Synthesis of 2,4- and 2,4,5-substituted oxazoles via a silver triflate mediated cyclization

Article abstract of DOI:10.1016/j.tetlet.2014.05.002

2,4- and 2,4,5-substituted oxazoles were prepared from a broad range of bromo-ketones and amides in high yield and purity.

Full text of DOI:10.1016/j.tetlet.2014.05.002

Accepted Manuscript
Synthesis of 2, 4- and 2, 4, 5- Substituted Oxazoles via a Silver Triflate Mediated
Cyclization
Jessica L. Bailey, Ravinder R. Sudini
PII:
S0040-4039(14)00778-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.002
TETL 44592
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 March 2014
1 May 2014
2 May 2014
Please cite this article as: Bailey, J.L., Sudini, R.R., Synthesis of 2, 4- and 2, 4, 5- Substituted Oxazoles via a Silver
Triflate Mediated Cyclization, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.002
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Graphical Abstract
Synthesis of 2, 4- and 2, 4, 5- Oxazoles via a
Silver Triflate Mediated Cyclization
Jessica L. Bailey and Ravinder R. Sudini
Leave this area blank for abstract info.

1
Tetrahedron Letters
jou rn al h om ep a ge : www .e ls e v ie r .c om
Synthesis of 2, 4- and 2, 4, 5- Substituted Oxazoles via a Silver Triflate Mediated
Cyclization
Jessica L. Bailey* and Ravinder R. Sudini
aGlaxoSmithKline, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406-0939
ARTICLE INFO
ABSTRACT
Article history:
Received
2, 4- and 2, 4, 5- substituted oxazoles were prepared from a broad range of bromo-ketones and
amides in high yield and purity.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
Oxazole
Silver triflate
Cyclization
Bromo-ketone
Amide
Substituted oxazoles are useful synthetic intermediates found
readily in natural products1 such as Diazonamide A and
Leucamide A as well as in several modern pharmaceuticals.
There are numerous ways to construct oxazoles but most
methodologies are multi-step and/or require harsh reaction
conditions.2 More recent techniques are milder but of limited
scope as they tend to require expensive catalysts and/or non-
trivial syntheses of key starting materials. Therefore, new
methodologies to construct oxazoles from readily available
starting materials remain a significant unmet need. Common
methods used for the synthesis of oxazoles depicted in Scheme 1
include the Cornforth and Cornforth protocol3 as well as (i) The
initial4 and modified5 Robinson-Gabriel synthesis which involves
an intramolecular cyclization of an α-acylaminoketone onto a
carbonyl followed by dehydration (ii) A rhodium catalyzed
synthesis of oxazoles6a via the reaction of nitriles6b-c or amides6d-e
O
H
N
R3
R2
R1
O
O
H
R1
N
R3
NH4OAc
(viii)
R2
+
CN
R1
R3
R1
O
"Au"
(vii)
(i)
O
"Rh"
R1
O
N
O
R2
N2
R3CONH2
(vi)
R3CN
R1
R2
Br
R3
(ii)
R2
R3COCl
R2
(iii)
(v)
O
1) "Cu"
2) I2
(iv)
R3
N=PPh3
R1
HN
R2
R1
O
with
α-diazo-β-keto-carbonyl
compounds
(iii)
R1
R2
X
Cycloisomerization of propargylamides7-9 (iv) Copper/iodine
catalyzed tandem oxidative cyclization10 (v) The aza-Wittig
reaction of vinyliminophosphoranes and acylchlorides11 (vi)
Thermal12 promoted cyclization of a bromo-ketone and a
primary amide (vii) Intermolecular gold catalyzed alkyne
oxidation13 (viii) The Davidson Oxazole synthesis14 which is the
reaction of α-acyloxylketones with ammonium acetate as well as
copper catalyzed oxidative cyclization of enamides,15 transition
H2N R3
O
+
Scheme 1. Common methods to construct oxazoles
Cyclization of bromo-ketones (vi, Scheme 1) was attractive to
us as we were searching for a reliable and cost effective method
to synthesize 2, 4- and 2, 4, 5- substituted oxazoles in high yield
and purity. Attempts to generate oxazoles via a thermal
cyclization were low yielding due to poor thermal stability of the
bromo-ketone starting material at the temperatures required for
cyclization (>100 °C) especially at larger scales. Our need for an
efficient method for the large scale preparation of substituted
metal
catalyzed
cross-coupling,16
direct
C-H
arylation/alkenylation,17 and many others.18
* Corresponding author. Tel.: +011 16102705614
E-mail address: Jessica.L.Bailey@gsk.com (J.L. Bailey)
oxazoles led us to the work of both Ritson19 and Hoffmann
20
who independently determined that silver salts could promote
cyclization. Ritson utilized silver salts to synthesize substituted

