A domino copper-catalyzed C-N and C-O cross-coupling for the conversion of primary amides into oxazoles

Article abstract of DOI:10.1055/s-2007-983782

A variety of oxazoles can efficiently be prepared, in a single step and in good yield, from primary amides and 1,2-dihaloalkenes using copper-catalysis. This new method allows the regioselective formation of a range of substituted oxazoles. The required 1,2-dihaloalkenes can prepared by simple treatment of alkynes with elemental bromine or iodine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983782

PAPER
2297
A Domino Copper-Catalyzed C–N and C–O Cross-Coupling for the
Conversion of Primary Amides into Oxazoles
Conversionof
P
rim
e
ary
A
mide
r
s
intoO
s
xazoles tin Schuh (née Müller), Frank Glorius*
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35032 Marburg, Germany
Fax +49(6421)2825629; E-mail: glorius@chemie.uni-marburg.de
Received 9 March 2007
Dedicated to Professor Paul A. Wender on the occasion of this 60th birthday
R2
R1
R2
R1
X
X
R2
R1
X
Abstract: A variety of oxazoles can efficiently be prepared, in a
single step and in good yield, from primary amides and 1,2-diha-
loalkenes using copper-catalysis. This new method allows the re-
gioselective formation of a range of substituted oxazoles. The
required 1,2-dihaloalkenes can prepared by simple treatment of
alkynes with elemental bromine or iodine.
O
N
O
O
R3
+
H2N
R3
N
H
R3
1
2
3
4
Scheme 1 Oxazole synthesis by successive C–N/C–O bond forma-
tions
Key words: oxazoles, C–N and C–O cross-coupling, copper, cy-
clization, domino reaction, heterocycles
The cyclization of halogen-substituted enamides has been
previously employed in the synthesis of oxazoles. Howev-
er, only activated substrates, namely those with the double
bond being part of a,b-unsaturated carbonyl compounds,
in which the addition of the amide carbonyl group can oc-
cur in a 1,4-fashion were suitable (Scheme 2).5 We envis-
aged a related transformation of non-activated substrates
by means of copper-catalyzed cross-coupling reactions.
The oxazole ring is an important structural motif present
in a vast number of natural and unnatural compounds.1,2
Many different methods for the synthesis of this moiety
have been developed, amongst which, cyclocondensation
methods such as the Robinson–Gabriel cyclocondensa-
tion of a-acylamino ketones are the most popular. Howev-
er, in many cases, rather harsh conditions for dehydration
are required and, therefore, there is a constant need for ad-
ditional methods for the synthesis of more sensitive ox-
azoles. Herein, we report an efficient copper-catalyzed
formation of oxazoles from 1,2-dihaloalkenes and prima-
ry amides, based on cross-coupling reactions.
Me
Br
Me
O
N
Et3N
O
Me
O
O
benzene, 80 °C
N
H
Me
OEt
OEt
Scheme 2 Uncatalyzed cyclization of activated enamides leading to
the formation of oxazoles
We aimed for a novel, one-pot synthesis of oxazoles 1.
Based on our experience with cross-coupling reactions,
we planned to build up the oxazole ring with two succes-
sive C–N/C–O bond formations from an alkene compo-
nent 3 and a primary carboxylic acid amide 4 (Scheme 1);
ideally both steps being catalyzed by the same transition-
metal catalyst. A related strategy has been successfully
used by us3a and others3b in the synthesis of benzoxazoles
from ortho-dihalobenzenes, thus complementing the tra-
ditional synthetic approaches to benzoxazoles. The cop-
per-catalyzed amidation of aryl halides, developed by
Buchwald et al., represents a powerful transformation and
has found widespread applications.4 Furthermore, the use
of alkenyl halides as substrate was also reported.4c,d Con-
sequently, our retrosynthetic analysis comprised of the
copper-catalyzed formation and cyclization an halide-
substituted enamide 2 (Scheme 1) and, ideally, two suc-
cessive C–N/C–O bond formations incorporated in a
domino process.
1,2-Dihalogenated olefins 3 are the key synthetic interme-
diates of this new oxazole synthesis. Fortunately, these
olefins can easily be prepared by the reaction of terminal
or internal alkynes with bromine or iodine in dichlo-
romethane at ambient temperature, resulting in 1,2-diha-
logenated olefins in good yields (Table 1).6 The
stereochemistry of the products obtained were determined
by comparison of the NMR data with literature values. In
many cases, the E-product was formed predominantly,
with the two iodinated olefins 3b and 3d being exclusive-
ly E-configured. In contrast, silylated olefin 3e was ob-
tained nearly exclusively as the Z-isomer (entry 6).
As a starting point for our investigation, 1,2-dibromophe-
nylethylene (3a) was reacted with benzamide under
copper catalysis. Copper(I) iodide, N,N¢-dimethylethyl-
enediamine (DMEDA), potassium carbonate, toluene and
heating (110 °C), conditions previously employed in the
synthesis of benzoxazoles by us,3a were found to be opti-
mal.7 It is important to note that it was beneficial to degas
the solvent in order to avoid butadiyne products resulting
from oxidative coupling. The highest yields were obtained
SYNTHESIS 2007, No. 15, pp 2297–2306
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x.
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x
.
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Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-983782; Art ID: C01507SS
© Georg Thieme Verlag Stuttgart · New York

2298
K. Schuh (née Müller), F. Glorius
PAPER
Table 1 Synthesis of 1,2-Dihalogenated Olefins
X
R2
X
CH2Cl2, r.t.
R1
R2
X2
+
R1
3
Entry
R1
Ph
Ph
R2
X
Olefin
3a
E/Za
63:37
Yield (%)b
1
2
3
4
5
6
7
8
H
Br
I
88
65
84
91
69
76
87
72
H
3b
100:0
77:23
100:0
1:99
n-Hex
n-Hex
Ph
H
Br
I
3c
H
3d
SiMe3
Ph
Br
Br
Br
Br
3e
Ph
3f
17:83
61:39
44:56
CO2Me
CH2OH
CO2Me
H
3g
3h
a Determinded by GC-MS.
b Isolated yield.
when 10 mol% of the copper catalyst were employed. Un- Table 2 Reaction of Primary Amides with 1,2-Dibromophenyl-
ethylene (3a)
der these conditions, an 11:1 ratio of regioisomeric 2,5-
and 2,4-diphenyloxazole was obtained in 70% yield
(Table 2, entry 1). Using the diiodo- instead of the dibro-
mo-substituted phenylethylene resulted in an equimolar
mixture of the two regioisomeric products (entry 2).
10 mol% CuI
20 mol% DMEDA
3 equiv K2CO3
Br
Ph
Ph
Br
O
O
N
O
N
+
R
R
+
H2N
R
toluene, 110 °C
13–62 h
Ph
A variety of different primary amides was reacted with
1,2-dibromophenylethylene (3a) under the same condi-
tions (Table 2). With substituted aromatic amides, compa-
rably good results were obtained (entries 3–5). Aliphatic
amides reacted as well, although with somewhat lower
yields (entries 6–12). In these cases, part of the reduced
yield was due to the formation of diamidation side-prod-
ucts.
3a
4
1
Entry
1
R
Product ratioa,b Oxazole
Yield (%)a,c
Ph
Ph
11:1
(1:1)
1a
1a
1b
1c
1d
1e
1f
70
2
(55)
72
3
4-MeOC6H4 6:1d
4
CH=CHPh
4-BrC6H4
H
6:1d
5:1d
10:1
10:1
(1:1)
8:1
71
Again, using 1,2-diiodophenylethylene (3b) instead of the
dibromo derivative 3a (entry 7) led to a change in the ratio
of regioisomeric products (entry 8). In the latter case, the
temperature was gradually increased from 40 °C to
110 °C. Investigation by means of GC-MS revealed that
the enamide corresponding to the 2,4-disubstituted ox-
azole was formed at 40 °C already, whereas the enamide
of the 2,5-disubstituted oxazole needed increased temper-
atures and formed at 80 °C. In addition, the former en-
5
54
6e
7e
8f
9e
32
Me
48
Me
1f
(34)
47
n-Pr
1g
1h
1i
amide cyclized at a temperature of 80 °C, whereas the 10
latter enamide cyclization required heating at 110 °C.
This observation of enamide intermediates by GC-MS en
t-Bu
6:1d
10:1
(1:4)
65
11e
CH=CH2
CH=CH2
28
route to the cyclization products was not observed in the
case of benzoxazoles.5a Discontinuation of this reaction
after 21 hours (instead of 45 h for complete conversion),
allowed the isolation of 22% of the enamide intermediate
product. This intermediate cyclized smoothly under stan-
dard conditions resulting in the desired product in 93%
yield (Scheme 3). Interestingly, the reaction of acryl-
amide with 1,2-diiodo-1,2-diphenylethylene resulted in
12
1i
(17)
a The results obtained with 1,2-diiodophenylethene (3b) are shown in
brackets.
b Ratio of 2,5- to 2,4-oxazole determined by GC-MS.
c Isolated combined yield.
d Ratio of isolated isomers.
e CuI (20 mol%) and DMEDA (40 mol%) were used.
f Temperature was gradually increased from 40 °C to 110 °C.
Synthesis 2007, No. 15, 2297–2306 © Thieme Stuttgart · New York

PAPER
Conversion of Primary Amides into Oxazoles
2299
20 mol% CuI
40 mol% DMEDA
3 equiv K2CO3
S
S
O
I
Ph
Ph
O
N
H2N
O
H2N
H2N
Ph
H2N
NH2
O
Me
toluene, 110 °C, 20 h
N
H
Me
O
O
S
93%
OH
Cl
H2N
NH2
2a
1f
H2N
O
O
Scheme 3 Cyclization of an intermediate enamide
O
O
O
the predominant formation of the 2,4-disubstituted ox-
azole (entry 12).
HN
H2N
NH2
H2N
O
Figure 1 Amides and amide substitutes that did not lead to the de-
sired products
Using dibromoalkenes as starting materials, a strong pref-
erence for the formation of the 2,5-disubstituted oxazoles
was observed, whereas with diiodoalkenes greatly dimin-
ished selectivities were obtained. In the former case, the
amide attacks the less sterically hindered position of the
alkene. The more reactive diiodo-substituted olefins,
however, react rather unselectively at both of the two al-
kene positions.
