Gold-catalyzed oxazoles synthesis and their relevant antiproliferative activities

Article abstract of DOI:10.1016/j.cclet.2013.06.026

Nine 5-aryl-2-methyloxazole derivatives were synthesized via gold-catalyzed alkyne oxidation. All of the compounds have been screened for their antiproliferative activities against MCF-7 cell (human breast carcinoma), A549 cell (human lung carcinoma) and

Full text of DOI:10.1016/j.cclet.2013.06.026

Chinese Chemical Letters 24 (2013) 1064–1066
Contents lists available at SciVerse ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Gold-catalyzed oxazoles synthesis and their relevant antiproliferative
activities
*
*
Chao Wu, Zhi-Wu Liang, Ying-Ying Xu, Wei-Min He , Jian-Nan Xiang
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Nine 5-aryl-2-methyloxazole derivatives were synthesized via gold-catalyzed alkyne oxidation. All of
the compounds have been screened for their antiproliferative activities against MCF-7 cell (human
breast carcinoma), A549 cell (human lung carcinoma) and Hela cell (human cervical carcinoma) lines in
vitro. The results revealed that compounds 1b, 1c and 1d exhibited strong inhibitory activities against
Received 3 May 2013
Received in revised form 5 June 2013
Accepted 15 June 2013
Available online 26 July 2013
the MCF-7 cell lines (with IC50 values of 4.6, 9.7 and 2.2
mmol/L, respectively).
ß 2013 Wei-Min He and Jian-Nan Xiang. Published by Elsevier B.V. on behalf of Chinese Chemical
Keywords:
Society. All rights reserved.
Oxazole
Synthesis
Gold-catalyzed
Biological activity
1. Introduction
reaction solvent, was reported, offering a generally efficient
synthesis of 2,5-disubstituted oxazoles [12]. To the best of our
knowledge, research on the synthesis and applications of gold-
catalyzed oxazoles has beenvirtuallynonexistent inpharmaceutical
literature. Herein, we report the gold-catalyzed synthesis of a
number of 5-aryl-2-methyloxazoles and their cytotoxic effects
against MCF-7, A549 and Hela cancer cell lines in vitro.
Among the multiple heterocyclic moieties of biological and
pharmacological interest, the oxazole ring has gained considerable
attention in past decades [1]. In particular, 2,5-disubstituted
oxazoles are important substructures in various natural products
[2] and show activity against inflammation [3], diabetes [4],
bacterial infection [5], cardiovascular disease [6], and cancer [7].
Accordingly, many strategies have been developed for their
synthesis [8]. Robinson–Gabriel oxazole synthesis is a widely
used method, but the reaction needs hazardous reagents such as
2. Experimental
The alkynes 2b–2g, 2i were prepared according to the strategy
described in Scheme 1 by a modified literature method [13]. In
general, reactions of halides 5, the starting materials, with
1.3 equiv. of trimethylsilylacetylene using catalytic quantities of
bis(triphenylphosphine) palladium(II) chloride and copper iodide
in diisopropyl-amine afforded protected alkynes 3. Hydrolysis of 3
in methanol using anhydrous potassium carbonate led to the
formation of the products alkynes 2b–2g, 2i, yield 78%–91% after
two steps. Ferrocenylacetylene 2h was prepared as shown in
H2SO4, PCl5 or POCl3 [9]. In addition, a-diazoketones, the starting
materials of the reaction, are dangerous and not readily commer-
cially available. Gold-mediated homogeneous catalysts, because of
their unique properties, have now become one of the hot topics in
the organic chemistry [10]. Among various types of gold catalysis,
the research of
a-oxo gold carbene intermediates has contributed
significantly to the diversity and versatility of gold chemistry. Gold
carbene intermediates generated via gold-catalyzed activation of
C–C multiple bonds and subsequently attacked by a nucleophilic
reagent such as imine and alkoxy, has proven to be an exceptionally
powerful method to construct new C–C and C–N bonds [11].
