Expedient synthesis of a 72-membered isoxazolino-β-ketoamide library by a 2·3-component reaction

Article abstract of DOI:10.1021/co200199h

An efficient 2·3-component reaction (2·3CR; a 2-component reaction followed, in one pot, by a3-component reaction) is presented for the synthesis of isoxazolino-β-ketoamides. This 2·3CR proceeds by (i) a Meldrum's acid-generated acyl ketene, which is trapped by an amine to form a β-ketoamide intermediate in a 2CR followed, in one pot, by (ii) a Mannich reaction followed by elimination of dimethyl amine·HCl to generate an α,β-unsaturated β-ketoamide dipolarophile that reacts in a nitrile oxide 1,3-dipolar cycloaddition reaction. This one-pot 2·3CR process delivers the targeted isoxazolino-β-ketoamide product. A total of 72 compounds are presented, all of which have been submitted to the NIH Molecular Libraries Small Molecule Repository for high-throughput biological screening.

Full text of DOI:10.1021/co200199h

Letter
pubs.acs.org/acscombsci
Expedient Synthesis of a 72-Membered Isoxazolino-β-ketoamide
Library by a 2·3-Component Reaction
John M. Knapp, Jie S. Zhu, Alex B. Wood, and Mark J. Kurth*
Department of Chemistry, University of California/Davis, One Shields Avenue, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: An efficient 2·3-component reaction (2·3CR;
a 2-component reaction followed, in one pot, by a
3-component reaction) is presented for the synthesis of
isoxazolino-β-ketoamides. This 2·3CR proceeds by (i) a
Meldrum’s acid-generated acyl ketene, which is trapped by
an amine to form a β-ketoamide intermediate in a 2CR
followed, in one pot, by (ii) a Mannich reaction followed
by elimination of dimethyl amine·HCl to generate an α,β-
unsaturated β-ketoamide dipolarophile that reacts in a nitrile oxide 1,3-dipolar cycloaddition reaction. This one-pot
2·3CR process delivers the targeted isoxazolino-β-ketoamide product. A total of 72 compounds are presented, all of
which have been submitted to the NIH Molecular Libraries Small Molecule Repository for high-throughput biological
screening.
KEYWORDS: 2·3-component reaction, isoxazolino-β-ketoamides, one pot, isoxazolino-β-ketoamide product
ulticomponent reactions offer an expedient route to
complex targets1 since the combination of three or
We recently reported a 4-component reaction (4CR) for the
synthesis of isoxazolino-β-ketoamides12 as outlined in Scheme 1.
M
more reactants within a single reaction typically leads to a
shorter reaction sequence and fewer purification steps.1
Moreover, multicomponent products are comparatively far
more elaborate than their starting material counterparts
and, by altering a single reactive component, a wide range of
diversity can be achieved. For these reasons, multi-
component reactions, such as the Biginelli,2 Passerni,3
Hantzche,4 and Ugi5 reactions, have been widely used for
the construction of combinatorial libraries.6 The develop-
ment of new multicomponent reactions has broad
implications in synthetic methodology, library production,
and biological screening.
Scheme 1. 4CR Route to Isoxazolino-β-ketoamides
Isoxazolines have little precedence as pharmacophores.
However, we have discovered that a class of isoxazolines func-
tion as a cystic fibrosis transmembrane conductance regulator
protein activator7 and others have previously shown this
substructure to be bioactive in various other systems.8 As an
under exploited heterocycle, isoxazolines could potentially find
various new applications and serve as future synthetic targets.
To address this possibility, expedient library synthesis is needed
to enable the requisite random screening.
This initial investigation was conducted as a proof-of-concept
study for the development of a multicomponent macro-
cylization reaction, which we have now evolved into a general
protocol for the synthesis isoxazolino-β-ketoamides. This
procedure incorporates an acyl ketene precursor (1) and an
amine (2) to form the β-ketoamide moiety, which then
undergoes a Mannich reaction with Eschenmoser’s salt (3)
followed by elimination of dimethyl ammonium chloride. The
Isoxazolines are synthons for β-amino acids9 and γ-amino
alcohols,10 which are abundant in natural products and
medicinal compounds.11 Consequently, the diversity oriented
synthesis of isoxazolines can have considerable significance.
