Synthesis of endo- and exo-N-Protected 5-Arylated 2-Aminothiazoles through Direct Arylation: An Efficient Route to Cell Differentiation Accelerators

Article abstract of DOI:10.1002/ejoc.201500283

An improved protocol for the direct arylation of N-phenyl-N-benzyl(thiazol-2-yl)amine by using aryl bromides as aryl donors is reported. The procedure was compared with a previously reported protocol in which aryl iodides were used as arylating agents. The improved direct arylation protocol was applied to structurally isomeric and nonaromatic 3-benzyl-N-phenylthiazol-2(3H)-imine. The two substrates for direct arylation were obtained from a common starting material, N-phenyl(thiazol-2-yl)amine, which was regioselectively benzylated either on the exo-cyclic or the endo-cyclic nitrogen by using two sets of reaction conditions. For the arylation of the isomeric nonaromatic 3-benzyl-N-phenylthiazol-2(3H)-imine, exclusive regioselectivity in the 5-position could be achieved.

Full text of DOI:10.1002/ejoc.201500283

FULL PAPER
DOI: 10.1002/ejoc.201500283
Synthesis of endo- and exo-N-Protected 5-Arylated 2-Aminothiazoles through
Direct Arylation: An Efficient Route to Cell Differentiation Accelerators
Toan Dao-Huy,[a] Birgit J. Waldner,[a,b] Laurin Wimmer,[a] Michael Schnürch,*[a] and
Marko D. Mihovilovic[a]
Keywords: Synthetic methods / Homogeneous catalysis / Arylation / C–H activation / Regioselectivity / Sulfur heterocycles
An improved protocol for the direct arylation of N-phenyl-
N-benzyl(thiazol-2-yl)amine by using aryl bromides as aryl
donors is reported. The procedure was compared with a pre-
viously reported protocol in which aryl iodides were used as
arylating agents. The improved direct arylation protocol was
applied to structurally isomeric and nonaromatic 3-benzyl-
N-phenylthiazol-2(3H)-imine. The two substrates for direct
arylation were obtained from a common starting material, N-
phenyl(thiazol-2-yl)amine, which was regioselectively benz-
ylated either on the exo-cyclic or the endo-cyclic nitrogen by
using two sets of reaction conditions. For the arylation of
the isomeric nonaromatic 3-benzyl-N-phenylthiazol-2(3H)-
imine, exclusive regioselectivity in the 5-position could be
achieved.
Introduction
Synthetic organic small molecules have been extremely
successful as bioactive compounds. In many of these sub-
stances an aromatic heterocyclic ring can be found, which
often contains nitrogen. Such heterocyclic substructures in-
troduce rigidity into the molecular scaffold and offer pos-
sibilities to interact with functional groups of an active site
through their heteroatom(s). Among the many possible het-
erocycles, thiazole is known to be of significant importance,
occurring in a number of biologically relevant molecules
such as thiamine (Vitamin B1),[1] ritonavir (an anti-HIV
protease inhibitor and one of the active compounds of the
blockbuster drug Kaletra),[2a,2b] and the cephalosporin anti-
biotic cefdinir.[2c,2d] Among the thiazole derivatives, those
carrying an amine functionality seem to be of exceptional
importance, as can be seen from the examples presented in
Figure 1.[3] In particular, arylated thiazolamines seem to be
predominant among the bioactive compounds containing
thiazole scaffolds.
Two of the examples shown in Figure 1 (IV and V) have
activity as cell differentiation modulators. The use of syn-
thetic small molecules (SySMs) to influence cell differentia-
tion processes would be of significant importance for thera-
peutic purposes. Intense research in this field is ongoing
Figure 1. Bioactive (thiazol-2-yl)amine derivatives.
[a] Institute of Applied Synthetic Chemistry, Vienna University of
Technology,
and an increasing number of such compounds are being
disclosed.[3f,3g,4]
Getreidemarkt 9/163-OC, 1060 Vienna, Austria
E-mail: michael.schnuerch@tuwien.ac.at
In terms of bioactive thiazoles, neuropathiazole IV was
reported to induce a differentiation of multipotent adult
hippocampal neural progenitor cells towards a neuronal
phenotype.[3f] In our group, we have synthesized N-benzyl-
5-aryl(thiazol-2-yl)amines of general structure V. Given that
http://www.ias.tuwien.ac.at/staff/3129565/
[b] Institut für Allgemeine, Anorganische und Theoretische
Chemie, Universität Innsbruck,
Innrain 82, 6020 Innsbruck, Austria
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500283.
Eur. J. Org. Chem. 2015, 4765–4771
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M. Schnürch et al.
FULL PAPER
their molecular geometry resembles that of neuropathiazol,
We explained the formation of this compound by con-
we were interested in studying a potentially similar bio- sidering that 1 is in equilibrium with its exo-cyclic imine
logical activity.[3g] Interestingly, the synthesized compounds form 1a (Scheme 2). Such an equilibrium has been reported
indeed had an influence on cell differentiation processes, previously for N-phenyl-(thiazol-2-yl)amine.[6] Both of these
however in an unexpected way. The compounds showed compounds can be deprotonated and subsequently benzyl-
good activity as differentiation accelerators of C2C12 mu- ated, leading to the two regioisomeric products observed.
rine skeletal muscle progenitor cells while at the same time As judged by their pKa values, compound 1 (pKa = 4.33)
showing no activity as neural differentiation modulators. In and 1a (pKa = 6.30)[7a] are reasonably acidic, making trieth-
this paper, we report an improved synthesis of compounds ylamine (pKa = 10.7)[7b,7c] sufficiently basic for their depro-
of general structure V and on the synthesis of regioisomers tonation. Nevertheless, the type of base used for deproton-
of these compounds bearing a benzyl protecting group on ation seems to have a pronounced influence on the selectiv-
the endo-cyclic nitrogen.
ity of the benzylation reaction.
