Mono- and trifluorination of the thiazole ring of 2,5-diarylthiazoles using N-fluorobenzenesulfonimide (NFSI)

Article abstract of DOI:10.1016/j.tetlet.2012.12.052

Fluorination of select 2,5-diarylthiazoles using the N-F reagent N-fluorobenzenesulfonimide (NFSI) has led to the formation of both the anticipated 4-fluorothiazole as well as a unique 4,4,5-trifluorothiazole. Selective monofluorination is best achieved using bromobenzene as solvent at 155 °C, while trifluorination is best achieved by performing the reaction without solvent at 135-140 °C. An X-ray crystal structure has been obtained on one of the trifluorinated products.

Full text of DOI:10.1016/j.tetlet.2012.12.052

Tetrahedron Letters 54 (2013) 1025–1028
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mono- and trifluorination of the thiazole ring of 2,5-diarylthiazoles using
N-fluorobenzenesulfonimide (NFSI)
⇑
Julie M. Hatfield, Cheryl K. Eidell, Chad E. Stephens
Department of Chemistry and Physics, Augusta State University, Augusta, GA 30904, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Fluorination of select 2,5-diarylthiazoles using the N–F reagent N-fluorobenzenesulfonimide (NFSI) has
led to the formation of both the anticipated 4-fluorothiazole as well as a unique 4,4,5-trifluorothiazole.
Selective monofluorination is best achieved using bromobenzene as solvent at 155 °C, while trifluorina-
tion is best achieved by performing the reaction without solvent at 135–140 °C. An X-ray crystal structure
has been obtained on one of the trifluorinated products.
Received 27 October 2012
Revised 12 December 2012
Accepted 17 December 2012
Available online 21 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Thiazole
Fluorination
N–F reagents
NFSI
Solvent free reaction
Introduction
less activated 2-alkyl-4-arylthiazole at the 5-position reportedly
failed (although the fluorination reagent used in this case was
The direct fluorination of aromatic compounds using N–F re-
agents (Fig. 1) has become increasingly common in recent
years.1–4 Due to the relative ease of handling and often improved
chemoselectivity offered by N–F reagents, especially compared to
elemental fluorine, many such reagents have been developed and
their general reactivity toward aromatic compounds has been
demonstrated.5–12 However, the majority of work in this area has
focused largely on the fluorination of benzene, or other carbocyclic,
derivatives. In contrast, there have been fewer examples involving
the direct fluorination of heteroaromatic compounds with N–F re-
agents.13–17 These few examples have also shown variable success,
with incomplete conversion to fluorinated product and/or low
mass recovery often being observed, especially with nitrogen het-
erocycles, which may undergo N-fluorination or ring oxidation as a
competing side reaction.16,17 The application of this chemistry to
heteroaromatics thus remains somewhat limited in scope.
To date, there have been only a few reports of the direct fluo-
rination of thiazoles with N–F reagents. 2-Acetamidothiazole, an
activated thiazole derivative, has been fluorinated at the 5-posi-
tion in 48% yield using Selectfluor (1), although this reaction
could not be driven to completion.18 Similarly, a 2-amino-4-aryl-
thiazole has also been fluorinated at the 5-position in 42% yield
using Selectfluor (1).19 However, a recent attempt to fluorinate a
not disclosed).20
Previously, we have described the direct fluorination of some
2,4-diarylthiazoles at the 5-position by reaction with Accufluor
(2).21 That reaction proceeded rather selectively, but provided
low to modest yields of the monofluorinated products (19–43%)
due to incomplete consumption of starting material. In another
study aimed at the direct fluorination of 3,5-diarylisoxazoles using
Selectfluor (1), we obtained not only the anticipated 4-fluoroisox-
azole derivatives, but also a unique 4,4,5-trifluoroisoxazole as a
minor byproduct, which was shown to be formed by formal addi-
tion of F2 to the monofluorothiazole.22
We have now explored the direct fluorination of some
2,5-diarylthiazoles, also using N–F reagents. As with the 3,5-diary-
lisoxazoles, but in contrast to our observations with the isomeric
2,4-diarylthiazoles, we have found that the 2,5-diarylthiazoles,
depending on the aryl substituents, also undergo the unique
4,4,5-trifluorination reaction in addition to monofluorination.23
Unfortunately, these mono- and trifluorinated thiazole products
have proven quite difficult to separate by chromatography, which
dramatically limits the isolated yield potential for each product.
