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Regioselective synthesis of 2,4,5-trisubstituted thiophenes from Morita–Baylis–Hillman adduct-derived phosphorous ylides and isothiocyanates
Tetrahedron Letters 56 (2015) 5799–5801
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Regioselective synthesis of 2,4,5-trisubstituted thiophenes from Morita–Baylis–Hillman adduct-derived phosphorous ylides and isothiocyanates Ko Hoon Kim, Jin Woo Lim, Su Yeon Kim, Jae Nyoung Kim ⇑ Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e
i n f o
Article history: Received 28 July 2015 Revised 1 September 2015 Accepted 4 September 2015 Available online 5 September 2015
a b s t r a c t The reaction of phosphorous ylides, derived from the Morita–Baylis–Hillman (MBH) carbonates, and isothiocyanates produced 2,4,5-trisubstituted thiophenes regioselectively in good yields in a one-pot reaction. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Thiophenes Morita–Baylis–Hillman adducts Phosphorous ylides Isothiocyanates
Recently, Morita–Baylis–Hillman (MBH) adducts have been used for the syntheses of various aromatic compounds including benzenes, naphthalenes, pyridines, quinolines, pyrroles, and furans.1 However, the synthesis of thiophene derivatives from MBH adducts has been somewhat limited.2 As shown in Scheme 1, we reported the synthesis of poly-substituted thiophenes from MBH acetates via a sequential SN20 reaction with ethyl mercaptoacetate, intramolecular Michael addition, and aromatization process.2a Later, Reddy and co-workers reported an efficient thioannulation approach to thiophenes from MBH acetates of acetylenic aldehyde.2b The MBH adduct-derived phosphorous ylide I (see Scheme 1) could be generated by the reaction of MBH bromide with tertiary phosphine in the presence of base.3 The MBH adduct-derived ylide has been used for the synthesis of Ramirez ylides,3a spirooxindoles,3b,c and poly-substituted aromatics3e–h by us and 1,3-dienes by others.3i,j The MBH carbonate 1 could also form ylide I without an external base,4 and the ylide has been used extensively for the synthesis of various compounds such as pyrazoles,4a isoquinolines,4b butenolides,4d and spirooxindoles.4n In these respects, we reasoned out that the reaction of phosphorous ylide I, derived from MBH carbonate 1, and isothiocyanate would produce 2-aminothiophene 3, as shown in Scheme 1. The syntheses of thiophenes and thiophene moiety-containing
⇑ Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389. E-mail address: [email protected] (J.N. Kim). http://dx.doi.org/10.1016/j.tetlet.2015.09.014 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
OAc R
COOMe
R 1CH2 SH DBU, DMF, rt
R
Kim (Ref. 2a)
R1
OAc COOMe
COOMe
KSAc, MeOH K2CO3 , rt Reddy (Ref. 2b)
R
COOMe
PPh3 benzene
R
PPh3
MBH carbonate 1
I
S COOMe
COOMe
COOMe
R
R1
S
R OBoc
COOMe
R DDQ
AcS R 1-N=C=S (2) This Work
S R H
MeOOC R
S
NHR1
3
Scheme 1. Synthetic approaches of thiophenes from MBH adducts.
compounds have received much attention due to their synthetic applications and interesting biological activities.2,5 In these respects, development of an efficient synthetic method of poly-functionalized thiophenes is especially important. At the outset of our experiment, the reaction of MBH carbonate 1a (R = phenyl) and phenyl isothiocyanate (2a, R1 = phenyl) was carried out in the presence of PPh3 (20 mol %).6 To our delight, thiophene 3a was obtained in good yield (83%) in short time (90 min) in refluxing benzene.7 Encouraged by the successful result various MBH carbonates 1a–j were prepared,4 and the reactions with some representative isothiocyanates 2a–c were examined, as summarized in Table 1.
5800
K. H. Kim et al. / Tetrahedron Letters 56 (2015) 5799–5801 Table 1 Synthesis of poly-substituted thiophenesa
H
EWG
R1 -N=C=S (2)
OBoc EWG
PPh3 , benzene reflux, 90 min. MBH carbonate 1 R
R
3
H
MeOOC
Ph N H 3c (45%, 1a + 2c) Ph
Ph
H
MeOOC N H
Ph N H 3i (0%, 1g + 2a) H
a b c
Ph
S
S
N
O
3h (75%, 1f + 2a)
H
NC Ph
H
MeOOC
Ph N H 3k (45%, 1i + 2a) b
Ph
H 3j (80%, 1h + 2a)
Ph
N H
S
H
3g (81%, 1e + 2a)
H
EtOOC
H
MeOOC Ph
N
S
3f (81%, 1d + 2a)
H
MeOOC
3d (80%, 1b + 2a)
Ph S
3e (83%, 1c + 2a)
Ph
Ph
N H
S
S
H S
H
MeOOC
H
MeOOC
S
MeOOC N H
Cl
N H 3b (84%, 1a + 2b)
H S
H
Ph
S
MeOOC
2a: R 1 = Ph, 2b: R 1 = 4-ClC 6H 4, 2c: R 1 = CH 2Ph
MeOOC
Ph N H 3a (83%, 1a + 2a) Ph
S
1a: R = Ph, EWG = COOMe, 1b: R = 4-biphenyl, EWG = COOMe 1c: R = 1-naphthyl, EWG = COOMe, 1d: R = 2-naphthyl, EWG = COOMe 1e: R = 2-thienyl, EWG = COOMe, 1f: R = 2-furanyl, EWG = COOMe 1g: R = H, EWG = COOMe, 1h: R = Ph, EWG = COOEt NHR1 1i: R = Ph, EWG = CN, 1j; R = PhCH=CH, EWG = COOMe
S
Ph
Ph N H 3l (52%, 1j + 2a)c S
Conditions: MBH carbonate 1 (0.5 mmol), isothiocyanate 2 (0.6 mmol), PPh3 (0.1 mmol), benzene, reflux, 90 min. Carried out at 50 °C (4 h). Reaction time was 3 h.
