On the preparation of ortho-trifluoromethyl phenyl triflate

Article abstract of DOI:10.1039/b406803c

In contrast to an earlier report advocating a copper-mediated trifluoromethylation of ortho-iodophenyl triflate, ortho-trifluoromethyl phenyl triflate may be prepared simply by reacting the corresponding phenol with triflic anhydride in the presence of a

Full text of DOI:10.1039/b406803c

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C O M M E N T
On the preparation of ortho-trifluoromethyl phenyl triflate
Duncan Gill,a Alison J. Hesterb and Guy C. Lloyd-Jones*b
a
AstraZeneca, Bakewell Road, Loughborough, Leicestershire, UK LE11 5RH
Organic & Biological Chemistry Section, The School of Chemistry, University of Bristol,
b
Cantock’s Close, Bristol, UK BS8 1TS. E-mail: guy.lloyd-jones@bris.ac.uk;
Fax: +44 (0)117 929 8611; Tel: +44 (0)177 928 8165
Received 6th May 2004, Accepted 1st July 2004
First published as an Advance Article on the web 4th August 2004
It is interesting to note that in the two-step procedure of Qing
In contrast to an earlier report advocating a copper-mediated
trifluoromethylation of ortho-iodophenyl triflate, ortho-
trifluoromethyl phenyl triflate may be prepared simply by
reacting the corresponding phenol with triflic anhydride in the
presence of a nucleophilic catalyst and stoichiometric base.
et al.,7 Scheme 2, the reaction of ortho-iodophenol (4) with Tf2O/
Et3N in CH2Cl2 proceeds smoothly (84% yield), as indeed do most
ortho-substituted phenols. It is thus curious that ortho-trifluoro-
methyl phenol (ortho-1) does not react in the manner desired. The
combination of an activated aromatic nucleus with the strongly
electron withdrawing trifluoromethyl group is known to induce
high reactivity. For example, both para-trifluoromethyl phenol
(para-1) and para-trifluoromethyl aniline readily polymerise on
mild thermolysis.8 Trifluoromethyl phenols are also photosensitive,
forming hydroxybenzoic acids in water via radical intermediates of
the type ArCF2.9 Furthermore, ortho-1 and para-1, but not meta-1,
are base labile, forming hydroxybenzoic acids in strong aqueous
base, but undergoing polymerisation in dilute base.8 This behav-
iour might thus appear to account for the failure of the reaction of
ortho-1 with Tf2O and Et3N in CH2Cl2 to yield ortho-2 as reported
by Qing et al.7
Organic triflates have long been of great interest and utility in
organic synthesis. Aryl and vinyl triflates1 in particular are notable
for their application in cross-coupling reactions where the triflate
acts as a pseudo halogen.2 Both the synthesis and reactivity of aryl
triflates may be viewed as complementary to the analogous halides:
the triflate is readily prepared from the appropriate phenol and with
the correct choice of palladium catalyst can be selectively cross-
coupled in the presence of the aryl bromide and vice versa.3
We have an ongoing interest in the anionic thia-Fries
rearrangement of aryl triflates4 and recently had reason to prepare
ortho-, meta- and para-trifluoromethyl phenyl triflates.5 Aryl
triflates are almost always prepared by reaction of the corresponding
phenol with a triflating agent, CF3SO2X, where X = halide, triflate,6
N-phenyl triflamide, etc., in the presence of a base, Scheme 1.
In our hands, ortho-trifluoromethyl phenol (ortho-1) is stable for
long periods in Et3N/CH2Cl2 solution, in the presence or absence of
Tf2O, as evidenced by 19F{1H} NMR monitoring with o-C6H4F2 as
an internal standard. On quenching such mixtures with water, we
obtained no evidence for the generation of ortho-hydroxybenzoic
acid and the bulk of the phenol (ortho-1) remains.† This then sug-
gests that the failed reaction of Qing et al.7 is a result not of the
instability of ortho-1 but rather its lack of reactivity towards Tf2O.
An experiment in which ortho-1 and ortho-chloro phenol (5)
competed for a limiting quantity of Tf2O demonstrated that the tri-
fluoromethyl group significantly reduces the nucleophilicity of the
phenol as compared to a chloro group, Scheme 3. Indeed, extensive
conversion of phenol 5 to triflate 6 occurred within a period of 12 h
at which point there was no ortho-2 detectable. This result strongly
supports the concept that neither ortho-1 nor its corresponding tri-
ethylammonium phenolate10 are sufficiently nucleophilic to react
with Tf2O.5 However, even with ortho-chloro phenol (5) these reac-
tion conditions (Et3N, TF2O, CH2Cl2, 0 to RT o/n) are not ideal as
pure 6 was isolated in only 30% yield after chromatography of the
crude product which contains numerous side-products.
