2,4- and 2,5-disubstituted arylthiazoles: Rapid synthesis by C-H coupling and biological evaluation

Article abstract of DOI:10.1002/ejoc.201402129

Life-threatening infections caused by bacteria that have developed resistance to common antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA), have become a serious problem in hospitals and other areas all over the world. Thus, the development of an effective class of antibiotics against these bacteria is an urgent subject. Herein, we report a step-economical and diversity-oriented synthesis of a series of 2-arylidenehydrazinyl-4- arylthiazole and 2-arylidenehydrazinyl-5-arylthiazole analogues that utilizes C-H coupling methodologies. A library of 54 new congeners were synthesized and tested for their biological potential. Moreover, new knowledge regarding the structure-activity relationships (SARs) of these heterobiaryl compounds was collected. Copyright

Full text of DOI:10.1002/ejoc.201402129

Job/Unit: O42129
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FULL PAPER
DOI: 10.1002/ejoc.201402129
2,4- and 2,5-Disubstituted Arylthiazoles: Rapid Synthesis by C–H Coupling
and Biological Evaluation
Lilia Lohrey,[a] Takahiro N. Uehara,[b] Satoshi Tani,[b] Junichiro Yamaguchi,*[b]
Hans-Ulrich Humpf,*[a] and Kenichiro Itami*[b,c]
Keywords: C–H arylation / Thiazoles / Antibiotics / Cross-coupling / Structure–activity relationships
Life-threatening infections caused by bacteria that have de-
veloped resistance to common antibiotics, such as methicil-
lin-resistant Staphylococcus aureus (MRSA), have become a
serious problem in hospitals and other areas all over the
world. Thus, the development of an effective class of antibi-
otics against these bacteria is an urgent subject. Herein, we
report a step-economical and diversity-oriented synthesis of
a series of 2-arylidenehydrazinyl-4-arylthiazole and 2-arylid-
enehydrazinyl-5-arylthiazole analogues that utilizes C–H
coupling methodologies. A library of 54 new congeners were
synthesized and tested for their biological potential. More-
over, new knowledge regarding the structure–activity rela-
tionships (SARs) of these heterobiaryl compounds was col-
lected.
Introduction
and, therefore, it is an attractive scaffold in the pharmaceu-
tical and chemical community.
The proliferation of resistance against different anti-
biotics posed by some bacteria strains has become an ur-
gent challenge in the medical community.[1] Methicillin-re-
sistant Staphylococcus aureus (MRSA), for instance, has re-
ceived growing attention owing to its multiresistance.
Furthermore, other bacteria strains, including Gram-nega-
tive Pseudomonas aeruginosa and some Escherichia coli spe-
cies have developed resistance against common antibiot-
ics.[1,2] Infections caused by these bacteria occur widely but
are naturally focused in hospital facilities. The design of
new antimicrobial agents against multidrug-resistant bacte-
ria is of great importance and provides a steadily growing
field of research for the chemical and pharmaceutical com-
munity. For the effective development of potential anti-
microbial agents, it is mandatory to establish efficient and
diversity-oriented syntheses of compound libraries as well
as fast biological screening systems.[3] In many natural
products and biologically active synthetic compounds, thi-
azole is an important structural motif and building block
Recently, Singh and co-workers as well as Lee and co-
workers reported a new class of 2-arylidenehydrazinyl-4-
arylthiazole analogues that exhibit strong antimicrobial ac-
tivities against S. aureus, Bacillus subtilis, and some Candida
spp.[4]
Other groups also showed the positive biological activity
of these 2,4-disubstituted thiazole derivatives.[5] Tradition-
ally, the synthesis of these thiazole derivatives is ac-
complished by the Hantzsch thiazole synthesis, and the tar-
get compounds are mostly obtained in high yield
(Scheme 1).[6] However, this strategy necessitates the prepa-
ration of a suitable reaction partner for the Hantzsch cycli-
zation for every single target. Moreover, the aryl group at
the C-4 position is fixed, for example, C-5-substituted thi-
azoles such as arylidenehydrazinyl-5-arylthiazole cannot be
generated by this method. The effort required to use this
[a] Institute of Food Chemistry, Westfälische Wilhelms-Universität
Münster,
Corrensstr. 45, 48149 Münster, Germany
E-mail: humpf@uni-muenster.de
http://www.uni-muenster.de/Chemie.lc/en/forschen/humpf/
[b] Institute of Transformative Bio-Molecules (WPI-ITbM) and
Department of Chemistry, Graduate School of Science, Nagoya
University,
Chikusa, Nagoya 464-8602, Japan
E-mail: junichiro@chem.nagoya-u.ac.jp
itami@chem.nagoya-u.ac.jp
http://synth.chem.nagoya-u.ac.jp/
[c] JST, ERATO, Itami Molecular Nanocarbon Project, Nagoya
University,
Nagoya 464-8602, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402129.
