Development of Multigram Scale Synthesis of Trifluoromethylthiolating Reagent: (bpy)CuSCF3

Article abstract of DOI:10.1021/acs.oprd.6b00052

A practical and reproducible procedure for the efficient preparation of (bpy)CuSCF₃ (1), a copper reagent for trifluoromethylthiolation reaction, is reported. All reaction parameters were optimized, and reagent 1 was synthesized in 26 g scale.

Full text of DOI:10.1021/acs.oprd.6b00052

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Full Paper
Development of Multigram Scale Synthesis of
Trifluoromethythiolating Reagent: (bpy)CuSCF3
Yunxiao Zhang, Kangji Gan, and Zhiqiang Weng
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00052 • Publication Date (Web): 15 Mar 2016
Downloaded from http://pubs.acs.org on March 16, 2016
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Development of Multigram Scale Synthesis of
Trifluoromethythiolating Reagent: (bpy)CuSCF3
Yunxiao Zhang, Kangji Gan, and Zhiqiang Weng*
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State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry,
Fuzhou University, Fuzhou, 350108, China
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ABSTRACT. A practical and reproducible procedure for the efficient preparation of
(
bpy)CuSCF 1, a copper reagent for trifluoromethylthiolation reaction, is reported. All reaction
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parameters were optimized, and reagent 1 was synthesized in 26 g scale. Finally, the utility of the
reagent 1 was highlighted in the synthesis of a Toltrazuril intermediate on a preparative scale.
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Keywords: trifluoromethylthiolation; copper; trifluoromethylthiolating reagent;
trifluoromethylthiocopper; multigram scale synthesis
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INTRODUCTION
The incorporation of fluoroalkyl moieties in organic scaffolds often deeply modifies the
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,2
chemical and physicochemical properties of organic molecules. Among the fluorinated
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functional groups, the trifluoromethylthio substituent (SCF ) possesses a highest Hansch
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parameter (π = 1.44).
The trifluoromethylthio functionality is widely present in
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,7
pharmaceuticals, agrochemicals, as well as in functional materials. The most popular and
general methods for the generation of aryl trifluoromethyl thioethers (ArSCF ) involve the
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nucleophilic and radical trifluoromethylation of aryl sulfides, disulfides, sulfenyl chlorides and
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19-23
thiocyanates
and reaction of trifluoromethylthiolate with aryl halides.
However, these
classical approaches suffer from inherent drawbacks, e.g., some of reactions reported are of
limited substrate scope with respect to the electron-poor aromatic groups, or rely on the use of
expensive and/or toxic reagents under harsh reaction conditions. Based on this, the transition
metal-mediated or catalyzed trifluoromethylthiolation has recently emerged as a promising
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,24,25,26
strategy to produce aryl trifluoromethyl thioethers.
The use of trifluoromethylthiocopper (CuSCF ) for the trifluoromethylthiolation has also
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proven to be very effective for the formation of the trifluoromethylthiolated products. Generally,
this copper reagent was prepared by heating a mixture of bis(trifluoromethylthio)mercury with
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copper power in autoclave (Scheme 1a),
the reaction of trifluoromethylthiosilver with copper
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bromide (Scheme 1b), or the reaction of bis(trifluoromethyl) disulfide with copper power
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(Scheme 1c).
Very recently, a novel method for the synthesis of CuSCF by a deoxygenative
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reduction of Langlois’ reagent CF SO Na was reported by Yang, and Vicic, and co-workers
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(
Scheme 1d). Though these methods effectively access this versatile reagent, they suffer some
limitations, like the use of highly toxic bis(trifluoromethyl) disulfide and mercury reagent, and
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the requirement of prerequisite synthesis of trifluoromethylthio derivatives of silver or mercury.
In this regard, the development of an alternative novel approach with readily available starting
materials is highly desirable.
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Scheme 1. Methods for synthesis of trifluoromethylthiocopper (CuSCF3).
Recently, our group has developed a strategy for the synthesis of the diimine-ligated copper(I)
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trifluoromethylthiolate complexes from readily available, inexpensive materials (Scheme 1e).
