Ligandless Nickel-Catalyzed Ortho-Selective Directed Trifluoromethylthiolation of Aryl Chlorides and Bromides Using AgSCF3

Article abstract of DOI:10.1021/acs.orglett.6b02689

A mild protocol for Ni-catalyzed trifluoromethylthiolation of aryl chlorides and bromides is described herein. The method utilizes AgSCF₃ as an easily accessible nucleophilic trifluoromethylthiolating reagent and does not require any ligands or additives. Ortho-selectivity is achieved using a variety of directing groups such as imines, pyridines, and oxazolines for 24 examples in up to 95% yield.

Full text of DOI:10.1021/acs.orglett.6b02689

Letter
pubs.acs.org/OrgLett
Ligandless Nickel-Catalyzed Ortho-Selective Directed
Trifluoromethylthiolation of Aryl Chlorides and Bromides Using
AgSCF3
Tin Nguyen, Weiling Chiu, Xinying Wang,† Madeleine O. Sattler,† and Jennifer A. Love*
Department of Chemistry, The University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
S
* Supporting Information
ABSTRACT: A mild protocol for Ni-catalyzed trifluoromethylth-
iolation of aryl chlorides and bromides is described herein. The
method utilizes AgSCF3 as an easily accessible nucleophilic
trifluoromethylthiolating reagent and does not require any ligands
or additives. Ortho-selectivity is achieved using a variety of
directing groups such as imines, pyridines, and oxazolines for 24
examples in up to 95% yield.
luorine has become increasingly prevalent in organic
Fcompounds; it is present in approximately 50% of all
agrochemicals and 25% of pharmaceuticals.1 Incorporation of
fluorine into bioactive molecules can significantly influence their
metabolism and physicochemical properties.2 Despite being the
most abundant halogen in the earth’s crust, it is present in only
about 30 natural products, which has necessitated the develop-
ment of numerous strategies to synthesize structurally diverse
organofluorine compounds.3 In recent years, the trifluoromethy-
thio-(−SCF3)groupanditsoxidizedanalogues[S(O)nCF3,n=0,
1, 2] have received notable attention due to their high
lipophilicity, electron-withdrawing ability, and bioavailability.4
Among fluorine-containing motifs, the SCF3 group possesses the
highest lipophilicity (π = 1.44), whereas the SO2CF3 group has
the strongest electron-withdrawing ability (σm = 0.79, σp = 0.93).5
In addition, these functional groups can be easily interconverted
through redox chemistry, rendering the construction of SCF3-
containing molecules a valuable synthetic target (Figure 1).4c,6
Traditional methods to incorporate the −SCF3 group in aryl
halides rely upon the fluorination of sulfur-containing substrates
either by halogen−fluorine exchange of chloro- or bromomethyl
sulfidesusinganucleophilicfluoridesuchasHF,SbF3,orTREAT·
HF,7 or the trifluoromethylation of thiols using a variety of
trifluoromethylating reagents such as biaryltrifluoromethyl-
sulfonium salts (Yagupolskii8 and Umemoto9 reagents), hyper-
valent iodine compounds (Togni’s reagent10), or silane
derivatives (Ruppert−Prakash reagent11).
More recently, the direct formation of C−SCF3 bonds has
emerged with the establishment of several strategies involving
electrophilic,12 nucleophilic,13 and oxidative cross-coupling.14
Nucleophilictrifluoromethylthiolation offersadirectandefficient
approach toward the synthesis of trifluoromethyl aryl sulfides
(ArSCF3) (Scheme 1).
Figure 1. Examples of biologically active compounds containing
aromatic SOnCF3 (n = 0, 1, 2).
Initially, the chemistry of these reagents was limited toaryl halides
bearing multiple electron-withdrawing moieties; however, in
recent years, the incorporation of chelating ligands or transition
metal complexes has extended the reactivity of trifluoromethyl-
thiolating reagents to substrates bearing electron-donating
groups as well as sensitive functional groups.15 Notwithstanding
these significant advances, nucleophilic trifluoromethylthiolation
protocols include high reaction temperatures and the use of
expensive ligands and are limited to aryl iodides and bromides,
which are typically more costly and less commercially available
than the analogous chlorides.
These synthetic methods require a readily available and easy-
to-use source of trifluoromethylthiolate anions. Early efforts
identified a variety of counterions (Cu2+, Ag+, Cs+, Me4N+,
TDAE2+) that could stabilize the trifluoromethylthiolate anion.
