Practical oxazole synthesis mediated by iodine from α-bromoketones and benzylamine derivatives

Article abstract of DOI:10.1039/c3ob41566j

The reagent system of I₂/K₂CO₃ could efficiently promote the oxazole synthesis from α-bromoketones and benzylamine derivatives in DMF. This method was not only suitable for 2,5-diaryl oxazole synthesis but also for 2,4,5-trisubstituted oxazole and 5-alkyl/alkenyl oxazole synthesis. Furthermore, this method was successfully applied to a one-step synthesis of a natural product halfordinol in 62% yield.

Full text of DOI:10.1039/c3ob41566j

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Organic & Biomolecular Chemistry
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DOI: 10.1039/C3OB41566J
The reagent system of I2/K2CO3 could efficiently promote the oxazole synthesis from α-bromoketones and
benzylamine derivatives in DMF.

Organic & Biomolecular Chemistry
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DOI: 10.1039/C3OB41566J
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ARTICLE TYPE
Practical Oxazole Synthesis Mediated by Iodine from -Bromoketones
and Benzylamine Derivatives
Wen-Chao Gao, Ruo-Lin Wang and Chi Zhang*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
The reagent system of I2/K2CO3 could efficiently promote the oxazole synthesis from -bromoketones
and benzylamine derivatives in DMF. This method was not only suitable for 2,5-diaryl oxazole synthesis
but also for 2,4,5-trisubstituted oxazole and 5-alkyl/alkenyl oxazole synthesis. Furthermore, this method
was successfully applied to a one-step synthesis of a natural product halfordinol in 62% yield.
thiazoles,9d,e imidazoles,9f and indoles.9g,h Particularly, Moses and
coworkers recently reported a silver-mediated one-step synthesis
10 Introduction
of oxazoles from -bromoketones and amide derivatives, which
had a broad substrate scope and tolerance to various functional
40 groups (Scheme 1a);9c however, the cost of stoichiometric silver
reagent impeded the large-scale preparation of oxazoles. And, the
in situ generation of α-iodo ketones and subsequent reaction with
amine compounds was also efficient for oxazole synthesis.7a-c Wu
and coworkers reported that the combination of DMSO/I2 could
45 promote an oxidative domino reaction for the synthesis of 2-aryl-
5-aryl-disubstituted oxazoles from aryl methyl ketones and
benzylamine derivatives;7b however, the employed substrates
were limited to aromatic methyl ketones, and either the alkyl
methyl ketone or the ketone bearing C-C double bond was not
50 tolerated under their conditions, which resulted in the
inaccessibility of 2,4,5-trisubstituted oxazoles and 5-alkyl/alkenyl
oxazoles. Quite recently, we reported a general method for the 2-
acylindole and 2-acylindoline synthesis by using I2/K2CO3
system in the solvent of methanol.10 As the continuing research
55 on the heterocycle synthesis with this reagent system, herein, we
disclose an alternative way to synthesize oxazoles especially for
2,4,5-trisubstituted oxazoles and 5-alkyl/alkenyl oxazoles from -
bromoketones and benzylamine derivatives (Scheme 1b).
Oxazole is an important five-membered heterocycle in nature.1 In
particular, 2,4,5-trisubstituted oxazoles can be found in many
natural products, drugs, and biologically active compounds, such
as the non-steroidal anti-inflammatory drug oxaprozin,2a the
15 peptide alkaloid (-)-muscoride A,2b and the anti-diabetic agent
AD-5061 (Figure 1).2c Accordingly, numerous synthetic methods
have been developed to construct a functionalized oxazole
skeleton. Among these methods, intramolecular cyclisation of
amide precursors,3 the oxidation of oxazolines,4 the transition-
20 metal catalyzed oxidative coupling of functionalized alkynes with
amides or nitriles,5 the oxidative cyclisation of imine,6 and
domino reaction of ketones, -keto esters or alkenes with
nitrogen-containing compounds7 are widely used. Despite these
processes being achieved, there is still considerable room for the
25 development of single-step method from readily available
materials.
