Conformationally flexible C 3-symmetric 1,3-oxazoles as molecular scaffolds

Article abstract of DOI:10.1055/s-0035-1560576

Flexible-arm, C ₃-symmetric tris-oxazoles are synthesized for their applications in supramolecular chemistry and materials science. The C ₃-symmetry is introduced starting from 1,3,5-trimethylbenzene and carrying out threefold reactions at each stage of the synthesis. The applicability of these tris-oxazoles is demonstrated by transforming a representative example into a highly fluorescent material. This is accomplished by conjugation with an aromatic moiety via palladium(0)-catalyzed direct arylation at C-2 of the oxazole. A unique molecular arrangement in the crystal structure is observed.

Full text of DOI:10.1055/s-0035-1560576

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Conformationally Flexible C3-Symmetric 1,3-Oxazoles as Molecu-
lar Scaffolds
Shailesh R. Shah*a
Ruchita R. Thakorea
Trupti A. Vyasa
Balasubramanian Sridharb
a Department of Chemistry, Faculty of Science, The
M. S. University of Baroda, Vadodara 390002, India
shailesh-chem@msubaroda.ac.in
b Indian Institute of Chemical Technology, Tarnaka,
Hyderabad 500007, India
Dedicated to Professor Leo Paquette on the occasion
of his 81st birthday
Received: 09.07.2015
Accepted after revision: 03.09.2015
Published online: 15.10.2015
have found valuable applications in the fields of biosensing,
supramolecular chemistry and metal-ion detection and
recognition.11
DOI: 10.1055/s-0035-1560576; Art ID: st-2015-d0530-l
Abstract Flexible-arm, C3-symmetric tris-oxazoles are synthesized for
their applications in supramolecular chemistry and materials science.
The C3-symmetry is introduced starting from 1,3,5-trimethylbenzene
and carrying out threefold reactions at each stage of the synthesis. The
applicability of these tris-oxazoles is demonstrated by transforming a
representative example into a highly fluorescent material. This is ac-
complished by conjugation with an aromatic moiety via palladium(0)-
catalyzed direct arylation at C-2 of the oxazole. A unique molecular ar-
rangement in the crystal structure is observed.
R
N
Ph
R
N
R
Ph
N
O
N
Ph
N
O
O
N
O
O
O
Key words C3-symmetric molecules, 1,3-oxazoles, tris-aromatic alde-
R = heterocycle
hydes, van Leusen synthesis, fluorescent materials
Figure 1 Representative flexi-arm tripodal host molecules6a,c
Symmetry has always been attractive and is found
widespread in Nature. Different C3-symmetric compounds
having a threefold rotational axis of symmetry have attract-
ed significant attention,1 not only for aesthetic reasons, but
also due to the various unique properties they possess and
the enormous potential in their applications in the fields of
supramolecular chemistry,2 catalysis,3 dendrimer chemis-
try4 and as new materials.5
In continuation of our interest in C3-symmetric com-
pounds12 in biologically potent compounds13 and in oxazole
chemistry,14 we report herein the synthesis and study of
flexible tripodal 1,3-oxazoles by employing 1,3,5-trimethyl-
benzene as the substrate for transformation into C3-sym-
metric scaffolds.
C3-Symmetric compounds with flexible podand groups
have greater possibility of having complementary supra-
molecular interactions to bind with guest entities (Figure
1).6 1,3-Oxazoles are five-membered heteroaromatic azoles
and have attracted plenty of attention in recent years due to
their presence in natural products and the diverse bioactiv-
ities that they exhibit.7 Although a number of C3-symmetric
compounds possessing various other heterocylic moieties
have been reported in the literature,8 flexibly disposed C3-
symmetric oxazole-containing compounds have not been
reported as yet.9 On the other hand, oxazoles with conju-
gated aromatic substitution at positions 2 and 5 result in
highly fluorescent materials.10 Such fluorescent materials
In an early attempt in this direction, we were the first to
synthesize and characterize C3-symmetric aryl ethers with
formyl functionalities as diverse synthetic building blocks
for a variety of C3-symmetric compounds.12a These building
blocks provided us with flexible tripodal trifunctional com-
pounds that could be employed for the construction of vari-
ous molecules with tris-heterocyclic pendant groups for a
range of diverse applications.
