Base-Promoted Oxidative C(sp3)–S Bond Cross-Coupling of Inactive Fluorenes and Thiols for the Synthesis of 9-Monothiolated Fluorenes

Article abstract of DOI:10.1002/ejoc.201801806

The highly efficient and selective C(sp³)–S bond cross-coupling method for the synthesis of 9-thiolated fluorenes through a direct thiolation at 9-C(sp³)–H of fluorenes with thiols is described. This reaction occurs at ambient conditions and shows good tolerance of functional groups including arylthiols and alkylthiols. A wide range of products is obtained in moderate to good yields. Besides, the reaction of benzothiophenol and fluorine generates unexpected 9-benzylidene-9H-fluorene by eliminating hydrogen sulfide.

Full text of DOI:10.1002/ejoc.201801806

A Journal of
Accepted Article
Title: Base-Promoted Oxidative C(sp3)−S Bond Cross-Coupling
of Inactive Fluorenes and Thiols for the Synthesis of 9-
Monothiolated Fluorenes
Authors: Yafeng Liu, Xinglong Yuan, Kexin Su, Yuan Tian, and Bao-
Hua Chen
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801806
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801806
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10.1002/ejoc.201801806
European Journal of Organic Chemistry
COMMUNICATION
Base-Promoted Oxidative C(sp3)−S Bond Cross-Coupling of
Inactive Fluorenes and Thiols for the Synthesis of 9-
Monothiolated Fluorenes
Yafeng Liu,[a] Xinglong Yuan,[a] Kexin Su,[a] Yuan Tian,[a] Baohua Chen*[a, b]
Abstract: The highly efficient and selective C(sp3)−S bond cross-
coupling method for the synthesis of 9-thiolated fluorenes through a
direct thiolation at 9-C(sp3)-H of fluorenes with thiols is described.
This reaction occurs at ambient conditions and shows good
tolerance of functional groups including arylthiols and alkylthiols. A
wide range of products are obtained in moderate to good yields.
Besides, the reaction of benzothiophenol and fluorine generates
unexpected 9-benzylidene-9H-fluorene by eliminating hydrogen
sulfide.
coupling reaction of fluorenes and thiols to synthesize 9-
monothiolated fluorenes through base-promoted C(sp3)−S bond
cross-coupling under mild conditions.
Results and Discussion
To identify the best reaction conditions, we started our
investigation from the reaction of 9H-fluorene 1a and
benzenethiol 2a in DMSO using 2.5 equivalent KOH as base at
ambient temperature under N2 atmosphere. To our delight, the
Introduction
Table 1. Optimization of the reaction conditions. [a]
The construction of the C–S bond is attracting much interest
from organic and medical chemists,[1] because the C–S bond is
widely present in a variety of natural products, biologically active
compounds and pharmaceuticals.[2] Organosulfur compounds,
especially thioethers, serve as useful synthetic intermediates
with applications in organic and medicinal chemistry.[3] In the
past decades, several strategies to construct C–S bond have
been successfully developed using various sulfenylating
reagents such as thiols,[4] sulfonyl chlorides,[5] disulfides,[6]
sulfonyl hydrazides[7] and so on. However, many of these
processes require prefunctionalized halides, expensive catalysts,
and harsh reaction conditions. Therefore, the metal-free direct
conversion of C–H bonds into C–S bonds under mild condition is
still desirable.
