Preparation of 5-substituted 2-(2-alkyl/aryl-1H-imidazol-4-yl)oxazoles and 5-substituted 2-(2-alkyl/arylthiazol-4-yl)oxazoles by utilizing 5-substituted 2-(2-bromo-1,1-diethoxyethyl)oxazole as a synthon

Article abstract of DOI:10.1055/s-0028-1088162

Synthetic access to oxazolyl-substituted heterocycles including oxazolylimidazoles, -thiazoles, and -oxazoles is gained from a masked α-halo ketone attached to the 2-position of the oxazole ring. 3-Bromo-2,2-diethoxy-N-(2-oxoalkyl)propionamides readily cy

Full text of DOI:10.1055/s-0028-1088162

PAPER
1445
Preparation of 5-Substituted 2-(2-Alkyl/aryl-1H-imidazol-4-yl)oxazoles and
5-Substituted 2-(2-Alkyl/arylthiazol-4-yl)oxazoles by Utilizing 5-Substituted
2-(2-Bromo-1,1-diethoxyethyl)oxazole as a Synthon
P
reparationof 2-Im
e
idazol-4-y
n
l- and 2-Thia
i
zol-4-y
s
loxazoles R. St. Laurent,* Jeffrey L. Romine
Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
Fax +1(203)6777702; E-mail: denis.stlaurent@bms.com
Received 20 October 2008; revised 18 December 2008
would allow for a broad range of functionality. Finally,
Abstract: Synthetic access to oxazolyl-substituted heterocycles in-
cluding oxazolylimidazoles, -thiazoles, and -oxazoles is gained
from a masked a-halo ketone attached to the 2-position of the ox-
azole ring. 3-Bromo-2,2-diethoxy-N-(2-oxoalkyl)propionamides
we envisioned the imidazole nucleus to be assembled by
standard procedures6 employing a-bromo ketones and
amidines or amidine alternatives.7 Herein we demonstrate
readily cyclize to generate the key 5-substituted 2-(2-bromo-1,1-di- the utility and diversity of masked a-bromo ketone 7 in
ethoxyethyl)oxazole intermediate.
the preparation of 5-substituted 2-(2-alkyl/aryl-1H-imida-
zol-4-yl)oxazoles 9 and 5-substituted 2-(2-alkyl/arylthia-
zol-4-yl)oxazoles 10.
Key words: 3-bromo-2,2-diethoxypropionic acid, a-halo ketones,
cyclizations, heterocycles, oxazoles
R1
O
R1
R1
R1
Little is reported about the construction of 5,5-bis-hetero-
cyclic ring systems wherein an oxazole ring is linked di-
rectly to heterocycles other than oxazoles.1 We were
especially interested in oxazolylimidazoles, where the 2-
position of the imidazole nucleus may be suitably substi-
tuted by either an aryl or alkyl group. A survey of the
literature2 failed to identify synthetic entries particular to
this core; however, we were intrigued by a strategy report-
ed by LaMattina3 utilizing a masked a-bromo ketone such
as 5-(2-bromo-1,1-diethoxyethyl)-3-methyl-1,2,4-oxadi-
azole (2), which bears a latent tether from which to ap-
pend a second ring, as incorporated in thiazole 3
(Scheme 1).3,4
NH2
N
HO
O
O
O
N
O
5
HN
Br
OEt
OEt
O
OEt
N
OEt
Br
X
OEt
Br
R2
OEt
4
6
7
9 X = NH
10 X = S
Scheme 2 Proposed synthetic strategy
3-Bromo-2,2-diethoxypropionic acid (4) was coupled
efficiently with a-amino ketones 5 by use of PyBOP8
(PyBOP = benzotriazolyl-1-oxy-tripyrrolidinophospho-
nium hexafluorophosphate) in tetrahydrofuran
(Scheme 3), and no further purification beyond extractive
workup was required.9 Cyclodehydration of amides 6a–l
to their respective 5-substituted 2-(2-bromo-1,1-diethoxy-
ethyl)oxazoles 7a–l was accomplished by use of Wipf’s
modification10 of the Robinson–Gabriel reaction
(Scheme 3). The ease of workup was facilitated by direct
application of the reaction mixture to a Biotage or Thom-
son silica gel cartridge followed by gradient elution to
give the products in generally good overall yields (see
Table 1). Moreover, the mild conditions were quite toler-
ant of not only the diethoxy ketal functionality, but also of
halide (e.g., 7d), nitro (e.g., 7b), ester (e.g., 7k), and the
Boc protecting group (e.g., 7l) (Table 1, entries 4, 2, 11,
and 12, respectively). Except for benzimidazole 7h, het-
erocycles such as pyridine (e.g., 7i), and indoles (e.g., 7j)
(Table 1, entries 8, 9, and 10, respectively) were also well
tolerated and did not interfere appreciably with the cy-
clization to form the oxazole nucleus.
NO2
N
N
N
O
N
O
OEt
N
O
O
S
OEt
Br
OEt
OEt
N
H2N
NH2
Br
NPBDP 1
2
3
Scheme 1 LaMattina precedent
Expanding on his work, we chose to prepare our pivotal,
masked a-bromo ketone 7 by directly coupling precursor
a-amino ketone 5 with 3-bromo-2,2-diethoxypropionic
acid (4)3,5 (Scheme 2). Cyclodehydration of the resultant
amide 6 would furnish the masked a-bromo ketone 7 in an
efficient two-step procedure under mild conditions that
Reversed-phase liquid chromatography solvents caused
partial hydrolysis, as depicted in the liquid chromatogra-
phy mass spectra of these ketals, but, in all cases, the pre-
SYNTHESIS 2009, No. 9, pp 1445–1458
Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088162; Art ID: M06408SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
9

1446
D. R. St. Laurent, J. L. Romine
PAPER
several months without noticeable deterioration when re-
frigerated.
R1
O
R1
R1
O
a
b
OEt
OEt
Br
O
O
OEt
OEt
The hydrolysis of ketals 7a–l to liberate a-bromo ketones
8a–l was quantitatively achieved in formic acid at 80 °C
by use of the conditions reported by LaMattina3
(Scheme 3). This mild procedure proved quite general,
and all functional groups under investigation proved sta-
ble (Table 2), the only exception being the pyridyl ring (in
7i), which presumably self-alkylated upon liberation of
the a-bromo ketone. The 2-bromo-1-oxazol-2-ylethan-
ones 8a–h,j,k thus formed were observed to be benchtop-
stable,12 but, as a precaution, they were carried forward
with a minimal need for purification and/or characteriza-
tion.13 Flash chromatography of parent a-bromo ketone
8a was performed for characterization purposes, and it
was isolated as a crystalline (plates) white solid. Notably,
the 1H NMR spectra of non-chromatographed samples (in
DMSO-d6) displayed three distinct sharp signals integrat-
ing to two protons for the methylene unit at d = 5.78 (0.1
H), 5.13 (0.37 H), and 4.87 (1.53 H); this is characteristic,
most probably, of the enolic cis- and trans-tautomers and
the parent ketone. These signals coalesced cleanly into
one sharp singlet at d = 4.87 (2.0 H) in chromatographed
NH2
N
H
N
Br
5
6
7
c
R1
R2
R1
O
N
O
O
d
NH
N
N
Br
R2C(O)NH2
8
9
11
Scheme 3 Synthetic strategy employed in the construction of 5-sub-
stituted 2-(2-substituted 1H-imidazol-4-yl)oxazoles 9 by methods A
and B. Reagents and conditions: (a) PyBop, HO2CC(OEt)2CH2Br (4),
NMM, THF, r.t.; (b) Ph3P, Cl3CCCl3, Et3N, CH2Cl2, r.t.; (c) HCO2H,
80 °C; (d) Method A: R2C(NH)NH2, KHCO3, THF–H2O, 80 °C or
Method B: R2CO2H, DIPEA, MeCN, r.t., then NH4OAc, xylene,
140 °C.
dominant signal was the parent.11 Multigram quantities of
2-(2-bromo-1,1-diethoxyethyl)-5-phenyloxazole
were thus readily prepared and used over the course of
(7a)
Table 1 Synthesis and Characterization of 5-Substituted 2-(2-Bromo-1,1-diethoxyethyl)oxazoles 7 and Their Precursors 6
R1
R1
O
O
N
O
Br
OEt
Br
OEt
N
H
EtO
EtO
6
7
Entry
R1
6
Yielda (%)
Mp (°C)
7
Yielda (%)
Mp (°C)
79–81
1
2
3
4
5
6
7
Ph
6a
6b
6c
6d
6e
6f
81
82
45
65
71
91
85
106–107
7a
7b
7c
7d
7e
7f
76
40
64
71
89
41
83
4-O2NC6H4
3-F3CC6H4
3-BrC6H4
2-MeC6H4
PMP
161–162
174–176
88–89
134–134.5
139–141
67–68
138.5–139.5
122–123
80–81
134–136
59–61
Naph
6g
135.5–137
7g
N
HN
8
6h
55
209–211
7h
22
ndb
9
10
11
3-pyridyl
6i
57
84
63
125–158
171–173
oil
7i
91
90
67
ndb
indol-3-yl
6j
6k
7j
7k
128–132
oil
(CH2)2CO2Me
12
6l
34
115–117.5
7l
43
61–63
N
Boc
a Isolated, unoptimized yield.
b nd = not determined.
Synthesis 2009, No. 9, 1445–1458 © Thieme Stuttgart · New York

PAPER
Preparation of 2-Imidazol-4-yl- and 2-Thiazol-4-yloxazoles
1447
idazoles cleanly and allowed for standard silica gel chro-
matography to be practiced.
Table 2 Liquid Chromatography MS Characterization of 2-Bromo-
1-(5-substituted oxazol-2-yl)ethanones 8a
R1
In contrast, method B (Scheme 3) involved two distinct
steps, but uses a larger pool of commercially available
carboxylic acids as a source of starting material and does
not suffer from competing amidine hydrolysis. Displace-
ment of the bromide ion in 8 by a carboxylic acid R2CO2H
with the aid of N,N-diisopropylethylamine proceeded well
at room temperature (Scheme 3).16a,c No purification was
necessary except for a quick, basic extractive workup. Ex-
posure to excess ammonium acetate in xylenes at 140 °C
in a screw-capped pressure vessel effected thermal cyclo-
dehydration.16b Either microwave irradiation17 or conven-
tional oil bath heating afforded the imidazole nucleus in
good yield. Concomitant oxazole formation (<5%) was
occasionally observed, but the byproduct was easily re-
moved by silica gel chromatography. The generality of
method B allowed for the separate preparation of both
proline enantiomers 9h and 9i in good overall yields with
very little loss in chirality (97.8% ee vs 98.4% ee, respec-
tively) (Table 3, entries 9 and 10).
Br
O
N
O
8
8
R1
Ph
tR (min)
2.45
Calcd (m/z) Found (m/z)
8a
8b
8c
8d
8e
8f
265.98
310.97
333.97
343.89
280.00
295.99
316.00
266.08
311.10
333.96
344.02
280.14
296.14
316.16
4-O2NC6H4
3-F3CC6H4
3-BrC6H4
2-MeC6H4
PMP
2.62
2.74
3.06
2.91
2.75
8g
Naph
3.17
N
HN
8h
1.46
320.01
319.93
Table 3 Synthesis and Characterization of 2-(2-Substituted 1H-im-
idazol-4-yl)-5-phenyloxazoles 9
8i
3-pyridyl
1.17
2.51
1.66
266.98
304.99
275.99
266.95b
304.97
275.95
R2
Ph
N
O
N
8j
8k
indol-3-yl
NH
(CH2)2CO2Me
9
Entry R2
9
Method Yielda
(%)
Mp
(°C)
8l
0.68
359.06
258.97c
N
1
2
3
4
5
6
7
8
Ph
3-pyridyl
9a
9b
9c
9d
9e
9f
A
A
A
A
A
A
B
B
44 (67)b 192–194
Boc
a LCMS: Shimadzu instrument [Phenomenex-Luna column (4.6 × 50
mm, S10), 4 mL/min, 220 nm, injection volume 5 mL]; solvent A:
0.1% TFA in H2O–MeOH, 90:10; solvent B: 0.1% TFA in H2O–
MeOH, 10:90; gradient: 0% B to 100% B over 3 min; m/z obtained
from ESI; calculated exact mass (m/z) of [M + H]+ based on 35Br iso-
tope.
50
57
46
88
49
24
22c
241–243
227–229
215–216
234–236
215–216
192–194
219–221
3-O2NC6H4
4-F3CC6H4
2-ClC6H4
PMP
b For 8i, some product, believed to be 2,2-dimethoxy-2-[5-(3-pyrid-
yl)oxazol-2-yl]ethyl formate, is seen at 1.14 min: m/z [M + H]+ calcd:
266.97, 268.97; found: 266.95, 268.95.
c Loss of Boc group observed.
Ph
9a
9g
i-Pr
samples; this is presumably due to the lack of residual for-
mic acid in the sample.
Boc
N
9
9h
B
B
38
123–125
Scheme 3 depicts two of the many well-precedented
methods to synthesize imidazole ring systems.14 In meth-
od A, condensation of a-bromo ketone 8a with various
amidines was conducted under basic reaction conditions,6
such as the use of potassium bicarbonate in tetrahydrofu-
ran, and offered the most direct route from commercially
available sources. However, amide 11 (Scheme 3) pro-
duced from concurrent hydrolysis of the amidine made
isolation of the product problematic, due to similar reten-
tion times on silica gel. Although reversed-phase prepara-
Boc
N
10
11
9i
9j
45
68
123–125
190–192
d
H
–
a Yields of isolated, single experiments; not optimized.
b Experiment performed a second time gave a higher yield shown in
parantheses.
tory HPLC was successful, an alternative workup c Only 3% isolated by method A.
d Prepared from a-bromo ketone 8a and formamide at reflux.
employing cationic exchange resins such as MCX
cartridges15 removed the neutral amide from the basic im-
Synthesis 2009, No. 9, 1445–1458 © Thieme Stuttgart · New York

