Cobalt-Catalyzed Direct C–H Thiolation of Aromatic Amides with

Letter Cite This: Org. Lett. 2018, 20, 6490−6493

pubs.acs.org/OrgLett

Cobalt-Catalyzed Direct C−H Thiolation of Aromatic Amides with Disulfides: Application to the Synthesis of Quetiapine Mingliang Li and Jun “Joelle” Wang* Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055, China

Downloaded via KAOHSIUNG MEDICAL UNIV on October 19, 2018 at 11:22:16 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: A direct C(sp2)−H thiolation of aromatic amides with disulfides was developed. The coupling reaction proceeds between the thioether radical and cobaltacycle intermediate. This method exhibits a relatively broad substrate scope and high functional group compatibility. A mechanistic study indicates that the cobalt(IV) intermediate is probably formed during the course of the reaction. The thiolation product can be transformed to Quetiapine, which is an atypical antipsychotic agent approved for the treatment of schizophrenia and bipolar disorder.

T

fore, transition-metal-catalyzed C(sp2)−S bond formation has recently received increasing attention.10−13 However, there are limited examples for cobalt-catalyzed C(sp2)−H thiolation.14 In 2016, Glorius and co-workers developed the cobaltcatalyzed chelation-assisted direct thiolation of indole derivatives with thiophenols (Scheme 1a).14b Yet this methodology

ransition-metal-catalyzed coupling of radical species with a cyclic metallacycle intermediate has emerged as a useful pathway for C−H bond activation.1−4 Nevertheless, there are rare reports utilizing this methodology for construction of the C−X bond (X = N, O, S).2,3b The coupling of a radical with a cyclic metallacycle intermediate is a single-electron oxidation process [Mn → M(n+1)], which provides a high-valent metal complex with unusual electronic and steric properties for promoting further synthetic transformation.5 It can be said that this method opens up an interesting avenue for C−H bond activation via a newfangled mechanism, in which a transition metal catalyst undergoes an unusual cyclic pathway [Mn → M(n+1) → M(n−1) → Mn].3−5 Additionally, applying the radical coupling to C−H bond activation could effectively expand the type of coupling partners to radical precursors and would accomplish rarely reported C−X bond formation (X = P, Si, B). Among transition-metal-catalyzed C−H activations, the C− X (X = N, O, S) bond formation is always accomplished by the reductive elimination of the key C−M−X intermediate, which is afforded via ligand exchange, transmetalation, oxidative addition, or metal-carbene formation with a cyclic metallacycle intermediate.6To date, there are a few reports aimed at C−X bond formation via the radical coupling of cyclic metallacycle species, especially in the area of employing a cobalt catalyst. In previous work, the cobalt(III) complex was found to couple with TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) effectively in delivering a cobalt(IV) intermediate.7 To further understand the interaction between a cyclic metallacycle intermediate and radical species, we turned our attention to the cobalt-catalyzed C(sp2)−H bond activation using a radical precursor as the coupling partner. The C(sp2)−S bonds widely exist in organic functionalized materials, pharmaceuticals, and bioactive molecules.8,9 There© 2018 American Chemical Society