Accordingly, in the present work, these tris-alde-
hydes12a,15 have been transformed into tris-1,3-oxazoles via
a single-step, threefold reaction protocol. The required C3-
symmetric aldehydes 2 were prepared12a in good yields
starting from 1,3,5-tris(bromomethyl)-2,4,6-trimethylben-
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zene (1)16 by coupling with different phenolic aldehydes,
and were characterized from spectroscopic and elemental
analyses12a,17,18 (Scheme 1, Table 1).
The tris-oxazole 3e has the peripheral aromatic rings
substituted with an oxazole at the ortho-position with re-
spect to the ether linkage on one side and a methoxy group
on the other side. The complementary orientation of the
podands can result in the product attaining a molecular
container shape (Figure 2).
4
CHO
5
3
2
6
R
R
O
Br
OH
Br
R
OHC
MeO
N
O
OHC
O
MeO
O
O
R
Br
O
O
OMe
N
1
2
O
CHO
O
Scheme 1 Synthesis of tris-aromatic aldehydes 2a–e. Reagents and
conditions: K2CO3, acetone, r.t., 3 h.
N
Figure 2 Tris-oxazole 3e depicted as a molecular container
Crystals of oxazole 3a suitable for single crystal X-ray
diffraction analysis were obtained by slow evaporation of
an ethyl acetate solution. The triclinic crystals of the tris-
oxazole (Figure 3)21 show a structure in which one of the
podand arms is orientated at a right angle to the central
ring, unlike the other two podand arms. The crystal packing
is governed by C–H·O interactions. Two sets of centrosym-
metric dimers are formed by C–H·O interactions: C19–
Table 1 Synthesis of C3-Symmetric Tris-aromatic Aldehydes 2a–e
Product
CHO Positiona
R
Yield (%)b
Mp (°C)c
2a12a
2b15c
2c15b
2d
4-
3-
2-
4-
2-
H
82
80
75
80
70
194
190
184
212
208
H
H
OMe
OMe
2e18
a Position of the CHO group; refer to Scheme 1.
b Yield of isolated product.
c Melting points were recorded in open capillary tubes and are uncorrected.
The van Leusen reagent, p-toluenesulfonylmethyl isocy-
anide (TosMIC), is a useful reagent for converting a formyl
group into a 1,3-oxazole in a single step.19 This reagent was
successfully employed for the threefold transformation of
the tris-aromatic aldehydes 2 into the desired 5-substituted
tris-oxazoles 3 in good yields (Scheme 2,Table 2).20 The
newly synthesized tris-oxazoles were characterized by vari-
ous analytical techniques and their symmetry was reflected
in their simple NMR spectra.17,20
Figure 3 Single crystal X-ray (ORTEP) diagram of compound 3a
N
4
CHO
5
4
O
3
3
2
5
2
R
6
6
R
O
O
TosMIC
R
R
K2CO3, MeOH
reflux, 3–4 h
O
O
O
OHC
N
O
R
O
R
CHO
N
2
3
O
Scheme 2 Synthesis of 1,3,5-tris(1,3-oxazoles) 3a–e
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N
O
N
O
Br
O
O
K2CO3, Pd(OAc)2
CuI, DMF
O
O
O
O
N
O
O
O
N
O
N
N
3a
4
Scheme 3 Pd(0)-catalyzed direct C–H arylation at C-2 of 1,3-oxazole 3a
H19…O2 [–x, –y + 2, –z + 1 ] and C23–H23…O1 [–x + 1, –y +
2, –z + 1]. These intermolecular interactions including
C–H…π-cloud (central ring) interactions result in a zigzag
molecular pattern (Figure 4).
Figure 5 (a) The absorption spectra of 3a and phenyl-conjugated ox-
azole 4. (b) The emission spectrum of a solution of 4 in dichlorometh-
ane (10–5 M)
The C3-symmetric oxazoles 3a–e were screened for an-
ticancer activity against 60 different cancer cell lines by the
National Cancer Institute at the National Institutes of
Health (USA). Among them, tris-2-(5-oxazolyl)-6-methoxy
compound 3e was found to show the highest activity
against a number of different cell lines.17 This could be due
to the closely placed heteroatoms in 3e offering comple-
mentary binding sites (Figure 2).
In conclusion, several new, flexible, terminal oxazole-
containing C3-symmetric compounds have been synthe-
sized from the corresponding tris-aromatic aldehydes and
have been characterized. The X-ray crystal structure of one
of the tris-oxazoles (3a) exhibits a unique crystal packing of
the molecules in a zigzag fashion. The oxazole scaffold 3a
was employed for palladium-mediated coupling resulting in
a conjugated fluorescent material.