Scheme 1. Structure and conventional synthesis of 2-arylidenehyd-
razinyl-4-arylthiazole.
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H.-U. Humpf, K. Itami et al.
FULL PAPER
conventional synthetic strategy and its limitations in the suitable aldehyde would deliver targets 1 and 2 (Scheme 2).
lack of suitable starting materials render a pathway for the We commenced our study by investigating the nucleo-
rapid synthesis of compound libraries from a small set of philic substitution of 2-alkoxy-4-arylthiazoles with hydraz-
building blocks highly desirable.[3a]
ine (Table 1). With 2-methoxy-4-phenylthiazole (5AaЈ) as
In recent years, the transition-metal-catalyzed direct C– the starting material, the treatment with anhydrous hydraz-
H arylation of heteroarenes has emerged as an attractive ine (10 equiv.) as nucleophile (Table 1, Entries 1 and 2) in
and promising alternative to well-established, traditional N,N-dimethylformamide (DMF) or dimethyl sulfoxide
cross-coupling reactions.[7,8] As the C-5 atom of the thiazole (DMSO) gave only trace amounts of the desired product
ring is the most electron-rich (nucleophilic) position, we be- 6Aa, whereas the demethylated product 7 formed in 75 and
came interested in the literature examples of C-5-selective 85% yield, respectively. To prevent demethylation, some
Pd-catalyzed C–H arylation of thiazoles with aryl halides.[9] Lewis acids were examined as additives (Table 1, Entries 3–
In contrast, the regioselective arylation of the least-reactive 5). However, none of the employed Lewis acids favored the
C-4 position has remained elusive. Recently, our group de- nucleophilic substitution and, thus, did not yield 6Aa. Next,
veloped the first example of a Pd-catalyzed C-4-selective a better leaving group was investigated, and the methoxy
oxidative C–H arylation of thiazoles with arylboronic acids. group was changed to a phenoxy group (compound 5Aa).
It is crucial to employ Pd(OAc)2/phen (phen = 1,10-phen- Surprisingly, the use of DMF resulted in no observable con-
anthroline) as a catalyst and 2,2,6,6-tetramethylpiperidine version of the starting material (Table 1, Entry 6), whereas
1-oxyl (TEMPO) as an oxidant, respectively.[8d]
DMSO gave the desired 6Aa in 52% yield without the for-
As a part of our program focusing on synthesis-oriented mation of 7 (Table 1, Entry 7). Finally, the yield can be im-
methodology development, we established a step-economi- proved to 85% by increasing the amount of hydrazine to
cal and rapid synthesis of a series of new 2-arylidenehydraz- 20 equiv. (Table 1, Entry 8).
inyl-4-arylthiazole and 2-arylidenehydrazinyl-5-arylthiazole
Table 1. Nucleophilic substitution of 2-alkoxy-4-phenylthiazole
analogues that utilizes C–H coupling methodologies. The
scope of this new method is demonstrated, and preliminary
with hydrazine.[a]
results of the biological screening are reported herein.
Results and Discussion
Our synthetic strategy toward 2-arylidenehydrazinyl-4-
arylthiazoles 1 as well as 2-arylidenehydrazinyl-5-arylthi-
Entry
R
Solvent
Lewis
acid
Yield of 6Aa
Yield of 7
azoles 2 is outlined in Scheme 2. With this plan in mind,
we developed a route for the synthesis of target compounds
1 and 2 from simple building blocks in a step-economical
fashion by utilizing C–H coupling methodologies.
To investigate and to compare the biological activity of
the structurally related compounds 1 and 2, the aryl group
introduced at the C-4 and C-5 positions should be identical.
