Electrophilic Trifluoromethylthiolation/Semipinacol Rearrangement: Preparation of β-SCF3 Carbonyl Compounds with α-Quaternary Carbon Center

Article abstract of DOI:10.1021/acs.orglett.8b01627

A new and modular electrophilic trifluoromethylthiolation/semipinacol rearrangement of allylic silyl ethers has been developed under mild conditions. This approach allows the formation of a number of β-SCF₃ carbonyl compounds with a cyclic and all-carbon quaternary center framework in moderate to good yields. It should be noted that this achievement is a metal-free process and just requires the use of simple acetyl chloride as an acidic promoter. Additionally, an interesting H-migration in competition with aryl-migration process was revealed.

Full text of DOI:10.1021/acs.orglett.8b01627

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Electrophilic Trifluoromethylthiolation/Semipinacol Rearrangement:
Preparation of β‑SCF Carbonyl Compounds with α‑Quaternary
3
Carbon Center
Chao-Chao Xi, Zhi-Min Chen,* Shu-Yu Zhang, and Yong-Qiang Tu*,†,‡
†
,‡
‡
†State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. China
‡
School of Chemistry and Chemical Engineering, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai
Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
*
S Supporting Information
ABSTRACT: A new and modular electrophilic trifluorome-
thylthiolation/semipinacol rearrangement of allylic silyl ethers
has been developed under mild conditions. This approach
allows the formation of a number of β-SCF3 carbonyl
compounds with a cyclic and all-carbon quaternary center
framework in moderate to good yields. It should be noted that
this achievement is a metal-free process and just requires the
use of simple acetyl chloride as an acidic promoter. Additionally, an interesting H-migration in competition with aryl-migration
process was revealed.
mong the numerous fluoroalkyl groups, the trifluorome-
Scheme 1. Previous Electrophilic Reactions Introducing
SCF3
A
thylthio group (SCF ) reveals the highest constant (π =
3
1
.44) and strong electron-withdrawing power. This property
can significantly improve the transmembrane permeability and
1
enhance the metabolic stability of drug candidates. Therefore,
trifluoromethylthiolated compounds play a unique and
important role in pharmaceuticals, agrochemicals, and
2
materials science (Figure 1). Consequently, great efforts
electrophilic SCF reagent reported to synthesize the β-SCF
3
3
substituted ketones compounds, in particular those with an all-
carbon α-quaternary center and aliphatic/aromatic multicyclic
frameworks. As shown in Figure 1, a parenteral cephalosporin
Cefazaflur sodium and a promising lead for an amebiasis
Figure 1. Examples of SCF -containing biologically active com-
pounds.
3
Methionine analogue are SCF -containing carbonyl derivatives.
3
So such a β-SCF carbonyl compound would be valuable for
3
bioactive or pharmaceutical study, but are difficult to access by
typical electrophilic substitution from a ketone substrate.
During the past two decades, we have been making efforts to
engage in the research of semipinacol rearrangements. This
reaction has become a remarkable strategy in the construction
of a variety of natural and non-natural compounds with
have been dedicated to exploring efficient and practical
strategies for incorporation of the SCF into organic
3
3
,4
frameworks. Traditionally, halogen−fluorine exchange re-
actions and trifluoromethylation of thiols are indirect path-
ways. Recently, a number of radical, nucleophilic, electro-
philic, and oxidative trifluoromethylthiolations have been
reported. Among them, the electrophilic trifluoromethylth-
iolation with alkenes represents a powerful synthetic approach.