1448
D. R. St. Laurent, J. L. Romine
PAPER
R1
R1
R2
R1
OEt
O
O
O
O
O
N
a
c
OEt
N
N
N
Br
Br
7
8
12
b
R2
R1
N
O
N
S
10
Scheme 4 General synthetic strategy employed in the construction of 5-substituted 2-(2-substituted thiazol-4-yl)oxazoles 10 and 5,2¢-disub-
stituted 2,5¢-bioxazoles 12. Reagents and conditions: (a) HCO2H, 80 °C; (b) R2C(S)NH2, KHCO3, EtOH, 80 °C; (c) R2C(O)NH2, neat, fusion
at 140 °C.
As with the parent oxazole nucleus, substituents on the
aryl ring such as halide (9e), nitro (9c), trifluoromethyl
(9d), and alkoxy (9f) were well tolerated under the reac-
tion conditions (Table 3, entries 5, 3, 4, and 6, respective-
ly); the aryl group could also be replaced with heteroaryls
such as pyridyl (9b) (entry 2). The electronic nature of
aryl substituents appeared to impart little effect on yields
(cf. 9d and 9f, entries 4 and 6, respectively). Of particular
note is that sterically congested imidazoles such as 9g
(Table 3, entry 8) could be obtained in better overall yield
with isobutyric acid (22%) than with isobutyrimidamide
(3%). Unlike the aliphatic carboxylic acids, benzoic acids
cyclized less effectively under method B conditions, as re-
flected in the twofold difference in yield of 9a prepared by
method A (44%) and that prepared by method B (24%)
(Table 3, entries 1 and 7, respectively). The chief isolated
byproduct was again the corresponding benzamide 11
(see Scheme 3), but this time it was generated by the ami-
nolysis of the intermediate ester with ammonium acetate.
Lastly, the unsubstituted, parent imidazole 9j was pre-
pared easily in 68% yield from a-bromo ketone 8a and
formamide at reflux (Table 3, entry 11).18
Table 4 Synthesis and Characterization of 2-(2-Substituted thiazol-
4-yl)-5-phenyloxazoles 10
Ph
R2
O
N
N
S
10
10
R2
Ph
Yielda (%) Mp (°C)
10a
10b
10c
10d
10e
10f
10g
10h
91
75
91
94
96
78b
19c
93
141–142
152–153.5
127–128
190–192
144–145
oil
3-pyridyl
3-F3CC6H4
PMP
2-ClC6H4
(CH2)2SCH2CO2Me
(CH2)2SCH2CO2Et
CH2OPv
oil
78–79
10i
85d
132–133
2-Oxazolylthiazoles 10a–m were furnished cleanly and
straightforwardly from a-bromo ketones 8 through simple
substitution of the amidine (as used in the synthesis of 9
by method A) with a thioamide (Scheme 4, Table 4).
These reactions19 were conducted in refluxing ethanol
buffered with base.
N
Boc
10j
(CH2)2NHBoc
(CH2)2NH2·AcOH·0.5H2O
CH2CN
90d
23e
82
158–159
146–147
161–162
148–149
10k
10l
Unlike the imidazoles 9 reported in Table 3, these prod-
ucts 10 proved quite crystalline, and were most commonly
isolated in analytically pure form upon precipitation from
the eluent after chromatography or from extractive work-
up to remove the inorganic salts. Thioamides such as 2-
chlorothiobenzamide furnished thiazoles (e.g., 10e) in ex-
cellent yield and without incident (Table 4). Under the re-
action conditions employed, the acid-sensitive Boc
protecting group in compound 10j was partially compro-
mised, but easily regenerated upon treatment with di-tert-
butyl dicarbonate prior to workup, thus enhancing the
overall yield of 10j to 90% (from 24%) (Table 4).
10m
NHAllyl
96
a Isolated, unoptimized yield.
b MeOH was used as the solvent.
c Compound 10f (59%) was also isolated (from transesterification).
d Boc2O was added prior to workup.
e Compound 10j (24%) was also isolated; some product was lost in ex-
tractive workup.
prevented by use of the appropriate solvent as reflected in
10g (19%) versus 10f (78%), when ethanol was replaced
by methanol (Table 4).
No change was necessary for sterically hindered esters
such as pivalate 10h (Table 4). 2-Aminothiazoles20 such
as 10m were easily prepared by substituting a suitably
Little impact on overall yield was observed for cyclic
(branched) or acylic (straight-chain) cases such as 10i and
10j respectively. Transesterification of ester moieties was
Synthesis 2009, No. 9, 1445–1458 © Thieme Stuttgart · New York

PAPER
Preparation of 2-Imidazol-4-yl- and 2-Thiazol-4-yloxazoles
1449
termined with the use of an Autopol IV polarimeter manufactured
by Rudolph Research Analytical. Chiral chromatography was per-
formed on a Chiralpak AD column (4.6 × 50 mm, 10 mm) using 2%
B (isocratic) at 1 mL/min where B = EtOH and A = heptane or a
Chiralcel OJ column (4.6 × 50 mm, 10 mm) using 5% B (isocratic)
at 1 mL/min where B = EtOH and A = heptane. Analytical chiral
chromatography was performed on a Chiralpak OJ-H column
(4.6 × 250 mm, 5 mm) using 7% MeOH in CO2 for 9 min at 35 °C
at 2.0 mL/min at 220 nm. Preparative HPLC was performed on a
Shimadzu instrument using a Phenomenex Gemini or Luma column
(30 × 100 mm, S10) operating at 40 mL/min at 220 nm with an in-
jection volume of 2000 mL and using 10 mM NH4OAc in H2O–
MeCN (95:5) as solvent A and 10 mM NH4OAc in H2O–MeCN
(10:90) as solvent B. The gradient changed from 20% to 100% B
over 14 min unless mentioned otherwise in the experimental proce-
dures. LCMS was performed on a Shimadzu instrument using a
Phenomenex-Luna column (4.6 × 50 mm, S10) operating at 4 mL/
min at 220 nm with a injection volume of 5 mL. Solvent A: 0.1%
TFA in H2O–MeOH (90:10), Solvent B: 0.1% TFA in H2O–MeOH
(10:90). All LCMS data were obtained under gradient conditions 1
except where indicated otherwise: gradient conditions 1: 0% to
100% B over 3 min, stop time 3 min; gradient conditions 2: 0% to
100% B over 2 min, stop time 3 min; gradient conditions 3: same as
2 except that a Phenomenex-Luna C18 (10 mm) column was used
instead. Qualitative HRMS experiments were performed using a
Leap Technologies CTC HTS PAL autosampler, a LEAP Technol-
ogies 4x Ultra pump, and a Thermo Fischer hybrid linear ion trap–
FT ion cyclotron resonance (FTICR) LTQ-Orbitrap mass spectro-
meter. The mass spectrometer operating conditions were optimized
by use of 1 mM reserpine (MeCN–H2O–HCO2H, 70:30:0.1). The
mass spectrometers were operated in positive-ion full-scan mode.
Data were acquired on both instruments (LTQ and LTQ-Orbitrap)
using the same source settings, these were as follows: spray voltage
5 kV, capillary voltage 30 V, tube lens voltage 150 V, capillary tem-
perature 300 °C, sheath gas flow 40 arbs, auxiliary gas flow 5 arbs,
sweep gas flow 2 arbs. Quantitative data were acquired in centroid
mode across the 100–1000 m/z range. The LTQ was operated with
3 microscans and a 500-ms ion time. Qualitative HRMS data were
acquired in profile mode on the Orbitrap mass spectrometer with the
instrument operating at 30000 FWHM resolution. The LTQ-Orbi-
trap was operated with the following scanning conditions, for the
LTQ 3 microscan, 500-ms ion time, for the Orbitrap 3 microscans,
100-ms ion time.
protected thiocarbamate such as N-allylthiocarbamate for
the thioamide. In this fashion, 10m was prepared unevent-
fully in good yield. Moreover, low-molecular-weight
thioamides such as 2-cyanothioacetamide reacted well to
afford 2-(cyanomethyl)thiazoles such as 10l in high yield
(Table 4).
Finally, the scope and utility of a-bromo ketone 8a was
further explored by fusing it with two equivalents of an
arene- or alkanecarboxamide (Scheme 4, Table 5). Biox-
azoles 12a and 12b were synthesized when benzamide
and valeramide, respectively, were heated with 8a at or
slightly over their melting points (Scheme 4). The modest
isolated yields compared favorably with the yields ob-
tained by other methods, such as the Hantzsch proce-
dure.1a,21 Furthermore, even branched alkanecarbox-
amides such as cyclohexanecarboxamide afforded the de-
sired bioxazole 12c in an acceptable yield considering its
short synthesis.
Table 5 Synthesis and Characterization of 2¢-Substituted 5-Phenyl-
2,5¢-bioxazoles 12
Ph
O
N
O
R2
N
12
12
R2
Yielda (%)
29 (32)b
26
Mp (°C)
168–170
66–68
12a
12b
12c
Ph
Bu
Cy
19
114–116
a Isolated, unoptimized yield.
b Experiment performed a second time gave a higher yield shown in
parantheses.
In summary, a series of 2-(2-substituted 1H-imidazol-4-
yl]-5-phenyloxazoles 9a–j and 2-(2-substituted thiazol-4-
yl)-5-phenyloxazoles 10a–m were constructed from a
versatile, common intermediate, 2-(2-bromo-1,1-dieth-
oxyethyl)-5-phenyloxazole (7a) by use of 3-bromo-2,2-
diethoxypropionic acid (4) as a synthon. In addition, 2¢-
substituted 5-phenyl-2,5¢-bioxazoles 12a–c could be rap-
idly generated from 8a, thus demonstrating the practicali-
ty of this useful methodology in the sparse arena of 5,5¢-
bis-heterocycles.
3-Bromo-2,2-diethoxy-N-(2-oxoalkyl)propionamides 6a–l and
5-Substituted 2-(2-Bromo-1,1-diethoxyethyl)oxazoles 7a–l
3-Bromo-2,2-diethoxy-N-(2-oxo-2-phenylethyl)propanamide
(6a); Typical Procedure
PyBOP (7.70 g, 14.8 mmol) was added in one portion to a stirred
soln of HO2CC(OEt)2CH2Br5 (4; 4.99 g, 20.72 mmol), 2-amino-1-
phenylethanone hydrochloride (2.0 g, 14.8 mmol), and NMM (3.28
mL, 29.6 mmol) in anhyd THF (50 mL) at r.t. under N2. The reac-
tion mixture was stirred for 18 h, diluted with EtOAc (100 mL), suc-
cessively washed with H2O (35 mL), 0.1 N aq HCl (35 mL), sat. aq
NaHCO3 (35 mL), and brine (35 mL), and then dried (Na2SO4).
Flash chromatography [Thomson silica gel cartridge, 110 g; 25% B
to 100% B over 1.5 L (A = hexanes, B = EtOAc)] gave 6a.
Anhyd reactions were performed under a N2 atmosphere, and Sure
Seal solvents purchased from Aldrich were used. A Biotage Incor-
porated Horizon Flash Collector system was used to conduct silica
gel flash chromatography. Melting points of samples in open capil-
lary tubes were determined with a Thomas-Hoover melting-point
apparatus and are not corrected. IR spectra were recorded on a Per-
kin-Elmer System 2000 FT spectrophotometer (KBr pellets or thin
Yield: 4.30 g (81%); off-white solid; mp 106–107 °C.
IR (KBr): 3404, 2978, 2933, 1699, 1681, 1530, 1257, 1229, 1198,
1094, 1047, 1020, 1001, 749, 687 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.24–8.20 (m, 1 H), 8.01 (d,
J = 7.3 Hz, 2 H), 7.70–7.65 (m, 1 H), 7.57–7.52 (m, 2 H), 4.67 (d,
J = 5.5 Hz, 2 H), 3.68 (s, 2 H), 3.64–3.47 (m, 4 H), 1.18 (t, J = 7.0
Hz, 6 H).
1
films). H and 13C NMR spectra were recorded on either Bruker
DPX-300, DPX-400, or DRX-500 Advance Digital instruments. El-
emental analyses were performed by the Robertson Microlit Lab
(29 Sampson Avenue, Madison, NJ 07940, USA) and are within
0.4% of theory, unless noted otherwise. Optical rotations were de-
13C NMR (125 MHz, CDCl3): d = 159.84, 152.03, 128.98, 128.82,
127.79, 124.59, 122.25, 98.62, 58.47, 32.85, 15.11.
Synthesis 2009, No. 9, 1445–1458 © Thieme Stuttgart · New York

