H), 2.78 (s, 6H). 13C NMR (100 MHz, CDCl3, δ) 185.9, 169.6, 164.6, 163.1, 155.2, 145.3, 132.5, 131.5, 126.9, 118.7, 113.6, 55.6, 52.6, 52.1, 43.8, 35.8. HRMS (EI) calcd for C19H21NO6S [M]+: 391.1084; found, 391.1086. Methyl 5-(4-Bromobenzoyl)-4-(dimethylamino)-2-(2-methoxy-2oxoethyl) thiophene-3-carboxylate (3fa). Yellow oil, 41.3 mg, 47% yield. 1H NMR (400 MHz, CDCl3, δ) 7.66 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 3.90−3.87 (m, 5H), 3.73 (s, 3H), 2.79 (s, 6H). 13 C NMR (100 MHz, CDCl3, δ) 185.4, 169.4, 164.5, 155.9, 146.5, 138.8, 131.6, 130.6, 127.0, 127.0, 118.1, 52.6, 52.2, 43.9, 35.8. HRMS (EI) calcd for C18H18BrNO5S [M]+: 439.0084; found, 439.0082. Dimethyl 3-(Dimethylamino)-5-(2-methoxy-2-oxoethyl) thiophene-2,4-dicarboxylate (3ga). Yellow oil, 54.8 mg, 87% yield. 1H NMR (400 MHz, CDCl3, δ) 3.89−3.84 (m, 5H), 3.81 (s, 3H), 3.73 (s, 3H), 2.93 (s, 6H). 13C NMR (100 MHz, CDCl3, δ) 169.6, 164.6, 161.4, 156.5, 144.6, 127.7, 111.1, 52.6, 52.1, 51.8, 43.8, 35.6. HRMS (EI) calcd for C13H17NO6S [M]+: 315.0771; found, 315.0775. 2-Ethyl 4-Methyl 3-(dimethylamino)-5-(2-methoxy-2-oxoethyl) thiophene-2,4-dicarboxylate (3ha). Yellow oil, 55.9 mg, 85% yield. 1 H NMR (400 MHz, CDCl3, δ) 4.27 (q, J = 7.1 Hz, 2H), 3.90−3.81 (m, 5H), 3.72 (s, 3H), 2.92 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3, δ) 169.7, 164.6, 161.0, 156.3, 144.4, 127.8, 112.0, 60.7, 52.6, 52.1, 43.8, 35.6, 14.5. HRMS (EI) calcd for C14H19NO6S [M]+: 329.0928; found, 329.0932. 2-tert-Butyl 4-Methyl 3-(dimethylamino)-5-(2-methoxy-2oxoethyl)thiophene-2,4-dicarboxylate (3ia). Yellow oil, 55.7 mg, 78% yield. 1H NMR (400 MHz, CDCl3, δ) 3.86−3.84 (m, 5H), 3.72 (s, 3H), 2.91 (s, 6H), 1.54 (s, 9H). 13C NMR (100 MHz, CDCl3, δ) 169.8, 164.6, 160.4, 155.5, 143.6, 127.9, 114.3, 81.2, 52.6, 52.0, 43.7, 35.6, 28.5. HRMS (EI) calcd for C16H23NO6S [M]+: 357.1241; found, 357.1243. 2-Benzyl 4-Methyl 3-(dimethylamino)-5-(2-methoxy-2-oxoethyl) thiophene-2,4-dicarboxylate (3ja). Yellow oil, 57.9 mg, 74% yield. 1H NMR (400 MHz, CDCl3, δ) 7.43−7.31 (m, 5H), 5.27 (s, 2H), 3.93− 3.82 (m, 5H), 3.72 (s, 3H), 2.93 (s, 6H). 13C NMR (100 MHz, CDCl3, δ) 169.6, 164.5, 160.6, 156.6, 144.8, 136.3, 128.7, 128.2, 128.0, 127.6, 110.8, 66.2, 52.6, 52.1, 43.8, 35.6. HRMS (EI) calcd for C19H21NO6S [M]+: 391.1084; found, 391.1086.