Recently, the first efficient intermolecular reaction of gold carbene
intermediates, using nitriles as both the reacting partner and the
Scheme
2 [14]. In the initial step, (2-formy-1-chlorovinyl)
ferrocene 6 was synthesized via the reaction of acetylferrocene
with Vielsmeier complex prepared from phosphorus oxychloride
and DMF in an ice bath. Then the treatment of the alkene 6 with
sodium hydroxide solution afforded the corresponding ferroceny-
lacetylene 2h.
Oxazoles 1 were prepared from alkynes under the reaction
conditions of Table 1 and the progress of the reaction was
monitored by TLC. Compounds 1 were purified by column
chromatography on silica gel in 68%–94% yield. All of them were
* Corresponding authors.
E-mail addresses: wmhe@hnu.edu.cn (W.-M. He), jnxiang@hnu.edu.cn
(J.-N. Xiang).
1001-8417/$ – see front matter ß 2013 Wei-Min He and Jian-Nan Xiang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.06.026

C. Wu et al. / Chinese Chemical Letters 24 (2013) 1064–1066
1065
a
b
R
X
R
TMS
R
5
3
2
5b: 2-bromonaphthalene
5d: 3-bromoquinoline
5c: 3-bromopyridine
5e: 3-bromothiophene
Scheme 2. Reagents and condition: (a) POCl3, DMF; (b) NaOH, dioxane, reflux.
5f: 3-bromobenzo[b]thiophene
5g: 3-iodo-1-tosyl-1H-indole 5i: 2-iodobenzo[d]thiazole
Table 2
Screening of reaction conditions.a
Scheme 1. Reagents and condition: (a) Pd(PPh3)2Cl2, CuI, (i-Pr)2NH, TMSacetylene;
(b) K2CO3, MeOH.
N
[Au] (5 mol %), [O] (1.3 equiv)
CH3CN, 60 oC, 3 h
Me
O
.
Table 1
R= H, 4a
Me, 4b
Gold-catalyzed synthesis of oxazoles 1.a
2a
1a
N
O
Et, 4c
N
R
i-Pr, 4d
Ph3PAuCl/AgSbF6 (5 %)
.
4c (1.3 eq), CH3CN, 60 oC
Entry
Gold catalyst
Oxidant
Yield (%)b
R
R
Me
O
1
c
1
2
Ph3PAuCl/AgNTf2
Ph3PAuCl/AgNTf2
Ph3PAuCl/AgNTf2
Ph3PAuCl/AgNTf2
Ph3PAuCl/AgNTf2
Cy3PAuCl/AgNTf2
(4-CF3Ph)3PAuCl/AgNTf2
Cy-JohnPhosAuCl/AgNTf2
XJohnPhosAuCl/AgNTf2
BrettPhosAuCl/AgNTf2
Ph3PAuCl/AgClO4
Ph3PAuCl/AgBF4
4b
4b
4a
4c
4d
4c
4c
4c
4c
4c
4c
4c
4c
4c
69
91
78
93
81
80
79
83
87
88
37
45
74
94d
2
Entry
1
Substrate
Product
Yield (%)b
91
3
4
2b
1b
1c
N
5
Me
6
O
7
2
2c
68
8
N
9
Me
N
O
10
11
12
13
14
N
3
4
5
2d
2e
2f
1d
1e
1f
72
81
73
Ph3PAuCl/AgOTf
O
Me
Ph3PAuCl/AgSbF6
N
a
Reaction conditions: In vial; [1a] = 0.1 mol/L.
Estimated by 1H NMR spectroscopy using diethyl phthalate as an internal
N
b
Me
N
O
reference.
S
c
Reaction at r.t.
d
Isolated yield of 93%.
Me
O
worked equally well, we chose Ph3PAuCl/AgSbF6 as the catalyst
for economic reasons.
