Preparation of substituted oxazoles by ritter reactions of α-oxo tosylates

Article abstract of DOI:10.1055/s-0029-1218682

The Lewis acid catalyzed Ritter reaction of α-oxo tosylates with nitriles forms the basis of an efficient synthesis of oxazoles. Oxazoles with various substituents can be readily prepared from inexpensive starting materials. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218682

PAPER
1449
Preparation of Substituted Oxazoles by Ritter Reactions of a-Oxo Tosylates
S
ubstituted O
x
i
azolesng-Shan Lai, Mark S. Taylor*
Department of Chemistry, Lash Miller Laboratories, University of Toronto, 80 St George St., Toronto ON, M5S 3H6, Canada
Fax +1(416)9788775; E-mail: mtaylor@chem.utoronto.ca
Received 20 November 2009; revised 24 December 2009
for the synthesis of oxazoles. Although Lora-Tamayo and
Abstract: The Lewis acid catalyzed Ritter reaction of a-oxo tosy-
coworkers described the tin (IV) chloride-mediated Ritter
lates with nitriles forms the basis of an efficient synthesis of ox-
azoles. Oxazoles with various substituents can be readily prepared
reaction of a-halo ketones more than 40 years ago,7 the
need for stoichiometric quantities of tin-based reagents to-
gether with the rather limited availability of a-halo ke-
tones appear to have discouraged the use of this method.8
A related transformation is the reaction of nitriles with re-
active unsubstituted a-oxo triflates generated in situ by
oxidation of methyl ketones with reagents based on thalli-
um(III),8 mercury(II),9 iodine(III),10 iron(III),11 or cop-
per(II).12 These methods provide moderate-to-good yields
of 2,4-disubstituted oxazoles, and they are useful in situa-
tions where the requisite a-hydroxy or a-sulfonyloxy car-
bonyl compound is not readily available. However, they
are limited in terms of the range of nitriles that can be
used, and they require the use of toxic and/or expensive
oxidants. In an example that is particularly relevant to the
work described here, trifluoromethanesulfonic anhydride
was used to oxidize 1-(methylsulfanyl)acetone to the cor-
responding triflate, which underwent Ritter reaction via a
sulfur-stabilized carbocation to generate the correspond-
ing methylsulfanyl-substituted oxazoles.13
from inexpensive starting materials.
Key words: heterocycles, cyclizations, nitriles, carbocations, ox-
azoles, Ritter reaction
The oxazole ring is widely found in medicinal agents, bio-
logically active natural products, and organic materials.1
Much effort has been devoted towards devising methods
for the synthesis of substituted oxazoles. Although vener-
able protocols such as the Robinson–Gabriel dehydration
of 2-acylamino ketones2 and the Cornforth method3 re-
main in widespread use, metal-catalyzed reactions are
growing rapidly in popularity and frequency of applica-
tion.4 Here, we report a general protocol for the synthesis
of oxazoles by means of the Ritter reaction of a-oxo car-
bocations.5 This approach permits the construction of a
range of trisubstituted oxazoles from two readily available
classes of organic feedstocks: nitriles and a-hydroxy car-
bonyl compounds.
Another relevant precedent is the metal- or Lewis acid
promoted decomposition of a-diazocarbonyl compounds
in nitrile solvents; this is a useful method, but one that re-
quires the preparation and/or handling of potentially haz-
ardous diazo compounds.14 We felt that the ability to
access oxazoles from nitriles and a-hydroxycarbonyl
compounds, many of which are readily available and in-
expensive, could represent a valuable addition to the set of
reactions available for the preparation of this important
class of heterocycle.15
In the course of developing carbon–carbon bond-forming
reactions of a-carbonyl carbocations as ‘reversed polari-
ty’ variants of the enolate alkylation reactivity pattern,6
we explored the reaction of the methyl mandelate-derived
tosylate 1a with allyl(trimethyl)silane catalyzed by
scandium trifluoromethanesulfonate in acetonitrile
(Scheme 1). The expected allylation product was not ob-
served; instead, oxazole 2a was obtained, presumably
through a Ritter reaction with the solvent, followed by
ring closure of the resulting nitrilium ion and loss of a pro-
ton.
