2-Oxazol-5-ylethanones by consecutive three-component amidation-coupling- cycloisomerization (ACCI) sequence

Article abstract of DOI:10.1055/s-0028-1083294

Substituted oxazol-5-ylethanones can be synthesized in a consecutive three-component sequence starting from propargylamine and various acid chlorides, both for amidation and cross-coupling. Therefore, this diversity-oriented one-pot approach to substitute

Full text of DOI:10.1055/s-0028-1083294

502
PRACTICAL SYNTHETIC PROCEDURES
2-Oxazol-5-ylethanones by Consecutive Three-Component
Amidation–Coupling–Cycloisomerization (ACCI) Sequence
T
hree-Compone
u
nt
O
xazole
g
S
ynthesis en Merkul, Oliver Grotkopp, Thomas J. J. Müller*
Lehrstuhl für Organische Chemie, Institut für Organische Chemie und Makromolekulare Chemie,
Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany
Fax +49(211)8114324; E-mail: ThomasJJ.Mueller@uni-duesseldorf.de
PSP
Received 4 September 2008; revised 5 September 2008
No145
Abstract: Substituted oxazol-5-ylethanones can be synthesized in a consecutive three-component sequence starting from propargylamine
and various acid chlorides, both for amidation and cross-coupling. Therefore, this diversity-oriented one-pot approach to substituted ox-
azoles can be considered as an amidation-coupling-cycloisomerization (ACCI) sequence.
Key words: C–C coupling, catalysis, cycloisomerization, multi-component reactions, oxazoles
O
O
(2)
Et3N, THF, 1 h
N
R1
Cl
Cl
H2N
R1
R2
O
O
1
then:
(2')
[PdCl2(PPh3)2, CuI]
Et3N, 1 h
3 (42–74%, 17 examples)
R2
then: PTSA·H2O, t-BuOH, 1 h
Scheme 1
argylamine (1) with acid chlorides 2, followed by
Sonogashira alkynylation of the acid chlorides 2¢ with the
Introduction
Oxazoles are prevalent substructures in natural products, propargyl amides 4 to give the alkynones 5 (Scheme 2).12
synthetic intermediates, and pharmaceuticals.1–3 Interest- By addition of one equivalent of p-toluenesulfonic acid
ingly, many macrocyclic derivatives either from bacteria monohydrate (PTSA·H2O) and tert-butyl alcohol to the
or from marine organisms containing oxazole units are reaction mixture and gentle heating, alkynones 5 cycloi-
highly cytotoxic, antitubuline, and antitumor active.4 But somerize to furnish the substituted oxazol-5-ylethanones
even simpler structures such as oxazolyl acetic acid and 3 (Scheme 2).
their (hetero)aromatic derivatives have been shown
to be antipyretic and antihyperglycemic.5 Besides the
Robinson–Gabriel synthesis,6,7 that is, the cyclocondensa-
tion of a-acylamino ketones with strongly dehydrating
Scope and Limitation
agents, milder methods for the preparation of highly func- Methodologically, the one-pot three-component ACCI
tionalized oxazoles are still highly desirable.8 In particu- synthesis of substituted oxazol-5-ylethanones 3 proceeds
lar, propargyl amides undergo cycloisomerization to 2,5- efficiently under mild conditions with a wide variety of
disubstituted oxazoles by acid or base catalysis, by palla- electronically diverse acid chlorides (Table 1). In addi-
dium-catalyzed coupling of aryl iodides in the presence of tion, acid chlorides with halogens (Table 1, entries 4, 6–
sodium tert-butoxide,9 or by gold catalysis.10 Recently, as 9), alkenes (entries 13, 15–17), and heterocycles (entries
part of our program directed to develop new one-pot 5, 11, 12, 14) as substituents can be carried through the se-
multi-component heterocycle syntheses initiated by quence without interference. However, the major advan-
alkyne coupling,11 we have disclosed a novel one-pot tage of this procedure is the use of only equimolar
three-component synthesis of substituted oxazol-5-yleth- amounts of reactants and additives. All this renders the
anones 3 (Scheme 1).12 This three-component method- one-pot process very economic and rapid (3 h).
ological extension of Wipf’s elegant synthesis of the
In summary, the consecutive three-component amida-
structural motif13 commences with the amidation of prop-
tion–coupling–cycloisomerization (ACCI) synthesis of
substituted oxazol-5-ylethanones opens a straightforward,
economical access to oxazoles and can serve as an entry
to more complex substituted heterocycles by oxazole
transformations.
