Synthesis of 5-Phenylthiazolamines by Using Thiourea as an α-Bromination Shuttle

Article abstract of DOI:10.1002/ejoc.201601410

A straightforward synthesis of 5-phenylthiazolamines by coupling thiourea with phenylacetones, phenylacetophenones, and β-tetralone has been developed. Thiourea acts as a substrate and an α-bromination shuttle by transferring a Br atom from CBrCl₃

Full text of DOI:10.1002/ejoc.201601410

A Journal of
Accepted Article
Title: Synthesis of 5-Phenylthiazolamines Using Thiourea as an ꢀα-
Bromination Shuttle
Authors: Irwan Iskandar Roslan, Kian-Hong Ng, Gaik-Khuan Chuah,
and Stephan Jaenicke
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601410
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Synthesis of 5-Phenylthiazolamines Using Thiourea as an -
Bromination Shuttle
Irwan Iskandar Roslan,[a] Kian-Hong Ng,[a] Gaik-Khuan Chuah*[a] and Stephan Jaenicke*[a]
Abstract: A straightforward synthesis of 5-phenylthiazolamines via
coupling of thiourea with phenylacetones, phenylacetophenones and
-tetralone has been developed. Thiourea acts as a substrate and
an -bromination shuttle, transferring Br from the brominating
reagent, CBrCl3, to the -carbon of the carbonyl moiety before
triggerring a series of steps to form the final product. Isolated yields
of 80 to 95 % were obtained. Key features of this protocol includes
the minimal use of reagents (substrates, CBrCl3 and CsHCO3 as
base), short reaction times under mild conditions (2-3 h at 80 C)
and ease of scale-up to gram quantities.
Introduction
The thiazolamine moiety is an important structural motif that is
present in many natural products, pharmaceuticals, and
synthetic intermediates.[1] Some of these compounds possess
medicinal and biological properties including antiHIV, anticancer,
Figure 1. Representative biologically active thiazolamines.
antimicrobial and antituberculosis activity (Figure 1).[2] In addition,
thiazolamines have also found use in areas such as dyes, films
and biophysical binding assays.[3] Due to the diverse properties
and applications of thiazolamines, it is of interest to develop
reliable and efficient protocols to construct these structural
motifs. Over the years, various methods were reported in the
literature, such as coupling of thiocyanates with vinyl azides[4] or
oxime acetates,[5] three-component reactions involving
thiocyanates, α-bromoketones and amines[6] and coupling of
isothiocyanates amidines/guanidines and halomethylenes.[7]
Nevertheless, the most commonly employed route is still the
Hantzsch-type condensation of 2-bromoacetophenones with
thioureas, forming 4-phenyl-thiazolamines.[8] The bromine at the
-carbon is necessary as a leaving group as no thiazolamine
product can be formed without it. The -bromoacetophenones
have to be presynthesized, although in-situ -halogenation of
acetophenones, 1,3 dicarbonyl compounds and styrenes has
since
been
reported.[9],[10]
N-bromosuccinimide,
N-
iodosuccinimide, NaICl2, I2 or hypervalent iodine reagents are
typically employed as the halogen source. Many of these
reagents are highly exothermic or reactive which makes them
difficult to handle and poses safety concerns when the reactions
are to be carried out on a large scale.
Scheme 1. Comparison of our previous and current work on the -Br shuttle,
including the reaction scheme for the latter.
[a]
Department of Chemistry, National University of Singapore, 3
Science Drive 3, Singapore 117543.
*E-mail: chmsj@nus.edu.sg; chmcgk@nus.edu.sg
http://www.chemistry.nus.edu.sg/people/academic_staff/jaenicke.htm;
http://www.chemistry.nus.edu.sg/people/academic_staff/chuahgk.htm
Instead of the common halogenation agents, we recently
reported the use of CBrCl3 as a convenient and safe bromine
source.[11] Together with 2-aminopyridine which serves a dual
role as a substrate and an -bromination shuttle, bromine is
transferred from CBrCl3 to the -carbon of its coupling partner,
Supporting information for this article is available on the WWW
under http://dx.doi.org/xxxx
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initiating a cascade reaction to form imidazo[1,2-a]pyridine
(Scheme 1). The coupling of various 2-aminopyridines with
dielectrophiles including 1,3-dicarbonyls, 1,3-cyclohexandione,
phenylacetones, phenylacetophenones, and β-tetralone was
successfully applied to give high yields of imidazo[1,2-
a]pyridines under mild conditions. This reaction was done in
one-pot without the need for transition metal catalysts and
stoichiometric amounts of oxidants.
