Synthesis of substituted oxazoles from N-benzyl propargyl amines and acid chlorides

Article abstract of DOI:10.1002/ejoc.201300285

The reaction between N-benzylpropargylamines and acid chlorides at elevated temperatures provides efficient, direct access to a variety of di- and tri-substituted oxazoles. The versatility of this reaction is explored and 21 examples are demonstrated. The usefulness of the methodology is showcased through the short and efficient formal syntheses of medicinally relevant drugs aleglitazar and romazarit. The reaction between N-benzylpropargylamines and acid chlorides at elevated temperatures gives oxazoles in up to 99 % yield. Twenty-one examples are demonstrated varying the substitution at all positions of the heterocycle. Copyright

Full text of DOI:10.1002/ejoc.201300285

FULL PAPER
DOI: 10.1002/ejoc.201300285
Synthesis of Substituted Oxazoles from N-Benzyl Propargyl Amines and Acid
Chlorides
Henrik v. Wachenfeldt,[a] Filip Paulsen,[a] Anders Sundin,[a] and Daniel Strand*[a]
Keywords: Synthetic methods / Cyclization / Heterocycles / Microwave chemistry
The reaction between N-benzylpropargylamines and acid
chlorides at elevated temperatures provides efficient, direct
access to a variety of di- and tri-substituted oxazoles. The
versatility of this reaction is explored and 21 examples are
demonstrated. The usefulness of the methodology is show-
cased through the short and efficient formal syntheses of me-
dicinally relevant drugs aleglitazar and romazarit.
reaction is a one-pot procedure with sequential addition of
ruthenium and gold.[9]
Introduction
Synthetic methods for the preparation of oxazoles con-
tinues to attract interest owing to the increasing importance
of such structures as subunits in functional molecules with
applications ranging from materials,[1] to detectors,[2] pept-
ide mimetics,[3] amino-alcohol precursors,[4] and drugs.[5]
Classical methods for oxazole synthesis include dehydration
of N-2-keto amides, often under forcing conditions.[6] More
recently, Lewis[7] or Brønsted[8] catalysis has been used to
form propargyl amides from acylamides and propargyl
alcohols/acetates with concomitant cycloisomerization to
give oxazole products (Scheme 1). A mild version of this
Catalytic cycloisomerization of propargyl amides has re-
ceived significant attention, and the topic has recently been
reviewed.[10] Examples of such processes include the gold-
catalyzed cycloisomerization of propargyl amides with both
terminal and internal alkynes.[11] The latter are interesting
because such cycloisomerization reactions have previously
been limited to terminal alkynes.[12] Additional protocols
for cycloisomerization of propargyl amides to oxazoles in-
clude the use of mercury,[13] palladium,[14] hypervalent
iodine,[15] cerium,[16] silica gel,[17] and bases.[18]
We recently disclosed a gold-catalyzed, three-component
reaction for the formation of oxazoles by merging imine-
alkyne couplings with a cycloisomerization manifold.[19]
The overall process is enabled by the loss of a sacrificial
benzyl group on the imine nitrogen in the form of benzyl
chloride (Scheme 2). As part of a mechanistic investigation
into this reaction, an N-benzylpropargylamine was treated
with an acid chloride, resulting in the clean formation of
the corresponding oxazole product. The operational conve-
nience, ease of access to starting materials (N-Bn-proparg-
ylamines and acid chlorides), and efficiency of the reaction
suggested that it might be an attractive procedure in its own
Scheme 1. Previous work.
[a] Centre for Analysis and Synthesis, Department of Chemistry,
Lund University,
P. O. Box 124, 22100 Lund, Sweden
Fax: +46-46-222-8209
E-mail: daniel.strand@chem.lu.se
Homepage: http://www.chem.lu.se/People/daniel%20strand/
strandgroup/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300285.
Scheme 2. The present study.
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Synthesis of Substituted Oxazoles
right. Herein, we report the optimization and substrate Table 1. Optimization of oxazole formation in the reaction between
1a–c and BzCl.[a]
scope of this reaction as well as a mechanistic investigation
of the cyclization step. The reaction produces di- and tri-
substituted oxazole products in up to 99% yield, is general
with respect to functional group tolerance (aryl, alkyl, het-
erocyclic and silyl), proceeds to completion within minutes,
and does not require solvent, catalyst, or additives. The use-
fulness of the methodology in an applied context is demon-
strated by short and, in principle, modular, formal synthe-
Entry Propargyl-
amine (R)
BzCl
[equiv.]
Solvent Temp. Time
[°C]
Yield
[%][b]
ses of the drugs romazarit and aleglitazar.
An attractive feature is also that the N-benzylproparg-
ylamine starting materials are conveniently accessed, typi-
cally in a single step, using catalytic protocols such as irid-
ium-catalyzed addition of alkynes to imines,[21] or three-
component coupling of aldehydes, alkynes and benzylamine
(A3-coupling).[22] Alternative methods include stoichiomet-
ric acetylide addition to imines.[20]
1[c]
2[c]
3[c]
4[c]
5[c]
6
1a (Bn)
1a (Bn)
1a (Bn)
1a (Bn)
1a (Bn)
1a (Bn)
1.3
1.3
1.3
1.3
1.3
1.3
toluene 90
toluene 150
dioxane 110
MeCN 110
16 h
16 h
16 h
16 h
16 h
16 h
15
60
63
53
15
50
DMF
–
110
110
7[d]
1a (Bn)
1.4
–
150
15 min
62
8[d]
1b (H)
1c (Me)
1.4
1.4
–
–
150
150
15 min
15 min 23
4
9[d]
Results and Discussion
[a] Reaction run on 1.0 mmol scale (amine). [b] Measured by NMR
spectroscopic analysis with methyl transcinnamate as internal stan-
dard. [c] Concentration 1.0 m (amine). [d] Microwave heating.
