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Synthesis 2013; 45(24): 3435-3441
DOI: 10.1055/s-0033-1340009
paper
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 5-Thienylfuran-3(2H)-ones via the Microwave-Assisted Tandem Reaction of Cyanopropargylic Alcohols with Thiophene-2-carboxylic Acids

Anastasiya G. Mal’kina
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian Federation   Fax: +7(3952)419346   Email: boris_trofimov@irioch.irk.ru
,
Olga G. Volostnykh
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian Federation   Fax: +7(3952)419346   Email: boris_trofimov@irioch.irk.ru
,
Anton V. Stepanov
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian Federation   Fax: +7(3952)419346   Email: boris_trofimov@irioch.irk.ru
,
Igor A. Ushakov
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian Federation   Fax: +7(3952)419346   Email: boris_trofimov@irioch.irk.ru
,
Konstantin B. Petrushenko
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian Federation   Fax: +7(3952)419346   Email: boris_trofimov@irioch.irk.ru
,
Boris A. Trofimov*
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian Federation   Fax: +7(3952)419346   Email: boris_trofimov@irioch.irk.ru
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Further Information

Publication History

Received: 14 August 2013

Accepted after revision: 23 September 2013

Publication Date:
23 October 2013 (online)

 
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Abstract

Tertiary cyanopropargylic alcohols undergo tandem reaction with thiophene-2-carboxylic and benzo[b]thiophene-2-carboxylic acids under microwave irradiation (MeCN, Et3N, 100 °C, 2.5–16 h) to afford 4-cyano-5-thienylfuran-3(2Н)-ones in 69–89%. The cyano function of the synthesized furanones is readily hydrolyzed (aq EtOH, KOH, 20–25 °C, 24 h) to give quantitatively the corresponding amides, 5,5-dialkyl-4-oxo-2-(2-thienyl)-4,5-dihydrofuran-3-carboxamides.


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Key words

tertiary cyanopropargylic alcohols - thiophene acids - tandem reaction - cyclization - furan-3(2H)-ones - amides

Furan-3(2Н)-ones are key structural units of numerous natural compounds[1] [2] [3] [4] [5] of pharmacological importance, e.g. bullatenone,[1] geiparvarin,[1f,2] eremantholide A,[1f] [3] jatrophone,[1f,4] and pseurotin.[1f,5] Many other furan-3(2Н)-one derivatives are prospective pharmaceutical targets as they are effective against cancer,[1b] [f] [2g] [i] [3e] [6] ulcers,[1c] allergies,[1f,7] and cataracts.[8] Some functionally substituted furan-3(2Н)-ones are recommended as nonsteroidal anti-inflammatory agents[9] and analgesics[9b] as well as for the treatment of metabolic disorders.[10] In the last decade, the chemistry and pharmacology of furan-3(2Н)-ones has become a subject of particularly intense research.[1f] [g] [2g] [h] [9b] [10] [11] Special attention has been paid to the development of novel effective and general methods for their synthesis and controlled functionalization.[11c] In this way, the cyclization of propargylic ketols,[12] α-hydroxyacetylenic[13] and allenic[1g] ketones, 2-oxobut-3-ynoic esters, and acetylenic diketones[14] catalyzed by Cu, Ag, Au, Hg, Pd, and Pt compounds have been extensively studied. However, these methods do not represent a uniform general methodology.

Recently, we revealed a one-pot easy tandem assembly of the furan-3(2Н)-one scaffold from available tertiary cyanopropargylic alcohols[15] and benzoic[16a] or naphthenecarboxylic[16b] acids. However, it remained unclear whether heteroaromatic carboxylic acids, especially thiophene-2-carboxylic and benzo[b]thiophene-2-carboxylic acids, can take part in this reaction. It might be assumed that the joining of furan-3(2Н)-one and thiophene moieties in a single molecule would give a somewhat synergistic effect. To the best of our knowledge, only three publications briefly mention the synthesis of furan-3(2Н)-ones containing thiophene substituents.[1c] [2g] [12b] However, their syntheses are laborious and multistep requiring butyllithium and transition metal salts. Here, due to the synthetic and pharmaceutical importance of certain thiophene derivatives (Mazaticol, Cetiedil, Carticaine, Tiamenidine),[17] we report a successful attempt to extend the above tandem sequence to thiophene-2-carboxylic and benzo[b]thiophene-2-carboxylic acids.

Unlike our previous protocols elaborated for and benzoic[16a] or naphthalenecarboxylic acids,[16b] here we have utilized microwave assistance to considerably shorten the reaction time. The reaction between tertiary cyanopropargylic alcohols 1a–c and thiophene-2-carboxylic acid (2a) or benzo[b]thiophene-2-carboxylic acid (2b) was carried out in acetonitrile in the presence of triethylamine at 100 °C; molar ratio 1/2/triethylamine = 1.2:1:1. The yields of the target 4-cyano-5-thienylfuran-3(2Н)-ones 3a–f were in the range 69–89%.

As seen from Table [1], under microwave irradiation the tandem assembly of 4-cyano-5-thienylfuran-3(2Н)-one 3d proceeds in 2.5 hours instead of 11.5 hours using conventional heating; the yields of the target compound 3d by both methods was almost identical.