Having shown the versatility of this -bromination shuttle
system to various dielectrophiles, we were interested in whether
thiourea could emulate the dual role played by 2-aminopyridine.
Replacing the sp2 N atom of the pyridine ring with the S atom of
the thioketone moiety would allow access to 5-
Table 1. Optimization parameters for the synthesis of phenylthiazolamine 3a[a]
Entry
1
Solvent
MeCN
Base
-
Yield of 3a (%)[b,c]
0
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
DCE
NaHCO3
KHCO3
16
2
78 (70)
95 (92)
57(39)
3
CsHCO3
K2CO3
4
phenylthiazolamines
instead
of
the
ubiquitous
4-
5
phenylthiazolamines.[9] Herein, we would like to report an
efficient and rapid method to access phenylthiazolamines from
the coupling of thiourea and its derivatives with phenylacetones,
phenylacetophenones and -tetralone (Scheme 1). To the best
of our knowledge, this is the first protocol for the synthesis of 5-
phenylthiazolamines that proceeds via in-situ -bromination. It
eliminates the need to employ -brominated derivatives, which
need to be presynthesized.
[d]
Cs2CO3
CsHCO3
CsHCO3
CsHCO3
CsHCO3
CsHCO3
CsHCO3
CsHCO3
CsHCO3
-
6
0
7
0
8
ethanol
dioxane
DMF
0
9
trace
96 (92)
95 (91)
94 (92)
67 (55)
10
11
12[e]
13[f]
14[g]
MeCN
MeCN
MeCN
Results and Discussion
[a] Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol) and base (1.1 mmol) in
3 mL of 1:14 (v/v) CBrCl3/solvent mixture (2.0 equiv wrt 1a) at 80 °C for 2 h.
[b] Yield (from GC) with respect to 1a. [c] Isolated yields in parenthesis.
[d] Reaction was very messy with lots of side products formed. [e] 1.25 equiv
of 2a. [f] 1.0 equiv of 2a. [g] 1.0 equiv of CBrCl3.
For the initial study, various bases were tested for the reaction
system comprising phenylacetone 1a (1 mmol) and thiourea 2a
(1.5 mmol) in a mixed solvent system of CBrCl3/acetonitrile (1:14
v/v) at 80 C (Table 1). Without a base, the desired product 3a
was not formed. The yield of the product increased in the order
NaHCO3 < KHCO3 < CsHCO3 and 92 % isolated yield was
obtained after 2 h (Table 1, entries 2 - 4). The stronger base,
K2CO3, was less suitable for the reaction with only 39 % isolated
yield of 3a while the reaction with Cs2CO3 gave several
unidentified side products (Table 1, entries 5 & 6).
Next, various solvents were tested at 80 °C. The reaction
was very sensitive to the type of solvent used. No reaction
occurred in non polar and polar protic solvents. Only polar
aprotic solvents such as DMF and MeCN were suitable (Table 1,
entries 4, 7-11). With almost identical yields when employing
DMF and MeCN as solvent, the latter was chosen due to its
lower boiling point. It was satisfying that the amount of thiourea
2a could be reduced to one equiv without a significant drop in
yield (Table 1, entries 12 & 13). This sharply contrasts with the
significant drop in yield when the reaction was conducted with
one equiv of CBrCl3 (Table 1, entry 14). Thus, the optimized
conditions employed for subsequent reactions were 1 mmol of
phenylacetone derivative, 1 mmol of thiourea 2a and 1.1 equiv
of CsHCO3 in 3 mL of 1:14 (v/v) CBrCl3/MeCN solvent mixture at
80 °C for 2 h.
bromo substituents at the para-position were well tolerated with
good yields (Table 2, 3f - 3h). It was gratifying that the “spicy
pentanone”, 4-methyl-1-phenyl-2-pentanone, used in food and
fragrances and -tetralone were also suitable coupling partners
with thiourea, forming 3i and 3j with 89 and 80 % yield,
respectively.