PPh3
1a
COOMe
Ph H H
- CO2
- tBuOH
S
COOMe
Ph
N
2a
PPh3
Ph
PPh3
Ph
II'
PPh3
Ph S
MeO
I
tBuO
N Ph COOMe
PPh3 O
2a Ph
COOMe
S
Ph S
H Ph N
H
nOe
3a
Ph N III
COOMe - PPh3
Ph COOMe
Ph S Ph
N
H II
PPh3
Ph
NH S
MeOOC H 3a' (trace)
N Ph MeOOC
Ph S
III'
Scheme 2. Proposed mechanism for the formation of 3a.
As shown in Table 1, the reaction of 1a and 4-chlorophenyl isothiocyanate (2b) afforded 3b in good yield (84%). In contrast to aryl isothiocyanates the reaction of 1a and benzyl isothiocyanate (2c) gave 3c in moderate yield (45%).8 The reactions of MBH carbonates 1b–d afforded the corresponding thiophenes 3d–f in good yields (80–83%). It is interesting to note that 2,20 -bithiophene 3g and 2-thienylfuran 3h were also obtained in good yields (81% and 75%, respectively).9 Unfortunately, the reaction of MBH carbonate 1g and 2a failed to give 5-unsubstituted thiophene 3i. The formation of many intractable polar compounds was observed. Ethyl ester 3j was obtained in a similar yield (80%), while the reaction of nitrile derivative 1i under the same reaction conditions (80 °C) showed the formation of many intractable side products. The thiophene 3k was obtained in a reasonable yield (45%) by carrying out the reaction at 50 °C (4 h). The reaction of 2a and MBH carbonate 1j, prepared form cinnamaldehyde, afforded 5-styrylthiophene 3l for 3 h in moderate yield (52%). The reaction mechanism can be proposed as shown in Scheme 2. An SN20 type reaction between 1a and PPh3 produced phosphonium salt, which was converted to the ylide I by tert-butoxide ion. The reaction of I and 2a produced iminothiolate intermediate
II,10 and a following intramolecular SN20 type cyclization to III and a subsequent proton transfer afforded 3a. In the reaction, the formation of regioisomeric thiophene 3a0 was observed in a trace amount; however, it could not be isolated in appreciable yield (vide infra). The structure of 3a was confirmed by NOE experiment, as also shown in Scheme 2. The proton at C-3 position of 3a showed NOE increment by irradiation of the proton of NHPh. As noted above, during the synthesis of 3a using MBH carbonate 1a (vide supra), the formation of regioisomeric thiophene 3a0 was observed in a trace amount (<5%). When we carried out the reaction with MBH bromide 4, thiophene 3a0 was obtained in an increased yield (15%) along with 3a in somewhat lower yield (34%), as shown in Scheme 3.11 The reason for difference in reactivity between MBH carbonate 1a and MBH bromide 4 is not clear at this stage. In summary, the reaction of phosphorous ylides, derived from the Morita–Baylis–Hillman carbonates, and isothiocyanates produced 2,4,5-trisubstituted thiophenes in a regioselective manner. The reaction proceeded in a sequential nucleophilic addition of ylide to isothiocyanate, an intramolecular cyclization, an elimination of triphenylphosphine, and a proton transfer process.
K. H. Kim et al. / Tetrahedron Letters 56 (2015) 5799–5801
Ph 4
COOMe
(i) PPh3 (1.1 equiv) CH3 CN, rt, 1 h
Br
(ii) PhNCS (1.2 equiv) K2 CO3 (2.0 equiv) reflux, 12 h
Ph 3a (34%) + Ph
NH S
no nOe
MeOOC H 3a' (15%)
Scheme 3. Formation of regioisomeric thiophene 3a0 . 6.
Acknowledgments This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2014R1A1A2053606). Spectroscopic data were obtained from the Korea Basic Science Institute, Gwangju branch.
7.