S
6
7
2g
2h
1g
1h
75
89
N
In the screening assay studies, a series of compounds 1a–1i
were evaluated against three cell lines: MCF-7 (Human breast
carcinoma), A-549 (Human lung carcinoma) and Hela (Human
cervical carcinoma). Cis-dichlorodiamineplatinum(II) (cis-DDP)
was used as the reference substance. As shown in Table 3,
compounds 1b, 1c, 1d, 1f and 1g are the active molecules against
various cell lines. The compound 1b exhibited excellent inhibitory
activity against all the cancer cell lines and the IC50 values even
compared well with cis-DDP.
S
Me
O
N
N
Me
O
Fe
8
2i
6
84
N
Introduction of a benzene group increased biological activity, as
demonstrated by the IC50 value difference between the pairs 1c and
1d and 1e–1f. It is interesting to note that the compounds with
nitrogen heterocyclic groups as the substituents exhibited higher
activities than those with sulfur heterocyclic groups. The compound
1d with quinoline showed the best selective cytotoxicity against
O
Me
TsN
a
In vial; [1] = 0.3 mol/L.
b
Isolated yields are given.
confirmed by 1H NMR and HRMS spectra [15]. The presence of
nitrogen or sulfur in heteroaryl substituents would reduce the
activity of gold catalyst.
Table 3
Cytotoxicity of oxazoles 1a–1i against MCF-7, A549 and Hela cancer cell.
3. Results and discussion
Compound
Cell line/IC50
MCF-7
(
m
mol/L)a
Based on Zhang’s work [12], we further screened the reaction
conditions, using phenylacetylene as the substrate. Compared to
ambient temperature, the reaction proceeded faster at 60 8C
(Table 2, entries 1 and 2).
Different quinoline N-oxides were tested (Table 2, entries 2–5),
8-ethylquinoline N-oxide (4c) was the best among the oxidants
examined. As the use of LAuCl/AgX is becoming more widespread
in gold chemistry [16], we envisioned the possibility of increasing
the chemical yield of the reaction sequence by examining the roles
of the ligand and counterion (Table 2, entries 6–14). Though other
gold catalysts (e.g., Ph3PAuCl/AgNTf2, BrettPhosAuCl/AgNTf2)
A549
Hela
1a
>100
>100
>100
1b
4.6 ꢀ 0.2
9.7 ꢀ 0.2
2.2 ꢀ 0.1
>100
6.5 ꢀ 0.1
85.6 ꢀ 1.0
32.9 ꢀ 0.5
>100
7.8 ꢀ 0.2
82.7 ꢀ 1.6
46.7 ꢀ 0.3
>100
1c
1d
1e
1f
28.7 ꢀ 0.3
32.9 ꢀ 0.4
>100
>100
>100
1g
64.6 ꢀ 0.6
79.0 ꢀ 0.6
46.7 ꢀ 0.2
6.8 ꢀ 0.4
92.4 ꢀ 1.1
83.2 ꢀ 0.5
78.0 ꢀ 0.3
3.7 ꢀ 0.2
1h
1i
82.9 ꢀ 0.3
2.3 ꢀ 0.1
cis-DDP
a
Data represent the mean values of three independent determinations.

1066
C. Wu et al. / Chinese Chemical Letters 24 (2013) 1064–1066
[10] (a) A.S.K. Hashmi, Gold-catalyzed organic reactions, Chem. Rev. 107 (2007)
MCF-7celllineswiththeIC50 valuesof2.2
slightly better than cis-DDP serving as a positive control. Except for
1b, the products exhibited poor activity against Hela and A549 cell
mmol/L, andthevaluewas
3180–3211;
(b) A. Corma, A. Leyva-Perez, M. Sabater, et al., Gold-catalyzed carbon–heteroat-
om bond-forming reactions, Chem. Rev. 111 (2011) 1657–1712;
(c) A.S.K. Hashmi, C. Hubbert, Gold and organocatalysis combined, Angew. Chem.
Int. Ed. 49 (2010) 1010–1012;
(d) B. Alcaide, P. Almendros, J. Alonso, Gold catalyzed oxycyclizations of alkynols
and alkyndiols, Org. Biomol. Chem. 9 (2011) 4405–4416.
lines (more than 30
mmol/L). Usually, ferrocene groups elicit a broad
range of biological activities, such as anti-inflammatory, anti-
malaria, antimicrobial, anticancer properties [17]. Unfortunately,
the compound 1h with a ferrocene group did not exhibit good
activity as expected.