Table 1 Microwave-Assisted Synthesis of Furan-3(2Н)-ones 3a–f

Acetylene

R1

R2

Thiophene-2-carboxylic acid

R3

Time (h)

Furan-3(2H)-one

Yield (%)

1a

Me

Me

2a

2-thienyl

 3

3a

84

1b

Et

Me

2a

2-thienyl

16

3b

89

1c

(CH2)5

2a

2-thienyl

 9

3c

69

1a

Me

Me

2b

2-benzothiophenyl

 2.5

3d

80

1a a

Me

Me

2b

2-benzothiophenyl

11.5

3d

78

1b

Et

Me

2b

2-benzothiophenyl

 7

3e

78

1c

(CH2)5

2b

2-benzothiophenyl

 6.5

3f

82

a Without microwave irradiation.

Noteworthy, the tandem assembly of furan-3(2Н)-ones 3a–f is possible even at room temperature and without microwave assistance, though the reaction lasts for 4–29 days, the yields were in the range 10–84% (Table [2]).

Table 2 Reaction of Tertiary Cyanopropargylic Alcohols 1a–c with Thiophenecarboxylic Acids 2a,b without Microwave Irradiation

Acetylene

Thiophene-2-carboxylic acid

Time (d)

Temp (°C)

Furan-3(2H)-one

Yield (%)

1a

2a

 4

20–25

3a

84

1b

2a

14

20–25

3b

73

1c

2a

28

20–25

3c

59

1a

2b

12

20–25

3d

23

1a

2b

 1.5

40–45

3d

40

1b

2b

29

20–25

3e

42

1b

2b

 2.5

40–45

3e

21

1c

2b

23

20–25

3f

10

1c

2b

 3

40–45

3f

17

Comparison with the results obtained for the same reaction with benzoic acids[16a] shows that the thiophene-2-carboxylic and benzo[b]thiophene-2-carboxylic acids are much less reactive and their assembly with tertiary cyanopropargylic alcohols to the corresponding furan-3(2Н)-ones does require acceleration by microwave assistance.

The reaction progress and its completion was monitored by IR spectroscopy (disappearance of the broad Csp-C≡C–CN bands at 2295–2280 cm–1 and appearance of the narrow Csp2-C=C–CN bands at 2223–2219 cm–1 corresponding to the starting and target compounds).

NMR (1H, 13C) spectra (2D COSY, NOESY, HMBC, HSQC techniques were also employed), IR, and MS data for furanones 3a–f, and the results of a UV/fluorescence study of furanones 3a,d, are in agreement with their structures. In the 1Н NMR spectra, the signals of alkyl protons and the thiophene ring are present. In the 13С NMR spectra of compounds 3a–f, the carbonyl carbons resonate in the region of δ = 198.5–198.7, and the signal of the cyano group carbon appears at δ = 112.3–112.4. In the IR spectra of the furan-3(2H)-ones 3a–f, the C≡N and C=O bands are observed at 2223–2219 and 1707–1699 cm–1, respectively. The bands of the C=C bonds in the furan-3(2H)-one moiety are overlapped with the thiophene ring vibrations at 1567–1515 cm–1.

Similar to benzoic[16a] and naphthenecarboxylic acids,[16b] the tandem sequence is apparently triggered by the nucleophilic addition of thiophenecarboxylic acid anions to the triple bond (catalyzed by the organic base Et3N) leading (after the proton transfer) to the initial adduct A that undergoes intermolecular transesterification to give the intermediate enol B. The keto form C is finally converted, via intramolecular condensation (somewhat resembling the Knoevenagel one), into the target furan-3(2H)-ones (Scheme [1]).

Zoom Image
Scheme 1 Tentative scheme of the tandem reaction between cyanopropargylic alcohols and thiophenecarboxylic acid

The slower reaction of tertiary cyanopropargylic alcohols with thiophene-2-carboxylic and benzo[b]thiophene-2-carboxylic acids compared to the same reaction with benzoic acid[16a] is in keeping with the above mechanism. Indeed, the anion of the stronger thiophene-2-carboxylic acid (relative to benzoic acid, pK a = 3.5 and 4.2,[18] respectively) is less nucleophilic (and hence less active in the nucleophilic addition reaction) than the anion of benzoic acid. This is why for synthetically suitable implementation of the reaction with thiophenecarboxylic acids additional microwave activation is required.

The synthesized furan-3(2H)-one/thiophene ensembles 3a–f represent unique molecules with competitive conjugation of the thiophene (or benzothiophene) rings and carbonyl or nitrile functions. To shed a light to peculiarities of electronic communication in such systems, both in the ground and excited states, we performed a preliminary study of electronic absorption and fluorescent spectra of two representatives of this series, 3a and 3d, containing thiophene and benzo[b]thiophene rings. Long-waves of absorption spectra of both furanones are intense and located in a near UV region, having a complex structurized shape (Table [3, ]Figure [1]). According to quantum-chemical calculations [B3LYP/6-31G+(d)], these band shapes result from two (for 3a) and three (for 3d) electron transitions. For 3a, the maximum of the band is determined by an intense ππ* transition S0→S2 (λ = 324.6, f = 0.43), while the lowest forbidden transition S0→S1 (λ = 347.7, f = 0.0001) bears nπ* character that causes extremely low nπ* fluorescence of this compound. Replacement of the thiophene ring by benzo[b]thiophene leads to a bathochromic shift of the long-wave band and an increase in its intensity. The quantum chemical calculations show that maximum of the band for 3d corresponds to ππ* transition S0→S3 (λ = 340.7, f = 0.65). The lowest transition becomes poorly resolved ππ* transition S0→S1 (λ = 366.9, f = 0.09), whereas nπ* transition S0→S2 (λ = 353.5, f = 0.0001) shifts to the shorter wave region relative to the ππ* transition. Such a distribution of energy levels corresponds to weak ππ* fluorescence of compound 3d in the visible spectral region.