Figure 1 The selected important molecules bearing oxazole skeleton
30 -Halo ketone is one kind of readily available compound. For
example, -bromoketones can be prepared by treating the
corresponding ketones with the reagents such as bromine,8a N-
bromosuccinimide (NBS),8b or cupric bromide.8c,d -Halo
ketones often served as the efficient building blocks for
35 constructing various heterocyclic rings such as oxazoles,9a-c
60
Scheme 1 Synthesis of oxazoles from -bromoketones
Results and discussion
Initially, the oxazole synthesis was examined using -
bromoacetophenone (1a) and benzylamine (2a) as the model
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Organic & Biomolecular Chemistry
substrates. It was found that 2,5-diphenyloxazole (3a) was
R2 was varied to other groups, such as phenyl, methyl, and ester
groups, the reaction also proceeded well and gave the 2,4,5-
trisubstituted oxazoles in moderate to goDodOI:y1i0e.l1d0s39(/3Cj3-lO).B4B1y566J
isolated in 46% yield by using 2.2 equiv of iodine and 2 equiv of
View Article Online
o
K2CO3 in DMF at 80 C (Table 1, entry 1). By contrast, 3a was
only isolated in the yield of 20% in the absence of K2CO3 (entry 40 contrast, the 2,4,5-triphenzyl oxazole (3j) was also tried to be
5
2). Notably, the conversion and yields were affected dramatically
by the amount of K2CO3 employed, and the best result (82%) was
obtained by employing 4 equiv. of K2CO3 (entry 4). The further
increase in the amount of K2CO3 did not give a better result
synthesized by using a simple ketone 1,2-diphenylethanone and
benzylamine in the presence of I2 (2.2 equiv.) in DMSO, the
standard reaction conditions for 2,5-disubstituted oxazoles
synthesis described by Wu and coworkers,7b however, 3j was not
(entry 5), and the excess benzylamine led to the lower yield of 3a 45 detected, and benzil and benzoic acid were obtained instead (for
10 (entry 6). Other bases such as Na2CO3 gave a comparable yield
(entry 7), while KHCO3, KOH, and Et3N were less effective to
promote this reaction (entries 8-10). The solvent was found to
have a big impact on the reaction efficiency. 3a was obtained in
details, see ESI†). Furthermore, the aliphatic methyl ketones were
also good substrates under the present conditions. When R1 was
tert-butyl or iso-propyl group, the desired products 3m and 3n
were produced in 70% and 50% yields respectively. As for the -
slightly lower yields in other polar aprotic solvents such as 50 bromoketone bearing C-C double bond, the oxazole product 3o
15 dimethylsulfoxide (DMSO), N,N-dimethyl acetamide (DMA),
and N-methyl-2-pyrrolidone (NMP) (entries 11-13 vs. entry 4),
while the solvents such as acetonitrile, 1,4-dioxane, ethanol, and
THF were found less effective, resulting in 3a being produced in
inferior yields (entries 14-17).
was isolated in 43% yield. In addition, we also tested different
benzylamine derivatives for this transformation. A variety of
benzylamine derivatives with various functional groups on the
phenyl ring, regardless of their electronic or steric properties,
55 proceeded smoothly to give their corresponding oxazoles in good
yields (3p-3s). 2-Furylamine was also suitable for this
transformation, and gave 3t in 72% yield. However, as for the
aliphatic amines such as n-hexamine and 2-phenylethylamine, no
desired oxazole products were detected under the standard
60 conditions.
20 Table 1 Optimization of reaction conditionsa
Table 2 Substrate scope for oxazole formationa
a The reaction was run with 0.5 mmol of 1a and 1.2 equiv. of 2a in 2 mL
of solvent. b Isolated yields. c 2.2 equiv. of benzylamine was used. d N-
benzyl-2-oxo-2-phenylacetamide was isolated in 31% yield. e N-benzyl-2-
oxo-2-phenylacetamide was isolated in 16% yield. f The reaction was run
25 at reflux.
With the optimal reaction condition in hand (Table 1, entry 4),
a series of -bromoketones and benzylamine derivatives were
tried for the synthesis of multi-substituted oxazoles. Various -
bromoacetophenone derivatives bearing electron-withdrawing or
30 electron-donating groups on the phenyl ring gave the desired
products in good yields (Table 2, 3b-f). 2-Bromo-2’-
acetonaphthone afforded the oxazole product 3g in 74% yield,
and other aromatic ring such as furyl and thienyl could also be
tolerated under the present conditions (3h and 3i). It was
35 noteworthy that this transformation was also suitable for the
preparation of 2,4,5-trisubstituted oxazoles. For example, when
a The reaction was run with 0.5 mmol of -bromoketone and 1.2 equiv. of
benzylamine derivative in 2 mL of DMF. b 2 equiv. of benzylamine was
used.