Results and Discussion
In our previous contribution[3g] we disclosed a new
method for the synthesis of 5-aryl-N-benzyl-N-phenyl-
(thiazol-2-yl)amines by regioselective direct C-5 arylation.
Under palladium acetate catalysis, a range of substituted 2-
aminothiazoles reacted with aryl iodides in the presence of
potassium acetate. No ligands were required in this reac-
tion. In agreement with previous reports,[5] the arylation
took place selectively at the 5-position of the substrate
(Scheme 1).
Scheme 2. Amine–imine equilibrium in 2-aminothiazole.
We were interested in developing reaction conditions that
lead to specific formation of either 2 or 3. We found the
best 2/3 selectivity of 5:1 was obtained by using NaH as
base in N,N-dimethylformamide (DMF) at room tempera-
ture for 5 h (Table 1, entries 3–5). While maintaining the
selectivity, the conversion of 66% (entry 3) was improved to
76% when NaH (2 equiv.) and a catalytic amount of NaI
were applied (entry 4). To invert the regioselectivity, a
change in base was most important: When the reaction was
conducted at 120 °C in dioxane using triethylamine as base,
GC-analysis showed the formation of the products in a 2/3
ratio of 1:7 after 24 h with a conversion of 76% (entry 1).
Longer reaction times led to slightly increased conversion
but also to a decrease in selectivity (2/3 ratio 1:4 after 48 h;
entry 2). This indicates that isomerization of the products
can occur under the applied reaction conditions. The out-
come of these experiments can be rationalized by a switch
in mechanism depending on the applied base. When NaH
is used for deprotonation, benzylation might take place,
whereas for deprotonation with triethylamine benzyl-
thiazolium formation could precede deprotonation. This
hypothesis is supported by the fact that the endo-cyclic
nitrogen can be expected to have a lower nucleophilicity
when compared with the corresponding anion and therefore
requires higher temperatures to react. We were able to iso-
late both benzylation products 2 and 3 by column
chromatography, although this was challenging because of
their very similar Rf values in common mobile phases. Both
2 and 3 could be crystallized from their mixture in dichloro-
methane and both were obtained in pure form.
Scheme 1. Direct arylation of N-benzyl-N-phenyl(thiazol-2-yl)
amine by using aryl iodides as the aryl source.
During the synthesis of the starting material 2 we ob-
served the formation of endo-cyclic benzylated compound 3
as a byproduct (Table 1).
Table 1. Synthesis of N-endo- and N-exo-benzylthiazolamine.[a]
Entry Base
Solvent
T [°C]
t [h]
Conv. [%][b] Ratio 2/3[b]
We have already reported the direct arylation of 2 by
using aryl iodides as aryl source.[3g] Before starting to inves-
tigate the direct arylation of 3, we tested whether we could
use the corresponding aryl bromides instead because they
are more abundantly available reagents. In our original pub-
lication,[3g] we noted that bromobenzene gave low conver-
sion under the applied reaction conditions [KOAc
(2 equiv.), Pd(OAc)2 (1 mol-%), anhydrous DMAc, 120 °C].
We now revisited this procedure and found that increasing
1
2
3
Et3N
Et3N
NaH
NaH
NaH
dioxane
dioxane
DMF
DMF
DMF
120
120
r.t.
r.t.
r.t.
24
48
5
5
7
76
78
66
75
76
1:7
1:4
5:1
5:1
5:1
4[c]
5[c]
[a] Reaction conditions: Substrate
1 (1 equiv.), benzyl bromide
(1.3 equiv.), base (1.3 equiv.) as 0.3 m solution in the respective solvent.
[b] Conversion and ratio of products was determined by GC analysis
with dodecane as internal standard. [c] Base (2.0 equiv.) was used and
NaI (0.1 equiv.) was added.
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Toward an Efficient Route to Cell Differentiation Accelerators
the temperature to 140 °C was sufficient to obtain good error; however, the reaction with iodo-precursors was more
yields of coupled products within 24 h by using only efficient by about 20% when compared to the bromotolu-
1.5 equiv. of aryl bromides. The results of the coupling pro- ene series. Three examples were performed with only aryl
tocol for both aryl halides are compared in Table 2.
bromides (entries 2, 5, and 7) and these gave generally good
yields. An excellent yield was obtained by using 2-fluoro-3-
iodopyridine as coupling partner. In this case, product 4k
was isolated in 94% yield.
Table 2. Direct arylation of 2.
We then set out to investigate the direct arylation of re-
gioisomeric imine substrate 3. 2-Iminothiazoles were pre-
viously synthesized by condensation of α-halo ketones and
thiourea derivatives through the Hantzsch reaction[9a–9f] or
Glaser–Hay oxidative coupling between aryl alkynes and an
N-hydroxythiourea.[9g] On the other hand, 2-iminothiazoles
were observed in the methylation reaction of 2-anilino-
thiazoles[10a] as well as in copper diacetate-catalyzed phen-
ylation of 2-aminothiazole with triphenylbismuth diacet-
ate.[10b] A selection of medicinally relevant compounds con-
taining the iminothiazole scaffold is shown in Figure 2.