Our experiments aimed at optimizing the lead result
shown in Scheme 1 are summarized in Table 1. Whereas
scandium triflate was not an adequate catalyst in the ab-
sence of allyl(trimethyl)silane (entry 1), other Lewis acids
promoted the desired transformation (entries 2–5). Varia-
tions in the stoichiometry of trimethylsilyl triflate (TM-
SOTf), the promoter of choice, revealed that 2.5
equivalents of this reagent were required to obtain high
yields (entries 6–8). We examined several solvents with
the aim of avoiding the use of the nitrile component as the
reaction medium (entries 9–14). The use of 12 equivalents
of acetonitrile in 1,2-dichloroethane (DCE) was found to
be optimal.
O
Ph
N
SiMe3
Ph
MeO
Sc(OTf)3 (20 mol%)
O
MeCN, 70 °C
MeO
OTs
1a
2a
30% yield
Scheme 1 Unexpected formation of oxazole 2a from methyl
mandelate-derived tosylate 1a
We were surprised to find, upon surveying the literature,
that this mode of reactivity is underexploited as a method
The optimized conditions proved to be applicable to the
synthesis of a wide range of trisubstituted oxazoles
(Table 2). Variations in the acyl substituent (R1), the cat-
SYNTHESIS 2010, No. 9, pp 1449–1452
Advanced online publication: 19.02.2010
DOI: 10.1055/s-0029-1218682; Art ID: M06109SS
x
x
.
x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

1450
P.-S. Lai, M. S. Taylor
PAPER
Table 1 Optimization of Reaction Conditions for the Synthesis of
Table 2 Preparation of Substituted Oxazoles by the Ritter Reaction
Oxazoles
R2
O
N
O
TMSOTf (2.5 equiv)
Ph
R2
OTs
O
R3
R3CN
(12 equiv)
+
R1
N
O
MeCN
DCE
80 °C
Ph
OTs
R1
MeO
promoter (x equiv)
solvent, temp
MeO
1
2
1a
2a
Entry R1
R2
R3
Product Yield
(%)a
Entry Promoter
(equiv)
Solvent
MeCN Temp
(equiv) (°C)
Yield
(%)a
1
2
OMe
Ph
Ph
Ph
Ph
Me
2a
2b
2c
2d
2e
2f
99
65
82
55
75b
84
77
89b
65b
92
76
90
97
82
1
Sc(OTf)3 (0.2)
BF3-OEt2 (2.5)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
THF
–
–
70
70
70
70
70
70
70
70
70
70
70
80
80
80
<5
95
OMe
OEt
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2
3
3
AlCl3 (2.5)
–
30
4
Oi-Pr
4
TsOH (2.5)
–
<5
<5
>95
35
5
piperidin-1-yl Ph
5
TiCl4 (2.5)
–
6
Ph
Ph
6
TMSOTf (2.5)
TMSOTf (1.5)
TMSOTf (1.0)
TMSOTf (2.5)
TMSOTf (2.5)
TMSOTf (2.5)
TMSOTf (2.5)
TMSOTf (2.5)
TMSOTf (2.5)
–
7
OEt
OEt
OEt
Ph
4-BrC6H4
4-MeOC6H4
2g
2h
2i
7
–
8
8
–
22
9
3,4-(OCH2O)C6H3 Ph
9
5
<5
<5
<5
60
10
11
12
13
14
Ph
Ph
Ph
Ph
Ph
Me
2j
10
11
12
13
14
5
Ph
Et
2k
2l
DME
5
Ph
hexyl
t-Bu
vinyl
DCE
5
Ph
2m
2n
DCE
10
12
80
Ph
DCE
>95
a Isolated yield after recrystallization or column chromatography. See
experimental section and Supporting Information for details.
