A new consecutive three-component oxazole synthesis by an amidation-coupling-cycloisomerization (ACCI) sequence

Article abstract of DOI:10.1039/b610839c

A novel consecutive three-component synthesis of 1-(hetero)aryl-2-(2- (hetero)aryl-oxazol-5-yl) ethanones starting from propargyl amine and acid chlorides, both for amidation and cross-coupling, is based upon an amidation-coupling-cycloisomerization (ACCI

Full text of DOI:10.1039/b610839c

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A new consecutive three-component oxazole synthesis by an amidation–
coupling–cycloisomerization (ACCI) sequence{
Eugen Merkul and Thomas J. J. Mu¨ller*
Received (in Cambridge, UK) 27th July 2006, Accepted 12th September 2006
First published as an Advance Article on the web 29th September 2006
DOI: 10.1039/b610839c
Sonogashira coupling of propargyl amides, derived from acid
chlorides 3 (substituent R1) and propargyl amine (4), and acid
chlorides 39 (substituent R2) (Scheme 1). Methodologically most
challenging, however, is the implementation of amidation, cross-
coupling, and cycloisomerization as a consecutive and one-pot
process.
A novel consecutive three-component synthesis of 1-(hetero)-
aryl-2-(2-(hetero)aryl-oxazol-5-yl) ethanones starting from
propargyl amine and acid chlorides, both for amidation and
cross-coupling, is based upon an amidation–coupling–cycloi-
somerization (ACCI) sequence.
Oxazoles are widespread structural units in natural products of
various sources, synthetic intermediates, and pharmaceuticals.1–3
Most remarkably, many macrocyclic compounds from bacteria or
of marine origin with oxazole units display significant cytotoxic,
antitubuline and antitumor activity.4 But also simple structures
such as oxazolyl acetic acid and their (hetero)aromatic derivatives
have proven to be antipyretic and antihyperglycemic.5 Among
several oxazole syntheses the Robinson–Gabriel synthesis, where
a-acylamino ketones are cyclocondensed with strongly dehydrat-
ing agents6,7 has remained the most popular method. Although,
widely used for the synthesis of 2,5-diaryloxazoles, the conditions
of cyclodehydration are relatively harsh and have lead to milder
methods for the preparation of highly functionalized oxazoles.8
Interestingly, propargyl amides can be cycloisomerized to 2,5-
disubstituted oxazoles by acid or base catalysis, by palladium
catalyzed coupling of aryl iodides in the presence of sodium tert-
butoxide,9 or by gold catalysis.10 However, efficient and concise
syntheses of oxazol-5-yl-carbonyl compounds, particularly as
diversity oriented one-pot processes, are still a methodological
challenge.11 As part of our program directed to develop new one-
pot multi-component heterocycle syntheses initiated by transition
metal catalyzed alkyne coupling,12 here, we communicate a novel
one-pot three-component synthesis of 1-(hetero)aryl-2-(2-(hetero)-
aryl-oxazol-5-yl) ethanones.
Hence, reaction of benzoyl chloride (3a) and propargyl amine
(4) in the presence of one equiv. of triethylamine gave
quantitatively the propargyl amide 5a. Subsequent addition of
another equiv. of 3a under modified Sonogashira conditions,
followed by rapid cycloisomerization of the presumed intermediate
2a, achieved by addition of one equiv. of PTSA (p-toluene sulfonic
acid) monohydrate and 1 mL of tert-butanol, gave 1-phenyl-2-(2-
phenyl-oxazol-5-yl) ethanone (1a) in 70% yield (Scheme 2, Table 1).
The coupling of acid chlorides and propargyl amides has been
known to give rise to the formation of the corresponding ynones in
good to excellent yields.14 However, no cycloisomerization was
observed to give the oxazol-5-yl-carbonyl compounds. Here, the
terminal cycloisomerization to the oxazole 1a proceeds after 5 days
in reasonable yields also without any further reagent addition
(entry 1). Just recently, Wipf et al.11 has reported an elegant
synthesis of oxazol-5-yl-carbonyl compounds by cycloisomeriza-
tion of acyl propargyl amides on silica, however, our optimization
studies revealed that these conditions (entry 2) proved to be
unsuccessful, but the presence of PTSA and tert-butanol as a non
nucleophilic protic solvent completes the conversion to the oxazole
at 60 uC within 1 h (entry 6).
