Efficient synthesis of di- and trisubstituted 2-aryloxazoles via ytterbium(III) triflate catalyzed cyclization of tertiary propargylic alcohols with aryl amides

Article abstract of DOI:10.1016/j.jorganchem.2010.09.059

An efficient synthetic method to prepare di- and trisubstituted 2-aryloxazoles based on Yb(OTf)₃ catalyzed cyclization of trisubstituted propargylic alcohols with aryl amides is described. The reaction was accomplished in moderate to excellent product yields and with complete regioselective control. The mechanism is suggested to involve activation of the starting alcohol by the metal catalyst that results in its ionization. Subsequent cyclization of this newly generated carbocationic species with the aryl amide then affords the oxazole. In view of the mild conditions along with the low cost, commercially availability of Yb(OTf)₃ and its high tolerance to air and moisture, the present synthetic approach offers an operationally simplistic and convenient route to this important aromatic heterocycle.

Full text of DOI:10.1016/j.jorganchem.2010.09.059

Journal of Organometallic Chemistry 696 (2011) 331e337
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Journal of Organometallic Chemistry
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Efficient synthesis of di- and trisubstituted 2-aryloxazoles via ytterbium(III)
triflate catalyzed cyclization of tertiary propargylic alcohols with aryl amides
*
Xiaoxiang Zhang, Wan Teng Teo, Philip Wai Hong Chan
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic method to prepare di- and trisubstituted 2-aryloxazoles based on Yb(OTf)3 cata-
lyzed cyclization of trisubstituted propargylic alcohols with aryl amides is described. The reaction was
accomplished in moderate to excellent product yields and with complete regioselective control. The
mechanism is suggested to involve activation of the starting alcohol by the metal catalyst that results in
its ionization. Subsequent cyclization of this newly generated carbocationic species with the aryl amide
then affords the oxazole. In view of the mild conditions along with the low cost, commercially availability
of Yb(OTf)3 and its high tolerance to air and moisture, the present synthetic approach offers an opera-
tionally simplistic and convenient route to this important aromatic heterocycle.
Received 25 August 2010
Received in revised form
24 September 2010
Accepted 24 September 2010
Available online 9 November 2010
Keywords:
2-Aryloxazoles
Aryl amides
Ó 2010 Elsevier B.V. All rights reserved.
Cyclizations
Homogenous catalysis
Propargylic alcohols
Ytterbium
1. Introduction
TsOH$H2O [12]. Although shown to be highly efficient, generating
H2O as potentially the only byproduct, a drawback in these
Oxazoles constitute an immensely important member of the
aromatic heterocycle family due to their presence in a myriad of
bioactive natural products, role as privileged pharmacophores and
ability to serve as versatile building blocks in organic synthesis
[1e12]. Accordingly, this has led to numerous synthetic methods
for constructing this aromatic heterocycle and the continued
pursuit of ever more efficient and flexible approaches [1e12].
Recently, this has hitherto included works describing oxazole
synthesis via cyclization of propargylic alcohols as pro-electro-
philes [13e41,44,47] with amides [10e12]. First reported by
Uemura and co-workers, oxazole formation from reaction of these
substrates was found be possible by employing a dual diruthenium
(II,III) and gold(III) catalytic system [10]. Following this work, Liu
and Kumar demonstrated a dual ruthenium(III) and zinc(II) catalyst
combination could also mediate the cyclization of propargylic
alcohols with amides that afforded the oxazole product in excellent
yields [11]. More recently, Zhan and co-workers described
a Brønsted acid mediated version of this ring forming reaction
could be achieved in the presence of a stoichiometric amount of p-
respective synthetic approaches was the need for two metal cata-
lysts, one to achieve alkyne propargylation and another for
subsequent cyclization of the resulting propargylated interme-
diate, or a stoichiometric amount of the Brønsted acid. Added to
this is the cost of the catalysts and a substrate scope limited to
terminal propargylic alcohols in reactions catalyzed by the dual
metal systems. In this regard, we envisioned ytterbium(III) triflate
would hold promise as a catalyst for cyclization of tertiary prop-
argylic alcohols with aryl amides. A low cost and commercially
available metal salt that has a high tolerance to air and moisture, Yb
(OTf)3 is one prominent member of the family of lanthanide salts
that has been shown to be versatile in mediating a wide variety of
organic transformations that make use of alcohol pro-electrophiles
in excellent yields and with high selectivity [19e27]. For example,
we recently reported Yb(OTf)3 to be an efficient catalyst for
the regioselective formation of indenols based on tandem
FriedeleCrafts arylation/hydroarylation of propargylic alcohols
with phenols [19]. As part of an ongoing program examining the
utility of alcohol pro-electrophiles in organic synthesis
[19,22,28e39], we report herein the use of Yb(OTf)3 for tandem
allenation/cycloisomerization of tertiary propargylic alcohols with
aryl amides (Scheme 1). The di- and trisubstituted 2-aryloxazole
products were obtained in moderate to excellent yields and as
* Corresponding author. Tel.: þ65 6316 8760; fax: þ65 6791 1961.
E-mail address: waihong@ntu.edu.sg (P.W.H. Chan).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.09.059

332
X. Zhang et al. / Journal of Organometallic Chemistry 696 (2011) 331e337
R2
R3
R1
OH
Yb(OTf)3 (5 mol%)
O
R1
R2
+
O
N
Ar
NH2
R3
PhMe, 100 °C
1-24 h
Ar
3
1
2
R1, R2 = aryl
R3 = H, alkyl, aryl, heteroaryl
Scheme 1. Synthesis of di- and tri substituted 2-aryloxazoles based on Yb(OTf)3
catalyzed cyclization of tertiary propargylic alcohols with aryl amides.
a single isomer with regiochemistry opposite to those reported for
the closely related dual metal and Brønsted acid promoted
synthetic methods [10e12].