Supplementary data Supplementary data (experimental procedures and characterization data for the compounds 3a–3l and 3a0 ) associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.tetlet.2015.09.014. References and notes 1. For general reviews on MBH reaction, see: (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811; (b) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447; (c) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511; (d) Kim, J. N.; Lee, K. Y. Curr. Org. Chem. 2002, 6, 627; (e) Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 1481; (f) Gowrisankar, S.; Lee, H. S.; Kim, S. H.; Lee, K. Y.; Kim, J. N. Tetrahedron 2009, 65, 8769; (g) Shi, M.; Wang, F.-J.; Zhao, M.-X.; Wei, Y. The Chemistry of the Morita– Baylis–Hillman Reaction; RSC Publishing: Cambridge, UK, 2011. 2. For synthesis of thiophenes from MBH adducts, see: (a) Lee, H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 6480; (b) Reddy, C. R.; Valleti, R. R.; Reddy, M. D. J. Org. Chem. 2013, 78, 6495. 3. For selected synthetic applications of the phosphorus ylide derived from MBH adducts, see: (a) Kim, K. H.; Lee, S.; Lee, J.; Kim, J. N. Tetrahedron Lett. 2015, 56, 4349; (b) Kim, K. H.; Moon, H. R.; Lee, J.; Kim, J.; Kim, J. N. Adv. Synth. Catal. 2015, 357, 1532; (c) Kim, K. H.; Moon, H. R.; Lee, J.; Kim, J. N. Adv. Synth. Catal. 2015, 357, 701; (d) Moon, H. R.; Kim, K. H.; Lee, J.; Kim, J. N. Bull. Korean Chem. Soc. 2015, 36, 219; (e) Kim, K. H.; Lim, C. H.; Lim, J. W.; Kim, J. N. Adv. Synth. Catal. 2014, 356, 697; (f) Lim, C. H.; Kim, K. H.; Lim, J. W.; Kim, J. N. Tetrahedron Lett. 2013, 54, 5808; (g) Lim, C. H.; Kim, S. H.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2013, 54, 2476; (h) Lim, C. H.; Kim, S. H.; Park, K. H.; Lee, J.; Kim, J. N. Tetrahedron Lett. 2013, 54, 387; (i) Sa, M. M.; Meier, L. Heteroat. Chem. 2013, 24, 384; (j) Crist, R. M.; Reddy, P. V.; Borhan, B. Tetrahedron Lett. 2001, 42, 619. 4. For selected synthetic applications of MBH carbonates, see: (a) Zhang, Q.; Meng, L.-G.; Wang, K.; Wang, L. Org. Lett. 2015, 17, 872; (b) Zhang, L.; Liu, H.; Qiao, G.; Hou, Z.; Liu, Y.; Xiao, Y.; Guo, H. J. Am. Chem. Soc. 2015, 137, 4316; (c) Zheng, J.; Huang, Y.; Li, Z. Chem. Commun. 2014, 5710; (d) Xiao, H.; Duan, H.-Y.; Ye, J.; Yao, R.-S.; Ma, J.; Yuan, Z.-Z.; Zhao, G. Org. Lett. 2014, 16, 5462; (e) Zhou, R.; Duan, C.; Yang, C.; He, Z. Chem. Asian J. 2014, 9, 1183; (f) Albertshofer, K.; Tan, B.; Barbas, C. F., III Org. Lett. 2013, 15, 2958; (g) Zhang, L.; Yu, H.; Yang, Z.; Liu, H.; Li, Z.; Guo, J.; Xiao, Y.; Guo, H. Org. Biomol. Chem. 2013, 11, 8235; (h) Lin, A.; Wang, J.; Mao, H.; Shi, Y.; Mao, Z.; Zhu, C. Eur. J. Org. Chem. 2013, 6241; (i) Zhong, F.; Chen, G.-Y.; Han, X.; Yao, W.; Lu, Y. Org. Lett. 2012, 14, 3764; (j) Xie, P.; Huang, Y.; Chen, R. Chem. Eur. J. 2012, 18, 7362; (k) Zhang, X.-N.; Deng, H.-P.; Huang, L.; Wei, Y.; Shi, M. Chem. Commun. 2012, 8664; (l) Zhou, R.; Wang, J.; Song, H.; He, Z. Org. Lett. 2011, 13, 580; (m) Wang, T.; Shen, L.-T.; Ye, S. Synthesis 2011, 3359; (n) Tan, B.; Candeias, N. R.; Barbas, C. F., III J. Am. Chem. Soc. 2011, 133, 4672; (o) Zhou, R.; Wang, C.; Song, H.; He, Z. Org. Lett. 2010, 12, 976; (p) Zheng, S.; Lu, X. Org. Lett. 2009, 11, 3978; (q) Feng, J.; Lu, X.; Kong, A.; Han, X. Tetrahedron 2007, 63, 6035; (r) Xie, P.; Huang, Y. Org. Biomol. Chem. 2015, 13, 8578. 5. For synthesis of poly-substituted thiophenes, see: Luo, X.; Ge, L.-S.; An, X.-L.; Jin, J.-H.; Wang, Y.; Sun, P.-P.; Deng, W.-P. J. Org. Chem. 2015, 80, 4611. and
8.
9.
10.
11.
5801
further references cited therein; (b) Ge, L.-S.; Wang, Z.-L.; An, X.-L.; Luo, X.; Deng, W.-P. Org. Biomol. Chem. 2014, 12, 8473; (c) Liang, C.; Tang, Z.; Qian, W.; Shi, C.; Song, H. J. Chem. Pharm. Res. 2014, 6, 798; (d) Ransborg, L. K.; Albrecht, L.; Weise, C. F.; Bak, J. R.; Jorgensen, K. A. Org. Lett. 2012, 14, 724; (e) Abaee, M. S.; Cheraghi, S. ARKIVOC 2014, iv, 1; (f) Rao, K. V.; Balakumar, C.; Narayana, B. L.; Kishore, D. P.; Rajwinder, K.; Rao, A. R. Tetrahedron Lett. 2013, 54, 1274; (g) Mancuso, R.; Gabriele, B. Molecules 2014, 19, 15687; (h) Mishra, R.; Jha, K. K.; Kumar, S.; Tomer, I. Der. Pharma Chem. 2011, 3, 38; (i) Zali-Boeini, H.; Fadaei, N. Synlett 2015, 1819. The use of an equiv. of PPh3 did not improve the yield, and the use of 10 mol % of PPh3 afforded 3a in lower yield (71%) as compared to that of the optimized one (83%). The use of dimethyl sulfide or tetrahydrothiophene instead of PPh3 showed no reaction. Typical procedure for the synthesis of 3a: A mixture of MBH carbonate 1a (146 mg, 0.5 mmol), phenyl isothiocyanate 2a (81 mg, 0.6 mmol), and PPh3 (26 mg, 0.1 mmol) in benzene (2.0 mL) was heated to reflux for 90 min. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/Et2O, 5:1), compound 3a was obtained as a yellow solid, 129 mg (83%). Other compounds were synthesized similarly, and the selected spectroscopic data of 3a, 3c, 3g, 3l, and 3a0 are as follows. Compound 3a: 83%; yellow solid, mp 110–112 °C; IR (KBr) 3352, 1711, 1601, 1497, 1261, 1217 cm1; 1H NMR (CDCl3, 300 MHz) d 3.73 (s, 3H), 5.71 (br s, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 2H), 7.10 (s, 1H), 7.27 (t, J = 7.5 Hz, 2H), 7.36–7.43 (m, 3H), 7.48–7.53 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 51.56, 115.05, 119.74, 120.52, 125.97, 127.95, 128.37, 129.41, 129.73, 133.24, 143.39, 144.29, 144.70, 163.64; ESIMS m/z 310 [M+H]+. Anal. Calcd for C18H15NO2S: C, 69.88; H, 4.89; N, 4.53. Found: C, 70.02; H, 4.75; N, 4.41. Compound 3c: 45%; yellow oil; IR (film) 3372, 1706, 1516, 1218, 1132 cm1; 1H NMR (CDCl3, 300 MHz) d 3.70 (s, 3H), 4.24 (br s, 1H), 4.32 (s, 2H), 6.44 (s, 1H), 7.28–7.40 (m, 8H), 7.42–7.47 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 51.41, 51.56, 105.65, 126.21, 127.65, 127.72, 127.81, 127.85, 128.69, 129.69, 133.55, 136.02, 128.09, 152.52, 163.97; ESIMS m/z 324 [M+H]+. Anal. Calcd for C19H17NO2S: C, 70.56; H, 5.30; N, 4.33. Found: C, 70.32; H, 5.54; N, 4.37. Compound 3g: 81%; yellow oil; IR (film) 3349, 1712, 1497, 1250, 1224 cm1; 1H NMR (CDCl3, 300 MHz) d 3.81 (s, 3H), 5.75 (br s, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 7.5 Hz, 2H), 7.04 (s, 1H), 7.05 (dd, J = 5.1 and 3.9 Hz, 1H), 7.27 (t, J = 7.5 Hz, 2H), 7.37 (dd, J = 5.1 and 1.2 Hz, 1H), 7.39 (dd, J = 3.9 and 1.2 Hz, 1H); 13 C NMR (CDCl3, 75 MHz) d 51.70, 115.32, 119.02, 120.79, 125.84, 127.01, 127.31, 128.88, 129.44, 132.05, 134.87, 144.05, 144.21, 163.41; ESIMS m/z 316 [M+H]+. Anal. Calcd for C16H13NO2S2: C, 60.93; H, 4.15; N, 4.44. Found: C, 60.80; H, 4.34; N, 4.17. Compound 3l: 52%; yellow oil; IR (film) 3345, 1708, 1601, 1546, 1498, 1469, 1215 cm1; 1H NMR (CDCl3, 300 MHz) d 3.88 (s, 3H), 5.81 (br s, 1H), 6.89 (d, J = 16.5 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.96 (s, 1H), 7.02 (d, J = 7.5 Hz, 2H), 7.24–7.38 (m, 5H), 7.52 (d, J = 7.5 Hz, 2H), 8.20 (d, J = 16.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 51.67, 115.66, 117.42, 120.98, 121.14, 126.61, 126.76, 128.04, 128.69, 129.46, 130.75, 136.73, 141.47, 143.12, 143.96, 163.79; ESIMS m/z 336 [M+H]+. Anal. Calcd for C20H17NO2S: C, 71.62; H, 5.11; N, 4.18. Found: C, 71.91; H, 5.36; N, 4.13. Compound 3a0 : 15%; yellow oil; IR (film) 3366, 1719, 1601, 1497, 1454, 1286, 1204 cm1; 1H NMR (CDCl3, 300 MHz) d 3.61 (s, 3H), 5.43 (br s, 1H), 6.77–6.84 (m, 3H), 7.11–7.23 (m, 4H), 7.24–7.33 (m, 3H), 7.69 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 51.53, 115.27, 120.57, 125.11, 127.50, 128.16, 129.33, 129.75, 130.66, 131.13, 134.20, 143.00, 144.87, 163.09; ESIMS m/z 310 [M+H]+. Anal. Calcd for C18H15NO2S: C, 69.88; H, 4.89; N, 4.53. Found: C, 69.79; H, 4.97; N, 4.38. A plausible iminothiolate intermediate II10 (see, Scheme 2) in the reaction has two nucleophilic centers, sulfur and nitrogen atoms. In the reaction with aryl isothiocyanate, sulfur atom acts as a nucleophile to produce thiophene as a major product. When we used benzyl isothiocyanate, an increased nucleophilicity of the nitrogen atom of the corresponding iminothiolate intermediate might increase the formation of side products. For selected synthesis and applications of 2,20 -bithiophenes and 2-thienylfurans, see: (a) Dong, Y.; Bolduc, A.; McGregor, N.; Skene, W. G. Org. Lett. 2011, 13, 1844; (b) Parry, P. R.; Bryce, M. R.; Tarbit, B. Org. Biomol. Chem. 2003, 1, 1447; (c) Eckert, K.; Schroder, A.; Hartmann, H. Eur. J. Org. Chem. 2000, 1327; (d) Effenberger, F.; Wurthner, F.; Steybe, F. J. Org. Chem. 1995, 60, 2082. For similar mechanism involving the synthesis of thiophenes, see: (a) Guan, X.-Y.; Shi, M. ACS Catal. 2011, 1, 1154; (b) Virieux, D.; Guillouzic, A.-F.; Cristau, H.-J. Heteroat. Chem. 2007, 18, 312; (c) Naya, S.-I.; Nitta, M. J. Chem. Soc. Perkin Trans. 2 2002, 1017. As compared to the reaction of MBH carbonate 1a, the reaction with MBH bromide 4 required the use of an equiv. of PPh3 and an external base.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Regioselective synthesis of 2,4,5-trisubstituted thiophenes from Morita–Baylis–Hillman adduct-derived phosphorous ylides and isothiocyanates Ko Hoon Kim, Jin Woo Lim, Su Yeon Kim, Jae Nyoung Kim ⇑ Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e
