DPO and POPOP carboxylate-analog sensors by sequential palladium-catalysed direct arylation of oxazole-4-carboxylates

Article abstract of DOI:10.1039/c1ob05261f

Sequential palladium-catalysed direct (het)arylation of oxazole-4-carboxylates is achieved to give rapid access to DPO and POPOP (di)carboxylate-analogs. Three novel DPO- and POPOP-type sensors with unusual Stokes shifts and high quantum yields are discov

Full text of DOI:10.1039/c1ob05261f

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DPO and POPOP carboxylate-analog sensors by sequential
palladium-catalysed direct arylation of oxazole-4-carboxylates†
Ce´cile Verrier, Catherine Fiol-Petit, Christophe Hoarau* and Francis Marsais
Received 18th February 2011, Accepted 30th June 2011
DOI: 10.1039/c1ob05261f
Sequential palladium-catalysed direct (het)arylation of
oxazole-4-carboxylates is achieved to give rapid access to
DPO and POPOP (di)carboxylate-analogs. Three novel
DPO- and POPOP-type sensors with unusual Stokes shifts
and high quantum yields are discovered.
new materials.4e,7 So far, the recent advances in transition metal-
catalysed direct C–H arylation of heterocycles8 that offer an al-
ternative reliable method to classical cross-coupling methodology
have been little exploited to design neat syntheses of heterocyclic
fluorophores.3e,9 Herein, highly valuable 4-carboxylated DPO and
POPOP (di)carboxylate-analogs including DapoxylTM analogs are
prepared by sequential palladium-catalyzed direct (het)arylation
of 5-arylated oxazole-4-carboxylates (Scheme 1) and their physical
properties are examined.
Fluorescent compounds are one of the most attractive tools for
quantifying molecular interaction events and they are currently
extensively used for detection of bioanalytes, receptor/ligand
binding and environmental contaminants.1 Among the wide
variety of synthetic or natural organic luminophores only a
few of them meet specific criteria1d,2 such as bisarylated oxa-
zole and thiazole scaffolds which exhibit the necessary fluores-
cence properties characterized by minimal overlap absorption
and emission spectra, as well as an increased value of the
Stokes fluorescence shift over the whole visible spectrum.3 2,5-
Diphenyloxazole (DPO) and 1,4-bis(5-phenyloxazol-2-yl)benzene
(POPOP) are thus major components of many commercially
available plastic and liquid scintillation cocktails serving as dye
laser agents, tracers and probes in medico-biological research and
radioanalytical chemistry.4 In recent years, the SPA (scintillation
proximity assay) procedure consisting of labeling the receptor
molecule with SPA beads has emerged as an alternative to the
use of costly and unfriendly scintillation cocktails. This elegant
approach which allows real-time quantitative dynamic detection
directly useful in ‘live’ cells attracts much more interest in the
preparation of functionalized DPO and POPOP analogs. Most
of the efforts have been directed towards the preparation of
4-functionalized DPO analogs in order to covalently or non-
covalently attach the sensor reporter to a protein, a polymer matrix
or an imprinted polymer to quantify receptor/ligand interaction,
or to an azacrown for potassium signaling for instance.4b,5 Other
DPO analogs have also been prepared such as water-soluble
Dapoxyl for bioanalyte detection, LysoSensor and 2- and 4-
PYMPO for pH probes.6 Therefore the preparation of more
synthetically challenging POPOP analogs remains sparse in spite
of their attractive potential as highly effective sensors as well as
Scheme 1 Preparation of DPO POPOP mono(di)carboxylate-analogs
through sequential Pd(0)-catalyzed direct (het)arylation of 1a–e with
halo(het)arenes.
A panel of 5-arylated oxazole-4-carboxylates 1a–e was first
prepared in high yield and multigram quantities by treating
commercially available ethyl isocyanoacetate with adequate 4-
substituted benzoyl chlorides under basic conditions.10 Initially,
the direct palladium-catalyzed phenylation of 1a with phenyl
iodide and chloride was investigated (Scheme 1) under Pd(OAc)2
pre-catalyst and Cs2CO3 base employing the three optimal lig-
and/solvent pairs, P(o-tol)3 in toluene and Buchwald’s JohnPhos
or IMes ligands in dioxane, previously designed for regioselective
C2 direct phenylations of the ethyl oxazole-4-carboxylate with
phenyl iodide.11 The results depicted in Table 1 (entries 1–
6) showed clearly that the IMes ligand is the most effective
ligand in direct phenylation of 1a with phenyl iodide providing
the DPO carboxylate-analog 2 in quantitative yield. The direct
coupling of all selected 5-arylated oxazole-4-carboxylates 1a–f
with iodo(het)arenes was then achieved using the IMes/dioxane
combination and successfully providing DPO carboxylate-analogs
3–6 including three Dapoxyl-analogs 4b, 5b and 6b in fair to high
yields (Table 1, entries 7–12).
