Isoxazolodihydropyridinones: 1,3-dipolar cycloaddition of nitrile oxides onto 2,4-dioxopiperidines

Article abstract of DOI:10.1021/co200200u

Practical and efficient methods have been developed for the diversity-oriented synthesis of isoxazolodihydropyridinones via the 1,3-dipolar cycloaddition of nitrile oxides onto 2,4-dioxopiperidines. A select few of these isoxazolodihydropyridinones were further elaborated with triazoles by copper-catalyzed azide-alkyne cycloaddition reactions. A total of 70 compounds and intermediates were synthesized and analyzed for drug likeness. Sixty-four of these novel compounds were submitted to the NIH Molecular Libraries Small Molecule Repository for high-throughput biological screening.

Full text of DOI:10.1021/co200200u

Research Article
pubs.acs.org/acscombsci
Isoxazolodihydropyridinones: 1,3-Dipolar Cycloaddition of Nitrile
Oxides onto 2,4-Dioxopiperidines
Keith C. Coffman, Timothy P. Hartley, Jerry L. Dallas, and Mark J. Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: Practical and efficient methods have been
developed for the diversity-oriented synthesis of isoxazolodi-
hydropyridinones via the 1,3-dipolar cycloaddition of nitrile
oxides onto 2,4-dioxopiperidines. A select few of these
isoxazolodihydropyridinones were further elaborated with
triazoles by copper-catalyzed azide−alkyne cycloaddition
reactions. A total of 70 compounds and intermediates were
synthesized and analyzed for drug likeness. Sixty-four of these
novel compounds were submitted to the NIH Molecular
Libraries Small Molecule Repository for high-throughput
biological screening.
KEYWORDS: isoxazole, triazole, heterocycle, 1,3-dipolar cycloaddition, Cu(I)-catalyzed azide−alkyne cycloaddition
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Isoxazoles are an important class of nitrogen containing
heterocycles found in many natural products and biologically
active compounds.1 While many methods have been developed
for isoxazole formation, the cycloaddition of nitrile oxides to
alkynes is the most effective.2 Emphasis has been placed on the
synthesis of highly substituted isoxazoles by Larock,3 Miyata,4
and others.5 While the reactions of nitrile oxides with cyclic 1,3-
diketones6 and β-ketoesters7 have been studied, the cyclo-
addition of nitrile oxides onto heterocyclic 1,3-dicarbonyl com-
pounds has, to our knowledge, not been reported. Although
other routes have been reported for the preparation of
isoxazolo[4,5-c]pyridinones,8 our method provides convergent
access to a variety of diversity points around the core scaffold.
We recently reported the hydrolytic opening of the amide of
an isoxazolodihydropyridinone substrate as a route to orthogo-
nally protected heterocyclic diamino acids.9 As a continuation
of this line of research, we report here the synthesis of a library
of isoxazolodihydropyridinones via the 1,3-dipolar cycloaddi-
tion of nitrile oxides onto 2,4-dioxopiperidine to yield eleven
novel 6,7-dihydroisoxazolo[4,5-c]2yridine-4(5H)-ones. Noting
the many recent synthetic applications of copper catalyzed
azide−alkyne cycloaddition (CuAAC) reactions for the rapid
diversification of library collections (→ triazole diversifica-
tion),10 we also report exploiting the CuAAC reaction to
diversify a subset of these isoxazolodihydropyridinones leading
to an additional 42 triazole-functionalized isoxazolodihydropyr-
idinones. The resulting collection has been added to the NIH
Molecular Libraries Small Molecule Repository for high-
throughput biological screening.
As a starting point, Boc-protected 2,4-dioxopiperidines were
synthesized from substituted β-amino acids by a three-step
process that commenced with Boc protection of β-alanines (1)
following a modified literature procedure (90−95% yield).11
These N-protected amino acids (2) were then coupled to
Meldrum’s acid using standard EDC and DMAP coupling
conditions.9 The resulting conjugates were immediately
dissolved in EtOAc and refluxed for four hours to yield Boc-
protected dioxopiperidines 3 in 85−90% yield over 2 steps (via
the presumed intermediacy of a Meldrum’s acid-derived
acylketene, which subsequently underwent intramolecular
cyclization with the Boc-protected amine moiety; Scheme 1).
