KO-t-Bu Catalyzed Thiolation of β-(Hetero)arylethyl Ethers via MeOH Elimination/hydrothiolation

Article abstract of DOI:10.1002/ejoc.202100597

Herein, we describe a KO-t-Bu catalyzed thiolation of β-(hetero)arylethyl ethers through MeOH elimination to form (hetero)arylalkenes followed by anti-Markovnikov hydrothiolation to afford linear thioethers. The system works well with a variety of β-(hetero)arylethyl ethers, including electron-deficient, electron-neutral, electron-rich, and branched substrates and a range of aliphatic and aromatic thiols.

Full text of DOI:10.1002/ejoc.202100597

Communications
doi.org/10.1002/ejoc.202100597
KO-t-Bu Catalyzed Thiolation of β-(Hetero)arylethyl Ethers
via MeOH Elimination/hydrothiolation
Masanori Shigeno,*[a] Yoshiteru Shishido,[a] Kazutoshi Hayashi,[a] Kanako Nozawa-Kumada,[a]
and Yoshinori Kondo*[a]
Herein, we describe a KO-t-Bu catalyzed thiolation of β-(hetero)
arylethyl ethers through MeOH elimination to form (hetero)
arylalkenes followed by anti-Markovnikov hydrothiolation to
afford linear thioethers. The system works well with a variety of
β-(hetero)arylethyl ethers, including electron-deficient, electron-
neutral, electron-rich, and branched substrates and a range of
aliphatic and aromatic thiols.
Introduction
Sulfur-containing organic substances are important synthetic
motifs with applications in pharmaceutical, agrochemical, and
material science research.[1,2] This has long motivated organic
chemists to develop efficient carbon-sulfur bond forming
reactions.[3] In particular, the well-established hydrothiolation of
(hetero)aryl alkenes with thiols, also known as thiol-ene
coupling reactions, regioselectively produces either the Markov-
nikov branched product or anti-Markovnikov linear product
depending on the reaction conditions.[4] To date, a variety of
Figure 1. (a) Conventional hydrothiolation of (hetero)aryl alkenes reported in
the literature, (b) our previous work on the t-Bu-P4 catalyzed amination of β-
(hetero)arylethyl ethers 1, and (c) this work on the KO-t-Bu catalyzed
thiolation of 1 via consecutive MeOH elimination/hydrothiolation processes.
protocols to form the latter product are available, namely
reactions mediated by photocatalysts,[5] transition-metals,[6]
radical initiators,[7] silica nanoparticles,[8] acids,[9] and bases;[10]
those using ionic liquids,[11] glycerol,[12] and H2O[13] as the
solvent; and the neat reaction[14] (Figure 1a). However, the
alkene unit is a relatively reactive and unstable functionality
that does not fit the multistep synthesis required for the
preparation of complex molecular structures. Hence, the
development of a hydrothiolation reaction using a robust
functionality in lieu of the alkene is intriguing.[15]
Our group previously reported that the phosphazene base
t-Bu-P4 catalyzes the amination of β-(hetero)arylethyl ethers 1,
chemically stable substrates compared with (hetero)aryl alkenes
(Figure 1b).[16–18] In this study we demonstrate that KO-t-Bu
achieves the thiolation of 1 through two consecutive steps,
MeOH elimination and hydrothiolation (Figure 1c).