These compounds and other members of the compound
class have been reported to possess activity as platelet
GPIIb/IIIa receptor antagonists,[11a] HIV-1 reverse tran-
scriptase inhibitors,[11b,11c] anti-inflammatory agents, kinase
inhibitors,[11d–11g] cytotoxic agents[11h,11i] and a range of
other activities.[12] Moreover, pifithrin (Pft-α), a compound
containing the 2-iminothiazole skeleton, has recently been
identified as a potent inhibitor of p53 in vivo. This might
be promising for the treatment of major neurodegenerative
disorders (Parkinson’s disease, Alzheimer’s disease).[13]
Entry
R
Product
Yield [%][a]
X = Br X = I
1
2
3
4
5
6
7
8
phenyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
70
88
80
62
60
78
83
59
85
n.i.[b]
60
3-chlorophenyl
4-ethylbenzoate
4-methoxyphenyl
m-tolyl
4-fluorophenyl
4-chlorophenyl
p-tolyl
o-tolyl
4-nitrophenyl
2-fluoropyridin-3-yl
47[c]
n.i.[b]
71
n.i.[b]
77
9
10
11
60
80
20
94
4j
4k
44
n.i.[b]
[a] Reaction conditions: Procedure A (reaction with ArBr): Substrate
2 (1.0 equiv.), ArBr (1.5 equiv.), KOAc (1.5 equiv.) and Pd(OAc)2
(0.01 equiv.) in DMAc (0.33 m) at 140 °C for 24 h. Procedure B (re-
action with ArI): Substrate 2 (1.0 equiv.), ArI (2.0 equiv.), KOAc
(2.0 equiv.) and Pd(OAc)2 (0.01 equiv.) in DMAc (0.33 m) at 120 °C
for 24 h. [b] n.i.: not investigated. [c] Reaction conducted as for Pro-
cedure B but with 10 mol-% catalyst loading.
In the case of substrate 2, there is no clear trend regard-
ing whether bromides or iodides are the preferred aryl
source. In several cases, yields were considerably higher
when using aryl bromides instead of the corresponding aryl
iodides (Table 2, entries 3, 4, 6, and 9), but other iodides
proved to be superior (entries 1 and 8).
Bromo- and iodobenzene gave product 4a in 70 and
85%, respectively (entry 1). Regarding other aryl halides,
both electron-deficient and -rich substrates were accepted
in the reaction. However, 4-iodoanisole required a higher
catalyst loading (10 mol-%), indicating that the reaction is
slower with electron-donating substituents. Furthermore, 4-
bromo- and 4-iodonitrobenzene gave lower yields of 4j
compared with the other examples, which can be explained
by the ability of the nitro group to coordinate metal cata-
lysts.[8] An ester functionality in the para-position was also
well tolerated, irrespective of the halide leaving group (4c,
entry 3). Bromobenzenes bearing a chloro- or fluoro- sub-
stituent also gave good yields in the reaction (4b, 4f, and
4g, entries 2, 6, and 7).
Figure 2. Bioactive 2-iminothiazolines derivatives.
In a preliminary experiment, we found that, under the
Products 4e, 4h, and 4i were obtained in essentially iden- experimental conditions used for the Pd-catalyzed arylation
tical yields (59–60%) in the coupling of 2-, 3-, and 4-bromo- of 2,2-iminothiazoles, 3 also formed an arylated product
toluene, which indicates that the reaction is not sensitive to with unknown regioselectivity. Due to the loss of aromatic-
sterically demanding reaction partners (entries 5, 8, and 9). ity in 3, the direct arylation can be considered as a Heck
In the case of 2-iodo- and 4-iodotoluene, products 4i and 4h cross-coupling on the only double bond left on the thiazole
were also obtained with the same yield within experimental ring. Both ends of the double bond are substituted with
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M. Schnürch et al.
FULL PAPER
heteroatoms, which makes prediction of the regiochemistry optimize the deprotection protocol further. The results of
1
difficult; both 5a and 6a are potential products (Figure 3).
the GC/MS analysis and the data from the H NMR and
13C NMR spectra of the two deprotection products were
compared and these turned out to be identical. Compound
7 was obtained in both cases, establishing that the direct
arylation of 3 occurred in position 5, giving access to com-
pound 5.
An arylation reaction such as this is, to our knowledge,
unprecedented; hence, we investigated its substrate scope.
In the case of substrate 3, aryl iodides gave considerably
higher yields compared with those of the corresponding
aryl bromides (Table 3), yields were slightly lower compared
with those of 2, especially in the case of aryl bromides as
reaction partners.
Figure 3. Possible arylation products of endo-N-benzyl(thiazol-2-
yl)amine.
We subjected 3 to the direct arylation conditions and
were very pleased to find that arylation of 3 occurred with
similar efficiency to that observed with 2, in spite of its
nonaromatic character, giving 55 and 79% yield using
bromobenzene and iodobenzene, respectively. However, as-
signment of regiochemistry was not possible at this point
because arylation could occur either in position 5 to give
5a or in position 4 to give 6a (Figure 3). Therefore, it was
necessary to determine the structure of the obtained prod-
uct unambiguously. Attempts to elucidate the structure by
comparison of NMR spectra with predicted values or by
2D-NMR experiments were inconclusive. We therefore de-
cided to cleave the benzyl group of 4a (product of amino-
thiazole arylation with proven regiochemistry) and 5a/6a
and to compare the deprotected products. If the arylation
of 3 had occurred in position 5, the same product should
be obtained after deprotection.[13]
Initially, reductive cleavage was attempted. However, 4a
and 5a/6a were completely unreactive, even under high pres-
sure (up to 100 bar H2), high temperature (100 °C) or high
loadings of the Pd/C catalyst in a continuous flow reactor.
The reason is likely catalyst poisoning by the sulfur-con-
taining thiazole moiety.[14] Alternatively, an oxidative
method for N-debenzylation was applied: Treatment of
compounds 4a and 5a/6a with potassium tert-butoxide and
oxygen in dimethyl sulfoxide (DMSO) at room temperature
gave the deprotected compounds,[15] albeit in low yield
(10% starting from 4a and 9% starting from 5a/6a;
Scheme 3).