2
oxazoles (1 equiv AgSbF6, DCE, microwave irradiation, 90 °C,
81 - 100% yield) while Hoffman generated oxazolones from
bromo-keto-esters and methylcarbamate (1 equiv AgOTf,
toluene, reflux, 30 - 68% yield) as shown below in Scheme 2.
The limited availability of AgSbF6, toxicity and carcinogenicity
of dichloroethane, generation of stoichiometric quantities of
silver bromide waste, serious concerns about the thermal stability
of bromo-ketones, and a strong desire to completely eliminate
microwave irradiation, led us to deem Ritson's method unsuitable
for our purposes, requiring the identification of an alternate
technique.
required for this process than for Ritson's approach (4+h vs 2h).
However, we felt this was less important due to the elimination
of microwave irradiation and dichloroethane, both of which are
undesirable at industrial scales. Additionally, the lower
temperatures required to initiate cyclization enable less stable
substrates to be used which in turn increases the number of
substituted oxazoles that can be synthesized using this
methodology.
As discussed above, excess amide and silver triflate is
required for best results and therefore an efficient means to purge
excess reagent needed to be identified. The amide could easily be
removed via a series of aqueous washes while the removal of
excess silver triflate was more difficult. As expected, attempts to
remove excess silver triflate using an extractive workup failed
due to uncontrolled precipitation of the silver salts during the
extractions. These issues were addressed by treating the reaction
mixture with aqueous brine (4-24h, 20 °C) to convert the excess
silver triflate into insoluble silver chloride which after filtration
quantitatively removed all of the silver salts (AgBr and AgCl).22
ICP analysis of the isolated product for silver confirmed that all
silver had been purged using this technique.23 Although the
stoichiometric quantities of silver waste produced by this process
are not ideal, it is our belief that this waste could be recycled to
minimize both the cost and environmental impact of the process
at industrial scales.
Scheme 2. Silver promoted cyclizations
Hoffman's20 conditions did not require microwave irradiation
and were thus more amenable to larger scale applications. We
were pleased to find that Hoffman's approach could also be used
to generate substituted oxazoles albeit in low yield (< 20%).
Better results were achieved when DCE was used as solvent and
the reaction mixture was protected from light, however, the yield
was still low (~40%) and the isolation problematic.21 Further
investigation indicated that these difficulties could be traced back
to poor stability of the bromo-ketone at the temperatures needed
to initiate cyclization and the use of chlorinated solvents
(dichloromethane, dichloroethane, or chloroform). Silver triflate
reacts with chlorinated solvents (DCM, DCE, or CHCl3) to
instantly produce a yellow paste (< 2 min). Charging additional
solvent was not beneficial leading us to conclude that chlorinated
solvents are not compatible with silver triflate and therefore
should be avoided for these types of reactions. It is further
postulated that chlorinated solvents react preferentially with
silver triflate during the cyclization to generate numerous
reactive species which produce large amounts of unidentified
impurities and ultimately produce oxazoles in low yield and
purity after isolation. A subsequent solvent screen identified both
ethyl acetate and toluene as suitable solvents for this
transformation. All other solvents (CPME, MiBK, diglyme,
DME, dioxane, THF, 2-Me-THF, dimethylcarbonate, ACN,
DMF, DMA, DMSO, NMP) produced oxazoles in low yield and
purity.
Table 1
Identification of optimal reaction conditions
Entry
Amide
(Equiv)
AgOTf
(Equiv)
Temp
(°C)
Time
(hrs)
Conversion
(%PAR)
1
2
3
4
5
6
7
1.0
1.25
1.25
1.0
1.0
1.25
1.25
1.25
1.5
60
20
50
50
60
60
60
4
21
4
93
95
97
94
99
98
99
4
1.5
3
1.25
2.0
1.5
3
2.0
1
Alternatives to silver triflate such as silver tetrafluoroborate,
silver acetate, or silver oxide, were also explored. As shown in
Table 2, silver tetrafluoroborate could also be used for this
transformation (4a, entry 6) but the reaction rate was slightly
slower than with silver triflate. All other silver salts investigated
failed to produce significant amounts of oxazole 4a (entries 1-5),
as did copper triflate.24 In the case of silver acetate, bromide
displacement with acetate rather than cyclization was the primary
outcome. Chloro-ketones may also be used for this
transformation but the reaction rate was significantly slower (4b,
entry 9) at the temperatures investigated. Lastly, substrates
containing chelating groups, such as pyridine, also reacted but
require a larger excess of silver triflate (2.25 equiv) and a slight
increase in temperature (70 °C) to push the reaction to
completion (4c, entry 10).
Optimal reaction conditions were identified for the synthesis
of oxazole 3 in ethyl acetate by examining the effect of
stoichiometry, temperature, and ambient light on the process. As
reported in Table 1, excellent conversion to oxazole 3 was
achieved in all instances while those examples conducted at
lower (ambient) temperature or those employing an equimolar
ratio of reagents (1:2:AgOTf) were slower to react (entries 1, 2).
Quantitative conversions could be achieved with a large excess (2
equiv) of either the amide (2) or silver triflate but the subsequent
workup and isolation of oxazole 3 was more difficult (entries 5,
7). Ambient light must also be excluded to prevent the reaction
from stalling. It is important to note that longer reaction times are