Table 3 Spectroscopic and Photophysical Characteristics of Furan-3(2H)-ones 3a and 3d in Acetonitrile

Furan-3(2H)-one

λmax,abs (nm)

Absorption coefficient (ε, M–1·cm–1)

λmax,fl (nm)

λmax,ex (nm)

Fluorescence quantum yielda (Φf)

3a

329

20500

400

330

<0.001

3d

352

27600

416

352

 0.006

a Anthracene as standard (Φf = 0.27, EtOH).[19]

Zoom Image
Figure 1 Normalized absorption spectrum of furan-3(2H)-one 3a (1), absorption spectrum (2), and fluorescence spectrum (3) of furan-3(2H)-one 3d in acetonitrile

The synthesized compounds 3a–f, due to their cyano substituent with its rich chemistry and high reactivity, are promising intermediates for further synthesis of novel families of diversely functionalized furan-3(2H)-ones. For example, furan-3(2H)-ones 3a–c are readily hydrolyzed at room temperature to the corresponding amides 4a–c (10 mol% KOH, aq EtOH) in almost quantitative yields 97–99% (Scheme [2]). Indeed, furanones with 4-carbonitrile or 4-carboxamide groups are considered as crucial derivatives since they allow modifications or can interact with hydrogen-bonding networks of proteins, respectively.

Zoom Image
Scheme 2 Hydrolysis of the cyano function of furan-3(2H)-ones 3a–c

The temperature dependent 1H NMR spectra for compound 4c in CDCl3 proves the presence of the amide group (see Supporting Information, p 17). In the 13С NMR spectra of compounds 4a–c, signals of the cyano group carbons are absent, and two carbon signals of two carbonyl groups are observed at δ = 193.1–193.5 for the keto group (C=O) and δ = 180.6–180.8 for the carboxamide group. The IR absorption bands are 3339–3195 (NH2), 1636–1619 (C=O), and 1593–1575 cm–1 (C=C).

In conclusion, the microwave-assisted tandem reaction between tertiary cyanopropargylic alcohols and thiophene-2-carboxylic and benzo[b]thiophene-2-carboxylic acids in the presence of triethylamine as a basic catalyst results in a one-pot formation of furan-3(2Н)-one/thiophene ensembles. The results confirm the general character of this methodology for the most straightforward synthesis of furan-3(2Н)-ones with cyano, aromatic, and heteroaromatic substituents, which due to the rich cyano group chemistry are promising intermediates for further synthesis of diversely functionalized furan-3(2Н)-ones.

1Н and 13С NMR spectra were recorded on a Bruker DPX-400 spectrometer (400.1 and 100.6 MHz, respectively) in acetone-d 6 or CDCl3 using (TMS)2O as internal references at 20–25 °C. The homo- and heteronuclear correlations (COSY, NOESY, HMBC, HSQC) were performed on a Bruker AV-400 instrument. For labeling of NMR assignments, see Figure [2].

Zoom Image
Figure 2 Compounds 3a–f and 4a–c showing numbering used in NMR spectra

IR spectra were measured on a Bruker Vertex-70 instrument in KВr pellets. Mass spectra were recorded on an Agilent 5975C spectrometer. Sample introduction was carried out through an Agilent 6890N gas chromatograph: column: HP-5MS (0.25 mm × 30 m × 0.25 μm); carrier gas: He, constant flow. Microwave-assisted syntheses were carried out in heavy-walled glass vials (10 mL) sealed with Teflon septa. Irradiation was carried out in a monomode microwave cavity Anton Paar ‘Monowave 300’ (magnetron frequency 2455 MHz, power up to 850 W). UV-Vis absorption spectra were measured on a Lambda-35 (Perkin-Elmer) spectrophotometer. The absorption coefficients were determined with ±100 M–1·cm–1 accuracy. Excitation and emission spectra were measured on a FLSP-920 fluorescence spectrometer (Edinburgh Instrument). All fluorescence and excitation spectra were corrected. In all the cases, the spectra of excitation of fluorescence fully complied with the absorption spectra. For samples, a right-angle configuration was used and, to avoid re-absorption, the maximum absorbance was kept below 0.1. The fluorescence­ quantum yields (Φf) of the furan-3(2H)-one systems were calculated using the following relationship:

Φf = Φref · F sampl · Aref · n 2 sampl/F ref · A sampl · n 2 ref

Here, F denotes the integral of the corrected fluorescence spectrum, A is the absorbance at the excitation wavelength, and n is the refractive index of the medium, ref and sampl denote parameters from the reference and unknown experimental samples, respectively. The reference system was anthracene (Φf = 0.27, EtOH).[19]

To reduce the computation time, quantum chemical calculations were performed for 4-oxo-2-[2-thienyl or 2-(1-benzothiophen-2-yl)]-4,5-dihydrofuran-3-carbonitrile (model compounds for furan­ones 3a,d, respectively). Calculations were performed using the Gaussian 03[20] and Turbomole v.6.1[21] software. The ground- and excited­-state minima were determined by B3LYP/def2-TZVP. Excited states were obtained with TD-B3LYP/def2-TZVP.