[11] (a) J. Xiao, X.W. Li, Gold a-oxo carbenoids in catalysis: catalytic oxygen-atom
transfer to alkynes, Angew. Chem. Int. Ed. 50 (2011) 7226–7236;
(b) B. Lu, C.Q. Li, L.M. Zhang, Gold-catalyzed highly regioselective oxidation of C–
C triple bonds without acid additives: propargyl moieties as masked a,b-unsat-
urated carbonyls, J. Am. Chem. Soc. 132 (2010) 14070–14072;
4. Conclusion
(c) L.W. Ye, W.M. He, L.M. Zhang, A flexible and stereoselective synthesis of
azetidin-3-ones through gold-catalyzed intermolecular oxidation of alkynes,
Angew. Chem. Int. Ed. 50 (2011) 3236–3239.
A series of 5-aryl-2-methyloxazoles were prepared and studied
for their cytotoxicity against various cancer cell lines. Of the
synthesized oxazoles, compound 1b was found to be most
cytotoxic against cancer cell lines. In addition, compound 1c and
1d were highly selective against MCF7 cancer cell lines. The
structure–activity relationship study showed that naphthalen-2-yl
and quinolin-3-yl at the C-5 position of the oxazole ring are
important for the activity and selectivity of 5-aryl-2-methylox-
azoles.
[12] W.M. He, C.Q. Li, L.M. Zhang, An efficient [2 + 2 + 1] synthesis of 2,5-disubstituted
oxazoles via gold-catalyzed intermolecular alkyne oxidation, J. Am. Chem. Soc.
133 (2011) 8482–8485.
[13] (a) T. Sakamoto, M. Shiraiwa, Y. Konodo, et al., A facile synthesis of ethynyl-
substituted six-membered n-heteroaromatic compounds, Synthesis (1983) 312–
314;
(b) A. Gangjee, J. Yu, R. Kisliuk, 2-Amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyn-
midines as potential inhibitors of thymidylate synthase, J. Heterocyclic Chem. 39
(2002) 833–840;
(c) J.J. Qi, C.H. Tung, Development of benzothiazole ‘click-on’ fluorogenic dyes,
Bioorg. Med. Chem. Lett. 21 (2011) 320–323.
[14] (a) M. Rosenblum, N. Brawn, J. Papenmeier, et al., Synthesis of ferrocenylacety-
lenes, J. Organometal. Chem. 6 (1966) 173–180;
Acknowledgments
(b) A. Aguilar, A. Allen, E. Cabrera, et al., Ferrocenylketene and ferrocenyl-1,2-
bisketenes: direct observation and reactivity measurements, J. Org. Chem. 70
(2005) 9556–9561.
This work was supported by NSFC (No. 21276068), Department
of Science and Technology Foundation of Hunan Province (No.
2010SK2001) and Hunan Natural Science Foundation (No.
11JJ5008).
[15] Spectroscopic data: 1a: 1H NMR (400 MHz, CDCl3): d 2.52 (s, 3H), 7.20 (s, 1H), 7.30
(t, 1H, J = 7.6 Hz), 7.40 (t, 2H, J = 7.6 Hz), 7.60 (d, 2H, J = 7.2 Hz). HRMS-EI: [M+]
Calcd. for C10H9NO 159.0679, Found 159.0680. 1b: 1H NMR (400 MHz, CDCl3): d
2.58 (s, 3H), 7.33 (s, 1H), 7.49 (m, 2H), 7.66 (d, 1H, J = 7.2 Hz), 7.72 (d, 2H,
J = 7.2 Hz), 7.87 (d, 1H, J = 7.6 Hz), 8.09 (s, 1H). HRMS-EI: [M+] Calcd. for C14H11NO
209.0836, Found 209.0838. 1c: 1H NMR (400 MHz, CDCl3): d 2.55 (s, 3H), 7.30 (s,
1H), 7.32–7.36 (m, 1H), 7.87 (d, 1H, J = 8.0 Hz), 8.53 (d, 1H, J = 6.8 Hz), 8.87 (s, 1H).