The reaction was optimized by using propargylamines
1a–c as substrates. Oxazole formation was found to proceed
efficiently in polar as well as nonpolar solvents (Table 1,
entries 1–5). More importantly, the yields were also retained yield of oxazole 2 (Table 1, entry 8). As one equivalent of
under solvent-free conditions. At 150 °C, using microwave HCl is released in this process, 50% conversion should, in
irradiation, the reaction time could be reduced to 15 min.
Addition of additives such as Bu4NCl, NaI, NaBr, or
principle, be possible.
Mechanistically, an HCl salt of 3 is presumed to be the
HCl (1.0 m in dioxane) did not have a significant impact on proton source that activates the alkyne for nucleophilic at-
the yield of the reaction. Use of pyridine as the solvent tack by the carbonyl (Scheme 3). When modeling the pro-
inhibited oxazole formation completely. Exchange of the Bn posed reaction pathway at the B3LYP/6-31G+* level, the
sacrificial group for an electron-rich pMeOBn substituent inductive effect of the benzyl substituent on 4a was found
(1b) gave a lower yield of oxazole 2 (47%). Because an ex- to stabilize the transition state of the carbonyl addition to
cess of pMeOBnCl (78%) compared to 2 was observed after the alkyne by 2.5 kcal compared with the corresponding TS
the complete consumption of starting materials, and pro- of the secondary propargyl amide 4b.[24] It is also note-
longed heating of the reaction mixture did not cause ob- worthy that the N-Bn substituent stabilizes the positive
servable decomposition of the product, the reduced yield in charge on 5a, thus lowering the relative energy of this inter-
this case is attributed to debenzylation side-reactions occur- mediate by 6.4 kcal compared with 5b. Moreover, the calcu-
ring prior the cyclization step. Use of a methyl substituent lations indicate that, in contrast to the cyclization of 4a, the
as the leaving group[23] (1c) also gave oxazole 2, albeit in cyclization of 4b is actually a slightly endothermic process
lower yield (23%). It is noteworthy that 3-phenylproparg- (2.5 kcal). These results are in line with earlier observations
ylamine (1b) under the optimized conditions only gave 4% by Ohno that the reaction time for an N-Bn carbamate to
Scheme 3. Proposed mechanism for oxazole formation.
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H. v. Wachenfeldt, F. Paulsen, A. Sundin, D. Strand
FULL PAPER
Table 2. Oxazole formation with varying substituents on the distal alkyne position.
[a] Reaction conditions: amine (1 mmol), BzCl (1.4 equiv.), microwave heating (150 °C, 15 min).
cyclize in an iodocarbamation reaction is an order of mag- Table 3. Oxazole formation with acyl chlorides.
nitude shorter than that of the corresponding N-H sub-
strate.[25] We cannot exclude the possibility that preorgani-
zation as a result of steric effects also plays a part in the
cyclization, but it is clear that the N-Bn group serves not
only as a chloride trap, but also facilitates cyclization under
the mildly acidic conditions.
Using the optimized protocol, the substrate scope of the
reaction was explored. A series of functionalities including
alkyl, aryl, ester, ketone, and silyl groups were found to be
well-tolerated at the distal alkyne position (Table 2). In par-
ticular, oxazole 8 formed in essentially quantitative yield
from the corresponding ester. The reaction could be run on
more than a gram scale with a slightly improved efficiency
(Table 2, entry 3). For cases in which lower yields were ob-
tained, particularly for substrates containing an electron-
donating group (Table 2, entry 7), the starting alkyne was
consumed and the remaining mass was comprised of a com-
plex mixture.
Aryl-, heterocyclic-, and aliphatic acyl chlorides were
well-tolerated in the reaction (Table 3). However, electron-
deficient pNO2BzCl failed to form the corresponding ox-
azole.
[a] Reaction conditions: amine (1 mmol), acyl chloride (1.4 equiv.),
microwave heating (150 °C, 15 min).
Oxazoles with aliphatic as well as aromatic substituents
at the C4-position were readily formed from the corre-
The acylation–cycloisomerization protocol was applied
sponding starting materials (Table 4). Under the standard to short formal syntheses of the medicinally relevant struc-
conditions, unisomerized 2-oxazoline 21 was formed in tures romazarit[26] (30) and aleglitazar[27] (34).
good yield from the corresponding alkyne. This compound
The synthesis of romazarit (30) commenced with the as-
could, however, be isomerized to oxazole 22 in the presence sembly of N-Bn-propargylamine 27 by using an A3-cou-
of acid. Using a gem-dimethyl-substituted propargylamine, pling (Scheme 4). From propargylamine 27, oxazole 28 was
the corresponding nonaromatic 5-benzylidene-2-oxazoline formed in good yield by reaction with pClPhCOCl under
26 was isolated as a single geometric isomer, albeit in mod- standard conditions. Conversion of the silyl group of 28
erate yield (Table 4, entry 6).
into the desired primary alcohol 29 was accomplished un-
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Synthesis of Substituted Oxazoles
Table 4. Cyclization with varying substituents at the proximal prop- lowed by Ir-catalyzed addition of TMS-acetylene to the en-
olizable imine proceeded smoothly[21] and quenching the re-
argylic position.
action by addition of a mixture of carbonate and methanol
removed the TMS group to give 31 in 52% isolated yield.
Oxazole 32 was then formed by the reaction of N-Bn-pro-
pargylamine 31 with benzoyl chloride using the standard
protocol. The completion of building block 33 was ac-
complished by hydrogenolysis of the benzyl group of 32
using Pearlmans catalyst.[29]
[a] Reaction conditions: amine (1 mmol), acyl chloride (1.4 equiv.),
microwave heating (150 °C, 15 min). [b] Formed from 21 with a
catalytic amount of pTSA.
der modified Tamao–Fleming conditions.[28] Alcohol 29 can
then be converted into the final structure 30 in a single step
by using known methodology.[26]
Scheme 5. Formal synthesis of aleglitazar (34).
