Combination of Lewis Basic Selenium Catalysis and Redox Selenium Chemistry: Synthesis of Trifluoromethylthiolated Tertiary Alcohols with Alkenes

Article abstract of DOI:10.1021/acs.orglett.7b02406

A new and efficient method for diaryl selenide catalyzed vicinal CF₃S hydroxylation of 1,1-multisubstitued alkenes has been developed. Various trifluoromethylthiolated tertiary alcohols could be readily synthesized under mild conditions. This method is also effective for the intramolecular cyclization of alkenes tethered by carboxylic acid, hydroxy, sulfamide, or ester groups and is associated with the introduction of a CF₃S group. Mechanistic studies have revealed that the pathway involves a redox cycle between Se(II) and Se(IV) and Lewis basic selenium catalysis.

Full text of DOI:10.1021/acs.orglett.7b02406

Letter
pubs.acs.org/OrgLett
Combination of Lewis Basic Selenium Catalysis and Redox Selenium
Chemistry: Synthesis of Trifluoromethylthiolated Tertiary Alcohols
with Alkenes
Zechen Zhu, Jie Luo, and Xiaodan Zhao*
Institute of Organic Chemistry & MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen
University, Guangzhou 510275, P. R. China
S
* Supporting Information
ABSTRACT: A new and efficient method for diaryl selenide
catalyzed vicinal CF3S hydroxylation of 1,1-multisubstitued
alkenes has been developed. Various trifluoromethylthiolated
tertiary alcohols could be readily synthesized under mild
conditions. This method is also effective for the intramolecular
cyclization of alkenes tethered by carboxylic acid, hydroxy,
sulfamide, or ester groups and is associated with the
introduction of a CF3S group. Mechanistic studies have revealed that the pathway involves a redox cycle between Se(II) and
Se(IV) and Lewis basic selenium catalysis.
rganoselenium catalysis has received considerable
attention from chemists because of its merits in organic
ization of alkenes is a great strategy to quickly construct these
molecules along with incorporation of a functional group. In
2015, our group reported that trifluoromethylthioamination of
alkenes could proceed smoothly to afford CF3S products under
Lewis basic selenium catalysis with the aid of acid.8a In
continuation of our interest in the synthesis of different CF3S
compounds, our new goal was to construct CF3S alcohols to
supplement the library of CF3S compounds available through
the oxytrifluoromethylthiolation of alkenes.
Because the hydroxytrifluoromethylthiolation of 1,1-dialkyl
and 1,1-aryl,alkyl-substituted alkenes is challenging and has not
been developed to date,11i,j we initiated HO-trifluoromethylth-
iolation by using (3-methylbut-3-en-1-yl)benzene (1a) as the
model substrate. When 1a was treated with known electrophilic
N-CF3S-saccharin (2) under conditions suitable to our previous
reactions on the CF3S amination of alkenes in the presence of
H2O,8a the desired product was observed in trace amounts,
even in different conventional solvents. We realized that the
former conditions were acidic and disfavored the formation of
product. The main reasons might lie in the two issues: (i) H2O
is a weak nucleophile and acid can further weaken the
nucleophilicity of H2O, and (ii) competitive elimination
promoted by acid could occur to form allyl products instead
of difunctionalization products particularly when an alkyl group
is connected to the double bond of the substrate.11a,13
O
synthesis: mild reaction conditions, good functional group
tolerance, and excellent selectivities.1 Furthermore, some
transformations which are difficult to achieve by other methods
could be accomplished by selenium catalysis.2 As an important
part of this field, systems that merge a catalytic amount of an
organoselenium compound and oxidants, i.e., N-halosuccini-
mide,3 peroxides,4 and fluoropyridinium salts,2d have been
frequently utilized for the synthesis of various valuable
compounds by delivering oxygen and halogen into substrates.
In these redox catalytic cycles, the selenium valence changes
between divalence and tetravalence.