A number of amides and amide derivatives, as well as 1,2-
dihalogenated olefins did not provide oxazoles under
these conditions (Figure 1); however, 1,2-dibrominated
tetrasubstituted alkenes did undergo this transformation
(Table 4). Since methods for the regioselective formation
of 2,4,5-trisubstituted oxazoles are especially desirable, it
was pleasing to find that 1,2-dibromo-1-trimethylsilyl-2-
phenylethylene (3e) reacted highly regioselectively to
give one oxazole only (entry 1); the other regioisomer
could not be detected. Acid mediated cleavage of the tri-
methylsilyl group of this oxazole product (p-TsOH,
MeOH, r.t.) allowed for the selective formation of 2,4-
diphenyl oxazole in 91% yield. This route is complemen-
tary to the results reported in Table 2 and Table 3, since it
provides ready access to the isomer previously formed as
the minor isomer. 1,2-Dibromo-1,2-diphenylethylene can
also react with benzamide to form the desired oxazole
product, albeit with reduced yield (entry 2). Presumably,
this is due to a reversal of the formation of the olefin sub-
strate back to tolane and bromine. Hydroxy-substituted
olefin 3h did not provide any product.
Intriguingly, E-, Z- or mixtures of E- and Z-configured di-
halogenated olefins all reacted to form the desired oxazole
products. In some cases, an isomerization of E- and Z-
configured substrates was observed under the reaction
conditions. However, no indication of isomerization of
the E-configured diiodinated olefins was observed.8 Thus,
an isomerization prior to enamide formation does not
seem to be a prerequisite for oxazole formation.
Dibromooctene (3c) has a much lower propensity to un-
dergo oxidative homo-coupling. In addition, it is less re-
active than the 1,2-dibromophenylethylene (3a) and
therefore higher reaction temperatures (130 °C) were re-
quired for the enamide to cyclize (Table 3). Again, the
formation of 2,5-disubstituted oxazoles was favored (en-
try 1). Use of the diiodo-substituted substrate still resulted
in the predominant formation of the 2,5-disubstituted ox-
azole (entry 2).
In summary, we have developed a new copper-catalyzed
method for the regioselective, single-step preparation of
2,5-disubstituted oxazoles from readily available 1,2-di-
halogenated olefins and primary amides. Many functional
groups such as halides, amino-, methoxy- and silyl groups
Table 3 Reaction of Primary Amides with Dibromooctene (3c)
10 mol% CuI,
20 mol% DMEDA,
n-Hex
Br
3 equiv K2CO3
n-Hex
Br
O
N
O
N
O
Table 4 Reaction of Benzamide with 1,2-Dibrominated Tetrasubsti-
tuted Alkenes
R
+
+
R
toluene,
130 °C
H2N
R
n-Hex
10 mol% CuI
13–47 h
R2
R1
20 mol% DMEDA
3 equiv K2CO3
R2
Br
3c
4
1
O
O
N
+
Ph
toluene, 110 °C
13–48 h
H2N
Ph
Product ratioa,b Oxazole
Yield (%)a,c
Br
R1
Entry
R
3
4
1
1
2
3
4
Ph
Ph
8:1
1j
1j
1k
1l
68
Entry
R1
R2
Oxazole
Yield (%)a
(3:1)
14:1
9:1
(42)
50
1
Ph
Ph
SiMe3
Ph
1m
1n
1o
56
24
12
4-H2NC6H4
2
t-Bu
30
3b
CO2Me
CO2Me
a Results obtained with 1,2-diiodo-n-hexylethene (3d) are shown in
brackets.
a Isolated yield.
b K3PO4 (3 equiv) was used as base.
b 2,5- to 2,4-Oxazole ratio determined by GC-MS.
c Isolated combined yield.
Synthesis 2007, No. 15, 2297–2306 © Thieme Stuttgart · New York

2300
K. Schuh (née Müller), F. Glorius
PAPER
13C NMR (75 MHz, CDCl3): d = 161.1 (OC=N), 151.2 (OC=C),
130.2 (HCAr), 128.8 (2 × HCAr), 128.7 (2 × HCAr), 128.3 (HCAr),
128.0 (Cq), 127.4 (Cq), 126.2 (2 × HCAr), 124.1 (2 × HCAr), 123.4
(HCAr).
MS (EI): m/z (%) = 221 (100) [M]+, 193 (11), 165 (52), 116 (21), 89
(58), 77 (87), 63 (55), 39 (44), 28 (10).
were tolerated. In addition, use of a silylated olefin al-
lowed the selective preparation of 2,4-disubstituted ox-
azoles after acid mediated protodesilylation. The required
dihalogenated olefins were easily prepared in high yields
from the corresponding alkynes by treatment with bro-
mine or iodine.
HRMS (EI): m/z calcd for C15H11NO: 221.0841; found: 221.0835.
Chemicals were purchased in commercially available qualities
(puriss., p.a. or purum) from Fluka, Aldrich, Acros, Lancaster and
Merck and were used without further purification. Solvents toluene
and CH2Cl2 were of technical quality and were distilled and dried
over CaH2. Solvents for extractions and column chromatography
were of technical quality and were distilled prior to use. Molecular
sieves (4 Å) were activated by microwave irradiation (3 × 3 min).
For flash chromatography, Merck silica gel 60 (230–400 mesh) was
used. NMR spectra were recorded on an ARX 300 or DRX 400
spectrometer (Bruker) in CDCl3; chemical shifts (d) are given in
ppm relative to TMS, and coupling constants (J) are given in Hertz.
For IR, a Bruker IFS 88 was used, with wavenumbers given in
cm–1. For MS (EI, 70 eV), a Varian CH7 was used and for HRMS,
a Finnigan LTQ FT or TSQ 700 was used.
2,4-Diphenyloxazole
Yield: 80 mg (36%); pale-yellow solid; Rf = 0.34 (pentane–EtOAc,
15:1).
IR (KBr): 2962 (w), 1670 (w), 1607 (w), 1586 (w), 1553 (s), 1488
(s), 1446 (s), 1339 (m), 1290 (w), 1262 (m), 1157 (w), 1123 (m),
1069 (s), 1022 (m), 929 (m), 782 (m), 755 (s), 718 (s), 705 (w), 691
(m) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.15–8.11 (m, 2 H, HCAr,2-Ph), 7.98
(s, 1 H, HCO), 7.85–7.82 (m, 2 H, HCAr,4-Ph), 7.51–7.41 (m, 5 H,
HCAr), 7.34 (tt, J = 7.5, 1.2 Hz, 1 H, HCAr,4-Ph).
13C NMR (75 MHz, CDCl3): d = 162.0 (OCH=N), 151.2 (Cq,
OC=C), 133.4, 131.2, 130.4, 128.7, 128.1, 127.5, 126.5, 125.7 (all
CAr).
MS (EI): m/z (%) = 221 (56) [M]+, 193 (52), 165 (9), 105 (23), 89
(100), 77 (19), 63 (26), 51 (17), 39 (17), 28 (28).
Synthesis of Oxazoles; General Procedure
K2CO3, CuI and amide were weighed into a vial under air. The vial
was evacuated and filled with argon, followed by the addition of di-
halogenated olefin, toluene (3 mL) and N,N¢-dimethylethylenedi-
amine (DMEDA). The vial was closed and the reaction mixture
stirred at 110 °C for the given reaction time. After cooling to r.t., the
reaction mixture was poured into aq NH4OH (25%, 10 mL), extract-
ed with EtOAc (3 × 20 mL), dried over Na2SO4 and filtered. The
solvent was removed under reduced pressure and the products were
purified by flash chromatography.
HRMS (EI): m/z calcd for C15H11NO: 221.0841; found: 221.0840.
2-(4-Methoxyphenyl)-4-phenyloxazole and 2-(4-Methoxyphe-
nyl)-5-Phenyloxazole (1b)
The general procedure described above (reaction time: 24 h) was
followed using dibromophenylethylene (3a; 259 mg, 0.99 mmol,
1.00 equiv),
4-methoxybenzamide
(165 mg,
1.09 mmol,
1.10 equiv), K2CO3 (411 mg, 2.97 mmol, 3.00 equiv), CuI
(18.8 mg, 0.10 mmol, 0.10 equiv) and DMEDA (21.5 mL,
0.20 mmol, 0.20 equiv). The products were obtained after purifica-
tion by flash chromatography (pentane–EtOAc, 10:1) on Et3N-im-
pregnated silica to give 2,4-1b and 2,5-1b in a 1:21 ratio (GC-MS).
2,4-Diphenyloxazole and 2,5-Diphenyloxazole (1a)
Synthesis with dibromophenylethylene: The general procedure de-
scribed above (reaction time: 13 h) was followed using 1,2-dibro-
mophenylethylene (3a; 261 mg, 1.00 mmol, 1.00 equiv),
benzamide (182 mg, 1.49 mmol, 1.49 equiv), K2CO3 (414 mg,
2.99 mmol, 2.99 equiv), CuI (19.8 mg, 0.10 mmol, 0.10 equiv) and
DMEDA (23 mL, 0.21 mmol, 0.21 equiv). The products were ob-
tained after purification by flash chromatography (pentane–EtOAc,
30:1) on Et3N-impregnated silica to give 2,5-1a (137 mg, 62%) and
2,4-1a (17 mg, 8%) in a 11:1 ratio (GC-MS).
2-(4-Methoxyphenyl)-5-phenyloxazole
Yield: 153 mg (62%); pale-yellow solid; Rf = 0.16 (pentane–
EtOAc, 10:1).
IR (KBr): 2968 (w), 2840 (w), 1610 (s), 1589 (w), 1469 (s), 1460
(w), 1442 (w), 1418 (w), 1350 (m), 1301 (m), 1251 (s), 1173 (m),
1154 (w), 1134 (w), 1107 (w), 1024 (s), 828 (m), 762 (m), 736 (m),
687 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.06–8.03 (m, 2 H, HCAr,2-Ph),
7.71–7.68 (m, 2 H, HCAr), 7.45–7.40 (m, 3 H, HCAr, HCN), 7.31 (tt,
J = 7.5, 1.6 Hz, 1 H, HCAr,5-Ph), 7.00–6.97 (m, 2 H, HCAr), 3.85 (s,
3 H, OCH3).
Synthesis with (E)-diiodophenylethylene: The general procedure de-
scribed above (reaction time: 13 h) was followed using diiodophe-
nylethylene (3b; 357 mg, 1.00 mmol, 1.00 equiv), benzamide
(184 mg, 1.51 mmol, 1.51 equiv), K2CO3 (415 mg, 3.00 equiv,
3.00 mmol), CuI (19.1 mg, 0.10 mmol, 0.10 equiv) and DMEDA
(22 mL, 0.20 mmol, 0.2 equiv). In contrast to the general procedure,
the olefin was weighed into the vial together with the other solids.
