Synthesis of 2-(Benzylthio)-4-(trifluoromethyl)thiazole-5-carboxylates Using S -Benzylisothiouronium Halides as Thiol Equivalents

Article abstract of DOI:10.1055/s-0034-1380748

S-Benzylisothiouronium halides are used as shelf-stable, odorless thiol equivalents. The method developed is used to access 2-(benzylthio)-4-(trifluoromethyl)thiazole carboxyl building blocks. Using the latent trifluoromethyl substituent the reactions could be monitored using ¹⁹F NMR spectroscopy.

Full text of DOI:10.1055/s-0034-1380748

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1759–1763
letter
1759
S. M. Hickey et al.
Letter
Synlett
Synthesis of 2-(Benzylthio)-4-(trifluoromethyl)thiazole-5-carbox-
ylates Using S-Benzylisothiouronium Halides as Thiol Equivalents
Shane M. Hickeya
Jonathan M. Whiteb
Frederick M. Pfeffera
odourless, shelf-stable thiol
equivalents!
Trent D. Ashton*a
R
H2N
S
O
O
a Research Centre for Chemistry and Biotechnology,
School of Life and Environmental Sciences, Deakin University,
Waurn Ponds, Victoria, 3216, Australia
t.ashton@deakin.edu.au
b Bio21 Institute, School of Chemistry, University of Melbourne,
Parkville, Victoria, 3010, Australia
X
NH2
S
N
S
N
R
EtO
F3C
EtO
F3C
Br
S
Et3N,
MeCN–PhCF3 (95:5),
MW, 130 °C, 30 min
43–86%
Received: 26.03.2015
Accepted after revision: 17.04.2015
Published online: 21.05.2015
Cl
Cl
O
O
S
S
N
DOI: 10.1055/s-0034-1380748; Art ID: st-2015-d0216-l
EtO
F3C
N
H
SR
SMe
Cl
N
Abstract S-Benzylisothiouronium halides are used as shelf-stable,
odorless thiol equivalents. The method developed is used to access 2-
(benzylthio)-4-(trifluoromethyl)thiazole carboxyl building blocks. Using
the latent trifluoromethyl substituent the reactions could be monitored
using 19F NMR spectroscopy.
F3C
1 R = Et
2 R = Bn
3
O
F3C
O
N
O
S
N
Key words thioether, isothiouronium halide, 19F NMR spectroscopy,
nucleophilic aromatic substitution, thiazole
EtO
NMe
S
F3C
OCH2CF3
4
The 4-(trifluoromethyl)-5-carboxyl-substituted thiazole
ring is a common component in compounds exhibiting an-
tifungal and insecticidal activity.1 However, there are limit-
ed examples in the literature in which the 2-position of
these substituted thiazole rings contains an S-alkylthio-
ether.2 For example, 2-ethylthiothiazole (1, Figure 1)2c and
the succinate dehydrogenase inhibitor, 2-methylthiothi-
azole (3, pI50 = 6.32 μM),1c were synthesized using the re-
spective alkylthiolate reagents. The notoriously pungent
odor and toxicity associated with alkylthiolates is a possible
deterrent for the investigation of thioethers during synthet-
ic campaigns.
Despite the utility of benzyl substituents in medicinal
chemistry, there are no benzylthioethers like compound 2
reported. To the best of our knowledge, the only benzyl-like
compound is sulfone 4 (Figure 1), which was patented as
part of a series of herbicidal compounds.2a In this case the
sulfone was introduced by nucleophilic aromatic substitu-
tion (SNAr) reaction with the corresponding sodium sulfi-
nate.
Figure 1 Examples of thiazoles bearing 2-alkylthioethers; compound 2
is the focus of this study
A method that allows access to simple 2-benzylthiol an-
alogues, such as 2 (Figure 1), in a manner suited to analogue
generation is reported. In addition, this method does not
require the synthesis or handling of malodorous and toxic
benzylthiols. The requisite thiol reagents are generated in
situ by base-mediated decomposition of S-benzylisothiou-
ronium salts. There has been renewed interest in this ap-
proach in recent years in synthesizing symmetrical3 or non-
symmetrical thioethers; through basic decomposition2a,4 or
in copper-5 and palladium-mediated processes.6 Analogous
methodology has also been extended to Michael addition
protocols7 as well as the synthesis of thioesters.8
Herein, the S-benzylisothiouronium halides were gen-
erated from thiourea and the appropriate benzyl halide. A
key practical advantage of this approach is that the number
of commercially available benzyl halides greatly exceeds
the number of benzyl thiols. Furthermore, the isothiouroni-
um halides are indefinitely stable at ambient temperature,
are nonhygroscopic, and have no vapor pressure or odor
that is typically associated with thiol reagents.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1759–1763

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S. M. Hickey et al.