This method not only directly constructs the C −SCF bond
but also introduces chloro-, amine-, oxy-, and allyl-
5
6
7
8
9
14
features of an α-quaternary carbon center, e.g., semipinacol
rearrangement of α-hydroxy epoxides, tandem aziridination/
semipinacol rearrangement, and halogenation/semipinacol
rearrangement for the formation of α-quaternary β-hydroxy,
3
sp
3
10
11
12
15
1
3
amino, and haloketo compounds. With this concept, we
functional groups, etc. (Scheme 1), affording a series of
aliphatic SCF -compounds. Despite these great achievements
3
in the structurally diverse synthesis of SCF -compounds,
Received: May 23, 2018
3
however, there has been no direct method using an
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01627
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hypothesize that the SCF3 reagent could be used as an
electrophile to promote a semipinacol rearrangement (Scheme
product was obtained in both cases (entries 1−2). We thought
a weaker acid might be suitable for the transformation. The
desired product 2a was obtained in 43% yield when HCl was
used as an acidic promoter (entry 3). Inspired by this result,
some other weaker acids were carefully examined. To our
delight, the desired product was produced in 53% yield using
AcCl as the initiator while TMSCl exhibited only a 40% yield
2
), which could provide a straightforward strategy for the
Scheme 2. Design of the Electrophilic
Trifluoromethylthiolation/Semipinacol Rearrangement
(
entries 4−5). The yield was further improved to 65%, when
allylic trimethylsilyl ether 1a was used as the substrate (entry
). However, the reaction time required 3 days. To further
6
improve the reaction outcome, we screened other solvents
such as MeNO , MeCN, and DMF (entries 7−9), which
2
showed that MeCN performed the best with an increase in the
yield to 81%; simultaneously, the reaction time reduced to 12 h
(
entry 8). Ultimately, optimization of the reaction by screening
more SCF reagents and other different reagents such as the
derivatives of A1 (A2−A4), N-trifluoromethylthiosaccharin
A5 pioneered by the work of Shen, and (PhSO ) NSCF A6
3
17
1
3b
2
2
3
8
g,18
synthesis of a broad range of β-SCF carbonyl compounds
containing the multiunits mentioned above. Herein, we report
our preliminary research results.
To initiate our investigation, allylic alcohol 1a was chosen as
developed by Shen and Zhao
failed to give any better
3
result. Regarding the role of AcCl in this transformation, we
surmised that PhNHSCF (A1) reacted with AcCl to form
3
19
more active reagent CF SCl in situ.
3
Having established the optimized reaction conditions (Table
1, entry 8), the scope of allylic silyl ethers was expanded (Table
a model substrate with PhNHSCF (A1) which developed by
3
16
Billard and Langlois as an electrophilic SCF reagent, and
3
2
). In general, the desired β-SCF carbonyl compounds were
3
dichloromethane as solvent at room temperature (Table 1).
First, the commonly used Bronsted acid TfOH and Lewis acid
obtained with moderate to good yields. Compared with the
model substrate (1a), the meta- or para-substitutions did not
have evident effect (2b and 2c), whereas the ortho-substitution
led to a decrease in yield (2d). Substrates with an electron-rich
aryl group performed better than those with an electron-
withdrawing aryl group (2e vs 2f, 2j). Meanwhile, multi-
substituted aryl substrates were also tolerable to this reaction
affording the desired products in good yields (2h and 2i). It
was found that the biphenyl and 2-naphthyl-substituted
substrates reacted smoothly and delivered the corresponding
products in moderate yields (2k and 2l). It was worth
mentioning that nonactivated alkene substrates, 1m and 1n,
were well-incorporated, giving the corresponding products 2m
and 2n in 60% and 39% yields, respectively. The trans-
formation also tolerated a number of substrates containing
different substituents at the cyclobutanol group affording the
products in moderate to good yields (2o−q). Next, cyclo-
propanol and cyclopentanol were subjected to the standard
conditions to give 2r and 2s in 83% and 21% yield,
respectively. The great disparities might result from the
expansion abilities of a three- and five-member ring.
Unfortunately, the trisubstituted alkene substrate was not
well-tolerated, resulting in a significant decrease of the yield
BF ·Et O were selected as acidic initiators for this trans-
3
2
formation, respectively. Unfortunately, the allylic alcohol
rapidly converted to a complex mixture and no desired
a
Table 1. Conditions Optimization
1
b
entry
R −SCF3
solvent
CH Cl
acid
yield (%)
1
2
3
4
5
A1
A1
A1
A1
A1
A1
A1
A1
A1
A2
A3
A4
A5
A6
TfOH
N.D.
N.D.
43
40
53
65
63
81
trace
69
2
2
2
2
2
2
2
CH Cl
BF ·Et O
2
3
2
CH Cl
HCl
2
(
2t). In particular, an acyclic tertiary alcohol also worked well
CH Cl
TMSCl
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
2
under the conditions, with aryl-migration product 2u
generated exclusively in 53% isolated yield.