Institut de Chimie Organique Fine (IRCOF) associe´ au CNRS (UMR
6014), INSA et Universite´ de Rouen, BP08 76131, Mont Saint Aignan,
France. E-mail: christophe.hoarau@insa-rouen.fr; Fax: (+33) 0235522462;
Tel: (+33) 0235522401
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c1ob05261f
The IMes ligand proved to be poorly effective in the direct
coupling of 1a with phenyl chloride (Table 1, entry 6). It was then
also selected to secure the selective direct coupling of 5-arylated
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Table 1 Preliminary study of direct palladium-catalyzed direct phenylation of 1a with phenyl idodide and chloride, preparation of DPO carboxylate-
analogs 2–7a
Entry
SM
X
W
L–Solv.
Product
Yieldb (%)
1
2
3
4
5
6
1a
1a
1a
1a
1a
1a
I
CH
CH
CH
CH
CH
CH
P–T
JP–D
I–D
P–T
JP–D
I–D
65
38
100
30
85
28
I
I
2
Cl
Cl
Cl
7
1b
I
C-OMe
I–D
3a
3b
83
8
1b
Br
C(NMe2)
I–D
24 (92)c
9
1c
1c
1d
1d
I
I
I
I
C(CN)
C(CN)
N
I–D
I-D
I–D
I–D
4a
4b
5a
5b
94
79
61
57
10
11
10
C(CN)
11
12
13
14
1e
1e
1a
1b
I
C(OMe)
C(NMe2)
C–Cl
I–D
I–D
I–D
I–D
6a
6b
7a
7b
82
45
87
66
Br
I
I
C–Cl
15
16
17
1c
1d
1e
I
I
I
C–Cl
C–Cl
C–Cl
I–D
I–D
I–D
7c
7d
7e
91d
90d
78
a Conditions: P = P(o-Tol)3, JP = Cy-JohnPhos, I = IMes, T = Toluene, D = dioxane, substrate (1 equiv.), Pd(OAc)2 (5 mol%), Cs2CO3 (2 equiv.), 110 ◦C,
18 h. b Yield of isolated product. c Cy-JohnPhos used. d 10% of Pd(OAc)2 and 20% of ligand.
oxazole-4-carboxylates with 1,4-iodo(bromo)chloroarenes to pre-
pare the chlorinated DPO carboxylate-analogs 7 (Scheme 1). Inter-
estingly, various chlorinated DPO carboxylate-analogs 7a–e were
produced in good yields (Table 1, entries 13–17). However, the use
of two equivalents of electrophile were sometimes required along
with increasing amounts of catalyst (10 mol%) to optimize the
yield of chlorinated oxazole-4-carboxylates 7a–e (Table 1, entries
15,16). Notably, the direct coupling remained highly selective on
the iodide and bromide atoms and moreover the 4-carboxylate
DPO chloro-anaolgs 7a–e were accompanied with small amounts
of their corresponding dimers (<10%) in spite of using an excess
of 1,4-iodo(bromo)chloroarenes. These latter chlorinated DPO-
analogs 7a–e were exploited to prepare the POPOP dicarboxylate-
analogs 8 by adding a second direct arylation step in dioxane
with the 5-arylated-4-carboxylates (Scheme 1). The Cy-JohnPhos
ligand was selected for this second operation on account of the
good performance of the JohnPhos/dioxane pairing in the direct
coupling of 1a with phenyl chloride (Table 1, entry 5).