Scheme 1. Synthesis of 2,4-Dioxopiperidines 3 (R1 = H and Me)
These dioxopiperidines were then treated with NaH in THF
followed by the slow addition of various N-hydroxybenzimidoyl
Received: November 24, 2011
Revised: January 26, 2012
Published: February 21, 2012
© 2012 American Chemical Society
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Research Article
chlorides 4{1−8} to give isoxazolodihydropyridinones 5{1−11}
in 43−76% yield (Table 1). The requisite N-hydroxybenzimi-
doyl chlorides 4{1−8} were prepared from the corresponding
benzaldehydes in 2 steps following well-established literature
procedures.12
the molecule. While many of the assignments could be made
1
from the H and 13C NMR spectra, we were unable to assign
carbons C3, C4, C5 and C6 (see Figure 1) from these spectra
alone. Therefore, several additional NMR experiments were
undertaken, including INADEQUATE,13 HSQC,14 HMBC,15
and COSY.16 From the two-dimensional INADEQUATE
experiment on 5{3} (Figure 1), we could assign all of its
carbons, including C3, C4, C5, and C6. By analogy, the insights
gained through this INADEQUATE proved useful in making
complete carbon assignments in all of the isoxazolodihydropyr-
idinones reported here; for example, we were able to com-
pletely assign carbons for alkyne derivative 6{1} (Figure 2). All
of the spectra obtained for 5{3} are available in the Supporting
Information.
A detailed NMR study of 5{3} was undertaken to verify its
structure and completely assign all carbons and protons within
Table 1. 1,3-Dipolar Cycloaddition of Nitrile Oxides onto
2,4-Dioxopiperidines
Three of the isoxazolodihydropyridinones delineated in
Table 1 (5{1−3}) were selected for diversification through
CuAAC reactions by first installing an alkyne moiety on the
dihydropyridinone nitrogen. As outlined in Scheme 2, this
chemistry commenced by first removing the Boc group with
TFA in CHCl3 (30 min) to yield the secondary amide in
quantitative yield. Each amide was then deprotonated with
NaH in dry THF and N-propargylated with propargyl bromide
to yield the alkyne- containing scaffold 6{1−3} in 50−55%
yield. Subsequent copper-mediated 1,3-dipolar cycloaddition to
these substrates with eight azides (7{1−8}) delivered triazole
products 8{1−3,1−8} in good to excellent yields (Table 2).
The azides employed in these CuACC reactions were gener-
ated in situ from the corresponding amines following one of
entry
compound
R1
R2
yield
1
5{1}
5{2}
5{3}
5{4}
5{5}
5{6}
5{7}
5{8}
5{9}
5{10}
5{11}
H
2-MeOC6H4
4-BrC6H4
52
64
58
54
50
68
50
55
76
43
64
2
H
3
H
2-FC6H4
4
H
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
2-NO2,5-ClC6H3
4-ClC6H4
5
H
6
H
7
H
8
H
9
Me
Me
Me
2-MeOC6H4
2-NO2,5-ClC6H3
4-ClC6H4
10
11
Figure 1. INADEQUATE-based assignments of C3, C4, C5, and C6 in 5{3}.
Figure 2. Assignments for 6{1} based on the INADEQUATE data from 5{3}.
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Scheme 2. CuAAC of the Isoxazolodihydropyridinones
Scheme 3. Azide Synthesis for CuAAC
13{1−2} in 64% and 69% yield, respectively. 2-Bromo-
1- morpholinoethanone 12 was prepared by dropwise addition
of morpholine to a solution of bromoacetyl bromide in dry
DCM under nitrogen (clear oil; 82% yield).19 Nine alkynes
(Scheme 3) were then used to diversify this azide set to give 16
additional triazole products (15{1−2,1−9}; Table 3).