CH Cl
2
c
,
d
6
7
8
9
1
1
1
1
1
CH Cl
2
d
d
d
To further broaden the scope of the substrates, we
investigated various secondary alcohol substrates (Table 3).
It is noteworthy that two different migration products could be
simultaneously obtained under the standard conditions. One
was the aldehyde generated from aryl-migration, the other was
the ketone formed from H-migration. When we carried out the
reaction with substrates bearing para-OMe instead of the
MeNO2
MeCN
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
d
d
d
d
d
0
1
2
3
4
trace
trace
44
−CF substituent (1v−y), the ratio of (2:2′) enhanced from
3
62
9
:1 to 1:28, meanwhile, the total yields of the two products
a
1
ranged from 83% to 44%. Based on the previous literature, the
electron-rich aryl groups migrate prior to the electron-poor aryl
group in cationic rearrangement. The results suggested that the
Conditions: compound 1a (0.1 mmol), R = H, R −SCF (0.2
3
mmol), acid (0.3 mmol) in solvent (2 mL) stirred at 25 °C for 12 h
under Ar. Isolated yield. Reaction time is 3 days. R = TMS.
b
c
d
B
DOI: 10.1021/acs.orglett.8b01627
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
,
a b
Table 3. Scope of Secondary Alcohols , ,
a b c
Table 2. Scope of Allylic Silyl Ethers
a
Reaction conditions (also please see SI): compound 1 (0.2 mmol),
A1 (0.4 mmol), and AcCl (0.6 mmol) in MeCN (4 mL) stirred at 25
b
c
1
°
C for 6 h under Ar. Isolated yield. Determined by crude H NMR.
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.8b01627.
Experimental details, analytical data, and NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*
E-mail: tuyq@lzu.edu.cn.
E-mail: chenzhimin221@sjtu.edu.cn.
*
ORCID
a
Shu-Yu Zhang: 0000-0002-1811-4159
Yong-Qiang Tu: 0000-0002-9784-4052
Notes
Reaction conditions (also please see Supporting Information (SI)):
compound 1 (0.2 mmol), A1 (0.4 mmol), and AcCl (0.6 mmol) in
b
MeCN (4 mL) stirred at 25 °C for 12 h under Ar. Isolated yield.
c
Determined by crude 19F NMR. Determined by crude H NMR.
For the relative stereochemistry of 2t, please see SI.
d
1
e
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
reaction should undergo a cationic 1,2-migration process. The
H-migration in competition with aryl-migration process was
We are grateful for financial support provided by the National
Natural Science Foundation of China (Nos. 21702135,
21290180).
20
revealed in this case which is different from previous reports.
Surprisingly, heteroaromatic 2-thiofuran also performed well
and only formed 2z in 36% yield.
REFERENCES
■
In summary, a novel and practical tandem electrophilic
trifluoromethylthiolation/semipinacol rearrangement of allylic
silyl ethers has been successfully developed, which expanded
the types of trifluoromethylthiolation reactions. This tandem
transformation is valuable since a broad range of cyclic β-SCF3
carbonyl compounds with different substituents were obtained
with moderate to good yields under mild conditions. This
(1) (a) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303.
(b) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (c) Yang, X.; Wu, T.;
Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826. (d) Champagne,
P. A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.; Paquin, J.-F. Chem.
Rev. 2015, 115, 9073.
2) (a) Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105,
27. (b) Landelle, G.; Panossian, A. Curr. Top. Med. Chem. 2014, 14,
(
8
941.
strategy enables the construction of an all-carbon quaternary
(
3) (a) Boiko, V. N. Beilstein J. Org. Chem. 2010, 6, 880. (b) Chu, L.;
3
center and a C −SCF bond in a single transformation.
sp
3
Qing, F.-L. Acc. Chem. Res. 2014, 47, 1513. (c) Toulgoat, F.; Alazet,
S.; Billard, T. Eur. J. Org. Chem. 2014, 2014, 2415. (d) Shao, X.; Xu,
C.; Lu, L.; Shen, Q.-L. Acc. Chem. Res. 2015, 48, 1227. (e) Xu, X.-H.;
Further studies on the development of an enantioselective
transformation are underway.