These complexes reacted with aryl and heteroaryl halides and alkyl halides to afford the
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corresponding trifluoromethyl thioethers in good to excellent yields.
To further investigate
the reactivity and application of this class of reagent, we required a synthetic process which
would produce large amounts of the desired copper(I) trifluoromethylthiolate complexes.
Described herein is a modified synthetic route now capable of providing multigram quantities
(
ca. 26 g) of (bpy)CuSCF 1 (bpy = 2,2′-bipyridine).
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RESULTS AND DISCUSSION
Our procedure for the synthesis of (bpy)CuSCF 1 was accomplished in combination strategy
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starting from CuF , elemental sulfur, SiMe CF , and bpy (Scheme 2). In a resealable Schlenk
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tube possessing a Teflon screw valve under nitrogen, the reaction of CuF , S , with SiMe CF in
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MeCN at 80 °C for 10 h produced a dark-brown reaction mixture whose F NMR spectrum
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showed a resonance at -27.5 ppm, characteristic of CuSCF species. The reaction mixture was
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then filtered through Celite. The addition of a 2,2’-bipyridine to the filterate led to the formation
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of 1 in 60% yield ( F NMR). Slow diffusion of Et O into the MeCN solution at -25 °C yielded
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dark-red crystals of 1 in 52% yield. Although complex 1 is air- and moisture-stable in solid state,
the synthetic procedure should be performed under rigorously anhydrous conditions in an inert
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atmosphere. Indeed, complex 1 was obtained in decreased yield (22%; F NMR) from the
reaction without the use of air-sensitive techniques.
Scheme 2. Synthesis of (bpy)CuSCF 1.
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Furthermore, the order of reagent addition was explored. Interestingly, employing a typical
procedure where the bpy was added to a reaction mixture of CuF , elemental sulfur, and
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SiMe CF at the beginning did not provide the product 1. This is probably due to aggregation of
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copper species that prevents the further reaction. These results imply that the order of reagent
introduction was crucial to the success of this transformation.
Subsequently, some parameters affecting the preparation reaction were also investigated.
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Screen of Copper Sources. A screen of different copper sources was performed at 80 °C in
MeCN with SiMe CF and elemental sulfur, with the subsequent addition of bpy. The resulting
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reaction mixture was analyzed by F NMR. Among the copper sources screened it was found
that only CuF provided the desired product 1 in 60% yield (Table 1, entry 6). Other copper(I)
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sources such as CuI, CuBr, CuCl, CuCN, and CuSCN did not react to afford the product 1 (Table
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, entries 1-5). Similarly, there was no reaction with other copper(II) complexes such as
Cu(TFA) , Cu(OTf) , and Cu(MeCN) PF (Table 1, entries 7-9). These results suggest that the
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copper(II) fluoride was an appropriate copper sources for the synthesis of 1.
a
Table 1. Copper source screen for the synthesis of 1
b
entry
copper source
CuI
yield of 1 (%)
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CuBr
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CuCl
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CuCN
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CuSCN
CuF2
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Cu(TFA)2
Cu(OTf)2
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Cu(MeCN) PF
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Reaction conditions: [Cu] (0.50 mmol), SiMe CF (1.5 mmol), S (0.50 mmol), bpy (0.50 mmol), CH CN
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(1.5 mL), 80 °C, 10 h, N . The yield was determined by F NMR spectroscopy with PhOCF as internal
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standard.
Screen of Solvents. We then screened solvents for optimization of the reaction conditions
Table 2). Of the solvents investigated, only MeCN worked well, and provided 1 in 60% yield
Table 2, entry 1). Reaction in other solvents such as acetone, CH Cl , Diglyme, THF, dioxane,
(
(
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DMF, DMSO, NMP, and toluene did not work (Table 2, entries 2-6 and 8-10) or provided lower
yield (Table 2, entry 7). This result can be explained in terms of the stability and the coordinating
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ability of CH CN to the CuSCF species.
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Table 2. Solvent screen for the synthesis of 1
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entry
solvent
MeCN
acetone
CH Cl
yield of 1 (%)
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DMSO
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toluene
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Reaction conditions: CuF (0.50 mmol), SiMe CF (1.5 mmol), S (0.50 mmol), bpy (0.50 mmol), solvent
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(
1.5 mL), 80 °C, 10 h, N . The yield was determined by F NMR spectroscopy with PhOCF as internal
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standard. Reaction at 45 °C.
