Nuclear fluorination of 2,4-diarylthiazoles with Accufluor

Article abstract of DOI:10.1016/j.jfluchem.2006.08.007

A series of 2,4-diphenylthiazole derivatives were synthesized and directly fluorinated at the 5-position by reaction with the N-F fluorinating reagent Accufluor. Although fluorination occurred selectively at the thiazole ring, it was always inc

Full text of DOI:10.1016/j.jfluchem.2006.08.007

Journal of Fluorine Chemistry 127 (2006) 1591–1594
www.elsevier.com/locate/fluor
Nuclear fluorination of 2,4-diarylthiazoles with Accufluor1
*
Timmeda F. Campbell, Chad E. Stephens
Department of Chemistry, Georgia State University, Atlanta, GA 30303, United States
Received 27 July 2006; received in revised form 30 August 2006; accepted 30 August 2006
Available online 3 September 2006
Abstract
A series of 2,4-diphenylthiazole derivatives were synthesized and directly fluorinated at the 5-position by reaction with the N–F fluorinating
reagent Accufluor1. Although fluorination occurred selectively at the thiazole ring, it was always incomplete and thus yields for the novel
fluorinated products were low to moderate (19–43%) following purification to remove starting material. Nonetheless, the target compounds were
obtained in a convenient and straightforward manner. Selectfluor1 was not as effective as Accufluor1 as it gave a trace amount of the 5-
chlorothiazole that was difficult to remove by chromatography.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Thiazole; Fluorination; Accufluor1; Selectfluor1; Substituent effects
1. Introduction
In addition, there has been a single report on the direct,
electrochemical fluorination of some thiazoles using an HF
adduct [4]. Considering the limited work with thiazoles, and
that direct fluorination of certain heterocycles using either
fluorine [16] or N–F reagents [15,17,18] is known to be
difficult, or to lead to unexpected addition products [19], we
have become interested in studying this ring system. Herein, we
report the results of our initial work in this area, which has
shown that 2,4-diarylthiazoles can be directly and selectively
fluorinated at the 5-position of the thiazole, albeit in modest
yield, by reaction with the N–F reagent Accufluor1.
Fluorinated compounds have become progressively incorpo-
rated into drug-discovery research as an approach to improving
the physiochemical properties of drug candidates [1,2]. The
synthesis and biological evaluation of fluorinated compounds is
also widespread in agrochemical research [3]. Thiazoles, on the
other hand, are known to possess a wide range of biological
activities, including, among others [4], antibacterial [5], antiviral
[6], anti-cancer [7], anti-diabetic [8], anti-obesity [9] and anti-
psychotic [10] properties. Considering the diverse biological
activityofthiazoles, andoffluorinatedcompoundsingeneral, the
development of methods for the direct fluorination of this ring
system should be useful in drug development.
2. Materials
To date, most fluorinated thiazoles have been prepared
indirectly using ring forming reactions [11,12], functional
group conversions [13], or halogen exchange reactions [13,14].
In contrast, preparations employing direct, electrophilic
fluorination, as often preferred in analogue preparation, are
quite rare. For example, the only report we have been able to
find involving thiazoles is the very recent fluorination of the
highly activated 2-acetamidothiazole using Selectfluor1 [15].
The N–F fluorinating reagents tested in this study (all
commercial) are shown in Fig. 1. As shown in Scheme 1, the
starting 2,4 diarylthiazoles were readily prepared by reaction of
variously substituted phenacyl bromides with thiobenzamide in
refluxing EtOH (i.e., the Hantzsch thiazole synthesis) [20].
3. Results and discussion
Our first attempts at fluorination of our 2,4-diarylthiazoles
involved reaction of the parent thiazole 7a with Selectfluor1
[21,22] (1.0–1.5 equiv.) in acetonitrile at about 50–60 8C
(Scheme 2). After about 2–3 h, TLC showed significant
formation of the 5-fluorothiazole, a trace byproduct, and a
* Corresponding author at: Department of Chemistry/Physics, Augusta State
University, Augusta, GA 30904, United States. Tel.: +1 706 667 4995;
fax: +1 706 667 4519.
E-mail address: cstephe7@aug.edu (C.E. Stephens).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.08.007