Figure 4 Molecular arrangement in the crystal packing of compound
3a
As 2,5-diaryl-1,3-oxazoles are excellent fluorescent
probes,10 and to demonstrate the applications of the newly
synthesized terminal tris-oxazoles, the reactive, free C-2
position of heterocycle 3a was utilized for the transforma-
tion into a fluorescent material. Palladium(0)-catalyzed di-
rect oxazole C–H functionalization was carried out in N,N-
dimethylformamide in the presence of copper(I) iodide
(CuI) and potassium carbonate with heating,22 resulting in
the highly fluorescent product 423 (Scheme 3).
The resulting tris-2-phenyl-5-substituted-1,3-oxazole 4
showed a strong absorption at 316 nm and strong photolu-
minescence at 430 nm (Figure 5), as a result of which its
solution was visibly fluorescent when exposed to UV radia-
tion (Figure 5, inset).
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Table 2 Synthesis of C3-Symmetric 1,3,5-Tris(1,3-oxazoles) 3a–ea
Product
Structure
Yield (%)b
Mp (°C)c
N
O
O
3a
75
195
O
O
O
N
O
N
O
N
O
3b
68
210
O
N
O
O
O
N
O
O
N
N
O
3c
65
205
O
O
N
O
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Table 2 (continued)
Product
Structure
Yield (%)b
Mp (°C)c
N
O
MeO
O
3d
70
200
O
OMe
O
OMe
O
N
O
N
O
MeO
O
N
N
3e20
O
60
210
O
OMe
O
O
OMe
N
a Overall structure is shown in Scheme 2
b Yield of isolated product.
.
c Melting points were recorded in open capillary tubes and are uncorrected.
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Acknowledgment
Financial support in the form of a BSR fellowship from UGC (New Del-
hi) to R.R.T. is gratefully acknowledged. We thank Dr. Balaram S.
Takale, AIMR, Tohoku University for useful discussions. Mass spectro-
metric analysis performed at the Zydus Research Centre, Ahmedabad,
is gratefully acknowledged. The 400 MHz NMR facility was supported
by a DST-FIST grant to the Department. The NCI at NIH, USA is ac-
knowledged for the in vitro anticancer screening.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560576.
S
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.
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MHz, CDCl3): δ = 2.45 (s, 9 H, –CH3), 3.96 (s, 9 H, –OCH3), 5.45 (s,
6 H, –OCH2–), 7.12–7.20 (m, 6 H), 7.39 (dd, J1 = 7.2 Hz, J2 = 2.0
Hz, 3 H), 10.15 (s, 3 H, –CHO). 13C NMR (50 MHz, CDCl3):
δ = 16.0 (–CH3), 56.0 (–OCH3), 77.0 (–OCH2), 118.1, 119.0, 123.2,
129.9, 132.1, 140.3, 151.4, 153.6, 190.9 (–CHO). Anal. Calcd for
C
36H36O9: C, 70.57; H, 5.92. Found: C, 69.91; H, 6.79.
(19) van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron
Lett. 1972, 2369.
(20) 1,3,5-Tris[6-methoxy-2-(1,3-oxazol-5-yl)phenyloxymethyl]-
2,4,6-trimethylbenzene (3e); Typical Procedure
To a two-necked round-bottomed flask were added tris-alde-
hyde 2e (0.1 g, 0.16 mmol), p-toluenesulfonylmethyl isocyanide
(TosMIC) (0.13 g, 0.65 mmol), K2CO3 (0.16 g, 1.2 mmol) and
MeOH. The resulting mixture was heated at reflux temperature
for 3–4 h. On completion of the reaction (TLC), the MeOH was
evaporated under reduced pressure and the residue was puri-
fied by column chromatography on silica (EtOAc–hexanes, 6:4
to 8:2) to give the corresponding tris-1,3-oxazole 3e.
(9) For the only previous report on rigid C3-symmetric oxazoles,
see: Kotha, S.; Shah, V. R. Synthesis 2007, 23, 3653.