Screen of Trifluoromethyl Sources. The nature of trifluoromethyl sources was also
evaluated for its influence in the reaction (Table 3). Of these trifluoromethyl sources studied, the
reaction worked best with SiMe CF , indicating that Ruppert-Prakash’s reagent is suited for the
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reaction (Table 3, entry 1). No product or low yields of product 1 were observed and unidentified
by-products that might have been formed in those reactions with using CF I, and CF SO Na as
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trifluoromethyl sources (Table 3, entries 2 and 3). Furthermore, the reaction using CF ClCO Et
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as trifluoromethyl source in the presence of CsF led to a trace amount of the desired product 1
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(
Table 3, entry 4). Similarly, the reaction of CuCl, t-BuOK, fluoroform (CF H), and elemental
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sulfur also did not produce 1 under the standard condition (Table 3, entry 5).
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Table 3. Screen of trifluoromethyl sources for the synthesis of 1
b
entry
[CF3]
yield of 1 (%)
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SiMe CF
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CF3I
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CF SO Na
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Reaction conditions: CuF (0.50 mmol), [CF ] (1.5 mmol), S (0.50 mmol), bpy (0.50 mmol), MeCN (1.5
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mL), 80 °C, 10 h, N . The yield was determined by F NMR spectroscopy with PhOCF as internal standard.
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CuCl was used instead of CuF2.
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Scale-up synthesis. The reagent 1 was previously synthesized in 7.0 mmol scale. To
determine the scalability of the reaction, we conducted the reaction on a large scale by raising the
reaction temperature to 90 °C. Pleasingly, the same level of reactivity was observed in a large
scale reaction (Table 4). At first, the synthesis of reagent 1 was carried out at a 19.7 mmol scale
(Table 4, entry 1). A suspension of CuF in CH CN reacted with 3 mol equiv of SiMe CF and 1
2 3 3 3
mol equiv of elemental sulfur at 90 °C for 10 h, giving dark-brown solution which was filtered
through Celite. The filterate was added 2,2′-bipyridine to form a dark-brown solution, from
which was obtained in 52% yield (3.33 g) of dark red crystals of 1. The same procedure was also
applied to the reactions on 49.2 mmol, 98.5 mmol, and 147.7 mmol, and the desired product 1
was obtained in good yields (Table 4, entries 2-4). Therefore, this method is easy to handle, and
adaptable to largescale synthesis of 1.
a
Table 4. Scale-up synthesis of 1
b
entry
amount of CuF2
yield of 1 (%)
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a
2.00 g, 19.70 mmol
5.00 g, 49.2 mmol
10.00 g, 98.5 mmol
15.00 g, 147.7 mmol
3.33 g, 52%
8.25 g, 52%
18.5 g, 57%
26.1 g, 54%
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b
Reaction conditions: CuF (1 equiv), [CF ] (3 equiv), S (1 equiv), bpy (1 equiv), 90 °C, 10 h, N . Isolated
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yield.
The preparative utility of the reagent 1 was exemplified on the synthesis of Toltrazuril
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intermediate 3,
which was previously synthesized by
a
palladium-catalyzed
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trifluoromethylthiolation of 1-(4-bromophenoxy)-2-methyl-4-nitrobenzene with AgSCF3.
The
preparative-scale reaction of 1 with 1-(4-iodophenoxy)-2-methyl-4-nitrobenzene 2 proceeded
well and furnished trifluoromethylthiolated product 1-(4-((trifluoromethyl)thio)phenoxy)-2-
methyl-4-nitrobenzene 3 in 73% yield (Scheme 3).
a
Scheme 3. Synthesis of Toltrazuril intermediate 3 on a preparative scale
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CONCLUSION
This paper describes a practical, efficient and scalable process for the preparation of
bpy)CuSCF 1 as trifluoromethylthiolating reagent. Under the optimization of reaction
(
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conditions, reagent 1 was synthesized even in 26 g scale. The utility of the reagent 1 has also
been demonstrated in the synthesis of a Toltrazuril intermediate on a preparative scale.