Scheme 3. Plausible Mechanism

followed by intermolecular nucleophilic ring-closing reaction to give key four-membered ring intermediate B. Further iodination of intermediate B undergoes via two different pathways, affording intermediate C and C’ through iodination of carbonyl α-carbon (path a)13 or iodination of sulfur,14 respectively. Intermediate C is further subjected to an unprecedented ring-expanding process through a 1,2-sulfur migration to form intermediate D. Alternatively, the intermediate C’ undergoes an intramolecular nucleophilic attack process to give intermediate D. Finally, the intermediate D undergoes an isomerization process to give the 1,2-sulfur migration product 3. In summary, we have successfully developed an efficient TBAI-catalyzed synthesis of polysubstituted thiophenes via a tandem thio-Michael addition/oxidative annulation and 1,2sulfur migration from readily available thioamides and allenes. This protocol features mild reaction conditions, broad substrate scope, and represents a novel synthetic strategy for the construction of 3-aminothiophenes, which would be of great importance for the drug discovery in terms of the structure diversity of thiophene derivatives.

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EXPERIMENTAL SECTION

General Information. Commercial reagents were used without further purification, unless otherwise noted. Melting points were obtained in open capillary tubes using a micromelting point apparatus which was uncorrected. The mass spectra were recorded on a TOF mass spectrometer using the EI method. 1H NMR was recorded using 400 M spectrometer at ambient temperatures and the CDCl3 as the solvent. Chemical shifts (in ppm) with internal TMS signal is 0.0 ppm as standard are reported as (s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet).13 NMR spectra were recorded on a 100 MHz spectrometer by broadband spin decoupling for CDCl3 at ambient temperatures. The standard of chemical shifts (in ppm) is the signal of internal chloroform which at 77.16 ppm. TLC was performed by using commercially prepared 100−400 mesh silica gel plates, and visualization was effected at 254 or 365 nm. General Procedure for the Preparation of Polysubstituted Thiophenes (3aa−3gb). Thioamides compounds 1 (0.2 mmol), allene 2 (0.3 mmol), and TBHP (0.4 mmol) were added to a solution of TBAI (0.04 mmol) in dry 1,4-dioxane (1 mL) under an air atmosphere. The mixture was then stirred at room temperature until the reaction was nearly completed monitored by the TLC. The resulting mixture was concentrated in vacuum and then purified by column chromatography on 100−200 mesh silica gel to afford the desired products 3. The preparation of β-ketothioamides 1 is based on references.15 1540