The products were obtained after purification by flash chromatog-
raphy (pentane–EtOAc, 15:1) to give 2,5-1a and 2,4-1a in a 1:1 ra-
tio (GC-MS).
13C NMR (75 MHz, CDCl3): d = 161.3 (Cq), 161.2 (Cq), 150.6 (Cq),
128.8 (CAr), 128.1 (2 × CAr), 127.9 (CAr), 124.0 (CAr), 123.2 (CAr),
120.2 (Cq), 114.2 (CAr), 55.3 (OCH3).
MS (EI): m/z (%) = 251 (100) [M]+, 236 (5), 181 (5), 77 (6), 28 (27).
HRMS (ESI): m/z calcd for C16H14NO2: 252.1019; found:
252.1016.
2,5-Diphenyloxazole
Yield: 41 mg, 19%; pale-yellow solid; Rf = 0.19 (pentane–EtOAc,
15:1).
2-(4-Methoxyphenyl)-4-phenyloxazole
Yield: 26 mg (10%); pale-yellow solid; Rf = 0.40 (pentane–EtOAc,
10:1).
IR (KBr): 3059 (w), 1609 (w), 1567 (w), 1542 (w), 1481 (m), 1447
(m), 1348 (w), 1153 (w), 1132 (m), 1069 (w), 1057 (w), 1026 (w),
952 (w), 907 (w), 822 (w), 775 (m), 760 (m), 707 (s), 685 (s), 479
(m) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.14–8.11 (m, 2 H, HCAr,2-Ph),
7.73–7.71 (m, 2 H, HCAr,5-Ph), 7.49–7.42 (m, 6 H, HCAr, HCN), 7.36
(t, J = 7.5 Hz, 1 H, HCAr,5-Ph).
IR (KBr): 3446 (w), 2926 (w), 1699 (m), 1605 (s), 1501 (m), 1467
(m), 1412 (w), 1256 (s), 1173 (s), 1112 (m), 1076 (w), 1028 (m),
942 (w), 931 (w), 841 (m), 756 (s), 740 (m), 711 (w), 694 (m), 951
(w) cm–1.
Synthesis 2007, No. 15, 2297–2306 © Thieme Stuttgart · New York

PAPER
Conversion of Primary Amides into Oxazoles
2301
1H NMR (300 MHz, CDCl3): d = 8.08–8.05 (m, 2 H, HCAr,2-Ph), 7.92
(s, 1 H, HCO) 7.83–7.81 (m, 2 H, HCAr), 7.45–7.39 (m, 2 H, HCAr),
7.33 (tt, J = 7.4, 1.2 Hz, 1 H, HCAr,5-Ph), 7.01–6.99 (m, 2 H, HCAr),
3.88 (s, 3 H, OCH3).
13C NMR (75 MHz, CDCl3): d = 162.0 (Cq), 161.4 (Cq), 141.8 (Cq),
132.9 (CAr), 131.3 (CAr), 128.7 (CAr), 128.2 (CAr), 128.0 (CAr), 125.6
(Cq), 120.4 (CAr), 114.2 (CAr), 55.4 (OCH3).
0.20 equiv). The products were obtained after purification by flash
chromatography (pentane–EtOAc, 30:1→20:1) to give 2,4-1d and
2,5-1d in a 1:14 ratio (GC-MS).
2-(4-Bromophenyl)-5-phenyloxazole
Yield: 135 mg (45%); orange solid; Rf = 0.13 (pentane–EtOAc,
20:1).
IR (KBr): 1667 (w), 1598 (m), 1539 (w), 1473 (s), 1447 (m), 1398
(m), 1278 (w), 1135 (m), 1110 (w), 1073 (m), 1056 (w), 1007 (m),
950 (s), 932 (w), 914 (w), 828 (s), 763 (s), 729 (s), 692 (s), 489 (m)
cm–1.
MS (EI): m/z (%) = 251 (100) [M+], 223 (18), 208 (19), 152 (7), 135
(20), 120 (13), 105 (16), 90 (15), 77 (15), 51 (9), 28 (53).
HRMS (EI): m/z calcd for C16H14NO2: 251.0947; found: 251.0945.
1H NMR (300 MHz, CDCl3): d = 7.98–7.94 (m, 2 H, HCAr,2-Ph),
7.72–7.69 (m, 2 H, HCAr,5-Ph), 7.63–7.60 (m, 2 H, HCAr,2-Ph), 7.47–
7.42 (m, 3 H, HCN, HCAr,5-Ph), 7.35 (tt, J = 7.4, 1.2 Hz, 1 H,
HCAr,5-Ph).
13C NMR (75 MHz, CDCl3): d = 160.2 (OC=N), 161.2 (Cq), 151.5
(OC=C), 132.1 (2 × CAr,2-Ph), 128.9 (2 × CAr,5-Ph), 128.6 (CAr,5-Ph),
127.8 (CAr,5-Ph), 127.7 (2 × CAr,2-Ph), 126.3 (Cq,Ar-2-Ph), 124.7 (CBr),
124.2 (2 × CAr,5-Ph), 123.5 (HCN).
2-Styryl-4-phenyloxazole and 2-Styryl-5-phenyloxazole (1c)
The general procedure described above (reaction time: 14 h) was
followed using dibromophenylethylene (3a; 260 mg, 0.99 mmol,
1.00 equiv), cinnamide (220 mg, 1.49 mmol, 1.50 equiv), K2CO3
(415 mg, 3.00 mmol, 3.03 equiv), CuI (18.8 mg, 0.10 mmol,
0.10 equiv) and DMEDA (22 mL, 0.20 mmol, 0.20 equiv). The
products were obtained after purification by flash chromatography
(pentane–EtOAc, 30:1→10:1) to give 2,4-1c and 2,5-1c in a 1:20
ratio (GC-MS).
MS (EI): m/z (%) = 301 (18) [M+], 299 (18) [M+], 192 (5), 165 (62),
105 (19), 89 (35), 77 (100), 62 (30), 50 (32), 39 (14), 28 (14).
2-Styryl-5-phenyloxazole
Yield: 150 mg (61%); pale-yellow solid; Rf = 0.18 (pentane–
EtOAc, 10:1).
HRMS (EI): m/z calcd for C15H10NOBr: 298.9946; found:
298.9947.
IR (KBr): 3444 (br s), 3099 (w), 3053 (w), 2924 (w), 1644 (w), 1534
(w), 1484 (w), 1447 (m), 1342 (m), 1279 (w), 1261 (w), 1235 (w),
1109 (w), 1069 (m), 1024 (m), 965 (m), 943 (m), 751 (s), 691 (s)
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.73–7.70 (m, 2 H, HCAr), 7.61–
7.55 (m, 3 H, HCAr, HCvin), 7.47–7.32 (m, 7 H, HCAr, HCN), 7.00
(d, J = 16.2 Hz, 1 H, HCvin).
13C NMR (75 MHz, CDCl3): d = 161.1 (OC=N), 150.9 (OC=C),
135.8, 135.6, 129.1, 128.9, 128.9, 128.4, 127.9, 127.2, 124.2, 123.7,
113.9 (Cvin).
2-(4-Bromophenyl)-4-phenyloxazole
Yield: 26 mg (9%); colorless solid; Rf = 0.23 (pentane–EtOAc,
30:1).
IR (KBr): 2924 (w), 1719 (w), 1601 (m), 1475 (s), 1446 (m), 1399
(m), 1263 (m), 1232 (w), 1122 (w), 1075 (s), 1009 (m), 943 (w), 932
(m), 914 (w), 833 (s), 762 (s), 736 (s), 694 (s), 657 (w), 540 (w)
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.00–7.97 (m, 3 H, HCAr,2-Ph
HCO), 8.84–8.01 (m, 2 H, HCAr,4-Ph), 7.63–7.60 (m, 2 H, HCAr,2-Ph),
7.46–7.41 (m, 2 H, HCAr,4-Ph), 7.34 (m, 1 H, HCAr,4-Ph).
,
MS (EI): m/z (%) = 246 (100) [M+], 115 (23), 77 (18), 28 (59).
13C NMR (75 MHz, CDCl3): d = 161.1 (OC=N), 142.2 (Cq), 133.6
(Cq, OC=C), 132.0, 128.8, 128.2, 128.0, 126.4, 124.7, 125.6, 124.9.
HRMS (EI): m/z calcd for C17H12NO: 246.0919; found: 246.0920.
MS (EI): m/z (%) = 301 (54) [M+], 299 (54) [M+], 271 (14), 192
(60), 165 (18), 105 (13), 89 (100), 77 (9), 63 (24), 51 (9), 39 (10),
28 (70).
2-Styryl-4-phenyloxazole
Yield: 25 mg (10%); pale-yellow solid; Rf = 0.17 (pentane–EtOAc,
30:1).
HRMS (EI): m/z calcd for C15H10NOBr: 298.9946; found:
298.9958.
IR (KBr): 3051 (w), 1659 (w), 1635 (w), 1605 (w), 1520 (s), 1479
(m), 1445 (m), 1357 (w), 1286 (w), 1161 (w), 1132 (w), 1074 (w),
1062 (w), 972 (s), 941 (m), 909 (w), 830 (m), 754 (s), 688 (s), 501
(s) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.90 (s, 1 H, HCO), 7.80–7.77 (m,
2 H, HCAr), 7.61–7.55 (m, 3 H, HCAr, HCvin), 7.46–7.32 (m, 6 H,
HCAr), 7.02 (d, J = 16.2 Hz, 1 H, HCvin).
13C NMR (75 MHz, CDCl3): d = 161.8 (OC=N), 142.1 (Cvin), 136.5
(OCH=C), 135.5, 133.1, 131.0, 129.2, 128.9, 128.8, 128.2, 127.2,
125.6 (all CAr), 113.9 (Cvin).