We have thus tried to optimize the reaction conditions with the
goal of forming each product in a more selective manner, and this
has led to modest improvements in both the mono- and trifluori-
nation of the parent 2,5-diphenylthiazole. Herein, we wish to
describe these results.24 We also present a crystal structure of
one of the unique 4,4,5-trifluorothiazole products.
⇑
Corresponding author. Tel.: +1 706 667 4995; fax: +1 706 434 5597.
E-mail address: cstephe7@aug.edu (C.E. Stephens).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.052

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J. M. Hatfield et al. / Tetrahedron Letters 54 (2013) 1025–1028
F
O
O
S
Cl
OH
O
O
N
S
N
N
2 BF4
N
2 BF4
N
F
F
1
2
3
(Selectfluor®)
(Accufluor ®)
Figure 1. Structures of commonly used N–F reagents.
(NFSI)
Considering that NFSI has good solubility in less polar solvents,
we next tried refluxing toluene (bp 111 °C) as solvent. With this
change, and by performing the reaction at relatively high dilution
(ꢀ15 mL of solvent per mmole of thiazole), the reaction was quite
selective for monofluorination, although a small amount of the tri-
fluorinated product was still formed. However, the reaction ap-
peared slow under these conditions. With a change of solvent to
refluxing chlorobenzene (bp 132 °C), the reaction appeared faster,
but still required several hours for maximum conversion according
to TLC. With bromobenzene (bp 156 °C) as solvent, still under fairly
dilute conditions, the reaction remained fairly selective for mono-
fluorination and reached maximum conversion after about 3 h at
155 °C (Scheme 2). Considering this outcome was the best we
had observed, we performed the reaction on preparative scale
and obtained the 4-fluorothiazole 5a in 21% isolated yield after
flash column chromatography to remove residual starting material
and minor traces of the trifluorinated product.27
We next turned our attention to maximizing the formation of
the unique 4,4,5-trifluorothiazole product 6a. We initially reacted
the parent 2,5-diphenylthiazole (4a) with 3 equiv of NFSI in either
ortho-dichlorobenzene or nitrobenzene at about 170–180 °C.
Although these high-temperature conditions provided a larger
amount of trifluoro product compared to monofluoro product
according to TLC analysis, we eventually found that we could ob-
tain a similar outcome by performing the reaction without solvent.
This was possible since the melting point of NFSI is 110 °C, and
thus a liquefied melt of the 2,5-diphenylthiazole 4a and NFSI could
be obtained upon heating the two reactants together at about
135 °C. After just 45 min at this temperature, a 37% isolated yield
of the parent 4,4,5-trifluorothiazole 6a was obtained following
flash chromatography (Scheme 2).28 Although still a fairly low
yield, we were nonetheless pleased to be able to prepare a pure
Results
Initially, we investigated the reaction of the parent 2,5-diphe-
nylthiazole25 (4a) with either Selectfluor (1) or Accufluor (2)
(1.1 equiv), conditions we used successfully in our previous stud-
ies. Reaction with either of these N–F reagents in refluxing aceto-
nitrile for several hours to overnight led to only minimal
amounts of the 4-fluorothiazole according to TLC, with a large
amount of starting material remaining unconsumed and some
decomposition (Scheme 1). On the other hand, increasing the reac-
tion temperature by heating in sulfolane21 at various temperatures
(100–140 °C) led to a complex mixture of the 4-fluorothiazole (5a),
the 4,4,5-trifluorothiazole (6a), and unreacted starting material
(Scheme 1). Thus, as with the 3,5-diarylisoxazoles,22 trifluorination
of the heterocyclic ring to give a non-aromatic product was ob-
served. Since isolation of analytically pure products from this com-
plex mixture using flash silica gel column chromatography was
quite difficult, we did not determine isolated yields for these pre-
liminary reactions. Instead, we pursued the development of other
reaction conditions with the goal of improving the reaction
selectivity.