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Yield: 0.07 g (60%); white solid; mp 210 °C. IR (KBr): 2939,
2834, 1589, 1560, 1503, 1471, 1265 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 2.45 (s, 9 H, –CH3), 3.94 (s, 9 H, –OCH3), 5.31 (s, 6 H,
–OCH2–), 6.97 (dd, J1 = 8.2 Hz, J2 = 1.2 Hz, 3 H), 7.13 (t, J = 8.0 Hz,
3 H), 7.30 (s, 3 H, oxazole H), 7.35 (dd, J1 = 8.2 Hz, J2 = 1.2 Hz,
3 H), 7.87 (s, 3 H, –N=CH–, oxazole H). 13C NMR (100 MHz,
CDCl3): δ = 16.1 (–CH3), 55.9 (–OCH3), 70.0 (–OCH2), 112.4,
118.2, 122.1, 123.9, 125.7, 132.5, 139.5, 145.1, 153.1. HRMS (Q-
TOF MS ES+): m/z [M]+ calcd for C42H39N3O9: 729.2686; found:
729.2677.
(21) Crystal data for compound 3a (CCDC 1403715): C39H33N3O6
(M = 639.68): triclinic space group P-1 (no. 2), a = 11.0751(12) Å,
b = 11.1638(12) Å, c = 13.9139(15) Å, α = 100.558(2)°, β = 108.883(2)°,
γ = 98.899(2)°, V = 1557.3(3) Å3, Z = 2, T = 294.15 K, μ(MoKα) = 0.093
mm–1, Dcalc = 1.364 g/mm3, 18425 reflections measured (3.2 ≤ 2θ
≤ 56.1), 7290 unique (Rint = 0.0235) which were used in all cal-
culations. The final R1 was 0.0659 [>2σ(I)] and wR2 was 0.1933
(all data).
(22) For similar coupling under microwave conditions, see:
Besselievre, F.; Mahuteau-Betzer, F.; Grierson, D. S.; Piguel, S. J.
Org. Chem. 2008, 73, 3278.
(23) 1,3,5-Tris[4-(2-phenyl-1,3-oxazol-5-yl)phenyloxymethyl]-
2,4,6-trimethylbenzene (4)
To a two-necked round-bottomed flask were added compound
3a (0.1 g, 0.19 mmol), bromobenzene (0.14 g, 0.86 mmol),
K2CO3 (1.6 g, 1.15 mmol), Pd(OAc)2 (6 mg, 15 mol%), CuI (0.10 g,
0.57 mmol) and DMF (4 mL). The resulting mixture was
degassed and then heated to 150 °C and stirred under an N2 atm
for 3 h. On completion of the reaction (TLC), the solids were
removed by filtration through Celite® followed by washing with
CH2Cl2. The filtrate and washings were evaporated under
vacuum and the residue purified by column chromatography on
silica (EtOAc–hexanes, 3:7) to afford tris(2-phenyl-1,3-oxazol-
5-yl) 4.
(15) (a) Bray, D. J.; Lindoy, L. F.; McMurtrie, J. C. Acta. Crystallogr.,
Sect. E 2004, 60, 6. (b) Samy, A. N.; Alexander, V. Dalton Trans.
2011, 40, 8630. (c) Cheng, F.; Chen, J.; Wang, F.; Tang, N.; Chen,
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(16) van der Made, A. W.; van der Made, R. H. J. Org. Chem. 1993, 58,
1262.
(17) See the Supporting Information for further details.
(18) 1,3,5-Tris[(2-formyl-6-methoxy)phenyloxymethyl)-2,4,6-
trimethylbenzene (2e); Typical Procedure
Yield: 0.05 g (35%); white solid; mp: 187 °C. IR (KBr): 2923,
To a stirred solution of a 2-hydroxy-3-methoxybenzaldehyde
1612, 1499, 1242, 1176 cm–1 1H NMR (400 MHz, CDCl3):
.
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δ = 2.52 (s, 9 H, –CH3), 5.20 (s, 6 H, –OCH2–), 7.13 (d, J = 8.8 Hz,
6 H), 7.37 (s, 3 H, oxazole H), 7.50 (d, J = 7.6 Hz, 9 H), 7.72 (d,
J = 9.2 Hz, 6 H), 8.12 (dd, J1 = 7.8 Hz, J2 = 2.0 Hz, 6 H). 13C NMR
(100 MHz, CDCl3): δ = 16.0 (–CH3), 65.1 (–OCH2), 115.1, 121.2,
122.1, 125.8, 126.1, 127.5, 128.8, 130.1, 131.6, 139.5, 151.2 and
159.3 (oxazole carbons), 160.6 (Ar–O–). HRMS (Q-TOF MS ES+):
m/z [M + H]+ calcd for C57H46N3O6: 868.3387; found: 868.2813;
m/z [M
890.2594.
+
Na]+ calcd for C57H45N3O6Na: 890.3206; found:
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 294–300