65
The mechanism of the present transformation is worth
discussing. Quite recently, Wu and coworkers reported that the
combination of DMSO and molecule iodine could promote the
synthesis of 2,5-disubstituted oxazoles from aryl methyl ketones
and benzylamine derivatives at 100 oC under the acidic
2
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Organic & Biomolecular Chemistry
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conditions.7b DMSO served as an essential oxidative solvent to 45 for 2,4,5-trisubstituted oxazoles from readily available -
accomplish the transformation from -iodo ketone to
phenylglyoxal,11 which then could react with benzylamine to
form the key intermediate -keto imine. However, since the
present transformation was run in the non-oxidative solvent DMF
bromoketones and benzylamine derivatives has been developed.
View Article Online
This transformation uses molecule iodine as the sole oxidant
DOI: 10.1039/C3OB41566J
under basic conditions and shows a broader scope of substrates.
Moreover, this method was also applied to the concise synthesis
5
under basic conditions, we believe the phenylglyoxal was not 50 of a natural product halfordinol. The ready availability of starting
involved (for details, see ESI†).
In 2010, Wang and coworker developed a method of oxazole
synthesis from the imine intermediate generated by the
materials, broad substrate scope, and operational simplicity make
the present method attractive to construct oxazole skeleton.
10 condensation of -amino ketone and aldehyde.6a Therefore, we
surmised that the similar imine intermediate B would be formed
by the iodine mediated oxidation of amine under basic condition.
Firstly, the SN2 reaction between -bromoacetophenone and
benzylamine proceeded to produce the intermediate A,12 which
15 could be oxidized to the keto imine B in the presence of iodine
and K2CO3.13 After the removal of -proton, the oxygen anion of
enolate would attack the imine functionality to form the
oxazoline D. Again, the iodine oxidation of D under basic
condition afforded the oxazole 3a (Scheme 2). Although 5 equiv.
20 of acid was produced theoretically, 4 equiv. of K2CO3 was
Acknowledgments
This work was financially supported by The National Natural
55 Science Foundation of China (21172110 and 21121002) and
Synergetic Innovation Center of Chemical
Engineering (Tianjin).
Science
and
Experimental
Representative Procedure for 3a
60 Iodine (279 mg, 1.1 mmol) was added to the mixture of -
bromoacetophenone (0.5 mmol, 100 mg), benzylamine (65 mg,
0.6 mmol) and K2CO3 (278 mg, 2 mmol) in 2 mL of DMF, and
then the mixture was stirred at 80 oC. After the reaction was
complete by TLC analysis, EtOAc (30 mL) was added to dilute
65 the reaction mixture, followed by the treatment of sat. Na2S2O3
solution to quench the reaction. The organic layer was separated,
washed by water (3×10 mL), and dried over anhydrous Na2SO4.
After removal of solvent under vacuo, the residue was purified by
flash column chromatography with petroleum ether/EtOAc (10:1)
70 to give the 2,5-diphenyloxazole (3a).
-
sufficient because its conjugated acid (HCO3 ) also worked in the
deprotonation process.
2,5-Diphenyloxazole (3a)7g
Yield: 82%; white solid; m.p. 64-67 oC; TLC, Rf = 0.5 (PE:
EtOAc = 10:1); H NMR (CDCl3, 400 MHz): δ 8.13 (d, 2H, J =
Scheme 2 Plausible mechanism for I2-mediated oxazole formation
1
25
The success in the functionalized oxazole synthesis inspired us
to explore the synthetic application of the present method.
Halfordinol (6), an oxazole alkaloid of Rutaceae, was first
isolated from the bark of Halfordia scleroxyla in 1963.14a This
natural product was first synthesized by Wenis and coworker by
8.0 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.45 (m, 6H), 7.35 (t, 1H, J =
75 7.2 Hz) ; 13C NMR (CDCl3, 100 MHz): δ 161.12, 151.22, 130.30,
128.91, 128.80, 128.42, 127.98, 127.41, 126.25, 124.16, 123.42.