SYNTHESIS 2009, No. 3, pp 0502–0507
Advanced online publication: 19.12.2008
DOI: 10.1055/s-0028-1083294; Art ID: Z20508SS
x
x
.
x
x
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Three-Component Oxazole Synthesis
503
O
O
Et3N (1 equiv)
THF, 0 °C to r.t., 1 h
N
H2N
R1
Cl
R1
R2
+
O
then: PdCl2(PPh3)2 (2 mol%), CuI (4 mol%)
R2COCl (2') (1.0 equiv) , Et3N (1.0 equiv)
then: PTSA·H2O (1.0 equiv)
1
2
3
t-BuOH, 60 °C, 1 h
cycloisomerization
O
amidation
O
O
2'
R2
Cl
NH
R1
O
NH
R1
[PdII, CuI]
coupling
R2
4
5
Scheme 2 One-pot three-component synthesis of substituted oxazol-5-ylethanones and mechanistic rationale
Table 1 One-Pot Three-Component Synthesis of Substituted Oxazol-5-ylethanones 3
Entry
First acid chloride
Second acid chloride
Oxazole product
Yield
(%)
2
R1
2¢
R2
3
O
N
1
2
2a
Ph
2a¢
Ph
3a
3b
70
58
Ph
Ph
O
O
N
2b
2c
2c
4-MeOC6H4
4-MeC6H4
4-MeC6H4
2c¢
2b¢
2d¢
4-MeC6H4
4-MeOC6H4
4-ClC6H4
O
MeO
Me
OMe
Cl
O
N
N
N
3
4
3c
72
74
O
O
O
Me
Me
O
3d
O
O
5
6
2c
4-MeC6H4
4-ClC6H4
2e¢
2a¢
2-thienyl
Ph
3e
3f
73
75
S
Me
Cl
N
N
2d
Ph
O
O
O
7
8
9
2d
2f
4-ClC6H4
2-FC6H4
2c¢
2c¢
2g¢
4-MeC6H4
4-MeC6H4
2-BrC6H4
3g
3h
3i
59
68
50
Cl
Me
O
N
O
Me
F
O
N
2c
4-MeC6H4
O
Me
Br
Synthesis 2009, No. 3, 502–507 © Thieme Stuttgart · New York

504
E. Merkul et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 One-Pot Three-Component Synthesis of Substituted Oxazol-5-ylethanones 3 (continued)
Entry
10
First acid chloride
Second acid chloride
Oxazole product
Yield
(%)
2
R1
2¢
R2
3
O
N
O
2h
4-O2NC6H4
2c¢
4-MeC6H4
3j
68
O
O2N
Me
N
11
12
2a
2h
Ph
2e¢
2e¢
2-thienyl
2-thienyl
3k
3l
53
56
S
Ph
O
O
N
O
2-O2NC6H4
S
O
O2N
N
13
14
2a
2e
Ph
2i¢
2-styryl
Ph
3m
3n
49
70
Ph
S
Ph
O
O
N
2-thienyl
2a¢
Ph
O
N
O
Ph
15
16
2i
2j
2-styryl
2c¢
2c¢
4-MeC6H4
4-MeC6H4
3o
3p
66
57
O
Me
O
N
cyclohexen-1-yl
O
Me
O
N
17
2k
ethenyl
2c¢
4-MeC6H4
3q
42
O
Me
All reactions involving water-sensitive compounds were carried out
in oven-dried Schlenk glassware under argon or nitrogen. THF and
Et3N were dried with ketylsodium according to standard
procedures14 and were distilled prior to use. Column chromatogra-
phy: silica gel 60 M (mesh 230–400) Macherey-Nagel. TLC: silica
gel layered aluminum foil (60 F254 Merck, Darmstadt). Melting
points (uncorrected): Reichert-Jung Thermovar and Büchi Melting
Point B-540. Propargylamine (1) and acid chlorides 2, PTSA·H2O,
PdCl2(PPh3)2, and CuI were purchased from ACROS, Aldrich Che-
mie GmbH, Fluka AG, Lancaster AG, or Merck KGaA and used
without further purification. 1H and 13C NMR spectra: Bruker
ARX250, Bruker DRX 300, Bruker DRX 300 or Bruker DRX 500
with CDCl3 as solvent. The assignments of quaternary C, CH, CH2,
and CH3 were made on the basis of DEPT spectra. MS: Jeol JMS-
700 und Finnigan TSQ 700. Elemental analyses were carried out in
the microanalytical laboratory of the Organisch-Chemisches Insti-
tut der Universität Heidelberg and in the microanalytical laboratory
of the Pharmazeutisches Institut of the Heinrich-Heine-Universität
Düsseldorf.