Scheme 1. Cobalt-Catalyzed C(sp2)−H Thiolation

Received: September 3, 2018 Published: October 4, 2018 6490

DOI: 10.1021/acs.orglett.8b02812 Org. Lett. 2018, 20, 6490−6493

Letter

Organic Letters Scheme 2. Scope of Aromatic Amidesa,b

cannot be expanded to the aromatic amides and required the use of an expensive cobalt catalyst [Cp*Co(CO)I2]. Therefore, we aim to accomplish the cobalt-catalyzed direct C−H thiolation of aromatic amides via the coupling of cobaltacycle intermediates with a thioether radical derived from disulfides in the presence of peroxide (Scheme 1b). We initially explored the coupling of 2-(2-methylbenzamido)pyridine 1-oxide (1a) with 1,2-diphenyldisulfane (2a). To our delight, the thiolation product 3a could be obtained in 42% yield in the presence of Co(OAc)2·4H2O (20 mol %), NaOAc (2.0 equiv), and DTBP (di-tert-butyl peroxide) (2.0 equiv) in toluene (Table S1, entry 1). When the catalyst loading of Co(OAc)2·4H2O was decreased to 10 mol %, the yield was improved to 74% (Table S1, entry 5). After surveying various cobalt catalysts [e.g., CoCl2, CoBr2, and Co(acac)2], CoBr2 was found to give the best yield of 83% (Table S1, entries 6−8). In the absence of DTBP, no desired product was obtained (Table S1, entry 10). The reaction yield was decreased to 18% when the reaction was carried out without NaOAc (Table S1, entry 10). Other bases proved to be less efficient (Table S1, entries 13−16). No product was obtained with silver salts such as Ag2CO3, Ag2O, AgNO3, and AgOAc as the oxidant (Table S1, entries 17−20). Under the optimized reaction conditions, the desired product could be afforded in 90% yield in the presence of CoBr2 (10 mol %), NaOAc (2.0 equiv), and DTBP (2.0 equiv) in dry toluene (Table S1, entry 25). Apart from the pyridine N-oxide, other directing groups including bidentate or monodentate were inefficient, and 2-methyl-N-(quinolin-8-yl)benzamide only provided the corresponding product in 9% yield under the optimized conditions (Table S2). With the optimized reaction conditions in hand, we next explored the scope of aromatic amides (Scheme 2). A variety of ortho-substituted benzamide derivatives provided the thiolation products in moderate-to-good yields (3a−d). It is noteworthy that the thiolation reaction only occurred at the C−H bond rather than the C−X (X = F, Cl, Br) bonds (3b− d), which offers opportunities for further subsequent transformation of the thiolation product. 2,3-Disubstituted or 2,4disubstituted aromatic amides all proceeded well to give the corresponding products except the 4-fluoro-2-methyl benzamide derivative (3e−m). The monothiolation product 3n could also be obtained when 2-benzamidopyridine 1-oxide (1n) was used as a coupling partner. Interestingly, 2-(1methyl-1H-indole-2-carboxamido)pyridine 1-oxide (1o) could also afford the desired product 3o in fair yield. Next, we turned our attention to the scope of disulfide substrates (Scheme 3). An array of 1,2-diaryldisulfides was able to efficiently couple with benzamide 1a to give the corresponding products (4a−i). The 1,2-diaryldisulfides with either electron-withdrawing or electron-donating groups at the phenyl ring all proceeded well to give the corresponding products in moderate-to-good yields (4a−f). It is noteworthy that this method was compatible with some functional groups such as F, Cl, Br, CF3, Me, and OMe. Interestingly, disulfides with bulky substituents such as mesityl, 2,4,6-triisopropylphenyl, and naphthalen-2-yl also worked well, giving the corresponding products 4g, 4h, and 4i in 86%, 79%, and 85% yields, respectively. The disulfides with a heteroaromatic moiety could also afford the corresponding products in medium yields (4j−k). Furthermore, 1,2-dibenzyldisulfane could also deliver the desired product in synthetically useful yield (4l). The relatively low yield was probably caused by the

a Reactions conditions: CoBr2 (10 mol %), NaOAc (2.0 equiv), DTBP (2.0 equiv), amide 1 (0.25 mmol), and 1,2-diphenyldisulfane (2a) (0.625 mmol) were stirred in dry toluene (1 mL) at 130 °C for 18 h. b Isolated yield. cCo(acac)2 (20 mol %). dReactions conditions: CoBr2 (5 mol %), Ni(OAc)2 (20 mol %), PPh3 (40 mol %), CsOAc (2.0 equiv), DTBP (2.0 equiv), amide 1n (0.25 mmol), and 1,2diphenyldisulfane 2a (0.625 mmol) were stirred in dry toluene (1 mL) at 130 °C for 24 h.

undesired transformation of the BnS radical in the presence of DTBP. To gain insight into the reaction mechanism, we conducted the H/D exchange experiments. When the reaction was carried out with benzamide 1a and D2O in the presence of CoBr2 (10 mol %) and NaOAc (2.0 equiv) in dry toluene, no H/D exchange was observed by 1H NMR [see Supporting Information (SI) IV, eq 1]. However, 15% of 1a was deuterated with the addition of DTBP (2.0 equiv) (Scheme 4a), which revealed that the reversible C−H bond cleavage was probably caused by the active cobalt(III) catalyst. Other KIE (kinetic isotope effect) experiments were performed with two independent reactions and the value was found to be 1.20, indicating that the C−H bond cleavage is probably not involved in the rate-determining step (Scheme 4b). Furthermore, a series of radical trap experiments were carried out with the addition of radical scavengers (Scheme 4c). The reaction yield of 1a with 2a was decreased to 13% in the presence of TEMPO (2,2,6,6-tetramethylpiperidine oxide) (1.0 equiv), and no desired product was observed with the addition of 4.0 equiv of TEMPO or 1,1-diphenylethylene. These results suggest that a free-radical pathway could be involved in the reaction. The key cobalt(IV) intermediate generated by coupling of a thioether radical with a cobaltacycle intermediate derived from C−H activation of 1a was detected 6491