i n f o
Article history: Received 28 July 2015 Revised 1 September 2015 Accepted 4 September 2015 Available online 5 September 2015
a b s t r a c t The reaction of phosphorous ylides, derived from the Morita–Baylis–Hillman (MBH) carbonates, and isothiocyanates produced 2,4,5-trisubstituted thiophenes regioselectively in good yields in a one-pot reaction. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Thiophenes Morita–Baylis–Hillman adducts Phosphorous ylides Isothiocyanates
Recently, Morita–Baylis–Hillman (MBH) adducts have been used for the syntheses of various aromatic compounds including benzenes, naphthalenes, pyridines, quinolines, pyrroles, and furans.1 However, the synthesis of thiophene derivatives from MBH adducts has been somewhat limited.2 As shown in Scheme 1, we reported the synthesis of poly-substituted thiophenes from MBH acetates via a sequential SN20 reaction with ethyl mercaptoacetate, intramolecular Michael addition, and aromatization process.2a Later, Reddy and co-workers reported an efficient thioannulation approach to thiophenes from MBH acetates of acetylenic aldehyde.2b The MBH adduct-derived phosphorous ylide I (see Scheme 1) could be generated by the reaction of MBH bromide with tertiary phosphine in the presence of base.3 The MBH adduct-derived ylide has been used for the synthesis of Ramirez ylides,3a spirooxindoles,3b,c and poly-substituted aromatics3e–h by us and 1,3-dienes by others.3i,j The MBH carbonate 1 could also form ylide I without an external base,4 and the ylide has been used extensively for the synthesis of various compounds such as pyrazoles,4a isoquinolines,4b butenolides,4d and spirooxindoles.4n In these respects, we reasoned out that the reaction of phosphorous ylide I, derived from MBH carbonate 1, and isothiocyanate would produce 2-aminothiophene 3, as shown in Scheme 1. The syntheses of thiophenes and thiophene moiety-containing
⇑ Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389. E-mail address: [email protected] (J.N. Kim). http://dx.doi.org/10.1016/j.tetlet.2015.09.014 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
OAc R
COOMe
R 1CH2 SH DBU, DMF, rt
R
Kim (Ref. 2a)
R1
OAc COOMe
COOMe
KSAc, MeOH K2CO3 , rt Reddy (Ref. 2b)
R
COOMe
PPh3 benzene
R
PPh3
MBH carbonate 1
I
S COOMe
COOMe
COOMe
R
R1
S
R OBoc
COOMe
R DDQ
AcS R 1-N=C=S (2) This Work
S R H
MeOOC R
S
NHR1
3
Scheme 1. Synthetic approaches of thiophenes from MBH adducts.
compounds have received much attention due to their synthetic applications and interesting biological activities.2,5 In these respects, development of an efficient synthetic method of poly-functionalized thiophenes is especially important. At the outset of our experiment, the reaction of MBH carbonate 1a (R = phenyl) and phenyl isothiocyanate (2a, R1 = phenyl) was carried out in the presence of PPh3 (20 mol %).6 To our delight, thiophene 3a was obtained in good yield (83%) in short time (90 min) in refluxing benzene.7 Encouraged by the successful result various MBH carbonates 1a–j were prepared,4 and the reactions with some representative isothiocyanates 2a–c were examined, as summarized in Table 1.
5800
K. H. Kim et al. / Tetrahedron Letters 56 (2015) 5799–5801 Table 1 Synthesis of poly-substituted thiophenesa
H
EWG
R1 -N=C=S (2)
OBoc EWG
PPh3 , benzene reflux, 90 min. MBH carbonate 1 R
R
3
H
MeOOC
Ph N H 3c (45%, 1a + 2c) Ph
Ph
H
MeOOC N H
Ph N H 3i (0%, 1g + 2a) H
a b c
Ph
S
S
N
O
3h (75%, 1f + 2a)
H
NC Ph
H
MeOOC
Ph N H 3k (45%, 1i + 2a) b
Ph
H 3j (80%, 1h + 2a)
Ph
N H
S
H
3g (81%, 1e + 2a)
H
EtOOC
H
MeOOC Ph
N
S
3f (81%, 1d + 2a)
H
MeOOC
3d (80%, 1b + 2a)
Ph S
3e (83%, 1c + 2a)
Ph
Ph
N H
S
S
H S
H
MeOOC
H
MeOOC
S
MeOOC N H
Cl
N H 3b (84%, 1a + 2b)
H S
H
Ph
S
MeOOC
2a: R 1 = Ph, 2b: R 1 = 4-ClC 6H 4, 2c: R 1 = CH 2Ph
MeOOC
Ph N H 3a (83%, 1a + 2a) Ph
S
1a: R = Ph, EWG = COOMe, 1b: R = 4-biphenyl, EWG = COOMe 1c: R = 1-naphthyl, EWG = COOMe, 1d: R = 2-naphthyl, EWG = COOMe 1e: R = 2-thienyl, EWG = COOMe, 1f: R = 2-furanyl, EWG = COOMe 1g: R = H, EWG = COOMe, 1h: R = Ph, EWG = COOEt NHR1 1i: R = Ph, EWG = CN, 1j; R = PhCH=CH, EWG = COOMe
S
Ph
Ph N H 3l (52%, 1j + 2a)c S
Conditions: MBH carbonate 1 (0.5 mmol), isothiocyanate 2 (0.6 mmol), PPh3 (0.1 mmol), benzene, reflux, 90 min. Carried out at 50 °C (4 h). Reaction time was 3 h.