mg, 0.02 mmol), CuI (8 mg, 0.04 mmol), acid chloride 2¢ (1.00
mmol), and Et3N (0.14 mL, 1.00 mmol) were successively added to
the reaction mixture and the stirring was continued for 1 h at r.t.
Then, to the brown mixture PTSA·H2O (190 mg, 1.00 mmol) and t-
BuOH (1 mL) were added and the stirring was continued for 1 h at
60 °C. After cooling to r.t., brine (20 mL) was added and the mix-
ture was extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were dried (Na2SO4) and after evaporation of the solvents the
residue was chromatographed on silica gel with hexanes–EtOAc as
eluent in variable ratios to give the analytically pure 1-(hetero)aryl-
2-oxazol-5-ylethanones 3.
3a13
Acid chlorides 2a (141 mg, 1.00 mmol) and 2a¢ (141 mg, 1.00
mmol) were used according to the general procedure to produce 185
mg (70%) of 3a as a colorless amorphous solid; mp 84–85 °C.
1H NMR (300 MHz, CDCl3): d = 4.43 (s, 2 H), 7.14 (s, 1 H), 7.39–
7.55 (m, 5 H), 7.57–7.65 (m, 1 H), 7.96–8.06 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 36.0, 126.2, 126.9 127.5, 128.5,
128.7, 128.8, 130.2, 133.7, 135.9, 145.5, 161.6, 193.7.
2-Oxazol-5-ylethanones; General Procedure
To a solution of propargylamine (1; 56 mg, 1.00 mmol) in anhyd de-
gassed THF (5 mL) in a flame-dried screw-cap vessel under argon
were successively added acid chloride 2 (1.00 mmol) and Et3N
(0.14 mL, 1.00 mmol) at 0 °C (external cooling with ice-water) (for
experimental details see Table 1). After stirring for 1 h at r.t., a col-
orless to pale yellow precipitate formed. Then, PdCl2(PPh3)2 (14
3b
Acid chlorides 2b (171 mg, 1.00 mmol) and 2c¢ (158 mg, 1.00
mmol) were used according to the general procedure to produce 179
mg (58%) of 3b as light yellow needles; mp 88 °C (CH2Cl2–pen-
tane).
Synthesis 2009, No. 3, 502–507 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Three-Component Oxazole Synthesis
505
1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3 H), 3.84 (s, 3 H), 4.38
(s, 2 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.06 (s, 1 H), 7.29 (d, J = 7.9 Hz,
2 H), 7.90–7.96 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 21.7, 35.9, 55.4, 114.1, 120.4,
126.5, 127.9, 128.6, 129.5, 133.5, 144.6, 145.1, 161.2, 161.6, 193.5.
mg (59%) of 3g as colorless platelets; mp 138 °C (CH2Cl2–pen-
tane).
1H NMR (500 MHz, CDCl3): d = 2.44 (s, 3 H), 4.42 (s, 2 H), 7.17
(s, 1 H), 7.31 (d, J = 7.9 Hz, 2 H), 7.42 (d, J = 8.7 Hz, 2 H), 7.86 (d,
J = 8.2 Hz, 2 H), 7.91 (d, J = 8.7 Hz, 2 H).