Six different phenylacetophenones were tested for their
suitability under this reaction protocol. Substrates with both
electron donating and electron withdrawing groups, including
methyl, methoxy, fluoro, chloro and bromo substituent at either
of the two phenyl moieties were all well tolerated and proceeded
with good to excellent yields (Table 2, 3k - 3p’).
Next, screening of various N-substituted thioureas and their
derivatives as coupling partners for 4-methoxyphenylacetone
and phenylacetophenone was carried out (Table 3). Both N-
methylthiourea and N-phenylthiourea were suitable coupling
partners
with
4-methoxyphenylacetone
and
phenylacetophenone proceeding with good to excellent yields
(Table 3, 3q - 3t). Gratifyingly, even N-acetylthiourea, a
substrate with an -carbon, was well tolerated under the
optimized conditions and coupled with 4-methoxyphenylacetone
and phenylacetophenone to form 3u and 3v with 85 % and 89 %
yields, respectively. These results show that the -carbon of 4-
methoxyphenylacetone and phenylacetophenone was more
Various phenylacetones were screened for their suitability
under the optimized conditions (Table 2). Phenylacetones with
methoxy substituent at the ortho-, meta- and para-position
proceeded smoothly (Table 2, 3b - 3e). Even ethyl, chloro and
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Table 2. Scope of reaction (phenylacetones, phenylacetophenones and -
Table 3. Scope of reaction (N-substituted thioureas, urea and selenourea).[a]
tetralone).[a]
[a] Reaction conditions: 1 (1.0 mmol), 2 (1.0 equiv) and CsHCO3 (1.1 equiv) in
3 mL of 1:14 (v/v) CBrCl3/MeCN mixture at 80 °C for 2 h. Percentage isolated
yields. [b] Additional experiments using DMF instead of MeCN and longer
reaction times of 24 h also produced traces of products or [c] no reaction.
group[10a] where both thiourea and selenourea coupled to -
ketoesters to form the thi/selen-azolamine products.
The reaction is proposed to follow a mechanism similar to
that of the 2-aminopyridine/CBrCl3 system (Figure 2). The
reaction begins with the initial bromination of thiourea 2a via a
radical chain mechanism to form the N-brominated intermediate
A.[12] An addition reaction of intermediate A with the enol form of
phenylacetone 1a forms the bromo-hemiaminal intermediate
B.[13] Other than a substrate, thiourea 2a doubles up as an -
bromination shuttle, transferring Br from CBrCl3 to 1a, releasing
CHCl3, which was detected via in-situ NMR.[11b]. Dehydration of
B forms the imine intermediate C. The S atom then attacks the
-carbon and an intramolecular cyclization ensues, forming the
ionic salt D. Deprotonation by CsHCO3 affords the desired
product along with CO2 and CsBr.
[a] Reaction conditions: 1 (1.0 mmol), 2a (1.0 equiv) and CsHCO3 (1.1 equiv)
in 3 mL of 1:14 (v/v) CBrCl3/MeCN mixture at 80 °C for 2 h. Percentage
isolated yields.
susceptible to in-situ -bromination than the acetyl moiety of N-
acetylthiourea. Unfortunately, urea was
a rather sluggish
substrate under the reaction protocol and only traces of 3w and
3x were seen. This result is expected as the O atom, being less
nucleophilic than S, makes urea a much weaker substrate under
this protocol. Interestingly, selenourea was unreactive and did
A scaled-up synthesis of 3t was conducted to demonstrate
the practical application of this protocol (Scheme 2). 15 mmol of
phenylacetophenone and N-phenylthiourea were reacted
not
couple
to
either
4-methoxyphenylacetone
or
phenylacetophenone. This is in contrast to the findings by Rao’s
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the synthesis of 3t gave an isolated yield of 94 %. Hence, this
protocol offers a practical and economical alternative to those
previously reported in the literature.