Initially, we examined the reaction conditions with the
trifluoromethyl-group-containing phenethyl ether 1a and
benzyl mercaptan 2a as the model substrates (Table 1). The
effects of the bases were first investigated in 1,3-dimethyl-2-
imidazolidinone (DMI) (entries 1–8). The phosphazene base t-
Bu-P2 was ineffective, while t-Bu-P4 provided the target
product 3aa in 70% yield. Subsequently, we investigated the
effect of inorganic bases. Screening of the hexamethyldisilazide
bases showed that NaHMDS and KHMDS smoothly underwent
the reactions in 85 and 84% yields, respectively (entries 3–5).[19]
The alkoxide and hydroxide bases were subsequently evaluated
(entries 6–10), wherein LiO-t-Bu and NaO-t-Bu afforded 3aa in
18 and 72% yields, respectively. In comparison, KO-t-Bu and
KOMe were found to be more effective, furnishing 3aa in 87%
yield.[20,21] Among the examined solvents, DMF and DMSO
provided 3aa in good yields of 71 and 83%, respectively
(entries 11–14), which, however, were inferior to that of DMI
(entry 8). A decrease in the catalytic amount of KO-t-Bu to
10 mol% and 5 mol% slightly lowered the product yield
(entries 15 and 16).[22,23]
[a] Dr. M. Shigeno, Y. Shishido, K. Hayashi, Dr. K. Nozawa-Kumada,
Prof. Dr. Y. Kondo
Department of Biophysical Chemistry
Graduate School of Pharmaceutical Science,
Tohoku University
6–3 Aoba, Sendai 980-8578, Japan
E-mail: yoshinori.kondo.a7@tohoku.ac.jp
masanori.shigeno.e5@tohoku.ac.jp
http://www.pharm.tohoku.ac.jp/~henkan/lab/henkan_top.html
With the optimized conditions in hand, the scope of the
thiols was next explored (Figure 2). The use of 4-meth-
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100597
Eur. J. Org. Chem. 2021, 3932–3935
3932
© 2021 Wiley-VCH GmbH

Communications
doi.org/10.1002/ejoc.202100597
Table 1. Optimization of thiolation of 1a with 2a.a
Entry
Base
Solvent
Yield [%]b
1
2
3
4
5
6
7
8
t-Bu-P2
t-Bu-P4
LiHMMDS
NaHMDS
KHMDS
LiO-t-Bu
NaO-t-Bu
KO-t-Bu
KOMe
DMI
DMI
DMI
DMI
DMI
DMI
DMI
DMI
DMI
DMI
DMF
DMSO
THF
Toluene
DMI
DMI
(3)c
70
13
85
84
18
72
87
87
69
71
83
(3)c
(0)c
74d
73e
9
10
11
12
13
14
15
16
KOH
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
[a] First-step conditions: 1a (0.20 mmol), base (0.04 mmol), solvent
(0.30 mL), rt, 1 h. Second-step conditions: 2a (0.40 mmol), rt, 12 h. [b]
Isolated yields. [c] Yields in parentheses were determined by 1H-NMR
spectroscopy using 1,1,2-trichloroethane as the internal standard. [d] KO-t-
Bu (0.02 mmol) was used. [e] KO-t-Bu (0.01 mmol) was used.
Figure 2. Scope of thiols.a,b [a] Reactions were conducted on a 0.2 mmol
°
scale. Second step was conducted at the designated temperature, T ( C). [b]
Isolated yields. [c] KO-t-Bu (40 mol%) was used. Second step was conducted
for 24 h.
oxybenzylthiol 2b provided the desired product 3ab in 84%
yield. Reactions with other aliphatic thiols were also carried out,
whereby the primary, secondary, and tertiary thiols, 2c–2f,
afforded the corresponding products 3ac–3af in good yields
(77–84%). Aromatic thiols were next investigated, whereby
benzenethiol 2g and 2-naphthalenethiol 2h afforded the
products in 78 and 84% yields, respectively.[24] Both the
toluenethiols (2i–2k) and methoxybenzenethiols (2l–2n) were
successfully employed in the reactions, irrespective of the
substituent position. Notably, the halogen atoms F, Cl, and Br
were compatible with the reaction conditions, forming products
3ao–3aq (66–86% yields), respectively.
Next, we verified the scope of the β-(hetero)arylethyl ethers
(Figure 3). Electron-deficient substrates 1b and 1c, with a cyano
group at the para- and ortho-positions, respectively, and
substrate 1d, with a trifluoromethyl group at the ortho-position,
were smoothly converted to the target products 3ba–3da.