We targeted a thiazole core bearing an alkoxy group at the
C-2 position. Subsequent to the C–H coupling reaction at
the C-4 or C-5 position of alkoxythiazoles 3, the alkoxy
group of the obtained coupling products 5A and 5B could
be readily displaced by hydrazine in a nucleophilic substitu-
[%][b]
[%][b]
1
2
Me
Me
Me
Me
Me
Ph
DMF
DMSO
DMSO BF3·OEt2
DMSO
DMSO
DMF
DMSO
DMSO
–
–
Ͻ1
Ͻ1
Ͻ1
Ͻ1
n.d.
75
85
46
68
20
n.d.
n.d.
n.d.
3[c]
4[c]
5[d]
6
Sc(OTf)3
Yb(OTf)3
–
–
–
Ͻ1
7
8
Ph
Ph
56 (52)
90 (85)[e]
[a] Reaction conditions: 5AaЈ (1.0 equiv.), Lewis acid (1.0 equiv.),
100 °C, 12 h. [b] Yields were determined by LC–UV–MS. The num-
bers in parentheses for Entries 7 and 8 are the yield of isolated
product; n.d.: not detected. [c] The reaction time was 6 h. [d] The
tion (6A and 6B), after which a final condensation with a reaction time was 21 h. [e] 20 equiv. of hydrazine was used.
Scheme 2. A C–H coupling strategy for the synthesis of target compounds 1 and 2.
2
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Synthesis of Disubstituted Arylthiazoles
Having the optimized conditions for the nucleophilic thiazole 3A (Scheme 4). Initially, our previous catalytic sys-
substitution in hand, we next examined the crucial step of tem PdCl2/2,2Ј-bipyridyl/Ag2CO3 afforded 5Ba in low
the C-4-selective C–H arylation of 2-phenoxythiazole (3A) yields (17%).[9e,10] Similar conditions published by Miura
on the basis of our previous work on the C-4-selective C– et al. in which Pd(OAc)2/PPh3/Cs2CO3 is used led to equally
H arylation of thiazoles.[8d] After a short optimization of unsatisfactory results and yielded 5Ba in 15% yield.[8a]
the reaction conditions, the best results were achieved with Eventually, the conditions reported by Greaney and co-
3A (R = Ph, 1.0 equiv.), phenylboronic acid (4a, 4.0 equiv.), workers in which [Pd(dppf)Cl2]·CH2Cl2/PPh3/Ag2CO3
LiBF4 (1.5 equiv.), and TEMPO (0.5 equiv.) in the presence [dppf = 1,1Ј-bis(diphenylphosphino)ferrocene] is employed
of 10 mol-% of Pd(OAc)2, and 1,10-phenanthroline (phen) gave full conversion and 96% isolated yield of 5Ba.[9b]
in dimethylacetamide (DMAc) at 100 °C for two days under
air, which led to an isolated yield of 40% of arylthiazole
5Aa with almost complete C-4-selectivity (Scheme 3). Sim-
ilar yields were obtained with electron-rich arylboronic ac-
ids (to yield products 5Ag, 5Ah, 5Ak, and 5Am), whereas
arylboronic acids bearing electron-deficient substituents re-
sulted in decreased yields (of products 5Ab, 5Ac, 5Ad, 5Ai,
5Aj), in accordance with our previous studies.[9] meta-Sub-
stituted arylboronic acids are not tolerated well and afford
low yields (of product 5Ae). Thus, thiazole 3A can be aryl-
ated regioselectively at the C-4 position by using the
Scheme 4. Screening of conditions for the direct C-5-selective C–H
arylation of thiazole 3A with haloarenes.
Pd(OAc)2/phen/TEMPO catalyst system and tolerates a
wide range of substituted arylboronic acids to afford the
products in good-to-moderate yields.
Under these promising conditions, 3A was treated with
various iodoarenes to give the corresponding C-5-arylated
thiazoles 5Ba–5Bo in good-to-excellent yields (Scheme 5).
Scheme 3. Scope of the reaction of 2-phenoxythiazole with respect
to arylboronic acid coupling partners.
As the C-5 atom of the thiazole ring is most accessible
to electrophiles, many protocols for the C-5-selective Pd-
catalyzed C–H arylation with haloarenes have been de-
Scheme 5. Scope of the reaction of 2-phenoxythiazole with respect
scribed;[9] among these, we tested several methods to arylate to iodoarene coupling partners.
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H.-U. Humpf, K. Itami et al.