The reaction was next attempted using N-fluorobenzenesulfoni-
mide (NFSI) (3), a less reactive fluorinating reagent that is most often
used to fluorinate carbanions,26 but which has also been used to
fluorinate neutral aromatics.14 Upon reaction of the parent
2,5-diphenylthiazole (4a) with NFSI (1.1 equiv) in sulfolane (at
140–150 °C), improved results were observed by TLC which
included increased conversion of starting material and less decom-
position. However, we were still left with a mixture of both mono-
and trifluorinated products, along with unreacted starting material.
Attempts to consume the starting material by using more equivalent
of NFSI led to formation of more of the trifluorination product.
F
N
S
1 or 2 (1 equiv.)
MeCN, reflux
N
5a
(trace)
+ starting material
S
F
F
4a
F
F
N
N
1 or 2 (1 equiv.)
Sulfolane
100-140 °C
+
S
S
5a
6a
+ starting material
(complex mixture)
Scheme 1. Original, unoptimized fluorination conditions. Purification not pursued to due limited product formation or formation of complex mixture.

J. M. Hatfield et al. / Tetrahedron Letters 54 (2013) 1025–1028
1027
F
N
S
R
R
5a (R = H) 21% yield
a (for 5a)
b (for
5c
(R = CF3) 7.4% yield
N
5c
)
S
F
F
4a R = H
4b
R
R
N
R = Cl
4c R = CF3
b
S
F
R
R
6a
(R = H) 37% yield
6b (R = Cl) 23% yield
Scheme 2. Reagents and conditions: (a) NFSI (1 equiv), bromobenzene (15 mL per mmole of thiazole), 155 °C, 3 h; (b) NFSI (3 equiv), 135–140 °C, 45 min, no solvent.
Figure 2. X-ray crystal structure of compound 6b.
sample of the trifluorinated product. We were also pleased to find
that NFSI is quite amenable to solvent-free fluorination reactions.29
To gain further insight into the unique trifluorination of the thi-
azole ring, we have briefly explored the effect of adding substituents
to the phenyl rings of parent diphenylthiazole. Reaction of thiazole
4b (R = Cl) with 3 equiv of NFSI in the absence of solvent (as with 4a)
led to the formation of trifluorinated product 6b in 23% isolated
yield (Scheme 2). However, when thiazole 4c (R = CF3) was sub-
jected to these same conditions, only a small 7.4% isolated yield of
monofluorinated product 5c was obtained,30 with no trifluorinated
product being observed by TLC (a large amount of starting material
remained). The lower reactivity of 4c is attributed to the strong elec-
tron withdrawing effects of the two CF3 substituents. Such a deacti-
vating effect for the CF3 group was also seen in our study on the
fluorination of 3,5-diarylisoxazoles.22
addition to spectral analysis, a crystal structure on trifluorothiazole
6b was also obtained (Fig. 2).31
Conclusion
In conclusion, direct fluorination of 2,5-diphenylthiazole using
N-fluorobenzenesulfonimide (NFSI) gives both the 4-fluorothiazole
and the non-aromatic 4,4,5-trifluorothiazole upon heating. After
some optimization of conditions, selective monofluorination was
achieved in 21% isolated yield using bromobenzene as solvent at
155 °C under fairly dilute conditions, while trifluorination was
achieved in 37% isolated yield by performing the reaction without
solvent at 135–140 °C. Using the solvent-free fluorination condi-
tions, the slightly deactivated 2,5-bis(4-chlorophenyl)thiazole
was also trifluorinated in 23% isolated yield, however the more
strongly deactivated 2,5-bis(4-trifluoromethylphenyl)thiazole
was only monofluorinated in very low yield (7.4%). To our knowl-
edge, this work represents the first example of the direct fluorina-
tion of thiazoles with NFSI. This work also illustrates the use of
bromobenzene for high temperature reactions using NFSI, as well
as the use of NFSI for solvent-free fluorinations.