Microanalyses were performed on a Flash 2000 elemental analyzer. Melting points were determined using a Kofler micro hot stage. The reaction was monitored by IR spectroscopy until disappearance of the absorption bands at 2295–2280 cm–1 belonging to the CN bond attached to the acetylene moiety. The solvent was MeCN (spectroscopic grade) from Scientific Production Company ‘Cryochrom’ (St. Petersburg, Russia). Thiophene-2-carboxylic and benzo[b]thiophene-2-carboxylic acids 2a,b are commercial reagents (Alfa Aesar­). Tertiary cyanopropargylic alcohols 1a–c were prepared according to a published method.[15a] [e] Commercially available starting materials were used without further purification.


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5,5-Dimethyl-4-oxo-2-(2-thienyl)-4,5-dihydrofuran-3-carbonitrile (3a); Typical Procedure

To a stirred solution of 2a (128 mg, 1 mmol) and 4-hydroxy-4-methylpent-2-ynenitrile (1a, 131 mg, 1.2 mmol) in MeCN (5 mL), Et3N (101 mg, 1 mmol) was added dropwise over 1 min. The mixture was microwave irradiated at 100 °C for 3 h (or was stirred at 20–25 °C for 4 d). The residue was concentrated and washed (pentane–acetone, 3:1) to give 3a as light yellow crystals; yield: 184 mg (84%) or 183 mg (84%, at 20–25 °C); mp 190–191 °C.

IR (KBr): 3118, 3083 (C=CH), 2988, 2936 (CH), 2222 (CN), 1705 (CО), 1566, 1530 (C=C), 1516, 1456, 1409, 1400, 1365, 1331, 1276, 1262, 1234, 1209, 1166, 1109, 1059, 1038, 996, 944, 913, 889, 860, 783, 766, 745, 682, 650, 612, 561, 530, 519, 427 cm–1.

1Н NMR (400.1 MHz, CDCl3): δ = 1.54 [s, 6 H, (CH3)2], 7.31 (dd, J = 5.0, 4.0 Hz, 1 H, H4′), 7.88 (dd, J = 5.0, 1.0 Hz, 1 H, H5′), 8.30 (dd, J = 4.0, 1.0 Hz, 1 H, H3′).

13С NMR (100.6 MHz, CDCl3): δ = 23.0 [(CH3)2], 85.4 (C5), 91.5 (C3), 112.4 (CN), 129.4 (C2′, C4′), 135.3 (C5′), 136.0 (C3′), 180.2 (C2), 198.7 (C4).

MS (EI): m/z (%) = 220 (24) [M]+1, 219 (100) [M]+, 135 (29), 134 (56), 133 (100), 111 (56), 94 (23), 83 (15), 69 (25), 58 (26).

Anal. Calcd for C11H9NO2S (219.26): C, 60.26; H, 4.14; N, 6.39; S, 14.62. Found: C, 60.28; H, 3.84; N, 6.44; S, 15.78.


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5-Ethyl-5-methyl-4-oxo-2-(2-thienyl)-4,5-dihydrofuran-3-carbonitrile (3b)

Following the typical procedure for 3a using 2a (128 mg, 1 mmol) and 4-hydroxy-4-methylhex-2-ynenitrile (1b, 148 mg, 1.2 mmol) in MeCN (5 mL), and Et3N (101 mg, 1 mmol) with microwave irradiation at 100 °C for 16 h (or was stirred at 20–25 °C for 14 d). The residue was concentrated and purified by column chromatography (silica gel, CHCl3–EtOAc, 1:3) to give 3b as a yellow powder: yield: 207 mg (89%) or 169 mg (73%, at 20–25 °C); mp 102–104 °C.

IR (KBr): 3108 (C=CH), 2978, 2935 (CH), 2222 (CN), 1700 (CО), 1565, 1520 (C=C), 1455, 1417, 1398, 1375, 1332, 1286, 1258, 1220, 1211, 1192, 1163, 1117, 1071, 1062, 1056, 1039, 1013, 999, 964, 901, 886, 860, 801, 774, 757, 740, 725, 688, 677, 626, 541, 519, 434 cm–1.

1Н NMR (400.1 MHz, CDCl3): δ = 0.90 (t, J = 7.5 Hz, 3 H, CH2CH 3), 1.51 (s, 3 H, CH3), 1.92 (m, 2 H, CH 2CH3), 7.32 (dd, J = 5.0, 4.0 Hz, 1 H, H4′), 7.89 (dd, J = 5.0, 1.0 Hz, 1 H, H5′), 8.30 (dd, J = 4.0, 1.0 Hz, 1 H, H3′).

13С NMR (100.6 MHz, CDCl3): δ = 7.3 (CH2 CH3), 21.5 (CH3), 30.1 (CH2CH3), 86.5 (C5), 94.5 (C3), 112.3 (CN), 129.4 (C2′, C4′), 135.2 (C5′), 135.9 (C3′), 180.8 (C2), 198.7 (C4).

MS (EI): m/z (%) = 233 (5) [M]+, 205 (59), 134 (12), 133 (100), 111 (24), 55 (10).

Anal. Calcd for C12H11NO2S (233.29): C, 61.78; H, 4.75; N, 6.00; S, 13.74. Found: C, 62.42; H, 5.10; N, 6.24; S, 14.65.


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4-Oxo-2-(2-thienyl)-1-oxaspiro[4.5]dec-2-ene-3-carbonitrile (3c)

Following the typical procedure for 3a using 2a (128 mg, 1 mmol) and 3-(1-hydroxycyclohexyl)prop-2-ynenitrile (1c, 179 mg, 1.2 mmol) in MeCN (5 mL), and Et3N (101 mg, 1 mmol) with microwave irradiation at 100 °C for 9 h (or was stirred at 20–25 °C for 28 d). The residue was concentrated and washed with (pentane–acetone­, 1:1) to give 3c as pale yellow crystals; yield: 180 mg (69%) or 154 mg (59%, at 20–25 °C); mp 163–164 °C.