Using organoselenium compounds as Lewis base catalysts is
another important part of selenium catalysis.5−8 The relevant
studies are most focused on the functionalization of alkenes. In
such catalysis, organoselenium compounds activate electro-
philic reagents such as halogenating and sulfenylating ones to
form selenium-captured ionic complexes, which trigger the
following alkene functionalization. Despite great achievements
in this direction, developing new reaction systems to solve
challenging synthesis is still highly desirable. Herein, we report
our discovery that the combination of Lewis basic selenium
catalysis and redox selenium chemistry enables difunctionaliza-
tion of multisubstituted alkenes to efficiently produce
trifluoromethylthiolated tertiary alcohols under oxidative
conditions.
Considering the above difficulties, we turned our attention to
conducting the reaction without the addition of extra acid
(Table 1). Not surprisingly, when 1a reacted with CF3S reagent
2 in the presence of H2O using electron-rich diaryl selenide as
the catalyst in various common solvents such as MeCN,
dichloromethane, THF, and toluene, the desired product 3a
The efficient synthesis of CF3S compounds has attracted
much attention in recent years9 and is quite important for the
discovery of pharmaceuticals and agrochemicals because a
fluorinated moiety can adjust the chemical, physical, and
biological properties of parent molecules.10 Until now, many
approaches have been developed to construct diverse CF3S
molecules.8,11,12 Among the developed methods, difunctional-
Received: August 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02406
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Organic Letters
Letter
a
Table 1. Condition Optimization
Scheme 1. Substrate Scope of Oxytrifluoromethylthiolation
of Alkenes
a
b
entry
cat.
C1
solvent
atmosphere
yield (%)
1
MeCN
under air
under air
under air
under air
under air
under air
under air
under air
under air
under air
under air
under air
under N2
O2 balloon
O2 balloon
0
2
C1
C1
C1
C1
C2
C3
C4
C5
C6
C7
none
C1
C1
C1
CH2Cl2
THF
0
3
0
4
toluene
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
0
74
5
6
28
7
50
8
47
9
58
10
11
12
13
14
0
0
0
17
87 (83)
52
c
15
a
Conditions: 1a (0.05 mmol), 2 (1.3 equiv), H2O (5 equiv), catalyst
b
(10 mol %), solvent (1 mL), room temperature, 24 h. Refers to NMR
yield using CH2Br2 as the internal standard. Isolated yield on 0.2 mmol
scale is in the parentheses. No additional H2O.
c
a
Conditions: alkene (0.2 mmol), 2 (1.3 equiv), H2O (5 equiv), C1
(10 mol %), MeNO2 (4 mL), O2 balloon, room temperature, 24 h.
b
c
From 2-phenyl-2-butene (Z/E = 2.7:1). From (Z)-oct-4-ene.
was not formed (entries 1−4). To our delight, the use of
MeNO2 as the solvent allowed the formation of product 3a in
good yield (entry 5). Encouraged by this outcome, further
optimization was carried out using MeNO2 as the solvent.
Several other selenium catalysts were screened (entries 6−11),
but the yield of 3a did not improve. It was found that less and
more electron-rich selenide catalysts led to lower yields than
catalyst C1 or even no product. The results indicate that the
efficiency of trifluoromethylthiolation depends on the catalyst,
with the appropriate electron density on the selenium atom
being essential. Product was not observed when the reaction
was performed in the absence of selenide (entry 12).
Interestingly, when the reaction was carried out under an N2
atmosphere, the product was obtained in only 17% yield (entry
13). In contrast, the yield improved to 87% under an O2
atmosphere (entry 14). These results show that O2 plays an
important role in the reaction. Furthermore, when no extra
water was added to the reaction, the product was still produced
in 52% yield (entry 15). The required trace water for the
reaction might come from solvent.