Conclusions
The reaction between N-Bn-propargylamines and acid
chlorides at elevated temperatures was investigated and
found to be a general method that can be used to rapidly
and conveniently assemble diversely substituted oxazoles
from readily available starting materials. The cyclization
step was investigated in silico and a benzyl group on the
propargylic nitrogen was found to facilitate the cyclization
by 2.5 kcal compared with a proton, which may, at least in
part, account for the superior efficiency of such substrates
in the reaction. The usefulness of the reaction in an applied
context was demonstrated through the short formal synthe-
ses of aleglitazar (34) and romazarit (30) by routes involving
three and four isolated intermediates, respectively. The step-
economical access to starting materials, short reaction
times, and operational convenience of the cycloisomeriza-
tion step should be of particular value for library genera-
tion.
Scheme 4. Formal synthesis of romazarit (30).
Experimental Section
The synthesis of the oxazole building block of aleglitazar
(34) started with formation of N-Bn-propargylamine 31 by
using a one-pot procedure (Scheme 5). Imine formation fol- oven-dried glassware under an atmosphere of nitrogen. Microwave
General Experimental Methods: All reactions were carried out in
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H. v. Wachenfeldt, F. Paulsen, A. Sundin, D. Strand
FULL PAPER
reactions were preformed with a Biotage Initiator. Mixtures were
concentrated by using a Heidolph rotary evaporator. NMR spectra
were recorded with a Bruker Ultrashield 400 plus (1H at 400 MHz
and 13C at 101 MHz). Spectra were processed using MestReNova.
Chemical shifts are reported in ppm downfield from SiMe4 using
(s, 2 H), 3.04–2.84 (m, 1 H), 1.29 (d, J = 6.9 Hz, 6 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 160.0, 143.9, 142.7, 138.1, 129.9,
128.8, 128.7, 128.5, 128.1, 126.8, 126.3, 31.3, 25.8, 22.5 ppm. IR
(CHCl3 film): ν = 2968 (m), 1553 (m), 1450 (m), 1053 (m) cm–1.
˜
HRMS (ESI): m/z calcd. for C19H20NO [M + H]+ 278.152; found
1
the residual peak of CDCl3 as reference (δ = 7.26 for H and δ =
278.150.
1
77.2 for 13C). H NMR spectra are reported as follows: chemical
4-Isopropyl-5-methyl-2-phenyloxazole (11): Yield 80% {Ͼ95% pure
by NMR spectroscopic analysis and a single spot by TLC [Rf =
0.28 (EtOAc/petroleum ether, 1:40)]}; pale-yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 8.06–7.91 (m, 2 H), 7.48–7.33 (m, 3 H),
2.95–2.82 (m, 1 H), 2.34 (s, 3 H), 1.28 (d, J = 6.9 Hz, 6 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 159.2, 141.9, 141.7, 129.6, 128.7,
shifts (δ, ppm), multiplicity (s = singlet, br. s = broad singlet, d =
doublet, t = triplet, q = quartet, dd = doublet of doublets, dt =
doublet of triplets, m = multiplet, app. = apparent), coupling con-
stant [Hz] and integration. 13C NMR spectra are reported as chem-
ical shifts (δ, ppm). The 13C NMR spectra for 31 contain signal
overlaps in the aromatic region. For known compounds (references
given), only 1H NMR data are reported. HRMS were recorded
with a Micromass Q-TOF spectrometer (ESI). IR spectra were re-
corded with a Bruker ALPHA-P and reported as follows: wave-
numbers (cm–1), description (w = weak, m = medium, s = strong,
br = broad). Melting points were measured with an Electrothermal
9100 melting point apparatus and are uncorrected. Reactions were
followed by TLC using aluminum-backed plates (Merck 60F254 sil-
ica gel) and visualized with UV (252 nm) and/or KMnO4. Prepara-
tive chromatography was preformed using silica gel (Acros 40–
60 μm, 60 Å) columns or a flash-purification system (Biotage Iso-
lera One). All other solvents and reagents were purchased from
commercial suppliers and used as received.
128.3, 126.1, 25.9, 22.3, 10.6 ppm. IR (CHCl film): ν = 2965 (m),
˜
3
2871 (w), 1555 (m), 1449 (m) cm–1. HRMS (ESI): m/z calcd. for
C13H16NO [M + H]+ 202.123; found 202.118.
5-Heptyl-4-isopropyl-2-phenyloxazole (12): Yield 68% {Ͼ95% pure
by NMR spectroscopic analysis and a single spot by TLC [Rf =
0.76 (EtOAc/petroleum ether, 1:10)]}; pale-yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 8.01–7.97 (m, 2 H), 7.45–7.32 (m, 3 H),
2.93–2.83 (m, 1 H), 2.66 (t, J = 7.4 Hz, 2 H), 1.71–1.61 (m, 2 H),
1.39–1.22 (m, 14 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 159.3, 146.1, 141.6, 129.6, 128.7, 128.4,
126.2, 32.0, 29.3, 29.2, 28.9, 25.8, 25.0, 22.8, 22.5, 14.3 ppm. IR
(CHCl3 film): ν = 2958 (s), 2924 (s), 2857 (m), 1555 (m), 1450
˜
(s) cm–1. HRMS (ESI): m/z calcd. for C19H28NO [M + H]+ 286.217;
General Procedure for the Preparation of Oxazoles: Under an atmo-
sphere of nitrogen, acyl chloride (1.4 equiv.) was added to N-benz-
ylpropargylamine (1 equiv.) in a microwave vial. The resulting mix-
ture was heated under microwave irradiation with a ceiling tem-
perature of 150 °C for 15 min. After cooling to ambient tempera-
ture, the mixture was diluted with CH2Cl2. A small amount of silica
was added to the reaction mixture and the resulting slurry was
concentrated under reduced pressure. The concentrate was added
to a silica gel column and eluted with a mixture of ethyl acetate
and petroleum ether. The product-containing fractions were pooled
and concentrated under reduced pressure to give the corresponding
oxazoles.
found 286.213.