IR (KBr): 3112, 3099 (C=CH), 2946, 2930, 2866, 2855 (CH), 2219 (CN), 1700 (СО), 1562, 1519 (C=C), 1448, 1442, 1419, 1398, 1367, 1331, 1279, 1269, 1238, 1204, 1170, 1149, 1129, 1070, 1055, 1046, 1033, 973, 943, 931, 910, 903, 863, 850, 827, 767, 752, 742, 724, 709, 675, 629, 551, 501, 460, 406 cm–1.

1Н NMR (400.1 MHz, CDCl3): δ = 1.41 (m, 1 H, H8), 1.60–1.89 (m, 9 H, H6, H7, H8, H9, H10), 7.32 (dd, J = 5.0, 4.0 Hz, 1 H, H4′), 7.89 (dd, J = 5.0, 1.0 Hz, 1 H, H5′), 8.29 (dd, J = 4.0, 1.0 Hz, 1 H, H3′).

13С NMR (100.6 MHz, CDCl3): δ = 21.3, 24.1, 31.7 (C6, C7, C8, C9, C10), 85.9 (C5), 93.4 (C3), 112.4 (CN), 129.3 (C4′), 129.7 (C2′), 135.0 (C5′), 135.7 (C3′), 180.1 (C2), 198.5 (C4).

MS (EI): m/z (%) = 259 (58) [M]+, 218 (29), 217 (60), 205 (20), 204 (100), 191 (22), 133 (88), 111 (63), 83 (15), 79 (15), 55 (25), 53 (18).

Anal. Calcd for C14H13NO2S (259.32): C, 64.84; H, 5.05; N, 5.40; S, 12.36. Found: C, 64.59; H, 5.36; N, 5.40; S, 12.02.


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2-(1-Benzothiophen-2-yl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-3-carbonitrile (3d)

Following the typical procedure for 3a using 2b (178 mg, 1 mmol) and 4-hydroxy-4-methylpent-2-ynenitrile (1a, 131 mg, 1.2 mmol) in MeCN (5 mL), and Et3N (101 mg, 1 mmol) with microwave irradiation at 100 °C for 2.5 h (or was stirred at 20–25 °C for 12 d, or at 40–45 °C for 1.5 d, or at 100 °C for 11.5 h). The residue was concentrated and washed (CHCl3–acetone, 1:1), and then recrystallized (CHCl3) to give 3d as a light yellow powder; yield: 215 mg (80%), or 63 mg (23%, at 20–25 °C), or 108 mg (40%, at 40–45 °C), or 210 mg (78%, at 100 °C); mp 238–241 °C.

IR (KBr): 3082, 3061 (C=CH), 2987, 2936 (CH), 2223 (CN), 1707 (CО), 1567, 1516 (C=C), 1466, 1458, 1430, 1413, 1389, 1376, 1334, 1323, 1295, 1268, 1249, 1219, 1195, 1156, 1141, 1125, 1105, 1067, 1033, 1013, 996, 949, 912, 901, 885, 869, 842, 766, 757, 725, 712, 695, 678, 666, 626, 570, 547, 524, 442 cm–1.

1Н NMR (400.1 MHz, CDCl3): δ = 1.58 [s, 6 H, (CH3)2], 7.48 (m, 1 H, H6′), 7.55 (m, 1 H, H5′), 7.93 (d, J = 8.0 Hz, 1 H, H7′), 7.97 (d, J = 8.0 Hz, 1 H, H4′), 8.56 (s, 1 H, H3′).

13С NMR (100.6 MHz, CDCl3): δ = 23.1 [(CH3)2], 87.0 (C5), 91.8 (C3), 112.3 (CN), 122.7 (C7′), 125.9 (C6′), 126.4 (C5′), 128.6 (C4′), 128.9 (C2′), 132.8 (C3′), 138.7 (C3a), 142.7 (C7a), 180.9 (C2), 198.7 (C4).

MS (EI): m/z (%) = 269 (51) [M]+, 194 (18), 183 (100), 161 (43), 139 (36), 133 (13), 89 (13)

Anal. Calcd for C15H11NO2S (269.05): C, 66.89; H, 4.12; N, 5.20; S, 11.91. Found: C, 68.82; H, 3.46; N, 5.42; S, 11.91.


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2-(1-Benzothiophen-2-yl)-5-ethyl-5-methyl-4-oxo-4,5-dihydrofuran-3-carbonitrile (3e)

Following the typical procedure for 3a using 2b (178 mg, 1 mmol) and 4-hydroxy-4-methylhex-2-ynenitrile (1b, 148 mg, 1.2 mmol) in MeCN (5 mL), and Et3N (101 mg, 1 mmol) with microwave irradiation at 100 °C for 7 h (or was stirred at 20–25 °C for 29 d, or at 40–45 °C for 2.5 d). The residue was concentrated to give solid matter (280 mg) containing the furan-3(2H)-one 3e and traces of carboxylic acid 2b (1H NMR). The mixture was dissolved in Et2O (30 mL) and washed with ~0.2% NaHCO3 solution (7 × 1 mL), then it was washed with small amount of H2O (neutral reaction on litmus paper). The organic solution was dried (MgSO4) and concentrated to give 3e as a yellow powder; yield: 221 mg (78%), or 120 mg (42%, at 20–25 °C), or 60 mg (21%, at 40–45 °C); mp 131–132 °C.