1450
D. R. St. Laurent, J. L. Romine
PAPER
ESI-LCMS: tR = 2.6 min; m/z [M + Na]+ = 380.01.
ESI-HRMS: m/z [M + H]+ calcd for C15H21BrNO4: 358.0654;
1 H), 4.84 (d, J = 4.9 Hz, 2 H), 3.65 (s, 2 H), 3.65–3.52 (m, 4 H),
1.27 (t, J = 7.0 Hz, 6 H).
ESI-LCMS: tR = 1.7 min (gradient conditions 3); m/z [M + Na]+ =
found: 358.0671.
449.72.
Anal. Calcd for C15H20BrNO4: C, 50.29; H, 5.62; N, 3.91. Found: C,
50.50; H, 5.78; N, 3.95.
Anal. Calcd for C16H19BrF3NO4: C, 45.08; H, 4.49; N, 3.28. Found:
C, 45.20; H, 4.28; N, 3.22.
2-(2-Bromo-1,1-diethoxyethyl)-5-phenyloxazole (7a); Typical
Procedure
2-(2-Bromo-1,1-diethoxyethyl)-5-[3-(trifluoromethyl)phe-
nyl]oxazole (7c)
Yield: 580 mg (64%, 2.1 mmol scale); mp 88–89 °C.
IR (KBr): 3447, 2978, 1653, 1332, 1171 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.89 (s, 1 H), 8.84 (d, J = 7.3 Hz,
1 H), 7.60 (d, J = 7.9 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.46 (s, 1
H), 3.90 (s, 2 H), 3.74–3.67 (m, 2 H), 3.53–3.47(m, 2 H), 1.27 (t,
J = 7.0 Hz, 6 H).
ESI-LCMS: tR = 1.9 min (gradient conditions 3); m/z [M – OEt]+ =
335.78.
Hexachloroethane (1.45 g, 6.14 mmol) was added in one portion to
a soln of 6a (1.1 g, 3.07 mmol), Et3N (1.1 mL, 15.35 mmol), and
Ph3P (1.45 g, 6.14 mmol) in anhyd CH2Cl2 (40 mL) under N2. The
reaction mixture was stirred at r.t. for 18 h before it was charged di-
rectly to a Thomson silica gel cartridge (80 g) and eluted with 15%
B to 60% B over 1 L (solvent A = hexanes; B = EtOAc); this gave
7a.
Yield: 833 mg (76%); pale yellow solid; mp 79–81 °C.
IR (KBr): 3441, 2975, 2936, 2893, 1491, 1448, 1424, 1343, 1286,
1246, 1192, 1165, 1159, 1121, 1097, 1059, 1047, 1011, 955, 938,
891, 767, 748, 693, 685, 675 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.74–7.72 (m, 3 H), 7.52–7.47
(m, 2 H), 7.39 (t, J = 7.3 Hz, 1 H), 4.03 (s, 2 H), 3.67–3.57 (m, 2 H),
3.47–3.37 (m, 2 H), 3.32 (s, 2 H), 1.15 (t, J = 7.14 Hz, 6 H).
ESI-HRMS: m/z [M + H]+ calcd for C16H17BrF3NO3: 408.0417;
found: 408.0422.
Anal. Calcd for C16H17BrF3NO3: C, 47.07; H, 4.19; N, 3.43. Found:
C, 47.14; H, 4.21; N, 3.32.
13C NMR (125 MHz, CDCl3): d = 178.84, 155.56, 155.16, 130.51,
3-Bromo-N-[2-(3-bromophenyl)-2-oxoethyl]-2,2-diethoxypro-
panamide (6d)
Yield: 6.4 g (65%, 10.6 mmol scale); white solid; mp 139–141 °C.
129.31, 126.38, 125.60, 124.34, 124.19, 45.58, 30.23.
ESI-LCMS: tR = 2.9 min; m/z [M + H]+ = 340.02.
ESI-HRMS: m/z [M + H]+ calcd for C15H19BrNO3: 340.0548;
IR (KBr): 3388, 2981, 1704, 1672, 1536, 1384, 1201, 1041 cm–1.
found: 340.0551.
1H NMR (500 MHz, DMSO-d6): d = 8.27 (t, J = 5.5 Hz, 1 H), 8.14
(t, J = 1.5 Hz, 1 H), 8.00 (dt, J = 7.9, 1.2 Hz, 1 H), 7.87 (dd, J = 8.8,
1.8 Hz, 1 H), 7.51 (t, J = 7.9 Hz, 1 H), 4.65 (d, J = 5.8 Hz, 2 H), 3.67
(s, 2 H) 3.58–3.46 (m, 4 H), 1.18 (t, J = 7.0 Hz, 6 H).
Anal. Calcd for C15H18BrNO3: C, 52.95; H, 5.33; N, 4.11. Found: C,
52.98; H, 5.37; N, 4.02.
3-Bromo-2,2-diethoxy-N-[2-(4-nitrophenyl)-2-oxoethyl]pro-
panamide (6b)
Yield: 2.2 g (82%, 6.9 mmol scale); elution A–B: hexane–EtOAc,
20–60% B; white solid; mp 161–162 °C.
ESI-LCMS: tR = 2.2 min; m/z [M + Na]+ = 459.76.
Anal. Calcd for C15H19Br2NO4: C, 41.21; H, 4.38; N, 3.20. Found:
C, 41.40; H, 4.16; N, 3.06. 61298–141.
IR (KBr): 3396, 2976, 2937, 1711, 1671, 1529, 1047 cm–1.
2-(2-Bromo-1,1-diethoxyethyl)-5-(3-bromophenyl)oxazole (7d)
Yield: 0.37 g (71%, 1.2 mmol scale); white solid; mp 67–68 °C.
IR (KBr): 2981, 2934, 2891, 1472, 1196, 1095, 1052, 793 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.96 (t, J = 1.8 Hz, 1 H), 7.86
(s, 1 H), 7.74 (dt, J = 8.1, 1.1 Hz, 1 H), 7.59 (dd, J = 8.1, 1.2 Hz, 1
H), 7.45 (t, J = 7.7 Hz, 1 H), 4.05 (s, 2 H), 3.67–3.57 (m, 2 H), 3.46–
3.36 (m, 2 H), 1.15 (t, J = 7.0 Hz, 6 H).
1H NMR (300 MHz, DMSO-d6): d = 8.35 (d, J = 8.8 Hz, 2 H), 8.33–
8.29 (m, 1 H), 8.24 (d, J = 8.8 Hz, 2 H), 4.72 (d, J = 5.5 Hz, 2 H),
3.67 (s, 2 H), 3.58–3.46 (m, 4 H), 1.18 (t, J = 6.95 Hz, 6 H).
ESI-LCMS: tR = 1.9 min (gradient conditions 2); m/z [M – H–] =
401.02.
Anal. Calcd for C15H19BrN2O6: C, 44.68; H, 4.74; N, 6.94. Found:
C, 44.71; H, 4.89; N, 6.81.
ESI-LCMS: tR = 2.4 min (gradient conditions 2); m/z [M + Na]+ =
441.73.
2-(2-Bromo-1,1-diethoxyethyl)-5-(4-nitrophenyl)oxazole (7b)
Anal. Calcd for C15H17Br2NO3: C, 42.98; H, 4.08; N, 3.34. Found:
C, 43.12; H, 3.99; N, 3.30.
Yield: 0.81 g (40%, 5.3 mmol scale); yellow solid; mp 174–176 °C.
1H NMR (300 MHz, DMSO-d6): d = 8.35 (d, J = 8.8 Hz, 2 H), 8.16
(s, 1 H), 8.01 (d, J = 9.1 Hz, 2 H), 4.06 (s, 2 H), 3.68–3.56 (m, 2 H),
3.48–3.58 (m, 2 H), 3.82 (s, 2 H), 1.16 (t, J = 7.3 Hz, 6 H).
3-Bromo-2,2-diethoxy-N-[2-(2-tolyl)-2-oxoethyl]propanamide
(6e)
ESI-LCMS (Method B): tR = 2.2 min (gradient conditions 2); m/z
Yield: 1.0 g (71%, 5.0 mmol scale); white solid; mp 138.5–
139.5 °C.
[M + Na]+ = 409.04.
Anal. Calcd for C15H17BrN2O5: C, 46.77; H, 4.44; N, 7.27. Found:
C, 46.56; H, 4.17; N, 7.51.
IR (KBr): 3394, 2980, 2927, 1716, 1673, 1525, 1199, 1093, 1046
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.29 (t, J = 5.5 Hz, 1 H), 7.78
(d, J = 7.7 Hz, 1 H), 7.44 (dt, J = 7.7, 1.1 Hz, 1 H), 7.31 (t, J = 7.3
Hz, 2 H), 4.45 (d, J = 5.5 Hz, 2 H), 3.65 (s, 2 H) 3.63–3.43 (m, 2 H),
3.42–3.29 (m, 2 H), 2.39 (s, 3 H), 1.14 (t, J = 7.0 Hz, 6 H).
ESI-LCMS: tR = 2.0 min (gradient conditions 2); m/z [M + Na]+ =
397.12.
3-Bromo-2,2-diethoxy-N-{2-oxo-2-[3-(trifluoromethyl)phe-
nyl]ethyl}propanamide (6c)
Yield: 1.4 g (44.5%, 7.4 mmol scale); mp 134.0–134.5 °C.
IR (KBr): 3397, 2979, 1705, 1673, 1523, 1329, 1135 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.24 (s, 1 H), 8.16 (d, J = 7.6 Hz,
1 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.84 (br s, 1 H), 7.66 (t, J = 7.6 Hz,
Anal. Calcd for C16H22BrNO4: C, 51.62; H, 5.95; N, 3.76. Found: C,
51.70; H, 6.25; N, 3.67.
Synthesis 2009, No. 9, 1445–1458 © Thieme Stuttgart · New York