2. Results and discussion
At the start of the study, we chose to examine the cyclization of
1,1,3-triphenylprop-2-yn-1-ol 1a with benzamide 2a by a variety of
Lewis acids to establish the reaction conditions (Table 1). This
revealed subjecting 1 equiv of 1a with 2 equiv of 2a in the presence
of 5 mol% of Yb(OTf)3 in toluene at 100 ꢀC for 24 h gave the best
result (entry 1). Under these conditions, 4-benzhydryl-2,5-diphe-
nyloxazole 3a was furnished in 88% yield (Table 1, entry 1),
comparable to those obtained for the closely related dual metal and
Brønsted acid mediated reactions [10e12]. The structure and
regiochemistry of the oxazole product was determined on the basis
of 1H NMR measurements and X-ray crystallographic analysis
(Fig. 1, Appendix). A comparable product yield was afforded on
replacing toluene with 1,2-dichloroethane as the solvent or
decreasing the amount of 2a from 2 to 1.2 equiv (Table 1, entries 2,
3). In contrast, markedly lower product yields were obtained when
the reaction was repeated in MeCN or MeNO2 in place of toluene as
solvent (Table 1, entries 4, 5). Low product yields were also found
on switching the Lewis acidic catalyst from Yb(OTf)3 to either
AgOTf, CuBr or FeCl3.6H2O (Table 1, entries 6e8). Moreover, a low
product yield of 54% furnished from a control experiment with
TfOH as the catalyst provided evidence that, in the presence of
Fig. 1. ORTEP drawing of 2-aryloxazole 3a with thermal ellipsoids at 50% probability
levels (Appendix).
potential TfOH formed in situ, the cationic Yb(III) complex is the
catalytically active species (Table 1, entry 9).
With the optimum conditions established, we next explored
the scope of the present reaction by examining a series of prop-
argylic alcohols 1beq and amides 2ael (Table 2). This showed that
reactions of 2a with propargylic alcohols bearing an electron-
withdrawing group on the carbinol or alkyne carbon gave the
corresponding 2-aryloxazoles in good to excellent yields (Table 2,
entries 1e7). Similarly, the analogous reactions of 2a with prop-
argylic alcohols where the carbinol or alkyne carbon contained
a pendant electron-donating group afforded the corresponding 2-
aryloxazoles in good to excellent yields (Table 2, entries 8e10).
Cyclizations of 2a with starting alcohols where the identity of R3
was either an alkyl or heterocycle functional group or a terminal
alkyne moiety were also found to proceed well and afford 3le3n in
51e88% yield (Table 2, entries 11e13). In contrast, reactions of 2a
with propargylic alcohols where either or both R1 and R2 was
a methyl functional group, as in 1o and 1p, gave either a mixture of
side products that could not be identified by 1H NMR analysis or
near quantitative recovery of the substrates (Table 2, entries 14,
15). Similarly, reaction of 2a with the secondary alcohol 1q led to
the preferential formation of the corresponding N-propargylation
adduct 4 in 31% yield in addition to recovery of the substrate in
31% yield (entry 16). An examination of reactions of 1a with
different aryl amides, on the other hand, gave the corresponding
2-aryloxazole adducts 3oet in moderate to excellent yields (Table
2, entries 17e22). Under the standard conditions, reactions of 1a
with the alkyl amides 2iek and urea 2l were the only instances
that resulted in the recovery of the starting alcohol in near
quantitative yields (entries 24e27). In addition, treating 1a with
the cyclic amide 2h was found to afford the ketoamide 5, structure
of which was confirmed by X-ray crystallography (Fig. 2,
Appendix), as the sole product in 69% yield (entry 23). A similar
outcome in product chemoselectivity leading to preferential
formation of the ketoamide adduct from reaction of a secondary
propargylic alcohol with cyclic amide 2h has also been reported
for the analogous p-TsOH$H2O-mediated approach [12].
Table 1
Optimization of reaction conditionsa
Ph
OH
Ph
Ph
catalyst
solvent
O
Ph
Ph
+
O
N
Ph
NH2
Ph
Ph
3a
1a
2a
.
Entry
Catalyst
Solvent
Yield (%)b
1
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
AgOTf
CuBr
FeCl3$6H2O
TfOH
PhMe
PhMe
(CH2Cl)2
MeCN
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
88
86
85
53
76
60
56
40
54
2c
3d
4d
5
6
7
8
9
a
All reactions were performed at 100 ꢀC for 24 h with catalyst/1/2 ratio ¼
1:20:40.
b
Isolated yield.
Reaction conducted with 1.2 equiv of 2a.
Reaction conducted at reflux temperature.
c
d

X. Zhang et al. / Journal of Organometallic Chemistry 696 (2011) 331e337
333
Table 2
Yb(OTf)3 Catalyzed Synthesis of Substituted Oxazoles 3beta
R2
N
O
Ph
O
R3
R1
OH
Yb(OTf)3 (5 mol%)
PhMe, 100 °C
O
R1
R2
HN
Ph
Ph
Ph
Ph
O
+
or
or
R4
NHR5
O
N
R3
R4
Ph
1
2
3
4
5
.