With the optimal conditions in hand, the substrate scope was
evaluated (Scheme 1). 1,1-Aryl,methyl-substituted alkenes
underwent difunctionalization to generate the corresponding
tertiary alcohols in 38−98% isolated yields (3b−l). An electron-
withdrawing group on the phenyl ring did not affect the
reaction much, but electron-rich aryl groups on substrates
lowered the yields of products (3k, 38%; 3l, 57%). A variety of
styrene derivatives with different substituents such as phenyl,
ethyl, propyl, isopropyl, and benzyl at the α position worked
efficiently to give the corresponding products in good yields
(3m−q, 73−87%). This method is effective for other 1,1-
dialkyl-substituted alkenes as well (3r, 52%). Other types of
alkenes such as tri-, tetra-, mono-, and 1,2-disubstituted ones
were tested under similar conditions. They afforded the desired
products in moderate to good yields (3s−v, 45−81%). It is
noteworthy that a sterically hindered tetrasubstituted alkene
still underwent difunctionalization to form the desired product
in moderate yield.
Similar conditions proved suitable for the intramolecular
cyclization of nucleophile-tethered alkenes (Table 2). All of the
alkenes with carboxylic acid, hydroxy, sulfamide, and ester
groups worked efficiently to give the corresponding products in
good to excellent yields. The selectivity was excellent for the
reactions. For example, when the olefinic carboxylic acid 4b was
utilized as the substrate, only the 5-exo-trig cyclization product
5b was formed in good yield (entry 2). In addition, by this
method, trifluoromethylthiolated tetrahydrofuran derivative 5d
and pyrrolidine derivative 5e could be prepared in high yields
(entries 4 and 5). Interestingly, olefinic ester 4f underwent the
cyclization to afford product 5a, which could be formed from
the reaction of acid 4a under similar conditions. It is noted that
hydroxylated products were not observed in these trans-
formations. The results indicate that this new method has good
generality.
B
DOI: 10.1021/acs.orglett.7b02406
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Organic Letters
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Table 2. CF3S-Lactonization, -Etherification, and -Amination
of Nucleophile-Tethered Alkenes
Scheme 3. Mechanistic Exploration
a
selenoxide 6 was formed in 2% NMR yield. This oxidation
occurred only in MeNO2. Other solvents such as dichloro-
methane and acetonitrile were not effective at all. Selenoxide 6
could be completely reduced to selenide C1 along with the
formation of TfOH and saccharin in less than 10 min when it
was treated with CF3S reagent (Scheme 3b). TfOH was
detected by 19F NMR. In our previous study,8 acid was essential
to assist the selenide catalyst in activating the CF3S reagent for
difunctionalization of the alkenes. The formation of trace TfOH
could be the reason that the selenide/O2/MeNO2 system is
efficient for oxytrifluoromethylthiolation of alkenes. When
selenoxide 6 served as the catalyst precursor, product 3a was
still formed under N2 atmosphere in moderate yield, which
further proved the reduction of selenoxide 6 in the reaction
(Scheme 3c). To elucidate the role of acid in these reactions,
they were carried out under an N2 atmosphere in the presence
of acid. When 1 mol % of TfOH was added to the reaction,
product 3a could be generated in 70% yield in MeNO2
(Scheme 3d). Under similar acidic conditions, the replacement
of MeNO2 with dichloromethane as the solvent led to no
product 3a at all and some allylic byproducts. Higher loading of
acid resulted in a lower yield. These results reflect that
appropriate loading of acid is important for the reaction.
On the basis of these mechanistic studies, a plausible reaction
pathway is proposed as shown in Scheme 4. Selenide C1 is first
oxidized under O2/MeNO2 conditions to produce the diaryl
selenoxide 6, after which the selenoxide is reduced to C1 by
a
Conditions: alkene (0.1 mmol), 2 (1.3 equiv), C1 (10 mol %),
b
MeNO2 (2 mL), O2 balloon, room temperature, 24 h. Isolated yield.