5-(4-Methoxyphenyl)-2-phenyloxazole (3b)7g
Yield: 65%; white solid; m.p. 78-79 oC; TLC, Rf = 0.35 (PE:
EtOAc = 10: 1); 1H NMR (CDCl3, 400 MHz): δ 8.09 (dd, 2H, J =
80 8.0, 2.0 Hz), 7.65 (d, 2H, J = 8.8 Hz), 7.44-7.50 (m. 3H), 7.33 (s,
1H), 6.97 (d, 2H, J = 8.8 Hz), 3.86 (s, 3H); 13C NMR (CDCl3,
100 MHz): δ 160.53, 159.78, 151.28, 130.09, 128.76, 127.54,
126.10, 125.72, 121.92, 120.85, 114.37, 55.35.
30 the use of Robinson-Gabriel method, with the overall yield of
1.94% after 5 steps.14b In 1971, Onaka developed a modified
Fisher method for the synthesis of halfordinol in 16.5% overall
yield from p-hydroxymandelonitrile and nicotinaldehyde by a
two-step one-pot procedure.14c However, the latter method
35 suffered from the use of dry HCl gas and long reaction time (> 2
days). From the commercially available 2-bromo-4’-
hydroxyacetophenone (4) and 3-(aminomethyl)pyridine (5),
halfordinol could be obtained in 62% yield after 4 h under the
present conditions, which was more efficient and practicable
40 compared with the previous methods (Scheme 3).
5-(4-Fluorophenyl)-2-phenyloxazole (3c)7g
85 Yield: 77%; white solid; m.p. 87-89 oC; TLC, Rf = 0.26 (PE:
1
EtOAc = 10: 1); H NMR (CDCl3, 400 MHz): δ 8.08-8.11 (m,
2H), 7.67-7.71 (m, 2H), 7.47-7.49 (m, 3H), 7.39 (s, 1H), 7.14 (t,
2H, J = 8.8 Hz); 13C NMR (CDCl3, 100 MHz): δ 162.61(d, J =
247.1 Hz), 161.11, 150.41, 130.36, 128.81, 127.32, 126.23,
90 126.05 (d, J = 8.3 Hz), 124.36, 123.07, 116.07 (d, J = 21.9 Hz);
19F NMR (CDCl3, 376 MHz): δ -112.81.
5-(4-Chlorophenyl)-2-phenyloxazole (3d)7g
Scheme 3 One-step synthesis of halfordinol
o
Yield: 84%; white solid; m.p. 102-104 C; TLC, Rf = 0.33 (PE:
1
Conclusions
EtOAc = 10: 1); H NMR (CDCl3, 400 MHz): δ 8.00-8.11 (m,
95 2H), 7.64 (d, 2H, J = 8.8 Hz), 7.47-7.49 (m, 3H), 7.44 (s, 1H),
In summary, the multi-substituted oxazole construction especially
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Organic & Biomolecular Chemistry
7.41 (d, 2H, J = 8.4 Hz); 13C NMR (CDCl3, 100 MHz): δ 161.35,
150.24, 134.15, 130.48, 129.19, 128.83, 127.22, 126.48, 126.30,
125.38, 123.81.
TLC, Rf = 0.38 (PE: EtOAc = 10: 1); 1H NMR (CDCl3, 400
MHz): δ 8.09 (dd, 2H, J = 8.0, 2.0 Hz), 7.69 (d, 2H, J = 7.2 Hz),
View Article Online
55 7.45-7.49 (m, 5H), 7.34 (t, 1H, J = 8.0 HDz)O,I:21.50.110(3s9, /3CH3O);B4131C566J
NMR (CDCl3, 100 MHz): δ 159.32, 145.43, 133.34, 130.21,
128.76, 128.73, 127.56, 127.43, 126.23, 125.30, 13.05.
5-(4-Bromophenyl)-2-phenyloxazole (3e)7g
o
5
Yield: 80%; white solid; m.p. 99-100 C; TLC, Rf = 0.40 (PE:
Ethyl 2,5-diphenyloxazole-4-carboxylate (3l)7e
1
EtOAc = 10: 1); H NMR (CDCl3, 400 MHz): δ 8.08-8.12 (m,
2H), 7.55-7.60 (m, 4H), 7.47-7.49 (m, 3H), 7.45 (s, 1H); 13C
Yield: 56%; pale yellow solid; m.p. 85-86 oC; TLC, Rf = 0.25 (PE:
1
NMR (CDCl3, 100 MHz): δ 161.40, 150.26, 132.12, 130.51, 60 EtOAc = 10: 1); H NMR (CDCl3, 400 MHz): δ 8.10-8.17 (m,
128.84, 127.20, 126.90, 126.32, 125.60, 123.92, 122.28.