C
DOI: 10.1021/acs.orglett.8b01627
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Matsuzaki, K.; Shibata, N. Chem. Rev. 2015, 115, 731. (f) Zhang, K.;
Xu, X.-H.; Qing, F.-L. Youji Huaxue 2015, 35, 556. (g) Barata-Vallejo,
S.; Bonesi, S.; Postigo, A. Org. Biomol. Chem. 2016, 14, 7150.
(d) Zhang, X.-M.; Tu, Y.-Q.; Zhang, F.-M.; Chen, Z.-H.; Wang, S.-H.
Chem. Soc. Rev. 2017, 46, 2272.
(16) Ferry, A. L.; Billard, T.; Langlois, B. R.; Bacque, E. J. Org. Chem.
2008, 73, 9362.
(17) Glenadel, Q.; Alazet, S.; Baert, F.; Billard, T. Org. Process Res.
Dev. 2016, 20, 960.
(18) Zhang, P.-P.; Li, M.; Xue, X.-S.; Xu, C.-F.; Zhao, Q.-C.; Liu, Y.-
F.; Wang, H.-Y.; Guo, Y.-L.; Lu, L.; Shen, Q.-L. J. Org. Chem. 2016,
(
h) Zhang, P.-P.; Lu, L.; Shen, Q.-L. Huaxue Xuebao 2017, 75, 744.
4) (a) Ferry, A.; Billard, T.; Langlois, B. R.; Bacque, E. Angew.
(
́
Chem., Int. Ed. 2009, 48, 8551. (b) Alazet, S.; Zimmer, L.; Billard, T.
Angew. Chem., Int. Ed. 2013, 52, 10814. (c) Yang, Y.-D.; Azuma, A.;
Tokunaga, E.; Yamasaki, M.; Shiro, M.; Shibata, N. J. Am. Chem. Soc.
8
(
1, 7486.
2013, 135, 8782. (d) Pluta, R.; Nikolaienko, P.; Rueping, M. Angew.
19) For detailed experimental results, please see SI.
Chem., Int. Ed. 2014, 53, 1650. (e) Guo, S.; Zhang, X.; Tang, P.-P.
Angew. Chem., Int. Ed. 2015, 54, 4065. (f) Wu, H.; Xiao, Z.; Wu, J.;
Guo, Y.; Xiao, J.-C.; Liu, C.; Chen, Q.-Y. Angew. Chem., Int. Ed. 2015,
(20) Li, J.; Fu, C.; Chen, G.; Chai, G.; Ma, S.-M. Adv. Synth. Catal.
2008, 350, 1376.
5
4, 4070. (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.
(
5) (a) Fluorverbindungen, U. Angew. Chem. 1939, 52, 457.
(
b) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984,
2
1
5, 2195. (c) Yang, J. J.; Kirchmeier, R. L.; Shreeve, J. J. Org. Chem.
998, 63, 2656.
(
6) (a) Yin, F.; Wang, X.-S. Org. Lett. 2014, 16, 1128. (b) Zhang, K.;
Liu, J.-B.; Qing, F.-L. Chem. Commun. 2014, 50, 14157. (c) Fuentes,
N.; Kong, W.; Fernandez-Sanchez, L.; Merino, E.; Nevado, C. J. Am.
Chem. Soc. 2015, 137, 964. (d) Jin, D.-P.; Gao, P.; Chen, D.-Q.; Chen,
S.; Wang, J.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2016, 18, 3486.
(
e) Wu, W.; Dai, W.; Ji, X.; Cao, S. Org. Lett. 2016, 18, 2918.
(
f) Honeker, R.; Garza-Sanchez, R. A.; Hopkinson, M. N.; Glorius, F.
Chem. - Eur. J. 2016, 22, 4395. (g) Pan, S.; Li, H.; Huang, Y.; Xu, X.-
H.; Qing, F.-L. Org. Lett. 2017, 19, 3247. (h) Liu, K.; Jin, Q.; Chen,
S.; Liu, P.-N. RSC Adv. 2017, 7, 1546.
(
7) (a) Teverovskiy, G.; Surry, D. S.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2011, 50, 7312. (b) Zhang, C.-P.; Vicic, D. A. J. Am. Chem.