Table 2. CuAAC Diversification of
Isoxazolodihydropyridinones
Table 3. Diversification of the Alkylated
Isoxazolodihydropyridinones
entry azide 8{1,1−8} % yield 8{2,1−8} % yield 8{3,1−8} % yield
1
2
3
4
5
6
7
8
{1}
{2}
{3}
{4}
{5}
{6}
{7}
{8}
28
85
95
76
92
74
74
79
89
89
92
79
88
76
94
77
92
a
57
52
46
76
78
84
70
a
entry
alkyne
m-N3 yield
p-N3 yield
Decomposed upon isolation.
1
2
3
4
5
6
7
8
9
{1}
{2}
{3}
{4}
{5}
{6}
{7}
{8}
{9}
28
69
51
89
36
57
68
47
85
79
47
99
99
32
93
99
65
62
two protocols: (i) alkyl 1°-amines were treated with the diazo-
transfer reagent imidazole-SO2N3 to yield the azide as reported
by Stick17 and (ii) aryl 1°-amines were treated with BuONO
t
+
and subsequent ArN2 → ArN3 conversion was effected with
TMS-N3 as reported by Moses.18 These in situ prepared azides,
the alkynes (6{1−3}), CuSO4, and sodium ascorbate were
combined and the ensuing 1,3-dipolar cycloaddition reactions
yielded triazole-substituted products 8{1−3,1−8} (Table 2).
Two additional isoxazolodihydropyridinones delineated in
Table 1 (5{4−5}) were selected for diversification through
CuAAC reactions by taking advantage of the nitro group for
azide entry. Isoxolopyridinones 5{4−5} were treated with Zn/
AcOH to deliver the m- and p-anilines 9{1−2} in quantitative
yields (Scheme 3). These anilines were then treated with
tBuONO and the targeted azides were obtained by displace-
ment of the diazonium salt with TMS-N3 to yield 10{1−2} in
45% and 87% yield (meta and para), respectively. The Boc
group in 10{1−2} was then removed by TFA treatment in
CHCl3 to give 11{1−2} in quantitative yield. At this juncture,
N-alkylation of the 2°-amide in 11{1−2} proceeded smoothly
by deprotonation with NaH in dry THF and subsequent
treatment with 2-bromo-1-morpholinoethanone (12) to give
A Lipinski rule-of-five analysis20 was performed to evaluate
the druglikeness of all compounds and intermediates reported
(Figure 3). Of the seventy compounds analyzed, fifty-eight
were within the parameters set by Lipinski. Of the remaining,
nine from chemset 15 had >10 hydrogen bond acceptors and
the remaining two compounds (also from chemset 15) had two
violations each (>10 acceptors and a mass >500 Da; both had
molecular weights of ∼560 g/mol). The other chemsets
combined had only one violation (e.g., 8{2,8}), suggesting
that this collection of compounds is very appropriate for high-
throughput screening to discover drug leads and biological
probes.
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Figure 3. Lipinski rules analysis for 70 compounds and intermediates; calculated using Molinspirations Online Molecular Properties Calculator
[http://www.molinspiration.com/cgi-bin/properties?textMode=1].
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A short, reliable, and efficient convergent method has been
Derivative KRIBB3, a Synthetic Molecule That Inhibits Hsp27
CONCLUSIONS
■
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intermediates synthesized were acceptable for submission to the
NIH Molecular Libraries Small Molecule Repository for high-
throughput biological screening; the unsubmitted 6 compounds
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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, characterization data, and 1H
and 13C NMR spectra of all compounds, including COSY,
INADEQUATE, HSQC, and HMBC for compound 5{3}. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mjkurth@ucdavis.edu.
Notes
■
The authors declare no competing financial interest.
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.
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Regioselective One-Pot Synthesis of 3-Substituted and 3,5-Disub-
stituted Isoxazoles. Org. Lett. 2009, 11, 3982−3985.
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