PAPER
Preparation of 2-Imidazol-4-yl- and 2-Thiazol-4-yloxazoles
1451
2-(2-Bromo-1,1-diethoxyethyl)-5-(2-tolyl)oxazole (7e)
Yield: 0.81 g (89%, 2.56 mmol scale); white solid; mp 80–81 °C.
Anal. Calcd for C19H20BrNO3: C, 58.47; H, 5.16; N, 3.58. Found: C,
58.59; H, 5.08; N, 3.25.
IR (KBr): 3437, 2979, 2931, 1486, 1416, 1199, 1054, 765 cm–1.
3-Bromo-2,2-diethoxy-N-[2-(2-methyl-1H-benzimidazol-6-yl)-
2-oxoethyl]propanamide (6h)
Yield: 0.61 g (55%, 2.64 mmol scale); white solid; mp 209–211 °C.
IR (KBr): 3384, 2975, 1693, 1672, 1522, 1048, 1020 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.20 (s, 1 H), 8.02 (br s, 1 H), 7.87
(d, J = 10.0 Hz, 1 H), 7.59 (d, J = 8.5 Hz, 1 H), 4.90 (d, J = 4.6 Hz,
2 H), 3.67 (s, 2 H), 3.67–3.62 (m, 2 H), 3.60–3.54 (m, 2 H), 2.67 (s,
3 H), 1.27 (t, J = 7.0 Hz, 6 H).
1H NMR (300 MHz, CDCl3): d = 7.76 (m, 1 H), 7.28–7.23 (m, 4 H),
3.87 (s, 2 H), 3.73–3.63 (m, 2 H), 3.53–3.43 (m, 2 H), 2.45 (s, 3 H),
1.24 (t, J = 7.0 Hz, 6 H).
ESI-LCMS: tR = 2.3 min (gradient conditions 2); m/z [M + Na]+ =
376.19.
Anal. Calcd for C16H20BrNO3: C, 54.25; H, 5.69; N, 3.95. Found: C,
54.21; H, 5.63; N, 4.05.
ESI-LCMS: tR = 1.4 min (gradient conditions 2); m/z [M + H]+ =
412.10.
ESI-HRMS: m/z [M + H]+ calcd for C49H23BrN3O4: 412.08664;
3-Bromo-2,2-diethoxy-N-[2-(4-methoxyphenyl)-2-oxoeth-
yl]propanamide (6f)
Yield: 1.7 g (91%, 5.0 mmol scale); white solid; mp 122–123 °C.
found: 412.08858.
IR (KBr): 3402, 2975, 1687, 1678, 1600, 1510, 1254, 1172, 1030,
832 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.16 (t, J = 5.5 Hz, 1 H), 7.99
(d, J = 8.8 Hz, 2 H), 7.06 (d, J = 9.1 Hz, 2 H), 4.63 (d, J = 5.5 Hz, 2
H), 3.85 (s, 3 H), 3.65 (s, 2 H), 3.60–3.50 (m, 4 H), 1.18 (t, J = 7.0
Hz, 6 H).
2-(2-Bromo-1,1-diethoxyethyl)-5-(2-methyl-1H-benzimidazol-
6-yl)oxazole (7h)
Yield: 0.12 g (22%, 1.44 mmol scale); white solid.
IR (KBr): 2978, 2930, 1630, 1550, 1248, 1169, 1048 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.82 (s, 1 H), 7.58–7.52 (m, 2 H),
7.32 (s, 1 H), 3.89 (s, 2 H), 3.73–3.65 (m, 2 H), 3.54–3.46 (m, 2 H),
2.65 (s, 3 H), 1.24 (t, J = 7.0 Hz, 6 H).
ESI-LCMS: tR = 1.5 min (gradient conditions 2); m/z [M + H]+ =
394.11.
ESI-LCMS: tR = 2.0 min (gradient conditions 2); m/z [M + Na]+ =
410.14.
Anal. Calcd for C16H22BrNO5: C, 49.49; H, 5.71; N, 3.60. Found: C,
49.43; H, 5.90; N, 3.61.
2-(2-Bromo-1,1-diethoxyethyl)-5-(4-methoxyphenyl)oxazole
(7f)
ESI-HRMS: m/z [M + H]+ calcd for C17H21BrN3O3: 394.0761;
found: 394.0763.
Yield: 0.30 g (41%, 2.0 mmol scale); white solid; mp 134–136 °C.
3-Bromo-2,2-diethoxy-N-[2-oxo-2-(3-pyridyl)ethyl]propan-
amide (6i)
Yield: 2.7 g (57%, 13.3 mmol scale); white solid; mp 125–128 °C.
IR (KBr): 3405, 2979, 2926, 1703, 1678, 1528, 1204, 1043, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.20 (d, J = 1.5 Hz, 1 H), 8.40 (dd,
J = 5.3, 1.5 Hz, 1 H), 8.27 (dt, J = 8.0, 2.0 Hz, 1 H), 7.81 (d, J = 4.8
Hz, 1 H), 7.48 (dd, J = 8.0, 0.75 Hz, 1 H), 4.83 (d, J = 4.8 Hz, 2 H),
3.64 (s, 2 H), 3.64–3.50 (m, 4 H), 1.27 (t, J = 7.0 Hz, 6 H).
IR (KBr): 2977, 2933, 1618, 1501, 1257, 1050, 832 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.67 (d, J = 8.8 Hz, 2 H), 7.57
(s, 1 H), 7.06 (d, J = 9.1 Hz, 2 H), 4.02 (s, 2 H), 3.80 (s, 3 H), 3.66–
3.56 (m, 2 H), 3.47–3.37 (m, 2 H), 1.15 (t, J = 7.3 Hz, 6 H).
ESI-LCMS: tR = 2.2 min (gradient conditions 2); m/z [M + Na]+ =
391.94.
Anal. Calcd for C16H20BrNO4·0.5H2O: C, 50.67; H, 5.58; N, 3.69;
H2O, 2.38. Found: C, 50.85; H, 5.46; N, 3.61; H2O, 2.50% (PMR).
ESI-LCMS: tR = 1.4 min (gradient conditions 2); m/z [M + Na]+ =
381.10.
3-Bromo-2,2-diethoxy-N-[2-(2-naphthyl)-2-oxoethyl]propan-
amide (6g)
ESI-HRMS: m/z [M + H]+ calcd for C14H20BrN2O4: 359.06010;
Yield: 1.7 g (85%, 5.0 mmol scale); white solid; mp 135.5–137 °C.
found: 359.06183.
IR (KBr): 2972, 1687, 1678, 1529, 1176, 1045, 1018 cm–1.
Anal. Calcd for C14H19BrN2O4·0.6H2O: C, 45.44; H, 5.50; N, 7.57;
H2O, 2.92. Found: C, 45.18; H, 5.17; N, 7.47; H2O, 2.21 (PMR).
1H NMR (300 MHz, DMSO-d6): d = 8.79 (s, 1 H), 8.29 (t, J = 5.5
Hz, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 8.06–7.98 (m, 3 H), 7.71–7.61
(m, 2 H), 4.82 (d, J = 5.7 Hz, 2 H), 3.70 (s, 2 H) 3.61–3.50 (m, 4 H),
1.18 (t, J = 7.3 Hz, 6 H).
ESI-LCMS: tR = 2.1 min (gradient conditions 2); m/z [M + Na]+ =
430.08.
2-(2-Bromo-1,1-diethoxyethyl)-5-(3-pyridyl)oxazole (7i)
Yield: 0.68 g (75%, 2.7 mmol scale); white foam.
IR (KBr): 2978, 1568, 1424, 1254, 1165, 1050, 705 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.91 (s, 1 H), 8.56 (d, J = 4.0
Hz, 1 H), 7.94 (d, J = 7.6 Hz, 1 H), 7.44 (s, 1 H), 7.35 (dd, J = 7.6,
4.9 Hz, 1 H), 3.87 (s, 2 H), 3.71–3.65 (m, 2 H), 3.50–3.44 (m, 2 H),
1.24 (t, J = 7.0 Hz, 6 H).
Anal. Calcd for C19H22BrNO4: C, 55.89; H, 5.43; N, 3.43. Found: C,
55.71; H, 5.62; N, 3.35.
2-(2-Bromo-1,1-diethoxyethyl)-5-(2-naphthyl)oxazole (7g)
Yield: 0.56 g (83%, 1.72 mmol scale); white solid; mp 59–61 °C.
ESI-LCMS: tR = 1.5 min (gradient conditions 2); m/z [M + H]+ =
341.13.
IR (KBr): 2977, 1250, 1165, 1095, 1050, 971 cm–1.
Anal. Calcd for C14H17BrN2O3: C, 49.28; H, 5.02; N, 8.21. Found:
C, 49.54; H, 4.91; N, 7.99.
1H NMR (300 MHz, DMSO-d6): d = 8.15 (s, 1 H), 7.90–7.87 (m, 2
H), 7.84–7.82 (m, 1 H), 7.73 (dd, J = 8.6, 1.5 Hz, 1 H), 7.53–7.49
(m, 2 H), 7.48 (s, 1 H), 3.94 (s, 2 H), 3.76–3.70 (m, 2 H), 3.56–3.50
(m, 2 H), 1.29 (t, J = 7.0 Hz, 6 H).
ESI-LCMS: tR = 2.4 min (gradient conditions 2); m/z [M + H]+ =
390.21.
3-Bromo-2,2-diethoxy-N-[2-(1H-indol-3-yl)-2-oxoethyl]pro-
panamide (6j)
Yield: 1.6 g (84%, 4.78 mmol scale); yellow solid; mp 171–173 °C.
IR (KBr): 3351, 3257, 2980, 1668, 1652, 1520, 1435, 1037, 741 cm–1.
Synthesis 2009, No. 9, 1445–1458 © Thieme Stuttgart · New York