Anal. Calcd for C19H17NO3 (307.3): C, 74.25; H, 5.58; N, 4.56.
Found: C, 74.02; H, 5.58; N, 4.55.
13C NMR (125 MHz, CDCl3): d = 22.2, 36.2, 125.8, 126.7, 128.1,
129.0, 129.6, 130.0, 133.7, 137.1, 145.3, 146.7, 161.1, 193.4.
Anal. Calcd for C18H14ClNO2 (311.8): C, 69.35; H, 4.53; N, 4.49.
Found: C, 69.27; H, 4.67; N, 4.37.
3c
Acid chlorides 2c (158 mg, 1.00 mmol) and 2b¢ (171 mg, 1.00
mmol) were used according to the general procedure to produce 222
mg (72%) of 3c as a yellow solid; mp 95 °C (CH2Cl2–pentane).
1H NMR (500 MHz, CDCl3): d = 2.39 (s, 3 H), 3.88 (s, 3 H), 4.38
(s, 2 H), 6.97 (d, J = 9.0 Hz, 2 H), 7.13 (s, 1 H), 7.24 (d, J = 8.0 Hz,
2 H), 7.91 (d, J = 8.2 Hz, 2 H), 8.01 (d, J = 8.9 Hz, 2 H).
3h
Acid chlorides 2f (159 mg, 1.00 mmol) and 2c¢ (158 mg, 1.00
mmol) were used according to the general procedure to produce 202
mg (68%) of 3h as colorless thin platelets; mp 88 °C (CH2Cl2–pen-
tane).
13C NMR (125 MHz, CDCl3): d = 20.5, 34.7, 54.7, 113.0, 123.2,
1H NMR (300 MHz, CDCl3): d = 2.43 (s, 3 H), 4.43 (d, J = 1.3 Hz,
2 H), 7.13–7.25 (m, 3 H), 7.30 (d, J = 7.9 Hz, 2 H), 7.36–7.45 (m, 1
H), 7.94 (d, J = 8.3 Hz, 2 H), 7.96–8.03 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.7, 35.9, 115.8 (d, J = 11.1 Hz),
116.8 (d, J = 22.1 Hz), 124.3 (d, J = 4.2 Hz), 126.9, 128.6, 129.5,
129.5 (d, J = 9.7 Hz), 131.7 (d, J = 8.3 Hz), 133.5, 144.7, 146.1,
157.8 (d, J = 4.2 Hz), 159.9 (d, J = 257.4 Hz), 193.2.
124.8, 125.3, 127.9, 128.5, 129.8, 139.9, 144.7, 160.7, 163.0, 191.1.
Anal. Calcd for C19H17NO3 (307.3): C, 74.25; H, 5.58; N, 4.56.
Found: C, 74.04; H, 5.61; N, 4.66.
3d
Acid chlorides 2c (158 mg, 1.00 mmol) and 2d¢ (177 mg, 1.00
mmol) were used according to the general procedure to produce 232
mg (74%) of 3d as light beige platelets; mp 139 °C (CH2Cl2–pen-
tane).
Anal. Calcd for C18H14FNO2 (295.3): C, 73.21; H, 4.78; N, 4.74.
Found: C, 73.42; H, 4.79; N, 4.77.
1H NMR (300 MHz, CDCl3): d = 2.39 (s, 3 H), 4.39 (s, 2 H), 7.10
(s, 1 H), 7.24 (d, J = 8.3 Hz, 2 H), 7.48 (d, J = 8.3 Hz, 2 H), 7.88 (d,
J = 8.3 Hz, 2 H), 7.97 (d, J = 8.3 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.5, 36.0, 124.7, 126.2, 126.8,
129.2, 129.5, 129.9, 134.2, 140.3, 140.6, 144.7, 161.9, 192.6.
3i
Acid chlorides 2c (158 mg, 1.00 mmol) and 2g¢ (220 mg, 1.00
mmol) were used according to the general procedure to produce 178
mg (50%) of 3i as brown columns; mp 86 °C (CH2Cl2–pentane).