Scheme 1 Conventional conditions for the preparation of aryl triflates.
We were thus somewhat surprised by a report from Qing et al.7
that ortho-trifluoromethyl phenol (ortho-1) does not yield ortho-
trifluoromethyl phenyl triflate (ortho-2) on reaction with Tf2O
and Et3N in CH2Cl2. Instead, they describe that ortho-1 is unstable
under these reaction conditions and that the sole isolable product
is ortho-hydroxybenzoic acid. On the basis of this result, Qing et
al. advocate the use of a copper-mediated trifluoromethylation,
Scheme 2. Although this procedure yields ortho-trifluoromethyl
phenyl triflate (ortho-2) in 84% yield, the requisite ortho-
iodophenyl triflate (3) must be prepared from ortho-iodophenol (4)
and moreover, 5 equivalents of both FSO2CF2CO2Me and HMPA
are required in the second step (3 to 2).
Scheme 3 Competition experiment between ortho-chloro-(5) and ortho-
trifluoromethyl (ortho-1) phenols for triflic anhydride.
By direct analogy with nucleophilic catalysis of acylation reac-
tions, we reasoned that an N-triflyl 4-N′,N′-dimethylaminopyri-
dinium intermediate would be substantially more reactive towards
phenols/triethylammonium phenolates than the neutral anhydride
Tf2O.11 Accordingly, 5 mol% DMAP12 was found to catalyse the
Scheme 2 The procedure of Qing et al.7 for the preparation of ortho-2.
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 4 7 – 2 5 4 8
2 5 4 7

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but starting with meta-1; (Found: N, 0.1; C, 32.4; H, 1.2%; C8H4F3O3S
requires N, 0; C, 32.7; H, 1.4%); max (film)/cm−1 1594w (benzene),
1324s (SO2), 1211s, 1174s (SO2O), 1128s (SO2), 909s (meta-disubstituted
benzene), 810s (meta-disubstituted benzene); H (400 MHz; CDCl3; Me4Si)
7.68 (d, J = 7.7 Hz, 4-H), 7.61 (dd, J = 8.0, 7.7 Hz, 5-H), 7.55 (s, 2-H),
7.50 (d, J = 8.0 Hz, 6-H); C (100 MHz; CDCl3; Me4Si) 149.35 (s, 1-C),
133.01 (q, JCF = 33.8 Hz, 3-C), 131.03 (s, 5-C), 125.26 (q, JCF = 3.8 Hz, 4-C)
124.86 (s, 6-C) 122.82 (q, JCF = 272.9 Hz, Ar–CF3), 118.73 (q, JCF = 3.8 Hz,
2-C), 118.68 (q, JCF = 320.5 Hz, SO2–CF3); F (376 MHz; CDCl3) −63.7 (s,
Ar–CF3), −73.6 (s, SO2–CF3);13 m/z (EI) 294 (M+, 70%), 275 (30), 230 (65),
161 (21), 145 (26), 133 (63), 113 (39), 69 (100)
reaction of ortho-1 with Tf2O to afford the desired triflate ortho-2
as the major product identifiable in the NMR spectrum of the crude
product after work-up, Scheme 4.
para-Trifluoromethyl phenyl triflate7 (para-2): obtained as a clear colour-
less liquid in 94% yield using an identical procedure to that described above,
but starting with para-1; (Found: N, 0.0; C, 32.4; H, 1.2%; C8H4F3O3S
requires N, 0; C, 32.7; H, 1.4%); max (film)/cm−1 1610w (benzene), 1323s
(SO2), 1211s, 1172s (SO2O), 1127s (SO2), 979s (Ar–H), 846s (para-disub-
stituted benzene); H (400 MHz; CDCl3; Me4Si) 7.75 (2H app. d, J = 8.5 Hz,
3-H and 5-H), 7.42 (2H, app. d, J = 8.5 Hz, 2-H and 6-H); C (100 MHz;
CDCl3; Me4Si) 151.5 (s, 1-C), 130.8 (q, JCF = 33.5 Hz, 4-C), 127.7 (q,
JCF = 3.6 Hz, 3-C and 5-C), 123.2 (q, JCF = 272.4 Hz, Ar–CF3) 121.9 (s, 2-C
and 6-C) 118.7 (q, JCF = 320.7 Hz, SO2–CF3);13 F (376 MHz; CDCl3;) −63.3
(s,Ar–CF3), −73.4 (s, SO2–CF3); m/z (EI) 294 (M+, 69%), 275 (17), 230 (59),
161 (14), 145 (27), 133 (60), 113 (34), 69 (100).