Products in Scheme 2 have been characterized by mp, 1H, 13C
and 19F NMR, as well as HRMS.27,28,30 As expected, the 19F NMR
of the monofluoro thiazoles (5a and 5c) each showed one singlet
for the lone fluorine, while the 19F NMR of the trifluorothiazoles
(6a–b) each showed three doublet of doublets (2JFF = ꢀ210 Hz;
3JFF = ꢀ9 Hz) due to coupling of the three non-equivalent fluorines.
The 13C NMR spectra each revealed extended 13C–19F coupling. As
for the fluorine-containing carbons, C-4 of the monofluoro thia-
zoles appeared as a doublet with a large coupling constant
(1JFC = ꢀ250 Hz), while C-4 and C-5 of the trifluorinated thiazoles
each appeared as a triplet of doublets, with both large and smaller
Note added in proof
During the preparation of this Letter, a patent document from
another group appeared online detailing the synthesis and
2
coupling constants (1JFC = ꢀ235–255 Hz; JFC = ꢀ25–45 Hz). In

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J. M. Hatfield et al. / Tetrahedron Letters 54 (2013) 1025–1028
anti-cancer properties of some similar 4,5,5-trifluorothiazoles.32
Those compounds were synthesized by direct fluorination of the
thiazole ring with Selectfluor (2.4 equiv) in refluxing acetonitrile
(3 h) in yields of 20–30%. Thus, the methodology we describe here
for 4,5,5-trifluorination of the thiazole ring using NFSI without sol-
vent represents an alternative synthetic method for the potential
synthesis of these unique compounds.
24. This Work was Presented in Preliminary Form at the 19th International Symposium
on Fluorine Chemistry; Hatfield, J. M.; Stephens, C. E. Abstract 244, 2009.
25. The 2,5-arylthiazoles (4a–c) used in this study were prepared by the Pd-
catalyzed Heck arylation of thiazole with 2 equiv of a bromobenzene: Yokooji,
A.; Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2003, 59,
5685.
26. Taylor, S. D.; Kotoris, G. Tetrahedron 1999, 55, 12431. b) Yamada, S.;
Gavryushin, A.; Knochel, P Angew. Chem. Int. Ed. 2010, 49, 2215.
27. Synthesis and analytical data for 5a: A mixture of 2,5-diphenylthiazole (0.24 g,
1.0 mmol) and NFSI (0.35 g, 1.1 mmol) in bromobenzene (15 mL) was heated at
155 °C (oil bath temp) under N2 for 3 h. The dark yellow solution was diluted
with water and extracted with EtOAc. The extract was evaporated onto silica
gel and subjected to flash chromatography on silica using hexanes as eluent to
Acknowledgments
give monofluoro thiazole 5a (0.055 g, 21% yield) as
Recrystallization from MeOH gave a fluffy yellow solid, mp 72.5–74 °C. IR
a yellow solid.
We thank the ASU Foundation for partial funding of this work,
Dr. Kenneth Hardcastle, Emory University X-ray Crystallography
Center, for determination of the crystal structure, and Dr. Siming
Wang, Georgia State University, for HRMS data.