1452
D. R. St. Laurent, J. L. Romine
PAPER
1H NMR (300 MHz, DMSO-d6): d = 12.06 (br s, 1 H), 8.49 (s, 1 H),
8.17–8.15 (m, 2 H), 8.49 (d, J = 7.0 Hz, 1 H), 7.25–7.19 (m, 2 H),
4.58 (d, J = 5.5 Hz, 2 H), 3.71 (s, 2 H), 3.63–3.53 (m, 4 H), 1.21 (t,
J = 7.0 Hz, 6 H).
ESI-LCMS: tR = 2.0 min (gradient conditions 2); m/z [M + Na]+ =
421.06.
tert-Butyl 2-[2-(2-Bromo-1,1-diethoxyethyl)oxazol-5-yl]pyrro-
lidine-1-carboxylate (7l)
Yield: 548 mg (43%, 2.2 mmol scale); mp 61–63 °C.
IR (KBr): 34446, 2981, 1695, 1402, 1163, 1115 cm–1.
1H NMR (500 MHz, CDCl3): d = 6.48 (s, 1 H), 5.01–4.91 (app br s,
1 H), 3.80 (s, 2 H), 3.66–3.60 (m, 2 H), 3.56–3.50 (m, 1 H), 3.50–
3.38 (m, 3 H), 2.19 (s, 1 H), 2.05–1.90 (m, 3 H), 1.43 and 1.36 (2 s,
9 H), 1.23–1.19 (m, 6 H).
ESI-HRMS: m/z [M + H]+ calcd for C17H22BrN2O4: 397.07575;
found: 397.07764.
ESI-LCMS: tR = 2.1 min (gradient conditions 2); m/z [M + Na]+ =
455.13.
ESI-HRMS: m/z [M + H]+ calcd for C18H30BrN2O5: 433.1333;
found: 433.1337.
2-(2-Bromo-1,1-diethoxyethyl)-5-(1H-indol-3-yl)oxazole (7j)
Yield: 0.87 g (90%, 2.52 mmol scale); white solid; mp 128–132 °C
(dec).
IR (KBr): 3421, 3169, 2927, 1635, 1616, 1567, 1452, 1253, 1113,
1047, 730 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.48 (br s, 1 H), 7.85 (d, J = 7.6
Hz, 1 H), 7.59 (d, J = 2.4 Hz, 1 H), 7.43 (d, J = 9.1 Hz 1 H), 7.30–
7.23 (m, 3 H), 3.93 (s, 2 H), 3.73–3.68 (m, 2 H), 3.56–3.50 (m, 2 H),
1.27 (t, J = 7.0 Hz, 6 H).
Anal. Calcd for C18H29BrN2O5: C, 49.89; H, 6.74; N, 6.46. Found:
C, 49.92; H 6.82; N, 6.35.
2-Bromo-1-(5-phenyloxazol-2-yl)ethanone (8a); Typical Proce-
dure
Oxazole 7a (2.0 g, 5.88 mmol) was taken up in 90% HCO2H (20
mL), and the mixture was heated to 80 °C for 2 h under N2 before it
was cooled to r.t. and concentrated in vacuo. The title compound
was isolated as an orange-tan solid which could be used as is; yield:
1.40 g (90%). It could also be purified further by flash chromatog-
raphy (silica gel, Biotage Horizon instrument, 25M column equili-
brated with 300 mL of 5% B; elution: 5% B for 60 mL, then 5% B
to 100% B for 720 mL; solvent B = EtOAc, A = hexanes; this fur-
nished pure 8a as a white solid (plates) upon suction filtration of the
precipitate formed after evaporation of the eluent to 25% volume.
ESI-LCMS: tR = 2.1 min (gradient conditions 2); m/z [M + Na]+ =
401.10.
Anal. Calcd for C17H19BrN2O3: C, 53.83; H, 5.05; N, 7.38. Found:
C, 53.81; H, 4.83; N, 7.27.
Methyl 5-[(3-Bromo-2,2-diethoxypropanoyl)amino]-4-oxopen-
tanoate (6k)
Yield: 2.5 g (62.5%, 11.0 mmol scale); colorless oil.
IR (KBr): 3395, 2976, 1741, 1735, 1677, 1529, 1220, 1202, 1048
cm–1.
Mp 99–100 °C.
IR (KBr): 3449, 2994, 1706, 1508, 1480, 1446, 1385, 1360, 1220,
1124, 1066, 1029, 1019, 958, 932, 860, 763, 690, 663 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.10 (s, 1 H), 7.89–7.88 (m, 2
H), 7.58–7.55 (m, 2 H), 7.52–7.49 (m, 1 H), 4.87 (s, 2 H).
1H NMR (300 MHz, CDCl3): d = 7.55 (br s, 1 H), 4.25 (d, J = 5.2
Hz, 2 H), 3.68 (s, 3 H), 3.61 (s, 2 H), 3.61–3.55 (m, 2 H), 3.54–3.48
(m, 2 H), 2.77 (t, J = 6.7 Hz, 2 H), 2.66 (t, J = 6.7 Hz, 2 H), 1.24 (t,
J = 7.0 Hz, 6 H).
ESI-LCMS (no chromophore): m/z [M + Na]+ = 389.95.
ESI-LCMS: tR = 2.45 min; m/z [M + H]+ = 266.08 and 268.08.
HRMS m/z calcd for C11H979BrNO2: 265.9817; found: 265.9806.
Anal. Calcd for C13H22BrNO6: C, 42.40; H, 6.02; N, 3.80. Found: C,
42.65; H, 6.30; N, 3.78.
Anal. Calcd for C11H8BrNO2: C, 49.65; H, 3.03; N, 5.26. Found: C,
49.71; H, 3.22; N, 5.19.
Methyl 3-[2-(2-Bromo-1,1-diethoxyethyl)oxazol-5-yl]propan-
oate (7k)
Yield: 1.68 g (67%, 6.79 mmol scale); colorless oil.
IR (film): 2978, 2933, 1736, 1436, 1159, 1049 cm–1
1H NMR (300 MHz, CDCl3): d = 6.80 (s, 1 H), 3.79 (s, 2 H), 3.67
(s, 3 H), 3.65–3.58 (m, 2 H), 3.44–3.37 (m, 2 H), 3.01 (t, J = 7.3 Hz,
2 H), 2.66 (t, J = 7.3 Hz, 2 H), 1.21 (t, J = 7.0 Hz, 6 H).
5-Phenyl-2-(2-phenyl-1H-imidazol-4-yl)oxazole (9a) by Method
A; Typical Procedure
a-Bromo ketone 8a (266 mg, 1.0 mmol) in THF (1 mL) was added
dropwise to a suspension of benzamidine hydrochloride (157 mg,
1.0 mmol) and KHCO3 (200 mg, 2.0 mmol) in THF (4 mL) and H2O
(1 mL) at 80 °C. The mixture was gently refluxed for 18 h before it
was cooled to r.t., diluted with EtOAc (20 mL), and washed with
sat. aq NaHCO3 (10 mL) and brine (10 mL) prior to drying
(Na2SO4) and solvent evaporation. Purification of the residue by
flash chromatography (silica gel, Biotage Horizon instrument, 25M
column equilibrated with 15% B for 300 mL; elution: 15% B to 50%
B for 720 mL, then 50% B to 100% B for 720 mL; B = EtOAc, A =
hexanes) followed by MCX extraction15 afforded the title com-
pound.
ESI-LCMS: tR = 1.8 min (gradient conditions 2); m/z [M – OEt] =
304.18.
Anal. Calcd for C13H20BrNO5: C, 44.58; H, 5.75; N, 4.00. Found: C,
44.63; H, 5.61; N, 3.92.
tert-Butyl 2-{2-[(3-Bromo-2,2-diethoxypropanoyl)ami-
no]acetyl}pyrrolidine-1-carboxylate (6l)
Yield: 1.2 g (34%, 7.8 mmol scale); mp 115–117.5 °C.
IR (KBr): 3404, 2980, 1737, 1692, 1522, 1402, 1047 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.53 (d, J = 15.3 Hz 1 H), 4.39–
4.18 (m, 3 H), 3.61 (s, 2 H), 3.60–3.44 (m, 6 H), 2.26–2.14 (m, 1 H),
2.0–1.85 (m, 3 H), 1.45 and 1.40 (2s, 9 H), 1.26 –1.21 (m, 6 H).
Yield: 191.5 mg (67%); amber-colored solid; mp 184–188 °C.
Further purification was accomplished if desired by preparative
HPLC (0% B to 100% B over 20 min); this afforded analytically
pure product.
IR (KBr): 3436, 3142, 3058, 2920, 1618, 1607, 1540, 1489, 1449,
1384, 1287, 1245, 1155, 1127, 1106, 1071, 1052, 1024, 983, 943,
920, 831, 803, 759, 739, 713, 690 cm–1.
ESI-LCMS: tR = 2.0 min (gradient conditions 2); m/z [M + Na]+ =
473.44.
1H NMR (500 MHz, DMSO-d6): d = 13.2 (br s, 1 H), 8.06 (d, J = 7.6
Hz, 2 H), 8.01 (br s, 1 H), 7.82 (d, J = 7.7 Hz, 2 H), 7.77 (s, 1 H),
7.53–7.50 (m, 4 H), 7.44–7.37 (series of m, 2 H).
ESI-HRMS: m/z [M + H]+ calcd 451.1438; found: 451.1452.
Anal. Calcd for C18H31BrN2O6: C, 47.90; H, 6.92; N, 6.20; found:
C, 48.27; H, 6.99; N, 6.09.
Synthesis 2009, No. 9, 1445–1458 © Thieme Stuttgart · New York

PAPER
Preparation of 2-Imidazol-4-yl- and 2-Thiazol-4-yloxazoles
1453
ESI-LCMS: tR = 2.41 min; m/z [M + H]+ = 288.21.
ESI-LCMS: tR = 2.74 min; m/z [M + H]+ = 333.24.
ESI-HRMS: m/z [M + H]+ calcd for C18H14N3O: 288.1137; found:
ESI-HRMS: m/z [M + H]+ calcd for C18H13N4O3: 333.0988; found:
288.1133.
333.0968.
Anal. Calcd for C18H13N3O·0.25H2O: C, 74.08; H, 4.66; N, 14.40;
H2O, 1.54. Found: C, 73.89; H, 4.99; N, 14.20; H2O, 0.57.
5-Phenyl-2-{2-[4-(trifluoromethyl)phenyl]-1H-imidazol-4-
yl}oxazole (9d)
Yield: 162.2 mg (46%); HPLC (0% B to 100% B over 25 min);
cream-colored solid; mp 215–216 °C (dec).
5-Phenyl-2-(2-phenyl-1H-imidazol-4-yl)oxazole (9a) by Method
B; Typical Procedure
DIPEA (87 mL, 0.50 mmol) was added in one portion to a stirred
soln of BzOH (61.1 mg, 0.50 mmol) and 8a (133 mg, 0.50 mmol)
in anhyd MeCN (2 mL) at r.t. under N2. The mixture was stirred at
r.t. for 3 h before it was concentrated to near dryness. The residue
was taken up in EtOAc (20 mL) and washed with sat. aq NaHCO3
(10 mL) and brine (10 mL) prior to drying (Na2SO4) and solvent
evaporation. This residue was dissolved in anhyd xylene (3 mL) and
treated with NH4OAc (193 mg, 2.5 mmol). The suspension was
heated to 140 °C in a thick-walled, screw-top tube for 2 h before it
was cooled to r.t. and concentrated in vacuo. The residue was taken
up in EtOAc (20 mL) and the mixture was washed with sat. aq
NaHCO3 (10 mL) and brine (10 mL), dried (Na2SO4), and concen-
trated. Purification of the residue by preparative HPLC (10% B to
100% B over 14 min) afforded the title compound.
IR (KBr): 3441, 3147, 3035, 2925, 1621, 1435, 1328, 1167, 1131,
1116, 1067, 841, 756, 732, 704, 686 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 13.43 (br s, 1 H), 8.27–8.26
(m, 2 H), 8.14 (s, 1 H), 7.89 (d, J = 8.5 Hz, 2 H), 7.82 (d, J = 7.6 Hz,
2 H), 7.78 (s, 1 H), 7.52 (t, J = 8.0 Hz, 2 H), 7.39 (t, J = 7.3 Hz, 1 H).
ESI-LCMS: tR = 2.90 min; m/z [M + H]+ = 356.26.
ESI-HRMS: m/z [M + H]+ calcd for C19H13F3N3O: 356.1011; found:
356.1007.
Anal. Calcd for C19H12F3N3O: C, 64.22; H, 3.40; N, 11.82. Found:
C, 63.97; H, 3.10; N, 11.72.
2-[2-(2-Chlorophenyl)-1H-imidazol-4-yl]-5-phenyloxazole (9e)
Yield: 296.1 mg (88%); HPLC (10% B to 100% B over 20 min);
off-white solid; mp 234–236 °C (dec).
Yield: 35.1 mg (24%, two steps); white solid; mp 192–194 °C.
IR (KBr): 3423, 3123, 3058, 2923, 1619, 1607, 1490, 1450, 1155,
1128, 1107, 944, 759, 712, 690 cm–1.
IR (KBr): 3432 (br), 3134, 3033, 1623, 1476, 1455, 1442, 1391,
1123, 1112, 1044, 948, 828, 808, 759, 729, 690 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.94–7.92 (m, 2 H), 7.76 (s, 1 H),
7.68–7.66 (m, 2 H), 7.42–7.36 (series of m, 6 H), 7.35 (s, 1 H),
7.33–7.28 (m, 1 H).
ESI-LCMS: tR = 2.34 min; m/z [M + H]+ = 288.13.
ESI-HRMS: m/z [M + H]+ calcd for C18H14N3O: 288.1137; found:
1H NMR (500 MHz, DMSO-d6): d = 12.94 (br m, 1 H), 8.00 (br s,
1 H), 7.86–7.78 (m, 3 H), 7.78–7.74 (m, 1 H), 7.66–7.59 (m, 1 H),
7.55–7.47 (m, 4 H), 7.42–7.34 (m, 1 H).
ESI-LCMS: tR = 2.43 min; m/z [M + H]+ = 322.07.
ESI-HRMS: m/z [M + H]+ calcd for C18H13N3OCl: 322.0742;
288.1135.
found: 322.322.0733.
Anal. Calcd for C18H13N3O·0.12MeOH·0.10AcOH: C, 74.05; H,
4.71; N, 14.14. Found: C, 73.81; H, 4.55; N, 14.33.
2-[2-(4-Methoxyphenyl)-1H-imidazol-4-yl]-5-phenyloxazole
(9f)
Yield: 154 mg (48.5%); HPLC (0% B to 100% B over 25 min);
cream-colored solid; mp 215–216 °C (dec).
5-Phenyl-2-[2-(3-pyridyl)-1H-imidazol-4-yl]oxazole (9b)
Yield: 143.4 mg (50%); HPLC (0% B to 100% B over 25 min); tan
solid; mp 241–243 °C (dec).
IR (KBr): 3427, 2928, 1618, 1498, 1462, 1430, 1294, 1249, 1175,
1126, 1107, 1031, 948, 832, 765, 731, 686 cm–1.
IR (KBr): 3441 (br), 3102, 3061, 2929, 2818, 1622, 1576, 1486,
1472, 1427, 1162, 1133, 1026, 943, 757, 711, 691, 684 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.6 (br s, 1 H), 9.24 (d, J = 1.5
Hz, 1 H), 8.62 (dd, J = 4.8, 1.9 Hz, 1 H), 8.39 (dt, J = 8.2, 1.9 Hz, 1
H), 8.09 (s, 1 H), 7.82 (d, J = 7.0 Hz, 2 H), 7.79 (s, 1 H), 7.56–7.53
(m, 1 H), 7.52 (t, J = 7.9 Hz, 2 H), 7.39 (t, J = 7.3 Hz, 1 H).
ESI-LCMS: tR = 2.14 min; m/z [M + H]+ = 289.23.
ESI-HRMS: m/z [M + H]+ calcd for C17H13N4O: 289.1090; found:
1H NMR (400 MHz, DMSO-d6, rotameric-like): d = 13.29 and
12.94 (2s, 1 H), 8.10–8.80 and 7.98–7.96 (2m, 2 H), 7.98 (s, 1 H),
7.84–7.83 and 7.80–7.78 (2m, 2 H), 7.74–7.72 (m, 1 H), 7.50 (t,
J = 7.6 Hz, 2 H), 7.37 (t, J = 7.3 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 2 H),
3.82 (s, 3 H).
ESI-LCMS: tR = 2.29 min; m/z [M + H]+ = 318.14.
ESI-HRMS: m/z [M + H]+ calcd for C19H16N3O2: 318.1237; found:
318.1238.
289.1086.
2-(2-Isopropyl-1H-imidazol-4-yl)-5-phenyloxazole (9g)
2-[2-(3-Nitrophenyl)-1H-imidazol-4-yl]-5-phenyloxazole (9c)
Yield: 237.8 mg (71.5%); HPLC (0% B to 100% B over 25 min);
yellow solid.
Yield: 28.2 mg (22%); HPLC (0% B to 100% B over 25 min); white
solid; mp 219–221 °C.
IR (KBr): 3445, 3166, 3118, 3048, 3015, 2965, 2903, 2805, 2761,
1622, 1609, 1554, 1491, 1479, 1448, 1419, 1395, 1380, 1167, 1156,
1127, 1088, 990, 945, 804, 757, 727, 686 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.74 and 12.26 (2 br s, 1 H),
7.77–7.74 (m, 3 H), 7.68 (s, 1 H), 7.49 (t, J = 7.6 Hz,, 2 H), 7.36 (t,
J = 7.3 Hz, 1 H), 3.04 (sept, J = 7.0 Hz, 1 H), 1.29 (d, J = 7.1 Hz, 6
H).
Further purification by preparative HPLC (0% B to 100% B over
25 min) afforded the product as a bright yellow solid; mp 227–
229 °C.
IR (KBr): 3403, 3083, 3039, 2900, 2864, 2821, 1618, 1527, 1492,
1479, 1449, 1438, 1347, 1132, 944, 869, 799, 761, 739, 711, 705,
686 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 13.58 (br s, 1 H), 8.92 (s, 1 H),
8.50 (d, J = 7.6 Hz, 1 H), 8.27 (dd, J = 8.3, 1.5 Hz, 1 H), 8.12 (br s,
1 H), 7.84–7.79 (m, 4 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.6
Hz, 1 H).
ESI-LCMS: tR = 1.97 min; m/z [M + H]+ = 254.25.
ESI-HRMS: m/z [M + H]+ calcd for C15H16N3O: 254.1294; found:
254.1286.
Synthesis 2009, No. 9, 1445–1458 © Thieme Stuttgart · New York

