Triflic anhydride-mediated synthesis of oxazoles

Article abstract of DOI:10.1016/j.tetlet.2008.12.080

N-Acyl amino acid esters undergo triflic anhydride-mediated cyclodehydration to form oxazoles and bisoxazoles in a simple one-pot transformation.

Full text of DOI:10.1016/j.tetlet.2008.12.080

Tetrahedron Letters 50 (2009) 1045–1047
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Tetrahedron Letters
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Triflic anhydride-mediated synthesis of oxazoles
*
´
Armin Thalhammer, Jasmin Mecinovic, Christopher J. Schofield
The Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Acyl amino acid esters undergo triflic anhydride-mediated cyclodehydration to form oxazoles and bis-
oxazoles in a simple one-pot transformation.
Received 7 November 2008
Revised 8 December 2008
Accepted 16 December 2008
Available online 24 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The oxazole group1 is a key element of a number of biologi-
cally active natural products, including diazonamides,2 inthomyc-
ins,3 calyculins and phorboxazoles (for a recent review see Ref. 4),
and has been extensively used in medicinal chemistry. In connec-
tion with studies on the inhibition of Fe(II) and 2-oxoglutarate-
dependent non-haem oxygenases, we required an efficient and
mild synthetic method for the preparation of 2-methoxycarbonyl
oxazoles and bisoxazoles from readily available N-oxalyl amino
acid esters.
A widely used approach for oxazole synthesis is the cyclodehy-
dration of peptide precursors, known as the Robinson–Gabriel syn-
thesis.5 A variety of dehydrating reagents, including H2SO4,5
POCl3,6 SOCl2,7 (CF3CO2)2O,8 COCl2,9 p-TsOH10 and CF3SO3H11, have
been applied for oxazole synthesis. In the total synthesis of oxa-
zole-based natural products, oxazoline formation from N-acylated
serine residues followed by mild oxidation to the desired oxazoles
has also been explored.4 Recently, oxazole formation via N,O-acyl-
ation of oximes with acyl chlorides followed by cyclodehydration
under microwave heating has been described.12
Initially, we optimized the conditions for the Tf2O-mediated
preparation of trisubstituted oxazole 2a from dimethyloxalylphe-
nylalanine 1a (Table 1). Et3N was found to be a suitable base
affording oxazole 2a in 69% yield after 3 h; slightly lower yields
were obtained when other bases, for example, pyridine, were used.
While the addition of a base might be desirable with acid-sensitive
substrates, the reaction also occurred in the absence of base to af-
ford 2a (57%). Treatment of 1a with 1 equiv of Tf2O in the presence
of 1.1 equiv of Et3N yielded only 28% of 2a, whereas the yield of 2a
was improved (to 91%) by employing 3 equiv of Tf2O. Of a selection
of commonly used organic solvents, CH2Cl2 gave the highest yields
and polymerization as occured with THF was not observed; nor did
it form a biphasic reaction mixture as observed with Et2O.
The optimized protocol16 was then used for the preparation
of di- and trisubstituted17 oxazoles 2b–i from the readily acces-
sible N-acyl amino acid methyl esters 1b–i (Table 2). The com-
patibility of the method with common amino acid derivatives
was studied first. When dimethyloxalylglycine 1b, an in vivo
inhibitor of HIF (hypoxia-inducible factor) hydroxylases,18,19
was treated with 2 equiv of Tf2O, oxazole 2b was formed in
56% and 74% yields, after 2 h and 4 h, in the presence of Et3N
and pyridine, respectively. The alanine derivative 2c, an interme-
diate in the synthesis of pyridoxine derivatives,9,20 was obtained
in 75% yield. In contrast, lower yields of 18–25% have been re-
ported with other dehydrating reagents.9 Up to 10% of N-meth-
yloxalyl dehydroalanine methyl ester was observed as a by-
product in the reaction with 2c.
The scope of the method was then tested with a set of N-acyl
substituents, giving oxazoles 2e–g in 41–80% yield. The N-formyl
derivative 1h afforded a complex mixture of oligomers under
standard reaction conditions, consistent with the reported for-
mation of oligomerization-prone isonitriles from formamides in
the presence of Tf2O/pyridine.21 Interestingly, N-Boc-protected
phenylalanine methyl ester underwent dimerization to form urea
6 under standard reaction conditions. This reaction may proceed
via imino triflate 3, which can undergo loss of its t-butyl group
to afford isocyanate 4 (Fig. 1). Nucleophilic addition of 1i and
Wipf and co-workers13 have reported the cyclization of N-acyl
amino acid esters using PPh3/I2/Et3N to give oxazoles under mild
conditions and have applied this protocol to the synthesis of the
peptide antibiotic (À)-muscoride A.14 Recently, Movassaghi et al.
reported the use of Tf2O/2-chloropyridine as a versatile and mild
dehydrating reagent for the formation of isoquinolines and b-carb-
olines;15 they also observed that N-benzoyl phenylalanine methyl
ester underwent oxazole formation under these conditions.
While oxazole formation from N-acyl aminoketones has been
explored extensively, comparatively little work has been done on
related N-acyl amino acid esters. Here, we describe studies on
the scope of Tf2O [(CF3SO2)2O] for the synthesis of trisubstituted
oxazoles and bisoxazoles from a set of readily prepared amino acid
and peptide derivatives.
* Corresponding author. Tel.: +44 1865 275625; fax: +44 1865 275674.
E-mail address: christopher.schofield@chem.ox.ac.uk (C.J. Schofield).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.080