In the past years, we have developed a modification of the
Sonogashira coupling of acid chlorides and terminal alkynes to
alkynones,12 where only one stoichiometricly necessary equivalent of
triethylamine as a hydrochloric acid scavenging base is applied.
Since ynones are key intermediates in heterocycle synthesis, a
multi-component approach to oxazol-5-yl-carbonyl compounds
should be feasible via Sonogashira coupling. Additionally, the
reaction medium for amide formation is highly compatible with
Sonogashira coupling.13 Retrosynthetically, this now suggests a
formation of oxazol-5-yl-carbonyl compounds 1 by cycloisome-
rization of propargyl amides 2 which, in turn, are accessible by
Scheme 1 Retrosynthetic analysis of oxazol-5-yl-carbonyl compounds 1.
Organisch-Chemisches Institut der Ruprecht-Karls-Universita¨t
Heidelberg, Im Neuenheimer Feld 270, D-69120, Heidelberg, Germany.
E-mail: Thomas.J.J.Mueller@oci.uni-heidelberg.de;
Fax: +49(0)6221546579; Tel: +49(0)6221546207
{ Electronic supplementary information (ESI) available: Experimental
procedures and characterization for compounds 1. See DOI: 10.1039/
b610839c
Scheme 2 Mechanistic rationale of the amidation–coupling–cycloisome-
rization sequence.
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The structures of the oxazole derivatives were unambiguously
supported by spectroscopic (1H, 13C and DEPT, COSY,
HETCOR and HMBC NMR experiments, IR, UV-vis, mass
spectrometry) and combustion analyses. Additionally, the mole-
cular structure was corroborated by an X-ray structure analysis of
compound 1b (Fig. 1).{
Methodologically, this new one-pot three-component ACCI
synthesis of 1-(hetero)aryl-2-(2-(hetero)aryl-oxazol-5-yl) ethanones
1 proceeds efficiently under mild conditions with a wide variety of
electronically diverse acid chlorides. In comparison, the existing
protocol for the synthesis of oxazoles 1 requires four steps
consisting of amidation of propargyl amine, addition of the
lithium acetylides to aldehydes, Dess–Martin oxidation of
the resulting propargyl alcohol, and cycloisomerization, and the
isolation of the intermediates is necessary.10 Furthermore, no polar
functionality is tolerated and the diversity of the methodology is
quite restricted. Here, however, halo (entry 3) and nitro groups
(entry 4) can be carried through the sequence without any
problem.
Table 1 Optimization of the coupling–cycloisomerization steps of
propargyl amide 5a and benzoyl chloride (3a) to give 1-phenyl-2-(2-
phenyl-oxazol-5-yl) ethanone (1a)
Oxazole
1aa
Entry Cross-coupling
Cycloisomerization
—
1
2
3
4
5
NEt3 (1 eq), rt, 5 d
NEt3 (1 eq), rt, 2 h 1 g of silica gel, rt, 16 h
NEt3 (1 eq), 1 h 60 uC, 21 h
56%
n.i.b
73%
NEt3 (1 eq), rt, 1 h 5 mol% PTSA?H2O, rt, 21 h n.i.b
NEt3 (1 eq), rt, 1 h PTSA?H2O (1 eq), 5 mL
methanol, rt, 21 h
60%
70%
6
NEt3 (1 eq), rt, 1 h PTSA?H2O (1 eq), 1 mL
tert-butanol, 60 uC, 1 h
7
NEt3 (1 eq), rt, 1 h 1 mL tert-butanol, 60 uC, 1 h n.i.b
a
Isolated yield after chromatography on silica gel (ethyl acetate–
hexanes 1 : 2). Product was not isolated; the cycloisomerization
was not complete according to thin layer chromatography.