Table 3. Direct arylation on 3.
Entry Ar
Product
Yield [%]
X = Br[a]
X = I[b]
1
2
3
4
5
7
6
8
phenyl
5a
5b
5c
5d
5e
5f
5g
5h
5i
55
58
49
21
56
34
50
52
50
79
n.i.[c]
58
3-chlorophenyl
4-ethylbenzoate
4-methoxyphenyl
m-tolyl
4-fluorophenyl
4-chlorophenyl
p-tolyl
o-tolyl
4-nitrophenyl
2-fluoropyridin-3-yl
41
n.i.[c]
51
n.i.[c]
68
9
10
11
73
86
51
5j
5k
41
n.i.[c]
[a] Reaction with ArBr: Substrate 3 (1.0 equiv.), ArBr (1.5 equiv.),
KOAc (1.5 equiv.) and Pd(OAc)2 (0.01 equiv.) in DMAc (0.33 m) at
140 °C for 24 h. [b] Reaction with ArI: Substrate 3 (1.0 equiv.), ArI
(2.0 equiv.), KOAc (2.0 equiv.) and Pd(OAc)2 (0.01 equiv.) in DMAc
(0.33 m) at 120 °C for 24 h. [c] n.i.: not investigated.
For some products, the differences in product yield were
particularly pronounced. 1-Bromo-4-fluorobenzene (5f; 34
vs. 51%; entry 7) and 4-bromoanisole (5d; 21 vs. 41%; en-
try 4) gave a notably lower yield. The most striking differ-
ence was observed for the reaction of 4-iodonitrobenzene,
for which a yield of 86% was obtained when compared with
41% for the corresponding bromide reaction (5j; entry 10).
2-Bromotoluene as a sterically demanding coupling partner
gave 50% yield (entry 9), which is in the same range as for
3-bromo- and 4-bromotoluene (56% 5e and 52% 5i; entries
5 and 8). This indicates that steric bulk is not an issue in
this coupling reaction.
Electron-deficient coupling partners, such as 4-nitro or
4-carboxyethyl-substituted benzenes were well tolerated
(49%, 5c; 41%, 5j; entries 3 and 11). Finally, 1-bromo-3-
chlorobenzene and 1-bromo-4-chlorobenzene worked as
Scheme 3. Deprotection of compounds 4a and 5a (6a).
The remaining starting materials were decomposed after well as most other aryl bromides (entries 2 and 6). As a
the reaction. Given that the only purpose of these reactions heteroaromatic example, 2-fluoro-3-iodopyridine (5k, 51%;
was to prove the regioselectivity of arylation, we did not entry 11) was well tolerated.
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Toward an Efficient Route to Cell Differentiation Accelerators
where some starting material was found as an impurity in the prod-
uct, Kugelrohr distillation was applied for purification.
Conclusions
We have described an improved method for the direct
arylation of N-phenyl-2-aminothiazole 2, applying aryl
bromides as arylating reagents. Compared with our pre-
viously disclosed protocol using aryl iodides, the new
method has the advantage of using less expensive and more
readily available reagents. In the direct arylation reaction of
2, comparable yields were obtained when using aryl brom-
ides or iodides. The same protocol was also used for the
arylation of iminothiazole 3 in position 5. In this case,
higher yields were achieved by using aryl iodides. The re-
gioselectivity of this reaction was unequivocally determined
by deprotection of 4a and 5a, which resulted in the forma-
tion of the same compound 7. Biological activity evaluation
of compounds of general structure 5 is underway. Prelimi-
nary results point to an activity as cell differentiation accel-
erators similar to that of compounds 4. Details of this bio-
logical study will be reported in due course.
Direct Arylation Using Aryl Iodides. General Procedure B: This pro-
cedure was similar to procedure A, but it involved the use of an aryl
iodide (1.0 mmol, 2.0 equiv.), KOAc (98 mg, 1.0 mmol, 2.0 equiv.)
instead of an aryl bromide (0.75 mmol, 1.5 equiv.), KOAc (74 mg,
0.76 mmol, 1.5 equiv.). Reaction heated to only 120 °C for 24 h.
The work-up and the procedures for the isolation of the products
were as described for Procedure A.
Representative Examples
N-Benzyl-N-phenylthiazol-2-amine (2): In a 7 mL vial equipped
with a screw cap with septum and a magnetic stir bar, N-phenyl-
thiazol-2-amine (1 g, 5.68 mmol), NaH 55% (0.48 g, 11 mmol) and
NaI (85 mmg, 0.57 mmol) were dissolved in DMF (5 mL), then
benzyl bromide (0.88 mL, 7.39 mmol) was added to the solution.
The reaction mixture was stirred at room temperature for 5 h. The
reaction was quenched with excess H2O, and the mixture was ex-
tracted with EtOAc (15 mL). The organic phase was washed with
saturated NH4Cl solution two times and with saturated Na2CO3,
then dried with Na2SO4. All solvent was evaporated under reduced
pressure to give a product mixture (1.133 g) containing N-benzyl-
N-phenylthiazol-2-amine (2) and N-[3-benzylthiazol-2(3H)-ylid-
ene]aniline (3) in a ratio of 5:1. The product mixture was dissolved
in the minimum amount of warm CH2Cl2 (2–3 mL), then cooled
to –5 °C and left to crystallize overnight. The crystals were col-
lected by filtration and washed three times with cold LP (–5 °C),
then dried under reduced pressure to give N-benzyl-N-phenylthi-
azol-2-amine (861 mg, 57% isolated yield) as yellow-brown needle
Experimental Section
General Methods: Chemicals were purchased from commercial sup-
pliers and used without further purification unless otherwise noted.