b Trifluoroacetate was used as the leaving group instead of tosylate.
a Yield (0.2 mmol scale) determined by GC/MS using dodecane as a
quantitative internal standard.
ion-stabilizing substituent (R2), and the nitrile substituent
(R3) were well tolerated. When cation-stabilizing 4-meth-
oxyphenyl or 3,4-(methylenedioxy)phenyl groups were
used, the preparation of the requisite a-oxo tosylates was
challenging. In these cases, the trifluoroacetate leaving
group proved to be a suitable replacement. The intrinsic
yields of these reactions are generally high; problems as-
sociated with the isolation of electron-rich oxazoles by
chromatography are responsible for some low yields (en-
tries 2, 5, and 9).
Heteroarene-substituted oxazoles are a class of targets
that are well suited to this method (Scheme 2). The
Me
O
Ph
O
HO
N
Ph
N
O
Me
(1.3 equiv)
TMSOTf (2.5 equiv)
Ph
H
toluene, 80 °C
MeCN, –78 °C then 23 °C
N
N
O
Me
Me
3
Et3N (1.5 equiv)
MeCN, 70 °C
42% yield
Ph
N
1) Et3N (1.5 equiv)
pyridine (1.5 equiv)
Ts2O (1.5 equiv)
toluene, 23 °C
Ph
Ph
OH
O
O
2) PhCN (12 equiv)
TMSOTf (2.5 equiv)
DCE, 23 °C then 80 °C
N
N
Me
Me
4
62% yield
Scheme 2 Preparation of indole-substituted oxazoles
Synthesis 2010, No. 9, 1449–1452 © Thieme Stuttgart · New York

PAPER
Substituted Oxazoles
1451
Information). 1H and 13C NMR were recorded by using Varian Mer-
cury 300- and 400-MHz spectrometers. Chemical shifts are reported
in ppm relative to TMS, and referenced to residual protium in the
solvent (CHCl3: d = 7.25) or the carbon resonances of the solvent
(CDCl3 d = 77.0). IR spectra were recorded on a Perkin-Elmer
Spectrum 100 instrument equipped with a single-reflection dia-
mond/ZnSe ATR accessory (intensity, s: strong, m: medium, w:
weak). HRMS were recorded on a VS 70-250S (double-focusing)
mass spectrometer at 70 eV.
Friedel–Crafts reaction of 1-methyl-1H-indole with
oxo(phenyl)acetaledehyde (phenylglyoxal) gave an ad-
duct that was sufficiently ionizable to undergo the Ritter
reaction below room temperature without prior O-sulfo-
nylation to give the oxazole 3, bearing an indolyl substit-
uent in the 4-position. Alternatively, base-catalyzed
isomerization of the Friedel–Crafts adduct followed by O-
sulfonylation and Ritter reaction generated oxazole 4,
bearing an indolyl substituent at the 5-position. As de-
scribed above, the modest yields of these reactions reflect
the moderate stabilities of these electron-rich oxazoles to
column chromatography.
2,4,5-Trisubstituted Oxazoles; General Procedure
DCE (2.5 mL), the nitrile (6 mmol), and TMSOTf (0.23 mL, 1.25
mmol) were added sequentially to a dry flask containing an alkyl 2-
aryl-2-(tosyloxy)acetate or 2-oxo-1,2-diphenylethyl tosylate (0.5
mmol, 1 equiv) at 23 °C. The resulting solution was stirred and
heated at 80 °C for 20 h, then cooled to 23 °C and diluted with
EtOAc (10 mL). The mixture was partitioned between EtOAc and
H2O. The organic phase was separated, and the aqueous layer was
extracted with EtOAc (2 × 10 mL). The combined organic extracts
were dried (Na2SO4), concentrated in vacuo, and purified by flash
chromatography (silica gel or basic activated alumina, 10% or 5%
EtOAc–pentane).
