Trifluoromethylthiodediazoniation: A simple, efficient route to trifluoromethyl aryl sulfides

Article abstract of DOI:10.1039/b002560g

Copper(I) trifluoromethanethiolate reacts with a range of diazonium salts containing electron-withdrawing groups to give the corresponding trifluoromethyl aryl sulfides in high yield; it is also possible to carry out the diazotisation and trifluoromethylthiolation in one pot directly from the anilines.

Full text of DOI:10.1039/b002560g

Trifluoromethylthiodediazoniation: a simple, efficient route to trifluoromethyl
aryl sulfides
Dave J. Adams, Andrew Goddard, James H. Clark* and Duncan J. Macquarrie
Clean Technology Centre, Chemistry Department, University of York, Heslington, York, UK YO10 5DD.
E-mail: jhc1@york.ac.uk
Received (in Liverpool, UK) 15th February 2000, Accepted 28th April 2000
Table 1 Yields of ArSCF3 from two-stage dediazoniations
Copper( ) trifluoromethanethiolate reacts with a range of
I
diazonium salts containing electron-withdrawing groups to
give the corresponding trifluoromethyl aryl sulfides in high
yield; it is also possible to carry out the diazotisation and
trifluoromethylthiolation in one pot directly from the
anilines.
Yield of
Yield of
Diazonium salt
ArSCF3a (%)
Diazonium salt
ArSCF3a (%)
1a
1b
1c
1d
1e
1f
89 (83)
97
98 (76)
95
98
92
1g
1h
1i
1j
1k
1l
60
95 (67)
91
17
7
Incorporation of a SCF3 group into an aromatic molecule is of
interest to the pharmaceutical and agrochemical industries,
where the high lipophilicity and high electron-withdrawing
ability of the group have important implications.1 Current
industrial methods for the formation of trifluoromethyl aryl
sulfides generally involve multi-step processes which requires
harsh conditions, restricting the nature of the other substituents
on the ring as well as being environmentally damaging.2 A
simple, direct method for the formation of these compounds is
thus highly desirable. One pot methods for preparing tri-
fluoromethyl aryl sulfides have been reported but these are
based on preformed thioaryl units (ArSCl and ArSCN) and
require excess quantities of both of the expensive reagents
CF3SiMe3 and Bu4NF.3 The Sandmeyer reaction is a well
known method for the formation of chloro-, bromo- and cyano-
3
a Yields calculated on the basis of GC area, unoptimised isolated yields in
parentheses.
all survived the reaction. Steric factors do not appear to have an
important effect: 2-, 3- and 4-nitrobenzenediazonium tetra-
fluoroborates all reacted immediately under the same conditions
to give very similar product yields and impurity profiles,
whereas it can be difficult to synthesise ortho-substituted
derivatives by traditional means.11
Unfortunately, when electron-donating groups are present,
the product yields are generally low (Table 1). This is due to a
lack of reaction selectivity, thus while 2-diazobiphenyl tetra-