DOI: 10.1021/acs.orglett.8b02812 Org. Lett. 2018, 20, 6490−6493

Letter

Organic Letters Scheme 3. Scope of Disulfidesa,b

Scheme 5. Plausible Mechanism

cobaltation to afford cobaltacycle species III. Subsequently, radical coupling of intermediate III with the thioether radical generated from disulfides in the presence of DTBP provides cobalt(IV) intermediate IV, which was detected by ESI-MS (see SI IV). Finally, reductive elimination of IV followed by protonation furnishes the desired product 3a and cobalt(II) catalyst to complete the catalytic cycle. The rate-determining step could be the reductive elimination of intermediate IV. To demonstrate the synthetic usefulness, we applied this newly established method in synthesizing Quetiapine, which is an atypical antipsychotic agent approved for the treatment of schizophrenia and bipolar disorder.15 The traditional synthetic route for accessing Quetiapine was based on the cross-coupling of benzenethiols with aryl halides,15a,16 while our synthetic strategy was based on the direct C−H thiolation of benzamides (Scheme 6). The thiolation of 2-benzamidopyridine 1-oxide

a Reactions conditions: CoBr2 (10 mol %), NaOAc (2.0 equiv), DTBP (2.0 equiv), amide 1a (0.25 mmol), and disulfides 2 (0.625 mmol) were stirred in dry toluene (1 mL) at 130 °C for 18 h. bIsolated yield. c CoBr2 (20 mol %). dCo(acac)2 (20 mol %), 140 °C.

Scheme 4. Mechanistic Experiments

Scheme 6. Synthesis of Quetiapine

(1n) with 1,2-diphenyldisulfane afforded the desired product 3n on gram scale. Then, benzoic acid derivative 5 was obtained by hydrolysis of amide 3o. Subsequently, Curtius rearrangement of the compound 5 and treatment with phenols delivered carbamate 6, which underwent polyphosphoric acid promoted cyclization and subsequent pseudohalogenation to give triflate 7. Finally, the desired Quetiapine product was obtained by nucleophilic substitution of the piperazine derivative with triflate 7.

by mass spectroscopic analysis of the reaction mixtures after 2 h. Based on the aforementioned mechanistic investigations and literature examples,4 a proposed mechanism is illustrated in Scheme 5. Initially, coordination of benzamide 1a with a cobalt(II) catalyst and a subsequent ligand exchange delivered intermediate I, which was detected by ESI-MS (see SI IV). Next, the cobalt(II) complex is oxidized by DTBP to generate cobalt(III) intermediate II, which undergoes a reversible C−H 6492