Fluorene derivatives as important polycyclic aromatic
hydrocarbons (PAHs) have received particular attentions in
material science and pharmaceutical industry.[8] Particularly, 9-
monosubstituted fluorene derivatives could be employed in the
pharmaceutical industry.[9] Recently, reports for these important
compounds are focused on the C-C bond formation, which are
achieved from the reaction of fluorenes with alkyl/aryl halides or
alcohols.[10] To the best of our knowledge, synthesis of 9-
monothiolated fluorenes through directly C-H functionalization is
less reported. Traditional methods for 9-monothiolated fluorenes
mainly involve the cross-coupling of thiols with 9-
halofluorenes,[11] which suffer from prehalogenation and harsh
conditions. Herein, we would like to communicate the first cross-
Entry
Oxidant
Base
Solvent
Yield (%) [b]
1
-
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
27
2
I2
KOH
39
3
TBHP [c]
KOH
81
4
H2O2
KOH
62
5
MnO2
KOH
71
6
70% TBHP [d]
70% TBHP [d]
70% TBHP [d]
70% TBHP [d]
70% TBHP [d]
70% TBHP [d]
70% TBHP [d]
70% TBHP [d]
70% TBHP [d]
KOH
85
7
K2CO3
K3PO4
DMAP [e]
DBU [f]
KOH
74
8
69
9
trace
trace
82
10
11
12
13
14 [g]
KOH
CH3CN
NMP
trace
trace
27
[a]
State Key Laboratory of Applied Organic Chemistry, Key laboratory
of Nonferrous Metal Chemistry and Resources Utilization of Gansu
Province, Department of Chemistry, Lanzhou University, Lanzhou,
Gansu, China.
KOH
KOH
DMSO
E-mail: chbh@lzu.edu.cn.
[a] Reaction conditions: 1a (0.20 mmol), 2a (0.36 mmol), oxidant (0.20
mmol), base (0.50 mmol), solvent (2 mL) at room temperature under N2 for
1.5 h. [b] Yields of isolated products. [c] 5.5 M TBHP in decane. [d] 70%
TBHP in water. [e] DMAP = 4-dimethylaminepyridine. [f] DBU = 1,8-
diazabicyclo[5.4.0]undec-7-ene. [g] under air condition. Entry in bold
highlights optimized reaction conditions, and the reaction time was
monitored by TLC.
[b]
Zhongwei High-Tech Institute of Lanzhou University, Zhongwei,
Ningxia 755500, China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201801806
European Journal of Organic Chemistry
COMMUNICATION
desired product 3aa was obtained in 27% yield (Table 1, entry 1). benzenethiols 2j and 2k underwent the reaction smoothly to
To improve the yield, several oxidants were screened and the
reaction using 70% TBHP as oxidant provided 3aa in the best
yield (Table 1, entries 2-6). Subsequently, extensive screening
revealed that KOH was the most effective base for this reaction
(Table 1, entries 7-10). In addition, a screening of solvents was
carried out, and the results illustrate that DMSO is superior to
DMF, CH3CN and NMP (Table 1, entries 11-13). Finally, the
replacement of N2 by air led to low yield due to the formation of
by-product (9H-fluoren-9-one) (Table 1, entry 14). So the
optimized reaction system was established as Table 1, entry 6.
With the optimized reaction conditions in hand, we first
examined the scope of thiols and results are summarized in
Table 2. In general, benzenethiols 2 bearing electron-donating
groups reacted smoothly with 1a and provided higher yields than
those with electron-withdrawing groups. Substrates 2b-2e
bearing methyl groups reacted well with 1a, giving
corresponding products 3ab-3ae in good yields. What’s more,
2f-2i with halogens, such as F, Cl, Br, were also tolerated well
and corresponding products 3af-3ai were obtained in 62-81%
yields. It was important to note that amino-substituted
generate the anticipated products 2aj and 2ak in 62% and 71%
yields, respectively. To our delight, alkyl-substituted thiols were
also compatible with this reaction conditions. A variety of alkyl-
substituted thiols 2l-2o were examined under the optimized
reaction conditions, furnishing the target products 3l-3o in 70-89%
yields. Unfortunately, Substrate 2p could not be transformed to
the desired product due to the steric hindrance.