4-Isopropyl-5-(4-nitrobenzyl)-2-phenyloxazole (13): Yield 79%
{Ͼ95% pure by NMR spectroscopic analysis and a single spot by
TLC [Rf = 0.39 (EtOAc/petroleum ether, 1:10)]}; white solid; m.p.
1
100.0–101.6 °C. H NMR (400 MHz, CDCl3): δ = 8.29–8.09 (m, 2
H), 8.06–7.90 (m, 2 H), 7.48–7.32 (m, 5 H), 4.15 (s, 2 H), 3.00–2.87
(m, 1 H), 1.30 (d, J = 6.9 Hz, 6 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 160.5, 145.6, 143.6, 141.9, 130.2, 129.3, 128.8, 127.8,
126.3, 124.1, 100.1, 31.1, 25.9, 22.4 ppm. IR (CHCl film): ν = 2964
˜
3
(m), 2927 (w), 2871 (w), 1599 (m), 1554 (w), 1518 (s), 1486 (m),
1449 (m), 1343 (s) cm–1. HRMS (ESI): m/z calcd. for C19H19N2O3
[M + H]+ 323.140; found 323.139.
Ethyl 2-(4-Isopropyl-2-phenyloxazol-5-yl)acetate (8): Yield 99%
{Ͼ95% pure by NMR spectroscopic analysis and a single spot by
TLC [Rf = 0.37 (EtOAc/petroleum ether, 1:10)]}; white solid; m.p.
72.5–73.1 °C. 1H NMR (400 MHz, CDCl3): δ = 8.06–7.93 (m, 2
H), 7.47–7.32 (m, 3 H), 4.19 (q, J = 7.1 Hz, 2 H), 3.73 (s, 2 H),
2.95–2.85 (m, 1 H), 1.37–1.21 (m, 9 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 169.0, 160.2, 144.2, 138.1, 129.9, 128.6, 127.8, 126.2,
4-Isopropyl-5-(4-methoxybenzyl)-2-phenyloxazole (14): Yield 27%
{Ͼ95% pure by NMR spectroscopic analysis and a single spot by
TLC [Rf = 0.50 (EtOAc/petroleum ether, 1:10)]}; white solid; m.p.
96.1–97.0 °C. 1H NMR (400 MHz, CDCl3): δ = 8.03–7.93 (m, 2
H), 7.46–7.34 (m, 3 H), 7.21–7.11 (m, 2 H), 6.91–6.81 (m, 2 H),
3.99 (s, 2 H), 3.79 (s, 3 H), 2.95 (hept, J = 6.9 Hz, 1 H), 1.30 (d, J
= 6.9 Hz, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 159.9,
158.5, 144.3, 142.5, 130.2, 129.8, 129.4, 128.7, 128.2, 126.3, 114.2,
61.4, 31.3, 25.7, 22.0, 14.1 ppm. IR (CHCl3 film): ν = 2966 (m),
˜
2871 (w), 1727 (s), 1552 (m) cm–1. HRMS (ESI): m/z calcd. for
55.4, 30.34, 25.8, 22.5 ppm. IR (CHCl3 film): ν = 3011 (w), 2967
˜
C16H20NO3 [M + H]+ 274.144; found 274.140.
(m), 2831 (w), 1611 (m), 1551 (m), 1510 (s), 1485 (w), 1461
(m) cm–1. HRMS (ESI): m/z calcd. for C20H22NO2 [M + H]+
308.165; found 308.164.
5-[(tert-Butyldimethylsilyl)methyl]-4-isopropyl-2-phenyloxazole (9):
Yield 81% {Ͼ95% pure by NMR spectroscopic analysis and a sin-
gle spot by TLC [Rf = 0.21 (EtOAc/petroleum ether, 1:40)]}; pale-
2-(4-Isopropyl-2-phenyloxazol-5-yl)-1-phenylethanone (15): Yield
56% {Ͼ95% pure by NMR spectroscopic analysis and a single
spot by TLC [Rf = 0.33 (EtOAc/petroleum ether, 1:10)]}; yellow
oil. 1H NMR (400 MHz, CDCl3): δ = 8.10–8.02 (m, 2 H), 8.02–
7.92 (m, 2 H), 7.66–7.56 (m, 1 H), 7.56–7.47 (m, 2 H), 7.47–7.35
(m, 3 H), 4.37 (s, 2 H), 2.98–2.86 (m, 1 H), 1.28 (d, J = 6.9 Hz, 6
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 194.6, 160.6, 144.7,
138.5, 136.2, 133.8, 130.0, 128.9, 128.74, 128.72, 128.0, 126.4, 35.8,
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 8.02–7.90 (m, 2 H),
7.47–7.30 (m, 3 H), 2.88–2.76 (m, 1 H), 2.08 (s, 2 H), 1.27 (d, J =
6.9 Hz, 6 H), 0.93 (s, 9 H), 0.06 (s, 6 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 158.6, 144.6, 139.9, 129.3, 128.7, 128.4, 125.8, 26.5,
25.7, 22.4, 16.8, 11.0, –5.6 ppm. IR (CHCl3 film): ν = 2956 (s),
˜
2928 (s), 2858 (m), 1556 (w), 1463 (m), 1256 (s) cm–1. HRMS (ESI):
m/z calcd. for C19H30NOSi [M + H]+ 316.210; found 316.213.
26.0, 22.2 ppm. IR (CHCl film): ν = 2966 (m), 2927 (w), 2872 (w),
˜
3
5-Benzyl-4-isopropyl-2-phenyloxazole (10): Yield 84% {Ͼ95% pure
by NMR spectroscopic analysis and a single spot by TLC [Rf =
0.33 (EtOAc/petroleum ether, 1:40)]}; white solid; m.p. 70.7–
1689 (s), 1554 (w), 1449 (m), 1212 (m) cm–1. HRMS (ESI): m/z
calcd. for C20H20NO2 [M + H]+ 306.149; found 306.146.