(ATR): 3053, 2921, 1599, 1572, 1547, 1361, 1332, 1040, 1023, 907, 754, 686,
674 cmÀ1 1H NMR (400 MHz, DMSO-d6): 7.38–7.40 (m, 1H), 7.45–7.52 (m, 5H),
.
7.61 (d, J = 8.0 Hz, 2H), 7.89–7.92 (m, 2H). 13C NMR (100 MHz, DMSO-d6): 113.6
(d, J = 26.2 Hz), 125.7 (s), 127.2 (d, J = 5.0 Hz), 128.4 (d, J = 5.0 Hz), 128.9 (s),
129.8 (s), 129.8 (s), 131.6 (s), 132.2 (s), 155.5 (d, J = 248 Hz), 161.2 (d,
J = 19.1 Hz). 19F NMR (282 MHz, DMSO-d6, C6F6 internal standard): 55.7 (s).
HRMS (ESI+) calcd for C15H11FNS: 256.0596; found: 256.0594.
References and notes
28. Synthesis and analytical data for 6a: A mixture of 2,5-diphenylthiazole (0.24 g,
1.0 mmol) and NFSI (3.0 mmol) was heated without solvent at 135 °C (oil bath
temp) under N2 for 3 h. Upon cooling, the resulting orange solid was dissolved
in EtOAc, evaporated onto silica gel, and then subjected to flash
chromatography on silica eluting with hexanes to give a pale yellow oil
(0.108 g, 37%) which, after standing overnight, became solid, mp 61–64 °C. IR
(ATR): 3063, 2925, 2850, 1595, 1575, 1449, 1263, 1194, 1162, 1108, 1000, 994,
1. Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737.
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960, 889, 760, 683 cmÀ1 1H NMR (400 MHz, CDCl3): 7.42–7.57 (m, 5H), 7.62–
.
7.68 (m, 1H), 7.69–7.76 (m, 2H), 8.01 (dd, J = 1.6, 0.4 Hz, 2H). 13C NMR
(150 MHz, CDCl3): 111.8–113.9 (ddd, J = 235, 44.6, 27.0 Hz), 127.1 (dd, J = 6.5,
1.5 Hz), 128.6 (s), 129.1 (s), 129.1 (s), 130.3–133.9 (ddd, J = 254, 250, 28.5 Hz),
130.6 (d, J = 24.2 Hz), 130.6 (s), 131.0 (s), 134.4 (s), 175.4 (dd, J = 18.8, 11.3 Hz).
19F NMR (282 MHz, CDCl3, C6F6 internal standard): 31.1–31.2 (dd, J = 9.3,
9.0 Hz), 57.9–58.7 (dd, J = 209, 9.3 Hz), 82.0–82.8 (dd, J = 208, 9.0 Hz). HRMS
(ESI+) calcd for C15H11F3NS: 294.0564; found: 294.0550.
29. For use of selectfluor and accufluor under solvent-free conditions, see: Stavber,
G.; Zupan, M.; Stavber, S. Tetrahedron Lett. 2007, 48, 2671.
12. Heravi, M. R. P. J. Fluorine Chem. 2008, 129, 217.
30. Analytical data for 5c: Mp 102–103 °C (hexanes). IR: 2923, 2851, 1615, 1548,
13. Zupan, M.; Iskra, J.; Stavber, S. Tetrahedron 1996, 52, 11341.
14. (a) O’Neill, P. M.; Storr, R. C.; Park, B. K. Tetrahedron 1998, 54, 4615; (b) Zhang,
Y.; Shibatomi, K.; Yamamoto, H. Synlett 2005, 2837.
15. (a) Baudoux, J.; Salit, A.-F.; Cahard, D.; Plaquevent, J.-C. Tetrahedron Lett. 2002,
43, 6573; (b) Sloop, J. C.; Jackson, J. L.; Schmidt, R. D. Heteroat. Chem. 2009, 20,
341.
16. Lange, K.; Hysell, M.; Druelinger, M. Abstract CHED-562. 213th National
Meeting of the American Chemical Society, Apr, 1997.