Encouraged by above results, we next investigated the scope
of fluorenes 1. As shown in Table 3, substrate 1b containing tert-
butyl at C-2 and C-7 position reacted smoothly with 2a in
moderate yield. Notably, halogen-substituted fluorenes 1c-1f
were more suitable for the optimal conditions than 1b, providing
target products 3ca-3fa in 87-94% yields. In order to expand the
substrate scope, further investigations were performed to
evaluate substituted fluorenes and various thiols. As has been
expected, benzenethiols 2c and 2f played well with substituted
fluorenes, generating desired products 3bc, 3cf, and 3fc in good
yields. At the same time, alkyl-substituted thiols 2m, 2n, and 2o
were employed to react with 1e and 1f, producing desired 9-
thiolated fluorenes 3em, 3en, and 3fo in 82-89% yields.
Next, we set out to explore the scope of this tandem reaction
by employing benzyl thiol 2q (Scheme 1). To our surprise, when
Table 2. Scope of substituted thiols. [a]
Table 3. Scope of substituted fluorenes and thiols. [a]
[a] Reaction conditions: 1a (0.20 mmol), 2 (0.36 mmol), KOH (2.5 equiv), 70%
TBHP (1.0 equiv), DMSO (2 mL) at room temperature under N2 for 2 h. [b]
Reaction conditions: 1a (0.20 mmol), 2 (0.46 mmol), CsOH (2.5 equiv), 70%
TBHP (1.0 equiv), DMF (2 mL) at room temperature under N2 for 2 h.
[a] Reaction conditions: 1 (0.20 mmol), 2 (0.36 mmol), KOH (2.5 equiv), 70%
TBHP (1.0 equiv), DMSO (2 mL) at room temperature under N2 for 2 h.
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10.1002/ejoc.201801806
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COMMUNICATION
phenylmethanethiol 2q was employed in this transformation, the
unexpected product 4 was isolated in 90% yield. Based on the
above result, we speculate that benzyl thiol 2q is transformed to
thionium intermediate 2q' in the presence of oxidants. Then,
product 4 is obtained through Knoevenagel-type reactions losing
H2S.[12]
Scheme 3. Proposed mechanism.
Based on the above experimental results and previous
studies,[13] a putative mechanism is outlined in Scheme 3.
Initially, phenthiol 2a is oxidized by TBHP to produce the
intermediate 1,2-diphenyldisulfane 2t. Meanwhile, the fluorene
releases hydrogen to furnish the anion A in the presence of
base, which then undergoes a nucleophilic attack on 2t to
product 3aa and releases the anion B. And B can be
transformed to the intermediate 2t in the presence of oxidant
finally.
Scheme 1. Reactions of 9H-fluorene and phenylmethanethiol.
Conclusions
In summary, we have developed a simple and highly efficient
C(sp3)−S bond cross-coupling method for the synthesis of 9-
monothiolated fluorenes through a direct thiolation at 9-C(sp3)-H
of fluorenes with thiols. This transformation features mild
reaction conditions, short reaction times, and good functional
group tolerance. Besides, benzothiophenol could react with
fluorine to get unexpected 9-benzylidene-9H-fluorene by
releasing hydrogen sulfide.
Experimental Section
A 10 mL schlenk tube equipped with a magnetic stir bar was charged
with 1a (0.20 mmol) and KOH (0.50 mmol). The tube was sealed with a
septum, evacuated, and backfilled with nitrogen three times. Then DMSO
(2 mL), 2a (0.38 mmol) and 70% TBHP (0.20 mmol) were added by a
syringe. Then the mixture was stirred at room temperature for 2 h. Upon
completion of the reaction, the reaction mixture was extracted with
saturated brine (10 mL) and ethyl acetate (3×15 mL). The combined
organic phase was dried over anhydrous Na2SO4. The solvent was
evaporated in vacuo and the crude product was purified by column
chromatography, eluting with petroleum ether/ethyl acetate (40 : 1) to
afford the desired product 3aa.
Scheme 2. Control experiments.
To probe the mechanism of this transformation, some control
experiments were carried out in Scheme 2. When 2.0 equiv of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-di-tert-butyl-
4-methyl-phenol (BHT) is added to the reaction system, the yield
of desired product 3aa didn’t decline (Scheme 2, a). These
experiments excluded any possibility of a radical pathway.