Experimental Section
General Information
Thin layer chromatography (TLC) was performed using TLC silica gel 60
F254 glass plates. Silica gel 60 (230 – 400 mesh) was used for column
chromatography. The 1H NMR and 13C NMR of samples in DMSO-d6
were measured using a Bruker Avance 300 (AV300) spectrometer with
1
tetramethylsilane as an internal standard. For H NMR spectra, chemical
shifts were reported in ppm (), multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet) and coupling constant (Hz). Peaks at
around 3.3 ppm correspond to water peak, which is inherent when using
DMSO-d6 solvent. Detection of compounds by gas chromatography was
performed using an Agilent 6890N gas chromatograph equipped with a
HP-5 column and an FID detector. Analysis of samples by gas
chromatography mass spectrometry was carried out using a Shimadzu
QP5000. Mass spectra measurements were recorded on Bruker
micrOTOFQII under electrospray ionization (ESI) mode. The following
chemicals were obtained from Alfa-Aesar, Sigma-Aldrich, GCE
Chemicals and TCI and used as received: CBrCl3, CsHCO3, MeCN,
phenylacetones, and derivatives of phenylacetophenone and thiourea.
Figure 2. Proposed mechanism.
together with 16.5 mmol of CsHCO3 as base in 45 mL of 1:14
(v/v) CBrCl3/MeCN solvent mixture at 80 °C for 3 h. An isolated
yield of 94 % of 3t was obtained as a yellow solid after work-up
and purification via column chromatography. This compares
favorably with the isolated yield of 89 % obtained by Kodomari et
al. from the coupling of silica-supported KSCN and alumina-
supported aniline with desyl bromide.[14] Another protocol where
N-phenylthiourea was coupled with desyl bromide gave an
isolated yield of 98 % but microwave irradiation was required.[15]
While all three methods give excellent yields of 3t, the present
protocol has the advantage that different phenylthiazolamines
can be easily formed by in-situ -bromination of the
corresponding phenylacetophenones. In contrast, the other two
methodologies would require derivatives of desyl bromide to be
presynthesized as they are not commercially available. However,
one limitation of our protocol is that it cannot be extended to
urea and selenourea.
General procedure for formation of 5-phenylthiazolamines: A 10 mL
round-bottomed flask was charged with phenylacetone 1a (133.7 μL, 1.0
mmol), thiourea 2a (76.1 mg, 1.0 mmol), CsHCO3 (213 mg, 1.1 mmol and
3 mL of CBrCl3/MeCN solvent mixture (1/14 v/v). The reaction mixture
was stirred at 80 °C for 2 h. Thereafter, it was diluted with H2O and
extracted with EtOAc (15 mL × 5). The combined organic layers were
washed with NaHCO3 and brine and dried with anhydrous Na2SO4. After
filtration, the solvent was removed by rotary evaporation and the residue
was cleaned up by column chromatography using ethyl acetate and
hexane (v/v = 4/1) as eluent to afford 3a in 92 % yield.
Procedure for scaled-up synthesis of 5-phenylthiazolamine 3t: A 100
mL round-bottomed flask was charged with 2-phenylacetophenone 1k
(2.94 g, 15.0 mmol), N-phenylthiourea 2c (2.28 g, 15.0 mmol), CsHCO3
(3.20 g, 16.5 mmol and 45 mL of CBrCl3/MeCN solvent mixture (1/14 v/v).
After stirring at 80 °C for 3 h, the reaction mixture was diluted with H2O
and extracted with EtOAc (200 mL × 5). The combined organic layers
were washed with NaHCO3 and brine and dried with anhydrous Na2SO4.
After filtration, the solvent was removed by rotary evaporation and the
residue was cleaned up by column chromatography using hexane and
ethyl acetate (v/v = 8/1) as eluent to afford 3t in 94 % yield.