Entry
1, R1/R2/R3
1b, 4-FC6H4/4-FC6H4/C6H5
1c, 4-ClC6H4/4-ClC6H4/C6H5
1d, 4-FC6H4/C6H5/C6H5
1e, 4-ClC6H4/C6H5/C6H5
1f, 4-BrC6H4/C6H5/C6H5
1i, C6H5/C6H5/4-FC6H4
1j, C6H5/C6H5/4-ClC6H4
1d, 4-MeC6H4/4-MeC6H4/C6H5
1h, 4-MeC6H4/C6H5/C6H5
1k, C6H5/C6H5/4-MeC6H4
1l, C6H5/C6H5/H
1m, C6H5/C6H5/n-Bu
1n, 4-ClC6H4/4-ClC6H4/2-thienyl
1o, Me/C6H5/C6H5
1p, Me/Me/C6H5
2, R4/R5
Time (h)
3/4/5
Yield (%)b
1
2
3
4
5
6
7
8
2a, Ph/H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b, 2-MeC6H4/H
2c, 3-MeC6H4/H
2d, 4-MeC6H4/H
2e, 4-MeOC6H4/H
2f, 4-BrC6H4/H
2g, 4-ClC6H4/H
2h, e(CH2CH2)e
2i, Me/H
7
24
6
29
23
24
24
1
24
24
24
20
24
24
24
24
1.5
1.5
24
24
24
2
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
e
80
73
91
88
84
65
75
70
88
81
51
73
88
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
c
-
d
e
-
1q, H/C6H5/C6H5
4
31e
70
60
37
64
79
66
69
ec
ec
ec
ec
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
3o
3p
3q
3r
3s
3t
5
24
24
24
24
24
e
2j, MeCOCH2/H
2k: Ph/CH2C^CH
2l, H2N/H
e
e
e
a
All reactions were performed at 100 ꢀC with Yb(OTf)3/1/2 ratio ¼ 1:20:40.
b
c
Isolated yield.
No reaction detected based on TLC and 1H NMR analysis and near quantitative recovery of the starting materials.
Mixture of unknown side products detected based on TLC and 1H NMR analysis.
Starting alcohol was recovered in 31% yield.
d
e
Although highly speculative, we tentatively propose the
present Yb(OTf)3 catalyzed oxazole forming reaction to proceed
by the mechanism outlined in Scheme 2. In a manner similar to
that proposed for the Yb(OTf)3 mediated tandem FriedeleCrafts
arylation/hydroarylation of propargylic alcohols with phenols,
this could involve initial activation of the propargylic alcohol
resulting from coordination of the Lewis acid to the hydroxyl
group [19]. This provides the Yb(III)-coordinated complex A which
can undergo elimination to furnish the alkynyl and allenic cation
species B and C as well as [Yb]-OH, which releases the metal
catalyst upon protodemetalation. Attack by the aryl amide at the
sterically less hindered carbon center of B or C followed by 5-exo-
trig cyclization of the newly formed allene intermediate D would
then deliver the oxazole product. The regioselective outcome of
the reaction could be due to nucleophilic attack at the sterically
less hindered carbon center of B or C when R1 and R2 ¼ aryl
[19,20,23,40e45]. In this manner, any unfavorable steric interac-
tions between the incoming nucleophile and the substituents of
the cationic species would be limited. Our earlier findings
showing preferential formation of the N-propargylation product 4
with the less sterically demanding secondary alcohol 1q would be
consistent with the influence of such steric interactions on the
regioselectivities obtained (entry 16 in Table 2). In addition, if the
cationic species that is involved in the nucleophilic addition step
Fig. 2. ORTEP drawing of ketoamide 5 with thermal ellipsoids at 50% probability levels
(Appendix).

334
X. Zhang et al. / Journal of Organometallic Chemistry 696 (2011) 331e337
OH
HO [Yb]
Yb(OTf)3
R1
R2
R1
R2
R3
R3
1
A
H
[Yb] +
[Yb] OH
H2O
R1
R2
R1
R2
R3
R3
B
C
for R1-R3 = Ph
O
Ar
NH2
and
O
N
H
2
2i
R2
Ph
Ar
Ph
O
H
H
R3
HN
R1
N
Ph
Ph
H2O
R1
R2
O
Ph
Ph
O
Ph
Ph
O
N
O
N
N
O
R3
Ph
[Yb]
(for X = Yb)
[Yb]
(for X = Yb)
[X]
Ar
3
[X]
D'
D
E
4
Scheme 2. Tentative mechanism for Yb(OTf)3 catalyzed cyclization of 1 with 2 and formation of 4.
is closer to intermediate C in character, a further consequence
would be attack of the aryl amide through the less nucleophilic
oxygen atom. We surmise that the formation of the ketoamide 5
could be due to facile ring opening of the iminium cation E by H2O
generated in situ from elimination of the OH functional group of
the propargylic substrate or the presence of trace amounts of H2O
in the toluene solvent, as shown in Scheme 2. A similar rationale
for the formation of the ketoamide adduct in the analogous
propargylic substrates reported in this work were prepared
following literature procedures [19,46]. Analytical thin layer chro-
matography (TLC) was performed using Merck 60 F254 pre-coated
silica gel plate. Visualization was achieved by UV light (254 nm).
Flash column chromatography was performed using Merck silica
gel 60 and a gradient solvent system (EtOAc/n-hexane as eluent).
Unless otherwise stated, 1H and 13C NMR spectra were recorded on
a Bruker Avance 300 MHz spectrometer with CDCl3 as solvent and
TMS as an internal standard unless specified. Chemical shifts were
reported in parts per million (ppm). Multiplicities are indicated as:
s (singlet), bs (broad singlet), d (doublet), t (triplet), dd (doublet of
doublets) or m (multiplet). The number of protons (n) for a given
resonance is indicated by nH and coupling constants are reported
as a J value in Hz. Infrared spectra was recorded on a Shimadzu IR
Prestige-21 FTIR spectrometer. Solid samples were examined as
a thin film between NaCl salt plates. Low resolution mass spectra
were determined on a Finnigan LCQ XP MAX mass to spectrometer
in the ESI mode and reported in units of mass to charge (m/z) ratio.
High resolution mass spectra (HRMS) were obtained on a Finnigan
MAT95XP LC/HRMS mass spectrometer.
p-TsOH$H2O-mediated reaction of
a secondary propargylic
alcohol with cyclic amide 2h was also put forward by Zhan and
co-workers [12].