IR (KBr): 3083, 3065 (C=CH), 2973, 2940 (CH), 2223 (CN), 1699 (CО), 1564, 1515 (C=C), 1462, 1452, 1434, 1416, 1382, 1337, 1324, 1315, 1288, 1257, 1246, 1201, 1187, 1140, 1125, 1116, 1067, 1057, 1033, 1014, 1001, 963, 949, 897, 867, 844, 769, 757, 749, 722, 715, 674, 649, 617, 546, 533, 455, 445 cm–1.

1Н NMR (400.1 MHz, CDCl3): δ = 0.92 (t, J = 7.5 Hz, 3 H, CH2CH 3), 1.54 (s, 3 H, CH3), 1.96 (m, 2 H, CH 2CH3), 7.49 (m, 1 H, H6′), 7.55 (m, 1 H, H5′), 7.93 (d, J = 8.0 Hz, 1 H, H7′), 7.98 (d, J = 8.0 Hz, 1 H, H4′), 8.57 (s, 1 H, H3′).

13С NMR (100.6 MHz, CDCl3): δ = 7.3 (CH2 CH3), 21.5 (CH3), 30.1 (CH2CH3), 88.0 (C5), 94.8 (C3), 112.3 (CN), 122.7 (C7′), 125.8 (C6′), 126.3 (C5′), 128.7 (C4′), 128.8 (C2′), 132.7 (C3′), 138.6 (C3a), 142.6 (C7a), 181.4 (C2), 198.7 (C4).

MS (EI): m/z (%) = 285 (13) [M]+1, 283 (43) [M]+, 256 (14), 255 (82), 183 (100), 161 (25), 139 (39), 133 (19), 89 (16).

Anal. Calcd for C16H13NO2S (283.34): C, 67.82; H, 4.62; N, 4.94; S, 11.32. Found: C, 67.53; H, 4.72; N, 5.02; S, 11.53.


#

2-(1-Benzothiophen-2-yl)-4-oxo-1-oxaspiro[4.5]dec-2-ene-3-carbonitrile (3f)

Following the typical procedure for 3a using 2b (178 mg, 1 mmol) and 3-(1-hydroxycyclohexyl)prop-2-ynenitrile (1c, 179 mg, 1.2 mmol) in MeCN (5 mL), and Et3N (101 mg, 1 mmol) with microwave irradiation at 100 °C for 6.5 h (or was stirred at 20–25 °C for 23 d, or at 40–45 °C for 3 d). The residue was concentrated to give solid matter (308 mg) containing the furan-3(2H)-one 3f and traces of carboxylic acid 2b (1H NMR). The mixture was dissolved in Et2O (40 mL) and washed with ~0.2% NaHCO3 solution (7 × 1 mL), then it was washed with small amount of H2O (neutral reaction on litmus paper). The organic solution was dried (MgSO4) and concentrated to give 3f as pale yellow crystals; yield: 254 mg (82%), or 31 mg (10%, at 20–25 °C), or 52 mg (17%, at 40–45 °C); mp 187–188 °C.

IR (KBr): 3079, 3058 (C=CH), 2937, 2860 (CH), 2220 (CN), 1704 (CО), 1566, 1516 (C=C), 1459, 1446, 1433, 1383, 1366, 1326, 1314, 1279, 1265, 1214, 1197, 1163, 1149, 1121, 1115, 1068, 1031, 985, 970, 950, 932, 909, 900, 868, 854, 845, 823, 774, 756, 723, 681, 672, 655, 548, 539, 497, 468, 428 cm–1.

1Н NMR (400.1 MHz, CDCl3): δ = 1.41 (m, 1 H, H8), 1.65–1.90 (m, 9 H, H6, H7, H8, H9, H10), 7.47 (m, 1 H, H6′), 7.53 (m, 1 H, H5′), 7.91 (d, J = 8.0 Hz, 1 H, H7′), 7.96 (d, J = 8.0 Hz, 1 H, H4′), 8.53 (s, 1 H, H3′).

13С NMR (100.6 MHz, CDCl3): δ = 21.4, 24.1, 31.8 (C6, C7, C8, C9, C10), 87.5 (C5), 93.8 (C3), 112.3 (CN), 122.6 (C7′), 125.8 (C6′), 126.3 (C5′), 128.6 (C4′), 129.1 (C2′), 132.5 (C3′), 138.6 (C3a), 142.6 (C7a), 180.7 (C2), 198.5 (C4).

MS (EI): m/z (%) = 310 (20) [M]+1, 309 (78) [M]+, 268 (22), 267 (32), 255 (16), 254 (100), 241 (11), 184 (15), 183 (79), 161 (43), 139 (23), 133 (20), 89 (11).

Anal. Calcd for C18H15NO2S (309.38): C, 69.88; H, 4.89; N, 4.53; S, 10.36. Found: C, 69.41; H, 4.83; N, 4.53; S, 10.82.


#

5,5-Dimethyl-4-oxo-2-(2-thienyl)-4,5-dihydrofuran-3-carboxamide (4a); Typical Procedure

To a stirred solution of 3a (32 mg, 0.15 mmol) in aq EtOH (2 mL), KOH (3 mg, 0.05 mmol) was added in one portion. The mixture was stirred at 20–25 °C for 24 h. The residue was concentrated and washed with distilled water to give 4a as a colorless powder; yield: 35 mg (97%); mp 159–161 °C.