Scheme 2. Scaled-up synthesis of N-phenyl-substituted phenylthiazolamine 3t.
4-Methyl-5-phenylthiazol-2-amine (3a)
Conclusions
1
Obtained as a brown solid; yield: 175 mg (95 %). H NMR (300 MHz,
DMSO-d6) δ 7.46-7.14 (m, 5H), 7.01 (s, 2H), 2.20 (s, J = 6.5 Hz, 3H); 13
NMR (300 MHz, DMSO-d6) δ165.8, 143.2, 133.1, 128.7, 127.9, 126.0,
117.6, 16.2. HRMS (ESI) calcd for C10H11N2S [M+H]+: 191.0637; found
191.0640.
C
In conclusion, we have demonstrated a straightforward protocol
for the synthesis of 5-phenylthiazolamines via the coupling of
thiourea with phenylacetones, phenylacetophenones and -
tetralones. This protocol employs
a
thiourea/CBrCl3 -
bromination system to construct phenylthiazolamines by C-N/C-
S bond formation. Thiourea has a dual role of a substrate and an
-bromination shuttle whereby the bromine atom is transferred
from CBrCl3 to the-carbon. The in-situ bromination avoids the
need to separately synthesize -brominated derivatives. Besides
a large scope, the reaction proceeds smoothly at relatively mild
conditions and short reaction times. The scale-up to 15 mmol for
5-(2-Methoxyphenyl)-4-methylthiazol-2-amine (3b)
Obtained as a brown solid; yield: 194 mg (88 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.31-7.18 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 7.4
Hz, 1H), 6.80 (s, 2H), 3.76 (s, 3H) 2.00 (s, 3H); 13C NMR (300 MHz,
DMSO-d6) δ 166.8, 156.5, 144.3, 131.4, 128.6, 121.4, 120.3, 113.2,
111.5, 55.3, 16.1. HRMS (ESI) calcd for C11H13N2OS [M+H]+: 221.0743;
found 221.0740.
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5-(3-Methoxyphenyl)-4-methylthiazol-2-amine (3c)
DMSO-d6) δ 166.3, 145.0, 135.5, 132.9, 129.0, 128.7, 128.5, 128.1,
127.3, 127.0, 119.2. HRMS (ESI) calcd for C15H13N2S [M+H]+: 253.0794;
found 253.0792.
Obtained as a brown solid; yield: 200 mg (91 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.27 (t, J = 7.8 Hz, 1H), 6.99 (s, 2H), 6.92-6.75 (m, 3H),
3.76 (s, 3H) 2.20 (s, 3H); 13C NMR (300 MHz, DMSO-d6) δ 165.8, 159.3,
143.4, 134.4, 129.7, 120.3, 117.4, 113.4, 111.6, 55.0, 16.3. HRMS (ESI)
calcd for C11H13N2OS [M+H]+: 221.0743; found 221.0745.
4-Phenyl-5-p-tolylthiazol-2-amine (3l)
Obtained as a yellow solid; yield: 251 mg (94 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.39 (d, J = 7.8 Hz, 2H), 7.29-7.19 (m, 3H), 7.13-7.01 (m,
6H), 2.27 (s, 3H); 13C NMR (300 MHz, DMSO-d6) δ 165.8, 144.5, 136.4,
135.5, 129.8, 129.3, 128.8, 128.4, 128.0, 127.2, 119.2, 20.7. HRMS (ESI)
calcd for C16H15N2S [M+H]+: 267.0950; found 267.0952.
5-(4-Methoxyphenyl)-4-methylthiazol-2-amine (3d)
Obtained as a brown solid; yield: 191 mg (87 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.24 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.85 (s,
2H), 3.76 (s, 3H) 2.13 (s, 3H); 13C NMR (300 MHz, DMSO-d6) δ 165.2,
157.7, 141.9, 129.3, 125.3, 117.3, 114.1, 55.1 15.9. HRMS (ESI) calcd
for C11H13N2OS [M+H]+: 263.0849; found 263.0846.