To address why this transformation needs oxygen and where
the hydroxy group comes from in the products, labeling
experiments were conducted with alkene 1l as the substrate
(Scheme 2). When the reaction of 1l with 2 was performed
Scheme 2. Labeling Experiments
Scheme 4. Proposed Reaction Mechanism
under an 18O2 atmosphere, in the presence of unlabeled H2O,
the alcohol product 3l was obtained without 18O labeling. In
contrast, when the reaction was run with unlabeled O2 in the
presence of H218O, the product was formed in 90% isotopic
purity with 18O labeling. These results clearly indicate that the
hydroxyl group in the products comes from water, not from
oxygen. The outcome rules out the hydroxy group originating
from O2 via a radical pathway.14
To further elucidate the role of O2 and the reaction
mechanism, more control experiments were carried out
(Scheme 3). It was found that electron-rich diaryl selenide
C1 could be oxidized under O2/MeNO2 conditions (Scheme
3a). The oxidation process was very slow. In 24 h, diaryl
C
DOI: 10.1021/acs.orglett.7b02406
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Organic Letters
Letter
Tetrahedron Lett. 2005, 46, 8665. (c) Santoro, S.; Santi, C.; Sabatini,
M.; Testaferri, L.; Tiecco, M. Adv. Synth. Catal. 2008, 350, 2881.
(d) Santi, C.; Lorenzo, R. D.; Tidei, C.; Bagnoli, L.; Wirth, T.
Tetrahedron 2012, 68, 10530. (e) Yu, L.; Wu, Y.; Cao, H.; Zhang, X.;
Shi, X.; Luan, J.; Chen, T.; Pan, Y.; Xu, Q. Green Chem. 2014, 16, 287.
(f) Yu, L.; Chen, F.; Ding, Y. ChemCatChem 2016, 8, 1033.
(5) (a) Denmark, S. E.; Collins, W. R. Org. Lett. 2007, 9, 3801.
(b) Denmark, S. E.; Kalyani, D.; Collins, W. R. J. Am. Chem. Soc. 2010,
132, 15752. (c) Denmark, S. E.; Kornfilt, D. J. P.; Vogler, T. J. Am.
Chem. Soc. 2011, 133, 15308. (d) Denmark, S. E.; Chi, H. M. J. Am.
Chem. Soc. 2014, 136, 3655. (e) Denmark, S. E.; Chi, H. M. J. Am.
Chem. Soc. 2014, 136, 8915. (f) Denmark, S. E.; Rossi, S.; Webster, M.
P.; Wang, H. J. Am. Chem. Soc. 2014, 136, 13016. (g) Denmark, S. E.;
Kornfilt, D. J. P. J. Org. Chem. 2017, 82, 3192. (h) Denmark, S. E.; Chi,
H. M. J. Org. Chem. 2017, 82, 3826.
(6) (a) Chen, F.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2013,
135, 1232. (b) Ke, Z.; Tan, C. K.; Chen, F.; Yeung, Y.-Y. J. Am. Chem.
Soc. 2014, 136, 5627.
(7) (a) Balkrishna, S. J.; Prasad, C. D.; Panini, P.; Detty, M. R.;
Chopra, D.; Kumar, S. J. Org. Chem. 2012, 77, 9541. (b) Verma, A.;
Jana, S.; Prasad, C. D.; Yadav, A.; Kumar, S. Chem. Commun. 2016, 52,
4179.
CF3S reagent 2 along with the formation of TfOH. Selenide C1
and the acid coactivate the CF3S reagent to form intermediate
I. Formation of the episulfonium ion II and attack by H2O
ultimately leads to product 3 and regenerates catalyst C1 and
TfOH.
In summary, we have developed an efficient approach of
selenide-catalyzed vicinal CF3S hydroxylation of alkenes under
unique O2/MeNO2 conditions. The desired products were
obtained in moderate to excellent yields. The developed system
merged redox selenium chemistry into Lewis basic selenium
catalysis to enable the challenging CF3S hydroxylation of
multisubstituted alkenes. Mechanistic studies have proven that
the redox cycle between Se(II) and Se(IV) is crucial for the
whole transformation.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02406.
(8) (a) Luo, J.; Zhu, Z.; Liu, Y.; Zhao, X. Org. Lett. 2015, 17, 3620.