3
stability issues were run at lower temperatures and extended
reactions times while those substrates containing chelating
groups (e.g. pyridyl-) required slightly higher temperatures to
achieve complete conversion. The desired 2, 4- or 2, 4, 5-
substituted oxazoles were generated from both electron rich and
electron poor amides including aromatic, heteroaromatic, cyclic,
and heterocyclic substrates in moderate to good yield (64-85%)
and high purity (>95%). We were gratified to note that several
sensitive functionalities such as cyclopropyl (oxazoles 9 & 16),
vinyl (oxazole 7), or cinnamyl (oxazoles 8 & 13), and even aryl
halides (oxazoles 5, 10, 11, & 20) are well tolerated under the
reaction conditions albeit in lower yield (45-65%).
Unfortunately, when bromo-ketones such as desyl bromide or
bromoethyl pyruvate were employed, the reaction was
unsuccessful (oxazoles 21-26). With these more reactive
substrates, poor conversion to the desired oxazaole products were
obtained due to the formation of numerous unidentified
byproducts. Attempts to tune the reactivity through the use of the
more stable chloro-ketone, alternative silver salts (AgO) or even
copper triflate were unsuccessful.
Table 2
Investigation of the effect of silver source and halide
Entry
R1
R2
X
Silver
Salt
Time (hrs)
Yieldb Pdt
(%)
1
2
Ph
Ph
H
H
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Br
AgOAc
AgBr
6
6
0
0
1
3
Ph
H
AgO
24
6
4
Ph
H
AgNO3
Ag2CO3
AgBF4
AgOTf
AgOTf
AgOTf
AgOTf
2
4a
5
Ph
H
6
0
6
Ph
H
6
95
97
98
94
85
7
Ph
H
4
In conclusion, we have developed a reliable silver triflate
promoted cyclization reaction that is suitable for the large scale
preparation of 2, 4- and 2, 4, 5- substituted oxazoles from a
variety of halo-ketones and primary amides. An efficient
isolation/workup was also developed to remove excess amide via
a series of aqueous washes and silver triflate through the
implementation of an aqueous brine treatment and removal of the
resulting silver salt byproducts by filtration. We anticipate that
this improved process, which no longer requires chlorinated
solvents or microwave irradiation, will find extensive industrial
applications and further benefit from the utilization of a readily
available, non-toxic silver source that can be recycled after use.
This methodology has broad applications to industry and enables
highly functionalized 2, 4- and 2, 4, 5- oxazoles to be synthesized
from easily accessible starting materials producing oxazoles in
both high yield and purity.
8
Me
Me
4-pyra
Me
Me
H
4
4b
4c
9
24
17
10
a 2.25 equiv AgOTf and 70 °C required
b Solution yield as determined by HPLC
The scope of this reaction was then challenged by evaluation
of several bromo-ketones and primary amides of varying
reactivity utilizing the optimal reaction conditions identified for
bromo acetophenone (1.25 equiv amide, 1.25 equiv AgOTf, 50
°C, EtOAc) and these results are depicted in Table 3. Good
results were achieved with the majority of the bromo-ketones and
amides evaluated. Exact conditions varied somewhat depending
on several factors but generally speaking substrates with thermal