fluoroborate completely reacts the major product is the amide
(Fig. 2). Such reactions have been reported to occur via reaction
of a diazonium salt with acetonitrile.12 In benzonitrile, no
reaction of this substrate with CuSCF3 was observed, with the
only detected product being 2-hydroxybiphenyl. This was also
the major product when the reaction was carried out in acetone.
Methylbenzenediazonium tetrafluoroborates reacted similar-
ily.
arenes via reaction of the diazonium salts with copper(
chloride, bromide or cyanide respectively.4 However, despite
copper( ) trifluoromethanethiolate (CuSCF3) being used for the
I)
I
formation of trifluoromethyl aryl sulfides via reaction with
iodobenzenes at high temperature5 there are no reports of its
reaction with diazonium salts. We have found that it is possible
to form trifluoromethyl aryl sulfides from the corresponding
diazonium tetrafluoroborates or directly in one pot from the
anilines simply by reacting with CuSCF3.
Addition of a solution of 2-nitrobenzenediazonium tetra-
fluoroborate 1a6 to an acetonitrile solution of CuSCF3 at 50 °C7
leads to rapid evolution of gas with concurrent formation of a
deep yellow colour8 1H NMR, 19F NMR and GC of the solution
all show that the major aromatic product is the 2-nitrophenyl
trifluoromethylsulfide 2a. Phenol, biphenyl or azo compounds,
which are often observed as byproducts in diazonium reactions,
were not formed in this system9 although a small amount of
nitrobenzene was detected.10 At room temperature, the reaction
is slower, but leads to a very similar product distribution. Other
diazonium salts (Fig. 1) containing electron-withdrawing
groups react similarily (Table 1). Halo, nitro and cyano groups
Fig. 2 Product from the reaction of 2-diazobiphenyl tetrafluoroborate with
CuSCF3.
In an effort to avoid the isolation of the diazonium
intermediate, we investigated other diazotisation methods.
Because CuSCF3 reacts with acids to give HSCF3, a non-protic
system was required. Although, classically, diazotisation is
achieved using sodium nitrite and a mineral acid, alternative
methods do exist.13 Doyle et al. have decribed the conversion of
aryl amines to the corresponding halides in one-pot using tert-
butyl nitrite and a copper(II) halide.14 We have found that it is
possible to effect a similar one-pot conversion of an aryl amine
to a trifluoromethyl aryl sulfide (Fig. 3). Hence, when tert-butyl
nitrite in acetonitrile was added to a pre-heated solution of
2-nitroaniline and CuSCF3 in acetonitrile at 50 °C, the solution
Fig. 1 Conversion of aryl diazonium tetrafluoroborates to trifluoromethyl
aryl sulfides.
Fig. 3 One-pot synthesis of trifluoromethyl aryl sulfides from anilines.
DOI: 10.1039/b002560g
Chem. Commun., 2000, 987–988
This journal is © The Royal Society of Chemistry 2000
987