DOI: 10.1021/acs.joc.7b02616 J. Org. Chem. 2018, 83, 1538−1542

Note

The Journal of Organic Chemistry Methyl 5-Acetyl-2-(2-methoxy-2-oxoethyl)-4-morpholinothiophene-3-carboxylate (3ka). Yellow solid, 146−148 °C; 55.2 mg, 81% yield. 1H NMR (400 MHz, CDCl3, δ) 3.91 (s, 2H), 3.89 (s, 3H), 3.83 (t, J = 4.7 Hz, 4H), 3.74 (s, 3H), 3.18 (t, J = 4.6 Hz, 4H), 2.59 (s, 3H). 13C NMR (100 MHz, CDCl3, δ) 189.2, 169.5, 164.7, 152.8, 144.7, 129.6, 129.5, 67.4, 52.7, 52.3, 51.5, 35.5, 29.9. HRMS (EI) calcd for C15H19NO6S [M]+: 341.0928; found, 341.0930. Dimethyl 5-(2-Methoxy-2-oxoethyl)-3-morpholinothiophene-2,4dicarboxylate (3la). Yellow solid, m.p: 150−152 °C; 64.9 mg, 91% yield. 1H NMR (400 MHz, CDCl3, δ) 3.89 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.82−3.78 (m, 4H), 3.73 (s, 3H), 3.27−3.17 (m, 4H).13C NMR (100 MHz, CDCl3, δ) 169.6, 164.5, 161.3, 154.8, 144.3, 128.6, 115.4, 67.6, 52.7, 52.2, 52.0, 51.6, 35.4. HRMS (EI) calcd for C15H19NO7S [M]+: 357.0877; found, 357.0883. Dimethyl 3-(Diethylamino)-5-(2-methoxy-2-oxoethyl) thiophene2,4-dicarboxylate (3ma). Yellow oil, 56.3 mg, 82% yield. 1H NMR (400 MHz, CDCl3, δ) 3.89 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.73 (s, 3H), 3.23 (q, J = 7.1 Hz, 4H), 1.06 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3, δ) 169.7, 164.6, 161.2, 155.4, 144.3, 129.7, 115.0, 52.6, 51.9, 51.7, 47.1, 35.6, 13.8. HRMS (EI) calcd for C15H21NO6S [M]+: 343.1084; found, 343.1091. Dimethyl 5-(2-Methoxy-2-oxoethyl)-3-(methyl(phenyl)amino) thiophene-2,4-dicarboxylate (3na). Yellow solid, mp 75−77 °C; 64.1 mg, 85% yield. 1H NMR (400 MHz, CDCl3, δ) 7.15 (dd, J = 7.3 Hz, 2H), 6.73 (d, J = 7.3 Hz, 1H), 6.59−6.53 (m, 2H), 4.08 (s, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.45 (s, 3H), 3.28 (s, 3H). 13C NMR (100 MHz, CDCl3, δ) 169.7, 163.2, 160.7, 150.2, 148.4, 146.4, 129.9, 129.0, 124.3, 118.1, 113.0, 52.7, 52.3, 51.9, 39.7, 35.4. HRMS (EI) calcd for C18H19NO6S [M]+: 377.0928; found, 377.0932. Methyl 5-(4-Bromobenzoyl)-4-(dimethylamino)-2-(2-methoxy-2oxoethyl) thiophene-3-carboxylate (3oa). Yellow oil, mp 75−77 °C; 53.2 mg, 57% yield. 1H NMR (400 MHz, CDCl3, δ) 7.67 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 3.89 (s, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 3.13 (q, J = 7.1 Hz, 4H), 1.06 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3, δ) 185.4, 169.6, 164.7, 154.9, 145.5, 138.8, 131.6, 130.6, 128.7, 126.9, 120.6, 52.7, 52.1, 47.2, 35.6, 13.4. HRMS (EI) calcd for C20H22BrNO5S [M]+: 467.0397; found, 467.0401. Methyl 4-(Dimethylamino)-5-(dimethylcarbamoyl)-2-(2-methoxy-2-oxoethyl) thiophene-3-carboxylate (3pa). Yellow oil, 51.2 mg, 78% yield. 1H NMR (400 MHz, CDCl3, δ) 3.90 (s, 2H), 3.88 (s, 3H), 3.72 (s, 3H), 3.06 (s, 6H), 2.79 (s, 6H). 13C NMR (101 MHz, CDCl3, δ) 170.0, 165.1, 164.4, 149.9, 140.9, 126.6, 117.6, 52.5, 52.0, 43.3, 35.5. HRMS (EI) calcd for C14H20N2O5S [M]+: 328.1087; found, 328.1092. 4-Ethyl 2-Methyl 3-(Dimethylamino)-5-(2-ethoxy-2-oxoethyl) thiophene-2,4-dicarboxylate (3gb). Yellow oil, 57.6 mg, 84% yield. 1 H NMR (400 MHz, CDCl3, δ) 4.32 (q, J = 7.2 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.87 (s, 2H), 3.81 (s, 3H), 2.93 (s, 6H), 1.37 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ) 169.1, 164.2, 161.4, 156.5, 144.4, 128.2, 111.2, 61.6, 61.3, 51.7, 43.8, 35.8, 14.3, 14.2. HRMS (EI) calcd for C15H21NO6S [M]+: 343.1084; found, 343.1091.

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Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by the National Natural Science Foundation of China (No. 21572053) and Natural Science Foundation of Shanghai (No. 17ZR1407600).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02616. Copies of 1H and 13NMR spectra data for all compounds (PDF) Crystallographic data for compound 3la (CIF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-Mail: [email protected]. *E-Mail: [email protected]. ORCID

Wei-Ping Deng: 0000-0002-4232-1318 1541

DOI: 10.1021/acs.joc.7b02616 J. Org. Chem. 2018, 83, 1538−1542

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DOI: 10.1021/acs.joc.7b02616 J. Org. Chem. 2018, 83, 1538−1542