3. Conclusion
In summary, we have developed an approach for di- and tri
substituted 2-aryloxazole synthesis that relies on the cyclization
of tertiary propargylic alcohols and aryl amides in the presence
of Yb(OTf)3 as the catalyst. The reactions were shown to proceed
in moderate to excellent product yields and be applicable to
a broad substrate scope that compliments the analogous dual
metal and Brønsted acid mediated versions of this ring forming
process [10e12]. The regiochemistry of 2-aryloxazole products
obtained were also found to be the opposite of those furnished
for the dual metal and Brønsted acid mediated reactions. With
the recent shift in emphasis in green chemistry for more rapid
and direct atom economical chemical processes that can make
use of ecologically benign, low cost and readily available
reagents and catalysts, the present Yb(OTf)3 strategy thus offers
one such method to this class of synthetically useful aromatic
heterocycles.
4.2. Representative experimental procedure for the synthesis of 2-
aryloxazoles 3
To a solution of 1 (0.25 mmol) and 2 (0.3 mmol) in toluene (3 mL)
was added Yb(OTf)3 (12.5 m
mol) and heated at 100 ꢀC for 24 h. Upon
completion, the reaction mixture was cooled to room temperature,
concentrated under reduced pressure and the resulting residue
was further purified by flash column chromatography on silica gel
(n-hexane/EtOAc: 20/1 /15/1) to give the title compound.
4. Experimental
4.3. Analytical data
4.1. General considerations
4.3.1. 4-Benzhydryl-2,5-diphenyloxazole 3a
Pale yellow solid; m.p. 167e168 ꢀC; 1H NMR (CDCl3, 300 MHz):
All reactions were performed under a nitrogen atmosphere.
Unless otherwise noted, all starting materials, reagents and
solvents were purchased from commercial sources and use as
received. N-(prop-2-ynyl)benzamide 2k and all substituted
d
5.65 (s, 1H), 7.19e7.23 (m, 2H), 7.24e7.36 (m, 5H), 7.38e7.47 (m,
9H), 7.62e7.64 (m, 2H), 8.07e8.10 (m, 2H); 13C NMR (CDCl3,
75 MHz): 48.2, 126.5, 126.6, 127.8, 128.3, 128.4, 128.7, 128.8,
128.9,129.2, 130.2, 138.4, 142.7, 146.6, 160.0; IR (neat): 3021, 1595,
d

X. Zhang et al. / Journal of Organometallic Chemistry 696 (2011) 331e337
335
1549, 1493, 1449, 1215, 1069, 924, 756, 669.3 cmꢁ1; MS (ESI) m/z
388 [M þ H]þ; HRMS (ESI) calcd for C28H22NO: 388.1701, found:
388.1720.
75 MHz) d 48.3, 126.6, 126.7, 127.2, 127.5, 127.7, 128.4, 128.7, 129.2,
130.3, 134.2, 138.9, 142.3, 145.5, 160.2; IR (neat): 3019, 1489, 1449,
1217, 1094, 772 cmꢁ1; MS (ESI) m/z 422 [M þ H]þ; HRMS (ESI) calcd
for C28H21ClNO: 422.1312, found: 422.1300.
4.3.2. 4-(Bis(4-fluorophenyl)methyl)-2,5-diphenyloxazole 3b
White solid; m.p. 175e176 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
5.59
(s, 1H), 6.96e7.02 (m, 4H), 7.33e7.41 (m, 10H), 7.42e7.61 (m, 2H),
8.06e8.09 (m, 2H); 13C NMR (CDCl3, 75 MHz):
46.7, 115.3 (1C, d,
4.3.9. 2,5-Diphenyl-4-(di-p-tolylmethyl)oxazole 3i
White solid; m.p. 192e193 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 2.30
d
(s, 6H), 5.58 (s, 1H), 7.10 (d, J ¼ 8.1 Hz, 4H), 7.20e7.36 (m, 5H),
JC-F ¼ 21.5 Hz), 126.5, 126.6, 127.6, 128.5, 128.6, 128.7, 129.0, 130.3,
130.6, 130.7, 138.0, 138.2, 146.6, 160.1, 162.0 (1C, d, JC-F ¼ 240.0 Hz);
IR (neat): 3019, 1601; 1551, 1506, 1447, 1217, 1157, 1094, 762,
670 cmꢁ1; MS (ESI) m/z 424 [M þ H]þ; HRMS (ESI) calcd for
C28H20F2NO: 424.1513, found: 424.1504.
7.39e7.45 (m, 5H), 7.63 (d, J ¼ 7.2 Hz, 2H), 8.07e8.10 (m, 2H); 13C
NMR (CDCl3, 75 MHz):
d 21.1, 47.5, 126.6, 127.8, 128.2, 128.6, 128.9,
129.0, 129.1, 130.1, 136.0, 138.8, 139.9, 146.4, 160.0; IR (neat): 3019,
1647, 1510, 1447, 1215, 1026, 772, 670 cmꢁ1; MS (ESI) m/z 416
[M þ H]þ; HRMS (ESI) calcd for C30H26NO: 416.2014, found: 416.2011.
4.3.3. 4-(Bis(4-chlorophenyl)methyl)-2,5-diphenyloxazole 3c
4.3.10. 2,5-Diphenyl-4-(phenyl(p-tolyl)methyl)oxazole 3j
White solid; m.p. 180e181 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
5.56
(s, 1H), 7.25e7.41 (m, 8H), 7.41e7.47 (m, 6H), 7.57e7.59 (m, 2H),
8.05e8.08 (m, 2H); 13C NMR (CDCl3, 75 MHz):
47.0, 126.5, 126.6,
Whitesolid;m.p.109e110 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 2.30(s,
3H), 5.62 (s,1H), 7.09e7.29 (m, 3H), 7.30e7.39 (m, 5H), 7.40e7.44 (m,
d
7H), 7.61e7.64 (m, 2H), 8.08e8.07 (m, 2H); 13C NMR (CDCl3, 75 MHz):
127.5, 128.4, 128.6, 128.7, 129.0, 130.4, 130.5, 132.7, 137.4, 140.7,
146.7, 160.3; IR (neat): 3018; 1653, 1591, 1489, 1215, 1090, 1015, 773,
670 cmꢁ1; MS (ESI) m/z 457 [M þ H]þ; HRMS (ESI) calcd for
C28H20Cl2NO: 456.0920, found: 456.0910.
d 21.2, 47.9, 126.5, 126.6, 127.8, 128.3, 128.4, 128.7, 128.9, 129.2, 129.3,
130.2, 136.2, 138.7, 139.7, 142.9, 146.5, 160.0; IR (neat): 3019, 1651,
1553, 1485, 1449, 1215, 756, 669 cmꢁ1; MS (ESI) m/z 402 [M þ H]þ;
HRMS (ESI) calcd for C29H24NO: 402.1858, found: 402.1846.