4H), 7.46-7.50 (m, 6H), 4.45 (q, 2H, J = 10.8 Hz), 1.42 (t, 3H, J =
7.2 Hz); 13C NMR (CDCl3, 100 MHz): δ 162.22, 159.72, 154.99,
130.98, 130.21, 128.73, 128.48, 128.32, 127.06, 126.79, 126.31,
126.43, 61.41, 14.23.
10 5-(4-Acetoaminophenyl)-2-phenyloxazole (3f)
o
Yield: 79%; white solid; m.p. 204-206 C; TLC, Rf = 0.15 (PE:
EtOAc = 2: 1); 1H NMR (CDCl3, 400 MHz): δ 8.07-8.10 (m, 2H),
7.59-7.68 (m, 5H), 7.45-7.48 (m, 3H), 7.38 (s, 1H), 2.20 (s, 3H);
13C NMR (CDCl3, 100 MHz): δ 168.40, 160.92, 150.92, 138.10,
15 130.28, 128.80, 127.36, 126.20, 124.94, 123.92, 122.82,119.99,
24.65; IR (neat) ν: 3440, 3318, 3110, 1693, 1605, 1537, 1503,
1414, 1321, 1265, 837 cm-1; HRMS (ESI) m/z calcd. for
C17H15N2O2 [M+H]+: 279.1128 found: 279.1125.
65 5-tert-Butyl-2-phenyloxazole (3m)15b
Yield: 70%; colorless oil; TLC, Rf = 0.5 (PE: EtOAc = 20: 1); 1H
NMR (CDCl3, 400 MHz): δ 7.99-8.02 (m, 2H), 7.40-7.46 (m, 3H),
6.79 (s, 1H), 1.35 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 160.92,
160.39, 129.80, 128.62, 127.90, 125.93, 120.94, 31.48, 28.70.
70 5-Isopropyl-2-phenyloxazole (3n)15c
5-(Naphthalen-2-yl)-2-phenyloxazole (3g)7g
Yield: 50%; colorless oil; TLC, Rf = 0.41 (PE: EtOAc = 20: 1);
1H NMR (CDCl3, 400 MHz): δ 8.00 (dd, 2H, J = 8.0, 2.0 Hz),
7.40-7.46 (m, 3H), 6.81 (s, 1H), 3.00-3.08 (m, 1H), 1.32 (d, 6H, J
= 6.8 Hz); 13C NMR (CDCl3, 100 MHz): δ 160.45, 158.29,
20 Yield: 74%; white solid; m.p. 98-99 oC; TLC, Rf = 0.25 (PE:
1
EtOAc = 10: 1); H NMR (CDCl3, 400 MHz): δ 8.16-8.20 (m,
3H), 7.89-7.92 (m, 2H), 7.85 (d, 1H, J = 7.6 Hz), 7.78 (dd, 1H, J
= 8.4, 1.2 Hz), 7.48-7.56 (m, 6H); 13C NMR (CDCl3, 100 MHz): 75 129.79, 128.62, 127.85, 125.92, 121.78, 26.07, 20.70.
δ 161.34, 151.36, 133.39, 133.09, 130.38, 128.84, 128.75, 128.20,
25 127.85, 127.43, 126.81, 126.50, 126.35, 125.28, 123.98, 122.92,
(E)-2-Phenyl-5-styryloxazole (3o)3k
o
o
Yield: 43%; yellow solid; m.p. 76-78 C (lit. 82 C); TLC, Rf =
122.06.