Substrates 1e and 1f, respectively comprising chloro and
bromo groups, were also suitable for the reaction. Use of the
electron-neutral phenyl, 4-biphenyl, and 2-naphthyl derivatives
afforded 2-vinylnaphthalene 4i in 88% yield (eq. 1).[26] When 4i
was subjected to the reaction conditions with t-BuOK and 2a,
3ia was obtained in 93% yield (eq. 2). These results show that
the present system is a two-step reaction process comprising
MeOH elimination and hydrothiolation.[27–30] The radical scav-
enger 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) did not inhibit
the reaction (eq. 3), confirming that both steps proceed via an
ionic and not a radical process.
The proposed mechanism is depicted in Figure 5. In the first
step, MeOH elimination from substrate 1 occurs by the tert-
butoxide base or methoxide formed in situ. In the second step,
thiolate anion A, generated by the deprotonation of 2, adds
onto aryl alkene 4 in an anti-Markovnikov addition manner.[31,32]
Subsequently, benzyl anion species B is protonated by 2,
furnishing 3 with the regeneration of A.
(1g–1i, respectively) afforded the target products in high yields Conclusion
(80–93%).[25] Furthermore, the current system worked well with
the electron-rich substrates 1j and 1k possessing tert-butyl and
methoxy groups, respectively. The reaction was also tolerated
with heteroaromatic substrates 1l–1o (2-pyridyl, 4-pyridyl, 2-
benzothiophenyl, and 2-indolyl substrates, respectively). Finally,
we tested the branched substrates 1p–1r, with methyl or
dimethyl groups at the α- or β-positions, which underwent the
reactions in moderate to high yields (48–94%), while 2,2-
diphenylethy ether 1s afforded the product in 95% yield.
To gain insight into the reaction mechanism, further experi-
ments were performed (Figure 4). Treatment of 1i with t-BuOK
In summary, we demonstrated the catalytic thiolation reaction
of β-(hetero)arylethyl ethers, comprising MeOH elimination/
hydrothiolation processes. The protocol transforms a diverse
range of β-(hetero)arylethyl ethers, ranging from electron-
deficient to electron-rich substrates and branched substrates.
Moreover, a variety of thiols, such as primary, secondary, and
tertiary aliphatic thiols and aromatic thiols bearing function-
alities (Me, OMe, F, Cl, and Br) are applicable.
Eur. J. Org. Chem. 2021, 3932–3935
www.eurjoc.org
3933
© 2021 Wiley-VCH GmbH

Communications
doi.org/10.1002/ejoc.202100597
Figure 5. Proposed mechanism.
(M.S.), The Research Foundation for Pharmaceutical Sciences
(M.S.), Daicel Corporation (M.S.), and also the Platform Project for
Supporting Drug Discovery and Life Science Research funded by
Japan Agency for Medical Research and Development (AMED)
(M.S., K.N.K., and Y.K.). K.H. thanks JSPS for a Fellowship for Young
Japanese Scientists (No. 20J20712).
Conflict of Interest
The authors declare no conflict of interest.
Figure 3. Scope of β-(hetero)arylethyl ethers 1.a,b [a] Reactions were con-
ducted on a 0.2 mmol scale. First and second steps were conducted at the
Keywords: Alkenes
Brønsted base · Elimination · Thioethers
·
Anti-Markovnikov hydrothiolation
·
°
designated temperatures T1 and T2 ( C), respectively. [b] Isolated yields. [c]
KO-t-Bu (30 mol%) was used with THF as the solvent. First step was
conducted for 2 h. [d] KO-t-Bu (40 mol%) was used. [e] 2a (3 equiv.) was
used. [f] First and second steps were conducted for 6 and 3 h, respectively.
[g] KO-t-Bu (10 mol%) was used. [h] Second step was conducted for 96 h.
[1] a) E. M. McGarrigle, E. L. Myers, O. Illa, M. A. Shaw, S. L. Riches, V. K.
Aggarwal, Chem. Rev. 2007, 107, 5841; b) R. G. Arrayás, J. C. Carretero,
Chem. Commun. 2011, 47, 2207; c) M. C. Carreño, Chem. Rev. 1995, 95,
1717; d) D. Kaiser, I. Klose, R. Oost, J. Neuhaus, N. Maulide, Chem. Rev.
2019, 119, 8701.