72.6 °C. 1H NMR (400 MHz, CDCl3): δ = 8.03–7.89 (m, 2 H), 5-Benzyl-2-(tert-butyl)-4-isopropyloxazole (16): Yield 81% {Ͼ95%
7.44–7.35 (m, 3 H), 7.35–7.28 (m, 2 H), 7.27–7.20 (m, 3 H), 4.05
pure by NMR spectroscopic analysis and a single spot by TLC
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Synthesis of Substituted Oxazoles
[Rf = 0.59 (EtOAc/petroleum ether, 1:10)]}; white solid; m.p. 62.7–
5-Methyl-2,4-diphenyloxazole (22): Yield 77% {Ͼ95% pure by
63.1 °C. 1H NMR (400 MHz, CDCl3): δ = 7.33–7.26 (m, 2 H), NMR spectroscopic analysis and a single spot by TLC [Rf = 0.48
7.25–7.18 (m, 1 H), 7.18–7.12 (m, 2 H), 3.94 (s, 2 H), 2.92–2.78 (m,
(EtOAc/petroleum ether, 1:10)]}; white solid; m.p. 66.8–68.1 °C. 1H
1 H), 1.32 (s, 9 H), 1.21 (d, J = 6.9 Hz, 6 H) ppm. 13C NMR NMR (400 MHz, CDCl3): δ = 8.22–8.05 (m, 2 H), 7.87–7.73 (m, 2
(101 MHz, CDCl3): δ = 169.2, 142.4, 140.6, 138.7, 128.7, 128.3, H), 7.55–7.45 (m, 5 H), 7.37 (t, J = 7.4 Hz, 1 H), 2.64 (s, 3 H) ppm.
126.5, 33.7, 31.2, 28.9, 26.0, 22.4 ppm. IR (CHCl film): ν = 2966
13C NMR (101 MHz, CDCl3): δ = 159.5, 144.1, 136.1, 132.5, 130.1,
˜
3
(s), 2870 (w), 1567 (m), 1495 (w), 1455 (m), 1053 (m) cm–1. HRMS
128.8, 128.7, 127.8, 127.4, 126.9, 126.3, 12.1 ppm. IR (CHCl3 film):
(ESI): m/z calcd. for C17H24NO [M + H]+ 258.186; found 258.182.
ν = 3057 (m), 2938 (w), 1557 (m), 1206 (m) cm–1. HRMS (ESI):
˜
m/z calcd. for C16H14NO [M + H]+ 236.108; found 236.107.
Methyl 2-(4-Isopropyl-[2,4Ј-bioxazol]-5-yl)acetate (17): Yield 64%
{Ͼ95% pure by NMR spectroscopic analysis and a single spot by
TLC [Rf = 0.39 (EtOAc/petroleum ether, 1:1)]}; pale-yellow oil. 1H
NMR (400 MHz, CDCl3): δ = 8.21 (dd, J = 6.9, 1.0 Hz, 1 H), 7.93
(t, J = 3.6 Hz, 1 H), 3.72 (s, 2 H), 3.70 (s, 3 H), 2.93–2.80 (m, 1
4-(4-Fluorophenyl)-5-methyl-2-phenyloxazole (25): Yield 72%
{Ͼ95% pure by NMR spectroscopic analysis and a single spot by
TLC [Rf = 0.48 (EtOAc/petroleum ether, 1:10)]}; white solid; m.p.
69.2–70.3 °C. 1H NMR (400 MHz, CDCl3): δ = 8.17–8.04 (m, 2
H), 1.25 (d, J = 6.9 Hz, 6 H) ppm. 13C NMR (101 MHz, CDCl3): H), 7.80–7.66 (m, 2 H), 7.56–7.41 (m, 3 H), 7.25–7.09 (m, 2 H),
δ = 169.3, 153.6, 151.7, 144.4, 138.4, 138.3, 130.7, 52.6, 30.9, 25.8,
2.59 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 162.2 (d,
4
22.0 ppm. IR (CHCl film): ν = 2966 (m), 2874 (w), 1740 (s), 1537
1JC,F = 246.7 Hz), 159.5, 143.7 (d, JC,F = 1.1 Hz), 135.3, 130.1,
˜
3
(w) cm–1. HRMS (ESI): m/z calcd. for C12H15N2O4 [M + H]+
128.8, 128.7, 128.6 (d, 3JC,F = 8.1 Hz), 127.7, 126.2, 115.6 (d, JC,F
2
251.103; found 251.107.
= 21.6 Hz), 12.0 ppm. IR (CHCl3 film): ν = 3063 (w), 2992 (w),
˜
2926 (w), 1556 (m), 1506 (s) cm–1. HRMS (ESI): m/z calcd. for
Methyl 2-[4-Isopropyl-2-(thiophen-2-yl)oxazol-5-yl]acetate (18):
Yield 81% {Ͼ95% pure by NMR spectroscopic analysis and a sin-
gle spot by TLC [Rf = 0.19 (EtOAc/petroleum ether, 1:10)]}; white
solid; m.p. 55.8–57.5 °C. 1H NMR (400 MHz, CDCl3): δ = 7.61
(dt, J = 5.6, 2.8 Hz, 1 H), 7.37 (dd, J = 5.0, 1.2 Hz, 1 H), 7.07 (dd,
C16H13FNO [M + H]+ 254.098; found 254.100.
5-[(tert-Butyldiphenylsilyl)methyl]-2-(4-chlorophenyl)-4-methylox-
azole (28): Yield 67% {Ͼ95% pure by NMR spectroscopic analysis
and a single spot by TLC [Rf = 0.41 (EtOAc/petroleum ether,
J = 5.0, 3.7 Hz, 1 H), 3.73 (s, 3 H), 3.72 (s, 2 H), 2.94–2.79 (m, 1 1:10)]}; pale-yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.63–
H), 1.27 (d, J = 6.9 Hz, 6 H) ppm. 13C NMR (101 MHz, CDCl3): 7.56 (m, 4 H), 7.53–7.46 (m, 2 H), 7.44–7.38 (m, 2 H), 7.38–7.32
δ = 169.5, 156.6, 144.4, 137.6, 130.5, 127.9, 127.8, 127.5, 52.6, 31.1,
(m, 4 H), 7.29–7.25 (m, 2 H), 2.67 (s, 2 H), 1.92 (s, 3 H), 1.09 (s, 9
25.9, 22.1 ppm. IR (CHCl film): ν = 2967 (m), 2946 (w), 2873 (w), H) ppm. 13C NMR (101 MHz, CDCl3): δ = 157.6, 145.3, 136.1,
˜
3
1736 (s), 1574 (m) cm–1. HRMS (ESI): m/z calcd. for C12H15N2O4
135.4, 134.0, 131.3, 129.6, 128.9, 127.8, 127.0, 126.3, 27.8, 18.5,
[M + H]+ 266.085; found 266.080.