EXPERIMENTAL SECTION
General Procedures. All manipulations were carried out under an inert atmosphere using a
nitrogen-filled glovebox or standard Schlenk techniques. All glassware was oven or flame dried
immediately prior to use. Solvents were freshly dried and degassed according to the procedures
in Purification of Laboratory Chemicals prior to use. Deuterated solvents were purchased from
Cambridge Isotope Laboratories, Inc., and were degassed and stored over activated 4 Å
molecular sieves. Unless otherwise noted, all reagents and starting materials were purchased
1
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1
from commercial sources and used without further purification. The H, F and C{ H}NMR
spectra were obtained at 293 K on a Bruker Avance 400 spectrometer, and chemical shifts were
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recorded relative to the solvent resonance. F NMR chemical shifts were determined relative to
CFCl as outside standard and low field is positive. GC-MS measurements were conducted on a
3
Shimadzu QP2010SE.
Synthesis of (bpy)CuSCF (1) on 147.7 mmol scale. In a glovebox, CuF (15.00 g, 147.7
3
2
mmol), S (4.730 g, 147.7 mmol) and 600 mL CH CN were added to an oven-dried resealable
8
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Schlenk tube (1 L) possessing a Teflon screw valve. CF SiMe (63.00 g, 443.1 mmol, 3 equiv)
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was added into this tube and the tube was sealed. The mixture was stirred in a preheated (90 °C)
oil bath for 10 h. The reaction mixture was then allowed to cool to room temperature and filtered
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through Celite. The volatiles were removed under reduced pressure and the resulting dark-brown
solid was washed with Et O (40 × 3 mL). The solid was re-dissolved in 100 mL CH CN and to
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3
this solution was added 2,2′-bipyridine (23.00 g, 147.7 mmol) in 500 mL of CH CN. The
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resulting solution was then cooled at -25 °C for 24 h. The resulting red crystals were, washed
1
with 50 × 3 mL of diethyl ether, and dried to give 26.1 g of 1 (54%). H NMR (400 MHz,
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CD Cl ) δ 8.72 (s, 2H), 8.26 (s, 2H), 8.05 (s, 2H), 7.55 (s, 2H). F NMR (376 MHz, CD Cl ) δ -
2
2
2
2
24.7 (s, 3F).
Procedure for the Synthesis of Toltrazuril Intermediate 3 on a Preparative Scale. In a dry
box, (bpy)CuSCF (1) (3.30 g, 8.60 mmol), 1-(4-iodophenoxy)-2-methyl-4-nitrobenzene 2 (2.60
3
g, 7.30 mmol), and 20 mL diglyme were added to a oven dried 100 mL test tube with Teflon
screw cap. The tube was sealed and the solution was placed into a preheated 130 °C oil bath for
24 h. Then the reaction mixture was filtered through a layer of Celite, eluted with diethyl ether.
The resulting mixture was extracted by diethyl ether (50 mL × 3), and the combined organic
layers was washed with water (50 mL × 3), and then dried over magnesium sulfate. The solvent
was removed by rotary evaporation and the resulting product was purified by column
chromatography on silica gel with n-pentane/Et O. 1-(4-((Trifluoromethyl)thio)phenoxy)-2-
2
1
methyl-4-nitrobenzene 3 was obtained in 73% yield (1.76 g). H NMR (400 MHz, CDCl ) δ 8.19
3
(d, J = 2.1 Hz, 1H), 8.06 (dd, J = 8.9, 2.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.8 Hz,
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2
H), 6.96 (d, J = 8.9 Hz, 1H), 2.40 (s, 3H). F NMR (376 MHz, CDCl ) δ -43.2 (s, 3F). GC-MS
3
+
m/z 328 (M -H).
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ASSOCIATED CONTENT
Supporting Information. Procedures for the synthesis of 2, and spectral data for products.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: zweng@fzu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the National Natural Science Foundation of China (NSFC) (grant number
21372044), the Research Fund for the Doctoral Program of Higher Education of China (grant
number 20123514110003), and Fuzhou University (grant number 022494) is gratefully
acknowledged.
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