17. Fields, S. C.; Lo, W. C.; Brewster, W. K.; Lowe, C. T. Tetrahedron Lett. 2010, 51, 79.
18. Briner, P. H.; Fyfe, M. C. T.; Martin, P.; Murray, P. J.; Naud, F.; Procter, M. J. Org.
Process Res. Dev. 2006, 10, 346.
19. Antipas, A. S.; Blumberg, L. C.; Brissette, W. H.; Brown, M. F.; Casavant, J. M.;
Doty, J. L.; Driscoll, J.; Harris, T. M.; Jones, C. S.; McCurdy, S. P.; McElroy, E.;
Mitton-Fry, M.; Munchhof, M. J.; Reim, D. A.; Reiter, L. A.; Ripp, S. L.; Shavnya,
A.; Smeets, M. I.; Trevena, K. A. Bioorg. Med. Chem. Lett. 2010, 20, 4069.
20. Cohen, F.; Koehler, M. F. T.; Bergeron, P.; Elliott, L. O.; Flygare, J. A.; Franklin, M.
C.; Gazzard, L.; Keteltas, S. F.; Lau, K.; Ly, C. Q.; Tsui, V.; Fairbrother, W. J. Bioorg.
Med. Chem. Lett. 2010, 20, 2229.
21. Campbell, T. F.; Stephens, C. E. J. Fluorine Chem. 2006, 127, 1591.
22. Stephens, C. E.; Blake, J. A. J. Fluorine Chem. 2004, 125, 1939.
23. For a related example of 2,5,5-trifluorination of thiazoles by electrolysis, see:
Riyadh, S. M.; Fuchigami, T. J. Org. Chem. 2002, 67, 9379.
1508, 1407, 1363, 1320, 1289, 1163, 1108, 1065, 1039, 835 cmÀ1 1H NMR
.
(300 MHz, DMSO-d6): 7.83 (s, 4H), 7.87 (d, J = 8.3 Hz, 2H), 8.10 (d, J = 8.2 Hz,
2H). 13C NMR (75 MHz, DMSO-d6): 113.4 (d, J = 26.7 Hz), 123.8 (q, J = 272 Hz),
123.9 (q, J = 272 Hz) 126.2 (s), 126.3 (m, 2C), 127.5 (d, J = 5.2 Hz), 128.5 (q,
J = 38.1 Hz), 130.8 (q, J = 32.2 Hz), 131.9 (d, J = 6.5 Hz), 135.1 (d, J = 1.4 Hz),
157.1 (d, J = 251 Hz), 160.0 (d, J = 19.8 Hz). 19F NMR (282 MHz, DMSO-d6, C6F6
internal standard): 58.7 (s), 101.1 (s, 3F), 101.3 (s, 3F). HRMS (ESI+) calcd for
C
17H9F7NS: 392.0344; found: 392.0349.
31. Good quality crystals of 6b (mp 88–89 °C) were obtained by recrystallization
from hexanes. Crystal data: monoclinic, a = 6.1553(3), b = 9.8572(6),
c = 24.6607(15) Å,
group P2(1)/n, Z = 4, Dcalcd = 1.611 mg/m3, abs coeff = 5.484 mmÀ1
a c
= 90o, b = 93.703(3)o, = 90°. V = 1493.14(15) Å3, space
,
F(000) = 728. Crystallographic data (excluding structure factors) for the
structure in this Letter have been deposited with the Cambridge
Crystallographic Data Centre as Supplementary publication no. CCDC
815178. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 (0)1223 336033 or e-
mail: deposit@ccdc.cam.ac.uk).
32. Santano, J. G.; Grifols, R. L.; Palomera, F. A.; Perarnau, A. P.; Gallego, S. P.;
Girones, D. G.; Iglesias-Serret, D.; Albalate, R. R. WO2012028757, 2012.