Scheme 4 The use of DMAP to catalyse the triflation of ortho-1. There is
no reaction in the absence of catalyst.
However, the isolated yield of ortho-2 was not good (30%) and
this suggested that polymerisation of ortho-1 may be a significantly
competing side reaction. A better procedure emerged to be the use
of pyridine as solvent, base and catalyst, Scheme 5, which gave
ortho-2 in 91% yield.‡ Using an analogous procedure, the meta- and
para-isomers of 2 were also prepared in excellent yield.
1 K. Ritter, Synthesis, 1993, 735.
2 (a) Transition Metals for Organic Synthesis, M. Beller and C. Bolm,
ed., Wiley-VCH, Weinheim, 1998; (b) J. Tsuji, Palladium Reagents and
Catalysts, John Wiley, Chichester, 1995.
3 T. Kamikawa and T. Hayashi, Tetrahedron Lett., 1997, 38, 7087.
4 J. P. H. Charmant,A. M. Dyke and G. C. Lloyd-Jones, Chem. Commun.,
2003, 380.
5 A survey of the literature revealed that these compounds (ortho-,
meta- and para-2) were first prepared by Qing et al. in 1997 (see ref. 7)
using the method shown in Scheme 2. Wu et al. have reported the use
of ortho-trifluoromethyl phenyl triflate (ortho-2) in cross-coupling
reactions (J. Wu, J.-F. Marcoux, I. W. Davies and P. J. Reider, Tetra-
hedron Lett., 2001, 42, 159). The compound (ortho-2) was prepared
by reacting phenol (ortho-1) with trifluoromethylsulfonyl chloride in
CH2Cl2/Et3N at 0 °C. The (unoptimised) yields were less than 50%:
J. Wu and J. Marcoux, personal communication. The fact that the reac-
tion proceeds with the chloride (CF3SO2Cl) in CH2Cl2/Et3N but not the
anhydride (Tf2O) is consistent with the low nucleophilicity of the phenol
(ortho-1) described herein.
Scheme 5 The ready preparation of trifluoromethyl phenyl triflates
(o-,m-,p-2) using pyridine as nucleophilic catalyst, solvent and base.
In summary, the previously reported difficulties in the prepara-
tion of ortho-trifluoromethyl phenyl triflate (ortho-2) from the
corresponding ortho-trifluoromethyl phenol (ortho-1) by base-
mediated reaction with Tf2O stem predominantly from low nucleo-
philicity rather than instability of 1 and its conjugate base.7 Pyridine
is commonly employed as a solvent for triflation1 of phenols and the
results presented herein suggest that the solvent may also participate
as a nucleophilic catalyst under standard conditions.
6 I. L. Baraznenok, V. G. Nenajdenko and E. S. Balenkova, Tetrahedron,
2000, 56, 3077.
We thank AstraZeneca for generous support of this work.
7 F.-L. Qing, J. Fan, H.-B. Sun and X.-J. Yue, J. Chem. Soc., Perkin Trans
1, 1997, 3053.
8 R. G. Jones, J. Am. Chem. Soc., 1947, 69, 2346.
Notes and references
9 P. Seiler and J. Wirz, Helv. Chim. Acta, 1972, 55, 2693.
† Although we did not isolate any ortho-hydroxybenzoic acid, we do not
dispute that Qing et al. may have done so, after aqueous work-up, as the
phenol is known to be sensitive to aqueous base and to light, vide supra. The
salient point is that 19F{1H} NMR analysis indicates that under the triflation
conditions (Tf2O, CH2Cl2, Et3N, RT) the phenol is relatively inert.
10 Titration experiments with Et3N (followed by 19F{1H} NMR in CD2Cl2)
showed no evidence for deprotonation of ortho-1 to give the phenolate.
11 To the best of our knowledge, nucleophilic catalysis of phenol triflation
employing triflic anhydride has not previously been noted. However,
the nucleophilic catalysis of sulfonation has been studied in depth. For
leading references, see: I. M. Gordon, H. Maskill and M.-F. Ruasse,
Chem. Soc. Rev., 1989, 18, 123; . A super-stoichiometric combination
of DMAP and Tf2O has been reported by Banwell et al. as an efficient
system for promoting Bischler–Naperialski cyclisation under mild
conditions, see: M. G. Banwell, B. D. Bissett, S. Busato, C. J. Cowden,
D. C. R. Hockless, J. W. Holman, R. W. Read and A. W. Wu, J. Chem.
Soc., Chem. Commun., 1995, 2551.