1H NMR (300 MHz, CDCl3): d = 2.39 (s, 3 H), 4.40 (d, J = 1.0 Hz,
2 H), 7.08 (s, 1 H), 7.24 (d, J = 7.5 Hz, 2 H), 7.27–7.47 (m, 3 H),
7.60–7.65 (m, 1 H), 7.87 (d, J = 8.3 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.5, 39.6, 118.8, 124.7, 126.2,
126.9, 127.6, 128.9, 129.4, 132.1, 133.8, 140.5, 140.5, 144.3, 161.9,
197.8.
Anal. Calcd for C18H14ClNO2 (311.8): C, 69.35; H, 4.53; N, 4.49;
Cl, 11.37. Found: C, 69.42; H, 4.59; N, 4.49; Cl, 11.16.
3e
Acid chlorides 2c (158 mg, 1.00 mmol) and 2e¢ (150 mg, 1.00
mmol) were used according to the general procedure to produce 205
mg (73%) of 3e as brown crystals; mp 104 °C (CH2Cl2–pentane).
Anal. Calcd for C18H14BrNO2 (356.2): C, 60.69; H, 3.96; N, 3.93;
Br, 22.43. Found: C, 60.68; H, 3.99; N, 3.98; Br, 22.26.
1H NMR (500 MHz, CDCl3): d = 2.39 (s, 3 H), 4.35 (s, 2 H), 7.13
(s, 1 H), 7.17 (m, 1 H), 7.24 (d, J = 8.3 Hz, 2 H), 7.71 (dd,
J = 1.0, 4.9 Hz, 1 H), 7.83 (dd, J = 1.0, 3.8 Hz, 1 H), 7.91 (d, J = 8.2
Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 21.9, 37.1, 124.8, 126.7, 126.7,
128.8, 129.9, 133.3, 135.2, 141.2, 143.3, 145.2, 162.3, 186.8.
3j
Acid chlorides 2h (186 mg, 1.00 mmol) and 2c¢ (158 mg, 1.00
mmol) were used according to the general procedure to produce 220
mg (68%) of 3j as a yellow solid; mp 190 °C (dec., CH2Cl2–pen-
tane).
1H NMR (300 MHz, CDCl3): d = 2.44 (s, 3 H), 4.46 (s, 2 H), 7.23
(s, 1 H), 7.32 (d, J = 8.3 Hz, 2 H), 7.94 (d, J = 8.3 Hz, 2 H), 8.16 (d,
J = 8.8 Hz, 2 H), 8.30 (d, J = 8.8 Hz, 2 H).
Anal. Calcd for C16H13NO2S (283.3): C, 67.82; H, 4.62; N, 4.94.
Found: C, 67.63; H, 4.56; N, 5.04.
3f
13C NMR (75 MHz, CDCl3): d = 21.8, 35.8, 124.2, 126.9, 127.9,
Acid chlorides 2d (177 mg, 1.00 mmol) and 2a¢ (141 mg, 1.00
mmol) were used according to the general procedure to produce 225
mg (75%) of 3f as colorless platelets; mp 128–129 °C (CH2Cl2–
pentane).
128.6, 129.6, 132.9, 133.3, 145.0, 147.6, 148.5, 159.5, 192.9.
Anal. Calcd for C18H14N2O4 (322.3): C, 67.08; H, 4.38; N, 8.69.
Found: C, 66.69; H, 4.35; N, 8.66.
1H NMR (300 MHz, CDCl3): d = 4.44 (d, J = 0.7 Hz, 2 H), 7.14 (s,
1 H), 7.40 (d, J = 8.7 Hz, 2 H), 7.47–7.55 (m, 2 H), 7.62 (tt, J = 2.1,
7.3 Hz, 1 H), 7.93 (d, J = 8.7 Hz, 2 H), 8.00–8.06 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 35.9, 126.8, 127.5, 127.9, 128.1,
128.5, 128.8, 130.1, 133.8, 135.9, 145.0, 157.8, 193.6.