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gradually became black. The formation of 2-nitrotrifluor-
omethylphenyl sulfide (29%) was detected, along with ni-
trobenzene (34%) and 2-nitrophenol (2%). It occurred to us that
while it is not possible to use a Brønsted acid to improve the
reaction, a Lewis acid may be beneficial. Repeating the one-pot
reaction of 2-nitroaniline in the presence of BF3 improved the
selectivity to the 2-nitrotrifluoromethylphenyl sulfide to 45%.
This method proved to be even more successful with 3-nitroani-
line (72%) and 4-nitroaniline (66%), and moderately successful
with other activated substrates and aniline itself (Table 2).15
Substrates containing electron donating groups gave no appre-
ciable yield of the desired trifluoromethyl aryl sulfide.
Notes and references
1 R. Filler, in Organofluorine Chemical and their Industrial Applications,
ed. R. E. Banks, Ellis Horwood Ltd, Chichester, 1979; B. E. Smart, in
Organofluorine Chemistry. Principles and Commercial Applications,
ed. R. E. Banks, B. E. Smart and C. Tatlow, Plenum Press, New York,
1994; R. M. DeMarinis and W. M. Bryan, J. Org. Chem., 1977, 42,
2024.
2 M. A. McClinton and D. A. McClinton, Tetrahedron, 1992, 37, 6555;
J. F. Harris, J. Org. Chem., 1967, 32, 2063; J. H. Clark, D. Wails and
T. W. Bastock, Aromatic Fluorination, CRC Press, New York, 1997.
3 T. Billard and B. R. Langlois, Tetrahedron Lett., 1996, 37, 6865; T.
Billard, S. Large and B. R. Langlois, Tetrahedron Lett., 1997, 38, 65.
4 A. F. Hegarty, in The Chemistry of the Diazonium and Diazo Groups,
ed. S. Patai, J. Wiley and Sons, Bristol, 1978.
Table 2 Yields of ArSCF3 from one-pot reactions of anilines
5 L. M. Yagupolskii, N. V. Kondratenko and V. P. Sabur, Synthesis, 1975,
721; D. C. Remy, K. E. Rittle, C. A. Hunt and M. B. Freedman, J. Org.
Chem., 1976, 41, 1644.
GC yield of
Aniline
ArSCF3 (%)
6 Diazonium salts were prepared via the method described in A. Roe, Org.
React., 1949, 5, 193.
Aniline
42
45
72
66
46
18
7 J. H. Clark, C. W. Jones, A. P. Kybett, M. A. McClinton, J. M. Miller,
D. Bishop and R. J. Blade, J. Fluorine Chem., 1990, 48, 249.
8 In a typical reaction, to a solution of CuSCF3 (0.165 g, 1.0 mmol) in
acetonitrile (3 ml) was added 1a (0.237 g, 1.0 mmol) in acetonitrile (2
ml) at 50 °C with stirring. Rapid evolution of gas was observed and the
solution became deep yellow. After stirring for 30 min, the solution was
diluted with diethyl ether (200 ml) and filtered through Celite. The
solvent was then removed to give 2a (0.1883 g, 83%). Selected
analytical data: 2-nitrophenyl trifluoromethyl sulfide 2a dF(254 MHz,
CD3CN) 241.3 (s); dH(270 MHz, CD3CN) 7.66–7.82 (m), 7.90 (m),
8.12 (m); m/z 223 (M+); Anal. Calc. for C7H4SF3NO2 m/z 222.991485;
Found m/z 222.991794; nmax/cm21 1570s (C–NO2), 1345s (C–NO2),
1103s (C–F), 777m (C–S).
9 H. Ku and J. R. Barrio, J. Org. Chem., 1981, 46, 5239.
10 H. H. Hodgson and A. P. Mahaderon, J. Chem. Soc., 1947, 173.
11 O. Schere, Angew. Chem., 1939, 52, 457.
12 W. E. Hanby and W. A Waters, J. Chem. Soc., 1939, 1792.
13 L. Friedman and J. F. Chelbowski, J. Org. Chem., 1968, 33, 1636.
14 M. P. Doyle, B. Siegfried and J. F Dellona, J. Org. Chem., 1977, 42,
2426.
2-Nitroaniline
3-Nitroaniline
4-Nitroaniline
3-Trifluoromethylaniline
3-Chloroaniline
In conclusion, we have demonstrated a new approach to
trifluoromethyl aryl sulfides which is applicable to a wide range
of substrates. This has advantages over current method-
ologies—the yields and product purity are high after a very
simple work up procedure; the route is shorter than the
traditional multi-step methods; and a wider range of functional
groups is accessible owing to the mild conditions utilised.
Unfortunately, this methodology is apparently restricted to
substrates which are not electron-rich. It is also possible to form
trifluoromethyl aryl sulfides in one pot directly from the
anilines in a clean, safe and efficient direct route to these
important compounds.
We gratefully acknowledge the support of the EPSRC
(ROPA grant), the EPSRC/RAEng (Clean Technology Fellow-
ship to J. H. C.) and the Royal Society (University Research
Fellowship to D. J. M.). We would also like to thank Alec
Taylor for helpful discussions.
15 In a typical reaction to a preheated solution of 2-nitroaniline (0.0553 g,
0.4 mmol) and CuSCF3 (0.0825 g, 0.5 mmol) in acetonitrile at 50 °C is
added BF3 etherate (0.4 mmol BF3), followed by tert-butyl nitrite in
acetonitrile. Evolution of a gas was observed and a darkening in the
colour of the reaction mixture. Samples for GC, GC–MS and NMR
analysis were first added to saturated calcium carbonate solution and
then extracted with diethyl ether.
988
Chem. Commun., 2000, 987–988
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