b
Encouraged by this optimization, the stage was set for a novel
three-component amidation–coupling–cycloisomerization (ACCI)
synthesis of 1-(hetero)aryl-2-(2-(hetero)aryl-oxazol-5-yl) ethanones
1 in a one-pot fashion. Therefore, after amidation of propargyl
amine (4) with an acid chloride 3, a second acid chloride 39 was
coupled under modified Sonogashira conditions, and finally, after
adding PTSA monohydrate and tert-butanol, reaction for 1 h at
60 uC gave rise to the formation of 1-(hetero)aryl-2-(2-(hetero)aryl-
oxazol-5-yl) ethanones 1 in moderate to good yields (Scheme 3,
Table 2).15,16
Finally, as a showcase for an alternative generation of ynones by
carbonylative alkynylation12b we probed an amidation–carbony-
lative alkynylation–cycloisomerization (ACACI) sequence in the
sense of a consecutive four-component reaction. Therefore,
amidation of propargyl amine (4) with trifluoroacetic anhydride
(6) followed by carbonylative alkynylation of p-iodo anisole (7)
and subsequent PTSA catalyzed cycloisomerization gave rise to
the formation of the oxazole derivative 8 in moderate yield, yet in a
one-pot fashion (Scheme 4).
In conclusion, we have developed a novel consecutive three-
component
amidation–coupling–cycloisomerization
(ACCI)
synthesis of 1-(hetero)aryl-2-(2-(hetero)aryl-oxazol-5-yl) ethanones.
In addition, this process can also be conducted in the sense of a
four-component amidation–carbonylative alkynylation–cycloi-
somerization (ACACI) sequence. Studies addressing the scope of
these new diversity oriented, consecutive multi-component accesses
to oxazole derivatives are currently under investigation.
The authors gratefully acknowledge the Fonds der Chemischen
Industrie, and Studienstiftung des Deutschen Volkes (scholarship
for E. M.).
Scheme 3 Amidation–coupling–cycloisomerization (ACCI) sequence to
1-(hetero)aryl-2-(2-(hetero)aryl-oxazol-5-yl) ethanones 1.
Table 2 One-pot three-component synthesis of 1-(hetero)aryl-2-(2-
(hetero)aryl-oxazol-5-yl) ethanones 1a
1-(hetero)aryl-2-
(2-(hetero)aryl-
oxazol-5-yl)
Entry
ethanone, 1
R1
R2
Yieldb
1
2
3
4
5
6
7
8
9
a
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Ph
p-MeC6H4
Ph
p-MeC6H4
2-thienyl
b-styryl
Ph
70%
58%
75%
68%
53%
49%
70%
66%
57%
p-MeOC6H4
p-ClC6H4
p-O2NC6H4
Ph
Ph
Fig. 1 Molecular structure of oxazole 1b. (Protons were omitted for
2-thienyl
b-styryl
1-cyclohexenyl
clarity, ORTEP: 50% probability.)
p-MeC6H4
p-MeC6H4
Reaction conditions: 1.0 equiv. of the propargyl amine (4) (0.2 M
in THF), 1 equiv. of acid chloride 3, 1 equiv. of triethylamine,
1 equiv. of acid chloride 39, 1 equiv. of triethylamine, 0.02 equiv. of
PdCl2(PPh3)2 and 0.04 equiv. of CuI,
monohydrate, and 1 mL of tert-butano1 were successively reacted
1 equiv. of PTSA
b
for 1 h at 0 uC, for 1 h at room temp, and for 1 h at 60 uC. Yields
refer to isolated yields of 1-(hetero)aryl-2-(2-(hetero)aryl-oxazol-5-yl)
ethanones
crystallization to be
1
after flash chromatography on silica gel and
95% pure as determined by NMR
¢
spectroscopy HRMS and/or elemental analysis.
Scheme 4 Four-component ACACI synthesis of oxazole 8.
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2001, 3, 2501; P.-Y. Coqueron, C. Didier and M. A. Ciufolini, Angew.
Chem., Int. Ed., 2003, 42, 1411.
Notes and references
10 A. S. K. Hashmi, J. P. Weyrauch, W. Frey and J. W. Bats, Org. Lett.,
2004, 6, 4391.