[2] a) G. Liu, J. T. Link, Z. Pei, E. B. Reilly, S. Leitza, B. Nguyen, K. C. Marsh,
G. F. Okasinski, T. W. von Geldern, M. Ormes, K. Fowler, M. Gallatin, J.
Med. Chem. 2000, 43, 4025; b) C. Zhao, K. P. Rakesh, L. Ravidar, W.-Y.
Fang, H.-L. Qin, Eur. J. Med. Chem. 2019, 162, 679; c) C. Jacob, Nat. Prod.
Rep. 2006, 23, 851; d) P. Devendar, G. F. Yang, Top. Curr. Chem. 2017,
375, 82; e) J. O. Jeppesen, M. B. Nielsen, J. Becher, Chem. Rev. 2004, 104,
5115.
[3] a) J. Clayden, P. MacLellan, Beilstein J. Org. Chem. 2011, 7, 582; b) A.
Wimmer, B. König, Beilstein J. Org. Chem. 2018, 14, 54; c) M. D.
McReynolds, J. M. Dougherty, P. R. Hanson, Chem. Rev. 2004, 104, 2239;
d) I. P. Beletskaya, V. P. Ananikov, Chem. Rev. 2011, 111, 1596; e) M.
Pramanik, K. Choudhuri, P. Mal, Org. Biomol. Chem. 2020, 18, 8771.
[4] a) A. K. Sinha, D. Equbal, Asian J. Org. Chem. 2019, 8, 32; b) K. Choudhuri,
M. Pramanik, P. Mal, J. Org. Chem. 2020, 85, 11997; c) R. Castarlenas,
A. D. Giuseppe, J. J. Pérez-Torrente, L. A. Oro, Angew. Chem. Int. Ed.
2013, 52, 211.
Figure 4. Mechanistic studies.a,b [a] Reactions were conducted on a 0.2 mmol
scale. [b] Isolated yields.
[5] a) E. L. Tyson, M. S. Ament, T. P. Yoon, J. Org. Chem. 2013, 78, 2046;
b) V. T. Bhat, P. A. Duspara, S. Seo, N. S. B. A. Bakar, M. F. Greaney, Chem.
Commun. 2015, 51, 4383; c) O. O. Fadeyi, J. J. Mousseau, Y. Feng, C.
Allais, P. Nuhant, M. Z. Chen, B. Pierce, R. Robinson, Org. Lett. 2015, 17,
5756; d) D. Limnios, C. G. Kokotos, Adv. Synth. Catal. 2017, 359, 323;
e) G. Zhao, S. Kaur, T. Wang, Org. Lett. 2017, 19, 3291; f) M. Singh, A. K.
Yadav, L. D. S. Yadav, R. K. P. Singh, Tetrahedron Lett. 2017, 58, 2206.
[6] a) C. Munro-Leighton, S. A. Delp, N. M. Alsop, E. D. Blue, T. B. Gunnoe,
Chem. Commun. 2008, 111; b) X. Zhang, K. Wang, RSC Adv. 2015, 5,
34439; c) B. Movassagh, A. Yousefi, Monatsh. Chem. 2015, 146, 135.
[7] a) T. Lanza, M. Minozzi, A. Monesi, D. Nanni, P. Spagnolo, C. Chiappe,
Curr. Org. Chem. 2009, 13, 1726; b) S. Chun, J. Chung, J. E. Park, Y. K.
Chung, ChemCatChem 2016, 8, 2476.
Acknowledgements
This work was financially supported by JSPS KAKENHI Grant
Number 19H03346 (Y.K.), JSPS KAKENHI Grant Number 19K06967
(M.S.), the Environment Research and Technology Development
Fund (JPMEERF20202R02) of the Environmental Restoration and
Conservation Agency of Japan (M.S.), The Uehara Memorial
Foundation (M.S.), The Tokyo Biochemical Research Foundation
[8] S. Banerjee, J. Das, R. P. Alvarez, S. Santra, New J. Chem. 2010, 34, 302.