1454
D. R. St. Laurent, J. L. Romine
PAPER
Yield: 276.2 mg (91%); pale yellow solid; mp 141–142 °C.
tert-Butyl (S)-2-[4-(5-Phenyloxazol-2-yl)-1H-imidazol-2-yl]pyr-
rolidine-1-carboxylate (9h)
IR (KBr): 3445, 3124, 1590, 1465, 1449, 1421, 1260, 1127, 1059,
990, 957, 937, 828, 773, 756, 723, 655 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.53 (s, 1 H), 8.08–8.06 (m, 2
H), 7.90 (s, 1 H), 7.87–7.86 (m, 2 H), 7.60–7.56 (m, 3 H), 7.55–7.52
(m, 2 H), 7.44–7.41 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 169.45, 156.95, 151.46, 144.62,
132.97, 130.65, 129.00, 128.94, 128.65, 127.81, 126.98, 124.47,
123.44, 119.20.
Yield: 72.3 mg (38%, two steps); white solid; mp 123–125 °C;
[a]D25 –46.71 (c 3.40, EtOH); 97.8% ee.
The product was purified further by preparative HPLC (0% B to
100% B over 25 min, Phenomenex Luna C18, 30 × 100 mm, S10;
10 mM NH4OAc–MeCN–H2O).
IR (KBr): 3423, 3141, 2977, 1696, 1624, 1558, 1397, 1366, 1256,
1161, 1123, 944, 762, 727, 691 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.75 (d, J = 7.7 Hz, 2 H), 7.74–
7.69 (m, 1 H), 7.69 (s, 1 H), 7.47 (t, J = 7.7 Hz, 2 H), 7.37–7.32 (m,
1 H), 4.90–4.75 (2m, 1 H), 3.61–3.47 (m, 1 H), 3.41–3.33 (m, 1 H),
2.32–2.13 (m, 1 H), 2.05–1.90 (m, 2 H), 1.86 (s, 2 H), 1.39 and 1.16
(2s, 9 H).
ESI-LCMS: tR = 3.21 min; m/z [M + H]+ = 305.27.
ESI-HRMS: m/z [M + H]+ calcd for C18H13N2OS: 305.0749; found:
305.0735.
Anal. Calcd for C18H12N2OS: C, 71.03; H, 3.97; N, 9.20; Found: C,
70.83; H, 4.07; N, 9.20.
ESI-LCMS: tR = 2.35 min; m/z [M + H]+ = 381.19.
ESI-HRMS: m/z [M + H]+ calcd for C21H25N4O3: 381.1927; found:
381.1918.
5-Phenyl-2-[2-(3-pyridyl)thiazol-4-yl]oxazole (10b)
Thionicotinamide (138 mg, 1.0 mmol) was added in one portion to
a stirred suspension of 8a (266 mg, 1.0 mmol) and powdered
KHCO3 (125 mg, 1.25 mmol) in absolute EtOH (4 mL). The mix-
ture was heated to 75 °C for 2 h before it was cooled to r.t. and con-
centrated in vacuo. The residue was taken up in EtOAc (20 mL) and
washed with sat. aq NaHCO3 (10 mL) and brine (10 mL) prior to
drying (Na2SO4) and solvent evaporation. This residue was taken up
in CH2Cl2 and flash chromatographed (silica gel, Biotage Horizon
instrument, 25M column pre-equilibrated with 300 mL of 10% B;
elution: 10% B for 60 mL, then 10% B to 50% B for 1050 mL, then
50% B to 100% B for 1050 mL, then 100% B for 750 mL; solvent
B = EtOAc; A = hexane); 10b was obtained as a solid after suction
filtration of the precipitate formed on concentration of the eluent to
25% volume.
tert-Butyl (R)-2-[4-(5-Phenyloxazol-2-yl)-1H-imidazol-2-yl]pyr-
rolidine-1-carboxylate (9i)
Yield: 86.4 mg (45%, two steps); white solid; mp 123–125 °C;
[a]D25 +45.27 (c 3.53, EtOH); 98.4% ee.
The product was purified further by preparative HPLC (0% B to
100% B over 25 min, Phenomenex Luna C18, 30 × 100 mm, S10;
10 mM NH4OAc–MeCN–H2O).
IR (KBr): 3430, 3142, 2977, 1696, 1624, 1558, 1479, 1396, 1366,
1256, 1201, 1161, 1124, 944, 762, 727, 691 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.75 (d, J = 7.4 Hz, 2 H), 7.74–
7.69 (m, 1 H), 7.69 (s, 1 H), 7.47 (t, J = 7.7 Hz, 2 H), 7.37–7.32 (m,
1 H), 4.90–4.75 (2m, 1 H), 3.61–3.47 (m, 1 H), 3.41–3.33 (m, 1 H),
2.32–2.13 (m, 1 H), 2.05–1.90 (m, 2 H), 1.87 (s, 2 H), 1.39 and 1.16
(2s, 9 H).
ESI-LCMS: tR = 2.36 min; m/z [M + H]+ = 381.19.
ESI-HRMS: m/z [M + H]+ calcd for C21H25N4O3: 381.1927; found:
Yield: 229.6 mg (75%); pale yellow solid; mp 152–153.5 °C.
IR (KBr): 3431, 3114, 1594, 1472, 1452, 1411, 1132, 1044, 1025,
959, 937, 844, 766, 759, 721, 695, 686, 656 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 9.25 (d, J = 1.9 Hz, 1 H), 8.75
(dd, J = 3.0, 1.5 Hz, 1 H), 8.62 (s, 1 H), 8.45–8.42 (m, 1 H), 7.91 (s,
1 H), 7.87 (d, J = 7.0 Hz, 2 H), 7.62 (dd, J = 7.5, 4.5 Hz, 1 H), 7.55–
7.52 (m, 2 H), 7.44–7.41 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 165.97, 156.60, 151.69, 151.43,
148.02, 145.07, 134.08, 129.06, 128.99, 128.79, 127.67, 124.49,
123.79, 123.48, 119.73.
381.1912.
2-(1H-Imidazol-4-yl)-5-phenyloxazole (9j)18
Yield: 152.1 mg (68%); HPLC (0% B to 100% B over 25 min); pale
tan solid; mp 190–192 °C.
IR (KBr): 3436, 3143, 3054, 3031, 2817, 2595, 1619, 1607, 1548,
1531, 1496, 1487, 1441, 1437, 1418, 1150, 1077, 1058, 987, 946,
842, 822, 788, 754, 735, 728, 685, 625 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 13.27 and 12.62 (2 br s, 1 H),
7.88 (s, 1 H), 7.85 (s, 1 H), 7.77 (d, J = 7.4 Hz, 2 H), 7.71 (s, 1 H),
7.49 (t, J = 7.6 Hz, 2 H), 7.37 (t, J = 7.3 Hz, 1 H).
ESI-LCMS: tR = 2.53 min; m/z [M + H]+ = 306.27.
ESI-HRMS: m/z [M + H]+ calcd for C17H12N3OS: 306.0701; found:
306.0690.
Anal. Calcd for C17H11N3OS: C, 66.86; H, 3.63; N, 13.76. Found:
C, 66.58; H, 3.75; N, 13.59.
ESI-LCMS: tR = 1.62 min; m/z [M + H]+ = 212.17.
5-Phenyl-2-{2-[3-(trifluoromethyl)phenyl]thiazol-4-yl}oxazole
(10c)
Yield: 342.0 mg (91%); flesh-colored solid; mp 127–128 °C.
ESI-HRMS: m/z [M + H]+ calcd for C12H10N3O: 212.0824; found:
212.0820.
Anal. Calcd for C12H9N3O: C, 68.23; H, 4.29; N, 19.89. Found: C,
67.93; H, 4.37; N, 19.77.
IR (KBr): 3448, 3119, 1636, 1593, 1491, 1453, 1413, 1329, 1239,
1180, 1160, 1152, 1118, 1069, 1004, 966, 886, 800, 770, 762, 721,
688, 666 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.62 (s, 1 H), 8.36 (d, J = 8.0
Hz, 1 H), 8.33 (s, 1 H), 7.94 (d, J = 7.9 Hz, 1 H), 7.90 (s, 1 H), 7.87
(d, J = 8.2 Hz, 2 H), 7.83 (t, J = 7.6 Hz, 1 H), 7.54 (t, J = 7.7 Hz, 2
H), 7.43 (t, J = 7.6 Hz, 1 H).
5-Phenyl-2-(2-phenylthiazol-4-yl)oxazole (10a); Typical Proce-
dure
Thiobenzamide (137 mg, 1.0 mmol) was added in one portion to a
stirred suspension of 8a (266 mg, 1.0 mmol) and powdered KHCO3
(125 mg, 1.25 mmol) in absolute EtOH (4 mL). The mixture was
heated to 75 °C for 18 h before it was cooled to r.t., diluted with
EtOAc (20 mL) and washed with sat. aq NaHCO3 (10 mL) and brine
(10 mL) prior to drying (Na2SO4) and solvent evaporation to a quar-
ter of the volume. The title compound was isolated as a solid by suc-
tion filtration.
ESI-LCMS: tR = 3.28 min; m/z [M + H]+ = 373.21.
ESI-HRMS: m/z [M + H]+ calcd for C19H12F3N2OS: 373.0617;
found: 373.0618.
Synthesis 2009, No. 9, 1445–1458 © Thieme Stuttgart · New York