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As illustrated in Scheme 1, the synthesis of isothiouro-
nium halide salts 6a–k was achieved by heating the benzyl
halide with an equimolar amount of thiourea in EtOH at
78 °C. After removal of the solvent, the products were easily
isolated by trituration (Et2O) in excellent yields (89–99%,
Scheme 1; see the Supporting Information for full details).
The reaction time was significantly reduced when the
reaction was heated using microwave irradiation; after two
hours at 100 °C, benzylthioether 2 was obtained in 83%
yield (Table 1, entry 4). A similar result (78% yield) was ob-
tained using EtOH in place of MeCN as the solvent (Table 1,
entry 5). The reaction also worked well at higher tempera-
tures (110–130 °C, Table 1, entries 6–8) with decreasing re-
action times (90–30 min), wherein yields were maintained
within the range of 75 to 82%.
RBnX, EtOH,
2 h, 78 °C
S
X
S
R
Up to this point, the reaction progress was first moni-
tored postreaction by H NMR spectroscopy after removal
H2N
NH2
H2N
NH2
6a–k (see SI)
89–99%
1
5
of the reaction solvent. This approach was necessitated due
to coincidental Rf values for the 2-bromothiazole 8 and
thioether 2, and whilst this is a specific case, an alternative
method of monitoring the substitution reaction was
sought.
Scheme 1 Formation of S-benzylisothiouronium salts
Using Sandmeyer chemistry, 2-bromothiazole
8
(Scheme 2) was synthesized from the 2-amino thiazole 7
which is commercially available or readily synthesized
from ethyl 2-chloro-3-oxo-4,4,4-trifluorobutyrate and
thiourea. The 2-aminothiazole 7 was treated with t-BuONO
(1.5 equiv) in the presence of CuBr2 (0.8 equiv) at 0 °C for
one hour then at 21 °C overnight to afford, after extractive
workup, 8 in 93% yield.
Due to the presence of the 4-trifluoromethyl substitu-
ent on 8, it was possible to monitor the reaction using 19F
NMR spectroscopy. By adding an internal standard (PhCF3)
to the solvent system it is possible to monitor the small, yet
observable, difference in chemical shift (Δδ = 0.05 ppm) be-
tween 8 (δF = –61.88 ppm) and 2 (δF = –61.93 ppm). Using a
mixture of MeCN–PhCF3 (95:5) the standard peak was only
ca. twofold that of the starting material and the reaction
could be monitored by dissolving 1–2 drops of the reaction
mixture into CDCl3 before acquiring the 19F NMR spectrum.
Using the mixed solvent system and heating at 120 °C for 60
minutes, compound 2 was obtained in 83% yield (Table 1,
entry 9) and is comparable to using MeCN (82%, Table 1, en-
try 7). A similar result was obtained when heating at 130 °C
for 30 minutes. Using MeCN–PhCF3, thioether 2 was ob-
tained in 80% (Table 1, entry 10) which compares favorably
to MeCN alone (75%, Table 1, entry 8).
Full characterization of benzylthioether 2 was compli-
cated by coincidental peaks in the 13C NMR spectrum from
C-5 of the thiazole and a C–H of the phenyl ring. Compound
2 was isolated as a clear oil in all instances, however, in one
circumstance the oil solidified on standing to give clear
prisms that were suitable for X-ray structural analysis (Fig-
ure 2). The X-ray crystal structure clearly shows the pres-
ence of the thioether at the 2-position of the thiazole ring.9
t-BuONO, CuBr2,
MeCN,
0–21 °C, 16 h
O
O
S
N
S
N
EtO
F3C
EtO
F3C
NH2
Br
93%
7
8
Scheme 2 Synthesis of 2-bromothiazole
When an equimolar amount of 2-bromothiazole 8, S-
benzylisothiouronium bromide (6a), and Et3N (1:1:1 ratio)
were heated in MeCN (Table 1, entry 1) at 82 °C for 12
hours, it was found that the isothiouronium was consumed
and that there was evidence of the desired benzylarylthio-
1
ether 2 (δH = 4.49 ppm for SCH2Ph) in the crude H NMR
spectrum. An additional singlet was present in the 1H NMR
spectrum at δH = 3.60 ppm, which can be attributed to the
formation of dibenzylsulfide as a byproduct.