Palladium catalysts and ligands were stored under argon in a desic-
cator and weighed in air. Reactions were followed by TLC
(0.25 mm silica gel 60-F plates). Visualization was accomplished
with UV light. Flash chromatography was carried out on silica gel
320–400 mesh by MPLC. All solvents for MPLC were distilled
prior to use. Kugelrohr distillation was carried out with Büchi
GKR-51 apparatus. 1H and 13C NMR spectra were recorded from
CDCl3 solutions with a Bruker AC 200. Chemical shifts (δ) are
reported in parts per million (ppm) with tetramethylsilane (TMS)
as internal standard. The abbreviations used to report the data are
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and
br. (broad). GC–MS spectra were recorded either with a Thermo
Finnigan Focus GC/DSQ II using a standard capillary column
BGB 5 (30 mϫ0.25 mm ID) or with a Thermo Trace 1300/ISQ LT
using a standard capillary column BGB 5 (30 mϫ0.25 mm ID).
HRMS for compounds that were not previously reported were ana-
lyzed by LC-IT-TOF-MS in only positive ion detection mode with
the recording of MS and MS/MS spectra. Melting points were de-
termined with a Stanford Research Systems MPA100 OptiMelt
Automatic Melting Point System. Data is given in 0.5 °C intervals.
1
crystals; m.p. 79–80 °C. H NMR (CDCl3, 200 MHz): δ = 5.19 (s,
2 H, CH2), 6.47 (d, J = 3.6 Hz, 1 H), 7.21–7.33 (m, 11 H) ppm.
13C NMR (CDCl3, 200 MHz): δ = 56.5 (CH2), 107.7, 126.1ϫ2,
126.8, 127.2, 127.7ϫ2, 128.5ϫ2, 129.8ϫ2, 137.6, 139.3, 145.3,
170.9 ppm. MS: m/z (%) = 266 (56) [M+], 174 (100), 167 (30),
131(11), 91(16). HRMS: m/z calcd. for [M + H]+ 267.0850; found:
267.0955, (difference: 1.87 ppm).
N-[3-Benzylthiazol-2(3H)-ylidene]aniline (3): In a 50 mL round-bot-
tom flask with magnetic stirrer bar and condenser, N-phenyl-
thiazol-2-amine (1 g, 5.68 mmol), benzyl bromide (0.90 mL,
7.58 mmol) and triethylamine (0.80 mL, 5.68 mmol) were dissolved
in 1,4-dioxane (15 mL). The mixture was heated to 120 °C for 24 h,
then the reaction was quenched with excess H2O and extracted with
EtOAc (15 mL). The organic phase was washed three times with
brine, then dried with Na2SO4. All solvent was evaporated under
reduced pressure to obtain the product mixture (1.178 g) contain-
ing 2 and 3 in a ratio of 1:7. The product mixture was dissolved in
the minimum amount of warm CH2Cl2 (2–3 mL), then cooled to
–5 °C and left to crystallize overnight. The crystals were filtered
and washed three times with cold LP (–5 °C) then dried under re-
duce pressure to obtain N-benzyl-N-phenylthiazol-2-amine
(831 mg, 55% isolated yield) as light-brown needle crystals; m.p.
94–95 °C. 1H NMR (CDCl3, 200 MHz): δ = 5.06 (s, 2 H, CH2),
6.50 (d, J = 4.9 Hz, 1 H), 6.85 (d, J = 4.9 Hz, 1 H), 7.04–7.10 (m,
3 H), 7.26–7.36 (m, 9 H) ppm. 13C NMR (CDCl3, 200 MHz): δ =
49.7 (CH2), 97.6, 121.4ϫ2, 122.9, 126.6, 127.8, 128.1ϫ2,
128.8ϫ2, 129.4ϫ2, 136.7, 151.6, 158.6 ppm. MS: m/z (%) = 266
(42) [M+], 167 (100), 131 (10), 91 (18), 15 (8). HRMS: m/z calcd.
for [M + H]+ 267.0950; found: 267.0954 (difference: 1.50 ppm).
Direct Arylation Using Aryl Bromides. General Procedure A: A
7 mL vial equipped with a screw cap, septum, and a magnetic stir
bar was charged with substrate N-benzyl-N-phenyl(thiazol-2-
yl)amine (2) or N-[3-benzylthiazol-2(3H)-ylidene]aniline (3)
(0.5 mmol, 1.0 equiv.), aryl bromide (0.75 mmol, 1.5 equiv.), KOAc
(74 mg, 0.76 mmol, 1.5 equiv.), and Pd(OAc)2 (1 mg, 0.005 mmol,
0.01 equiv.). The vial was closed with a septum, evacuated, and
flushed with argon three times. Anhydrous DMAc (3 mL) was
added by using a syringe and the mixture was heated to 140 °C for
24 h. The reaction mixture was cooled to room temperature and
then diluted with ethyl acetate (5 mL) and filtered through a pad
of Celite. The organic phase was washed with saturated ammonium
chloride three times and with brine, then dried with sodium sulfate.
The solvent was removed under reduced pressure. Purification was
conducted by MPLC on silica gel with light petroleum (LP)/EtOAc
mixtures containing 1vol.-%. triethylamine (TEA). In several cases,
N-Benzyl-N,5-diphenylthiazol-2-amine (4a): This compound was
synthesized according to General Procedure A starting from N-
benzyl-N-phenylthiazol-2-amine (2) (266 mg, 1.0 mmol), bromo-
benzene (105 μL, 157 mg, 1.5 mmol), KOAc (147 mg, 1.5 mmol),
and Pd(OAc)2 (2.2 mg, 0.01 mmol). Purification was carried out in
Eur. J. Org. Chem. 2015, 4765–4771
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4769

M. Schnürch et al.
FULL PAPER
man, G. B. McGaughey, K. E. Coll, T. J. Koester, W. F. Hoff-
man, R. W. Hungate, R. L. Kendall, R. C. McFall, K. W. Rick-
ert, R. Z. Rutledge, K. A. Thomas, Bioorg. Med. Chem. Lett.