3k
Acid chlorides 2a (141 mg, 1.00 mmol) and 2e¢ (150 mg, 1.00
mmol) were used according to the general procedure to produce 143
mg (53%) of 3k as a yellow solid; mp 118 °C (CH2Cl2–pentane).
1H NMR (300 MHz, CDCl3): d = 4.36 (d, J = 0.8 Hz, 2 H), 7.14 (s,
1 H), 7.17 (dd, J = 3.8, 4.9 Hz, 1 H), 7.40–7.46 (m, 3 H), 7.70 (dd,
J = 1.1, 5.1 Hz, 1 H), 7.83 (dd, J = 1.1, 3.8 Hz, 1 H), 7.97–8.03 (m,
2 H).
Anal. Calcd for C17H12ClNO2 (297.7): C, 68.58; H, 4.06; N, 4.70;
Cl, 11.91. Found: C, 68.21; H, 4.02; N, 4.68; Cl, 12.12.
3g
13C NMR (75 MHz, CDCl3): d = 36.7, 126.2, 126.9, 127.4, 128.4,
Acid chlorides 2d (177 mg, 1.00 mmol) and 2c¢ (158 mg, 1.00
mmol) were used according to the general procedure to produce 183
128.7, 130.2, 132.9, 134.8, 142.9, 145.1, 161.7, 186.4.
HRMS: m/z calcd for C15H11NO2S: 269.0510; found: 269.0490.
Synthesis 2009, No. 3, 502–507 © Thieme Stuttgart · New York

506
3l
E. Merkul et al.
PRACTICAL SYNTHETIC PROCEDURES
3q
Acid chlorides 2h (186 mg, 1.00 mmol) and 2e¢ (150 mg, 1.00
mmol) were used according to the general procedure to produce 177
mg (56%) of 3l as an orange solid; mp 167 °C (CH2Cl2–pentane).
Acid chlorides 2k (94 mg, 1.00 mmol) and 2c¢ (158 mg, 1.00 mmol)
were used according to the general procedure to produce 95 mg
(42%) of 3q as a yellow oil.
1H NMR (500 MHz, CDCl3): d = 4.40 (d, J = 0.8 Hz, 2 H), 7.18 (dd,
J = 3.8, 4.9 Hz, 1 H), 7.23 (t, J = 0.8 Hz, 1 H), 7.72 (d, J = 1.1, 4.9
Hz, 1 H), 7.83 (d, J = 1.1, 3.8 Hz, 1 H), 8.14 (d, J = 8.7 Hz, 2 H),
8.27 (d, J = 8.7 Hz, 2 H).
1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3 H), 4.33 (s, 2 H), 5.56
(d, J = 11.4 Hz, 1 H), 6.10 (dd, J = 0.9, 17.5 Hz, 1 H), 6.55 (dd,
J = 11.4, 17.5 Hz, 1 H), 7.03 (s, 1 H), 7.28 (d, J = 8.8 Hz, 2 H), 7.90
(d, J = 8.3 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 36.9, 124.6, 127.3, 128.2, 128.9,
133.0, 133.4, 135.5, 143.1, 147.3, 149.0, 156.0, 186.3.
13C NMR (75 MHz, CDCl3): d = 21.7, 35.8, 121.3, 123.4, 126.6,
128.6, 129.5, 133.4, 144.7, 145.5, 160.9, 193.3.
Anal. Calcd for C15H10N2O4S (314.3): C, 57.32; H, 3.21; N, 8.91.
Found: C, 57.26; H, 3.04; N, 8.79.
HRMS: m/z calcd for C14H13NO2: 227.0946; found: 227.0968.
3m13
Acknowledgment
Acid chlorides 2a (141 mg, 1.00 mmol) and 2i¢ (170 mg, 1.00
mmol) were used according to the general procedure to produce 143
mg (49%) of 3m as a yellow solid; mp 97 °C.
1H NMR (300 MHz, CDCl3): d = 4.09 (s, 2 H), 6.84 (d, J = 15.8 Hz,
1 H), 7.13 (s, 1 H), 7.35–7.48 (m, 6 H), 7.52–7.58 (m, 2 H), 7.70 (d,
J = 15.8 Hz, 1 H), 7.98–8.05 (m, 2 H).