Soc. 2012, 134, 183. (c) Saravanan, P.; Anbarasan, P. Adv. Synth.
Catal. 2015, 357, 3521. (d) Liu, J.-B.; Xu, X.-H.; Chen, Z.-H.; Qing,
F.-L. Angew. Chem., Int. Ed. 2015, 54, 897.
(
8) (a) Baert, F.; Colomb, J.; Billard, T. Angew. Chem., Int. Ed. 2012,
5
1, 10382. (b) Shao, X.; Wang, X.-Q.; Yang, T.; Lu, L.; Shen, Q.-L.
Angew. Chem., Int. Ed. 2013, 52, 3457. (c) Wang, X.; Yang, T.; Cheng,
X.; Shen, Q.-L. Angew. Chem., Int. Ed. 2013, 52, 12860. (d) Zhu, S.-
Q.; Xu, X.-H.; Qing, F.-L. Eur. J. Org. Chem. 2014, 2014, 4453.
(
e) Xiang, H.; Yang, C. Org. Lett. 2014, 16, 5686. (f) Jiang, L.; Qian,
J.; Yi, W.; Lu, G.; Cai, C.; Zhang, W. Angew. Chem., Int. Ed. 2015, 54,
4965. (g) Liu, X.; An, R.; Zhang, X.; Luo, J.; Zhao, X.-D. Angew.
1
Chem., Int. Ed. 2016, 55, 5846. (h) Li, M.; Xue, X.-S.; Cheng, J.-P.
ACS Catal. 2017, 7, 7977.
(
9) (a) Chen, C.; Xie, Y.; Chu, L.-L.; Wang, R.-W.; Zhang, X.; Qing,
F.-L. Angew. Chem., Int. Ed. 2012, 51, 2492. (b) Chen, C.; Chu, L.;
Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 12454. (c) Zhao, M.-Z.;
Zhao, X.-M.; Zheng, P.-R.; Tian, Y.-W. J. Fluorine Chem. 2017, 194,
7
3. (d) Liu, X.-G.; Li, Q.; Wang, H. Adv. Synth. Catal. 2017, 359,
1
942.
(
10) (a) Glenadel, Q.; Alazet, S.; Billard, T. J. Fluorine Chem. 2015,
79, 89. (b) Jia, Y.; Qin, H.; Wang, N.; Jiang, Z.-X.; Yang, Z.-G. J. Org.
Chem. 2018, 83, 2808.
11) (a) Yang, Y.; Jiang, X.; Qing, F.-L. J. Org. Chem. 2012, 77, 7538.
1
(
(
(
(
b) Luo, J.; Zhu, Z.; Liu, Y.; Zhao, X.-D. Org. Lett. 2015, 17, 3620.
c) Xiao, Q.; He, Q.; Li, J.; Wang, J. Org. Lett. 2015, 17, 6090.
d) Luo, J.; Liu, Y.; Zhao, X.-D. Org. Lett. 2017, 19, 3434.
(
12) (a) Xu, C.; Shen, Q.-L. Org. Lett. 2015, 17, 4561. (b) Lubcke,
̈
M.; Yuan, W.; Szabo, K. J. Org. Lett. 2017, 19, 4548. (c) Zhu, Z.; Luo,
J.; Zhao, X.-D. Org. Lett. 2017, 19, 4940.
(
13) (a) Liu, J.; Chu, L.; Qing, F.-L. Org. Lett. 2013, 15, 894. (b) Xu,
C.; Ma, B.; Shen, Q.-L. Angew. Chem., Int. Ed. 2014, 53, 9316.
c) Arimori, S.; Takada, M.; Shibata, N. Org. Lett. 2015, 17, 1063.
14) (a) Overman, L. E. Acc. Chem. Res. 1992, 25, 352. (b) Overman,
L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143.
15) (a) Wang, B.-M.; Tu, Y.-Q. Acc. Chem. Res. 2011, 44, 1207.
(
(
(
(
(
b) Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523.
c) Wang, S.-H.; Li, B.-S.; Tu, Y.-Q. Chem. Commun. 2014, 50, 2393.
D
DOI: 10.1021/acs.orglett.8b01627
Org. Lett. XXXX, XXX, XXX−XXX