2004, 14, 2941–2945.
two steps: First MPLC was carried out (silica gel; LP/EtOAc with
1vol.-%. TEA as eluent), which yielded the product mixture
(262 mg) containing the desired product 4a and starting material.
The product mixture was purified by Kugelrohr distillation at
100 °C in vacuo to obtain N-benzyl-N,5-diphenylthiazol-2-amine
(239 mg, 70%) as a light-brown solid; m.p. 65–66 °C; Rf = 0.45
(LP/EtOAc, 5:2). 1H NMR (200 MHz, CDCl3): δ = 5.20 (s, 2 H,
CH2), 7.26–7.39 (m, 15 H), 7.46 (s, 1 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 49.7 (CH2), 97.6, 121.4ϫ2, 122.9, 126.6, 127.8,
128.1ϫ2, 128.8ϫ2, 129.4ϫ2, 136.7, 151.6, 158.6 ppm. MS: m/z
(%) = 343 (9), 342 (38) [M+], 252 (17), 251 (85), 250 (61), 219 (16),
167 (77), 134 (20), 91 (100). HRMS: m/z calcd. for [M + H]+
343.1263; found: 343.1281 (difference 5.25 ppm).
[4] a) S. Shah, A. Solanki, P. K. Sasmal, K.-B. Lee, J. Am. Chem.
Soc. 2013, 135, 15682–15685; b) M. Koley, A. K. Mike, P.
Heher, X. Koenig, M. Schön, M. Schnürch, K. Hilber, G.
Weitzer, M. D. Mihovilovic, MedChemComm 2013, 4, 1189–
1195; c) S. W. Oh, J. B. Lee, B. Kim, S. Jeon, M.-K. Kim, K.-
H. Nam, J.-R. Ha, M. Bhatia, G. T. Oh, D.-Y. Kim, Arch.
Pharmacal Res. 2012, 35, 1979–1988; d) D. Petrik, Y. Jiang,
S. G. Birnbaum, C. M. Powell, M.-S. Kim, J. Hsieh, A. J. Eisch,
FASEB J. 2012, 26, 3148–3162; e) E. Willems, J. Cabral-Teix-
eira, D. Schade, W. Cai, P. Reeves, P. J. Bushway, M. Lanier, C.
Walsh, T. Kirchhausen, J. C. Izpisua Belmonte, J. Cashman, M.
Mercola, Cell Stem Cell 2012, 11, 242–252; f) C.-P. Cheng, H.-
S. Huang, Y.-C. Hsu, M.-J. Sheu, D.-M. Chang, J. Clin. Immu-
nol. 2012, 32, 762–777; g) C. A. Lyssiotis, L. L. Lairson, A. E.
Boitano, H. Wurdak, S. Zhu, P. G. Schultz, Angew. Chem. Int.
Ed. 2011, 50, 200–242; h) W. W.-Y. Yau, M. K. Tang, E. Chen,
Y. Yao, I. W.-C. Wong, H. S.-S. Lee, K. K.-H. Lee, Proteome
Sci. 2011, 9, 3; i) H. Wang, J. Hao, C. C. Hong, ACS Chem.
Biol. 2011, 6, 192–197; j) H. Sadek, B. Hannack, E. Choe, J.
Wang, S. Latif, M. G. Garry, D. J. Garry, J. Longgood, D. E.
Frantz, E. N. Olson, J. Hsieh, J. W. Schneider, Proc. Natl. Acad.
Sci. USA 2008, 105, 6063–6068.
[5] For selectivity of Pd-catalyzed direct arylation reactions of thi-
azole derivatives, see: a) M. Parisien, D. Valette, K. Fagnou, J.
Org. Chem. 2005, 70, 7578–7584; b) B. Liegault, D. Lapointe,
L. Caron, A. Vlassova, K. Fagnou, J. Org. Chem. 2009, 74,
1826–1834; c) N. Primas, A. Bouillon, J.-C. Lancelot, H. El-
Kashef, S. Rault, Tetrahedron 2009, 65, 5739–5746; d) L.
Théveau, C. Verrier, P. Lassalas, T. Martin, G. Dupas, O. Quer-
olle, L. Van Hijfte, F. Marsais, C. Hoarau, Chem. Eur. J. 2011,
17, 14450–14463; e) J. Roger, F. Pozgan, H. Doucet, J. Org.
Chem. 2009, 74, 1179–1186.
N-[3-Benzyl-5-(2-fluoropyridin-3-yl)thiazol-2(3H)-ylidene]aniline
(5j): Synthesized according to General Procedure B on a 0.26 mmol
scale, yield 48 mg (51%); light-brown solid; m.p. 139–140 °C. 1H
NMR (200 MHz, CDCl3): δ = 5.06 (s, 2 H, CH2), 6.98–7.07 (m, 4
H, ArH), 7.16 (d, JH,F = 1.2 Hz, 1 H, H-4), 7.18–7.42 (m, 8 H,
ArH), 7.86–7.90 (m, 1 H, Pyr-H6) ppm. 13C NMR (50 MHz,
3
2
CDCl3): δ = 50.0 (CH2), 106.9 (d, JC,F = 8.6 Hz), 115.6 (d, JC,F
4
= 28 Hz), 121.3 (2 C), 121.8 (d, JC,F = 4.1 Hz), 123.6, 127.8 (d,
3JC,F = 16.1 Hz), 128.1 (3 C), 128.9 (2 C), 129.6 (2 C), 136.2 (d,
3
4JC,F = 3.8 Hz), 136.3, 143.6 (d, JC,F = 15.2 Hz), 151.1, 155.7,
158.7 (s, 1JC,F = 240.6 Hz) ppm. MS: m/z (%) = 361 (26) [M+], 269
(30), 167 (100), 110 (8), 91 (75). HRMS: m/z calcd. for [M + H]+
362.1114; found: 388.1118 (difference: 1.03 ppm).