PPh3
1a
COOMe
Ph H H
- CO2
- tBuOH
S
COOMe
Ph
N
2a
PPh3
Ph
PPh3
Ph
II'
PPh3
Ph S
MeO
I
tBuO
N Ph COOMe
PPh3 O
2a Ph
COOMe
S
Ph S
H Ph N
H
nOe
3a
Ph N III
COOMe - PPh3
Ph COOMe
Ph S Ph
N
H II
PPh3
Ph
NH S
MeOOC H 3a' (trace)
N Ph MeOOC
Ph S
III'
Scheme 2. Proposed mechanism for the formation of 3a.
As shown in Table 1, the reaction of 1a and 4-chlorophenyl isothiocyanate (2b) afforded 3b in good yield (84%). In contrast to aryl isothiocyanates the reaction of 1a and benzyl isothiocyanate (2c) gave 3c in moderate yield (45%).8 The reactions of MBH carbonates 1b–d afforded the corresponding thiophenes 3d–f in good yields (80–83%). It is interesting to note that 2,20 -bithiophene 3g and 2-thienylfuran 3h were also obtained in good yields (81% and 75%, respectively).9 Unfortunately, the reaction of MBH carbonate 1g and 2a failed to give 5-unsubstituted thiophene 3i. The formation of many intractable polar compounds was observed. Ethyl ester 3j was obtained in a similar yield (80%), while the reaction of nitrile derivative 1i under the same reaction conditions (80 °C) showed the formation of many intractable side products. The thiophene 3k was obtained in a reasonable yield (45%) by carrying out the reaction at 50 °C (4 h). The reaction of 2a and MBH carbonate 1j, prepared form cinnamaldehyde, afforded 5-styrylthiophene 3l for 3 h in moderate yield (52%). The reaction mechanism can be proposed as shown in Scheme 2. An SN20 type reaction between 1a and PPh3 produced phosphonium salt, which was converted to the ylide I by tert-butoxide ion. The reaction of I and 2a produced iminothiolate intermediate
II,10 and a following intramolecular SN20 type cyclization to III and a subsequent proton transfer afforded 3a. In the reaction, the formation of regioisomeric thiophene 3a0 was observed in a trace amount; however, it could not be isolated in appreciable yield (vide infra). The structure of 3a was confirmed by NOE experiment, as also shown in Scheme 2. The proton at C-3 position of 3a showed NOE increment by irradiation of the proton of NHPh. As noted above, during the synthesis of 3a using MBH carbonate 1a (vide supra), the formation of regioisomeric thiophene 3a0 was observed in a trace amount (<5%). When we carried out the reaction with MBH bromide 4, thiophene 3a0 was obtained in an increased yield (15%) along with 3a in somewhat lower yield (34%), as shown in Scheme 3.11 The reason for difference in reactivity between MBH carbonate 1a and MBH bromide 4 is not clear at this stage. In summary, the reaction of phosphorous ylides, derived from the Morita–Baylis–Hillman carbonates, and isothiocyanates produced 2,4,5-trisubstituted thiophenes in a regioselective manner. The reaction proceeded in a sequential nucleophilic addition of ylide to isothiocyanate, an intramolecular cyclization, an elimination of triphenylphosphine, and a proton transfer process.
K. H. Kim et al. / Tetrahedron Letters 56 (2015) 5799–5801
Ph 4
COOMe
(i) PPh3 (1.1 equiv) CH3 CN, rt, 1 h
Br
(ii) PhNCS (1.2 equiv) K2 CO3 (2.0 equiv) reflux, 12 h
Ph 3a (34%) + Ph
NH S
no nOe
MeOOC H 3a' (15%)
Scheme 3. Formation of regioisomeric thiophene 3a0 . 6.
Acknowledgments This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2014R1A1A2053606). Spectroscopic data were obtained from the Korea Basic Science Institute, Gwangju branch.
7.