4.3.4. 4-((4-Fluorophenyl)(phenyl)methyl)-2,5-diphenyloxazole 3d
4.3.11. 4-Benzhydryl-2-phenyl-5-p-tolyloxazole 3k
White solid; m.p. 93e94 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
5.62 (s,
White solid; m.p. 151e152 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 2.38
1H), 6.95e7.00 (m, 2H), 7.19e7.28 (m, 1H), 7.30e7.45 (m, 12H), 7.61
(s, 3H), 5.63 (s, 1H), 7.18e7.32 (m, 8H), 7.38e7.43 (m, 7H), 7.51 (d,
(d, J ¼ 7.3 Hz, 2H), 8.06e8.09 (m, 2H); 13C NMR (CDCl3, 75 MHz):
J ¼ 8.1 Hz, 2H), 8.05e8.09 (m, 2H); 13C NMR (CDCl3, 75 MHz):
d 21.4,
d
47.5,126.6,126.8,127.7,128.4,128.5,128.7,129.0,129.1,130.3,130.7,
48.2,126.0,126.6, 127.9, 128.4, 128.6,129.2, 130.0, 137.9,138.3, 142.8,
146.8, 159.8, 160.0; IR (neat): 3021, 1638, 1508, 1485, 1449, 1215,
752, 667 cmꢁ1; MS (ESI) m/z 402 [M þ H]þ; HRMS (ESI) calcd for
C29H24NO: 402.1858, found: 402.1841.
130.8, 138.2, 138.4, 138.5, 142.5, 146.6, 160.1, 163.3; IR (neat): 3019,
1638, 1056, 1449, 1215, 752, 670 cmꢁ1; MS (ESI) m/z 406 [M þ H]þ;
HRMS (ESI) calcd for C28H21FNO: 406.1607, found: 406.1613.
4.3.5. 4-((4-Chlorophenyl)(phenyl)methyl)-2,5-diphenyloxazole 3e
4.3.12. 4-Benzyhydryl-2-phenyloxazole 3l
White solid; m.p. 119e120 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
5.60
Yellow solid; m.p. 102e103 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
5.43
(s, 1H), 7.15 (s, 1H), 7.15e7.33 (m, 10H), 7.40e7.42 (m, 3H),
8.00e8.03 (m, 2H); 13C NMR (CDCl3, 75 MHz):
49.6, 126.5, 126.8,
127.6, 128.5, 128.7, 128.9, 130.3, 136.7, 142.1, 145.0, 162.0; IR (neat):
3061, 3021, 1599, 1585, 1557, 1450, 1348, 1215, 754, 669 cmꢁ1; MS
(ESI) m/z 312 [M þ H]þ; HRMS (ESI) calcd for C22H18NO: 312.1388,
found: 312.1390.
(s, 1H), 7.20e7.31 (m, 4H), 7.33e7.38 (m, 4H), 7.41e7.46 (m, 7H),
7.60 (d, J ¼ 7.2 Hz, 2H), 8.06e8.09 (m, 2H); 13CNMR (CDCl3,
d
75 MHz):
d
47.6, 126.6, 126.8, 127.6, 128.4, 128.5, 128.6, 128.7, 129.0,
129.1, 130.3, 130.7, 132.5, 137.9, 141.2, 142.2, 146.7, 160.2; IR (neat):
3019, 1643, 1638, 1489, 1449, 1215, 752, 670 cmꢁ1; MS (ESI) m/z 422
[M þ H]þ; HRMS (ESI) calcd for C28H21ClNO: 422.1312, found:
422.1308.
4.3.13. 4-Benzhydryl-5-butyl-2-phenyloxazole 3m
4.3.6. 4-((4-Bromophenyl)(phenyl)methyl)-2,5-diphenyloxazole 3f
Yellow solid; m.p. 56e57 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 0.84
White solid; m.p. 121e122 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
5.58
(s, 1H), 7.14e7.46 (m, 17H), 7.61(d, J ¼ 8.4 Hz, 2H), 8.06e8.09 (m,
2H); 13C NMR (CDCl3, 75 MHz):
47.7, 120.6, 126.6, 126.9, 127.6,
(t, J ¼ 7.2 Hz, 3H), 1.22e1.29 (m, 2H), 1.48e1.55 (m, 2H), 2.46 (t,
J ¼ 7.8 Hz, 2H), 5.39 (s, 1H), 7.18e7.22 (m, 2H), 7.25e7.38 (m, 11H),
d
7.98e8.01 (m, 2H); 13C NMR (CDCl3, 75 MHz):
d 13.8, 22.4, 24.8,
128.3, 128.5, 128.6, 128.7, 129.0, 129.1, 130.3, 131.1, 131.5, 137.8, 141.8,
142.1, 146.7, 160.2; IR (neat): 3019, 1630, 1485, 1450, 1215, 752,
669 cm‑1; MS (ESI) m/z 466 [M þ H]þ; HRMS (ESI) calcd for
C28H21BrNO: 466.0807, found: 466.0801.
30.7, 48.4, 126.2, 126.5, 128.1, 128.3, 128.4, 128.6, 129.2, 129.7, 137.3,
142.7, 149.0, 159.4; IR (neat): 3019, 2959, 1655, 1601, 1557, 1493,
1449, 1215, 772, 700 cmꢁ1; MS (ESI) m/z 368 [M þ H]þ; HRMS (ESI)
calcd for C26H26NO: 368.2014, found: 368.2010.