Received: September 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02689
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Organic Letters
Letter
Scheme 1. Transition-Metal-Mediated Nucleophilic
Trifluoromethylthiolation of Aryl Halides
Table 2. Optimization of Additive, Ligand, and AgSCF3
Loading for the Trifluoromethylthiolation of 1a
AgSCF3
(equiv)
additive
(1.1 equiv)
conversion
a
entry
ligand
(%)
1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
2.0
2.0
2.0
KI
−
−
−
−
−
−
−
−
0
12
15
2
2
KBr
3
KCl
4
(Me4N)I
5
(Me4N)Br
(Me4N)Cl
(i-Pr4N)PF6
(n-Bu4N)PF6
(n-Bu4N)PF6
(n-Bu4N)PF6
(n-Bu4N)PF6
(n-Bu4N)PF6
(n-Bu4N)PF6
(n-Bu4N)PF6
(n-Bu4N)PF6
(n-Bu4N)PF6
(n-Bu4N)PF6
−
14
26
34
50
4
6
7
8
9
neocuproine
10
11
12
13
14
15
16
17
18
phenanthroline
12
21
30
32
51
65
83
84
86
bpy
SPhos
PPh3
PCy3
−
−
−
−
Table 1. Screening Solvent and Catalyst Loading for the
Trifluoromethylthiolation of 1a
b
a
All reactions were performed on a 0.1 mmol scale. Percentages
represent conversion based upon the ratio of the imine proton
a
entry
Ni(cod)2 (mol %)
solvent
conversion (%)
resonances between the product and reactant using 1H NMR
b
1
2
3
4
5
6
7
−
5
THF
0
spectroscopy and are an average of 2 runs. 1.5 equiv of (n-Bu4N)PF6
THF
13
37
43
30
12
1
was used.
10
20
10
10
10
THF
THF
vents at room temperature (Table 1). AgSCF3 is the primary
precursor to several other trifluoromethylthiolating reagents and
was chosen as the nucleophile due to its ease of access and
stability. Evaluation of product conversion in different solvents
revealed THF to be the best solvent for our catalytic system. Aryl
trifluoromethylthiolation was not observed in the absence of
Ni(cod)2 orinthepresenceofaNi(II)precatalyst, suggestingthat
the catalytic cycle is accessed via a Ni(0) catalytic species. A
catalyst loading of 10 mol % (Table 1, entry 3) was considered to
be the most suitable despite the highest product conversion with
20 mol % Ni(cod)2 (entry 4), due to an unidentifiable fluorine-
containing species that was detected at high Ni(cod)2 loading.
Next, we were prompted to explore a variety of ligands and
additives, which have been shown to improve the reaction yield,
presumably by enhancing the activity of the catalyst and/or the
trifluoromethylthiolating reagent (Table 2).
Despite literature precedence for improved yields with the
addition of halide salts, there was no observable effect under our
conditions (Table 2, entries 1−6). However, the yield increased
to 50% upon the addition of n-Bu4PF6, which possibly aids in
solubilizing the active trifluoromethylthiolating species (entry 8).
Notably, the addition of both n-Bu4PF6 and bidentate nitrogen-
based ligands decreased the yield considerably (entries 9−11).
Phosphine-based ligands fared slightly better, but offered no
significant improvement than the absence of any ligand (entries
12−14). Increasing the amount of AgSCF3 from 1.1 to 2.0 equiv
improved the yield to a respectable 83% (entries 8, 15, and 16).
Notably, we discovered that the yields of the trifluoromethyl-
thiolated product were independent of the additive or ligand
DME
dioxane
MeCN
a
All reactions were performed on a 0.1 mmol scale. Percentages
represent conversion based upon the ratio of the imine proton
resonances between the product and reactant using 1H NMR
spectroscopy and are an average of 2 runs.
Realizing the constraints of these reported methods and
inspired by our previous work on ortho-selective C−F activation
and cross-coupling using nickel,16 we anticipated that the
judicious choice of a directing group would permit the
establishment of a new nucleophilic trifluoromethylthiolation
protocol that can be extended to aryl chlorides under mild
reaction conditions. While the ortho-directing strategy has been
successful in the trifluoromethylthiolation of arenes via Csp2−H
functionalization, the protocols demand high reaction temper-
atures and the use of toxic gases.17 Schoenebeck and co-workers
recently reported the first nucleophilic trifluoromethylthiolation
of aryl chlorides, without the need for a directing group.18 This
protocolusesNi(cod)2,(Me4N)SCF3,anddppfastheligandat45
°C. We have found that aryl chlorides and bromides undergo
trifluoromethylthiolation at ambient temperature using a ligand-
and additive-free Ni catalyst when directing groups are used. We
anticipate that our studies will be of particular use when additives,
ligands, or higher temperatures are not tolerated.
We initiated our investigation by examining the catalytic
activity of Ni(cod)2 toward the reaction between AgSCF3 and N-
benzyl-1-(2-chlorophenyl)methanimine (1a) in different sol-
B
DOI: 10.1021/acs.orglett.6b02689
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Organic Letters
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Table 3. Influence of Directing Groups in Ni-Catalyzed
Trifluoromethylthiolation Using AgSCF3
Table 4. Substrate Scope of Aryl and N-Heteroaryl Halides
with Imine, Pyridyl, and Amide Directing Groups
a
a
a
Isolated yield was based on the average of two trials on a 0.20 mmol
scale. For imine directing substrates, the isolated yield is the yield of
b
the aldehyde upon hydrolysis. Yield was determined by 19F NMR
spectroscopy; 3-fluoronitrobenzene was used as an internal standard.
c
The delay time for 19F nuclei was set at 18 s. N/R denotes that no
reaction occurred.