To this end, we present here the synthesis of a seventy-two
membered library of isoxazolino-β-ketoamides prepared by a
modified multicomponent reaction with the ability for easy
diversification.
Received: November 23, 2011
Revised: December 17, 2011
Published: December 19, 2011
© 2011 American Chemical Society
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ACS Combinatorial Science
Letter
resulting doubly activated Michael acceptor then serves as a
dipolarophile in a nitrile oxide cycloaddition (⇒ 4) to, in one-
pot, deliver the isoxazolino-β-ketoamide target (5). Our previously
reported yields for this 4CR reaction ranged from 39 to 50%.
Herein, we demonstrate modification and expansion of this
versatile transformation.
The combination of four reactants can lead to undesirable
side-product formation and, consequently, lower isoxazoli-
no-β-ketoamide yields. Despite these inherent limitations,
our 4CR produces modest yields (39−50%) of the targeted
product because of the high reactivity of the acyl ketene
with the amine nucleophile. This high acyl ketene/amine
reactivity effectively suppresses side reactions that form
isoxazol-5(2H)-ones (6) and N-hydroxyimidamides (7).
That said, we report here a modified method that delivers
isoxazolino-β-ketoamides in both higher average yields and
cleaner reactions, advancements that enable efficient library
synthesis.
said that an alternative mechanism where the amine attacks
first, followed by loss of CO2 and acetone, is possible.
Subsequent addition of Eschenmoser’s salt and chlorooxime
reagents, to the same flask, results in a 3CR (collectively, a
2·3CR) that delivers the isoxazolino-β-ketoamide product. This
2·3CR modification essentially avoids both the chlorooxime +
acyl ketene cycloaddition side reaction (→ isoxazol-5(2H)-
ones; 6; Scheme 1) and the amine + chlorooxime side reaction
(→ N-hydroxyimidamides; 7; Scheme 1), while proficiently
effecting the desired transformation (→ isoxazolino-β-ketoa-
mide; 5; Scheme 2).
In addition to the 2·3CR synthetic modification, we wanted
to expand the scope of this reaction by utilizing an array of
diverse reactants (Figure 1). A total of eight amines were used.
Both aliphatic and aromatic amines worked well; however,
yields dropped when aminothiazole, ethanolamine, or acetohy-
drazide where used. For the library reported here, three
different acyl ketene precursors (p-methoxyphenyl,13 cyclo-
propyl,14 and methyl) as well as three different chlorooximes
(o-pyridinyl,15 o-trifluoromethylphenyl,16 and carboethoxy17)
were used. We also demonstrate that these substituted acyl
ketenes and chlorooximes tolerate the 2·3CR reaction
conditions. Isolated yields for all variations are shown in
Table 1.
Scheme 2. Isoxazolino-β-ketoamides by a Multicomponent
(2·3CR) Process
Considerable functional group diversity is represented in this
library in which product molecular weights range from 272 to
496. Manipulation of the acyl ketene-, amine-, and chloroox-
ime-derived R-groups allow for dramatic alteration of the
isoxazolino-β-ketoamide three-dimensional shape. Together,
the ease of altering functional groups, molecular weights, and
molecular geometry with this 2·3CR-based methodology allows
for the rapid assembly of a library of biological relevant
isoxazolino-β-ketoamides.
We have successfully synthesized a library of seventy-two
isoxazolino-β-ketoamides with novel 2·3CR-based method-
ology. This library effectively expands the scope of our
multicomponent methodology and demonstrates its applica-
tion in diversity-oriented synthesis. Compared to its 4CR
variant, this one-pot 2·3CR method delivers the targeted
scaffold with much improved yields − as much as 38% in
side-by-side comparative reactions. The compounds reported
here have been deposited in the NIH Molecular Libraries Small
Molecule Repository for high-throughput biological screening
and assay results for these molecules and similar analogs will
likely follow.