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T.F. Campbell, C.E. Stephens / Journal of Fluorine Chemistry 127 (2006) 1591–1594
Fig. 1. Structures of N–F reagents tested.
Scheme 1.
Scheme 2.
considerable amount of starting material. Continued heating
after this point did not lead to any further reaction. The use of a
larger excess of Selectfluor1 did not help drive the reaction, nor
did a change in solvent to nitromethane. Starch paper confirmed
that the Selectfluor1 was being consumed by some mechanism,
perhaps involving attack by the thiazole nitrogen [17], although
no other product could be observed. A similar incomplete
conversion upon reaction of 2-acetamidothiazole with Select-
fluor1 was noted by others [15]. Despite our incomplete
reaction, we were able to isolate 5-fluorothiazole (8a) in 23%
yield following chromatography, with the structure being
reaction of this reagent that has apparently not been described
in the literature before.
In an attempt to improve the fluorination reaction and
eliminate the formation of the chlorinated byproduct, other N–F
reagents were examined. Compared to Selectfluor1, only a
small amount of fluorination occurred when parent thiazole
(7a) was reacted under similar conditions with N,N-difluoro-
2,2-bipyridinium bis(tetrafluoroborate) (5) or with 1-fluoro-
2,6-dichloropyridinium triflate (6). On the other hand, a similar
to larger amount of fluorination occurred when Accufluor1 [1-
fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetra-
fluoroborate)] [24] (4) was used, although the reaction still
did not proceed to completion. However, considering that no
chlorinated byproduct was formed, nor would it be expected
using this reagent, chromatography to remove the residual
starting material was simplified and a 43% yield of the 5-fluoro
adduct 8a was achieved (Scheme 3).
With this respectable outcome in hand, fluorination of the
other thiazoles in the series was next examined. Using
Accufluor1, the yield for 8b was improved to 33% yield,
and the 4-methyl analogue 8c was obtained in 40% yield. The
reaction with the activated 4-methoxy analogue 7d was found
to occur at room-temperature, with the Accufluor1 being
consumed after just 2 h (starch paper test). Purification gave
1
confirmed by GC–MS, H, 13C, 19F NMR, IR, and elemental
analysis (vida infra).
A similar reaction of 4-bromo thiazole (7b) with Select-
fluor1 gave fluorinated thiazole (8b) in 8.5% isolated yield,
with the lower yield largely due to the tedious chromatographic
separation from the trace byproduct (recrystallization was
found to be an insufficient alternative). The trace byproduct was
also isolated from this experiment and was identified using GC-
MS and 1H NMR as 5-chlorothiazole (9b). This assignment was
confirmed by HRMS, and by GC–MS comparison with an
authentic sample, which we prepared by reaction of thiazole
(7b) with N-chlorosuccinimide [23]. Thus, the chlorine of
Selectfluor1 was being introduced into the thiazole, a side