1
0.31 (PE: EtOAc = 20: 1); H NMR (CDCl3, 400 MHz): δ 8.09-
5-(Furan-2-yl)-2-phenyloxazole (3h)7g
8.12 (m, 2H), 7.47-7.52 (m, 5H), 7.39 (t, 2H, J = 7.6 Hz), 7.30 (t,
Yield: 57%; white solid; m.p. 73-75 oC; TLC, Rf = 0.44 (PE: 80 1H, J = 7.2 Hz), 7.17 (d, 1H, J = 16.0 Hz), 7.16 (s, 1H), 6.94 (d,
1
EtOAc = 10: 1); H NMR (CDCl3, 400 MHz): δ 8.07-8.10 (m,
30 2H), 7.46-7.50 (m, 4H), 7.35 (s, 1H), 6.70 (d, 1H, J = 3.2 Hz),
6.52 (dd, 1H, J = 3.2, 1.6 Hz); 13C NMR (CDCl3, 100 MHz): δ
160.72, 143.68, 142.85, 130.41, 128.80, 127.13, 126.33, 123.37,
111.58, 107.27.
1H, J = 16 Hz); 13C NMR (CDCl3, 100 MHz): δ 161.11, 150.37,
136.40, 130.44, 129.50, 128.84, 128.26, 127.35, 126.54, 126.48,
126.42, 113.09.
5-Phenyl-2-p-tolyloxazole (3p)7g
85 Yield: 79%; white solid; m.p. 69-71 oC; TLC, Rf = 0.40 (PE:
EtOAc = 20: 1); H NMR (CDCl3, 400 MHz): δ 8.00 (d, 2H, J =
8.0 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.42-7.46 (m, 3H), 7.28-7.36
(m, 3H), 2.42 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 161.39,
150.92, 140.62, 129.51, 128.89, 128.29, 128.10, 126.23, 124.75,
5-(Thiophen-2-yl)-2-phenyloxazole (3i)
1
35 Yield: 63%; white solid; m.p. 70-71 oC; TLC, Rf = 0.37 (PE:
EtOAc = 10: 1); H NMR (CDCl3, 400 MHz): δ 8.07-8.10 (m,
1
2H), 7.46-7.48 (m, 3H), 7.37 (d, 1H, J = 3.6 Hz), 7.34 (dd, 1H, J
= 4.8, 0.8 Hz), 7.31 (s, 1H), 7.10 (dd, 1H, J = 4.8, 3.6 Hz); 13C 90 124.11, 123.31, 21.52.
NMR (CDCl3, 100 MHz): δ 160.63, 146.76, 130.36, 129.87,
5-Phenyl-2-o-tolyloxazole (3q)6a
40 128.79, 127.83, 127.15, 126.27, 125.61, 124.27, 123.10; IR (neat)
ν: 3442, 3100, 1631, 1589, 1446, 1127, 1064, 911, 816 cm-1;
HRMS (ESI) m/z calcd. for C17H15N2O2 [M+H]+: 228.0478 found:
228.0475.
Yield: 79%; yellow solid; m.p. 86-87 oC; TLC, Rf = 0.40 (PE:
EtOAc = 20: 1); H NMR (CDCl3, 400 MHz): δ 8.09-8.11 (m,
1H), 7.72 (d, 2H, J = 7.2 Hz), 7.49 (s, 1H), 7.45 (t, 2H, J = 8.0
95 Hz), 7.31-7.37 (m, 4H), 2.77 (s, 3H); 13C NMR (CDCl3, 100
MHz): δ 161.57, 150.81, 137.28, 131.68, 129.92, 128.92, 128.76,
128.34, 128.07, 126.41, 126.00, 124.12, 123.14, 22.11.
1
2,4,5-Triphenyloxazole (3j)7g
o
45 Yield: 83%; white solid; m.p. 112-114 C; TLC, Rf = 0.5 (PE:
EtOAc = 20: 1); H NMR (CDCl3, 400 MHz): δ 8.16-8.20 (m,
2H), 7.76 (d, 2H, J = 7.2 Hz), 7.71 (d, 2H, J = 7.2 Hz), 7.47-7.50
(m, 3H), 7.35-7.44 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ
160.12, 145.52, 136.75, 132.54, 128.95, 128.74, 128.66, 128.60,
50 128.21, 128.12, 127.35, 126.52, 126.43.