Financial support of the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie, and the Studienstiftung des Deut-
schen Volkes (scholarship for E.M.) is gratefully acknowledged.
We also cordially thank BASF AG for generous donation of chemi-
cals.
13C NMR (75 MHz, CDCl3): d = 38.4, 124.3, 126.2, 126.7, 127.4,
128.5, 128.7, 129.0, 130.2, 130.9, 134.0, 144.4, 145.5, 161.7, 193.3.
References
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A., Ed.; Academic Press: New York, 1989, 259. (b) Wipf,
P. Chem. Rev. 1995, 95, 2115. (c) Jin, Z. Nat. Prod. Rep.
2003, 20, 584. (d) Oxazoles: Synthesis, Reactions, and
Spectroscopy, Part A, Vol. 60; Palmer, D. C., Ed.; Wiley:
Hoboken NJ, 2003.
(2) (a) Oxazoles: Synthesis, Reactions, and Spectroscopy, Part
B, Vol. 60; Palmer, D. C., Ed.; Wiley: Hoboken NJ, 2004.
(b) Boyd, G. V. In Science of Synthesis, Vol. 11;
Schaumann, E., Ed.; Georg Thieme Verlag: Stuttgart, 2002,
383. (c) Hartner, F. W. Jr. In Comprehensive Heterocyclic
Chemistry II, Vol. 3; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V., Eds.; Elsevier: Oxford, 1996, 261. (d) Maryanoff,
B. E. Chemistry of Heterocyclic Compounds, Vol. 45;
Turchi, I. J., Ed.; Wiley: Chichester, 1986, 963. (e) Turchi,
I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389.
(3) See, for example: (a) Dalvie, D. K.; Kalgutkar, A. S.;
Khojasteh-Bakht, S. C.; Obach, R. S.; O’Donnell, J. P.
Chem. Res. Toxicol. 2002, 15, 269. (b) McGovern, S. L.;
Caselli, E.; Grigorieff, N.; Shoichet, B. K. J. Med. Chem.
2002, 45, 1712. (c) Murcia-Soler, M.; Perez-Gimenez, F.;
Garcia-March, F. J.; Salabert-Salvador, M. T.; Diaz-
Villanueva, W.; Castro-Bleda, M. J.; Villanueva-Pareja, A.
J. Chem. Inf. Comput. Sci. 2004, 44, 1031.
(4) (a) For syntheses of oxazole containing macrocycles and
their biological activity, see, for example, ref. 1b. (b) For a
recent synthesis, see, for example: Wipf, P.; Graham, T. H.
J. Am. Chem. Soc. 2004, 126, 15346.
3n
Acid chlorides 2e (150 mg, 1.00 mmol) and 2a¢ (141 mg, 1.00
mmol) were used according to the general procedure to produce 190
mg (70%) of 3n as a brown solid; mp 108 °C (EtOAc–pentane).
1H NMR (500 MHz, CDCl3): d = 4.42 (s, 2 H), 7.06–7.11 (m, 2 H),
7.39 (d, J = 4.9 Hz, 1 H), 7.51 (t, J = 7.7 Hz, 2 H), 7.59–7.64 (m, 2
H), 8.03 (d, J = 7.7 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 35.9, 126.8, 127.5, 127.9, 128.1,
128.5, 128.8, 130.1, 133.8, 135.9, 145.0, 157.8, 193.6.
HRMS: m/z calcd for C15H11NO2S: 269.0510, found: 269.0502.
3o
Acid chlorides 2i (170 mg, 1.00 mmol) and 2c¢ (158 mg, 1.00
mmol) were used according to the general procedure to produce 200
mg (66%) of 3o as a yellow solid; mp 101 °C.