4-(4-Fluorophenyl)-5-phenylthiazol-2-amine (3m)
Obtained as a yellow solid; yield: 237 mg (88 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.48-7.37 (m, 2H), 7.32-7.12 (m, 7H), 7.06 (t, J = 8.9 Hz,
2H); 13C NMR (300 MHz, DMSO-d6) δ 166.3, 162.9, 159.7, 143.9, 132.7,
131.9, 131.8, 130.5, 130.4, 129.0, 128.8, 127.1, 119.0, 115.1, 114.8.
HRMS (ESI) calcd for C15H12FN2S [M+H]+: 271.0700; found 271.0697.
5-(3,4-Dimethoxyphenyl)-4-methylthiazol-2-amine (3e)
Obtained as a brown solid; yield: 208 mg (83 %). 1H NMR (300 MHz,
DMSO-d6) δ 6.94 (d, J = 8.1 Hz, 1H), 6.91-6.80 (m, 4H), 3.77 (s, 3H),
3.75 (s, 3H), 2.17 (s, 3H); 13C NMR (300 MHz, DMSO-d6) δ 165.3, 148.7,
147.5, 142.2, 125.6, 120.6, 117.7, 112.1, 55.6, 55.5, 16.1. HRMS (ESI)
calcd for C12H15N2O2S [M+H]+: 251.0849; found 251.0852.
4-(4-Chlorophenyl)-5-phenylthiazol-2-amine (3n)
Obtained as a yellow solid; yield: 261 mg (91 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.39 (d, J = 8.4 Hz, 2H), 7.32-7.13 (m, 9H); 13C NMR (300
MHz, DMSO-d6) δ 166.3, 143.5, 134.2, 132.5, 131.8, 130.1, 129.0, 128.8,
128.1, 127.2, 119.7. HRMS (ESI) calcd for C15H12ClN2S [M+H]+:
287.0404; found 287.0407.
5-(4-Ethylphenyl)-4-methylthiazol-2-amine (3f)
Obtained as a brown solid; yield: 197 mg (90 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.26-7.16 (m, 4H), 6.91 (s, 2H), 2.58 (q, J = 7.5 Hz, 2H),
2.17 (s, 3H), 1.17 (t, J = 7.5 Hz, 3H); 13C NMR (300 MHz, DMSO-d6) δ
165.5, 142.6, 141.7, 130.4, 128.0, 127.9, 117.6, 27.8, 16.2, 15.5. HRMS
(ESI) calcd for C12H15N2S [M+H]+: 219.0950; found 219.0953.
4-(4-Bromophenyl)-5-phenylthiazol-2-amine (3o)
Obtained as a yellow solid; yield: 289 mg (87 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.42 (d, J = 8.1 Hz, 2H), 7.36-7.15 (m, 9H); 13C NMR (300
MHz, DMSO-d6) δ 166.3, 143.6, 134.6, 132.5, 131.0, 130.4, 129.0, 128.8,
127.2, 120.4, 119.8. HRMS (ESI) calcd for C15H12BrN2S [M+H]+:
330.9899; found 330.9895.
5-(4-Chlorophenyl)-4-methylthiazol-2-amine (3g)
Obtained as a yellow orange solid; yield: 196 mg (87 %). 1H NMR (300
MHz, DMSO-d6) δ 7.38 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.07
(s, 2H), 2.18 (s, 3H); 13C NMR (300 MHz, DMSO-d6) δ 166.0, 144.0,
132.0, 130.5, 129.4, 128.6, 116.2, 16.2. HRMS (ESI) calcd for
C10H10ClN2S [M+H]+: 225.0248; found 225.0250.
4-(4-Methoxyphenyl)-5-phenylthiazol-2-amine (3p)
Obtained as a yellow solid; yield: 257 mg (91 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.40-7.18 (m, 7H), 7.12 (s, 2H), 6.81 (d, J = 7.5 Hz, 2H),
3.72 (s, 3H); 13C NMR (300 MHz, DMSO-d6) δ 167.0, 158.5, 144.8,
133.1, 129.7, 128.9, 128.7, 127.9, 126.8,117.7, 113.4, 55.0. HRMS (ESI)
calcd for C16H15N2OS [M+H]+: 283.0900; found 283.0903.