Acknowledgments
T. D.-H. thanks the Austrian OeAD (Scholarship Fund) for finan-
cial support.
[6] a) L. Forlani, P. De Maria, A. Fini, J. Chem. Soc. Perkin Trans.
2 1980, 8, 1156–1158; b) A. A. Mohamed, A. W. El-Harby,
THEOCHEM 2007, 817, 125–136; c) A. A. Mohamed, A. W.
El-Harby, THEOCHEM 2008, 849, 52–61; d) Y. Zeng, Y. Ren,
Int. J. Quantum Chem. 2007, 107, 247–258.
[7] For pKa of compounds, see: a) R. G. Button, J. P. Cairns, P. J.
Taylor, J. Chem. Soc. Perkin Trans. 2 1985, 10, 1555–1558; b)
J. Speight, Section 8: Electrolytes, electromotive force, and chem-
ical equilibrium, in: Lange’s Handbook of Chemistry, 70th Anni-
versary Edition, McGraw-Hill Companies, Inc., United States,
2004, p. 8.70; c) M. B. Smith, J. March, in: March’s Advanced
Organic Chemistry, chapter 8: Acids and Bases, 6th ed., Wiley
Interscience, United States, 2007, p. 356–366.
[1] a) R. R. Williams, J. K. Cline, J. Am. Chem. Soc. 1936, 58,
1504–1505; b) M. Fujiwara, Bitamin 1999, 73, 177–198.
[2] a) S. Ren, E. J. Lien, Prog. Drug Res. 1998, 51, 1–31; b) H.
Gatanaga, S. Aizawa, Y. Kikuchi, N. Tachikawa, I. Genka, S.
Yoshizawa, Y. Yamamoto, A. Yasuka, S. Oka, AIDS Res. Hum.
Retroviruses 1999, 15, 1493–1498; c) G. Xiao, Celdinir, in:
Handbook of Metabolic Pathways of Xenobiotics, Wiley, Chich-
ester, UK, 2014, vol. 3, p. 1085–1087; d) M. Baumann, I. R.
Baxendale, S. V. Ley, N. Nikbin, Beilstein J. Org. Chem. 2011,
7, 442–495.
[3] For bioactive 2-aminothiazole derivatives, see: a) M. Biagetti,
C. P. Leslie, A. Mazzali, C. Seri, D. A. Pizzi, J. Bentley, T. Gen-
ski, R. D. Fabio, L. Zonzini, L. Caberlotto, Bioorg. Med.
Chem. Lett. 2010, 20, 4741–4744; b) S. Mahboobi, S. Dove, A.
Sellmer, M. Winkler, E. Eichhorn, H. Pongratz, T. Ciossek, T.
Baer, T. Maier, T. Beckers, J. Med. Chem. 2009, 52, 2265–2279;
c) M. P. Hay, S. Turcotte, J. U. Flanagan, M. Bonnet, D. A.
Chan, P. D. Sutphin, P. Nguyen, A. J. Giaccia, W. A. Denny, J.
Med. Chem. 2010, 53, 787–797; d) C. B. Andersen, Y. Wan,
J. W. Chang, B. Riggs, C. Lee, Y. Liu, F. Sessa, F. Villa, N.
Kwiatkowski, M. Suzuki, L. Nallan, R. Heald, A. Musacchio,
N. S. Gray, ACS Chem. Biol. 2008, 3, 180–192; e) A. Satoh, Y.
Nagatomi, Y. Hirata, S. Ito, G. Suzuki, T. Kimura, S. Maehara,
H. Hikichi, A. Satow, M. Hata, H. Ohta, H. Kawamoto, Bi-
oorg. Med. Chem. Lett. 2009, 19, 5464–5468; f) M. Warashina,
K. H. Min, T. Kuwabara, A. Huynh, F. H. Gage, P. G. Schultz,
S. Ding, Angew. Chem. Int. Ed. 2006, 45, 591–593; Angew.
[8] L. Costanzo, A. Giuffrida, G. Guglielmo, V. Ricevuto, Inorg.
Chim. Acta 1979, 33, 29–33.
[9] For the synthesis of 2-iminothiazolines by using cyclization
methods, see: a) J. AbbasiShiran, A. Yahyazadeh, M. Mamagh-
ani, M. Rassa, J. Mol. Struct. 2013, 1039, 113–118; b) S. Bala-
laie, S. Nikoo, S. Haddadi, Synth. Commun. 2008, 38, 2521–
2528; c) H. A. Samimi, M. Mamaghani, K. Tabatabaeian, Het-
erocycles 2008, 75, 2825–2833; d) S. Murru, C.-B. Singh, V.
Kavala, B. K. Patel, Tetrahedron 2008, 64, 1931–1942; e) X. C.
Wang, F. Wang, Z. J. Quan, Z. Zhang, M. G. Wang, J. Hetero-
cycl. Chem. 2006, 43, 1473–1477; f) S. H. Kim, H. Son, G.
Nam, D. Y. Chib, J. H. Kim, Bioorg. Med. Chem. Lett. 2000,
10, 1143–1145; g) J. Quinton, S. Kolodych, M. Chaumonet, V.