In an effort to circumvent this byproduct formation, a
mixture of 8/6a/Et3N (1:2:2) was used (Table 1, entry 2).
The H NMR spectrum of the crude reaction mixture indi-
1
cated that more of the desired product had formed though
some of the bromide 8 still remained. It appeared that the
byproduct formation was occurring at a similar rate as the
desired reaction. Unfortunately, it was not possible to sepa-
rate the bromide 8 from the benzylthioether 2 by conven-
tional chromatographic techniques. As such, the reaction
conditions had to be refined to ensure that starting material
was consistently consumed. Pleasingly, when 8/6a/Et3N in a
1:2:4 ratio was used (Table 1, entry 3), the starting material
was completely consumed within 48 hours (as per 1H NMR
spectrum) and the desired benzylthioether 2 was isolated
in 76% yield after purification by column chromatography.
Figure 2 ORTEP drawing of 2 (CCDC 1055990); thermal ellipsoids are
at the 30% probability level
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S. M. Hickey et al.
Letter
Synlett
Table 1 Optimization of the Benzylthioether Formation from 8a
O
O
6a, Et3N, solvent,
MW, T, t
S
N
S
N
EtO
F3C
EtO
F3C
Br
S
8 δF –61.88 ppm
2 δF –61.93 ppm
Entry
6a (equiv)
Et3N (equiv)
Solvent
Temp (°C)
Time (h)
Yield (%)
1
2
1.0
2.1
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
2.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
MeCN
82b
82b
12
48
48
2
n.d.c
n.d.c
76d
83
MeCN
3
MeCN
82b
4
MeCN
100
100
110
120
130
120
130
5
EtOH
2
78
6
MeCN
1.5
1
79
7
MeCN
82
8
MeCN
0.5
1
75
9
MeCN–PhCF3 (95:5)
MeCN–PhCF3 (95:5)
83
10
0.5
80
a Reactions were performed using 8 (0.50 mmol) in solvent (5 mL).
b Conventional reflux.
c n.d. = not determined: 6a was consumed before 8.
d Bn2S was isolated from this reaction.
6b–j, Et3N,
MeCN–PhCF3 (95:5),
conditions A or B
O
O
Interestingly, the distance between the bivalent oxygen
of the ester and the sulfur atom of the thiazole was found to
be 2.82 Å (sum of van der Waals radius 3.32 Å) and the di-
hedral angle for S–C–C–O was almost coplanar at 6.90°.
These measurements indicate a potential n→σ* interaction
which could be influencing the conformation of the ester
substituent.10
S
N
S
EtO
F3C
EtO
Br
S
R
A: 120 °C, 60 min
B: 130 °C, 30 min
N
F3C
8
9–17
F
F
With confirmation of the successful reaction and estab-
lishment of a method, substituted benzyl derivatives were
investigated (Scheme 3). Using the aforementioned proto-
col, benzylthioethers bearing 3-fluoro (9) and 4-fluoro sub-
stituents (10) were isolated in yields of 81 and 77%, respec-
tively. Similarly, the 4-bromo and 4-trifluoromethyl ana-
logues (1211 and 13) were obtained in 84 and 77%,
respectively. When the 3,4-dichloro-substituted salt was
used, compound 14 was isolated in 80% yield. The 2,5-diflu-
orobenzylthioether 11 was obtained in a slightly reduced
yield of 72%. A lower yield (69%) was also obtained with the
2-methyl derivative 15, suggesting that a substituent in the
2-position of the phenyl ring may encumber the reaction
slightly. When the 3-phenyl substituent was present the re-
action also proceeded smoothly to give the biphenyl 16 in
77% yield. When a 3-methoxy substituent was present, the
corresponding thioether 17 was isolated in a lower yield
(44%) than previous examples. This poorer result is at-
tributed to complications in the isolation of 17 that are due
to the formation of bis(3-methoxybenzyl)sulfide, which ex-
hibited an Rf value similar to 17.
F
F
9 81% (A)
12 84% (A)
15 69% (A)
10 77% (B)
11 72% (B)
Br
CF3
Cl
Cl
13 77% (A)
14 80% (B)
17 44% (A)
Ph
OMe
16 77% (B)
Scheme 3 Synthesis of substituted benzylthioether thiazoles
Ester hydrolysis of 2 and 12 was achieved using LiOH·H2O
(5.0 equiv) in EtOH at ambient temperature for five hours
(Scheme 4). Carboxylic acids 18 and 19 were obtained in
high yields (97 and 98%, respectively) using an extractive
workup. As high conversions could be achieved during the
SNAr step, which can be monitored by 19F NMR spectrosco-
py, as well as excellent yields for hydrolysis, we reasoned
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1759–1763

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S. M. Hickey et al.