5-Phenyloxazole (1e)
The general procedure described above (reaction time: 13 h) was
followed using dibromophenylethylene (3a; 263 mg, 1.00 mmol,
1.00 equiv), formamide (60 mL, 1.51 mmol, 1.51 equiv), K2CO3
(415 mg, 3.00 mmol, 3.00 equiv), CuI (38.9 mg, 0.20 mmol,
0.20 equiv) and DMEDA (44 mL, 0.40 mmol, 0.40 equiv). In con-
trast to the general procedure, formamide was added after the addi-
tion of toluene. The product was obtained after purification by flash
chromatography (pentane–EtOAc, 10:1). 4-Phenyloxazole was not
isolated. 2,4-1e and 2,5-1e were obtained as a mixture in a ratio of
1:10 (GC-MS).
MS (EI): m/z (%) = 246 (49) [M+], 218 (9), 115 (100), 104 (20), 89
(47), 77 (11), 63 (17), 51 (10), 39 (12).
HRMS (EI): m/z calcd for C17H12NO: 246.0919; found: 246.0917.
Yield: 47 mg (32%); pale-yellow oil; Rf = 0.18 (pentane–EtOAc,
10:1).
2-(4-Bromophenyl)-4-phenyloxazole and 2-(4-Bromophenyl)-5-
phenyloxazole (1d)
IR (KBr): 3131 (w), 3062 (w), 2926 (w), 1703 (s), 1600 (w), 1506
(m), 1485 (m), 1449 (m), 1315 (w), 1273 (m), 1177 (w), 1105 (m),
1023 (w), 942 (m), 916 (w), 824 (w), 763 (s), 714 (m), 692 (s), 641
(s) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.92 (s, 1 H, OCH=N), 7.67–7.64
(m, 2 H, HCAr), 7.46–7.32 (m, 4 H, HCAr, C=HCN).
The general procedure described above (reaction time: 40 h) was
followed using dibromophenylethylene (262 mg, 1.00 mmol,
1.00 equiv), 4-bromobenzamide (221 mg, 1.10 mmol, 1.10 equiv),
CuI (19.5 mg, 0.10 mmol, 0.10 equiv), K2CO3 (414 mg,
3.00 mmol, 3.00 equiv) and DMEDA (22 mL, 0.20 mmol,
Synthesis 2007, No. 15, 2297–2306 © Thieme Stuttgart · New York

2302
K. Schuh (née Müller), F. Glorius
PAPER
13C NMR (75 MHz, CDCl3): d = 151.7 (OHC=N), 150.5 (OC=C),
128.9 (2 × HCAr), 128.6 (HCAr), 127.8 (Cq,Ar), 124.4 (2 × HCAr),
121.5 (C=CHN).
MS (EI): m/z (%) = 145 (5) [M+], 117 (5), 90 (5), 77 (5), 32 (21), 28
(100).
2-Propyl-4-phenyloxazole and 2-Propyl-5-phenyloxazole (1g)
The general procedure described above (reaction time: 24 h) was
followed using dibromophenylethylene (3a; 263 mg, 1.00 mmol,
1.00 equiv), butyramide (96.6 mg, 1.11 mmol, 1.11 equiv), K2CO3
(418 mg, 3.03 mmol, 3.03 equiv), CuI (38.3 mg, 0.20 mmol,
0.20 equiv) and DMEDA (44 mL, 0.40 mmol, 0.40 equiv). Purifica-
tion by flash chromatography (pentane–EtOAc, 30:1→10:1) gave
2,4-1g and 2,5-1g in a ratio of 1:8 (GC-MS).
HRMS (EI): m/z calcd for C9H7NO: 145.0528; found: 145.0531.
2-Methyl-4-phenyloxazole and 2-Methyl-5-phenyloxazole (1f)
Synthesis with dibromophenylethylene: The general procedure de-
scribed above (reaction time: 24 h) was followed using dibro-
mophenylethylene (3a; 278 mg, 1.06 mmol, 1.00 equiv), acetamide
(75.4 mg, 1.28 mmol, 1.21 equiv), K2CO3 (440 mg, 3.19 mmol,
3.01 equiv), CuI (41.6 mg, 0.22 mmol, 0.21 equiv) and DMEDA
(48 mL, 0.44 mmol, 0.42 equiv). Purification by flash chromatogra-
phy (pentane–EtOAc, 10:1) gave 2,4-1f and 2,5-1f in a 1:10 ratio
(GC-MS). 2-Methyl-5-phenyloxazole (81 mg, 48%) was obtained
as a colorless solid. 2-Methyl-4-phenyloxazole was not isolated.
2-Propyl-5-phenyloxazole
Yield: 74.2 mg (40%); colorless oil; Rf = 0.21 (pentane–EtOAc,
10:1).
IR (film): 3061 (w), 2965 (s), 2934 (m), 2874 (w), 1697 (s), 1578
(w), 1557 (s), 1489 (m), 1449 (m), 1382 (w), 1274 (w), 1198 (w),
1134 (m), 1083 (m), 1054 (w), 1026 (w), 967 (w), 942 (w), 762 (s),
692 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.62–7.59 (m, 2 H, HCAr), 7.42–
7.37 (m, 2 H, HCAr), 7.31–7.26 (m, 1 H, HCAr), 7.22 (s, 1 H, HCN),
2.80 (t, J = 7.4 Hz, 2 H, CH2CH2CH3), 1.85 (sext, J = 7.4 Hz, 2 H,
CH2CH2CH3), 1.03 (t, J = 7.4 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 164.5 (OC=N), 151.0 (OC=C),
128.8 (2 × HCAr), 128.2 (Cq,Ar), 128.0 (HCAr), 123.9 (2 × HCAr),
121.7 (HCN), 30.1 (CH2CH2CH3), 20.5 (CH2CH2CH3), 12.6 (CH3).
MS (EI): m/z (%) = 187 (37) [M+], 172 (10), 159 (100), 103 (77), 89
(9), 77 (45), 51 (8), 32 (16), 28 (100).
Synthesis with diiodophenylethylene: The general procedure de-
scribed above (reaction time: 45 h) was followed using diiodophe-
nylethylene (3a; 357 mg, 1.00 mmol, 1.00 equiv), acetamide
(66.1 mg, 1.12 mmol, 1.12 equiv), K2CO3 (415 mg, 3.01 mmol,
3.01 equiv), CuI (38.6 mg, 0.20 mmol, 0.20 equiv) and DMEDA
(44 mL, 0.40 mmol, 0.40 equiv). In contrast to the general proce-
dure, the olefin was weighed into the vial together with the other
solids. The products 2,4-1f and 2,5-1f were obtained after purifica-
tion by flash chromatography (pentane–EtOAc, 30:1) in a ratio of
1:1 (GC-MS).
HRMS (EI): m/z calcd for C12H13NO: 187.0991; found: 187.0994.
2-Propyl-4-phenyloxazole
Yield: 13 mg (7%); colorless oil; Rf = 0.44 (pentane–EtOAc, 10:1).
2-Methyl-5-phenyloxazole
Yield: 33 mg (21%); pale-yellow solid; Rf = 0.12 (pentane–EtOAc,
10:1).
IR (film): 3100 (w), 2923 (w), 1717 (w), 1644 (w), 1577 (w), 1534
(w), 1484 (w), 1447 (m), 1342 (m), 1261 (w), 1235 (w), 1109 (w),
1069 (m), 1024 (w), 965 (m), 943 (m), 912 (w), 751 (s), 690 (s), 525
(m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.82 (s, 1 H, HCO), 7.73–7.71 (m,
2 H, HCAr), 7.42–7.37 (m, 2 H, HCAr), 7.32–7.26 (m, 1 H, HCAr),
2.80 (t, J = 7.5 Hz, CH2CH2CH3), 1.84 (sext, J = 7.5 Hz,
CH2CH2CH3), 1.02 (t, J = 7.4 Hz, CH2CH2CH3).
IR (KBr): 3120 (w), 3061 (w), 2926 (m), 2854 (w), 1689 (s), 1578
(m), 1560 (s), 1486 (m), 1451 (s), 1372 (w), 1337 (w), 1278 (m),
1217 (m), 1132 (m), 1061 (m), 942 (m), 765 (s), 694 (s), 674 (m)
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.62–7.68 (m, 2 H, HCAr), 7.42–
7.37 (m, 2 H, HCAr), 7.32–7.27 (m, 1 H, HCAr), 7.20 (s, 1 H, HCO),
2.52 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 165.3 (OC=N), 140.5 (C=CN),
133.0 (HCO), 131.3 (Cq,Ar), 128.7 (2 × HCAr), 127.8 (HCAr), 125.5
(2 × HCAr), 30.2 (CH2CH2CH3), 20.6 (CH2CH2CH3), 13.7 (CH3).
13C NMR (75 MHz, CDCl3): d = 161.0 (OC=N), 151.1 (OC=C),
128.8 (2 × HCAr), 128.1 (Cq,Ar), 128.1 (HCAr), 123.9 (2 × HCAr),
121.8 (HCN), 14.0 (CH3).
MS (EI): m/z (%) = 159 (100) [M+], 130 (25), 104 (49), 90 (17), 77
(24), 54 (8), 51 (16), 27 (7).
MS (EI): m/z (%) = 187 (89) [M+], 172 (20), 159 (100), 130 (85),
104 (29), 90 (53), 77 (18), 63 (18), 51 (9), 39 (21), 27(21).
HRMS (EI): m/z calcd for C12H13NO: 187.0997; found: 187.0995.
HRMS (EI): m/z calcd for C10H9NO: 159.0684; found: 159.0685.
2-tert-Butyl-4-phenyloxazole and 2-tert-Butyl-5-phenyloxazole
(1h)
2-Methyl-4-phenyloxazole
Yield: 21 mg (13%); pale-yellow solid; Rf = 0.28 (pentane–EtOAc,
The general procedure described above (reaction time: 62 h) was
followed using dibromophenylethylene (3a; 259 mg, 0.99 mmol,
1.00 equiv), pivalamide (116 mg, 1.14 mmol, 1.15 equiv), K2CO3
(411 mg, 2.97 mmol, 3.00 equiv), CuI (19.6 mg, 0.10 mmol,
0.10 equiv) and DMEDA (22 mL, 0.20 mmol, 0.20 equiv). The
product was obtained after purification by flash chromatography
(pentane–EtOAc, 30:1→10:1).
10:1).