Eur. J. Org. Chem. 2021, 3932–3935
www.eurjoc.org
3934
© 2021 Wiley-VCH GmbH

Communications
doi.org/10.1002/ejoc.202100597
[9] a) R. Upadhyay, R. Rana, A. Sood, S. K. Maurya, ACS Omega 2019, 4,
[22] When the reaction of 1a and 2a was carried out in a one-step
procedure similar to our previous amination,[16a] no desired product 3aa
was obtained and 1a was quantitatively recovered (Scheme S1). This is
because 2a is more acidic than the amine nucleophiles, as shown by
the pKa values (2a, 15.4 in DMSO;[22a] pyrrole, 23.05;[22b] N-methylaniline,
29.5[22b]), and thus, the thiolate anion generated by the deprotonation
of 2a is less basic than their formed amide anions and insufficiently
reactive to promote MeOH elimination from 1a. For the pKa values, see:
a) X. Li, H. Deng, X.-Q. Zhu, X. Wang, H. Liang, J.-P. Cheng, J. Org. Chem.
2009, 74, 4472; b) F. G. Bordwell, J.-P. Cheng, G.-Z. Ji, A. V. Satish, X.
Zhang, J. Am. Chem. Soc. 1991, 113, 9790.
15101; b) C. C. Silveira, S. R. Mendes, F. M. Líbero, Synlett 2010, 5, 790;
c) K. Kuciński, P. Pawluć, G. Hreczycho, Adv. Synth. Catal. 2015, 357,
3936; d) Z. S. Qureshi, K. M. Deshmukh, K. P. Dhake, B. M. Bhanage, RSC
Adv. 2011, 1, 1106; e) C. H. Rosa, M. L. B. Peixoto, G. R. Rosa, B. Godoi,
F. Z. Galetto, M. G. M. D’Oca, M. Godoi, Tetrahedron Lett. 2017, 58, 3777.
[10] B. Wang, C. Shen, J. Yao, H. Yin, Y. Zhang, Org. Lett. 2014, 16, 46.
[11] R. Kumar, Saima, A. Shard, N. H. Andhare, Richa, A. K. Sinha, Angew.
Chem. Int. Ed. 2015, 54, 828.
[12] E. J. Lenardão, R. G. Jacob, K. D. Mesquita, R. G. Lara, R. Webber, D. M.
Martinez, L. Savegnago, S. R. Mendes, D. Alves, G. Perin, Green Chem.
Lett. Rev. 2013, 6, 269.
[13] a) B. C. Ranu, T. Mandal, Synlett 2007, 925; b) B. Movassagh, M. Navidi,
Arkivoc. 2008, 15, 47.
[14] K. Choudhuri, A. Mandal, P. Mal, Chem. Commun. 2018, 54, 3759.
[15] Sinha et al. recently described that the 1-phenylethyl alcohol derivative
reacts with thiol in neutral ionic liquids to yield the linear thioether. See
reference 11.
[16] a) M. Shigeno, R. Nakamura, K. Hayashi, K. Nozawa-Kumada, Y. Kondo,
Org. Lett. 2019, 21, 6695; b) M. Shigeno, K. Hayashi, K. Nozawa-Kumada,
Y. Kondo, Chem. Eur. J. 2019, 25, 6077; c) M. Shigeno, K. Hayashi, K.
Nozawa-Kumada, Y. Kondo, Org. Lett. 2019, 21, 5505; d) M. Shigeno, K.
Hayashi, K. Nozawa-Kumada, Y. Kondo, Org. Lett. 2020, 22, 9107.
[23] Substrates comprising ethoxy, (tert-butyldimethylsilyl)oxy, acetate, and
benzoate leaving groups instead of a methoxy group were tested in the
thiolation reaction, forming 3aa in respective yields of 71, 46, 19, and
18% (Table S1).
[24] When the second step of the reaction of 2g was performed at room
temperature, the yield of 3ag decreased to 20%.
[25] When the second step of the reaction of 1i was carried out at room
temperature, 3ia was obtained in a lower yield of 32%. The first step
also requires heating to proceed smoothly, see reference 26.
[26] When the reaction of 1i with t-BuOK was conducted at room temper-
ature, 4i was obtained in a lower yield of 48%.