4.3.7. 4-Benzhydryl-5-(4-fluorophenyl)-2-phenyloxazole 3g
4.3.14. 4-(Bis(4-chlorophenyl)methyl)-2-phenyl-5- (thiophen-3-yl)
oxazole 3n
White solid; m.p. 161e162 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 5.57
(s,1H), 7.10e7.16 (m, 2H), 7.22e7.26 (m, 2H), 7.28e7.33 (m, 4H), 7.40
Orange solid; m.p. 150e151 ꢀC; 1H NMR (CDCl3, 300 MHz):
(d, J ¼ 7.4 Hz, 7H), 7.55e7.60 (m, 2H), 8.06e8.09 (m, 2H). 13C NMR
d
5.54 (s, 1H), 7.25e7.27 (m, 8H), 7.29e7.35 (m, 1H), 7.38e7.43 (m,
(CDCl3, 75 MHz):
d
48.2, 115.8 (1C, d, JC-F ¼ 21.7 Hz), 125.0, 126.5,
5H), 8.03e8.06 (m, 2H); 13C NMR (CDCl3, 75 MHz):
d
47.1, 122.3,
126.6, 127.6, 128.3, 128.4, 128.5, 128.6, 129.2, 130.2, 138.2, 142.5,
145.7, 160.0; IR (neat): 3019, 1643, 1601, 1504, 1495, 1449, 1215,
1159, 1074, 768, 669 cmꢁ1; MS (ESI) m/z 406 [M þ H]þ; HRMS (ESI)
calcd for C28H22FNO: 406.1607, found: 406.1601.
125.7, 126.5, 126.9, 127.4, 128.7, 128.8, 129.1, 130.4, 130.5, 132.8,
136.8, 140.5, 143.6, 159.8; IR (neat): 3019, 1647, 1489, 1449, 1215,
1092, 752, 710, 669 cmꢁ1; MS (ESI) m/z 462 [M þ H]þ; HRMS (ESI)
calcd for C26H18NOSCl2: 462.0486, found: 462.0480.
4.3.8. 4-Benzhydryl-5-(4-chlorophenyl)-2-phenyloxazole 3h
Pale yellow solid; m.p. 178e179 ꢀC; 1H NMR (CDCl3, 300 MHz):
4.3.15. 4-Benzhydryl-5-phenyl-2-o-tolyloxazole 3o
Yellow solid; m.p.121e122 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
2.7 (s,
3H), 5.65 (s,1H), 7.18e7.35 (m,10H), 7.40e7.46 (m, 6H), 7.62e7.65 (m,
2H), 8.03e8.06 (m,1H); 13C NMR (CDCl3, 75 MHz):
22.4, 48.4,125.9,
d
5.58 (s, 1H), 7.22e7.25 (m, 2H), 7.28e7.33 (m, 4H), 7.38e7.43 (m,
9H), 7.52e7.55 (m, 2H), 8.05e8.09 (m, 2H); 13CNMR (CDCl3,
d

336
X. Zhang et al. / Journal of Organometallic Chemistry 696 (2011) 331e337
126.5, 126.6,128.3, 128.4,128.7, 128.9,129.0,129.2,129.8,131.7, 137.7,
138.0, 142.9, 146.0, 160.3; IR (neat): 3053, 3019, 1595, 1537, 1487,
1445, 1215, 845, 754, 694 cmꢁ1; MS (ESI) m/z 402 [M þ H]þ; HRMS
(ESI) calcd for C29H24NO: 402.1858, found: 402.1850.
75 MHz): d 18.1, 30.7, 43.3, 50.1, 55.7, 126.8, 127.0, 128.1, 128.2, 128.6,
128.7, 128.9, 129.2, 133.7, 135.6, 140.3, 140.7, 174.8, 195.5; IR
(neat):3019, 1674, 1597, 1495, 1265, 1215, 752, 669 cmꢁ1; MS (ESI)
m/z 370 [M þ H]þ; HRMS (ESI) calcd for C25H24NO2: 370.1807,
found: 370.1806.
4.3.16. 4-Benzhydryl-5-phenyl-2-m-tolyloxazole 3p
White solid; m.p. 169e170 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 2.39
Acknowledgements
(s, 3H), 5.65 (s, 1H), 7.19e7.24 (m, 3H), 7.28e7.34 (m, 6H), 7.37e7.46
(m, 6H), 7.63 (d, J ¼ 7.2 Hz, 2H), 7.88 (d, J ¼ 9.2 Hz, 2H); 13C NMR
This work is supported by a University Research Committee
Grant (RG55/06) from Nanyang Technological University and
Science and Engineering Research Council Grant (092 1010 053)
from A*STAR, Singapore. A Yousef Jameel Scholarship (to WTT) is
also gratefully acknowledged.
(CDCl3, 75 MHz):
d 21.4, 48.2, 123.7, 126.6, 127.1, 127.7, 128.3, 128.4,
128.6, 128.9, 129.3, 131.0, 138.4, 142.7, 146.5, 160.2; IR (neat): 3019,
1638, 1551, 1493, 1447, 1215, 752, 698 cmꢁ1; MS (ESI) m/z 402
[M þ H]þ; HRMS (ESI) calcd for C29H24NO: 402.1858, found:
402.1866.
Appendix A. Supplementary material
4.3.17. 4-Benzhydryl-5-phenyl-2-p-tolyloxazole 3q
White solid; m.p. 184e185 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 2.38
CCDC 784654 and 784655 contain the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif. Supplementary data asso-
ciated with this article can be found in the online version, at
doi:10.1016/j.jorganchem.2010.09.059.