4
Tetrahedron Letters
Table 3
Full scope of AgOTf mediated oxazole synthesisa
a Isolated yields unless otherwise specified
b Solution yield as determined by HPLC
c 2.25 equiv AgOTf, 70 °C, overnight required for complete conversion
d Numerous unidentified impurities also generated
e 22°C reaction temperature
f Slurry of AgOTf added to solution of amide and bromo-ketone over at least 30 minutes
14, 4478 Selected SiO2 catalyzed: (b) Wipf, P.; Aoyama, Y.; Benedum,
T.E.; Org. Lett.; 2004, 6, 3593
References and notes
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Selected Pd catalyzed examples: (a) Arcadi, A.; Cacchi, S.; Cascia, L.;
Fabrizi, G.; Marinelli, F.; Org. Lett. 2001, 3, 2501 (b) Saito, A.; Iimura,
K.; Hanzawa, Y.; Tet. Lett. 2010, 51, 1471 (c) Beccalli, E.M.; Borsini,
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73, 4746
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J.S.; Beresis, R.T.; J. Org. Chem. 1996, 61, 6496
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H.; Kim, Y.; Moon, D.; Rhee, Y.M.; Ahn, K.H.; Angew Chem., Int. Ed.
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5232 (f) Luo, Y.; Ji, K.; Li, Y.; Zhang, L.; J. Am. Chem. Soc. 2012,
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14. (a) Davidson, D.; Weiss, M.; Jelling, M.; J. Org. Chem. 1937, 2, 328 (b)
Aldous, D.L.; Reibsomer, J.L.; Castle, R.N.; J. Org. Chem. 1960, 25,
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Hsiao, J-S-.; Vandavasi, J.K.; Chen, C-Y.; Wang, J-J.; Org. Lett. 2012,