Bevilacqua, M.-C. Nevers, H. Volland, S. Gabillet, P. Thuéry,
C. Créminon, F. Taran, Angew. Chem. Int. Ed. 2012, 51, 6144–
6148.
Chem. 2006, 118, 605; g) M. Schnürch, B. Waldner, K. Hilber, [10] For the synthesis of 2-iminothiazolines by using substitution
M. D. Mihovilovic, Bioorg. Med. Chem. Lett. 2011, 21, 2149–
2154; h) P. Furet, G. Bold, T. Meyer, J. Roesel, V. Guagnano,
J. Med. Chem. 2006, 49, 4451–4454; i) B. Narayana, K. K. Vi-
methods, see: a) R. F. Hunter, E. R. Parken, J. Chem. Soc.
1934, 1175–1177; b) A. Miloudi, D. El-Abed, G. Boyer, J. P.
Finet, J. P. Galy, D. Siri, Eur. J. Org. Chem. 2004, 1509–1516.
jaya Raj, B. V. Ashalatha, N. S. Kumari, B. K. Sarojini, Eur. J. [11] For bioactivities of 2-iminothiazolines, see: a) A. Manaka, M.
Med. Chem. 2004, 39, 867–872; j) M. T. Bilodeau, L. D. Rod-
Sato, M. Aoki, M. Tanaka, T. Ikeda, Y. Toda, Y. Yamane, S.
4770
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4765–4771

Toward an Efficient Route to Cell Differentiation Accelerators
Nakaike, Bioorg. Med. Chem. Lett. 2001, 11, 1031–1035; b) N.
Masuda, O. Yamamato, M. Fujii, T. Ohgami, J. Fujiyasu, T.
Kontani, A. Moritomo, M. Orita, H. Kurihara, H. Koga, H.
Nakahara, S. Kageyama, M. Ohta, H. Inoue, T. Hatta, H. Su-
zuki, K. Sudo, Y. Shimizu, E. Kodama, M. Matsuoka, M. Fuji-
wara, T. Yokota, S. Shigeta, M. Baba, Bioorg. Med. Chem.
2004, 12, 6171–6182; c) N. Masuda, O. Yamamato, M. Fujii,
T. Ohgami, J. Fujiyasu, T. Kontani, A. Moritomo, M. Orita,
H. Kurihara, H. Koga, H. Nakahara, S. Kageyama, M. Ohta,
H. Inoue, T. Hatta, H. Suzuki, K. Sudo, Y. Shimizu, E. Kod-
ama, M. Matsuoka, M. Fujiwara, T. Yokota, S. Shigeta, M.
Baba, Bioorg. Med. Chem. 2005, 13, 949–961; d) S. M. Sondhi,
N. Singh, A. M. Lahoti, K. Bajaj, A. Kumar, O. Lozach, L.
Meijer, Bioorg. Med. Chem. 2005, 13, 4291–4299; e) S. M.
Sondhi, J. Singh, A. Kumar, H. Jamal, P. P. Gupta, Eur. J. Med.
Chem. 2009, 44, 1010–1015; f) S. M. Sondhi, R. Rani, P. P.
Gupta, S. K. Agrawal, A. K. Saxena, Mol. Diversity 2009, 13,
357–366; g) S. M. Sondhi, A. D. Dwivedi, J. Singh, P. P. Gupta,
Indian J. Chem. Sect. B 2010, 49, 1076–1082; h) Q. Zhao, C.
Shen, H. Zheng, J. Zhang, P. Zhang, Carbohydr. Res. 2010, 345,
437–441; i) M. M. Ramla, M. A. Omar, A.-M. M. El-Khamry,
H. I. El-Diwani, Bioorg. Med. Chem. 2006, 14, 7324–7332.
[12] For bioactivity of other 2-iminothiazolines, see: a) D. Durr, W.
Traber, Ectoparasiticidal agent containing thiazoline compounds,
CH 615086 A5, 1980 (CAN 92:175787); b) G. B. Chandrakant,
J. G. Naresh, Bioorg. Med. Chem. 2004, 12, 2151–2161; c) A.
Mohsen, E. Omar, N. H. Eshba, J. Pharm. Sci. 1984, 73, 1166–
1168; d) H.-L. Liu, Z. Li, T. Anthonsen, Molecules 2000, 5,
1055–1061.
For bioactivities of pifithrin-α, see: a) P. G. Komarov, E. A.
Komarova, R. V. Kondratov, K. Chritov-Tselkov, J. S. Coon,
M. V. Chernov, A. V. Gudkov, Science 1999, 285, 1733–1737;
b) X. X. Zhu, Q. S. Yu, R. G. Culter, C. W. Culmsee, H. W.
Holloway, D. K. Lahiri, M. P. Mattson, N. H. Greig, J. Med.
Chem. 2002, 45, 5090–5097; c) S. D. Barchechath, R. I. Tawa-
tao, M. Corr, D. A. Carson, H. B. Cottam, J. Med. Chem.
2005, 48, 6409–6422; d) N. Pietrancosta, A. Moumen, R.
Dono, P. Lingor, V. Planchamp, F. Lamballe, M. Bahr, J. L.
Kraus, F. Maina, J. Med. Chem. 2006, 49, 3645–3652.
[13]
[14]
M. T. Bilodeau, L. Rodman, Preparation of thiazole tyrosine
kinase
143:387019).
inhibitors,
US 20050228031 A1,
2005
(CAN
[15] A. A. Haddach, A. Kellemanb, M. V. Deaton-Rewolinski, Tet-
rahedron Lett. 2002, 43, 399–402.
Received: March 3, 2015
Published Online: June 12, 2015
Eur. J. Org. Chem. 2015, 4765–4771
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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