(s, 3H), 5.64 (s, 1H), 7.19e7.23 (m, 4H), 7.27e7.32 (m, 5H), 7.36e7.43
(m, 6H), 7.62 (d, J ¼ 8.1 Hz, 2H), 7.97 (d, J ¼ 8.1 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): d 21.6, 48.2, 125.1, 126.5, 128.2, 128.4, 128.8, 129.2,
129.3, 138.3, 140.4, 142.7, 146.3, 160.2; IR (neat): 3019, 1638, 1497,
1215, 756, 669 cmꢁ1; MS (ESI) m/z 402 [M þ H]þ; HRMS (ESI) calcd
for C29H24NO: 402.1858, found: 402.1870.
References
4.3.18. 4-Benzhydryl-2-(4-methoxyphenyl)-5-phenyloxazole 3r
White solid; m.p. 191e192 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 3.84
[1] G. Xu, K. Chen, H. Zhou, Synthesis (2009) 3565e3570.
[2] V. Yeh, R. Iyengar, Five-membered rings with two heteroatoms, each with
their fused carbocyclic derivatives. in: R. Katrizky, C.W. Rees, E.F.V. Scriven,
R.J.K. Taylor (Eds.), Comprehensive Heterocyclic Chemistry III, vol. 4. Perga-
mon, New York, 2008, pp. 487e543.
(s, 3H), 5.63 (s, 1H), 6.94 (d, J ¼ 8.9 Hz, 2H), 7.19e7.27 (m, 1H),
7.30e7.32 (m, 5H), 7.32e7.36 (m, 7H), 7.40e7.63 (m, 2H), 8.02 (d,
J ¼ 8.9 Hz, 2H); 13C NMR (CDCl3, 75 MHz):
d 48.2, 55.4, 114.0, 120.7,
[3] Z. Jin, Nat. Prod. Rep. 23 (2006) 464e496.
[4] V.S.C. Yeh, Tetrahedron 60 (2004) 11995e12042.
126.4, 126.5, 128.1, 128.2, 128.4, 128.8, 128.9, 129.2, 138.2, 142.7,
146.0, 160.1, 161.2; IR (neat): 3019, 1638, 1612, 1497, 1254, 1215,
1273, 1024, 756, 698 cmꢁ1; MS (ESI) m/z 418 [M þ H]þ; HRMS (ESI)
calcd for C29H24NO2: 418.1807, found: 418.1816.
[5] D.C. Palmer (Ed.), Oxazoles: Synthesis, Reactions and Spectroscopy, Part B,
John Wiley & Sons, Hoboken, New Jersey, 2004.
[6] D.C. Palmer, S. Venkatraman, Oxazoles: synthesis, reactions and spectroscopy.
in: D.C. Palmer (Ed.), The Chemistry of Heterocyclic Compounds, A Series of
Monographs, Part A. Wiley & Sons, Hoboken, 2003.
[7] T. Eicher, S. Hauptmann, The Chemistry of Heterocycles: Structures, Reactions,
Synthesis, and Applications, second ed. Wiley-VCH, Weinheim, 2003.
[8] P. Wipf, Chem. Rev. 95 (1995) 2115e2134.
4.3.19. 4-Benzhydryl-2-(4-bromophenyl)-5-phenyloxazole 3s
White solid; m.p. 176e177 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 5.64
(s,1H), 7.19e7.27 (m, 2H), 7.30e7.41 (m, 4H), 7.41e7.45 (m, 7H), 7.54
[9] J.R. Lewis, Nat. Prod. Res. 12 (1995) 135e163.
[10] M.D. Milton, Y. Inada, Y. Nishibayashi, S. Uemura, Chem. Commun. (2004)
2712e2713.
(d, J ¼ 8.7 Hz, 2H), 7.60e7.62 (m, 2H), 7.93 (d, J ¼ 8.4 Hz, 2H); 13C
NMR (CDCl3, 75 MHz): d 48.2, 124.6, 126.6, 126.7, 128.0, 128.4, 128.5,
[11] M.P. Kumar, R.-S. Liu, J. Org. Chem. 71 (2006) 4951e4955.
[12] Y.M. Pan, F.J. Zheng, H.X. Lin, Z.P. Zhan, J. Org. Chem. 74 (2009) 3148e3151.
[13] M. Bandini, M. Tragni, Org. Biomol. Chem. 7 (2009) 1501e1507.
[14] N. Ljungdahl, N. Kann, Angew. Chem. Int. Ed. 48 (2009) 642e644.
[15] J. Muzart, Tetrahedron 64 (2008) 5815e5849.
128.6, 129.0, 131.9, 138.6, 142.5, 146.9, 159.2; IR (neat): 3019, 1599,
1492, 1479, 1447, 1396, 1310, 1215, 1011, 837, 770 cmꢁ1; MS (ESI) m/z
466 [M þ H]þ; HRMS (ESI) calcd for C28H21NOBr: 466.0807, found:
466.0802.
[16] J. Muzart, Eur. J. Org. Chem. (2007) 3077e3089.
[17] J. Muzart, Tetrahedron 61 (2005) 4179e4212.
[18] Y. Tamaru, Eur. J. Org. Chem. (2005) 2647e2656.
4.3.20. 4-Benzhydryl-2-(4-chlorophenyl)-5-phenyloxazole 3t
White solid; m.p. 175e176 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 5.64
[19] X. Zhang, W.T. Teo, P.W.H. Chan, Org. Lett. 11 (2009) 4990e4993.
[20] M. Yoshimatsu, T. Yamamoto, A. Sawa, T. Kato, G. Tanabe, O. Muraoka, Org.
Lett. 11 (2009) 2952e2955.
[21] S.Y. Wang, Y.X. Zhu, Y.G. Wang, P. Lu, Org. Lett. 11 (2009) 2615e2618.
[22] W. Rao, X. Zhang, E.M.L. Sze, P.W.H. Chan, J. Org. Chem. 74 (2009)
1740e1743.
[23] W. Huang, Q.S. Shen, J.L. Wang, X.G. Zhou, J. Org. Chem. 73 (2008)
1586e1589.