IR (KBr): 3059 (w), 1609 (w), 1587 (m), 1481 (s), 1445 (s), 1348
(m), 1153 (m), 1132 (s), 1100 (w), 1069 (m), 1058 (m), 1026 (m),
952 (m), 822 (m), 775 (m), 760 (s), 707 (s), 685 (s), 479 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.81 (s, 1 H, HCO), 7.72–7.69 (m,
2 H, HCAr), 7.42–7.37 (m, 2 H, HCAr), 7.30 (tt, J = 7.4, 1.4 Hz, 1 H,
HCAr), 2.52 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 161.9 (OC=N), 140.7 (C=CN),
133.1 (HCO), 131.2 (Cq,Ar), 128.7 (2 × HCAr), 127.9 (HCAr), 125.4
(2 × HCAr), 13.9 (CH3).
2-tert-Butyl-5-phenyloxazole
Yield: 112 mg (56%); colorless oil; Rf = 0.24 (pentane–EtOAc,
10:1).
IR (film): 3448 (w), 3061 (w), 2972 (s), 2932 (w), 1715 (w), 1590
(m), 1566 (m), 1478 (m), 1449 (m), 1396 (w), 1367 (w), 1294 (w),
1247 (w), 1140 (m), 1110 (m), 1071 (w), 942 (m), 743 (s), 693 (s)
cm–1.
MS (EI): m/z (%) = 159 (94) [M+], 130 (32), 103 (14), 90 (84), 77
(23), 63 (15), 51 (17), 43 (9), 39 (17), 32 (11), 28 (100).
HRMS (EI): m/z calcd for C10H9NO: 159.0684; found: 159.0696.
Synthesis 2007, No. 15, 2297–2306 © Thieme Stuttgart · New York

PAPER
Conversion of Primary Amides into Oxazoles
2303
1H NMR (300 MHz, CDCl3): d = 7.63–7.60 (m, 2 H, HCAr), 7.42–
7.37 (m, 2 H, HCAr), 7.32–7.26 (tt, J = 7.5, 1.2 Hz, 1 H, HCAr), 7.21
(s, 1 H, HCN), 1.45 [s, 9 H, C(CH3)3].
13C NMR (75 MHz, CDCl3): d = 170.7 (OC=N), 150.6 (OC=C),
128.7 (2 × HCAr), 128.4 (Cq,Ar), 128.0 (HCAr), 123.9 (2 × HCAr),
121.4 (HCN), 33.8 [C(CH3)3], 28.6 [C(CH3)3].
weighed into the vial with the other solids. After addition of aq
NH4OH (25%, 5 mL) and extraction into EtOAc (3 × 10 mL), the
product was purified by flash chromatography (pentane–EtOAc,
30:1) to give 2,4-1i and 2,5-1i in a ratio of 1:10 (GC-MS). 2-Vinyl-
5-phenyloxazole was not isolated.
Yield: 9 mg (17%); reddish oil; Rf = 0.21 (pentane–EtOAc, 30:1).
MS (EI): m/z (%) = 201 (41) [M+], 186 (100), 105 (13), 96 (46), 77
(40), 69 (54), 57 (40), 51 (19), 41 (90), 29 (52).
IR (film): 3293 (br s), 3063 (w), 2960 (w), 2927 (m), 2856 (w), 1634
(s), 1598 (w), 1489 (w), 1449 (m), 1406 (w), 1261 (s), 1178 (w),
1072 (w), 1027 (w), 801 (w), 756 (s), 696 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.86 (s, 1 H, HCO), 7.76–7.73 (m,
2 H, HCAr), 7.44–7.39 (m, 2 H, HCAr), 7.32 (tt, J = 7.4, 1.2 Hz, 1 H,
HCAr), 6.67 (dd, J = 18, 12 Hz, 1 H, HC=CHH), 6.24 (dd, J = 18,
0.9 Hz, 1 H, HC=CHH, Z), 5.65 (dd, J = 12, 0.9 Hz, 1 H,
HC=CHH, E).
13C NMR (75 MHz, CDCl3): d = 161.2 (OC=N), 141.8 (C=CN),
133.1 (HCO), 130.9 (Cq,Ar), 128.7 (2 × HCAr), 128.1 (HCAr), 125.5
(2 × HCAr), 123.4 (HC=CH2), 122.2 [HC=CH2].
HRMS (EI): m/z calcd for C13H15NO: 201.1154; found: 201.1152.
2-tert-Butyl-4-phenyloxazole
Yield: 18 mg (9%); pale-yellow oil; Rf = 0.30 (pentane–EtOAc,
30:1).
IR (film): 3061 (w), 2972 (s), 2932 (m), 2905 (m), 2871 (w), 1550
(s), 1490 (m), 1448 (m), 1367 (m), 1244 (m), 1147 (s), 1121 (s),
1061 (m), 1027 (w), 962 (m), 945 (w), 824 (w), 764 (s), 749 (s), 691
(s) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.80 (s, 1 H, HCO), 7.75–7.72 (m,
2 H, HCAr), 7.41–7.36 (m, 2 H, HCAr), 7.31–7.26 (m, 1 H, HCAr),
1.43 [s, 9 H, C(CH3)3].
13C NMR (75 MHz, CDCl3): d = 171.5 (OC=N), 140.2 (C=CN),
132.7 (HCO), 131.5 (Cq,Ar), 128.6 (2 × HCAr), 127.7 (HCAr), 125.6
(2 × HCAr), 33.8 [C(CH3)3], 28.6 [C(CH3)3].
MS (EI): m/z (%) = 171 (69) [M+], 143 (41), 115 (8), 105 (12), 90
(43), 77 (13), 63 (23), 51 (13), 39 (43), 32 (15), 28 (100).
HRMS (EI): m/z calcd for C11H9NO: 171.0682; found: 171.0683.
2-Phenyl-4-hexyloxazole and 2-Phenyl-5-hexyloxazole (1j) from
Dibromo-1-octene
The general procedure described above (reaction time: 13 h) was
followed using 1,2-dibromo-1-octene (3c; 266 mg, 0.99 mmol,
1.00 equiv), benzamide (132 mg, 1.08 mmol, 1.09 equiv), K2CO3
(408 mg, 2.95 mmol, 2.98 equiv), CuI (19.2 mg, 0.10 mmol,
0.10 equiv) and DMEDA (22 mL, 0.20 mmol, 0.20 equiv). In con-
trast to the general procedure, the reaction was performed at 130 °C.
Purification by flash chromatography (hexane) on Et3N-impregnat-
ed silica gave 2,4-1j (21 mg, 9%) and 2,5-1j (134 mg, 59%) as pale-
yellow liquids in a 1:8 ratio (GC-MS).
MS (EI): m/z (%) = 201 (89) [M+], 186 (60), 172 (23), 158 (24), 145
(52), 117 (28), 105 (18), 90 (31), 77 (18), 69 (11), 57 (100), 51 (19),
41 (52), 29 (56).
HRMS (EI): m/z calcd for C13H15NO: 201.1153; found: 201.1158.
2-Vinyl-5-phenyloxazole (1i)
The general procedure described above (reaction time: 14 h) was
followed using dibromophenylethylene (3a; 85.1 mg, 0.32 mmol,
1.00 equiv), acrylamide (25.1 mg, 0.35 mmol, 1.09 equiv), K2CO3
(132 mg, 0.95 mmol, 2.98 equiv), CuI (13 mg, 0.07 mmol,
0.21 equiv) and DMEDA (15 mL, 0.14 mmol, 0.43 equiv) in tolu-
ene (1 mL). After addition of aq NH4OH (25%, 5 mL) and extrac-
tion into EtOAc (3 × 10 mL), the product was purified by flash
chromatography (pentane–EtOAc, 10:1) to give 2,4-1i and 2,5-1i in
a ratio of 1:10 (GC-MS). 2-Vinyl-4-phenyloxazole was not isolated.
2-Phenyl-4-hexyloxazole and 2-Phenyl-5-hexyloxazole (1j) from
(E)-Diiodo-1-octene
The general procedure described above (reaction time: 24 h) was
followed using 1,2-diiodo-1-octene (3d; 359 mg, 0.99 mmol,
1.00 equiv), benzamide (134 mg, 1.10 mmol, 1.11 equiv), K2CO3
(415 mg, 3.00 mmol, 3.04 equiv), CuI (20.1 mg, 0.11 mmol,
0.11 equiv) and DMEDA (24 mL, 0.22 mmol, 0.22 equiv). In con-
trast to the general procedure, the reaction was performed at 130 °C.
Purification by flash chromatography (pentane–EtOAc, 30:1) gave
2,4-1j (26 mg, 11%) and 2,5-1j (68 mg, 31%) in a 1:3 ratio (GC-
MS)
Yield: 15 mg (28%); colorless oil; Rf = 0.29 (pentane–EtOAc,
10:1).
IR (film): 3120 (w), 3062 (w), 2928 (w), 1701 (s), 1589 (w), 1551
(m), 1517 (m), 1488 (s), 1449 (s), 1315 (w), 1278 (m), 1178 (w),
1125 (s), 1061 (s), 1027 (s), 983 (w), 943 (s), 826 (m), 760 (s), 691
(s) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.68–7.65 (m, 2 H, HCAr), 7.45–
7.39 (m, 2 H, HCAr), 7.36–7.30 (m, 2 H, HCAr, HCN), 6.64 (dd,
J = 18, 12 Hz, 1 H, HC=CHH), 6.25 (dd, J = 18, 0.9 Hz, 1 H,
HC=CHH, Z), 5.65 (dd, J = 12, 1.1 Hz, 1 H, HC=CHH, E).
13C NMR (75 MHz, CDCl3): d = 160.5 (OC=N), 150.9 (OC=C),
128.9 (2 × HCAr), 128.5 (Csp2), 127.9 (Cq,Ar), 124.2 (2 × HCAr),
123.4 (Csp2), 123.2 (Csp2), 121.4 (Csp2).
MS (EI): m/z (%) = 171 (90) [M+], 143 (12), 116 (32), 105 (19), 90
(21), 77 (78), 63 (9), 51 (24), 39 (24), 32 (15), 28 (100).
2-Phenyl-5-hexyloxazole
Pale-yellow liquid; Rf = 0.10 (pentane–EtOAc, 30:1).