5
Reactions in Heterocyclic Chemistry II, 2011, 221 (e) Huang, W.; Pei,
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3866 (d) Zheng, Y.; Li, X.; Ren, C.; Zhang-Negrerie, D.; Du, Y.; Zhao,
K. J. Org. Chem. 2012, 77, 10353
25. General procedure for oxazole cyclization: A mixture of bromo-
ketone (0.6 g, 2.9 mmol), amide (0.55 g, 3.6 mmol, 1.25 equiv), and
silver triflate (0.9 g, 3.6 mmol, 1.25 equiv) in ethyl acetate (4 mL) was
heated to 50 – 70 °C. After the reaction was deemed complete by HPLC
analysis, the mixture was cooled to ~20 °C and diluted with ethyl
acetate (3 mL). A solution of sat’d NaCl (3-4 mL) was added and the
mixture stirred at ~20 °C for at least 4h. The silver salts (AgBr & AgCl)
are removed by filtration and the resulting biphasic solution transferred
to a separatory funnel and the layers separated. The organic layer is then
washed with water (4 mL), 5% NaHCO3 (4 mL), 1N HCl (4 mL), and
water (4 mL). The organic layer is concentrated to dryness and the
residue purified by flash column chromatography (5% EtOAc/hexanes)
to obtain pure oxazole product. 2-(4-methoxyphenyl)-5-methyl-4-
16. (a) Lee, K.; Counceller, C.M.; Stambuli, J.P.; Org. Lett., 2009, 11, 1457
(b) Reeder, M.R.; Gleaves, H.E.; Hoover, S.A.; Imbordino, R.J.;
Pangborn, J.J.; Org. Process Res. Dev. 2003, 7, 696 (c) Liu, X.; Cheng,
R.; Zhao, F.; Zhang-Negrerie, D.; Du, Y.; Zhao, K.; Org. Lett., 2012,
14, 5480
17. (a) Besselievre, F.; Piguel, S.; Mahuteau-Betzer, F.; Grierson, D.S. Org.
Lett. 2008, 10, 4029 (b) Flegeau, E.F.; Popkin, M.E.; Greaney, M.F.
Org. Lett. 2008, 10, 2717 (c) Ackermann, L.; Barfusser, S.; Pospech, J.
Org. Lett. 2010, 12, 724 (d) Cui, S.; Wojtas, L.; Antilla, J.C. Org. Lett.
2011, 13, 5040 (e) Besselievre, F.; Piguel, S. Angew. Chem. Int. Ed.
2009, 48, 9553
18. (a) Herrera, A.; Martinez-Alvarez, R.; Ramiro, P.; Molero, D.; Almy, J.
J. Org. Chem. 2006, 71, 3026 (b) Misra, N.C.; Ila, H.; J. Org. Chem.,
2010, 75, 5195 (c) Zhou, W.; Xie, C.; Han, J.; Pan, Y. Org. Lett. 2012,
14, 4766 (d) El Kaim, L.; Grimaud, L.; Patil, P. Synlett, 2012, 23, 1361
(e) Hu, Y.; Yi, R.; Wu, F.; Wan, B.; J. Org. Chem. 2013, 78, 7714
19. (a) Ritson, D.J.; Spiteri, C.; Moses, J.E.; J. Org. Chem. 2011, 76, 3519
(b) Spiteri, C.; Ritson, D.J.; Awaad, A.; Moses, J.E.; J. Saud. Chem.
Soc. 2011, 15, 375
1
phenyloxazole (6) H NMR (300 MHz, DMSO-d6) δ 2.61 (s, 3H), 3.90
(s, 3H), 7.12 (m, 2H), 7.37 (m, 1H), 7.48 (m, 2H), 7.75 (m, 2H), 7.95
(m, 2H). 13C NMR (75 MHz, DMSO-d6) δ 12.16, 55.73, 114.91,
119.89, 126.67, 127.65, 127.79, 129.05, 132.26, 135.02, 144.16, 158.88,
161.25. 4-cyclopropyl-2-(4-methoxyphenyl)oxazole (16) 1H NMR (300
MHz, DMSO-d6) δ 0.8 – 0.9 (m, 4H), 1.85 (sextet or m, 1H), 3.83 (s,
3H), 7.06 (m, 2H), 7.8 – 7.9 (m, 3H). 13C NMR (75 MHz, DMSO-d6) δ
6.79, 7.26, 55.70, 114.16, 129.69, 134.09, 143.58, 163.19, 167.36. 2-
(4-bromophenyl)-4-(pyridine-4-yl)oxazole (20) 1H NMR (300 MHz,
DMSO-d6) δ 7.38 (m, 1H), 7.8 – 8.1 (m, 6H), 8.6 (m, 1H), 8.8 (s, 1H).
13C NMR (75 MHz, DMSO-d6) δ 120.18, 123.71, 124.85, 128.44,
132.71, 137.70, 138.66, 142.17, 150.04, 161.32.
20. Okonya, J.F.; Hoffman, R.V.; Johnson, M.C.; J. Org. Chem. 2002, 67,
1102
21. Polymeric impurities and black tar was produced under these reaction
conditions
22. Alternatively, an aqueous potassium bromide solution can be used in the
workup to convert the unreacted silver triflate to silver bromide. The
silver bromide can then be recovered by filtration and recycled.
23. Typical amounts of residual silver were 10-20ppm (ICP analysis)
24. Copper triflate likely also promotes cyclization but likely requires
significantly higher temperatures (>100 °C) in order to achieve a
reasonable reaction rate.

6
Tetrahedron Letters
Graphical Abstract
Synthesis of 2, 4- and 2, 4, 5- Oxazoles via a
Silver Triflate Mediated Cyclization
Leave this area blank for abstract info.
Jessica L. Bailey and Ravinder R. Sudini