(b) Wu, J.-J.; Xu, J.; Zhao, X. Chem. - Eur. J. 2016, 22, 15265. (c) Liu,
X.; An, R.; Zhang, X.; Luo, J.; Zhao, X. Angew. Chem., Int. Ed. 2016, 55,
5846. (d) Luo, J.; Liu, Y.; Zhao, X. Org. Lett. 2017, 19, 3434.
(9) For selected reviews, see: (a) Boiko, V. N. Beilstein J. Org. Chem.
2010, 6, 880. (b) Toulgoat, F.; Alazet, S.; Billard, T. Eur. J. Org. Chem.
2014, 2014, 2415. (c) Xu, X.-H.; Matsuzaki, K.; Shibata, N. Chem. Rev.
2015, 115, 731. (d) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem.
Rev. 2015, 115, 826. (e) Barata-Vallejo, S.; Bonesi, S.; Postigo, A. Org.
Biomol. Chem. 2016, 14, 7150.
(10) (a) Jeschke, P. ChemBioChem 2004, 5, 570. (b) Hagmann, W. K.
J. Med. Chem. 2008, 51, 4359. (c) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (d) Manteau, B.;
Pazenok, S.; Vors, J.-P.; Leroux, F. R. J. Fluorine Chem. 2010, 131, 140.
(11) For selected examples, see: (a) Ferry, A.; Billard, T.; Langlois, B.
Experimental details, characterization data, and NMR
spectra of new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhaoxd3@mail.sysu.edu.cn.
ORCID
Xiaodan Zhao: 0000-0002-2135-5121
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
R.; Bacque, E. Angew. Chem., Int. Ed. 2009, 48, 8551. (b) Chen, C.;
We thank Sun Yat-Sen University, the “One Thousand Youth
Talents” Program of China, and the Natural Science
Foundation of Guangdong Province (Grant No.
2014A030312018) for financial support.
Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 12454. (c) Yang, Y.-
D.; Azuma, A.; Tokunaga, E.; Yamasaki, M.; Shiro, M.; Shibata, N. J.
Am. Chem. Soc. 2013, 135, 8782. (d) Danoun, G.; Bayarmagnai, B.;
Gruenberg, M. F.; Goossen, L. J. Chem. Sci. 2014, 5, 1312. (e) Xu, C.;
Ma, B.; Shen, Q. Angew. Chem., Int. Ed. 2014, 53, 9316. (f) Xu, C.;
Shen, Q. Org. Lett. 2015, 17, 4561. (g) Yin, G.; Kalvet, I.; Englert, U.;
Schoenebeck, F. J. Am. Chem. Soc. 2015, 137, 4164. (h) Mukherjee, S.;
Maji, B.; Tlahuext-Aca, A.; Glorius, F. J. Am. Chem. Soc. 2016, 138,
16200. (i) Honeker, R.; Garza-Sanchez, R. A.; Hopkinson, M. N.;
Glorius, F. Chem. - Eur. J. 2016, 22, 4395. (j) Zhang, P.; Li, M.; Xue,
X.-S.; Xu, C.; Zhao, Q.; Liu, Y.; Wang, H.; Guo, Y.; Lu, L.; Shen, Q. J.
Org. Chem. 2016, 81, 7486.
REFERENCES
■
(1) For selected reviews, see: (a) Wirth, T., Ed. Organoselenium
Chemistry: Synthesis and Reactions; Wiley-VCH: Weinheim, 2011.
(b) Freudendahl, D. M.; Santoro, S.; Shahzad, S. A.; Santi, C.; Wirth,
T. Angew. Chem., Int. Ed. 2009, 48, 8409. (c) Santi, C.; Santoro, S.;
Battistelli, B. Curr. Org. Chem. 2010, 14, 2442. (d) Tan, C. K.; Yeung,
Y.-Y. Chem. Commun. 2013, 49, 7985. (e) Breder, A.; Ortgies, S.
Tetrahedron Lett. 2015, 56, 2843. (f) Luo, J.; Liu, X.; Zhao, X. Synlett
2017, 28, 397. (g) Guo, R.; Liao, L.; Zhao, X. Molecules 2017, 22, 835.