IR (film): 3436 (w), 3064 (w), 2930 (s), 2858 (m), 1567 (m), 1550
(m), 1487 (m), 1467 (m), 1449 (m), 1378 (w), 1353 (w), 1122 (m),
1099 (w), 1065 (m), 1025 (w), 988 (m), 825 (m), 775 (m), 712 (s),
692 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.02–7.99 (m, 2 H, HCAr), 7.46–
7.40 (m, 3 H, HCAr), 6.84 (s, 1 H, HCN), 2.71 [t, J = 7.5 Hz, 2 H,
CH2(CH2)4CH3], 1.70 [quint, J = 7.5 Hz, 2 H, CH2CH2(CH2)3CH3],
1.42–1.29 [m, 6 H, CH2CH2(CH2)3CH3], 0.92–0.88 (m, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 160.5 (OC=N), 153.2 (OC=C),
129.8 (HCAr), 128.6 (2 × HCAr), 127. 8 (Cq,Ar), 125.9 (2 × HCAr),
123.5 (HCN), 31.4, 28.7, 27.6, 25.6, 22.5 (all CH2), 14.0 (CH3).
MS (EI): m/z (%) = 229 (28) [M+], 158 (100), 131 (9), 117 (20), 105
(20), 89 (11), 77 (11), 41 (7), 27 (6).
HRMS (EI): m/z calcd for C11H9NO: 171.0685; found: 171.0686.
2-Vinyl-4-phenyloxazole (1i)
The general procedure described above (reaction time: 24 h) was
followed using diiodophenylethylene (3b; 108 mg, 0.30 mmol,
1.00 equiv), acrylamide (25.6 mg, 0.36 mmol, 1.20 equiv), K2CO3
(124 mg, 0.90 mmol, 3.00 equiv), CuI (11.9 mg, 0.06 mmol,
0.21 equiv) and DMEDA (13 mL, 0.12 mmol, 0.40 equiv) in tolu-
ene (1 mL). In contrast to the general procedure, the olefin was
HRMS (EI): m/z calcd for C15H19NO: 229.1473; found: 229.1470.
2-Phenyl-4-hexyloxazole
Pale-yellow liquid; Rf = 0.47 (hexane–EtOAc, 10:1).
Synthesis 2007, No. 15, 2297–2306 © Thieme Stuttgart · New York

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K. Schuh (née Müller), F. Glorius
PAPER
IR (film): 3429 (w), 3064 (w), 2928 (s), 2857 (m), 1689 (w), 1590
(m), 1553 (m), 1486 (m), 1467 (m), 1450 (m), 1378 (w), 1345 (m),
1286 (w), 1103 (m), 1062 (m), 1023 (w), 934 (m), 778 (m), 713 (s),
691 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.04–8.01 (m, 2 H, HCAr), 7.47–
7.41 (m, 4 H, HCAr, HCO), 2.60 [t, J = 7.7 Hz, 2 H,
CH2(CH2)4CH3], 1.73–1.63 [m, 2 H, CH2CH2(CH2)3CH3], 1.41–
1.25 [m, 6 H, CH2CH2(CH2)3CH3], 0.91–0.87 (m, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 161.3 (OC=N), 142.7 (C=CN),
133.8 (HCO), 130.0 (HCAr), 128. 7 (2 × HCAr), 127.8 (Cq,Ar), 126.3
(2 × HCAr), 31.6, 29.0, 28.4, 26.5, 22.6 (all CH2), 14.0 (CH3).
2-(tert-Butyl)-5-hexyloxazole (1l)
The general procedure described above (reaction time: 47 h) was
followed using 1,2-dibromo-1-octene (3c; 270 mg, 1.00 mmol,
1.00 equiv), pivalamide (112 mg, 1.10 mmol, 1.10 equiv), K2CO3
(416 mg, 3.01 mmol, 3.01 equiv), CuI (38.4 mg, 0.20 mmol,
0.20 equiv) and DMEDA (54 mL, 0.50 mmol, 0.50 equiv). Purifica-
tion by flash chromatography (pentane) on Et3N-saturated silica
gave 2,4-1l and 2,5-1l in a 1:9 ratio (GC-MS). 2-(tert-Butyl)-4-hex-
yloxazole (2,4-1l) was not isolated.
Yield: 62 mg (30%); colorless oil; Rf = 0.14 (pentane–EtOAc,
30:1).
IR (film): 3438 (w), 3118 (w), 2960 (s), 2931 (s), 2860 (m), 1693
(w), 1607 (w), 1563 (m), 1461 (m), 1395 (w), 1365 (m), 1262 (w),
1214 (w), 1142 (s), 1113 (m), 1030 (m), 975 (m), 820 (m), 751 (w),
728 (w) cm–1.
MS (EI): m/z (%) = 229 (18) [M+], 200 (16), 186 (15), 172 (15), 159
(100), 130 (14), 105 (50), 77 (19), 41 (9), 28 (18).
HRMS (EI): m/z calcd for C15H19NO: 229.1470; found: 229.1468.
1H NMR (300 MHz, CDCl3): d = 6.55 (s, 1 H, HCN), 2.57 [t,
J = 7.5 Hz, 2 H, CH2(CH2)4CH3], 1.66 [quint, J = 7.5 Hz, 2 H,
CH2CH2(CH2)3CH3], 1.64–1.28 [m, 15 H, CH2CH2(CH2)3CH3,
C(CH3)3], 0.89–0.84 (m, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 169.9 (OC=N), 152.3 (OC=C),
121.3 (HCN), 33.5 [C(CH3)3], 31.4 (CH2), 28.7 (CH2), 28.5
[C(CH3)3], 27.5 (CH2), 25.5 (CH2), 22.5 (CH2) 14.0 (CH3).
2-(4-Aminophenyl)-4-hexyloxazole and 2-(4-Aminophenyl)-5-
hexyloxazole (1k)
The general procedure described above (reaction time: 38 h) was
followed using 1,2-dibromo-1-octene (3c; 271 mg, 1.00 mmol,
1.00 equiv), 4-aminobenzamide (150 mg, 1.00 mmol, 1.10 equiv),
K2CO3 (414.2 mg, 3.00 mmol, 3.00 equiv), CuI (19.5 mg,
0.10 mmol, 0.10 equiv) and DMEDA (22 mL, 0.20 mmol,
0.20 equiv). In contrast to the general procedure, the reaction was
performed at 130 °C. The products were obtained after purification
by flash chromatography (pentane–EtOAc, 1:1) in a 2,4-1k to 2,5-
1k ratio of 1:14 (GC-MS).
MS (EI): m/z (%) = 209 (5) [M+], 194 (29), 139 (8), 111 (11), 102
(28), 97 (16), 85 (11), 69 (21), 57 (100), 41 (49), 29 (27).
HRMS (EI): m/z calcd for C13H23NO: 209.1779; found: 209.1778.
5-(Trimethylsilyl)-2,4-diphenyloxazole (1m)
2-(4-Aminophenyl)-5-hexyloxazole
The general procedure described above (reaction time: 21 h) was
followed using 1,2-dibromo-1-(trimethylsilyl)-2-phenylethylene
(3e; 295 mg, 0.88 mmol, 1.00 equiv, melted), benzamide (134 mg,
1.10 mmol, 1.25 equiv), K2CO3 (417 mg, 3.01 mmol, 3.43 equiv),
CuI (19.8 mg, 0.10 mmol, 0.11 equiv) and DMEDA (22 mL,
0.20 mmol, 0.23 equiv). Purification by flash chromatography
(pentane–EtOAc, 50:1) gave 2,4-1m. No 2,5-1m was detected (GC-
MS).
Yield: 107 mg (44%); brown solid; Rf = 0.22 (pentane–EtOAc,
1:1).
IR (KBr): 3474 (s), 3380 (s), 3316 (w), 3208 (m), 3108 (w), 2955
(s), 2929 (s), 2857 (m), 1608 (s), 1580 (w), 1500 (s), 1466 (w), 1437
(w), 1377 (w), 1306 (m), 1172 (m), 1116 (m), 833 (m), 742 (m), 707
(m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.80–7.77 (m, 2 H, HCAr), 6.74 (s,
1 H, HCN=C), 6.70–6.67 (m, 2 H, HCAr), 3.85 (br s, 2 H, NH2),
2.66 [t, J = 7.5 Hz, 2 H, CH2(CH2)4CH3], 1.66 [quint, J = 7.4 Hz,
2 H, CH2CH2(CH2)3CH3], 1.40–1.27 [m, 6 H, CH2CH2(CH2)3CH3],
0.91–0.86 (m, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 161.1 (OC=N), 152.0 (OC=C),
148.1 (CNH2), 127.5 (2 × HCAr), 122.9 (HCN), 118.3 (Cq), 114.7
(2 × HCAr), 31.4, 28.7, 27.6, 25.6, 22.5 (all CH2), 13.9 (CH3).
MS (EI): m/z (%) = 244 (43) [M+], 173 (100), 145 (7), 120 (19), 104
(6), 27 (11).
Yield: 143 mg (56%); colorless solid; Rf = 0.19 (pentane–EtOAc,
50:1).
IR (KBr): 2924 (m), 1587 (w), 1554 (m), 1486 (m), 1446 (m), 1336
(m), 1253 (m), 1138 (w), 1082 (w), 1067 (w), 1025 (w), 976 (m),
919 (m), 845 (s), 779 (w), 761 (m), 720 (m), 700 (m), 687 (m), 634
(m) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.17–8.13 (m, 2 H, HCAr), 7.70–
7.67 (m, 2 H, HCAr), 7.52–7.35 (m, 6 H, HCAr), 0.37 [s, 9 H,
Si(CH3)3].
13C NMR (75 MHz, CDCl3): d = 164.2 (OC=N), 151.3 (OC=C),
149.8, 133.1, 130.2, 128.6, 128.2, 128.1, 127.8, 126.6, 29.7, –1.09
[Si(CH3)3].
HRMS (EI): m/z calcd for C15H20ON2: 244.1564; found: 244.1570.
2-(4-Aminophenyl)-4-hexyloxazole
Yield: 18 mg (6%); brown solid; Rf = 0.34 (pentane–EtOAc, 1:1).
MS (EI): m/z (%) = 293 (58) [M+], 278 (31), 175 (54), 145 (8), 105
IR (film): 3342 (br s), 3222 (br s), 2954 (m), 2928 (s), 2857 (m),
1611 (s), 1500 (s), 1439 (w), 1298 (w), 1177 (m), 1103 (w), 1068
(w), 934 (w), 835 (m), 729 (m), 616 (w), 519 (m) cm–1.
(20), 89 (27), 77 (14), 73 (100), 63 (10), 45 (30) cm–1.
HRMS (EI): m/z calcd for C18H19NOSi: 293.1236; found: 293.1227.