11.4, 9.8 ppm. IR (CHCl film): ν = 2960 (w), 2930 (m), 2857 (m),
˜
3
1624 (w), 1547 (w), 1483 (m), 1427 (m), 1105 (s), 1092 (s) cm–1.
HRMS (ESI): m/z calcd. for C27H29ClNOSi [M + H]+ 446.171;
found 446.170.
5-Benzyl-2-butyl-4-isopropyloxazole (19): Yield 50% {Ͼ95% pure
by NMR spectroscopic analysis and a single spot by TLC [Rf =
0.43 (EtOAc/petroleum ether, 1:10)]}; pale-yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.30 (ddd, J = 7.5, 4.5, 1.2 Hz, 2 H), 7.25–
7.19 (m, 1 H), 7.17 (dd, J = 7.8, 1.0 Hz, 2 H), 3.92 (s, 2 H), 2.93–
2.77 (m, 1 H), 2.66 (dd, J = 8.0, 8.0 Hz, 2 H), 1.74–1.62 (m, 2 H),
1.41–1.28 (m, 2 H), 1.22 (d, J = 6.9 Hz, 6 H), 0.90 (t, J = 7.4 Hz,
3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 163.4, 142.9, 140.8,
138.4, 128.7, 128.4, 126.6, 31.1, 29.6, 28.3, 25.5, 22.5, 22.4,
4-[2-(Benzyloxy)ethyl]-5-methyl-2-phenyloxazole (32): Yield 71%
{Ͼ95% pure by NMR spectroscopic analysis and a single spot by
TLC [Rf = 0.26 (EtOAc/petroleum ether, 1:10)]}; pale-yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.00–7.94 (m, 2 H), 7.46–7.37
(m, 3 H), 7.36–7.30 (m, 4 H), 7.29–7.25 (m, 1 H), 4.54 (s, 2 H),
3.77 (t, J = 7.0 Hz, 2 H), 2.82 (t, J = 6.9 Hz, 2 H), 2.34 (s, 3
13.9 ppm. IR (CHCl film): ν = 2961 (m), 2872 (w), 1572 (m), 1460 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 159.5, 144.8, 138.6,
˜
3
(m) cm–1. HRMS (ESI): m/z calcd. for C17H24NO [M + H]+ 133.4, 129.82, 128.78, 128.5, 128.0, 127.73, 127.65, 126.0, 73.2,
258.186; found 258.183.
69.4, 27.0, 10.4 ppm. IR (CHCl film): ν = 2952 (w), 2921 (m), 2864
˜
3
(m), 1553 (w), 1485 (w), 1450 (m), 1098 (s) cm–1. HRMS (ESI): m/z
5-Benzyl-4-isopropyl-2-(4-methoxyphenyl)oxazole (20): Yield 56%
{Ͼ95% pure by NMR spectroscopic analysis and a single spot by
TLC [Rf = 0.54 (EtOAc/petroleum ether, 1:10)]}; white solid; m.p.
66.0–66.7 °C. 1H NMR (400 MHz, CDCl3): δ = 8.00–7.89 (m, 2
H), 7.39–7.31 (m, 2 H), 7.31–7.22 (m, 3 H), 7.02–6.90 (m, 2 H),
calcd. for C19H20NO2 [M + H]+ 294.149; found 294.147.
General Procedure for the Preparation of Oxazolines 21 and 26: Un-
der an atmosphere of nitrogen, acyl chloride (1.4 equiv.) was added
to N-benzylpropargylamine (1 equiv.) in a microwave vial. The re-
4.06 (s, 2 H), 3.86 (s, 3 H), 3.05–2.88 (m, 1 H), 1.32 (d, J = 6.9 Hz, sulting mixture was heated under microwave irradiation with a ceil-
6 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 161.0, 160.1, 143.2,
142.5, 138.3, 128.8, 128.5, 127.9, 126.7, 121.1, 114.1, 55.5, 31.2,
ing temperature of 150 °C for 15 min. After cooling to ambient
temperature, the mixture was diluted with CH2Cl2. A small amount
25.8, 22.5 ppm. IR (CHCl film): ν = 2964 (m), 2934 (w), 2837 (w), of silica was added to the reaction mixture and the resulting slurry
˜
3
1613 (m), 1560 (w), 1500 (s), 1251 (s) cm–1. HRMS (ESI): m/z
was concentrated under reduced pressure. The concentrate was
added to a silica gel column and eluted with a mixture of ethyl
acetate and petroleum ether. The product-containing fractions were
pooled and concentrated under reduced pressure to give the corre-
sponding oxazoline.
+
calcd. for C20H22NO2 [M + H]+ 308.165; found 308.165.