{ Crystal data 1b: C19H17NO3, M = 307.3, orthorhombic, space group
˚
P212121, a = 4.6910(1), b = 10.5327(2), c = 31.2403(6) A, a = b = c = 90u,
3
V = 1543.55(4) A , T = 200(2) K, Z = 4, r = 1.32 g cm23, crystal
11 P. Wipf, Y. Aoyama and T. E. Benedum, Org. Lett., 2004, 6, 3593.
12 A. S. Karpov, E. Merkul, T. Oeser and T. J. J. Mu¨ller, Eur. J. Org.
Chem., 2006, 2991; A. S. Karpov, E. Merkul, F. Rominger and
T. J. J. Mu¨ller, Angew. Chem., Int. Ed., 2005, 44, 6951; A. S. Karpov,
E. Merkul, T. Oeser and T. J. J. Mu¨ller, Chem. Commun., 2005, 2581;
A. S. Karpov, T. Oeser and T. J. J. Mu¨ller, Chem. Commun., 2004, 1502;
A. S. Karpov and T. J. J. Mu¨ller, Synthesis, 2003, 2815; A. S. Karpov
and T. J. J. Mu¨ller, Org. Lett., 2003, 5, 3451.
˚
dimensions 0.38 6 0.12 6 0.12 mm3, Mo Ka radiation, m = 0.09 mm21, l =
˚
0.71073 A. Data were collected on a Bruker Smart APEX diffractometer
and a total of 2738 of the 13309 reflections were unique [R(int) = 0.049].
Refinement on F2, wR2 = 0.074 (observed reflections), R1 = 0.035 for [I .
2s(I)]. CCDC 615998. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/b610839c
13 For lead reviews on Sonogashira couplings, see e.g. S. Takahashi,
Y. Kuroyama, K. Sonogashira and N. Hagihara, Synthesis, 1980, 627;
K. Sonogashira, in Metal catalyzed Cross-coupling Reactions, ed.
F. Diederich and P. J. Stang, Wiley-VCH, Weinheim, 1998, p. 203;
K. Sonogashira, J. Organomet. Chem., 2002, 653(1–2), 46.
14 R. J. Cox, D. J. Ritson, T. A. Dane, J. Berge, J. P. H. Charmant and
A. Kantacha, Chem. Commun., 2005, 1037.
15 All new compounds have been fully characterized spectroscopically and
by correct elemental analysis and/or HRMS.
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16 Typical procedure (Compound 1h): to a solution of 56 mg (1.00 mmol)
of propargylamine (4) in 5 mL of dry degassed THF in a flame dried
screw-cap vessel under argon were successively added 170 mg
(1.00 mmol) of 3g and 0.14 mL (1.00 mmol) of triethylamine at 0 uC
(external cooling with ice/water). After stirring for 1 h at room temp a
colorless to pale yellow precipitate had formed. Then, 14 mg (0.02 mmol)
of PdCl2(PPh3)2, 8 mg (0.04 mmol) of CuI, 158 mg (1.00 mmol) of 3c,
and 0.14 mL (1.00 mmol) of triethylamine were successively added to
the reaction mixture and stirring was continued for 1 h at room temp.
Then, 190 mg (1.00 mmol) of PTSA monohydrate and 1 mL of tert-
butanol were added and stirring was continued for 1 h at 60 uC. After
cooling to room temp, aqueous workup, extraction with dichloro-
methane, and chromatography on silica gel (ethyl acetate–hexane 1 : 2)
4 For syntheses of oxazole containing macrocycles and their biological
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1
200 mg (66%) of 1h were obtained as a yellow solid, mp 101 uC. H
NMR (CDCl3, 300 MHz): d (ppm) 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 (CDCl3, 75 MHz): d (ppm) 21.7 (CH3), 35.9 (CH2), 114.0 (CH),
126.9 (CH), 127.1 (CH), 128.6 (CH), 128.8 (CH), 129.1 (CH), 129.5
(CH), 133.4 (Cquat), 135.6 (CH), 135.6 (Cquat), 144.7 (Cquat), 145.4
(Cquat), 161.4 (Cquat), 193.3 (Cquat). EI MS (m/z (%)): 303 (M+, 28), 184
(M+ 2 C7H7CO, 18), 130 (11), 120 (16), 119 (C7H7CO+, 100), 91
(C7H7+, 37), 65 (C5H5+, 10). IR (KBr): v˜ 1686 (s) cm21, 1644 (m), 1607
(s), 1589 (m), 1521 (m), 1447 (m), 1372 (m), 1331 (m), 1228 (s), 1204 (m),
1184 (s), 1113 (m), 1009 (m), 966 (s), 814 (m), 756 (s), 713 (m), 690 (s),
634 (m). 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.
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This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 4817–4819 | 4819