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Electron-rich (to yield 5Bf–5Bh, 5Bk, and 5Bm) as well as Gram-negative bacterial strains, P. aeruginosa and E. coli.
electron-poor iodoarenes (to yield 5Bb–5Be, 5Bi, and 5Bj) Furthermore, the activities against one yeast strain, Can-
were tolerated. Surprisingly, the sterically hindered 1- dida glabrata, and one dermatophytic fungus, Trichophyton
naphthyl iodide (to yield 5Bn) and the strongly coordinat- mentagrophytes, were also tested. The cytotoxicity of these
ing heteroarene 3-iodopyridine (to yield 5Bo) could be in- compounds was evaluated on a human colon adenocarci-
stalled successfully on the thiazole ring in good yields.
noma cell line (HT-29) as well as on a mouse fibroblast
With the above C-4- and C-5-arylated thiazoles in hand, cell line (NIH-T3). The screening was performed at three
we performed the nucleophilic substitution with hydrazine, different concentration levels of the compounds (10, 50, and
and the corresponding 2-hydrazinyl-4-arylthiazoles 3A and 100 μm) in triplicate. The inhibitory activities are displayed
2-hydrazinyl-5-arylthiazoles 3B were obtained. The conden- in relation to specified control substances for which the
sation of 3A and 3B with p-bromobenzaldehyde and p-anis- highest inhibition is 100%. The antibacterial screening re-
aldehyde afforded the corresponding products 1A, 1B, 2A, vealed that none of the newly synthesized compounds exhi-
and 2B in high yields after purification by reversed-phase bit activity against Gram-negative bacteria strains, a finding
liquid chromatography (Table 2).
that is in agreement with previous studies.[4] In contrast,
The newly synthesized compounds (1A, 1B, 2A, and 2B) moderate-to-good inhibitory activities were observed
were tested for their activity (Figure 1) against two Gram- against Gram-positive bacteria strains. As Gram-negative
positive bacterial strains, B. subtilis and MRSA, and two bacteria have an inner and outer cell membrane, as opposed
Table 2. Synthesis of 2-arylidenehydrazinyl-4-arylthiazole (1A and 1B) and 2-arylidenehydrazinyl-5-arylthiazole (2A and 2B).
Entry
Compound
Ar
R
Yield [%]
Entry
Compound
Ar
R
Yield [%]
1
2
3
4
5
6
7
8
1Aa
1Ab
1Ac
1Ad
1Ae
1Af
1Ag
1Ah
1Ai
C6H5
4-ClC6H4
4-BrC6H4
4-FC6H4
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
71
53
73
47
65
66
69
69
70
59
29
33
61
70
67
72
47
48
49
65
70
34
31
62
39
56
89
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
1Ba
1Bb
1Bc
1Bd
1Be
1Bf
1bg
1Bh
1Bi
C6H5
4-ClC6H4
4-BrC6H4
4-FC6H4
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
63
49
61
49
67
50
69
55
61
50
28
36
60
83
73
65
65
49
42
60
78
32
30
50
48
59
60
3-ClC6H4
3-ClC6H4
4-MeC6H4
3,5-(Me)2C6H3
4-tBuC6H4
4-CF3C6H4
4-OCF3C6H4
4-NHAcC6H4
4-OMeC6H4
C6H5
4-ClC6H4
4-BrC6H4
4-FC6H4
3-ClC6H4
4-MeC6H4
3,5-(Me)2C6H3
4-tBuC6H4
4-CF3C6H4
4-OCF3C6H4
4-NHAcC6H4
4-MeC6H4
3,5-(Me)2C6H3
4-tBuC6H4
4-CF3C6H4
4-OCF3C6H4
4-NHAcC6H4
4-OMeC6H4
C6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
3-ClC6H4
4-MeC6H4
3,5-(Me)2C6H3
4-tBuC6H4
4-CF3C6H4
4-OCF3C6H4
4-NHAcC6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
1Aj
1Bj
1Ak
1Am
2Aa
2Ab
2Ac
2Ad
2Ae
2Af
2Ag
2Ah
2Ai
2Aj
2Ak
2Al
2Am
2An
2Ao
1Bk
1Bm
2Ba
2Bb
2Bc
2Bd
2Be
2Bf
2Bg
2Bh
2Bi
2Bj
2Bk
2Bl
2Bm
2Bn
2Bo
benzo[d][1,3]dioxole Br
benzo[d][1,3]dioxole OMe
4-OMeC6H4
1-naphthalenyl
3-pyridyl
Br
Br
Br
4-OMeC6H4
1-naphthalnyl
3-pyridyl
OMe
OMe
OMe
4
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Synthesis of Disubstituted Arylthiazoles
to the single membrane of Gram-positive bacteria, we as- activity was observed against B. subtilis. Of 54 compounds
sume that the additional membrane could be one limiting examined, 14 compounds showed an inhibition of more
factor for the activity of this class of compounds. The best than 50% for all three concentrations tested. The most po-
Figure 1. Biological activities of 1Aa–1Am, 1Ba–1Bm, 2Aa–2Ao, and 2Ba–2Bo.