DOI: 10.1021/acs.orglett.8b02812 Org. Lett. 2018, 20, 6490−6493

Letter

Organic Letters

(5) (a) Poli, R. Angew. Chem., Int. Ed. 2006, 45, 5058. (b) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299. (c) Weix, D. J. Acc. Chem. Res. 2015, 48, 1767. (d) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58. (e) Tellis, J. C.; Kelly, C. B.; Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A. Acc. Chem. Res. 2016, 49, 1429. (f) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. J. Org. Chem. 2016, 81, 6898. (6) (a) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (b) Louillat, M.-L.; Patureau, F. W. Chem. Soc. Rev. 2014, 43, 901. (c) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040. (d) He, G.; Wang, B.; Nack, W. A.; Chen, G. Acc. Chem. Res. 2016, 49, 635. (e) Le Bras, J. L.; Muzart, J. Eur. J. Org. Chem. 2018, 2018, 1176. (f) Rit, R. K.; Shankar, M.; Sahoo, A. K. Org. Biomol. Chem. 2017, 15, 1282. (g) Moghimi, S.; Mahdavi, M.; Shafiee, A.; Foroumadi, A. Eur. J. Org. Chem. 2016, 2016, 3282. (h) Timsina, Y. N.; Gupton, B. F.; Ellis, K. C. ACS Catal. 2018, 8, 5732. (7) Li, M.; Kwong, F. Y. Angew. Chem., Int. Ed. 2018, 57, 6512. (8) For selected examples, see: (a) Murphy, A. R.; Fréchet, J. M. Chem. Rev. 2007, 107, 1066. (b) Nair, D. P.; Podgórski, M.; Chatani, S.; Gong, T.; Xi, W.; Fenoli, C. R.; Bowman, C. N. Chem. Mater. 2014, 26, 724. (c) Mori, T.; Nishimura, T.; Yamamoto, T.; Doi, I.; Miyazaki, E.; Osaka, I.; Takimiya, K. J. Am. Chem. Soc. 2013, 135, 13900. (9) For selected examples, see: (a) Nagao, T.; Sato, M.; Nakajima, H.; Kiyomoto, A. Chem. Pharm. Bull. 1973, 21, 92. (b) Bharathi, C.; Prabahar, K. J.; Prasad, C. S.; Rao, M. S.; Trinadhachary, G. N.; Handa, V. K.; Dandala, R.; Naidu, A. Pharmazie 2008, 63, 14. (c) Thomas, G. L.; Spandl, R. J.; Glansdorp, F. G.; Welch, M.; Bender, A.; Cockfield, J.; Lindsay, J. A.; Bryant, C.; Brown, D. F. J.; Loiseleur, O.; Rudyk, H.; Ladlow, M.; Spring, D. R. Angew. Chem., Int. Ed. 2008, 47, 2808. (d) Woo, C. M.; Gholap, S. L.; Herzon, S. B. J. Nat. Prod. 2013, 76, 1238. (e) Bontemps, N.; Gattacceca, F.; Long, C.; Thomas, O. P.; Banaigs, B. J. Nat. Prod. 2013, 76, 1801. (10) Shen, C.; Zhang, P.; Sun, Q.; Bai, S.; Hor, T. S. A.; Liu, X. Chem. Soc. Rev. 2015, 44, 291. (11) (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (b) Li, Z.; Hong, J.; Zhou, X. Tetrahedron 2011, 67, 3690. (c) Ranjit, S.; Lee, R.; Heryadi, D.; Shen, C.; Wu, J.; Zhang, P.; Huang, K.-W.; Liu, X. J. Org. Chem. 2011, 76, 8999. (d) Tran, L. D.; Popov, I.; Daugulis, O. J. Am. Chem. Soc. 2012, 134, 18237. (12) Zhang, C.; McClure, J.; Chou, C. J. J. Org. Chem. 2015, 80, 4919. (13) (a) Yang, K.; Wang, Y.; Chen, X.; Kadi, A. A.; Fun, H.-K.; Sun, H.; Zhang, Y.; Lu, H. Chem. Commun. 2015, 51, 3582. (b) Yan, S.-Y.; Liu, Y.-J.; Liu, B.; Liu, Y.-H.; Shi, B.-F. Chem. Commun. 2015, 51, 4069. (c) Zhu, J.; Chen, Y.; Lin, F.; Wang, B.; Chen, Z.; Liu, L. Org. Biomol. Chem. 2015, 13, 3711. (d) Lin, C.; Li, D.; Wang, B.; Yao, J.; Zhang, Y. Org. Lett. 2015, 17, 1328. (e) Reddy, V. P.; Qiu, R.; Iwasaki, T.; Kambe, N. Org. Biomol. Chem. 2015, 13, 6803. (14) (a) Zhang, G.; Liu, C.; Yi, H.; Meng, Q.; Bian, C.; Chen, H.; Jian, J.-X. J. Am. Chem. Soc. 2015, 137, 9273. (b) Gensch, T.; Klauck, F. J. R.; Glorius, F. Angew. Chem., Int. Ed. 2016, 55, 11287. (c) Hu, L.; Chen, X.; Yu, L.; Yu, Y.; Tan, Z.; Zhu, G.; Gui, Q.; Wu, L.-Z.; Lei, A. Org. Chem. Front. 2018, 5, 216. (d) Wang, T.; Chen, J.; Wang, J.; Xu, S.; Lin, A.; Yao, H.; Jiang, S.; Xu, J. Org. Biomol. Chem. 2018, 16, 3721. (15) (a) Warawa, E. J.; Migler, B. M.; Ohnmacht, C. J.; Needles, A. L.; Gatos, G. C.; McLaren, F. M.; Nelson, C. L.; Kirkland, K. M. J. Med. Chem. 2001, 44, 372. (b) Vieta, E.; Parramon, G.; Padrell, E.; Nieto, E.; Martinez-Arán, A.; Corbella, B.; Colom, F.; Reinares, M.; Goikolea, J. M.; Torrent, C. Bipolar Disord. 2002, 4, 335. (16) (a) Niphade, N. C.; Mali, A. C.; Pandit, B. S.; Jagtap, K. M.; Jadhav, S. A.; Jachak, M. N.; Mathad, V. T. Org. Process Res. Dev. 2009, 13, 792. (b) Kandula, V. R.; Fondekar, K. P. Org. Chem. Ind. J. 2015, 11, 211.

