New four-component condensations leading to 2,4,5-trisubstituted oxazoles

Article abstract of DOI:10.1016/S0040-4039(03)01751-9

A one-pot reaction leading to the title compounds has been developed based on the in situ acylation and hydroxyarylation of 5-aminooxazoles at the 4-position of the heterocycle.

Full text of DOI:10.1016/S0040-4039(03)01751-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6829–6832
New four-component condensations leading to 2,4,5-trisubstituted
oxazolesꢀ
Qunzhao Wang and Bruce Ganem*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, USA
Received 25 June 2003; revised 12 July 2003; accepted 15 July 2003
Abstract—A one-pot reaction leading to the title compounds has been developed based on the in situ acylation and hydroxyaryl-
ation of 5-aminooxazoles at the 4-position of the heterocycle.
© 2003 Elsevier Ltd. All rights reserved.
Multiple component condensations play a central role
in combinatorial chemistry and diversity oriented syn-
thesis.1 Such reactions, ‘in which three or more reac-
tants come together in a single reaction vessel to form
a new product that contains portions of all the compo-
nents,’2 remain relatively rare in organic chemistry, but
are instrumental in assembling libraries of small
molecules used in pharmaceutical discovery and
development.
Electrophilic substitution at C-4 in 5-aminooxazoles
was first demonstrated in the trifluoroacetic anhydride-
promoted cyclization of a-acylaminoamides 9 (Scheme
2). Under the conditions reported, the initially formed
In the preceding paper, we describe two useful three-
component condensations of isocyanoacetamides 1 and
carbonyl compounds with either chlorosilanes or
amines and an appropriate acid promoter (Scheme 1).3
The former reaction leads to 2-oxyalkyl-5-aminooxa-
zoles (e.g. 2, 3) and the latter to 2-aminoalkyl-5-
aminooxazoles (e.g. 4, 5).
Here we demonstrate that the 4-position of such oxa-
zoles can be further substituted using aldehydes or acid
chlorides to afford a broad array of 2,4,5-trisubstituted
oxazoles 6–8. Besides being active pharmacophores in
their own right,4 such heterocycles can also serve as
precursors for oxazolines5 and pyrrolopyridines,6 as
well as hexasubstituted benzenes.7 Moreover, by appro-
priate adjustment of reaction conditions it is possible to
prepare polysubstituted oxazoles like 6–8 in one reac-
tion vessel by four- and even five-component condensa-
tions incorporating diversity elements from several
building blocks.
Scheme 1.
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/S0040-4039(03)01751-9
* Corresponding author. E-mail: bg18@cornell.edu
Scheme 2.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01751-9

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Q. Wang, B. Ganem / Tetrahedron Letters 44 (2003) 6829–6832
Scheme 4.
Scheme 3.
Substituted 5-aminooxazoles like 4a (Scheme 1) pre-
pared by reaction of 1a with iminium ions also gave
trisubstituted oxazoles with aromatic aldehydes
(Scheme 4). The formation of 8a in 54% yield from 4a
demonstrated that cross-condensation products could
be prepared that introduced both nitrogen and oxygen
functionality around the heterocyclic core. In this
instance, the serial, one-pot process gave 8a directly
from 1a in only 19% yield.
5-aminooxazole 10 reacted with excess anhydride to
furnish 11.8 To explore the scope and generality of such
enamine-like substitutions, the behavior of 5-aminooxa-
zoles 2–5 was investigated in reactions with a variety of
electrophiles.
An earlier observation3 that the 5-aminooxazole formed
in the reaction of 1a with benzaldehyde underwent a
second carbonyl addition at C-4 led us to investigate a
one-pot, four-component process involving the serial
condensation of 1 with two different carbonyl com-
pounds using R3SiCl/Zn(OTf)2 as promoter. Reaction
of 1a with cyclohexanone and benzaldehyde led to the
trisubstituted heterocycle 6f (18–20%) as well as a sec-
ond product, bis-oxazole 12 (20%, Scheme 3), which
likely arose by condensation of 6f with 2a.
The acylation of substituted 5-aminooxazoles was also
investigated (Table 2). Oxazoles 2 and 3 reacted with a
broad range of aliphatic and aromatic acid chlorides,
including crotonyl, cinnamoyl, phenoxyacetyl, and
phenacetyl chlorides, giving products 7a–k in good
yields. By contrast, acylations of diaminooxazoles 4
and 5 were problematic, and formed decomposition
products likely arising from acylammonium complexes
of the benzylic nitrogen substituent.
Adding more N-ethylmorpholine with the second car-
bonyl compound suppressed formation of 12, raising
the yield of 6f to 55%. Replacing TMSCl with Et3SiCl
and adding supplemental Zn(OTf)2 gave 6f in 72%
yield. However, reactions with the more electron rich
isonitrile 1b gave predominantly dimers like 12 and
higher-order condensation products. Table 1 summa-
rizes condensations using 1a with a variety of aldehydes
and ketones demonstrating the scope of this new MCC
reaction.
Since in some cases similar reaction conditions could be
used for heterocycle-forming and subsequent ring
acylation steps, it was of interest to investigate a one-
pot, four-component process for assembling trisubsti-
tuted oxazoles 7 (Scheme 5) using an isonitrile,
carbonyl compound, silane, and acid chloride
Several successful examples are shown in Table 3. In
the one-pot procedure, both CꢀC bond-forming steps
are promoted using Zn(OTf)2/Et3SiCl/N-ethylmorpho-
line. As expected (entries 1 and 2), using Et3SiOTf in
place of Zn(OTf)2/Et3SiCl gave similar results.10 The
desired trisubstituted oxazoles were obtained pure by
careful flash column chromatography.
Aromatic aldehydes gave the best results in the second
condensation step, since enolizable aliphatic aldehydes
or ketones rapidly formed the corresponding enol silyl
ether derived from (CH3)3SiCl or Et3SiCl.9 Those con-
ditions led to the results summarized in Table 1.
Table 1. One-pot synthesis of trisubstituted oxazoles 6a
RNC
R3COR4/R3SiCl
R5CHO/R3SiCl
Product (yield)
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
(CH3)3CCHO/Et3SiCl
Ph(CH2)2CHO/Et3SiCl
PhCHO/TMSCl
PhCHO/Et3SiCl
PhCHO/Et3SiCl
PhCHO/TMSCl
PhCHO/Et3SiCl
p-MeOC6H4CHO/Et3SiCl
PhCHO/TMSCl
PhCHO/Et3SiCl
p-MeOC6H4CHO/Et3SiCl
p-ClC6H4CHO/Et3SiCl
PhCHO/Et3SiCl
6a (51%)
6b (61%)
6c (54%)
6d (40%)
6e (43%)
6f (55%)
6g (72%)
6h (35%)
6i (50%)
6j (54%)
PhCHO/Et3SiCl
p-MeOC6H4CHO/Et3SiCl
Cyclohexanone/TMSCl
Cyclohexanone/Et3SiCl
Cyclohexanone/Et3SiCl
Cyclohexanone/Et3SiCl
Cyclohexanone/TMSCl
a Conditions: (i) Zn(OTf)2 (0.5 equiv.), R3SiCl (2 equiv.), N-ethylmorpholine, (2.1 equiv.) CH2Cl2, R3R4CO (1.3 equiv.), rt, 2 h; (ii) N-ethylmor-
pholine (3 equiv.), R3SiCl (2 equiv.), R5CHO (1.5 equiv.), Zn(OTf)2 (0.5 equiv.), 12 h.