1H NMR (300 MHz, CDCl3): d = 7.83–7.80 (m, 2 H, HCAr), 7.32 (s,
1 H, HCO), 6.71–6.68 (m, 2 H, HCAr), 3.90 (br s, 2 H, NH2), 2.54
[t, J = 7.5 Hz, 2 H, CH2(CH2)4CH3], 1.68–1.61 [m, 2 H,
CH2CH2(CH2)3CH3], 1.33–1.29 [m, 6 H, CH2CH2(CH2)3CH3],
0.91–0.84 (m, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 161.9 (OC=N), 148.2 (CNH2),
142.2 (C=CN), 132.7 (HCO), 127. 9 (2 × HCAr), 118.3 (Cq,Ar), 114.7
(2 × HCAr), 31.6, 29.0, 28.4, 26.6, 22.6 (all CH2), 14.0 (CH3).
2,4,5-Triphenyloxazole (1n)
The general procedure described above (reaction time: 44 h) was
followed using 1,2-dibromo-1,2-diphenylethylene (3f; 340 mg,
1.01 mmol, 1.00 equiv), benzamide (136 mg, 1.11 mmol,
1.10 equiv), K2CO3 (422 mg, 3.05 mmol, 3.02 equiv), CuI
(20.5 mg, 0.11 mmol, 0.10 equiv) and DMEDA (24 mL, 0.22 mmol,
0.22 equiv). In contrast to the general procedure, the olefin was
weighed into the vial with the other solids. The product was ob-
tained after purification by flash chromatography (pentane–EtOAc,
100:1).
MS (EI): m/z (%) = 244 (28) [M+], 187 (24), 174 (86), 145 (12), 120
(100), 104 (9), 91 (11), 65 (8), 41 (11), 28 (10).
Yield: 70 mg (24%); colorless solid; Rf = 0.20 (Pentane–EtOAc,
100:1).
HRMS (EI): m/z calcd for C15H20ON2: 244.1576; found: 244.1578.
Synthesis 2007, No. 15, 2297–2306 © Thieme Stuttgart · New York

PAPER
Conversion of Primary Amides into Oxazoles
2305
IR (KBr): 3054 (w), 1704 (w), 1600 (w), 1552 (w), 1501 (w), 1486
(m), 1447 (m), 1365 (w), 1326 (w), 1244 (w), 1086 (w), 1069 (m),
1054 (w), 1023 (m), 965 (m), 769 (s), 728 (m), 714 (m), 693 (s), 607
(w) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.20–8.17 (m, 2 H, HCAr), 7.77–
7.69 (m, 4 H, HCAr), 7.52–7.35 (m, 9 H, HCAr).
13C NMR (75 MHz, CDCl3): d = 160.1 (OC=N), 145.6, 136.8,
132.6, 130.3, 129.0, 128.7, 128.7, 128.6, 128.5, 128.2, 128.1, 127.4,
126.6, 126.5 (all CAr).
MS (EI): m/z (%) = 297 (100) [M+], 269 (11), 165 (88), 105 (10), 89
(20), 77 (16), 63 (8), 51 (6), 28 (27).
Na2SO4 and concentrated under reduced pressure. The product was
recrystallized (MeOH) to give 3b.
Yield: 11.7 g (65%); colorless product; Rf = 0.32 (pentane).
1H NMR (300 MHz, CDCl3): d = 7.30–7.27 (m, 5 H, HCAr), 7.19 (s,
1 H, HCvin).
13C NMR (75 MHz, CDCl3): d = 143.1 (Cq,Ar), 128.9 (CAr), 128.5
(CAr), 128.4 (CAr), 96.2 (Cq,vin), 80.7 (Cvin).
1,2-Dibromo-1-octene (3c)9
To a solution of 1-octyne (3.67 g, 33.4 mmol, 1.04 equiv) in CH2Cl2
(150 mL) was added a solution of Br2 (5.12 g, 32.0 mmol, 1.00
equiv) in CH2Cl2 (150 mL). After stirring at r.t. for 16 h, the solu-
tion was concentrated under reduced pressure and purified by flash
chromatography (pentane) to give 3c.
HRMS (EI): m/z calcd for C21H15NO: 297.1154; found: 297.1157.
Dimethyl 2-Phenyloxazole-4,5-dicarboxylate (1o)
The general procedure described above (reaction time: 48 h) was
followed using 2,3-dibromobut-2-enedimethylester (3g; 477 mg,
1.58 mmol, 1.45 equiv), benzamide (133 mg, 1.09 mmol,
1.00 equiv), CuI (20.5 mg, 0.11 mmol, 0.10 equiv) and DMEDA
(24 mL, 0.22 mmol, 0.20 equiv). In contrast to the general proce-
dure, K3PO4 (694 mg, 3.27 mmol, 3.00 equiv) was used as base.
The product was obtained after purification by flash chromatogra-
phy (hexane–EtOAc, 5:1).
Yield: 7.27 g (84%); colorless liquid; Rf = 0.58 (E) and 0.47 (Z)
(pentane); E/Z = 77:23 (GC-MS).
1H NMR (300 MHz, CDCl3): d = 6.56 (s, 1 H, HCvin, E), 6.40 (s,
1 H, HCvin, Z), 2.59 [t, J = 7.2 Hz, 2 H, CH2(CH2)4CH3, E], 2.50 [t,
J = 7.4 Hz, 2 H, CH2(CH2)4CH3, Z], 1.60–1.53 (m, 3 H, CH2), 1.36–
1.29 (m, 10 H, CH2), 0.92–0.87 (m, 5 H, CH3).
13C NMR (75 MHz, CDCl3): d = 134.1 (Cq,vin, Z), 127.0 (Cq,vin, E),
105.2 (HCvin, Z), 102.1 (HCvin, E), 41.2, 36.9, 31.5, 28.0, 27.0, 22.5,
14.0 (all Calk).
Yield: 33 mg (12%); pale-yellow solid; Rf = 0.09 (hexane–EtOAc,
5:1).
(E)-1,2-Diiodo-1-octene (3d)10
IR (KBr): 2955 (w), 1760 (s), 1606 (w), 1533 (m), 1481 (m), 1441
(m), 1349 (s), 1324 (m), 1301 (m), 1263 (m), 1225 (s), 1138 (m),
1091 (s), 1073 (s), 965 (w), 828 (m), 794 (m), 769 (m), 719 (s), 692
(m) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.17–8.14 (m, 2 H, HCAr), 7.57–
7.45 (m, 3 H, HCAr), 4.00 (s, 3 H, CH3), 3.99 (s, 3 H, OCH3).
13C NMR (75 MHz, CDCl3): d = 162.5 (C=O), 161.0 (C=O), 157.2
(OC=N), 141.9 (OC=CN), 137.3 (OC=CN), 132.1 (HCAr), 128.9
(2 × HCAr), 127.5 (2 × HCAr), 125.4 (Cq,Ar), 52.9 (OCH3),
52.8 (OCH3).
MS (EI): m/z (%) = 261 (49) [M+], 202 (100), 174 (34), 146 (14),
115 (6), 105 (14), 89 (6), 77 (19), 51 (6), 28 (11).
To a solution of I2 (10.23 g, 40.3 mmol, 1.00 equiv) in CH2Cl2
(200 mL) was added a solution of 1-octyne (4.87 g, 44.2 mmol,
1.10 equiv) in CH2Cl2 (100 mL). After stirring at r.t. for 69 h, aq
Na2S2O3 (10%, 300 mL) was added and the organic layer was sep-
arated, washed with H2O (2 × 200 mL), dried over MgSO4 and con-
centrated under reduced pressure. Purification by flash
chromatography (hexane) gave the product 10.
Yield: 13.4 g (91%); reddish liquid; Rf = 0.45 (hexane).
1H NMR (300 MHz, CDCl3): d = 6.80 (s, 1 H, HCvin), 2.50 (t,
J = 6.0 Hz, 2 H, CH2Cvin), 1.54 (quint, J = 6.6 Hz, 2 H,
CH2CH2Cvin), 1.36–1.29 (m, 6 H, 3 × CH2), 0.93–0.88 (m, 3 H,
CH3).
13C NMR (75 MHz, CDCl3): d = 104.4 (Cq,vin), 78.9 (HCvin), 44.7,
31.6, 28.1, 27.8, 22.5, 14.1 (all Calk).
HRMS (EI): m/z calcd for C13H11NO5: 261.0627; found: 261.0632.
1,2-Dibromophenylethylene (3a)9
To a solution of phenylacetylene (4.45 g, 43.6 mmol, 1.05 equiv) in
CH2Cl2 (150 mL) was added a solution of Br2 (6.55 g, 41.0 mmol,
1.00 equiv) in CH2Cl2 (250 mL). After stirring at r.t. for 2 h, aq
Na2S2O3 (10%, 300 mL) was added and the organic layer was sep-
arated, washed with H2O (2 × 200 mL), dried over Na2SO4 and con-
centrated under reduced pressure. Purification by flash
chromatography (pentane) gave the product 3a.
1,2-Dibromo-1-(trimethylsilyl)-2-phenylethylene (3e)11
A
solution of 1-(trimethylsilyl)-2-phenylacetylene (1.70 g,
9.75 mmol, 1.00 equiv) in CH2Cl2 (20 mL) was cooled to –10 °C
and a solution of Br2 (9.3 mL, 9.77 mmol, 1.00 equiv) in CH2Cl2
(c = 1.05 mol/L) was added. The reaction mixture was stirred at
–10 °C for 30 min then allowed to warm to r.t., concentrated under
reduced pressure and the residue was purified by flash chromatog-
raphy (pentane) to give 3e.
Yield: 9.47 g (88%); pale-yellow liquid; Rf = 0.69 (E) and 0.62 (Z)
(pentane); E/Z = 63:37 (GC-MS).
1H NMR (300 MHz, CDCl3): d = 7.54–7.50 (m, 5 H, HCAr, Z),
7.41–7.35 (m, 5 H, HCAr, E), 7.07 (s, 1 H, HCvin, Z), 6.81 (s, 1 H,
HCvin, E).
13C NMR (75 MHz, CDCl3): d = 138.1 (Cq,Ar, Z), 137.0 (Cq,Ar, E),
131.1 (HCAr, Z), 129.4 (HCAr, E + Z), 129.1 (HCAr, E), 128.5 (HCAr,
Z), 128.2 (HCAr, E), 127.7 (HCq,vin, Z), 121.3 (HCq,vin, E), 108.8
(HCvin, Z), 103.0 (HCvin, E).