Supplementary data Supplementary data (experimental procedures and characterization data for the compounds 3a–3l and 3a0 ) associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.tetlet.2015.09.014. References and notes 1. For general reviews on MBH reaction, see: (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811; (b) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447; (c) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511; (d) Kim, J. N.; Lee, K. Y. Curr. Org. Chem. 2002, 6, 627; (e) Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 1481; (f) Gowrisankar, S.; Lee, H. S.; Kim, S. H.; Lee, K. Y.; Kim, J. N. Tetrahedron 2009, 65, 8769; (g) Shi, M.; Wang, F.-J.; Zhao, M.-X.; Wei, Y. The Chemistry of the Morita– Baylis–Hillman Reaction; RSC Publishing: Cambridge, UK, 2011. 2. For synthesis of thiophenes from MBH adducts, see: (a) Lee, H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 6480; (b) Reddy, C. R.; Valleti, R. R.; Reddy, M. D. J. Org. Chem. 2013, 78, 6495. 3. For selected synthetic applications of the phosphorus ylide derived from MBH adducts, see: (a) Kim, K. H.; Lee, S.; Lee, J.; Kim, J. N. Tetrahedron Lett. 2015, 56, 4349; (b) Kim, K. H.; Moon, H. R.; Lee, J.; Kim, J.; Kim, J. N. Adv. Synth. Catal. 2015, 357, 1532; (c) Kim, K. H.; Moon, H. R.; Lee, J.; Kim, J. N. Adv. Synth. Catal. 2015, 357, 701; (d) Moon, H. R.; Kim, K. H.; Lee, J.; Kim, J. N. Bull. Korean Chem. Soc. 2015, 36, 219; (e) Kim, K. H.; Lim, C. H.; Lim, J. W.; Kim, J. N. Adv. Synth. Catal. 2014, 356, 697; (f) Lim, C. H.; Kim, K. H.; Lim, J. W.; Kim, J. N. Tetrahedron Lett. 2013, 54, 5808; (g) Lim, C. H.; Kim, S. H.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2013, 54, 2476; (h) Lim, C. H.; Kim, S. H.; Park, K. H.; Lee, J.; Kim, J. N. Tetrahedron Lett. 2013, 54, 387; (i) Sa, M. M.; Meier, L. Heteroat. Chem. 2013, 24, 384; (j) Crist, R. M.; Reddy, P. V.; Borhan, B. Tetrahedron Lett. 2001, 42, 619. 4. For selected synthetic applications of MBH carbonates, see: (a) Zhang, Q.; Meng, L.-G.; Wang, K.; Wang, L. Org. Lett. 2015, 17, 872; (b) Zhang, L.; Liu, H.; Qiao, G.; Hou, Z.; Liu, Y.; Xiao, Y.; Guo, H. J. Am. Chem. Soc. 2015, 137, 4316; (c) Zheng, J.; Huang, Y.; Li, Z. Chem. Commun. 2014, 5710; (d) Xiao, H.; Duan, H.-Y.; Ye, J.; Yao, R.-S.; Ma, J.; Yuan, Z.-Z.; Zhao, G. Org. Lett. 2014, 16, 5462; (e) Zhou, R.; Duan, C.; Yang, C.; He, Z. Chem. Asian J. 2014, 9, 1183; (f) Albertshofer, K.; Tan, B.; Barbas, C. F., III Org. Lett. 2013, 15, 2958; (g) Zhang, L.; Yu, H.; Yang, Z.; Liu, H.; Li, Z.; Guo, J.; Xiao, Y.; Guo, H. Org. Biomol. Chem. 2013, 11, 8235; (h) Lin, A.; Wang, J.; Mao, H.; Shi, Y.; Mao, Z.; Zhu, C. Eur. J. Org. Chem. 2013, 6241; (i) Zhong, F.; Chen, G.-Y.; Han, X.; Yao, W.; Lu, Y. Org. Lett. 2012, 14, 3764; (j) Xie, P.; Huang, Y.; Chen, R. Chem. Eur. J. 2012, 18, 7362; (k) Zhang, X.-N.; Deng, H.-P.; Huang, L.; Wei, Y.; Shi, M. Chem. Commun. 2012, 8664; (l) Zhou, R.; Wang, J.; Song, H.; He, Z. Org. Lett. 2011, 13, 580; (m) Wang, T.; Shen, L.-T.; Ye, S. Synthesis 2011, 3359; (n) Tan, B.; Candeias, N. R.; Barbas, C. F., III J. Am. Chem. Soc. 2011, 133, 4672; (o) Zhou, R.; Wang, C.; Song, H.; He, Z. Org. Lett. 2010, 12, 976; (p) Zheng, S.; Lu, X. Org. Lett. 2009, 11, 3978; (q) Feng, J.; Lu, X.; Kong, A.; Han, X. Tetrahedron 2007, 63, 6035; (r) Xie, P.; Huang, Y. Org. Biomol. Chem. 2015, 13, 8578. 5. For synthesis of poly-substituted thiophenes, see: Luo, X.; Ge, L.-S.; An, X.-L.; Jin, J.-H.; Wang, Y.; Sun, P.-P.; Deng, W.-P. J. Org. Chem. 2015, 80, 4611. and
8.
9.
10.
11.
5801
further references cited therein; (b) Ge, L.-S.; Wang, Z.-L.; An, X.-L.; Luo, X.; Deng, W.-P. Org. Biomol. Chem. 2014, 12, 8473; (c) Liang, C.; Tang, Z.; Qian, W.; Shi, C.; Song, H. J. Chem. Pharm. Res. 2014, 6, 798; (d) Ransborg, L. K.; Albrecht, L.; Weise, C. F.; Bak, J. R.; Jorgensen, K. A. Org. Lett. 2012, 14, 724; (e) Abaee, M. S.; Cheraghi, S. ARKIVOC 2014, iv, 1; (f) Rao, K. V.; Balakumar, C.; Narayana, B. L.; Kishore, D. P.; Rajwinder, K.; Rao, A. R. Tetrahedron Lett. 2013, 54, 1274; (g) Mancuso, R.; Gabriele, B. Molecules 2014, 19, 15687; (h) Mishra, R.; Jha, K. K.; Kumar, S.; Tomer, I. Der. Pharma Chem. 2011, 3, 38; (i) Zali-Boeini, H.; Fadaei, N. Synlett 2015, 1819. The use of an equiv. of PPh3 did not improve the yield, and the use of 10 mol % of PPh3 afforded 3a in lower yield (71%) as compared to that of the optimized one (83%). The use of dimethyl sulfide or tetrahydrothiophene instead of PPh3 showed no reaction. Typical procedure for the synthesis of 3a: A mixture of MBH carbonate 1a (146 mg, 0.5 mmol), phenyl isothiocyanate 2a (81 mg, 0.6 mmol), and PPh3 (26 mg, 0.1 mmol) in benzene (2.0 mL) was heated to reflux for 90 min. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/Et2O, 5:1), compound 3a was obtained as a yellow solid, 129 mg (83%). Other compounds were synthesized similarly, and the selected spectroscopic data of 3a, 3c, 3g, 3l, and 3a0 are as follows. Compound 3a: 83%; yellow solid, mp 110–112 °C; IR (KBr) 3352, 1711, 1601, 1497, 1261, 1217 cm1; 1H NMR (CDCl3, 300 MHz) d 3.73 (s, 3H), 5.71 (br s, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 2H), 7.10 (s, 1H), 7.27 (t, J = 7.5 Hz, 2H), 7.36–7.43 (m, 3H), 7.48–7.53 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 51.56, 115.05, 119.74, 120.52, 125.97, 127.95, 128.37, 129.41, 129.73, 133.24, 143.39, 144.29, 144.70, 163.64; ESIMS m/z 310 [M+H]+. Anal. Calcd for C18H15NO2S: C, 69.88; H, 4.89; N, 4.53. Found: C, 70.02; H, 4.75; N, 4.41. Compound 3c: 45%; yellow oil; IR (film) 3372, 1706, 1516, 1218, 1132 cm1; 1H NMR (CDCl3, 300 MHz) d 3.70 (s, 3H), 4.24 (br s, 1H), 4.32 (s, 2H), 6.44 (s, 1H), 7.28–7.40 (m, 8H), 7.42–7.47 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 51.41, 51.56, 105.65, 126.21, 127.65, 127.72, 127.81, 127.85, 128.69, 129.69, 133.55, 136.02, 128.09, 152.52, 163.97; ESIMS m/z 324 [M+H]+. Anal. Calcd for C19H17NO2S: C, 70.56; H, 5.30; N, 4.33. Found: C, 70.32; H, 5.54; N, 4.37. Compound 3g: 81%; yellow oil; IR (film) 3349, 1712, 1497, 1250, 1224 cm1; 1H NMR (CDCl3, 300 MHz) d 3.81 (s, 3H), 5.75 (br s, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 7.5 Hz, 2H), 7.04 (s, 1H), 7.05 (dd, J = 5.1 and 3.9 Hz, 1H), 7.27 (t, J = 7.5 Hz, 2H), 7.37 (dd, J = 5.1 and 1.2 Hz, 1H), 7.39 (dd, J = 3.9 and 1.2 Hz, 1H); 13 C NMR (CDCl3, 75 MHz) d 51.70, 115.32, 119.02, 120.79, 125.84, 127.01, 127.31, 128.88, 129.44, 132.05, 134.87, 144.05, 144.21, 163.41; ESIMS m/z 316 [M+H]+. Anal. Calcd for C16H13NO2S2: C, 60.93; H, 4.15; N, 4.44. Found: C, 60.80; H, 4.34; N, 4.17. Compound 3l: 52%; yellow oil; IR (film) 3345, 1708, 1601, 1546, 1498, 1469, 1215 cm1; 1H NMR (CDCl3, 300 MHz) d 3.88 (s, 3H), 5.81 (br s, 1H), 6.89 (d, J = 16.5 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.96 (s, 1H), 7.02 (d, J = 7.5 Hz, 2H), 7.24–7.38 (m, 5H), 7.52 (d, J = 7.5 Hz, 2H), 8.20 (d, J = 16.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 51.67, 115.66, 117.42, 120.98, 121.14, 126.61, 126.76, 128.04, 128.69, 129.46, 130.75, 136.73, 141.47, 143.12, 143.96, 163.79; ESIMS m/z 336 [M+H]+. Anal. Calcd for C20H17NO2S: C, 71.62; H, 5.11; N, 4.18. Found: C, 71.91; H, 5.36; N, 4.13. Compound 3a0 : 15%; yellow oil; IR (film) 3366, 1719, 1601, 1497, 1454, 1286, 1204 cm1; 1H NMR (CDCl3, 300 MHz) d 3.61 (s, 3H), 5.43 (br s, 1H), 6.77–6.84 (m, 3H), 7.11–7.23 (m, 4H), 7.24–7.33 (m, 3H), 7.69 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 51.53, 115.27, 120.57, 125.11, 127.50, 128.16, 129.33, 129.75, 130.66, 131.13, 134.20, 143.00, 144.87, 163.09; ESIMS m/z 310 [M+H]+. Anal. Calcd for C18H15NO2S: C, 69.88; H, 4.89; N, 4.53. Found: C, 69.79; H, 4.97; N, 4.38. A plausible iminothiolate intermediate II10 (see, Scheme 2) in the reaction has two nucleophilic centers, sulfur and nitrogen atoms. In the reaction with aryl isothiocyanate, sulfur atom acts as a nucleophile to produce thiophene as a major product. When we used benzyl isothiocyanate, an increased nucleophilicity of the nitrogen atom of the corresponding iminothiolate intermediate might increase the formation of side products. For selected synthesis and applications of 2,20 -bithiophenes and 2-thienylfurans, see: (a) Dong, Y.; Bolduc, A.; McGregor, N.; Skene, W. G. Org. Lett. 2011, 13, 1844; (b) Parry, P. R.; Bryce, M. R.; Tarbit, B. Org. Biomol. Chem. 2003, 1, 1447; (c) Eckert, K.; Schroder, A.; Hartmann, H. Eur. J. Org. Chem. 2000, 1327; (d) Effenberger, F.; Wurthner, F.; Steybe, F. J. Org. Chem. 1995, 60, 2082. For similar mechanism involving the synthesis of thiophenes, see: (a) Guan, X.-Y.; Shi, M. ACS Catal. 2011, 1, 1154; (b) Virieux, D.; Guillouzic, A.-F.; Cristau, H.-J. Heteroat. Chem. 2007, 18, 312; (c) Naya, S.-I.; Nitta, M. J. Chem. Soc. Perkin Trans. 2 2002, 1017. As compared to the reaction of MBH carbonate 1a, the reaction with MBH bromide 4 required the use of an equiv. of PPh3 and an external base.