Q. Wang, B. Ganem / Tetrahedron Letters 44 (2003) 6829–6832
6831
Table 3. One-pot, four-component condensation leading to
trisubstituted oxazoles 7 (R= Et)a
Table 2. Condensations of oxazoles 2 and 3 with acid
chloridesa
RNC R3R4CO R5COCla
Product
%
Yield
Oxazole
Acid chloride
Butyryl
Product
% Yield
74
2a R=Et
R3, R4=(CH2)5
7a
1a
Cyclohexanone Butyryl-Cl
(A)
7a
43
R5=n-C3H7
NR2=morph
7b
R3, R4=(CH2)5
R5=n-C3H7
7a
2a
Isobutyryl
Butyryl
Acetyl
68
70
72
71
74
63
35
1a
1a
Cyclohexanone Butyryl-Cl
(B)
48
35
R5=i-C3H7
NR2=morph
7c
Pivalaldehyde
PhOCH2-COCl 7l
2b R=Et
(C)
R3=H
R3=H
R5=n-C3H7
NR2=morph
7d
R4=(CH3)3C
R5=PhOCH2
7d
R4=n-C9H19
3a R=Et
1b
1b
Hydrocinnam-
aldehyde
Acetyl-Cl
(A)
35
36
R3=H,
R5=CH3
NR2=NMe2
7e
R3=H
R4=Ph(CH2)2
3b R=Et
R4=Ph(CH2)2
R5=CH3
Benzoyl
Acetyl
R3R4=(CH2)5
R5=Ph
Isobutyr-
aldehyde
Cinnamoyl-Cl 7m
(A)
NR2=NMe2
7f
R3=H
3b
3b
3b
R4=i-C3H7
R5=CH3
NR2=NMe2
7g
R5=PhCHꢁCH
Butyryl
Crotonyl
a Conditions: (A) (i) Zn(OTf)2 (0.3 equiv.), N-ethylmorpholine (1.6
equiv.), Et3SiCl (1.2 equiv.), R3R4CO (1.2 equiv.), CH2Cl2, rt, 2 h,
(ii) pyridine (3.5 equiv.), R5COCl (2.5 equiv.), THF, rt; (B)
Et3SiOTf (1.2 equiv.) replaced Zn(OTf)2 and Et3SiCl; (C) TMSCl
replaced Et3SiCl.
R5=n-C3H7
NR2=NMe2
7h
R5=CH3CHꢁ
CH
NR2=NMe2
7i
3b
3b
Cinnamoyl
79
77
R5=PhCHꢁCH
7j
PhOCH2COCl
R5=PhOCH2
NR2=NMe2
7k
availability of these well-known families of compounds
should make it possible to assemble libraries of phar-
maceutically interesting heterocyclic systems from sim-
ple starting materials.
3b
PhCH2COCl
47
R3=H
R4=PhCH2
a Conditions: Zn(OTf)2 (0.3 equiv.), RCOCl (2.5 equiv.), pyridine (3.5
equiv.), 1:1 CH2Cl2/THF, rt.
Acknowledgements
We thank the National Institutes of Health (DK 55823)
for partial support of this work. Major instrumentation
in the Cornell NMR Facility was funded by NSF (CHE
7904825; PGM 8018643) and NIH (RR02002).
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Q. Wang, B. Ganem / Tetrahedron Letters 44 (2003) 6829–6832
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