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H.-U. Humpf, K. Itami et al.
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tent compound was 2Bn with 78% inhibition at 10 μm incu- exhibited the highest inhibition relative to that of the speci-
bation and 95% inhibition at 100 μm incubation relative to fied control substance. At concentration levels of 10 μm, in-
the control substance. Furthermore, good inhibitory activi- hibitions of 31 (1Ba) and 29% (1Bf) were obtained; at
ties were detected for 1Aj (65% inhibition at 10 μm and 100 μm concentration, inhibitions of 100 (1Ba) and 93%
81% inhibition at 100 μm), 2Bj (65% inhibition at 10 μm (1Bf) were observed. Compound 2Bo also showed moderate
and 48% inhibition at 100 μm), and 2Ad (70% inhibition at activity (65% inhibition at 100 μm). One can assume that
10 μm and 32% inhibition at 100 μm). Surprisingly, the two the methoxy group at the R position is mandatory for ac-
latter compounds showed less activity at higher concentra- tivity against T. mentagrophytes as the structural analogues
tions, possibly because of solubility issues in the given me- of the active compounds with a bromine tom at the R posi-
dium. This phenomenon of reduced or steady inhibition as tion (1Ab, 1Af, and 2Ao) showed no activity.
the concentration increased was also observed for other
The cytotoxicity evaluation was performed with two dif-
substances (2Ab, 2Bb, 2Ac, 2Bc, 2Ad, 2Ae, 2Af, 2Bi, 2Aj, ferent cell lines (NIH-3T3 and HT-29) at two different con-
2Bj, and 2An). Concerning the structure–activity relation- centration levels (10 and 50 μm). At a concentration of
ship (SAR) of the tested compounds against B. subtilis, it 10 μm, no effect was observed against both cell lines. At
is noticeable that the aryl group at the C-5 position is man- 50 μm, it is worth noting that nine compounds showed no-
datory for activity (2Ab, 2Bb, 2Ae, 2Ad, 2Ac, 2Bc, 2Bi, 2Aj, table activities (over 50%) against NIH-3T3, and 2Bh
2Bj, 2Bh, 2An, 2Bn, and 2Af), as the structural analogues (90%) was the most potent. Among all tested compounds,
of these compounds (i.e., those arylated at the C-4 position) only 2Bh exhibited moderate activity against HT-29 cells
showed less or no activity. Interestingly and in contrast to (53%). The SAR of the cytotoxicity evaluation revealed
these observations, 1Aj exhibits similar activity at 10 μm that compounds arylated at the C-5 position of the thiazole
concentration (65%) and even stronger activity at 100 μm showed higher cytotoxicity than their analogues arylated at
concentration (81%) than its structural analogue 2Bj (68% the C-4 position.
at 10 μm and 75% at 100 μm). Regarding the substituents
Finally, the highest biologically active compounds
at the C-5 phenyl ring, it can be concluded that electron- against B. subtilis, MRSA, dermatophyte T. mentagrophytes,
withdrawing substituents such as halogens (in 2Ab, 2Bb, and NIH-3T3 are summarized in Figure 2.
2Ae, 2Ad, 2Ac, and 2Bc) or a trifluoromethoxy group (in
1Aj, 2Aj, and 2Bj) showed higher activity compared to
compounds without any substituents (2Aa, 2Ba, 1Aa, and
1Ba). This might be due to the higher lipophilicity of these
compounds, which is an important parameter in medicinal
chemistry because it facilitates cellular penetration.[11]
Compounds with electron-donating substituents (2Bh, 2An,
2Bn, and 2Af) also exhibited good activities against B. sub-
tilis. Owing to the comparable activity of 2Ab (para-Cl sub-
stitution) and 2Ae (meta-Cl substitution), the activity is
likely not dependent on the position of the substituent.