As delineated in Scheme 2, performing the multicomponent
reaction as a 2·3CR (a 2-component reaction followed by a
3-component reaction), instead of a 4CR, results in isoxazolino-
β-ketoamide yields up to 88% as well as excellent product purity.
This 2·3CR was accomplished as a one-pot procedure by
heating a DMF solution of the acyl ketene precursor in the
presence of only the amine nucleophile, thus preforming the
β-ketoamide in a 2CR. While it is known that dioxolinones and
Meldrum’s acids fragment thermally to acyl ketenes, it must be
Figure 1. 2·3CR diversity inputs.
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ACS Combinatorial Science
Letter
Table 1. Library of Isoxazolino-β-ketoamides
Table 1. continued
entry
acyl ketene
chloro-oxime
amine
product
yield (%)
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{1}
{1}
{1}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{6}
{7}
{8}
{1}
{2}
{3}
{4}
{5}
{6}
{7}
{8}
{1}
{2}
{3}
{4}
{5}
{6}
{7}
{8}
5{3,1,6}
5{3,1,7}
5{3,1,8}
5{3,2,1)
5{3,2,2)
5{3,2,3}
5{3,2,4}
5{3,2,5}
5{3,2,6}
5{3,2,7}
5{3,2,8}
5{3,3,1)
5{3,3,2)
5{3,3,3}
5{3,3,4}
5{3,3,5}
5{3,3,6}
5{3,3,7}
5{3,3,8}
44
52
62
77
70
18
39
35
43
54
62
76
62
9
entry
acyl ketene
chloro-oxime
amine
product
yield (%)
1
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{3}
{3}
{3}
{3}
{3}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{2}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{3}
{1}
{1}
{1}
{1}
{1}
{1}
{2}
{3}
{4}
{5}
{6}
{7}
{8}
{1}
{2}
{3}
{4}
{5}
{6}
{7}
{8}
{1}
{2}
{3}
{4}
{5}
{6}
{7}
{8}
{1}
{2}
{3}
{4}
{5}
{6}
{7}
{8}
{1}
{2}
{3}
{4}
{5}
{6}
{7}
{8}
{1}
{2}
{3}
{4}
{5}
{6}
{7}
{8}
{1}
{2}
{3}
{4}
{5}
5{1,1,1)
5{1,1,2)
5{1,1,3}
5{1,1,4}
5{1,1,5}
5{1,1,6}
5{1,1,7}
5{1,1,8}
5{1,2,1)
5{1,2,2)
5{1,2,3}
5{1,2,4}
5{1,2,5}
5{1,2,6}
5{1,2,7}
5{1,2,8}
5{1,3,1)
5{1,3,2)
5{1,3,3}
5{1,3,4}
5{1,3,5}
5{1,3,6}
5{1,3,7}
5{1,3,8}
5{2,1,1)
5{2,1,2)
5{2,1,3}
5{2,1,4}
5{2,1,5}
5{2,1,6}
5{2,1,7}
5{2,1,8}
5{2,2,1)
5{2,2,2)
5{2,2,3}
5{2,2,4}
5{2,2,5}
5{2,2,6}
5{2,2,7}
5{2,2,8}
5{2,3,1)
5{2,3,2)
5{2,3,3}
5{2,3,4}
5{2,3,5}
5{2,3,6}
5{2,3,7}
5{2,3,8}
5{3,1,1)
5{3,1,2)
5{3,1,3}
5{3,1,4}
5{3,1,5}
80
79
30
40
40
51
76
88
75
76
31
44
31
50
78
83
81
80
19
48
41
38
75
75
30
50
8
2
3
4
5
6
7
34
69
32
63
40
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, characterization data, and 1H
and13C NMR spectra of 20 representative compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mjkurth@ucdavis.edu.
ACKNOWLEDGMENTS
■
The authors thank the National Institutes of Health (GM0891583
and RR1973) and the National Science Foundation [CHE-
0910870; and CHE-0443516, CHE-0449845, CHE-9808183, and
DBIO 722538 for NMR spectrometers] for their generous support.
15
35
44
55
64
60
58
17
31
30
33
60
60
62
42
12
46
60
45
70
68
49
78
23
31
37
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