[24] M. Noji, Y. Konno, K. Ishii, J. Org. Chem. 72 (2007) 5161e5167.
[25] W. Huang, J. Wang, Q. Shen, X. Zhou, Tetrahedron Lett. 48 (2007) 3969e3973.
[26] T. Tsuchimoto, K. Tobita, T. Hiyama, S. Fukuzawa, J. Org. Chem. 62 (1997)
6997e7005.
[27] T. Tsuchimoto, K. Tobita, T. Hiyama, S. Fukuzawa, Synlett (1996) 557e559.
[28] X. Zhang, W.T. Teo, Sally, P.W.H. Chan, J. Org. Chem. 75 (2010) 6290e6293.
[29] P. Kothandaraman, W. Rao, S.J. Foo, P.W.H. Chan, Angew. Chem. Int. 49 (2010)
4619e4623.
[30] W. Rao, P.W.H. Chan, Org. Biomol. Chem. 8 (2010) 4016e4025.
[31] P. Kothandaraman, S.J. Foo, P.W.H. Chan, J. Org. Chem. 74 (2009) 5947e5952.
[32] S.R. Mothe, P.W.H. Chan, J. Org. Chem. 74 (2009) 5887e5893.
(s, 1H), 7.19e7.27 (m, 2H), 7.30e7.35 (m, 4H), 7.37e7.46 (m, 9H),
7.61 (d, J ¼ 7.2 Hz, 2H), 8.00 (d, J ¼ 8.7 Hz, 2H); 13C NMR (CDCl3,
75 MHz): d 48.2, 126.3, 126.6, 127.8, 128.4, 128.6, 128.9, 129.2, 136.2,
138.6, 142.5, 146.9, 159.1; IR (neat): 3021, 1638, 1481, 1404, 1215,
1094, 837, 752, 669 cmꢁ1; MS (ESI) m/z 423 [M þ H]þ; HRMS (ESI)
calcd for C28H21NOCl: 422.1312, found: 422.1305.
4.3.21. N-(1,3-diphenylprop-2-ynyl)benzamide 4 [47]
1H NMR (400 MHz, CDCl3):
J ¼ 8.4 Hz, 1H), 7.33e7.51 (m, 11H), 7.66 (d, J ¼ 7.5 Hz, 2H), 7.83 (d,
J ¼ 7.5 Hz, 2H); 13C NMR (CDCl3, 100 MHz): 45.6, 85.4, 87.0, 122.4,
127.1, 127.2, 128.2, 128.3, 128.7, 128.8, 131.9, 133.8, 139.0, 166.2.
d
¼ 6.49 (d, J ¼ 8.4 Hz, 1H), 6.73 (d,
4.3.22. 1-(1-Oxo-1,3,3-triphenylpropan-2-yl)pyrrolidin-2-one 5
White solid; m.p. 178e179 ꢀC; 1H MNR (CDCl3, 300 MHz):
[33] X. Zhang, W. Rao, Sally, P.W.H. Chan, Org. Biomol. Chem.
7 (2009)
4186e4193.
[34] P. Kothandaraman, W. Rao, X. Zhang, P.W.H. Chan, Tetrahedron 65 (2009)
1833e1838.
[35] W. Rao, P.W.H. Chan, Chem. Eur. J 14 (2008) 10486e10495.
[36] W. Wu, W. Rao, Y.Q. Er, K.J. Loh, P.W.H. Chan, Tetrahedron Lett. 49 (2008)
2620e2624; Tetrahedron Lett.49(2008), 4981.
d
1.49e1.53 (m,1H),1.67e1.71 (m,1H),1.92e2.03 (m,1H), 2.09e2.17
(m, 1H), 3.12e3.28 (m, 2H), 4.88 (d, J ¼ 11.7 Hz, 1H), 6.60 (d,
J ¼ 11.7 Hz, 1H), 7.01 (m, 1H), 7.10e7.19 (m, 3H), 7.21e7.40 (m, 4H),
7.42e8.08 (m, 5H), 8.10 (d, J ¼ 8.1 Hz, 2H); 13C NMR (CDCl3,

X. Zhang et al. / Journal of Organometallic Chemistry 696 (2011) 331e337
337
[37] W. Rao, P.W.H. Chan, Org. Biomol. Chem. 6 (2008) 2426e2433.
[38] X. Zhang, W. Rao, P.W.H. Chan, Synlett 6 (2008) 2204e2208 (Special Issue).
[39] W. Rao, A.H.L. Tay, P.J. Goh, J.M.L. Choy, J.K. Ke, P.W.H. Chan, Tetrahedron Lett.
49 (2008) 122e126; Tetrahedron Lett. 49 (2008) 5115.
[43] T. Ishikawa, M. Okano, T. Aikawa, S. Saito, J. Org. Chem. 66 (2001) 4635e4642.
[44] M. Edens, D. Boerner, C.R. Chase, D. Nass, M.D. Schiavelli, J. Org. Chem. 42
(1977) 3403e3408.
[45] C.U. Pittman Jr., G. Wilemon, J.E. Fojtasek, L.D. Kispert, J. Phys. Chem. 79 (1975)
[40] M. Yoshimatsu, T. Otani, S. Matsuda, T. Yamamoto, A. Sawa, Org. Lett. 10
(2008) 4251e4254.
2443e2446.
[46] A. Bacchi, M. Costa, B. Gabriele, G. Pelizzi, G. Salerno, J. Org. Chem. 67 (2002)
[41] R. Sanz, D. Miguel, A. Martínez, J.M. Álvarez-Gutiérrez, F. Rodríguez, Org. Lett.
9 (2007) 727e730.
4450e4457.
[47] Z. Zhan, J. Yu, H. Liu, Y. Cui, R. Yang, W. Yang, J. Li, J. Org. Chem. 71 (2006)
[42] T. Ishikawa, T. Aikawa, Y. Mori, S. Saito, Org. Lett. 5 (2003) 51e54.
8298e8301.