Letter
Synlett
that we could telescope both reaction steps. This has the
advantage of obtaining the carboxylic acid handle and
avoiding chromatographic purification.
cess to include the hydrolysis of the ethyl ester. It is likely
that this approach can be exploited for other heterocyclic
systems as a means of generating benzylthioether ana-
logues.
O
R
S
EtO
Acknowledgment
S
LiOH•H2O,
N
F3C
EtOH,
S.M.H., F.M.P., and T.D.A. thank the ARC (LP100100087) and the Stra-
tegic Research Centre for Chemistry and Biotechnology (Deakin Uni-
versity) for financial support and a top-up scholarship for S.M.H. The
authors would also like to thank the ARC for funding Deakin Universi-
ty’s Nuclear Magnetic Resonance Facility through LIEF grant
LE110100141, as well as for additional equipment support related to
this project (LE120100213).
21 °C, 5 h
2
R = H
12 R = Br
O
R
S
N
HO
F3C
S
18 R = H 97%
19 R = Br 98%
Supporting Information
Scheme 4 Carboxylic acid synthesis
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380748.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
The microwave reaction of 3-methoxybenzylisothiouro-
nium chloride (6j) and 2-bromothiazole 8 was repeated.
The solvent was removed from the reaction mixture and
the crude material was reconstituted in EtOH and treated
with LiOH·H2O for five hours (Scheme 5). The carboxylic
acid was isolated in 43% yield after extractive workup,
which was comparable to the isolated ester with an extra
step and without isolation of the intermediate. The analo-
gous procedure was then performed using 4-methoxyben-
zylisothiouronium chloride (6k) to give the corresponding
carboxylic acid 21 in 76% yield.
References and Notes
(1) (a) Phillips, W. G.; Rejda-Heath, J. M. Pestic. Sci. 1993, 38, 1.
(b) Liu, C.-L.; Li, Z.-M.; Zhong, B. J. Fluorine Chem. 2004, 125,
1287. (c) Liu, C.-L.; Li, M.; Chi, H.-W.; Hou, C.-Q.; Li, Z.-M. J. Fluo-
rine Chem. 2006, 127, 796.
(2) (a) Elliott, A. C.; Hughes, P.; Plant, A. WO 2006/123088A2, 2006.
(b) Cage, P.; Furber, M.; Luckhurst, C.; Perry, M.; Springthorpe,
B. WO 2007/102767A1, 2007. (c) Lee, L. F.; Schleppnik, F. M.;
Howe, R. K. J. Heterocycl. Chem. 1985, 22, 1621. (d) Koshio, H.;
Tsukamoto, I.; Kakefuda, A.; Akamatsu, S.; Saitoh, C. WO
2004/096775A1, 2004.
As EtOH could be used as the solvent for both the SNAr
(Table 1, entry 5) and the hydrolysis reactions (Scheme 4),
we envisaged that the use of EtOH–PhCF3 (95:5) as the sol-
vent system would facilitate a one-pot process. After the
completion of the thioether formation using 6k and 8 at
130 °C for 30 minutes (Scheme 5), LiOH·H2O was added to
the flask and stirring was continued for 6.5 hours. The car-
boxylic acid was isolated from an extractive workup in 78%
yield in a one-pot procedure.
Through the use of odorless, shelf-stable S-benzyliso-
thiouronium salts as masked thiol reagents, a methodology
has been developed for the synthesis of 2-(benzylthio)-4-
(trifluoromethyl)-1,3-thiazole-5-carboxyl building blocks.
The method described is exemplified by a series of ana-
logues that are synthesized in typically high yields (ca.
80%). The method is extendable to a two-step, one-pot pro-
(3) Lu, G.-P.; Cai, C. Green Chem. Lett. Rev. 2012, 5, 481.
(4) (a) Bertenshaw, S. R.; Talley, J. J.; Rogier, D. J.; Graneto, M. J.;
Koboldt, C. M.; Zhang, Y. Bioorg. Med. Chem. Lett. 1996, 6, 2827.
(b) Eccles, K. S.; Elcoate, C. J.; Lawrence, S. E.; Maguire, A. R.