PAPER
Preparation of 2-Imidazol-4-yl- and 2-Thiazol-4-yloxazoles
1455
Anal. Calcd for C19H11F3N2OS: C, 61.29; H, 2.98; N, 7.52. Found:
C, 61.03; H, 3.05; N, 7.34.
Anal. Calcd for C17H16N2O3S2: C, 56.64; H, 4.47; N, 7.77. Found:
C, 56.29; H, 4.65; N, 7.73.
2-[2-(4-Methoxyphenyl)thiazol-4-yl]-5-phenyloxazole (10d)
Yield: 317.7 mg (94%); reddish-brown solid; mp 190–192 °C.
Ethyl ({2-[4-(5-Phenyloxazol-2-yl)thiazol-2-yl]ethyl}sulfa-
nyl)acetate (10g) and Methyl ({2-[4-(5-Phenyloxazol-2-yl)thiaz-
ol-2-yl]ethyl}sulfanyl)acetate (10f)
IR (KBr): 3448, 3122, 1654, 1608, 1591, 1520, 1465, 1448, 1412,
1302, 1259, 1197, 1174, 1131, 1112, 1070, 1057, 1026, 1012, 990,
958, 938, 827, 764, 727, 687, 673, 657 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.43 (s, 1 H), 8.00 (d, J = 9.2
Hz, 2 H), 7.88 (s, 1 H), 7.86 (d, J = 7.0 Hz, 2 H), 7.53 (t, J = 7.5 Hz,
2 H), 7.42 (t, J = 7.5 Hz, 1 H), 7.12 (d, J = 8.9 Hz, 2 H), 3.86 (s, 3
H).
Methyl 2-[(3-amino-3-thioxopropyl)sulfanyl]acetate (97 mg, 0.5
mmol) was added in one portion to a stirred suspension of 8a (133
mg, 0.5 mmol) and powdered K2CO3 (50 mg, 0.5 mmol) in absolute
EtOH (2 mL). The mixture was heated to 75 °C for 3 h before it was
cooled to r.t., diluted with MeOH (10 mL), filtered through a sy-
ringe filter, distributed into two preparative HPLC vials, and sub-
jected to preparative HPLC (10% B to 100% B over 14 min). Upon
speed evaporation of the eluent, 10g and 10f were isolated.
ESI-LCMS: tR = 3.16 min; m/z [M + H]+ = 335.22.
ESI-HRMS: m/z [M + H]+ calcd for C19H15N2O2S: 335.0849; found:
335.0851.
10g
Yield: 35.5 mg (19%); pale tan solid; mp 89–92 °C.
Anal. Calcd for C19H14N2O2S·0.05EtOAc: C, 68.07; H, 4.28; N,
8.27. Found: C, 67.80; H, 4.47; N, 8.00.
IR (film): 2997, 2917, 1732, 1456, 1271, 1130, 1027, 764, 723, 691
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.88 (s, 1 H), 7.72–7.69 (m, 2 H),
7.43–7.38 (m, 2 H), 7.43 (s, 1 H), 7.34–7.29 (m, 1 H), 4.18 (q,
J = 7.3 Hz, 2 H), 3.39 (t, J = 7.3 Hz, 2 H), 3.26 (s, 2 H), 3.12 (t,
J = 7.3 Hz, 2 H), 1.26 (t, J = 7.3 Hz, 3 H).
ESI-LCMS: tR = 2.89 min; m/z [M + H]+ = 375.11.
ESI-HRMS: m/z [M + H]+ calcd for C18H19N2O3S2: 375.0837;
2-[2-(2-Chlorophenyl)thiazol-4-yl]-5-phenyloxazole (10e)
Yield: 324.3 mg (96%); pale yellow solid; mp 144–145 °C.
IR (KBr): 3446, 3116, 1591, 1484, 1450, 1435, 1411, 1275, 1203,
1133, 1060, 1035, 959, 939, 829, 758, 726, 713, 688, 667, 657 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.68 (s, 1 H), 8.33–8.31 (m, 1
H), 7.90 (s, 1 H), 7.87–7.86 (m, 2 H), 7.72–7.70 (m, 1 H), 7.61–7.57
(m, 2 H), 7.55–7.52 (m, 2 H), 7.44–7.41 (m, 1 H).
found: 375.0827.
13C NMR (125 MHz, CDCl3): d = 164.70, 157.04, 151.59, 143.44,
132.16, 131.51, 131.36, 130.97, 130.69, 129.02, 128.74, 127.87,
127.26, 124.55, 123.55, 121.04.
ESI-LCMS: tR = 3.35 min; m/z [M + H]+ = 339.23.
ESI-HRMS: m/z [M + H]+ calcd for C18H12ClN2OS: 339.0359;
10f
Yield: 105.2 mg (59%); amber-colored solid.
IR (film): 3035, 2951, 2931, 1734, 1670, 1435, 1283, 1201, 1131,
764, 723, 691 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.89 (s, 1 H), 7.72–7.69 (m, 2 H),
7.43 (s, 1 H), 7.43–7.39 (m, 2 H), 7.35–7.30 (m, 1 H), 3.73 (s, 3 H),
3.39 (t, J = 7.5 Hz, 2 H), 3.28 (s, 2 H), 3.12 (t, J = 7.3 Hz, 2 H).
found: 339.0354.
Anal. Calcd for C18H11ClN2OS: C, 63.81; H, 3.27; N, 8.26. Found:
C, 63.78; H, 3.37; N, 8.16.
ESI-LCMS: tR = 2.75 min; m/z [M + H]+ = 361.10.
ESI-HRMS: m/z [M + H]+ calcd for C17H17N2O3S2: 361.0681;
found: 361.0694.
Methyl ({2-[4-(5-Phenyloxazol-2-yl)thiazol-2-yl]ethyl}sulfa-
nyl)acetate (10f)
Methyl 2-[(3-amino-3-thioxopropyl)sulfanyl]acetate (193 mg, 1.0
mmol) was added in one portion to a stirred suspension of 8a (266
mg, 1.0 mmol) and powdered KHCO3 (125 mg, 1.25 mmol) in ab-
solute MeOH (4 mL). The mixture was heated to 75 °C for 2 h be-
fore it was cooled to r.t. and concentrated in vacuo. The residue was
taken up in CH2Cl2 and flash chromatographed (silica gel, Biotage
Horizon instrument, 25M column pre-equilibrated with 300 mL of
5% B; elution: 5% B for 60 mL, then 5% B to 100% B for 720 mL;
B = EtOAc, A = hexanes); this furnished 10f as a pale yellow liquid,
which upon evaporation of the eluent gradually solidified to an am-
ber-colored solid in the freezer.
[4-(5-Phenyloxazol-2-yl)thiazol-2-yl]methyl Pivalate (10h)
Yield: 318.4 mg (93%); pale yellow solid; mp 78–79 °C.
IR (KBr): 3422, 3352, 3023, 2973, 1732, 1638, 1606, 1479,1280,
1129, 1108, 831, 762, 729, 688 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.49 (s, 1 H), 7.87 (s, 1 H), 7.82
(d, J = 8.0 Hz, 2 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.41 (t, J = 7.0 Hz, 1
H), 5.49 (s, 2 H), 1.24 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 177.76, 167.24, 156.72, 151.63,
143.81, 129.02, 128.79, 127.75, 124.56, 123.49, 120.19, 62.95,
38.95, 27.21.
Yield: 283.1 mg (79%); amber solid; mp 56–60°C.
ESI-LCMS: tR = 3.03 min; m/z [M + H]+ = 343.30.
ESI-HRMS: m/z [M + H]+ calcd for C18H19N2O3S: 343.1116; found:
IR (film): 3113, 2949, 1734, 1590, 1559, 1505, 1489, 1435, 1280,
1191, 1155, 1131, 1070, 1007, 941, 838, 764, 723, 691 cm–1.
343.1113.
1H NMR (500 MHz, DMSO-d6): d = 8.34 (s, 1 H), 7.84 (s, 1 H),
7.83–7.81 (m, 2 H), 7.53–7.50 (m, 2 H), 7.42–7.39 (m, 1 H), 3.67
and 3.66 (2s, 3 H), 3.49 (s, 2 H), 3.39 (t, J = 7.3 Hz, 2 H), 3.08 (t,
J = 7.3 Hz, 2 H).
Anal. Calcd for C18H18N2O3S: C, 63.13; H, 5.29; N, 8.18. Found: C,
63.05; H, 4.96; N, 8.04.
tert-Butyl 4-[4-(5-Phenyloxazol-2-yl)thiazol-2-yl]piperidine-1-
carboxylate (10i)
Yield: 352.6 mg (85%); mp 132–133 °C.
13C NMR (125 MHz, DMSO-d6): d = 170.54, 169.88, 156.29,
142.06, 129.62, 128.60, 127.20, 123.98, 123.92, 121.24, 51.99,
32.51, 32.38, 31.11.
IR (KBr): 3448, 3105, 2972, 2929, 2848, 1692, 1592, 1478, 1452,
1397, 1366, 1304, 1275, 1259, 1237, 1210, 1165, 1120, 1110, 1025,
940, 840, 830, 778, 762, 726, 692 cm–1.
ESI-LCMS: tR = 2.74 min; m/z [M + H]+ = 361.23.
ESI-HRMS: m/z [M + H]+ calcd for C17H17N2O3S2: 361.0681;
found: 361.0666.
Synthesis 2009, No. 9, 1445–1458 © Thieme Stuttgart · New York

1456
D. R. St. Laurent, J. L. Romine
PAPER
1H NMR (500 MHz, DMSO-d6): d = 8.36 (s, 1 H), 7.83 (s, 1 H), 7.82
(d, J = 8.0 Hz, 2 H), 7.52 (t, J = 7.7 Hz, 2 H), 7.41 (t, J = 7.7 Hz, 1
H), 4.05 (d, J = 10.6 Hz, 2 H), 2.93 (br m, 2 H), 2.10 (d, J = 12.5 Hz,
2 H), 1.61 (qd, J = 12.4, 4.0 Hz, 2 H), 1.43 (s, 9 H).
ESI-HRMS: m/z [M + Na]+ calcd for C19H21N3O3SNa: 394.1201;
found: 394.1192.
Anal. Calcd for C19H21N3O3S: C, 61.44; H, 5.70; N, 11.31. Found:
C, 61.22; H, 5.90; N, 11.35.
ESI-LCMS: tR = 3.09 min; m/z [M + H]+ = 412.36.
10k
ESI-HRMS: m/z [M + H]+ calcd for C22H26N3O3S: 412.1689; found:
Yield: 41.2 mg (23%); white solid; mp 146–147 °C.
412.1693.
IR (film): 3431, 3004, 2919, 1590, 1492, 1406, 1135, 764, 718, 688,
648 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.86 (s, 1 H), 7.70–7.67 (m, 2 H),
7.43–7.38 (m, 2 H), 7.41 (s, 1 H), 7.34–7.29 (m, 1 H), 5.74 (br s, 4
H), 3.31 (s, 4 H), 1.99 (s, 4 H).
Anal. Calcd for C22H25N3O3S: C, 64.21; H, 6.12; N, 10.21. Found:
C, 64.28; H, 6.29; N, 10.23.
tert-Butyl {2-[4-(5-Phenyloxazol-2-yl)thiazol-2-yl]ethyl}car-
bamate (10j)
tert-Butyl (3-amino-3-thioxopropyl)carbamate (204 mg, 1.0 mmol)
was added in one portion to a stirred suspension of 8a (266 mg, 1.0
mmol) and powdered KHCO3 (125 mg, 1.25 mmol) in absolute
EtOH (4 mL). The mixture was gently refluxed for 2 h before it was
cooled to r.t. and treated with Boc2O (38.4 mg, 0.18 mmol) and ad-
ditional powdered KHCO3 (100 mg, 1.0 mmol). The mixture was
stirred at r.t. for 2 h before it was diluted with CH2Cl2 (10 mL) and
flash chromatographed (silica gel, Biotage Horizon instrument,
25M column pre-equilibrated with 300 mL of 5% B; elution: 5% B
for 60 mL, then 5% B to 100% for 1100 mL, then 100% B for 750
mL; solvent B = EtOAc, A = hexanes); this furnished 10j as a solid
after suction filtration of the precipitate formed by evaporation of
the eluent to 25% volume.
ESI-LCMS: tR = 1.93 min; m/z [M + H]+ = 272.10.
ESI-HRMS: m/z [M + H]+ calcd for C14H14N3OS: 272.0858; found:
272.0853.
Anal. Calcd for C14H13N3OS·1.0AcOH·0.50H2O: C, 56.46; H, 5.33;
N, 12.34. Found: C, 56.39; H, 4.95; N, 12.28.
2-[4-(5-Phenyloxazol-2-yl)thiazol-2-yl]acetonitrile (10l)
Yield: 218.9 mg (82%); pale yellow solid; mp 161–162 °C.
IR (KBr): 3430, 3117, 2932, 2908, 2254, 1592, 1490, 1454, 1422,
1255, 1157, 1132, 1079, 1072, 1053, 944, 934, 843, 822, 768, 757,
723, 684, 659 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.48 (s, 1 H), 7.88 (s, 1 H),
7.84–7.82 (m, 2 H), 7.54–7.51 (m, 2 H), 7.43–7.40 (m, 1 H), 4.71
(s, 2 H).
13C NMR (100 MHz, CDCl3): d = 159.26, 156.08, 151.83, 144.37,
129.00, 128.89, 127.51, 124.51, 123.47, 120.49, 115.00, 22.53.
ESI-LCMS: tR = 2.34 min; m/z [M + H]+ = 268.26.
ESI-HRMS: m/z [M + H]+ calcd for C14H10N3OS: 268.0545; found:
Yield: 334.8 mg (90%); pale yellow solid; mp 158–159 °C.
IR (KBr): 3421, 3301, 2970, 2910, 1700, 1653, 1521, 1497, 1456,
1362, 1268, 1250, 1162, 1136, 952, 766, 720 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.34 (s, 1 H), 7.85 (s, 1), 7.82
(d, J = 8.0 Hz, 2 H), 7.52 (t, J = 7.5 Hz, 2 H), 7.41 (t, J = 7.5 Hz, 1
H), 7.08–7.06 (m, 1 H), 3.37–3.34 (m, 2 H), 3.19 (t, J = 7.0 Hz, 1
H), 1.37 (s, 9 H).
268.0554.
13C NMR (100 MHz, CDCl3): d = 169.44, 156.87, 155.85, 151.38,
143.60, 128.93, 128.65, 127.75, 124.43, 123.36, 119.23, 79.52,
39.89, 33.70, 28.41.
Anal. Calcd for C14H9N3OS: C, 62.90; H, 3.39; N, 15.72. Found: C,
62.79; H, 3.50; N, 15.67.
ESI-LCMS: tR = 2.83 min; m/z [M + H]+ = 372.31.
ESI-HRMS: m/z [M + H]+ calcd for C19H22N3O3S: 372.1382; found:
N-Allyl-4-(5-phenyloxazol-2-yl)thiazol-2-amine (10m)
Yield: 271.9 mg (96%); white solid; mp 148–149 °C.
372.1398.
IR (KBr): 3432, 3192, 3127, 2972, 1596, 1576, 1464, 1416, 1132,
922, 762, 684 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 7.71–7.69 (m, 2 H), 7.43–7.41
(m, 2 H), 7.40 (s, 1 H), 7.33–7.30 (m, 1 H), 7.23 (s, 1 H), 5.96–5.89
(m, 1 H), 5.79–5.75 (m, 1 H), 5.33 (dd, J = 17.5, 1.2 Hz, 1 H), 5.22
(dd, J = 10.0, 1.2 Hz, 1 H), 3.99–3.97 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 170.15, 157.39, 151.00, 139.98,
133.36, 128.95, 128.51, 128.00, 124.42, 123.37, 117.52, 108.12,
48.54.
Anal. Calcd for C19H21N3O3S: C, 61.43; H, 5.69; N, 11.31. Found:
C, 61.37; H, 5.59; N, 11.22.
tert-Butyl {2-[4-(5-Phenyloxazol-2-yl)thiazol-2-yl]ethyl}car-
bamate (10j) and 2-[2-(2-Aminoethyl)thiazol-4-yl]-5-phenyl-
oxazole (10k)
tert-Butyl (3-amino-3-thioxopropyl)carbamate (102 mg, 0.5 mmol)
was added in one portion to a stirred suspension of 8a (133 mg, 0.5
mmol) and powdered KHCO3 (50 mg, 0.5 mmol) in absolute EtOH
(2 mL). The mixture was heated to 75 °C for 3 h before it was
cooled to r.t., diluted with MeOH (10 mL), filtered through a sy-
ringe filter, distributed into two preparative HPLC vials, and sub-
jected to preparative HPLC (10% B to 100% B over 14 min). Upon
speed evaporation of the eluent, 10j and 10k were obtained.
ESI-LCMS: tR = 2.63 min; m/z [M + H]+ = 284.12.
ESI-HRMS: m/z [M + H]+ calcd for C15H14N3O32S: 284.0852;
found: 284.0847.
Anal. Calcd for C15H13N3OS: C, 63.58; H, 4.62; N, 14.83. Found:
C, 63.63; H, 4.58; N, 14.86.
10j
Yield: 46.7 mg (24%); white solid; mp 157–158 °C.
2¢,5-Diphenyl-2,5¢-bioxazole (12a); Typical Procedure
Benzamide (242 mg, 2.0 mmol) and 8a (266 mg, 1.0 mmol) were
fused at 120 °C for 2 h under N2. The residue was cooled to r.t. be-
fore it was taken up in CH2Cl2 and flash chromatographed (silica
gel, Biotage Horizon instrument, 25M column equilibrated with
300 mL of 5% B; elution: 5% B to 100% B for 1500 mL; B =
EtOAc, A = hexanes); this furnished 12a after solvent evaporation.
IR (KBr): 3301, 2975, 2909, 1701, 1520, 1497, 1455, 1445, 1363,
1268, 1250, 1162, 1137, 952, 766, 720 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.88 (s, 1 H), 7.72–7.70 (m, 2 H),
7.44–7.39 (m, 2 H), 7.43 (s, 1 H), 7.35–7.29 (m, 1 H), 5.03 (br s,
0.75 H), 3.64–3.58 (m, 2 H), 3.27 (t, J = 6.4 Hz, 2 H), 1.41 (s, 9 H).
ESI-LCMS: tR = 2.83 min; m/z [M + H]+ = 372.13.
Yield: 82.4 mg (29%); pale yellow solid; mp 168–170 °C.
Synthesis 2009, No. 9, 1445–1458 © Thieme Stuttgart · New York