(entries 16−18). By monitoring reaction progress via 1H NMR
spectroscopy, we observed complete product formation within 6
h, and henceforth all reactions were halted after 6 h.
Sequentially, we explored a variety of directing groups for
catalytic trifluoromethylthiolation of aryl chlorides and bromides
a
Isolated yield was based on the average of two trials on a 0.20 mmol
scale. For imine directing substrates, the isolated yield is the yield of
the aldehyde upon hydrolysis. Yield was determined by H NMR
spectroscopy due to coelution of product and starting material.
b
1
C
DOI: 10.1021/acs.orglett.6b02689
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Organic Letters
Letter
(2) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.;
̃
(Table 3). Moderate to excellent yields of trifluoromethyl-
thiolated products were observed with a variety of directing
groups bearing an ortho-nitrogen including imine, pyridyl,
pyrimidyl, amide, and oxazoline directing groups. In stark
contrast, esters and aldehydes were ineffective as directing
groups, presumably due to their weaker coordination to Ni.
Acidicgroups(Table3,entries4and6)weretolerated, butonly
to a certain extent. In the absence of any directing group (entry
10), no product was obtained under the established conditions,
evenforarylbromides, emphasizingtheneedforadirectinggroup
under mild conditions. Moreover, such nitrogen-based directing
groupsarereadilyamenabletofurthersyntheticmanipulationand
are also common structural motifs in bioactive compounds.
Notably, although Ni(0) complexes are known to activate Csp2−
H and Csp2−S bonds, we did not observe any side products or
product decomposition during the reaction.
Encouraged by our results, we sought to determine the
functional group compatibility of the catalytic system. Various
aryl chlorides containing potentially reactive functional groups
were tested (Table 4). We were pleased to observe that the
method is highly selective for substituting ortho-chlorides, even in
the presence of other halides (entries 1, 2, 5, 6, 10, and 12). The
method can also be expanded toward nitrogen-containing
heterocycles, with comparable yields observed for 2-chloro- and
2-bromonicotinaldehyde (entry 11) and moderate yields for 2-
chloronicotinamide (entry 12).
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In summary, we have established a simple protocol for the
ortho-selective trifluoromethylthiolation of aryl chlorides and
bromides using Ni(cod)2 and AgSCF3 under mild reaction
conditions, in the absence of any ligand or additive. A range of aryl
and heteroaryl halides were converted to the corresponding
trifluoromethylaryl sulfides in moderate to excellent yields.
Mechanistic investigations, along with the development of a
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aryl chlorides selectively, are currently ongoing.
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ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b02689.
Full experimental details (PDF)
́
A.; Medebielle, M.; Kirsch, P.; Lork, E.; Roschenthaler, G.-V. Perkin
̈
AUTHOR INFORMATION
Corresponding Author
■
Trans. 1 2000, 2183−2185. (i) Tyrra, W.; Naumann, D.; Hoge, B.;
Yagupolskii, Y. L. J. Fluorine Chem. 2003, 119, 101−107. (j) Zhang, C.-P.;
Vicic, D. A. J. Am. Chem. Soc. 2012, 134, 183−185. (k) Zhang, M.; Weng,
Z. Adv. Synth. Catal. 2016, 358, 386−394.
*E-mail: jenlove@chem.ubc.ca.
Author Contributions
(14) (a) Chen, Q.-Y.; Duan, J.-X. J. Chem. Soc., Chem. Commun. 1993,
918−919. (b) Chen, C.; Xie, Y.; Chu, L.; Wang, R.-W.; Zhang, X.; Qing,
F.-L. Angew. Chem. 2012, 124, 2542−2545. (c) Zhai, L.; Li, Y.; Yin, J.; Jin,
K.; Zhang, R.; Fu, X.; Duan, C. Tetrahedron 2013, 69, 10262−10266.
(d)Danoun, G.;Bayarmagnai, B.;Gruenberg, M. F.;Goossen, L. J. Chem.
Sci. 2014, 5, 1312−1316. (e) Zhong, W.; Liu, X. Tetrahedron Lett. 2014,
55, 4909−4911.
†X.W. and M.O.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Council of
Canada (Discovery, CREATE, Research Tools and Instruments)
and the University of British Columbia for supporting this
research. W.C. is grateful to the CREATE Sustainable Synthesis
Program for their support.
(15) Teverovskiy, G.;Surry, D. S.;Buchwald, S. L. Angew. Chem., Int. Ed.
2011, 50, 7312−4.
(16) (a) Sun, A. D.; Love, J. A. Org. Lett. 2011, 13, 2750−2753. (b) Sun,
A. D.; Leung, K.; Restivo, A. D.; LaBerge, N. A.; Takasaki, H.; Love, J. A.
Chem. - Eur. J. 2014, 20, 3162−3168.
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DOI: 10.1021/acs.orglett.6b02689
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