ARKIVOC 2010, (ix), 216. (c) Lu, G.-P.; Cai, C. RSC Adv. 2014, 4,
59990.
(5) (a) Mondal, J.; Modak, A.; Dutta, A.; Basu, S.; Jha, S. N.;
Bhattacharyya, D.; Bhaumik, A. Chem. Commun. 2012, 48, 8000.
(b) Mondal, J.; Borah, P.; Modak, A.; Zhao, Y.; Bhaumik, A. Org.
Process Res. Dev. 2014, 18, 257.
(6) (a) Wang, L.; Zhou, W.-Y.; Chen, S.-C.; He, M.-Y.; Chen, Q. Adv.
Synth. Catal. 2012, 354, 839. (b) Feng, J.; Lv, M.; Lu, G.; Cai, C. Eur.
J. Org. Chem. 2014, 5312.
(7) (a) Azizi, N.; Yadollahy, Z.; Rahimzadeh-Oskooee, A. Tetrahedron
Lett. 2014, 55, 1722. (b) Firouzabadi, H.; Iranpoor, N.; Abbasi, M.
Adv. Synth. Catal. 2009, 351, 755. (c) Firouzabadi, H.; Iranpoor,
N.; Abbasi, M. Tetrahedron 2009, 65, 5293.
(8) Lu, G.-P.; Cai, C. Adv. Synth. Catal. 2013, 355, 1271.
6j or k, Et3N,
MeCN–PhCF3 (95:5), MW,
130 °C, 30 min
i) 6k, Et3N,
EtOH–PhCF3 (95:5)
MW, 130 °C, 30 min
O
O
O
OMe
S
N
S
N
S
N
R
HO
F3C
EtO
F3C
HO
F3C
S
Br
S
LiOH•H2O, EtOH,
ii) LiOH•H2O,
21 °C, 6.5 h
21 °C, 5 h
20 R = 3-OMe
21 R = 4-OMe
43%
76%
8
21 78%
Scheme 5 One-pot sequential nucleophilic aromatic substitution and hydrolysis.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1759–1763

1763
S. M. Hickey et al.
Letter
Synlett
(9) The crystal structure for compound 2 has been deposited at the
Cambridge Crystallographic Data Centre. CCDC 1055009 con-
tains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(10) (a) Burling, F. T.; Goldstein, B. M. J. Am. Chem. Soc. 1992, 114,
2313. (b) Nagao, Y.; Hirata, T.; Goto, S.; Sano, S.; Kakehi, A.;
Iizuka, K.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 3104.
(c) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529. (d) Reid, R. C.;
Yau, M.-K.; Singh, R.; Lim, J.; Fairlie, D. P. J. Am. Chem. Soc. 2014,
136, 11914. (e) Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.;
Pennington, L. D.; Meanwell, N. A. J. Med. Chem. 2015, 58, in
press; DOI: 10.1021/jm501853m.
(11) Example Procedure: Ethyl 2-[(4-Bromobenzyl)thio]-4-(tri-
fluoromethyl)thiazole-5-carboxylate (12)
A mixture of 2-bromothiazole 8 (152 mg, 0.50 mmol), Et3N
(0.28 mL, 2.0 mmol, 4.0 equiv), and 6e (326 mg, 1.00 mmol, 2.0
equiv) in MeCN–PhCF3 (5 mL, Table 1) was heated at 120 °C for
60 min using MW irradiation. The reaction mixture was diluted
using MeOH and concentrated onto SiO2 and then purified by
column chromatography using CH2Cl2–petroleum spirits (1:3 to
1
1:1) to give 12 (178 mg, 84%) as a clear oil. H NMR (500 MHz,
CDCl3): δ = 7.47–7.44 (m, 2 H), 7.31–7.28 (m, 2 H), 4.43 (s, 2 H),
4.35 (q, J = 7.1 Hz, 2 H), 1.36 (t, J = 7.1 Hz, 3 H). 13C NMR (125
2
MHz, CDCl3): δ = 169.2, 158.5, 145.7 (q, JCF = 37.9 Hz), 134.6,
1
131.8, 130.9, 129.3, 122.0, 119.5 (q, JCF = 271.1 Hz), 62.6, 37.2,
13.9. 19F NMR (470 MHz, CDCl3): δ = –61.93 (s). ESI-HRMS: m/z
calcd for
425.9446.
C +
14H1179BrF3NO2S2 [M H+]: 425.9439; found:
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1759–1763