1H NMR (300 MHz, CDCl3): d = 2.43 (s, 3 H), 4.37 (d, J = 0.9 Hz,
2 H), 6.91 (d, J = 16.2 Hz, 1 H), 7.07 (s, 1 H), 7.26–7.41 (m, 5 H),
7.44 (d, J = 16.7 Hz, 1 H), 7.48–7.53 (m, 2 H), 7.92 (d, J = 8.3 Hz,
2 H).
13C NMR (75 MHz, CDCl3): d = 21.7, 35.9, 114.0, 126.9, 127.1,
128.6, 128.8, 129.1, 129.5, 133.4, 135.6, 135.6, 144.7, 145.4, 161.4,
193.3.
Anal. Calcd for C20H17NO2 (303.4): C, 79.19; H, 5.65; N, 4.62.
Found: C, 78.96; H, 5.65; N, 4.57.
(5) (a) Brown, W. K. (John Wyeth & Brothers Ltd.); US Patent
3p
3574228, 1971; Chem. Abstr. 1969, 71, 124422.
Acid chlorides 2j (145 mg, 1.00 mmol) and 2c¢ (158 mg, 1.00
mmol) were used according to the general procedure to produce 161
mg (57%) of 3p as a yellow oil.
1H NMR (300 MHz, CDCl3): d = 1.59–1.77 (m, 4 H), 2.16–2.25 (m,
2 H), 2.40–2.49 (m, 5 H), 4.30 (d, J = 0.9 Hz, 2 H), 6.67–6.73 (m, 1
H), 6.96 (t, J = 0.9 Hz, 1 H), 7.28 (d, J = 7.9 Hz, 2 H), 7.90 (d,
J = 8.3 Hz, 2 H).
(b) Meguro, K.; Fujita, T. (Takeda Chemical Ind.); US
Patent 4596816, 1986; Chem Abstr. 1984, 100, 121045.
(6) Wasserman, H. H.; Vinick, F. J. J. Org. Chem. 1973, 38,
2407.
(7) Dow, R. L. J. Org. Chem. 1990, 55, 386.
(8) (a) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604.
(b) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558.
(c) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams,
D. R. Org. Lett. 2000, 2, 1165. (d) Wipf, P.; Methot, J.-L.
Org. Lett. 2001, 3, 1261.
13C NMR (75 MHz, CDCl3): d = 21.7, 21.8, 22.1, 24.5, 25.4, 35.9,
125.9, 126.0, 126.2, 128.6, 129.5, 131.0, 133.5, 144.6, 162.9, 193.6.
HRMS: m/z calcd for C18H19NO2: 281.1416; found: 281.1424.
Synthesis 2009, No. 3, 502–507 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Three-Component Oxazole Synthesis
507
(9) (a) Wipf, P.; Rahman, L. T.; Rector, S. R. J. Org. Chem.
1998, 63, 7132. (b) Arcadi, A.; Cacchi, S.; Cascia, L.;
Fabrizi, G.; Marinelli, F. Org. Lett. 2001, 3, 2501.
(c) Coqueron, P.-Y.; Didier, C.; Ciufolini, M. A. Angew.
Chem. Int. Ed. 2003, 42, 1411.
Attanasi, O. A.; Spinelli, D., Eds.; Italian Society of
Chemistry: Rome, 2006, 54. (d) Müller, T. J. J.; D’Souza,
D. M. Pure Appl. Chem. 2008, 80, 609.
(12) Merkul, E.; Müller, T. J. J. Chem. Commun. 2006, 4817.
(13) Wipf, P.; Aoyama, Y.; Benedum, T. E. Org. Lett. 2004, 6,
3593.
(10) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W.
Org. Lett. 2004, 6, 4391.
(14) Becker, H. G. O.; Beckert, R.; Domschke, G.; Fanghänel, E.;
Habicher, W. D.; Metz, P.; Pavel, D.; Schwetlick, K.
Organikum, 21st ed.; Wiley-VCH: Weinheim, 2001.
(11) For reviews, see: (a) D’Souza, D. M.; Müller, T. J. J. Chem.
Soc. Rev. 2007, 36, 1095. (b) Müller, T. J. J. Chim. Oggi/
Chem. Today 2007, 25, 70. (c) Müller, T. J. J. In Targets in
Heterocyclic Systems: Chemistry and Properties, Vol. 10;
Synthesis 2009, No. 3, 502–507 © Thieme Stuttgart · New York