HRMS-EI: [M+] Calcd. for C9H8N2O 160.0632, Found 160.0633. 1d: 1H NMR
(400 MHz, CDCl3): d 2.59 (s, 3H), 7.42 (s, 1H), 7.57 (t, 1H, J = 8.8 Hz), 7.671 (t,
1H, J = 8.2 Hz), 7.85 (d, 1H, J = 8.4 Hz), 8.10 (d, 1H, J = 8.4 Hz), 8.31 (s, 1H), 9.14 (s,
1H). HRMS-EI: [M+] Calcd. for C13H10N2O 210.0788, Found 210.0789. 1e: 1H NMR
(400 MHz, CDCl3): d 2.50 (s, 3H), 7.05 (s, 1H), 7.25–7.27 (m, 1H), 7.35–7.37 (m,
1H), 7.46–7.47 (m, 1H). HRMS-EI: [M+] Calcd. for C8H7NOS 165.0243, Found
165.0242. 1f: 1H NMR (400 MHz, CDCl3): d 2.51 (s, 3H), 7.32 (s, 1H), 7.40–7.44 (m,
1H), 7.46–7.50 (m, 1H), 7.69 (s, 1H), 7.90 (d, 1H, J = 9.6 Hz), 8.05 (d, 1H, J = 8.0 Hz).
HRMS-EI: [M+] Calcd. for C12H9NOS 215.0400, Found 215.0401. 1g: 1H NMR
(400 MHz, CDCl3): d 2.50 (s, 3H), 7.29 (s, 1H), 7.43–7.61 (m, 2H), 7.86 (d, 1H,
J = 7.8 Hz), 8.03 (d, 1H, J = 7.4 Hz). HRMS-EI: [M+] Calcd. for C11H8N2OS 216.0352,
Found 216.0351. 1h: 1H NMR (400 MHz, CDCl3): d 2.48 (s, 3H), 4.12 (s, 5H), 4.30 (s,
2H), 4.56 (s, 2H), 6.82 (s, 1H). HRMS-EI: [M+] Calcd. for C14H13FeNO 267.0342,
Found 267.0344. Procedure to synthesis of 1i: A solution of NaOH (1.0 mol/L,
3 mL) was added to a stirring solution of 2-methyl-5-(1-tosyl-1H-indol-3-yl)ox-
azole 6 (106 mg, 0.3 mmol) in 5 mL of methanol and heated to reflux at 80 8C
under nitrogen overnight until starting material was consumed as monitored by
TLC. Methanol was removed in vacuo and product was extracted with ether
(3 ꢁ 20 mL), washed with brine, dried over magnesium sulfate, and concentrated
in vacuo to give 56 mg (95% yield) of a yellow solid. 1H NMR (400 MHz, CDCl3): d
2.58 (s, 3H), 7.16 (s, 1H), 7.22–7.32 (m, 2H), 7.46 (d, 1H, J = 7.6 Hz), 7.52 (d, 1H,
J = 7.6 Hz), 7.78 (d, 1H, J = 8.0 Hz), 8.38 (s, 1H). HRMS-EI: [M+] Calcd. for
References
[1] (a) D. Kumar, M. Kumar, K.H. Chang, et al., An expeditious synthesis and anti-
cancer activity of novel 4-(30-indolyl)oxazoles, Eur. J. Med. Chem. 45 (2010) 1244–
1249;
(b) Z. Jin, Muscarine, imidazole, oxazole, and thiazole alkaloids, Nat. Prod. Rep. 28
(2011) 1143–1191;
(c) V.S.C. Yeh, Recent advances in the total syntheses of oxazole-containing
natural products, Tetrahedron 60 (2004) 11995–12042;
(d) B. Wang, T. Hansen, T. Wang, et al., Total synthesis of phorboxazole A via de
novo oxazole formation: strategy and component assembly, J. Am. Chem. Soc. 133
(2011) 1484–1505.