Yield: 2.26 g (69%); colorless solid; Rf = 0.40 (pentane); E/Z =
1:99 (GC-MS).
1H NMR (300 MHz, CDCl3): d = 7.56–7.46 (m, 5 H, HCAr), 0.15 [s,
9 H, (CH3)3Si].
13C NMR (75 MHz, CDCl3): d = 141.4 (Cq,Ar), 133.5 (Cq,vin), 131.4
(Cq,vin), 129.2 (HCAr), 128.9 (HCAr), 128.2 (HCAr), 0.12 [Si(CH3)3].
1,2-Dibromo-1,2-diphenylethylene (3f)11
Tolane (5.14 g, 28.8 mmol, 1.00 equiv) was dissolved in CH2Cl2
(60 mL) at –10 °C and a solution of Br2 (5.59 g, 35.0 mmol,
1.21 equiv) in CH2Cl2 (40 mL) was added dropwise over 15 min.
The reaction mixture stirred at –10 °C for a further 30 min then al-
lowed to warm to r.t. and the precipitated product was filtrated. Aq
Na2S2O3 (10%, 100 mL) was added to the filtrate and the organic
layer was separated. The aqueous layer was washed with pentane
(E)-1,2-Diiodophenylethylene (3b)9
To a solution of phenylacetylene (5.16 g, 50.5 mmol, 1.00 equiv) in
CH2Cl2 (150 mL) was added a solution of I2 (12.8 g, 50.4 mmol,
1.00 equiv) in CH2Cl2 (350 mL), dropwise, over 1 h. After stirring
at r.t. for 2.5 h, aq Na2S2O3 (10%, 300 mL) was added and the or-
ganic layer was separated, washed with H2O (200 mL), dried over
Synthesis 2007, No. 15, 2297–2306 © Thieme Stuttgart · New York

2306
K. Schuh (née Müller), F. Glorius
PAPER
(2 × 150 mL) and the combined organic layers were dried over
MgSO4, concentrated under reduced pressure and the residue was
recrystallized (EtOH) to give 3f.
W.; Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996,
261. (e) Wipf, P. Chem. Rev. 1995, 95, 2115. (f) Turchi, I.
J. Oxazoles in Heterocyclic Compounds, Vol. 45; Turchi, I.
J., Ed.; Wiley: New York, 1986. (g) Turchi, I. J.; Dewar, M.
J. S. Chem. Rev. 1975, 75, 389.
Yield: 7.36 g (76%); colorless solid; Rf = 0.18 (pentane); E/Z =
17:83 (GC-MS).
1H NMR (300 MHz, CDCl3): d = 7.56–7.52 (m, 4 H, HCAr), 7.47–
7.38 (m, 6 H, HCAr).
13C NMR (75 MHz, CDCl3): d = 140.8 (Cq,Ar), 129.1 (HCAr), 128.9
(Cq,Ar), 128.4 (HCAr), 118.1 (CvinBr).
(2) For recent reviews on the synthesis of oxazole containing
natural products, see: (a) Jin, Z. Nat. Prod. Rep. 2006, 23,
464. (b) Yeh, V. S. C. Tetrahedron 2004, 60, 11995.
(3) (a) Altenhoff, G.; Glorius, F. Adv. Synth. Catal. 2004, 346,
1661. (b) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71,
1802.
(4) (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 7421. (b) Kwong, F. Y.; Klapars, A.;
Buchwald, S. L. Org. Lett. 2002, 4, 581. (c) Jiang, L.; Job,
G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667.
(d) Han, C.; Shen, R.; Su, S.; Porco, A. Jr. Org. Lett. 2003,
6, 27. For profound reviews on Cu-catalyzed C–N, C–O and
C–S couplings, see: (e) Ley, S. V.; Thomas, A. W. Angew.
Chem. Int. Ed. 2003, 42, 5400. (f) Kunz, K.; Scholz, U.;
Ganzer, D. Synlett 2003, 2428.
Dimethyl 2,3-Dibromobut-2-endicarboxylate (3g)12
To a solution of Br2 (6.00 g, 37.5 mmol, 1.04 equiv) in CH2Cl2
(160 mL) was added a solution of dimethyl acetylenedicarboxylate
(5.15 g, 36.2 mmol, 1.00 equiv) in CH2Cl2 (35 mL). After stirring at
r.t. for 16 h, aq Na2S2O3 (10%, 250 mL) was added and the organic
layer was separated. The aqueous layer was extracted with CH2Cl2
(3 × 75 mL) and the combined organic layers were dried over
MgSO4, concentrated under reduced pressure and the residue was
purified by flash chromatography (pentane–EtOAc, 10:1).
(5) For example, see: (a) Shin, C.-G.; Sato, Y.; Sugiyama, H.;
Nanjo, K.; Yoshumura, J. Bull. Chem. Soc. Jpn. 1977, 50,
1788. (b) Chattopadhyay, S. K.; Kempson, J.; McNeil, A.;
Pattenden, G.; Reader, M.; Rippon, D. E.; Waite, D. J.
Chem. Soc., Perkin Trans. 1 2000, 2415.
Yield: 9.55 g (87%); colorless solid; Rf = 0.43 (E + Z; pentane–
EtOAc, 5:1); E/Z = 61:39 (GC-MS).
1H NMR (300 MHz, CDCl3): d = 3.88 (s, 3 H, CH3, E), 3.83 (s, 3 H,
CH3, Z).
13C NMR (75 MHz, CDCl3): d = 162.6 (C=O), 162.5 (C=O), 125.0
(Cvin, Z), 112.6 (Cvin, E), 53.8 (CH3), 53.6 (CH3).
(6) For related syntheses and mechanistic investigations, see:
(a) Uemura, S.; Okazaki, H.; Okano, M. J. Chem. Soc.,
Perkin Trans. 1 1987, 1278. (b) Bianchini, R.; Chiappe, C.;
Lo Moro, G.; Lenoir, D.; Lemmen, P.; Goldberg, N. Chem.
Eur. J. 1999, 5, 1570. (c) Selina, A. A.; Sergey, S. K.;
Gauchenova, E. V.; Churakov, A. V.; Kuz’mina, L. G.;
Howard, A. K.; Lorberth, J.; Zaitseva, G. S. Heteroat. Chem.
2004, 15, 43. (d) Barluenga, J.; Rodriuez, M. A.; Campos, P.
J. J. Org. Chem. 1990, 55, 3104. (e) Kodomari, M.;
Sakamoto, T.; Yoshitomi, S. Bull. Chem. Soc. Jpn. 1989, 62,
4053. (f) Pagni, R. M.; Kabalka, G. W.; Boothe, R.;
Gaetano, K.; Stewart, L. J.; Conaway, R.; Dial, C.; Gray, D.;
Larson, S.; Luidhardt, T. J. Org. Chem. 1988, 53, 4477.
(g) Al-Hassan, M. I. J. Organomet. Chem. 1989, 372, 183.
(7) Parameters screened: Ligands: DMEDA (optimal), rac-1,2-
diaminocyclohexane (lower conversion, more side
products), phenanthroline (no reaction); bases: K2CO3
(optimal), K3PO4 (lower conversion, more side products),
Cs2CO3 (lower conversion), Et3N and NaOAc (no reaction).
Reaction temperature: <110 °C conversion was found to be
incomplete; solvents: toluene (optimal), chlorobenzene
(lower conversion), t-BuOH, dioxane (much lower
conversion), DMF (no conversion).
2,3-Dibromoprop-2-en-1-ol (3h)12
To a solution of Br2 (13.4 g, 83.1 mmol, 1.00 equiv) in CH2Cl2
(350 mL) was added a solution of propargyl alcohol (5.37 g,
95.8 mmol, 1.15 equiv) in CH2Cl2 (100 mL). After stirring at r.t. for
17 h, the solution was concentrated under reduced pressure and the
residue was purified by flash chromatography (pentane–EtOAc,
5:1) to give 3h.
Yield: 12.9 g (72%); colorless liquid; Rf = 0.28 and 0.36 (pentane–
EtOAc, 5:1); E/Z = 44:56 (GC-MS).
1H NMR (300 MHz, CDCl3): d = 6.96 (s, 1 H, HCvin, Z), 6.56 (s,
1 H, HCvin, E), 4.42 (s, 2 H, CH2, E), 4.26 (s, 2 H, CH2, Z), 3.64–
3.12 (m, 2 H, OH).
13C NMR (75 MHz, CDCl3): d = 131.7 (Cvin), 124.9 (Cvin), 108.6
(Cvin), 104.4 (Cvin), 67.4 (OCH2), 63.6 (OCH2).
Acknowledgment
Generous financial support by the Fonds der Chemischen Industrie
(Dozentenstipendium), Lilly Germany (Lilly Lecture Award) and
the BASF AG (BASF Catalysis Award) as well as donations by
Bayer AG, Heraeus and Degussa are gratefully acknowledged. The
research of F.G. was also supported by the Alfried Krupp Prize for
Young University Teachers of the Alfried Krupp von Bohlen und
Halbach Foundation.
(8) In a series of experiments, a range of olefins were heated at
110 °C with and without CuI and DMEDA. Whereas (E)-
1,2-diiodophenylethylene did not isomerize to the Z-isomer,
an isomerization of 1,2-dibromophenylethylene was
obtained in cases of older substrates or if small amounts of
bromine were added. Bromine-catalyzed isomerizations of
dihaloalkenes have previously been described, see: Uemura,
S.; Okazaki, H.; Okano, M. J. Chem. Soc., Perkin Trans. 1
1978, 1278.
References
(9) Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A.
V. Tetrahedron 1999, 55, 11127.
(10) Pagni, R. M.; Kabalka, G. W.; Boothe, R.; Gaetano, K.;
Stewart, L. J.; Conaway, R.; Dial, C.; Gray, D.; Larson, S.;
Luidhardt, T. J. Org. Chem. 1988, 53, 4477.
(11) Al-Hassan, M. I. J. Organomet. Chem. 1989, 372, 183.
(12) Kodomari, M.; Sakamoto, T.; Yoshitomi, S. Bull. Chem.
Soc. Jpn. 1989, 62, 4053.
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Vol. 60; Palmer, D. C., Ed.; J. Wiley & Sons: Hoboken,
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Synthesis 2007, No. 15, 2297–2306 © Thieme Stuttgart · New York