[27] Previously, a stoichiometric amount of base was employed for MeOH
elimination from β-arylethyl ethers, see: a) C. Margot, M. Rizzolio, M.
Schlosser, Tetrahedron 1990, 46, 2411; b) J. W. Barlow, A. P. McHugh, O.
Woods, J. J. Walsh, Eur. J. Med. Chem. 2011, 46, 1545.
[17] The catalytic transformations of (hetero)arylethyl ethers
1 were
previously demonstrated by using transition-metal catalysts. See: a) S.
Luo, D.-G. Yu, R.-Y. Zhu, X. Wang, L. Wang, Z.-J. Shi, Chem. Commun.
2013, 49, 7794; b) Y. Ogiwara, T. Kochi, F. Kakiuchi, Org. Lett. 2011, 13,
3254. Also see:; c) R. Zhao, B.-L. Zeng, W.-Q. Jia, H.-Y. Zhao, L.-Y. Shen,
X.-J. Wang, X.-D. Pan, RSC Adv. 2020, 10, 34938.
°
[28] The reaction of 4i and 2a in the absence of a base at 100 C afforded a
low 3ia yield (34%), demonstrating that the second hydrothiolation
step was also promoted by the presence of a base.
[18] Bandar et al. recently showed that t-Bu-P4 and KO-t-Bu catalyze the
reversible addition of MeOH to (hetero)arylalkene in DMSO. See: a) C.
Luo, J. S. Bandar, J. Am. Chem. Soc. 2018, 140, 3547; b) T. R. Puleo, A. J.
Strong, J. S. Bandar, J. Am. Chem. Soc. 2019, 141, 1467.
[19] In the reactions, HMDS bases initially mediate the formation of aryl
alkene corresponding to 4 in Figure 5, and the formed methoxide bases
(NaOMe and KOMe) subsequently act as the base.
[20] In this study, KO-t-Bu was used as an optimal base, since it is cheaper
than KOMe: Prices for KO-t-Bu (>98% purity) and KOMe (>95% purity)
are $ 17.1/mol and $ 33.9/mol, respectively, based on their largest
quantities available from Sigma Aldrich (May 7, 2021).
[21] For examples of KO-t-Bu catalyzed or mediated reactions, see: a) S.
Thiyagarajan, V. Krishnakumar, C. Gunanathan, Chem. Asian J. 2020, 15,
518; b) A. A. Toutov, W.-B. Liu, K. N. Betz, A. Fedorov, B. M. Stoltz, R. H.
Grubbs, Nature 2015, 518, 80; c) H. Ito, Y. Horita, E. Yamamoto, Chem.
Commun. 2012, 48, 8006; d) T. Ghosh, S. Jana, J. Dash, Org. Lett. 2019,
21, 6690; e) B. Suchand, G. Satyanarayana, Eur. J. Org. Chem. 2017, 3886;
f) G. C. Midya, A. Kapat, S. Maiti, J. Dash, J. Org. Chem. 2015, 80, 4148;
g) J. Madasu, S. Shinde, R. Das, S. Patel, A. Shard, Org. Biomol. Chem.
2020, 18, 8346.
[29] In the reactions forming 3ea, 3fa, 3ja, 3ka, 3ra, and 3sa, aryl alkene
products corresponding to 4 in Figure 5 were formed in respective
yields of 2%, 2%, 15%, 1%, 16%, and 2%, which were determined by
the 1H-NMR analysis of crude materials.
[30] Benzyl methyl ether and methyl 3-phenylpropyl ether were also used as
substrates, but the thiolated product was not obtained (Scheme S2).
[31] In this addition step, the interaction of potassium cation with alkene π-
system might be involved.
[32] The regioselectivity presumably originates from the higher thermody-
namic stability of the benzylic anionic species B than that of the
homobenzylic anionic species formed in
manner.
a Markovnikov addition
Manuscript received: May 17, 2021
Revised manuscript received: July 13, 2021
Accepted manuscript online: July 16, 2021
Eur. J. Org. Chem. 2021, 3932–3935
www.eurjoc.org
3935
© 2021 Wiley-VCH GmbH