1
2-(4-Fluorophenyl)-5-phenyloxazole (3r)7g
Yield: 84%; white solid; m.p. 71-73 oC; TLC, Rf = 0.41 (PE:
100 EtOAc = 10: 1); 1H NMR (CDCl3, 400 MHz): δ 8.10 (dd, 2H, J =
8.8, 5.2 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.43-7.47 (m, 3H), 7.35 (t,
1H, J = 7.6 Hz), 7.18 (t, 2H, J = 8.8 Hz); 13C NMR (CDCl3, 100
MHz): δ 165.29, 161.56 (d, J = 245.7 Hz), 151.35, 128.95,
128.50, 128.37 (d, J = 8.7 Hz), 127.90, 124.17, 123.39, 116.02 (d,
4-Methyl-2,5-diphenyloxazole (3k)15a
Yield: 64%; pale yellow solid; m.p. 69-72 oC (Lit. 75-77 C);
o
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Organic & Biomolecular Chemistry
Page 6 of 6
J = 22.2 Hz); 19F NMR (CDCl3, 376 MHz): δ -109.43.
2-(4-Methoxyphenyl)-5-phenyloxazole (3s)7g
2012, 77, 4271-4277; (e) A. Saito, A. Taniguchi, Y. Kambara and Y.
Hanzawa, Org. Lett., 2013, 15, 2672-2675.
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6
7
View Article Online
65
70
75
80
85
90
Yield: 70%; pale yellow solid; m.p. 91-93 oC; TLC, Rf = 0.35 (PE:
1
EtOAc = 10: 1); H NMR (CDCl3, 400 MHz): δ 7.90 (d, 2H, J =
From ketones, see: (a) W.-J. Xue, Q. Li, Y.-P. Zhu, J.-G. Wang and
A.-X. Wu, Chem. Commun., 2012, 48, 3485-3487; (b) Q.-H. Gao, Z.
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Zhang, S. Wang, J. Fan and Z. Wang, Org. Lett. 2010, 12, 2338-2341;
(f) J. Xie, H. Jiang, Y. Cheng and C. Zhu, Chem. Commun., 2012, 48,
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Qi, Org. Lett., 2010, 12, 5561-5563.
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638.
The synthesis of heterocyclic compounds from -halo ketones, see:
(a) F. O. Blümlein, Ber., 1884, 17, 2578-2581; (b) M. Lewy, Ber.,
1887, 20, 2576-2580; (c) D. J. Ritson, C. Spiteri and J. E. Moses, J.
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Li, C. K.-F. Chiu, R. F. Hank, J. Murry, J. Roth and H. Tobiassen,
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5
8.8 Hz), 7.56 (d, 1H, J = 7.2 Hz), 7.29 (t, 2H, J = 8.0 Hz), 7.18 (t,
1H, J = 7.2 Hz), 6.85 (d, 2H, J = 8.8 Hz), 3.73 (s, 3H); 13C NMR
(CDCl3, 100 MHz): δ 161.32, 161.23, 150.68, 134.39, 131.19,
128.86, 128.17, 127.92, 124.00, 123.23, 120.24, 114.21, 55.36.
2-(Furan-2-yl)-5-phenyloxazole (3t)6a
10 Yield: 72%; white solid; m.p. 61-63 oC; TLC, Rf = 0.20 (PE:
1
EtOAc = 10: 1); H NMR (CDCl3, 400 MHz): δ 7.70 (d, 2H, J =
8.8 Hz), 7.58 (d, 1H, J = 0.8 Hz), 7.41-7.45 (m, 3H), 7.34 (t, 1H,
J = 7.2 Hz), 7.08 (d, 1H, J = 3.2 Hz), 6.56 (dd, 1H, J = 3.2, 1.6
Hz); 13C NMR (CDCl3, 100 MHz): δ 153.92, 150.79, 144.39,
15 142.93, 128.91, 128.52, 127.62, 124.20, 123.19, 111.87, 111.37.
8
9
Halfordinol14c
Yield: 62%; pale yellow solid; m.p.: 253-255 oC; TLC, Rf = 0.45
1
(PE: EtOAc = 2: 1); H NMR (DMSO-d6, 400 MHz): δ 9.21 (s,
1H), 8.67 (d, 1H, J = 4.4 Hz), 7.67 (d, 2H, J = 8.0 Hz), 7.63 (s,
20 1H), 7.55 (dd, 1H, J = 7.6, 5.2 Hz), 6.88 (d, 2H, 8.4 Hz); 13C
NMR (DMSO-d6, 100 MHz): δ 158.20, 157.13, 151.96, 150.77,
146.60, 133.01, 126.01, 124.13, 123.18, 121.91, 118.29, 115.93.
10 W.-C. Gao, S. Jiang, R.-L. Wang and C. Zhang, Chem. Commun.,
2013, 49, 4890-4892.
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