Fortunately, the intermediate 1,2-diphenyldisulfane 2t was
detected by GC-MS analysis (m/z = 218) (Figure S1), which was
also isolated by column chromatography and identified by 1H
NMR and 13C NMR spectroscopy (see the Supporting
Information). Then benzenethiol 2a was employed as the
substrate under optimized conditions and the intermediate 2t
was afforded in 92% yield (Scheme 2, c). When 1a was treated
with 1,2-diphenyldisulfane 2t without oxidant (Scheme 2, d), the
product 3aa was obtained in 71% yield. So 1,2-diphenyldisulfane
2t should be the intermediate for this transformation.
Acknowledgments
We are grateful for the sponsorship by the National Natural
Science Foundation of China (Nos. 21372102) for this project.
Keywords: Cross-coupling • sulfur • Electrophilic substitution •
C-H activation
[1]
a) K. Inamoto, Y. Arai, K. Hiroya, T. Doi, Chem. Commun. 2008, 43,
5529; b) K. Inamoto, C. Hasegawa, K. Hiroya, T. Doi, Org. Lett. 2008,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801806
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COMMUNICATION
10, 5147; c) L. L. Joyce, R. A. Batey, Org. Lett. 2009, 11, 2792; d) R.
Samanta, A. P. Antonchick, Angew. Chem. Int. Ed. 2011, 50, 5217;
Angew. Chem. 2011, 123, 5323; e) C. Shen, H. Xia, H. Yan, X. Chen, S.
Ranjit, X. Xie, D. Tan, R. Lee, Y. Yang, B. Xing, Chem. Sci. 2012, 3,
2388; f) R. Xu, J.-P. Wan, H. Mao, Y. Pan, J. Am. Chem. Soc. 2010,
132, 15531; g) Y. Yang, W. Hou, L. Qin, J. Du, H. Feng, B. Zhou, Y. Li,
Chem. Eur. J. 2014, 20, 416; h) J. Zhu, Z. Chen, H. Xie, S. Li, Y. Wu,
Org. Lett. 2010, 12, 2434; i) C. Qi, T. Guo, W. Xiong, Synlett 2016, 27,
2626; j) W. Tan, J. Wei, X. Jiang, Org. Lett. 2017, 19, 2166; k) P.-F.
Wang, X.-Q. Wang, J.-J. Dai, Y.-S. Feng, H.-J. Xu, Org. Lett. 2014, 16,
4586.
P. Sang, Z. Chen, J. Zou, Y. Zhang, Green Chem. 2013, 15, 2096; d) S.
Zhang, P. Qian, M. Zhang, M. Hu, J. Cheng, J. Org. Chem. 2010, 75,
6732; e) W. Ge, Y. Wei, Green Chem. 2012, 14, 2066; f) X. Zhou, X. Li,
RSC Adv. 2014, 4, 1241.
[7]
[8]
a) X. Li, Y. Xu, W. Wu, C. Jiang, C. Qi, H. Jiang, Chem.–Eur. J. 2014,
20, 7911; b) F. L. Yang, S.-K. Tian, Angew. Chem. Int. Ed. 2013, 52,
4929; Angew. Chem. 2013, 125, 5029; c) X. Kang, R. Yan, G. Yu, X.
Pang, X. Liu, X. Li, L. Xiang, G. Huang, J. Org. Chem. 2014, 79, 10605.
a) T. Yu, L. Liu, Z. Xie, Y. Ma, Sci. Chi. Chem. 2015, 58, 907; b) R.
Rathore, V. J. Chebny, S. H. Abdelwahed, J. Am. Chem. Soc. 2005,
127, 8012; c) S. Ni, Y. Yuan, J. Huang, X. Mao, M. Lv, J. Zhu, X. Shen,
J. Pei, L. Lai, H. Jiang, J. Li, J. Med. Chem. 2009, 52, 5295; d) L. C.
Colis, C. M. Woo, D. C. Hegan, Z. Li, P. M. Glazer, S. B. Herzon, Nat.