In conclusion, we have developed a cobalt-catalyzed direct C(sp2)−H thiolation of aromatic amides with disulfides. This reaction exhibits a relatively extensive substrate scope and high functional group compatibility. Disulfides with bulky substituents such as mesityl or 2,4,6-triisopropylphenyl are also found to be compatible under these reaction conditions. Mechanistic study indicates that the C(sp2)−S bond is probably formed by the coupling of a cobaltacycle intermediate with a thioether radical and subsequent reductive elimination. In addtion, this direct C(sp2)−H thiolation of aromatic amides with disulfides was successfully applied as the key step in the synthesis of Quetiapine. Further extension of this method toward drug synthesis is ongoing in our laboratory.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02812. Experimental procedures, characterization data, and copies of NMR (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jun “Joelle” Wang: 0000-0001-9723-4054 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work is supported by Shenzhen Basic Research Program (JCYJ20170817112532779 and JCYJ20170412152435366) and the Shenzhen Nobel Prize Scientists Laboratory Project (C17783101).

■

REFERENCES

(1) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.; Lei, A. Chem. Rev. 2017, 117, 9016 and references cited therein . (2) For recent selected examples using palladium catalyst, see: (a) Yan, Y.; Feng, P.; Zheng, Q.-Z.; Liang, Y.-F.; Lu, J.-F.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2013, 52, 5827. (b) Seth, K.; Nautiyal, M.; Purohit, P.; Parikh, N.; Chakraborti, A. K. Chem. Commun. 2015, 51, 191. (c) Liu, W.; Yu, Q.; Hu, L.; Chen, Z.; Huang, J. Chem. Sci. 2015, 6, 5768. (d) Sharma, U. K.; Gemoets, H. P. L.; Schröder, F.; Noël, T.; Van der Eycken, E. V. V. ACS Catal. 2017, 7, 3818. (e) Xia, H.; An, Y.; Zeng, X.; Wu, J. Chem. Commun. 2017, 53, 12548. (3) For recent selected examples using nickel catalyst, see: (a) Wu, X.; Zhao, Y.; Ge, H. J. Am. Chem. Soc. 2014, 136, 1789. (b) Wu, X.; Zhao, Y.; Ge, H. Chem. - Eur. J. 2014, 20, 9530. (c) Aihara, Y.; Tobisu, M.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2014, 136, 15509. (d) Xu, Z.-Y.; Jiang, Y.-Y.; Yu, H.-Z.; Fu, Y. Chem. - Asian J. 2015, 10, 2479. (e) Kubo, T.; Chatani, N. Org. Lett. 2016, 18, 1698. (f) Soni, V.; Jagtap, R. A.; Gonnade, R. G.; Punji, B. ACS Catal. 2016, 6, 5666. (4) For selected examples using cobalt or copper catalyst, see: (a) Ackermann, L. J. Org. Chem. 2014, 79, 8948. (b) Zhang, J.; Chen, H.; Lin, C.; Liu, Z.; Wang, C.; Zhang, Y. J. Am. Chem. Soc. 2015, 137, 12990. (c) Li, Q.; Hu, W.; Hu, R.; Lu, H.; Li, G. Org. Lett. 2017, 19, 4676. (d) Kommagalla, Y.; Yamazaki, K.; Yamaguchi, T.; Chatani, N. Chem. Commun. 2018, 54, 1359. (e) Li, S.; Wang, B.; Dong, G.; Li, C.; Liu, H. RSC Adv. 2018, 8, 13454. (f) Zhang, H.-J.; Su, F.; Wen, T.B. J. Org. Chem. 2015, 80, 11322. 6493

DOI: 10.1021/acs.orglett.8b02812 Org. Lett. 2018, 20, 6490−6493