IR (KBr): 3338, 3195 (NH2), 3096, 3076 (C=CH), 2987, 2941 (CH), 1619 [CО, NH2, C(O)NH2], 1595 (C=C), 1521, 1500, 1419, 1378, 1363, 1293, 1277, 1237, 1224, 1201, 1153, 1122, 1085, 1063, 1046, 994, 901, 880, 854, 803, 790, 726, 713, 675, 647, 614, 588, 565, 453 cm–1.

1Н NMR (400.1 MHz, acetone-d 6): δ = 1.43 [s, 6 H, (CH3)2], 3.38 (br s, 2 H, NH2), 7.16 (dd, J = 5.0, 3.9 Hz, 1 H, H4′), 7.75 (dd, J = 5.0, 1.0 Hz, 1 H, H5′), 9.07 (dd, J = 3.9, 1.0 Hz, 1 H, H3′).

13С NMR (100.6 MHz, acetone-d 6): δ = 23.5 [(CH3)2], 89.3 (C5), 93.2 (C3), 128.5 (C4′), 133.3 (C5′), 133.7 (C3′), 146.7 (C2′), 180.1 (C2), 180.7 [C(O)NH2], 193.5 (C4).

MS (EI): m/z (%) = 238 (15) [M]+1, 237 (83) [M]+, 236 (88), 151 (100), 123 (12), 111 (81), 69 (13), 68 (14).

Anal. Calcd for C11H11NO3S (237.27): C, 55.68; H, 4.67; N, 5.90; S, 13.51. Found: C, 55.53; H, 4.73; N, 5.39; S, 14.99.


#

5-Ethyl-5-methyl-4-oxo-2-(2-thienyl)-4,5-dihydrofuran-3-carboxamide (4b)

Following the typical procedure for 4a using 3b (72 mg, 0.31 mmol), aq EtOH (2 mL), and KOH (7 mg, 0.12 mmol) gave 4b as a yellow powder; yield: 77 mg (99%); mp ~160 °C.

IR (KBr): 3322, 3184 (NH2), 3101 (C=CH), 2973, 2921 (CH), 1630 [CО, NH2, C(O)NH2], 1593, 1575 (C=C), 1486, 1415, 1463, 1455, 1433, 1415, 1380, 1368, 1356, 1335, 1290, 1252, 1210, 1167, 1144, 1048, 1031, 994, 958, 926, 899, 878, 870, 848, 805, 794, 783, 751, 728, 697, 676, 611, 574, 565, 505, 491, 424, 394, 387 cm–1.

1Н NMR (400.1 MHz, acetone-d 6): δ = 0.83 (t, J = 7.4 Hz, 3 H, CH2CH 3), 1.40 (s, 3 H, CH3), 1.81 (m, 2 H, CH 2CH3), 2.99 (br s, 2 H, NH2), 7.16 (dd, J = 5.0, 3.9 Hz, 1 H, H4′), 7.75 (dd, J = 5.0, 1.0 Hz, 1 H, H5′), 9.07 (dd, J = 3.9, 1.0 Hz, 1 H, H3′).

13С NMR (100.6 MHz, acetone-d 6): δ = 7.4 (CH2 CH3), 22.2 (CH3), 30.4 (CH2CH3), 91.9 (C5), 94.8 (C3), 128.5 (C4′), 133.3 (C5′), 133.7 (C3′), 146.7 (C2′), 180.4 (C2), 180.6 [C(O)NH2], 193.1 (C4).

MS (EI): m/z (%) = 251 (40) [M]+, 223 (68), 151 (64), 139 (84), 111 (100), 83 (14), 68 (14).

Anal. Calcd for C12H13NO3S (251.30): C, 57.35; H, 5.21; N, 5.57; S, 12.76. Found: C, 57.16; H, 5.40; N, 5.57; S, 12.31.


#

4-Oxo-2-(2-thienyl)-1-oxaspiro[4.5]dec-2-ene-3-carboxamide (4c)

Following the typical procedure for 4a using 3c (70 mg, 0.27 mmol), aq EtOH (2 mL), and KOH (7 mg, 0.12 mmol) gave 4c as a white powder; yield: 73 mg (97%); mp ~178 °C.

IR (KBr): 3339, 3183 (C=CH, NH2), 2938, 2859, 2846 (CH), 1636 [CО, NH2, C(O)NH2], 1593 (C=C), 1511, 1484, 1460, 1448, 1436, 1417, 1367, 1353, 1333, 1278, 1257, 1239, 1150, 1131, 1078, 1059, 1044, 943, 913, 889, 857, 825, 797, 784, 748, 707, 662, 619, 610, 565, 515, 493, 455, 410, 386 cm–1.

1Н NMR (400.1 MHz, acetone-d 6): δ = 1.36 (m, 1 H, H8), 1.50–1.80 (m, 9 H, H6, H7, H8, H9, H10), 3.27 (br s, 2 H, NH2), 7.16 (dd, J = 5.0, 3.9 Hz, 1 H, H4′), 7.75 (dd, J = 5.0, 1.0 Hz, 1 H, H5′), 9.07 (dd, J = 3.9, 1.0 Hz, 1 H, H3′).