Some of the tested compounds exhibited activity against
MRSA. Compound 1Aj showed the highest inhibition of
78% at 10 μm and 90% at 100 μm; this was similar to the
activity of 1Ai, which displayed high inhibition at 10 μm
(76%) but no inhibition at 100 μm, possibly because of solu-
bility issues as already mentioned above. In general, the fol-
lowing can be stated about the SAR of the compounds
against MRSA: of all tested compounds, the ones that are
arylated at the C-4 position and have a bromine substituent
at the R position (1Ab, 1Ae, 1Ad, 1Aj, and 1Ai) showed
good activities. In contrast, structural analogues that are
arylated at the C-5 position or have a methoxy substituent
at the R position showed less activity or no activity. In ad-
dition, we observed that the introduction of electron-with-
drawing groups (halogen, CF3, or OCF3) led to higher ac-
tivities.
The antifungal screening results revealed that none of the
synthesized compounds showed activity against the yeast C.
Figure 2. Summary of the biological testing.
Conclusions
We have established a new step-economical and diversity-
glabrata, whereas we observed moderate activities at lower oriented synthesis of 2-arylidenehydrazinyl-4-arylthiazoles
concentrations (10 μm, 50 μm) and good activities at higher 1 and 2-arylidenehydrazinyl-5-arylthiazoles 2 that utilizes
concentrations (100 μm) of some compounds against the C-4-selective and C-5-selective C–H coupling methodolo-
dermatophyte T. mentagrophytes. Compounds 1Ba and 1Bf gies. The coupling of different arylboronic acids and aryl
6
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Synthesis of Disubstituted Arylthiazoles
5Ba–5Bo (1.0 equiv.) and DMSO (0.5 mL). To this solution, anhy-
drous hydrazine (20 equiv.) was added, and the reaction mixture
was stirred at 100 °C for 12 h in an eight-well reaction block. Purifi-
cation by preparative MPLC afforded the desired thiazoles 6Aa–
6Am or 6Ba–6Bo. To a stirred solution of 6Aa–6Am or 6Ba–6Bo
in EtOH/MeOH (v/v 1:1, 4 mL), the corresponding aldehyde
(1.2 equiv.) and a catalytic amount of AcOH were added, and the
reaction mixture was stirred at 80 °C for 1 h in an eight-well reac-
tion block. Purification by preparative MPLC afforded the corre-
sponding 2-(arylidenehydrazinyl)-arylthiazoles 1Aa–1Am, 1Ba–
iodides with 2-phenoxythiazole (1) and subsequent nucleo-
philic substitution with hydrazine and condensation with
p-bromobenzaldehyde or p-anisaldehyde led to the target
compounds. The present work highlights the power of C–
H-functionalization to medicinal chemistry and drug devel-
opment; it allows an efficient and facile coupling of simple
and readily available components and, thereby, facilitates
the setup of highly diverse substance libraries. By applica-
tion of this strategy, we were able to rapidly create a library
of 54 new 2-arylidenehydrazinyl-4-arylthiazole (1Aa–m and 1Bm, 2Aa–2Ao, and 2Ba–2Bo.
1Ba–m) and 2-arylidenehydrazinyl-5-arylthiazole (2Aa–o
Supporting Information (see footnote on the first page of this arti-
and 2Ba–o) analogues, which were tested extensively for
their biological activity. In particular, the thiazole derivative
1Aj, arylated at the C-4 position with a 4-trifluoromethoxy-
phenyl substituent and a bromine atom at the R position,
exhibited high antibacterial activity against Gram-positive
bacteria strains. The thiazole derivative 1Ba was the most
potent compound in the antifungal screening. The evalu-
ation of the cytotoxicity revealed the high activity exhibited
by thiazole derivative 2Bh. Moreover, important infor-
mation about the structure-activity relationship of these
classes of thiazoles has been gained by this biological evalu-
cle): Experimental details and copies of the 1H and 13C NMR spec-
tra of all new compounds.