(2) (a) Singh, F. V.; Wirth, T. Org. Lett. 2011, 13, 6504. (b) Trenner,
J.; Depken, C.; Weber, T.; Breder, A. Angew. Chem., Int. Ed. 2013, 52,
8952. (c) Yu, L.; Li, H.; Zhang, X.; Ye, J.; Liu, J.; Xu, Q.; Lautens, M.
Org. Lett. 2014, 16, 1346. (d) Cresswell, A. J.; Eey, S. T.-C.; Denmark,
S. E. Nat. Chem. 2015, 7, 146. (e) Deng, Z.; Wei, J.; Liao, L.; Huang,
H.; Zhao, X. Org. Lett. 2015, 17, 1834. (f) Guo, R.; Huang, J.; Huang,
H.; Zhao, X. Org. Lett. 2016, 18, 504. (g) Kawamata, Y.; Hashimoto,
T.; Maruoka, K. J. Am. Chem. Soc. 2016, 138, 5206. (h) Liao, L.; Guo,
R.; Zhao, X. Angew. Chem., Int. Ed. 2017, 56, 3201.
(12) (a) Bootwicha, T.; Liu, X.; Pluta, R.; Atodiresei, I.; Rueping, M.
Angew. Chem., Int. Ed. 2013, 52, 12856. (b) Wang, X.; Yang, T.;
Cheng, X.; Shen, Q. Angew. Chem., Int. Ed. 2013, 52, 12860. (c) Deng,
Q.-H.; Rettenmeier, C.; Wadepohl, H.; Gade, L.-H. Chem. - Eur. J.
2014, 20, 93. (d) Zhu, X.-L.; Xu, J.-H.; Cheng, D.-J.; Zhao, L.-J.; Liu,
X.-Y.; Tan, B. Org. Lett. 2014, 16, 2192. (e) Zhao, B.-L.; Du, D.-M.
Org. Lett. 2017, 19, 1036.
(13) (a) Bowers, A.; Ringold, H. J. Tetrahedron 1958, 3, 14.
(b) Pacheco, M. C.; Purser, S.; Gouverneur, V. Chem. Rev. 2008, 108,
1943. (c) Zi, W.; Wang, Y.-M.; Toste, F. D. J. Am. Chem. Soc. 2014,
136, 12864.
(14) (a) Ueda, M.; Miyabe, H.; Shimizu, H.; Sugino, H.; Miyata, O.;
Naito, T. Angew. Chem., Int. Ed. 2008, 47, 5600. (b) Xi, H.; Deng, B.;
Zong, Z.; Lu, S.; Li, Z. Org. Lett. 2015, 17, 1180. (c) Liu, C.; Lu, Q.;
Huang, Z.; Zhang, J.; Liao, F.; Peng, P.; Lei, A. Org. Lett. 2015, 17,
6034. (d) Wang, H.; Lu, Q.; Qian, C.; Liu, C.; Liu, W.; Chen, K.; Lei,
A. Angew. Chem., Int. Ed. 2016, 55, 1094.
(3) (a) Hori, T.; Sharpless, K. B. J. Org. Chem. 1979, 44, 4208.
(b) Tunge, J. A.; Mellegaard, S. R. Org. Lett. 2004, 6, 1205.
(c) Barrero, A. F.; Quílez del Moral, J. F.; Mar Herrador, M.; Cortes
́
,
M.; Arteaga, P.; Catalan, J. V.; Sanchez, E. M.; Arteaga, J. F. J. Org.
́
́
Chem. 2006, 71, 5811. (d) Balkrishna, S. J.; Prasad, C. D.; Panini, P.;
Detty, M. R.; Chopra, D.; Kumar, S. J. Org. Chem. 2012, 77, 9541.
(4) (a) ten Brink, G.-J.; Vis, J.-M.; Arends, I. W. C. E.; Sheldon, R. A.
J. Org. Chem. 2001, 66, 2429. (b) Ichikawa, H.; Usami, Y.; Arimoto, M.
D
DOI: 10.1021/acs.orglett.7b02406
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