Chem. 2014, 6, 504; e) S. B. Herzon, C. M. Woo, Nat. Prod. Rep. 2012,
29, 87; f) Y. Shechter, M. Mironchik, S. Rubinraut, A. Saul, H. Tsubery,
M. Fridkin, Bioconjugate Chem. 2005, 16, 913.
[2]
a) M. Halim, D. J. Yee, D. Sames, J. Am. Chem. Soc. 2008, 130, 14123;
b) M. S. C. Pedras, Q.-A. Zheng, S. Strelkov, J. Agric. Food Chem.
2008, 56, 9949; c) X. Wang, L. Cui, N. Zhou, W. Zhu, R. Wang, X. Qian,
Y. Xu, Chem. Sci. 2013, 4, 2936; d) A. J. Wilson, J. K. Kerns, J. F.
Callahan, C. J. Moody, J. Med. Chem. 2013, 56, 7463; e) X. Wang, L.
Cui, N. Zhou, W. Zhu, R. Wang, X. Qian, Y. Xu, Chem. Sci. 2013, 4,
2936; f) E. J. Block, Sulfur Chem. 2013, 34, 158; (f) Y. F. Liu, X. L.
Yuan, X. Guo, X. G. Zhang, B. H. Chen, Tetrahedron 2018, 74, 6057.
a) S. Iimura, K. Manabe, S. Kobayashi, Org. Lett. 2003, 5, 101; b) V. P.
Mehta, A. Sharma, E. Van der Eycken, Adv. Synth. Catal. 2008, 350,
2174; c) T. H. Graham, W. Liu, D.-M. Shen, Org. Lett. 2011, 13, 6232;
d) M. N. Burhardt, R. H. Taaning, T. Skrydstrup, Org. Lett. 2013, 15,
948; e) F. Pan, Z.-J. Shi, ACS Catal. 2013, 4, 280; f) J. Sayers, R. E.
Thompson, K. J. Perry, L. R. Malins, R. J. Payne, Org. Lett. 2015, 17,
4902.
[9]
a) R. M. Burch, M. Weitzberg, N. Blok, R. Muhlhauser, D. Martin, S. G.
Farmer, J. M. Bator, J. R. Connor, M. Green, C. Ko, Proc. Natl. Acad.
Sci. U. S. A. 1991, 88, 355; b) J. R. Epperson, M. A. Bruce, J. D. Catt, J.
A. Deskus, D. B. Hodges, G. N. Karageorge, D. J. Keavy, C. D. Mahle,
R. J. Mattson, A. A. Ortiz, M. F. Parker, K. S. Takaki, B. T. Watson, J. P.
Yevich, Bioorg. Med. Chem. 2004, 12, 4601; c) A. Suresh, S.
Srinivasarao, N. Agnieszka, A. K. Ewa, M. Alvala, C. Lherbet, K. V. G.
C. Sekhar, Chem. Biol. Drug. Des. 2018, 91, 1078; d) C. Z. Sun, Y.
Liang, N. Hao, L. Xu, F. Cheng, T. Su, J. Cao, W. X. Cao, Y. J. Pu, B.
He, Org. Biomol. Chem. 2017, 15, 9176.
[3]
[4]
a) G. L. Khatik, R. Kumar, A. K. Chakraborti, Org. Lett. 2006, 8, 2433; b)
X. F. Wang, Q. L. Hua, Y. Cheng, X. L. An, Q. Q. Yang, J. R. Chen, W.
J. Xiao, Angew. Chem. Int. Ed. 2010, 49, 8379; Angew. Chem. 2010,
122, 8557; c) S. Bonollo, D. Lanari, F. Pizzo, L. Vaccaro, Org. Lett.
2011, 13, 2150; d) W. Xi, M. Krieger, C. J. Kloxin, C. N. Bowman,
Chem. Commun. 2013, 49, 4504; e) P. Chauhan, S. Mahajan, D.
Enders, Chem. Rev. 2014, 114, 8807; f) C.-K. Chen, Y.-W. Chen, C.-H.