‡ ortho-Trifluoromethyl phenyl triflate7 (ortho-2): to a stirred solution
of ortho-trifluoromethyl phenol (ortho-1) (3.45 g, 21 mmol) in anhydrous
pyridine (10 cm3) at 0 °C was added trifluoromethanesulfonic anhydride
(3.8 ml, 23 mmol) dropwise over 5 min. The clear colourless solution
changed to a dark orange colour and was allowed to return slowly to room
temperature. After 48 h the reaction was quenched with water, extracted into
CH2Cl2 (5 × 15 cm3) and the organic phase washed with 1 M hydrochloric
acid (20 cm3), water (20 cm3) and brine (10 cm3). The organic phase was
dried over anhydrous magnesium sulfate, filtered and the solvent removed
in vacuo to give a pale yellow liquid. After purification by flash chromato-
graphy, eluting with 10% ethyl acetate in hexanes, ortho-trifluoromethyl
phenyl triflate (ortho-2) (5.62 g, 91% yield) was obtained as a clear
colourless liquid. (Found: N, 0.1; C, 32.8; H, 1.3%; C8H4F3O3S requires
N, 0; C, 32.7; H, 1.4%); max (film)/cm−1 1616w (benzene), 1318s (SO2),
1211s, 1184s (SO2O), 1132s (SO2), 1115s, 882s, 765s (ortho-disubstituted
benzene); H (400 MHz; CDCl3; Me4Si) 7.74 (1H, d, J = 7.7 Hz, 3-H), 7.65
(1H, dd, J = 8.2, 7.9 Hz, 5-H), 7.50 (1H, d, J = 8.2 Hz, 6-H), 7.49 (1H,
dd, J = 7.9, 7.7 Hz, 4-H); C (100 MHz; CDCl3; Me4Si) 146.08 (s, 1-C),
133.95 (s, 5-C), 128.19 (s, 6-C), 128.00 (q, JCF = 4.9 Hz, 3-C), 123.17 (q,
JCF = 32.7 Hz, 2-C), 122.33 (s, 4-C), 122.03 (q, JCF = 272.9 Hz, Ar–CF3),
118.41 (q, JCF = 320.2 Hz, SO2–CF3); F (376 MHz; CDCl3) −61.5 (s,
Ar–CF3), −74.3 (s, SO2–CF3);13 m/z (EI) 294 (M+, 58%), 230 (33), 142 (97),
133 (48), 114 (100).
12 For leading references, see: M. R. Heinrich, H. S. Klisa, H. Mayr,
W. Steglich and H. Zipse, Angew. Chem., Int. Ed., 2003, 42, 4826.
13 Qing et al. (see ref. 7) assign 19F shifts of −93.2, −91.5 and −91.9 ppm for
the Ar–CF3 groups and −80.3, −81.7 and −81.8 ppm for the ArOSO2CF3
groups in ortho-, meta- and para-2, respectively. Similar shifts are
assigned to a range of analogous aryl triflates and aryl trifluromethanes.
In our hands, Ar–OSO2CF3 compounds have 19F shifts in the range −73
to −75 ppm (F CCl3F = 0 ppm), see, for example: J. P. H. Charmant,
I. A. Fallis, N. J. Hunt, G. C. Lloyd-Jones, M. Murray and T. Nowak,
J. Chem. Soc., Dalton Trans., 2000, 1723–1732; The 19F shift of
Ph–CF3 is −64 ppm (M. Hesse, H. Meier and B. Zeeh, translated by
A. Linden and M. Murray, Spectroscopic Methods in Organic Chem-
istry, George Thieme, Stuttgart, 1997). Our assignment of −61.5, −63.7
and −63.3 ppm for the Ar–CF3 groups and −74.3, −73.6 and −73.4 ppm
for the ArOSO2CF3 groups in ortho-, meta- and para-2, respectively, is
thus consistent with both sets of chemical shifts. We suggest that all of
the 19F spectra of Qing et al. in ref. 7 have been mis-referenced.
meta-Trifluoromethyl phenyl triflate7 (meta-2): obtained as a clear colour-
less liquid in 92% yield using an identical procedure to that described above,
2 5 4 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 4 7 – 2 5 4 8