Surprisingly the first assay of the subsequent direct arylation
of 7a with 5-phenyloxazole-4-carboxylates 1a using the John-
Phos/dioxane pair produced the expected POPOP-carboxylate-
analog 8a in 19% very poor yield. However, pleasingly, both
symmetrical dimethoxylated and diaminated POPOP carboxylate-
analogs 8b and 8c were prepared quantitatively following the
same procedure (Table 2, entries 2,3). In the same way, the
unsymmetrical POPOP dicarboxylate-analogs 8d–g were also
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Table 2 Preparation of POPOP dicarboxylate-analogs 8a–ga
Entry
1
Cl-DPO 7
5-Ar-Oxa. 1a–e
POPOP analogs
Yieldb (%)
22
7a
1a
8a
8b
2
3
7c
7d
1c
1d
98
99
8c
8d
4
7b
7c
7b
7d
7e
7c
7e
7d
1c
1b
1d
1b
1c
1e
1d
1e
39
86
36
95
77
92
87
98
5
6
8e
8f
7
8
9
10
11
8g
a Conditions: substrate (1 equiv.), Pd(OAc)2 (5 mol%), Cy-JohnPhos ligand (10% mol), Cs2CO3 (2 equiv.), 110 ◦C, 18 h. b Yield of isolated product.
Table 3 Luminescent properties of DPO dicarboxylate-analogs 2–6 and POPOP dicarboxylate-analogs 8 in CH2Cl2
max
c
Entry
Analogs
e (M-1 cm-1)
l
(nm)
lem (nm)a
Stokes shift (nm)
f
abs
1
2
3
4
5
6
7
8
DPO
2
3a
3b
4a
4b
5a
5b
6a
6b
POPOP
8a
8d
8e
8f
8g
31 632
28 127
5853/6236
19 082/14 311
25 189
13 848
17 419
11 438/18 220
18 809/18 420
17 950/14 711
48 575
307
300
268/337
300/379
334
325
383
246/380
275/323
310/366
361
330
355
365b
368b
421
541
429
58
68
84
162
95
85
135
110
132
150
58
0.78
0.48
0.42
0.48
0.27
0.37
0.62
0.87
0.34
0.71
0.77
0.69
0.80
0.32
0.60
0.37
410
518
490
9
407b
516
10
11
12
13
14
15
16
419
14 848
45 933
28 426
62 528
385/409
467
434
55
112
109
104
110
325
350
320/365
454
50 618/43 213
430b/530b
a Excitation at 360 nm. The quantum yields of fluorescence were determined at 25 ◦C with harmane in H2SO4 0.1 M (f = 0.90) as the reference standard.
b Excitation at 300 nm. c 10%.
successfully prepared (Table 2, entries 4–11) including notably
two pyridinated POPOP dicarboxylate-analogs 8f–g isolated in
almost quantitative yield through two distinct routes, the direct
coupling of the electron-withdrawing 7b,7e as well as the electron-
donating 7c, 7d chlorinated DPO carboxylate-analogs with the
corresponding electrophiles (Table 2, entries 8–11).
The optical properties of the novel DPO carboxylate-analogs
2–6 were first evaluated (Table 3-entries 1–10). Two highly
luminescent novel DPO carboxylate-Dapoxyl-analogs 5b, 6b with
larger Stokes shifts than DPO (110, 150 nm respectively vs. 58 nm
for the DPO reference), maintaining notably high quantum yields
(0.87 and 0.71 respectively vs. 0.78 for DPO reference), were
identified. Consequently, the emission maxima of 5b and 6b were
then located at 490 and 516 nm as shown in Fig. 1. Remarkably,
the unsymmetrical DPO carboxylate-analog 3b flanked with cyano
and dimethylamino functions as electron-acceptor and electron-
donor groups exhibits a rare Stock shift in this series (542 nm) but
the quantum yield is lower than the DPO reference (0.48 vs. 0.78).
In contrast with the DPO carboxylate-analog series, the evalua-
tion of the optical properties of the POPOP-dicarboxylate-analogs
8 (Table 3, entries 11–16) revealed that the unsymmetrical cyanated
and dimethoxylated POPOP dicarboxylate-analog 8d exhibits a
much larger Stokes shift than the cyanated and aminated POPOP
dicarboxylate-analog 8e as well as both pyridinylated POPOP
dicarboxylate-analogs 8f and 8g. This trend suggests that the
luminescence of the POPOP dicarboxylate-analogs is not based
upon an intrinsic electron long displacement from the electron-
donating to the electron-withdrawing group. In summary, we
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