1Н NMR (400.1 MHz, CDCl3): δ = 1.27–1.40 (m, 1 H, H8), 1.46–1.93 (m, 9 H, H6, H7, H8, H9, H10), 6.39 (br s, 1 H, NH2), 7.14 (dd, J = 5.2, 4.3 Hz, 1 H, H4′), 7.60 (dd, J = 5.2, 1.1 Hz, 1 H, H5′), 8.95 (dd, J = 4.3, 1.1 Hz, 1 H, H3′), 9.47 (br s, 1 H, NH2).

13С NMR (100.6 MHz, acetone-d 6): δ = 22.1, 25.0, 32.5 (C6, C7, C8, C9, C10), 90.9 (C5), 93.8 (C3), 128.5 (C4′), 133.3 (C5′), 133.7 (C3′), 146.8 (C2′), 180.3 (C2), 180.8 [C(O)NH2], 193.3 (C4).

MS (EI): m/z (%) = 278 (15) [M]+1, 277 (92) [M]+, 236 (15), 222 (56), 176 (16), 165 (13), 152 (16), 151 (24), 138 (74), 111 (100), 108 (18), 81 (20).

Anal. Calcd for C14H15NO3S (277.34): C, 60.63; H, 5.40; N, 5.04; S, 11.55. Found: C, 60.95; H, 5.47; N, 4.79; S, 11.37.


#
#

Acknowledgment

This work was supported by the President of the Russian Federation (program for the support of leading scientific schools, Grant No. NSh-1550.2012.3), the Russian Foundation for Basic Research (Grant No. 11-03-00203), and the Presidium of RAS (Program 28) and Integration Projects No. 5.9. The main results were obtained using the equipment of Baikal analytical center of collective using SB RAS.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
  • Supporting Information

  • References

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  • References

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    CrossrefSearch in Google Scholar
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      CrossrefSearch in Google Scholar
    • 9b Shin SS, Byun Y, Lim KM, Choi JK, Lee K.-W, Moh JH, Kim JK, Jeong YS, Kim JY, Choi YH, Koh H.-J, Park Y.-H, Oh YI, Noh M.-S, Chung S. J. Med. Chem. 2004; 47: 792
      CrossrefPubMedSearch in Google Scholar
    • 9c Shamshina JL, Snowden TS. Tetrahedron Lett. 2007; 48: 3767
      CrossrefSearch in Google Scholar
  • 10 Jung J.-K, Semple G, Johnson BR. US 7,803,837, 2010
    • 13a Silva F, Reiter M, Mills-Webb R, Sawicki M, Klar D, Bensel N, Wagner A, Gouverneur V. J. Org. Chem. 2006; 71: 8390
      CrossrefSearch in Google Scholar
    • 13b Marson CM, Edaan E, Morrell JM, Coles SJ, Hursthouse MB, Davies DT. Chem. Commun. 2007; 2494
  • 14 Liu Y, Liu M, Guo S, Tu H, Zhou Y, Gao H. Org. Lett. 2006; 8: 3445
    CrossrefPubMedSearch in Google Scholar
    • 15a Landor SR, Demetriou B, Grzeskowiak R, Pavey D. J. Organomet. Chem. 1975; 93: 129
      CrossrefSearch in Google Scholar
    • 15b Trofimov BA, Mal’kina AG, Skvortsov YuM. Zh. Org. Khim. 1993; 29: 1268 ; Chem. Abstr. 1994, 120, 216196n
      Search in Google Scholar
    • 15c Hopf H, Witulski B. Functionalized Acetylenes in Organic Synthesis - The Case of the 1-Cyano- and 1-Halogenoacetylenes. In Modern Acetylene Chemistry. Stang PJ, Diederich F. VCH; Weinheim: 1995: 33-66
      CrossrefSearch in Google Scholar
    • 15d Trofimov BA, Mal’kina AG. Heterocycles 1999; 51: 2485
      CrossrefSearch in Google Scholar
    • 15e Trofimov BA, Andriyankova LV, Shaikhudinova SI, Kazantseva TI, Mal’kina AG, Afonin AV. Synthesis 2002; 853
  • 17 Kleemann A, Engel J, Kutscher B, Reichert D In Pharmaceutical Substances: Syntheses, Patents, Applications . Georg Thieme Verlag; Stuttgart: 2001: 332-333 and 956–958
    Search in Google Scholar
  • 18 Katritzky AR, Ramsden CA, Joule J, Zhdankin VV In Handbook of Heterocyclic Chemistry . 3rd ed. Elsevier; The Netherlands: 2010: 455
    Search in Google Scholar
  • 19 Berlman IB In Handbook of Fluorescence Spectra of Aromatic Molecules . Academic Press; New York: 1971: 415
    Search in Google Scholar
  • 20 Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA, Vreven TJr, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PM. W, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA. Gaussian 03, Revision B.03 . Gaussian Inc; Pittsburgh: 2003
    Search in Google Scholar
  • 21 Ahlrichs R, Bär M, Häser M, Horn H, Kölmel C. Chem. Phys. Lett. 1989; 162: 165
    CrossrefSearch in Google Scholar

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Zoom Image
Scheme 1 Tentative scheme of the tandem reaction between cyanopropargylic alcohols and thiophenecarboxylic acid
Zoom Image
Figure 1 Normalized absorption spectrum of furan-3(2H)-one 3a (1), absorption spectrum (2), and fluorescence spectrum (3) of furan-3(2H)-one 3d in acetonitrile
Zoom Image
Scheme 2 Hydrolysis of the cyano function of furan-3(2H)-ones 3a–c
Zoom Image
Figure 2 Compounds 3a–f and 4a–c showing numbering used in NMR spectra