5-(4-Bromophenyl)-4-methylthiazol-2-amine (3h)16
1
Obtained as an yellow orange solid; yield: 239 mg (89 %)/ H NMR (300
MHz, DMSO-d6) δ 7.51 (d, J = 6.9 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 7.07
(s, 2H), 2.18 (s, 3H); 13C NMR (300 MHz, DMSO-d6) δ 166.0, 144.0,
132.4, 131.5, 129.7, 118.9, 116.2, 16.3. HRMS (ESI) calcd for
C10H10BrN2S [M+H]+: 268.9743; found 268.9746.
4,5-bis(4-Methoxyphenyl)thiazol-2-amine (3p’)
Obtained as a yellow solid; yield: 286 mg (92 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.31 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H) 6.99 (s,
2H), 6.87 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 3.79 (s, 3H), 3.72
(s, 3H); 13C NMR (300 MHz, DMSO-d6) δ 165.4, 158.3, 158.2, 143.8,
130.3, 129.5, 127.9, 125.1, 117.6, 114.2, 113.4, 55.1, 55.0. HRMS (ESI)
calcd for C17H17N2O2S [M+H]+: 313.1005; found 313.1004.
4-Isobutyl-5-phenylthiazol-2-amine (3i)
Obtained as a brown solid; yield: 208 mg (89 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.40-7.28 (m, 4H), 7.23 (t, J = 6.9 Hz, 1H), 6.95 (s, 2H),
2.37 (d, J = 7.2 Hz, 2H), 2.10-1.96 (m, 1H), 0.82 (d, J = 6.6 Hz, 6H); 13
C
NMR (300 MHz, DMSO-d6) δ 165.9, 146.8, 133.0, 128.6, 126.4, 118.4,
38.1, 27.9, 22.4. HRMS (ESI) calcd for C13H17N2S [M+H]+: 233.1107;
found 233.1105.
5-(4-Methoxyphenyl)-N,4-dimethylthiazol-2-amine (3q)
Obtained as a brown solid; yield: 197 mg (84 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.37 (q, J = 4.2 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H), 6.94 (d, J
= 8.1 Hz, 2H), 3.76 (s, 3H), 2.80 (d, J = 4.2 Hz, 3H), 2.16 (s, 3H); 13C
NMR (300 MHz, DMSO-d6) δ 166.3, 157.8, 142.5, 129.4, 125.2, 116.9,
114.2, 55.1, 30.7, 16.2. HRMS (ESI) calcd for C12H15N2OS [M+H]+:
235.0900; found 235.0897.
4,5-Dihydronaphtho[2,1-d]thiazol-2-amine (3j)
Obtained as a brown solid; yield: 162 mg (80 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.20 (s, 2H), 7.16-7.07 (m, 2H), 6.98 (t, J = 7.5 Hz, 1H),
6.87 (d, J = 7.5 Hz, 1H), 2.89 (t, J = 7.8 Hz, 2H), 2.65 (t, J = 7.8 Hz, 2H);
13C NMR (300 MHz, DMSO-d6) δ 167.2, 149.6, 132.4, 131.0, 127.5,
126.8, 124.6, 121.7, 115.8, 28.3, 24.9. HRMS (ESI) calcd for C11H11N2S
[M+H]+: 203.0637; found 203.0639.
N-Methyl-4,5-diphenylthiazol-2-amine (3r)
Obtained as a yellow solid; yield: 266 mg (90 %). 1H NMR (300 MHz,
DMSO-d6) δ 7.63 (q, J = 4.2 Hz, 1H), 7.44-7.37 (m, 3H), 7.32-7.17 (m,
8H), 2.88 (d, J = 4.2 Hz, 3H); 13C NMR (300 MHz, DMSO-d6) δ 166.9,
145.3, 135.5, 132.7, 128.9, 128.6, 128.5, 128.0, 127.3, 127.0, 118.6,
4,5-Diphenylthiazol-2-amine (3k)16
1
Obtained as a yellow solid; yield: 239 mg (95 %). H NMR (300 MHz,
DMSO-d6) δ 7.40 (d, 2H), 7.29-7.13 (m, 10H); 13C NMR (300 MHz,
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10.1002/ejoc.201601410
European Journal of Organic Chemistry
FULL PAPER
30.8. HRMS (ESI) calcd for C16H15N2S [M+H]+: 267.0950; found
267.0953.