Acknowledgments
This work was supported by the Japan Society for the Promotion of
Science (JSPS) through the Funding Program for Next Generation
World-Leading Researchers from (grant 220GR049, to K. I.) and
by Japanese Ministry of Education, Culture, Sports, Science and
Technology (MEXT) through a Grant-in-Aid for Scientific Re-
search on Innovative Areas “Molecular Activation Directed toward
ation. As a result of this new synthetic pathway and the Straightforward Synthesis” (grant 25105720, to J. Y.) and KAK-
ENHI (grant 25708005 to J. Y.). The ITbM is supported by the
World Premier International Research Center (WPI) Initiative, Ja-
pan. This work was performed within the framework of the Inter-
national Research Training Group (IRTG) “Complex Functional
Systems in Chemistry: Design, Synthesis and Applications” in col-
laboration with the University of Nagoya. The authors thank the
Deutsche Forschungsgemeinschaft (DFG) for funding (GRK1143,
IRTG Münster–Nagoya) and the Kiel drug center at the Helmholtz
Centre of Ocean Research (GEOMAR) for biological screening.
gathered SAR knowledge, this work will be beneficial for
the future design and synthesis of new analogues to pro-
mote the discovery of new antimicrobial agents.
Experimental Section
General Procedure for C-4-Selective C–H Arylation of 3A with Aryl-
boronic Acids: To a sealed tube, Pd(OAc)2 (22.5 mg, 0.1 mmol, 10
mol-%), 1,10-phenanthroline (18.0 mg, 0.1 mmol, 10 mol-%),
LiBF4 (140.6 mg, 1.5 mmol, 1.5 equiv.), the corresponding aryl-
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boronic acid
4 (4 mmol, 4.0 equiv.), 2-phenoxythiazole (3A;
177 mg, 1 mmol, 1.0 equiv.), TEMPO (78 mg, 0.5 mmol,
0.5 equiv.), and DMAc (2 mL) were added, and the mixture was
heated at 100 °C for 48 h in an eight-well reaction block. After
cooling, the mixture was filtered through a short silica gel pad with
EtOAc (50 mL). Concentration of the filtrate under reduced pres-
sure and purification by silica gel flash column chromatography
afforded the desired 2-phenoxy-4-arylthiazole 5A.
General Procedure for C-5-Selective C–H Arylation of 3A with Aryl
Iodides: To a sealed tube, [Pd(dppf)Cl2]·CH2Cl2 (20.4 mg, 25 μmol,
5 mol-%), PPh3 (13 mg, 50 μmol, 10 mol-%), Ag2CO3 (275.8 mg,
1.0 mmol, 2.0 equiv.), the corresponding aryl iodide 4 (0.6 mmol,
1.2 equiv.), 3A (88.5 mg, 0.5 mmol, 1.0 equiv.), and H2O (3 mL)
were added, and the mixture was stirred at 60 °C for 24 h in an
eight-well reaction block. After cooling to room temperature, the
mixture was filtered through a short Celite pad, washed with
CH2Cl2 (15 mL) and acetone (15 mL), and concentrated under re-
duced pressure. CH2Cl2 (10 mL) and brine (10 mL) were added to
the solid residue, and the organic layer was separated. The aqueous
layer was extracted with CH2Cl2 (2ϫ 10 mL). The organic layers
were combined and dried with Na2SO4, and the volatiles were re-
moved under reduced pressure. Purification by flash column
chromatography afforded the desired 2-phenoxy-5-arylthiazoles 5B.
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azoles: To a flame-dried screw-capped test tube equipped with a
magnetic stir bar was added 2-phenoxy-arylthiazole 5Aa–5Am or
Eur. J. Org. Chem. 0000, 0–0
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Date: 10-04-14 18:56:44
Pages: 9
H.-U. Humpf, K. Itami et al.
FULL PAPER
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Received: February 21, 2014
Published Online: ᭿
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Pages: 9
Synthesis of Disubstituted Arylthiazoles
C–H Activation
L. Lohrey, T. N. Uehara, S. Tani,
J. Yamaguchi,* H.-U. Humpf,*
K. Itami* .......................................... 1–9
2,4- and 2,5-Disubstituted Arylthiazoles:
Rapid Synthesis by C–H Coupling and
Biological Evaluation
Keywords: C–H arylation / Thiazoles /
Antibiotics / Cross-coupling / Structure–
activity relationships
We have established a step-economical and
diversity-oriented synthesis of 2-arylid-
enehydrazinyl-4-arylthiazoles and 2-arylid-
enehydrazinyl-5-arylthiazoles that utilizes
C-4- and C-5-selective C–H coupling meth-
odologies. A rapidly created library of 54
new 2-arylidenehydrazinyl-4-arylthiazole
and 2-arylidenehydrazinyl-5-arylthiazole
analogues were tested extensively for their
biological activity.
Eur. J. Org. Chem. 0000, 0–0
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