1046
A. Thalhammer et al. / Tetrahedron Letters 50 (2009) 1045–1047
Table 1
Optimization of reaction conditions for Tf2O-mediated oxazole formation
Entry
Tf2O (equiv)
Base (equiv)
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
2
2
2
1
2
3
2
2
2
0
Pyridine (2.2)
2-Chloropyridine (2.2)
K2CO3 (2.2)
Et3N (1.1)
Et3N (2.2)
Et3N (3.3)
Et3N (2.2)
Et3N (2.2)
None
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
THF
CH2Cl2
CH2Cl2
3
3
3
3
3
3
2
2
2
15
52
50
28
69
91
14b
0c
Figure 1. Proposed mechanism for formation of urea 6 from NBoc–Phe–OMe with
Tf2O and base, showing a possible isocyanate intermediate.
57
0
10
Pyridine or Et3N (2.2)
24
a
Isolated yields.
b
c
Addition of Tf2O resulted in an apparently biphasic reaction mixture.
Reaction mixture underwent apparent polymerization.
Table 2
Scope of the Tf2O-mediated synthesis of oxazoles
Entry
1/2
R1
R2
Base
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1b/2b
1b/2b
1b/2b
1c/2c
1c/2c
1c/2c
1d/2d
1d/2d
1d/2d
1e/2e
1e/2e
1e/2e
1f/2f
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Me
H
H
H
Me
Me
Me
Et3N
Pyridine
—
2
4
2
2
2
4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
4
56
74
51
75
33
50
56
64
57
49
63
41
67
73
47
52
80
49
0
Et3N
Pyridine
Pyridine
Et3N
Pyridine
—
Et3N
Pyridine
—
Et3N
Pyridine
—
Et3N
Pyridine
—
Figure 2. Proposed outline mechanism for oxazole formation.
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
pyridine,23,24 where analogues of 8 and/or 9 were suggested in
the formation of the pyridinium intermediate 10. It is therefore
possible that oxazoles 2 are formed by intramolecular attack of
the ester carbonyl oxygen on the electrophilic carbon of intermedi-
ates 8 and/or 9. The formation of urea 6 as described above is con-
sistent with this mechanism.
Me
Me
Ph
Ph
1f/2f
1f/2f
Ph
1g/2g
1g/2g
1g/2g
1h/2h
1h/2h
1i/2i
CH2Ph
CH2Ph
CH2Ph
H
H
OtBu
OtBu
We then turned our attention to the application of Tf2O-medi-
ated oxazole formation to synthetically more challenging bisoxaz-
oles, exemplified by compounds 12a–e (Table 3). Bisoxazoles of
type 12a–b are attractive scaffolds for designing bidentate metallo-
enzyme inhibitors, because the corresponding bisamides 11a–e
can be prepared easily from amino acid derivatives. Bisoxazoles
have been prepared previously by oxidation of in situ-generated
bisoxazolidines25 or by cyclodehydration of activated amide deriv-
atives.26 Formation of two adjacent symmetrical oxazole rings as in
12a was achieved with Tf2O/Et3N (31%, unoptimized, 48 h). When
the reaction was quenched after 6 h, a mixture of starting material
and a monocyclized oxazole was obtained. The preparation of bis-
oxazoles with longer alkyl linkers proceeded faster, although in
mediocre yields. Attempted cyclization of malonyl and succinyl
bisamides 11b and 11c, respectively, resulted in the formation of
highly coloured products, possibly via cyclization followed by
Tf2O-mediated oxidation of the bridging methylene protons to
yield conjugated aromatic systems.
Et3N
Pyridine
Et3N
0
0b
0b
1i/2i
Pyridine
a
Isolated yields.
b
Formation of urea 6 (Fig. 1) was observed in 63% yield (with Et3N) and 77% yield
(with pyridine).
subsequent N-deprotection can then afford urea 6 rather than
oxazole 2i.
Wasserman and co-workers have shown by isotope labelling
studies that the cyclodehydration of N-acyl-2-aminoketones with
sulfuric acid proceeds via nucleophilic addition/elimination of the
amide oxygen onto the carbonyl group.22 In contrast, in the reac-
tion of N-acyl amino acid esters with Tf2O, activation of the amide
rather than ester moiety is likely. An initially formed O-triflylimin-
ium triflate 7 can undergo deprotonation to the imino triflate 8,
which can subsequently eliminate triflate to form the nitrilium
ion 9 (Fig. 2). This proposal is in agreement with previous studies
on electrophilic activation of simple secondary amides with Tf2O/
Overall, we conclude that Tf2O is a suitable reagent for the syn-
thesis of highly functionalized oxazoles from N-acyl amino acid
esters.