Electron-rich alkoxy- and amino-substituted oxazoles,
which are obtained in high yields by this method (Table 2,
entries 1–5 and 7–9), are useful partners in cycloaddition
reactions with alkynes to give furans after expulsion of a
nitrile by a retro-[4 + 2] cycloaddition (Scheme 3).16
Furans 5a and 5b were obtained in good yields from 1a in
a two-step process without purification of the intermedi-
ate oxazole.
5-Methoxy-2-methyl-4-phenyl-1,3-oxazole (2a)
The general procedure was carried out on 0.5 mmol scale using
MeCN (0.31 mL, 6 mmol, 12 equiv) and methyl 2-phenyl-2-(tosyl-
oxy)acetate (160 mg, 0.5 mmol). After 20 h at 80 °C, the mixture
was worked up as described above. The residue was purified by pre-
cipitation from 10% EtOAc–pentane to give a colorless solid; yield:
94 mg (99%).
RCN (12 equiv)
O
O
MeO
R
TMSOTf (2.5 equiv)
Ph
OTs
MeO
N
DCE, 23 °C then 80 °C
Ph
CO2Me
MeO2C
(2 equiv)
toluene, 110 °C
IR (solid): 3059 (m), 2983 (m), 1739 (w), 1629 (s), 1489 (s), 1381
(s) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.70 (m, 2 H), 7.47 (m, 2 H), 7.40
(m, 1 H), 4.23 (s, 3 H), 2.90 (s, 3 H).
O
MeO
R
13C NMR (100 MHz, CDCl3): d = 157.3, 154.2, 129.7, 129.6, 125.5,
MeO2C
CO2Me
123.5, 110.6, 62.2, 13.5.
5a R = Me, 69%
5b R = Ph, 73%
HRMS (EI): m/z calcd for C11H11NO2: 189.0790; found: 189.0790.
Scheme 3 Cycloaddition of electron-rich oxazoles
1-(2,4-diphenyl-1,3-oxazol-5-yl)piperidine (2e)
The general procedure was carried out on 0.5 mmol scale using ben-
zonitrile (0.62 mL, 6 mmol, 12 equiv) and 2-oxo-1-phenyl-2-pipe-
ridin-1-ylethyl 2,2,2-trifluoroacetate 1e (158 mg, 0.5 mmol). After
20 h at 80 °C, the mixture was worked up as described above. The
residue was purified by flash chromatography (basic activated alu-
mina, 5% EtOAc–pentane) to give a colorless solid; yield: 114 mg
(75%).
In conclusion, the Ritter reaction of a-carbonyl carboca-
tions represents a useful strategy for the preparation of
trisubstituted oxazoles. The yields are generally high, and
the a-hydroxycarbonyl compounds and nitriles required
as starting materials are inexpensive and readily available.
Carbocations bearing a carbonyl or carboxyl group in the
a-position are an interesting class of reactive intermedi-
ates that have not been extensively exploited in synthesis.
Efforts to explore their application in other processes are
underway in our laboratories.
IR (solid): 3056 (w), 2939 (m), 2849 (m), 1607 (s), 1596 (s), 1447
(s), 1382 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.01 (m, 4 H), 7.44 (m, 5 H), 7.23
(m, 1 H), 3.13 (m, 4 H), 1.75 (m, 4 H), 1.63 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 155.4, 152.8, 132.7, 129.8, 128.8,
128.5, 128.3, 126.8, 126.2, 126.0, 124.1, 51.6, 26.2, 24.2.