5-Benzyl-4-methyl-2-phenyloxazole (21): Yield 59% {Ͼ95% pure by
NMR spectroscopic analysis and a single spot by TLC [Rf = 0.25
(EtOAc/petroleum ether, 1:10)]}; pale-yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 8.07–7.86 (m, 2 H), 7.45–7.37 (m, 3 H), (Z)-5-Benzylidene-2,4-di-tert-butyl-4,5-dihydrooxazole (21): Yield
7.35–7.29 (m, 2 H), 7.28–7.21 (m, 3 H), 4.03 (s, 2 H), 2.21 (s, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 159.9, 145.6, 137.8,
133.1, 130.0, 128.84, 128.82, 128.5, 127.9, 126.9, 126.2, 31.2,
80%; white solid; m.p. 66.9–67.9 °C; Rf = 0.63 (EtOAc/petroleum
ether, 1:10). H NMR (400 MHz, CDCl3): δ = 7.54 (d, J = 7.2 Hz,
2 H), 7.38–7.29 (m, 2 H), 7.18 (t, J = 7.4 Hz, 1 H), 5.57 (d, J =
1
11.6 ppm. IR (CHCl film): ν = 3006 (w), 2925 (w), 2834 (w), 1553 1.9 Hz, 1 H), 4.32 (d, J = 1.9 Hz, 1 H), 1.33 (s, 9 H), 0.98 (s, 9
˜
3
(m), 1493 (m), 1450 (m) cm–1. HRMS (ESI): m/z calcd. for
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.7, 154.8, 135.4,
128.6, 128.1, 126.1, 103.3, 78.6, 36.0, 33.6, 27.9, 25.8 ppm. IR
C17H16NO [M + H]+ 250.123; found 250.122.
Eur. J. Org. Chem. 2013, 4578–4585
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4583

H. v. Wachenfeldt, F. Paulsen, A. Sundin, D. Strand
FULL PAPER
(CHCl film): ν = 2972 (m), 2903 (w), 2870 (w), 1691 (s), 1667 (m), (1.5 equiv.) was added and the mixture was stirred for an additional
˜
3
1600 (w) cm–1. HRMS (ESI): m/z calcd. for C18H26NO [M + H]+
272.201; found 272.201.
48 h. Upon complete consumption of the imine, K2CO3 (0.3 equiv.)
in MeOH (0.02 m) was added. After 5 h, water (10 mL/mmol alde-
hyde) was added and the mixture was extracted with CH2Cl2 (4ϫ
20 mL/mmol aldehyde). The organic layer was washed with brine
(40 mL/mmol aldehyde), dried using a phase separator, and con-
centrated under reduced pressure. Purification by silica gel
chromatography (EtOAc/petroleum ether) gave the product, yield
52% {Ͼ95% pure by NMR spectroscopic analysis and a single
spot by TLC [Rf = 0.19 (EtOAc/petroleum ether, 1:10)]}; clear oil.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.21 (m, 10 H), 4.50 (s, 2
H), 4.04 (d, J = 12.9 Hz, 1 H), 3.80 (d, J = 12.9 Hz, 1 H), 3.77–
3.58 (m, 3 H), 2.33 (d, J = 2.1 Hz, 1 H), 2.03–1.91 (m, 2 H), 1.55
(br. s, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 140.1, 138.5,
128.54, 128.52, 127.8, 127.7, 127.1, 85.1, 73.2, 71.9, 67.4, 51.5, 47.1,
(Z)-5-Benzylidene-4,4-dimethyl-2-phenyl-4,5-dihydrooxazole (26):
Yield 48% {Ͼ95% pure by NMR spectroscopic analysis and a sin-
gle spot by TLC [Rf = 0.57 (EtOAc/petroleum ether, 1:10)]}; pale-
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 8.19–8.06 (m, 2 H),
7.70–7.65 (m, 2 H), 7.62–7.48 (m, 3 H), 7.47–7.37 (m, 2 H), 7.27–
7.22 (m, 1 H), 5.57 (s, 1 H), 1.56 (s, 6 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 160.8, 160.0, 135.2, 132.0, 128.8, 128.7,
128.4, 128.1, 127.0, 126.3, 99.5, 71.1, 29.8 ppm. IR (CHCl3 film):
ν = 2973 (m), 2929 (w), 2857 (w), 1695 (m), 1651 (s), 1454 (m),
˜
1448 (m) cm–1. HRMS (ESI): m/z calcd. for C18H18NO [M + H]+
264.139; found 264.135.
Isomerization of 21 to 5-Benzyl-2,4-di-tert-butyloxazole (22): To a
solution of 21 (1.48 g, 5.45 mmol) in toluene (25 mL) was added
p-toluenesulfonic acid monohydrate (200 mg, 1.05 mmol) and the
mixture was heated to reflux. After 24 h the mixture was cooled to
ambient temperature and NaHCO3 (0.5 g, 5.95 mmol) was added.
The mixture was filtered and concentrated under reduced pressure.
Purification by silica gel chromatography (EtOAc/petroleum ether,
1:20) gave 22, yield 1.30 g (88%); Ͼ95% pure by NMR spectro-
scopic analysis and a single spot by TLC [Rf = 0.74 (EtOAc/petro-
leum ether, 1:10)]; white solid; m.p. 47.7–48.5 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.32–7.26 (m, 2 H), 7.25–7.19 (m, 1 H),
7.16–7.09 (m, 2 H), 4.08 (s, 2 H), 1.32 (s, 9 H), 1.28 (s, 9 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 142.9, 141.8, 139.2, 129.2, 128.6,
35.9 ppm. IR (CHCl film): ν = 3292 (m), 2864 (m), 1453 (m), 1100
˜
3
(s) cm–1. HRMS (ESI): m/z calcd. for C19H22NO [M + H]+ 280.170;
found 280.169.
Preparation of [2-(4-Chlorophenyl)-4-methyloxazol-5-yl]methanol
(29): Silane 28 (44.8 mg, 0.100 mmol) was dissolved in BF3·
(AcOH)2 (1 mL, 36% BF3 basis) and heated to 100 °C. After 1 h,
the mixture was poured onto NaHCO3 (aq. satd. 10 mL), extracted
with CH2Cl2 (2ϫ 10 mL), dried using a phase separator, and con-
centrated. The crude mixture was dissolved in THF (0.5 mL) and
MeOH (0.5 mL), NaHCO3 (8.40 mg, 0.100 mmol), KF (17.4 mg,
0.300 mmol), and H2O2 (35% in H2O, 85.6 μL, 1.00 mmol) were
added sequentially. The resulting mixture was heated to reflux. Af-
ter 30 min, the reaction mixture was cooled to room temperature,
poured onto water (10 mL), extracted with CH2Cl2 (2ϫ 10 mL),
dried using a phase separator, and concentrated under reduced
pressure. Purification by silica gel chromatography (EtOAc/petro-
leum ether, 1:1) gave 29 (21.0 mg, 94%) as a white solid; m.p.