PAPER
Preparation of 2-Imidazol-4-yl- and 2-Thiazol-4-yloxazoles
1457
IR (KBr): 3126, 3098, 1636, 1557, 1495, 1448, 1334, 1135, 1122,
1108, 1061, 944, 931, 917, 778, 763, 709, 694, 686 cm–1.
Brenzovich, W. E.; Giuseppone, N.; Giannakakou, P.;
O’Brate, A. J. Am. Chem. Soc. 2004, 126, 12897.
(c) Nicolaou, K. C.; Chen, D. Y.-K.; Huang, X.; Ling, T.;
Bella, M.; Snyder, S. A. J. Am. Chem. Soc. 2004, 126,
12888. (d) Liu, P.; Celatka, C. A.; Panek, J. S. Tetrahedron
Lett. 1997, 38, 5445. (e) Boto, A.; Ling, M.; Meek, G.;
Pattenden, G. Tetrahedron Lett. 1998, 39, 8167.
1H NMR (500 MHz, DMSO-d6): d = 9.04 (s, 1 H), 8.11–8.09 (m, 2
H), 7.89 (s, 1 H), 7.84 (d, J = 7.4 Hz, 2 H), 7.63–7.61 (m, 3 H), 7.54
(t, J = 8.0 Hz, 2 H), 7.43 (t, J = 7.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 162.80, 154.77, 151.52, 138.04,
131.90, 131.06, 128.94, 128.86, 128.69, 127.67, 126.92, 126.67,
124.46, 123.28.
ESI-LCMS: tR = 3.06 min; m/z [M + H]+ = 289.26.
ESI-HRMS: m/z [M + H]+ calcd for C18H13N2O2: 289.0972; found:
(2) No analogues of 2-(1H-imidazol-4-yl)oxazole were found
with a CrossFire database search and only a limited number
of 2-(thiazol-4-yl)oxazole analogs were found. See: Gorb,
L. T.; Romanov, N. N.; Tolmachev, A. I. Chem. Heterocycl.
Compd. 1979, 15, 1081; and references cited therein.
(3) (a) LaMattina, J. L.; Mularski, C. J. Tetrahedron Lett. 1983,
24, 2059. (b) LaMattina, J. L.; Mularski, C. J.; Muse, D. E.
Tetrahedron 1988, 44, 3073. (c) LaMattina, J. L.; Mularski,
C. J. J. Org. Chem. 1984, 49, 4800. (d) LaMattina, J. L.;
Weeks, P. D. US Patent 4443621, 1984; Chem. Abstr. 1984,
101, 22994. (e) LaMattina, J. L.; Mularski, C. J. J. Org.
Chem. 1986, 51, 413. (f) LaMattina, J. L.; Muse, D. E.
J. Org. Chem. 1987, 52, 3479.
(4) For examples of other masked a-bromo ketones, such as 2-
bromo-1-(thiazol-2-yl)ethanone, see: (a) Menasse, R.; Prijs,
B.; Erlenmeyer, H. Helv. Chim. Acta 1957, 40, 554. For 2-
bromo-1-(furan-2-yl)ethanone, for example, see: (b) Devi,
S. K. C.; Rajasekharan, K. N. Synth. Commun. 2002, 32,
1523. For 2-bromo-1-(2-methyl-1H-imidazol-4-yl)ethan-
one, for example, see: (c) Lipinski, C. A.; LaMattina, J. L.;
Oates, P. J. J. Med. Chem. 1986, 29, 2154.
(5) Compound 4 was prepared exactly as described in ref. 3a,
except, in our hands, the product contained approximately
25% of ethyl ester, which could not be purified by
recrystallization from cyclohexane without significant loss
of product. Adding an additional 25–30% of 4 to the reaction
mixture did compensate adequately for our stock source of 4.
(6) (a) Li, B.; Chiu, C. K.-F.; Hank, R. F.; Murry, J.; Roth, J.;
Tobiassen, H. Org. Synth. 2004, 81, 105. (b) Weinstein,
D. S.; Liu, W.; Ngu, K.; Langevine, C.; Combs, D. W.;
Zhunang, S.; Chen, C.; Madsen, C. S.; Harper, T. W.; Robl,
J. A. Bioorg. Med. Chem. Lett. 2007, 17, 5115.
289.0970.
Anal. Calcd for C18H12N2O2: C, 74.98; H, 4.19; N, 9.71; Found: C,
74.83; H, 4.59; N, 9.51.
2¢-Butyl-5-phenyl-2,5¢-bioxazole (12b)
Yield: 70.3 mg (26%); HPLC (5% B to 100% B over 30 min); pale
yellow solid; mp 66–68 °C.
IR (KBr): 3130, 3104, 3052, 2954, 2871, 1639, 1584, 1498, 1449,
1136, 1123, 1099, 943, 915, 760, 729, 691 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.79 (s, 1 H), 7.79 (d, J = 8.3
Hz, 2 H), 7.51 (t, J = 8.0 Hz, 2 H), 7.41 (m, 1 H), 2.86 (t, J = 7.5 Hz,
2 H), 1.74 (q, J = 7.5 Hz, 2 H), 1.38 (sext, J = 7.5 Hz, 2 H), 0.93 (t,
J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.41, 154.91, 151.31, 137.80,
130.51, 128.88, 128.58, 127.70, 124.41, 123.18, 29.00, 27.84,
22.23, 13.65.
ESI-LCMS: tR = 2.97 min; m/z [M + H]+ = 269.30.
ESI-HRMS: m/z [M + H]+ calcd for C16H17N2O2: 269.1285; found:
269.1282.
Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C,
71.57; H, 5.72; N, 10.37.
2¢-Cyclohexyl-5-phenyl-2,5¢-bioxazole (12c)
Yield: 28.4 mg (19%); mp 114–116°C.
IR (KBr): 3448, 3140, 2924, 2853, 1638, 1570, 1498, 1450, 1280,
1251, 1199, 1132, 1119, 1104, 944, 917, 891, 838, 760, 730, 692
cm–1.
(7) Geilen, H.; Alonso-Alija, C.; Hendrix, M.; Niewöhner, U.;
Schauss, D. Tetrahedron Lett. 2002, 43, 419; and references
cited therein.
1H NMR (500 MHz, DMSO-d6) d 8.79 (s, 1 H), 7.83 (s, 1 H), 7.79
(d, J = 7.0 Hz, 2 H), 7.51 (t, J = 7.7 Hz, 2 H), 7.41 (t, J = 7.3 Hz, 1
H), 2.93 (tt, J = 11.0, 3.7 Hz, 1 H), 2.06–2.03 (m, 2 H), 1.77 (dt,
J = 13.2, 3.7 Hz, 2 H), 1.68 (dt, J = 12.5, 3.7 Hz, 1 H), 1.58 (qd,
J = 12.0, 3.3 Hz, 2 H), 1.41 (qt, J = 12.0, 3.3 Hz, 2 H), 1.28 (tt,
J = 12.2, 3.7 Hz, 1 H).
ESI-LCMS: tR = 3.13 min; m/z [M + H]+ = 295.31.
ESI-HRMS: m/z [M + H]+ calcd for C18H19N2O2: 295.1441; found:
(8) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447.
(9) After an initial aqueous workup, precursor amides 6 were
often pure enough to be used in further reactions, but to
obtain samples for characterization they were most often
subjected to flash column chromatography, for which either
Biotage or Thomson silica gel cartridges were used (Biotage
25M silica gel cartridges, Biotage Company; Single-Step
Thomson 80 g silica gel cartridges, Thomson Instrument
Company).
(10) Wipf, P.; Methot, J. L. Org. Lett. 2001, 3, 1261.
(11) The intrinsic instability of the ketal moiety was sometimes
noted in liquid chromatography mass spectra, which where
frequently complicated (with shoulders) by the partial or full
substitution of the ethoxy groups with water or methanol
arising from the liquid chromatography solvent system, but
in all cases the predominant signal was the parent.
(12) The 5-substituted 2-(2-bromo-1,1-diethoxyethyl)oxazoles
and their respective 2-bromo-1-oxazol-2-ylethanones were
also refrigerated at –10 °C as an added precaution.
(13) The liquid chromatography mass spectra were sometimes
complicated by the partial or full addition of methanol or
water arising from the liquid chromatography solvent
system, but, as with precursors 7, the predominant signal
was the parent.
295.1443.
Acknowledgment
The authors would like to thank Discovery Analytical Sciences for
analytical support, in particular Mr Edward Koslowski, Ms Julia
Nielson, and Dr Xiahua (Stella) Huang.
References
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Synthesis 2009, No. 9, 1445–1458 © Thieme Stuttgart · New York