A. Thalhammer et al. / Tetrahedron Letters 50 (2009) 1045–1047
1047
Table 3
Formation of bisoxazoles with Tf2O (4 equiv) and base
Entry
11/12
n
Base (equiv)
Time (h)
Yielda (%)
1
2
3
4
5
11a/12a
11b/12b
11c/12c
11d/12d
11e/12e
0
1
2
3
Pyridine (4.4)
Pyridine (4.4)
Et3N (4.4)
Et3N (4.4)
Et3N (4.4)
48
6
6
3
14
31
0
0
33
42
10
a
Isolated yields.
9. Maeda, I.; Takehara, M.; Togo, K.; Asai, S.; Yoshida, R. Bull. Chem. Soc. Jpn. 1969,
42, 1435–1437.
Acknowledgements
10. Kumar, D.; Sundaree, S.; Patel, G.; Rao, V. S. Tetrahedron Lett. 2008, 49, 867–
869.
We greatly appreciate financial support from Cancer Research
UK (A.T.), the Newton-Abraham Fund (J. M.) and the Biotechnology
and Biological Sciences Research Council. We thank Professor Tho-
mas Helleday and Dr. Timothy D.W. Claridge for encouragement
and discussions.
11. Keni, M.; Tepe, J. J. J. Org. Chem. 2005, 70, 4211–4213.
12. Wipf, P.; Fletcher, J. M.; Scarone, L. Tetrahedron Lett. 2005, 46, 5463–5466.
13. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604–3606.
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16. Representative typical procedure: To a stirred solution of 1a (100 mg, 0.38 mmol,
1 equiv) and Et3N (116
l
L, 0.83 mmol, 2.2 equiv) in dry CH2Cl2 (1 mL) under a
nitrogen atmosphere at 0 °C was added Tf2O (127
lL, 0.75 mmol, 2 equiv). The
Supplementary data
resulting solution was stirred vigorously and allowed to warm to room
temperature. After 3 h, the mixture was washed with 1 M HCl (3 mL) and satd
NaHCO3 (3 mL). The organic layer was purified by column chromatography
General experimental section, general procedures and spectral
characterization data for all new compounds (1H, 13C NMR, IR,
HRMS data). Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2008.12.080.
(silica gel, hexane/ethyl acetate) to afford oxazole 2a (64 mg, 69%) as
colourless liquid.
a
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