124.4–127.4 °C; Ͼ95% pure by NMR spectroscopic analysis and a
single spot by TLC [Rf = 0.44 (EtOAc/petroleum ether, 1:1)]. 1H
NMR (400 MHz, CDCl3): δ = 8.03–7.88 (m, 2 H), 7.49–7.35 (m, 2
H), 4.69 (s, 2 H), 2.24 (s, 3 H), 1.93 (br. s, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 159.9, 145.8, 136.7, 135.5, 129.3, 127.8,
128.1, 126.3, 33.5, 32.4, 31.9, 30.4, 28.8 ppm. IR (CHCl film): ν
˜
3
= 2967 (s), 2869 (w), 1573 (m), 1495 (m), 1455 (m), 1160 (s) cm–1.
HRMS (ESI): m/z calcd. for C18H26NO [M + H]+ 272.201; found
272.201.
Procedure for the Preparation of N-Benzyl-4-(tert-butyldiphenylsil-
yl)but-3-yn-2-amine (27): Under an atmosphere of nitrogen, alkyne
(1.6 equiv.), benzylamine (1.3 equiv.) and aldehyde (1 equiv.) were
added to a suspension of CuBr·SMe2 (0.2 equiv.) in toluene (1 m).
The mixture was heated under microwave irradiation for 25 min at
150 °C. After cooling to ambient temperature a small amount of
silica was added and the resulting slurry was concentrated under
reduced pressure. The concentrate was added to a silica gel column
and eluted with ethyl acetate and petroleum ether. Fractions con-
taining the product were pooled and concentrated under reduced
pressure, yield 25% {Ͼ95% pure by NMR spectroscopic analysis
and a single spot by TLC [Rf = 0.28 (EtOAc/petroleum ether,
1:10)]}; pale-yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.96–
7.77 (m, 4 H), 7.54–7.25 (m, 11 H), 4.16 (d, J = 12.6 Hz, 1 H), 3.95
(d, J = 12.6 Hz, 1 H), 3.69 (q, J = 6.9 Hz, 1 H), 1.51 (d, J = 6.9 Hz,
3 H), 1.40 (br. s, 1 H), 1.14 (s, 9 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 140.0, 135.8, 133.7, 129.7, 128.69, 128.65, 127.9, 127.3,
126.0, 54.5, 11.6 ppm. IR (CHCl film): ν = 3215 (s, br), 1547 (w),
˜
3
1483 (m), 1408 (m), 1092 (s) cm–1. HRMS (ESI): m/z calcd. for
C11H11ClNO2 [M + H]+ 224.048; found 224.046.
Preparation of 2-(5-Methyl-2-phenyloxazol-4-yl)ethanol (33):[30] To
a stirred solution of benzyl ether 32 (13.5 mg, 0.0460 mmol) in
EtOH (3 mL) under a nitrogen atmosphere was added Pd(OH)2 (1
spatula tip, 30% w/w on C). The atmosphere was changed to H2
(purged three times using H2 from a balloon). The reaction mixture
was stirred for 30 min, after which TLC showed complete con-
sumption of starting material, and the H2 atmosphere was changed
back to N2 (purged three times). The reaction mixture was filtered
through a short plug of Celite (washed with EtOAc), and concen-
trated under reduced pressure. The crude mixture was purified by
silica gel chromatography (EtOAc/petroleum ether, 25–33%) and
the product-containing fractions were pooled and concentrated un-
der reduced pressure to leave the primary alcohol 33 (8.9 mg, 95%)
as a pale-yellow solid; m.p. 66.0–67.7 °C; Ͼ95% pure by NMR
spectroscopic analysis and a single spot by TLC [Rf = 0.32 (EtOAc/
petroleum ether, 1:1)]. 1H NMR (400 MHz, CDCl3): δ = 8.03–7.92
(m, 2 H), 7.50–7.36 (m, 3 H), 3.93 (dt, J = 5.8, 5.8 Hz, 2 H), 3.27
(t, J = 6.1 Hz, 1 H), 2.72 (t, J = 5.5 Hz, 2 H), 2.34 (s, 3 H) ppm.
113.3, 82.4, 51.8, 45.6, 27.2, 22.6, 18.6 ppm. IR (CHCl film): ν =
˜
3
2956 (w), 2928 (m), 2856 (m), 2156 (m), 1428 (m), 1108 (s) cm–1.
HRMS (ESI): m/z calcd. for C27H32NSi [M + H]+ 398.230; found
398.232.
Preparation of N-Benzyl-5-(benzyloxy)pent-1-yn-3-amine (31): To a
suspension of benzylamine (1 equiv.) and molecular sieves (0.5 g/
mmol, 4 Å, pellets) in THF (0.33 m) was added 3-benzyloxy-prop-
ionaldehyde (1 equiv.) in THF (1 m). After 2.5 h stirring at room
temperature, the molecular sieves were separated by filtration and
the filtrate was added to a vial containing [Ir(COD)Cl]2 (5 mol-%).
Ethynyltrimethylsilane (1.5 equiv.) was added in one portion, and
the resulting light-yellow mixture was stirred at room temperature.
After 22 h, conversion was measured by NMR spectroscopy. When
unreacted imine remained, additional ethynyltrimethylsilane
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and spectroscopic data for N-benzyl-
propargylamines. 1H and 13C NMR spectra for all new compounds.
Full details of the computational work.
4584
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4578–4585

Synthesis of Substituted Oxazoles
M. C. B. Jaimes, A. M. Schuster, F. Rominger, J. Org. Chem.
2012, 77, 6394–6408.
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