T.F. Campbell, C.E. Stephens / Journal of Fluorine Chemistry 127 (2006) 1591–1594
1593
data. Confirmation that fluorination occurred on the thiazole
nucleus is based on the fluorine signal in the 19F NMR being a
singlet, and by the absence of the singlet for the original 5-H
1
proton in the H NMR. The relatively large C–F coupling
constants (ꢀ300 Hz) observed for the fluorine bearing carbon
in the 13C NMR of the products is further evidence that the
fluorine is not located on a phenyl ring. Finally, the presence of
a peak for M+ À 103 (M+ À PhCN) in the mass spectrum of
each product indicates that fluorination did not occur on the 2-
phenyl ring.
Scheme 3.
34% yield of methoxy compound 8d. Lastly, the reaction of the
4-nitro thiazole (7e) with Accufluor1 (at 60 8C) did not proceed
as much as did the other substrates, and fluoro adduct 8e was
obtained in only 19% yield. Nonetheless, this was satisfying as
the strong electron withdrawing group could have inhibited the
reaction altogether [19].
4. Conclusion
In conclusion, we have described the synthesis and
characterization of a series of 2,4-diaryl-5-fluorothiazoles via
direct, electrophilic fluorination with Accufluor1. Fluorination
of this triaryl system occurred selectively at the 5-position of
the thiazole; however, as the reaction could not be driven to
completion, the yields were low to moderate (19–43%).
Nonetheless, as the compounds can be readily purified by
Physical and analytical data for the 5-fluorothiazoles
prepared are shown in Tables 1 and 2. Purity and formula
were confirmed by GC–MS, combustion analysis, and NMR
Table 1
Yield, mp, combustion analysis and mass spectral data for 5-fluorothiazoles (8a–e)
Product
R
% yield
mp (8C)
Formula (MW)
Combustion analysis calculated and found
m/z
8a
8b
H
43
33
84–85
C15H10NSF (255.32)
C15H9BrFNS (334.21)
C: 70.57, H: 3.95, N: 5.49; C: 70.81, H: 3.99, N: 5.42
C: 53.91, H: 2.71, N: 4.19; C: 53.89, H: 2.87, N: 4.12
255 (M+)
333 (M+),
335 (M+)
269 (M+)
285 (M+)
300 (M+)
Br
114–115
8c
8d
8e
CH3
40
34
19
81–83
62–63
C16H12NSF (269.34)
C16H12NOSF (285.34)
C15H9N2O2SF (300.31)
C: 71.35, H: 4.49, N: 5.20; C: 71.68, H: 4.77, N: 4.92
C: 67.35, H: 4.24, N: 4.91; C: 67.18, H: 4.30, N: 4.88
C: 59.99, H: 3.02, N: 9.33; C: 59.75, H: 2.93, N: 9.19
OCH3
NO2
140–141
Table 2
IR, 1H, 13C, and 19F NMR data for 5-fluorothiazoles (8a–e)
Product
IR (KBr) (cmÀ1
)
1H NMR (DMSO-d6)
13C NMR (DMSO-d6)
19F NMR (DMSO-d6)
À147.0 (s)
8a
3086, 3062, 3026, 1556, 1490, 1351,
1305, 1198, 970, 759, 706 690, 661
7.38–7.43 (m, 1H), 7.49–7.54
(m, 5H), 7.90–7.93 (m, 4H)
156.7 (d, J = 302 Hz), 154.8 (d, J = 12 Hz),
135 (d, J = 4.6 Hz), 132.6 (s), 131.1
(d, J = 5.7 Hz), 130.7 (s), 129.3 (s),
129.0 (s), 128.4 (s), 126.6 (d,
J = 5.7 Hz), 125.7 (d, J = 1.1 Hz)
157.2 (d, J = 303 Hz), 155.2 (d,
8b
8c
3057, 3021, 1551, 1484, 1338, 1297,
1196, 1076, 827, 758, 689, 657
7.52–7.54 (m, 3H), 7.73
(d, J = 8.4 Hz, 2H), 7.87
(d, J = 8.4 Hz, 2H),
À145.5 (s)
À147.8 (s)
J = 9.8 Hz), 134.0 (d, J = 4.6 Hz), 132.5 (s),
132.0 (s), 130.8 (s), 130.3 (d, J = 5.7 Hz),
129.4 (s), 128.5 (d, J = 5.8 Hz),
7.88–7.95 (m, 2H)
125.7 (s), 121.6 (d, J = 2.55 Hz)
3063, 3029, 2923, 2857, 1558,
1502, 1477, 1339, 1303, 1190, 975,
815, 756, 687, 661, 490
2.34 (3H), 7.31
156.2 (d, J = 302 Hz), 154.7
(d, J = 8.1 Hz, 2H), 7.50–7.52
(m, 3H), 7.79 (d,
(d, J = 9.8 Hz), 138.0 (d, J = 1.1 Hz),
135.2 (d. J = 4.6 Hz), 132.7 (s),
J = 8.1 Hz, 2H),
130.7 (s), 129.5 (d, J = 16.6 Hz), 128.5
(d, J = 5.2 Hz), 126.5 (d, J = 5.7 Hz),
125.7 (d, J = 1.2 Hz), 20.9 (s)
7.90–7.92 (m, 2H)
8d
8e
3076, 3040, 2998, 2957, 2835,
1559, 1501, 1466, 1250, 1031,
835, 767, 696 668
3.81 (3H), 7.07 (d,
159.2 (d, J = 1.2 Hz), 155.3
À149.3 (s)
À141.3 (s)
J = 8.7 Hz, 2H),
(d, J = 300 Hz), 154.5 (d, J = 9.8 Hz),
135.0 (d, J = 4.6 Hz), 132.7 (s), 130.6 (s),
129.3 (s), 128.0 (d, J = 5.2 Hz), 125.6 (s),
123.8 (d, J = 5.7 Hz), 114.4 (s), 55.2 (s)
159.6 (d, J = 307 Hz), 156.5 (d, J = 9.15 Hz),
146.8 (s), 137.3 (d, J = 5.7 Hz), 133.3
(d, J = 3.3 Hz), 132.5 (s), 131.3 (s), 129.6 (s),
127.8 (d, J = 6.8 Hz), 126.1 (s), 124.6 (s)
7.50–7.53 (m, 3H), 7.85 (d,
J = 8.7 Hz, 2H), 7.86–7.93
(m, 2H)
3060, 1600, 1517, 1487, 1343,
859, 847, 756, 686
7.51–7.54 (m, 3H), 7.90–7.93
(m, 2H), 8.14 (d, J = 8.7 Hz,
2H), 8.33 (d, J = 8.4 Hz, 2H)

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T.F. Campbell, C.E. Stephens / Journal of Fluorine Chemistry 127 (2006) 1591–1594
chromatography, this represents a convenient method for
preparation of these fluorinated derivatives. Finally, Accu-
fluor1 was found to be superior to Selectfluor1 for fluorination
of these compounds as the latter gave a trace amount of the 5-
chloro adduct that was difficult to remove by chromatography.
NMR data of 9b were also identical to that of an authentic
sample [23].
Acknowledgements
Funding from the Department of Chemistry, Georgia State
University is gratefully acknowledged. Selectfluor1 was a
generous gift from Air Products and Chemicals, Inc.
5. Experimental
Accufluor1 (50% on alumina) was purchased from
SynQuest Laboratories, Inc. and Selectfluor1 was obtained
as a gift from Air Products and Chemicals, Inc. Acetonitrile was
distilled from calcium hydride. Selecto silica gel (230–
400 mesh) was used for column chromatography. All NMR
spectra were recorded on a Varian Unity +300 instrument at
ambient temperature. Chemical shifts for 19F-NMR were
measured from hexafluorobenzene as internal standard and
converted to the d-scale with CFCl3 as reference by the
conversion relation d(CFCl3) = d(C6F6) À 162.9 ppm [19].
GC–MS data were obtained on a Shimadzu GC-17A/QP-
5000 instrument operating in EI mode (70 eV). Other details
are as previously described [19].
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1
(MH+): 349.9406. Observed: 349.9394. The GC–MS and H