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5-(4-Methoxyphenyl)-4-methyl-N-phenylthiazol-2-amine (3s)
Obtained as a yellow solid; yield: 261 mg (88 %). 1H NMR (300 MHz,
DMSO-d6) δ 10.14 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.36-7.26 (m, 4H),
7.00-6.89 (m, 3H), 3.75 (s, 3H), 2.29 (s, 3H); 13C NMR (300 MHz, DMSO-
d6) δ 160.1, 158.2, 142.4, 141.2, 129.8, 128.9, 124.4, 121.1, 119.0,
116.9, 114.2, 55.1, 16.2. HRMS (ESI) calcd for C17H17N2OS [M+H]+:
297.1056; found 297.1058.
N-4,5-triphenylthiazol-2-amine (3t)
Obtained as a yellow solid; yield: 313 mg (95 %). 1H NMR (300 MHz,
DMSO-d6) δ 10.40 (s, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 7.8 Hz,
2H), 7.41-7.19 (m, 10H), 6.98 (t, J = 7.4 Hz, 1H); 13C NMR (300 MHz,
DMSO-d6) δ 161.1, 145.1, 141.1, 135.2, 132.1, 129.2, 129.0, 128.7,
128.5, 128.2, 127.5, 121.4, 120.6, 117.1. HRMS (ESI) calcd for
C21H17N2S [M+H]+: 329.1107; found 329.1109.
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N-(5-(4-Methoxyphenyl)-4-methylthiazol-2-yl)acetamide (3u)
Obtained as a brown solid; yield: 223 mg (85 %). 1H NMR (300 MHz,
DMSO-d6) δ 12.02 (s, 1H) 7.36 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.7 Hz,
2H), 3.78 (s, 3H), 2.30 (s, 3H), 2.13 (s, 3H); 13C NMR (300 MHz, DMSO-
d6) δ 168.2, 158.5, 154.5, 141.0, 129.8, 124.3, 123.3, 114.3, 55.2,
22.4,15.8. HRMS (ESI) calcd for C13H15N2O2S [M+H]+: 263.0848; found
263.0846.
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N-(4,5-Diphenylthiazol-2-yl)acetamide (3v)
Obtained as a yellow solid; yield: 263 mg (89 %). 1H NMR (300 MHz,
DMSO-d6) δ 12.29 (s, 1H), 7.44-7.26 (m, 10H), 2.18 (s, 3H); 13C NMR
(300 MHz, DMSO-d6) δ 168.7, 155.8, 143.7, 134.7, 131.9, 129.2, 128.9,
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Acknowledgements
Financial support from the Ministry of Education ARC Tier 1
grant numbers R-143-000-603-112 and R-143-000-550-112 is
gratefully acknowledged.
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Keywords: cyclization • bromination • C-S bond formation • C-H
activation • sulphur heterocycles
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10.1002/ejoc.201601410
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Layout 1:
FULL PAPER
A wide array of 5-phenylthiazolamines
with 80 to 95 % isolated yields was
obtained via coupling of thiourea with
phenylacetones, phenylaceto-
phenones and -tetralone. Thiourea
acts as a substrate and an -
In-situ bromination
Irwan Iskandar Roslan, Kian-Hong Ng,
Gaik-Khuan Chuah*, Stephan Jaenicke*
Page No. – Page No.
Synthesis of 5-Phenylthiazolamines
Using Thiourea as an-Bromination
Shuttle
bromination shuttle, transferring Br
from CBrCl3 to the -carbon of the
carbonyl moiety.
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