Lin, H.-P. Lin, C.-F. Lee, Chem. Commun. 2010, 46, 282; g) A. Correa,
O. G. Mancheno, C. Bolm, Chem. Soc. Rev. 2008, 37, 1108; h) P. F.
Larsson, A. Correa, M. Carril, P. O. Norrby, C. Bolm, Angew. Chem. Int.
Ed. 2009, 48, 5691; Angew. Chem. 2009, 121, 5801; i) M. Sayah, M. G.
Organ, Chem.–Eur. J. 2011, 17, 11719.
[10] a) Y.-Y. Ji, L.-L. Lu, Y.-C. Shi, L.-X. Shao, Org. Biomol. Chem. 2014, 12,
8488; b) X. Ji, T. Huang, W. Wu, F. Liang, S. Cao, Org. Lett. 2015, 17,
5096; c) J. Chen, Y. Li, S. Li, J. Liu, F. Zheng, Z. Zhang, Q. Xu, Green
Chem. 2017, 19, 623; d) J.-J. Chen, S. Onogi, Y.-C. Hsieh, C.-C. Hsiao,
S. Higashibayashi, H. Sakurai, Y.-T. Wu, Adv. Synth. Catal. 2012, 354,
1551.
[11] a) M. Blain, H. Yau, L. Jean-Grard, R. Auvergne, D. Benazet, P. R.
Schreiner, S. Caillol, B. Andrioletti, ChemSusChem 2016, 9, 1; b) J. L.
Kice, H. Lotey, J. Org. Chem. 1988, 53, 3593.
[12] Z. Li, H. Li, X. Guo, L. Cao, R. Yu, H. Li, S. Pan, Org. Lett. 2008, 10,
803.
[13] a) R. Y. Tand, Y. X. Xie, Y. L. Xie, J. N. Xiang, J. H. Li, Chem. Commun.
2011, 47, 12867; b) J. X. Zou, Y. Q. Wang, L. T. Huang, Y. Jiang, J. H.
Chen, L. Q. Zhu, Y. H. Yang, Y. Y. Feng, X. Peng, Z. Wang, Org. Chem.
Front. 2018, 5, 2317; c) J. Feng, G. P. Lu, C. Cai, RSC Adv. 2014, 4,
54409; d) J. C. Deng, S. B. Zhuang, Q. Z. Liu, Z. W. Lin, Y. L. Su, J. H.
Chen, R. Y. Tang, RSC Adv. 2017, 7, 54013; e) Y. Z. Yu, Y. Zhou, Z. Q.
Song, G. Liang, Org. Biomol. Chem. 2018, 16, 4958.
[5]
[6]
a) M. Chen, Z.-T. Huang, Q.-Y. Zheng, Chem. Commun. 2012, 48,
11686; b) D. Zhang, X. Cui, Q. Zhang, Y. Wu, J. Org. Chem. 2015, 80,
1517; c) Q. Wu, D. Zhao, X. Qin, J. Lan, J. You, Chem. Commun. 2011,
47, 9188; d) M. Chen, Z.-T. Huang, Q.-Y. Zheng, Chem. Commun.
2012, 48, 11686.
a) W. Ge, Y. Wei, Green Chem. 2012, 14, 2066; b) D. Huang, J. Chen,
W. Dan, J. Ding, M. Liu, H. Wu, Adv. Synth. Catal. 2012, 354, 2123; c)
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
C−S Bond Cross-Coupling
Yafeng Liu,[a] Xinglong Yuan,[a] Kexin
Su,[a] Yuan Tian,[a] Baohua Chen*[a, b]
Page No. – Page No.
Base-Promoted Oxidative C(sp3)−S
Bond Cross-Coupling of Inactive
Fluorenes and Thiols for the
Synthesis of 9-Monothiolated
Fluorenes
Text for Table of Contents (about 350 characters)
A highly efficient and selective C(sp3)−S bond cross-coupling method for the synthesis of 9-thiolated fluorenes through a
direct thiolation at 9-C(sp3)-H of fluorenes with thiols is described.
This article is protected by copyright. All rights reserved.