All reactions were carried out in oven-dried round-bottomed flasks
or Schlenk tubes. The flasks were fitted with rubber septa, and reac-
tions were conducted under a positive pressure of N2 unless other-
wise noted. Stainless-steel syringes were used to transfer air- and
moisture-sensitive liquids. Flash chromatography was carried out
using neutral silica gel (Silicycle) or basic activated alumina gel
(Sigma-Aldrich). HPLC-grade DCE was purchased from Sigma-
Aldrich Chemical and dried over oven-activated MS. All other sol-
vents were dried under argon with a solvent-purification system
equipped with columns of activated alumina (Innovative Technolo-
gy, Inc.). Commercial reagents were purchased from Sigma-
Aldrich, Alfa Aesar, or Lancaster, and used as received. Starting
materials were prepared by literature procedures (see Supporting
HRMS (EI): calcd for C20H20N2O: 304.1576; found: 304.1569.
1-Methyl-3-(2-methyl-5-phenyl-1,3-oxazol-4-yl)-1H-indole (3)
MeCN (2.5 mL) and TMSOTf (0.23 mL, 1.25 mmol) were added
sequentially to a dry flask containing 2-hydroxy-2-(1-methyl-1H-
indol-3-yl)-1-phenylethanone (133 mg, 0.5 mmol) at –78 °C. The
resulting solution was allowed to warm slowly to 23 °C and stirred
at this temperature for 20 h. The solution was then diluted with
EtOAc (10 mL) and concentrated in vacuo. Purification of the resi-
due by flash chromatography (basic activated alumina, 10%
EtOAc–pentane) gave a yellow solid; yield: 61 mg (42%).
Synthesis 2010, No. 9, 1449–1452 © Thieme Stuttgart · New York

1452
P.-S. Lai, M. S. Taylor
PAPER
IR (solid): 3043 (w), 2921 (s), 2850 (m), 1584 (s), 1466 (s), 1336
(m), 1265 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59 (m, 2 H), 7.39 (m, 7 H), 7.05
(t, J = 8.4 Hz, 1 H), 3.84 (s, 3 H), 2.57 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.9, 137.0, 129.4, 128.5, 128.4,
128.4, 127.5, 125.9, 125.7, 121.8, 119.7, 109.3, 107.3, 33.0, 14.1.
2501. (b) Hashmi, S. K.; Weyrauch, J. P.; Frey, W.; Bats, J.
W. Org. Lett. 2004, 6, 4391. (c) Lee, Y. R.; Yoon, S. H.;
Seo, Y.; Kim, B. S. Synthesis 2004, 2787. (d) Milton, M.
D.; Inada, Y.; Nishibayashi, Y.; Uemura, S. Chem. Commun.
2004, 2712. (e) Black, D. A.; Arndtsen, B. A. Tetrahedron
2005, 61, 11317. (f) Kumar, M. P.; Liu, R.-S. J. Org. Chem.
2006, 71, 4951. (g) Martín, R.; Cuenca, A.; Buchwald, S. L.
Org. Lett. 2007, 9, 5521. (h) Lee, K.; Counceller, C. M.;
Stambuli, J. P. Org. Lett. 2009, 11, 1457.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2O: 289.1335; found:
289.1327.
(5) For a review on the Ritter reaction, see: (a) Krimen, L. I.;
Cota, D. J. Org. React. (N. Y.) 1969, 17, 213. For a Ritter–
cyclization cascade that generates pyrroles, see: (b) Yu, M.;
Pagenkopf, B. L. Org. Lett. 2003, 5, 5099.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
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Creary, X. J. Org. Chem. 1979, 44, 3938.
(7) Lora-Tamayo, M.; Madroñero, R.; Leiprand, H. Chem. Ber.
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Acknowledgment
We gratefully acknowledge funding from NSERC (Discovery
Grants Program), Merck Research Laboratories (Canadian Acade-
mic Development Program), the Canadian Foundation for Innova-
tion, the Ontario Research Foundation, and the University of
Toronto (Connaught Fund).
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Synthesis 2010, No. 9, 1449–1452 © Thieme Stuttgart · New York