[2] (a) R. Misra, H.Y. Xiao, K. Kim, et al., N-(cycloalkylamino)acyl-2-aminothiazole
inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-dimethylethyl)-2-oxazo-
lyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS-387032), a highly
efficacious and selective antitumor agent, J. Med. Chem. 47 (2004) 1719–1728;
(b) Y. Koyama, K. Yokose, L. Dolby, et al., Isolation, characterization and synthesis
of pimprinine, pimprinethine and pimprinaphine, metabolites of Streptoverticil-
lium olivoreticuli, Agric. Biol. Chem. 45 (1981) 1285–1287.
[3] A.O.D. Souza, M.T.C. Pedrosa, J.B. Alderete, et al., Cytotoxicity, antitumoral and
antimycobacterial activity of tetrazole and oxadiazole derivatives, Pharmazie 60
(2005) 396–397.
[4] K. Atul, A. Pervez, M.A. Ram, et al., Novel 2-aryl-naphtho[1,2-d]oxazole deriva-
tives as potential PTP-1B inhibitors showing antihyperglycemic activities, Eur. J.
Med. Chem. 44 (2009) 109–116.
[5] L.S. Boulos, M.H.N. Arsanious, E.F. Ewies, Studies on phosphonium Ylides XXV: the
behavior of active phosphacumulene and stabilized alkylidenephosphoranes
towards 5-(4H)-oxazolones, Phosphorus Sulfur Silicon Relat. Elem. 184 (2009)
275–290.
C
12H10N2O 198.0788, Found 198.0790.
[16] D.J. Gorin, B.D. Sherry, F.D. Toste, Ligand effects in homogeneous Au catalysis,
Chem. Rev. 108 (2008) 3351–3378.
[17] (a) M. Patra, G. Gasser, N. Metzler-Nolte, Small organometallic compounds as
antibacterial agents, Dalton Trans. 41 (2012) 6350–6358;
(b) R.D. Miao, J. Wei, M.H. Lv, et al., Conjugation of substituted ferrocenyl to
thiadiazine as apoptosis-inducing agents targeting the Bax/Bcl-2 pathway, Eur. J.
Med. Chem. 46 (2011) 5000–5009;
(c) B.H. Long, C.L. He, Y.B. Yang, et al., Synthesis, characterization and antibacte-
rial activities of some new ferrocene-containing penems, Eur. J. Med. Chem. 45
(2010) 1181–1188;
(d) B.H. Long, S.Z. Liang, D.C. Xin, et al., Synthesis, characterization and in vitro
antiproliferative activities of new 13-cis-retinoyl ferrocene derivatives, Eur. J.
Med. Chem. 44 (2009) 2572–2576;
(e) S.L. Shen, J. Zhu, M. Li, et al., Synthesis of ferrocenyl pyrazole-containing chiral
aminoethanol derivatives and their inhibition against A549 and H322 lung cancer
cells, Eur. J. Med. Chem. 54 (2012) 287–294.
[6] M. Natesan, Z. Gu, P. Stein, Biphenylsulfonamide endothelin receptor antagonists.
2. Discovery of 40-oxazolyl biphenylsulfonamides as a new class of potent, highly
selective ETA antagonists, J. Med. Chem. 43 (2000) 3111–3117.
[7] W.S. Yang, K. Shimada, D. Delva, et al., Identification of simple compounds with
microtubule-binding activity that inhibit cancer cell growth with high potency,
ACS Med. Chem. Lett. 3 (2012) 35–38.
´
[8] I. Cano, E. Alvarez, M.C. Nicasio, et al., Regioselective formation of 2,5-disubsti-
tuted oxazoles via copper(i)-catalyzed cycloaddition of acyl azides and 1-alkynes,
J. Am. Chem. Soc. 133 (2011) 191–193.
[9] E.E. Wiegand, D.W. Rathburn, Polyphosphoric acid cyclization of acetamidoke-
tones to 2,5-dimethyl-1,3-oxazoles, Synthesis 2 (1970) 648–649.