An Intramolecular Wittig Approach toward Heteroarenes: Synthesis of Pyrazoles, Isoxazoles, and Chromenone-oximes

Article abstract of DOI:10.1021/acs.orglett.9b01395

α-Halohydrazones/ketoximes are transformed into trisubstituted pyrazoles/disubstituted isoxazoles by treatment with phosphine, acyl chloride, and a base. Mechanistic investigations revealed the in situ formation of azo/nitroso olefin intermediates which underwent a tandem phospha-Michael/N- or O-acylation/intramolecular Wittig reaction to afford the heteroarenes in moderate to good yields. Further, proper functionalization of α-haloketoximes and a change of conditions allowed the chemoselective synthesis of chromenone-oximes as well as rearranged isoxazoles, thereby realizing a diversity-oriented synthesis.

Full text of DOI:10.1021/acs.orglett.9b01395

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
An Intramolecular Wittig Approach toward Heteroarenes: Synthesis
of Pyrazoles, Isoxazoles, and Chromenone-oximes
Pankaj V. Khairnar, Tsai-Hui Lung, Yi-Jung Lin, Chi-Yi Wu, Srinivasa Rao Koppolu,
Athukuri Edukondalu, Praneeth Karanam, and Wenwei Lin*
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei 11677, Taiwan R.O.C.
S
* Supporting Information
ABSTRACT: α-Halohydrazones/ketoximes are transformed into trisub-
stituted pyrazoles/disubstituted isoxazoles by treatment with phosphine,
acyl chloride, and a base. Mechanistic investigations revealed the in situ
formation of azo/nitroso olefin intermediates which underwent a tandem
phospha-Michael/N- or O-acylation/intramolecular Wittig reaction to
afford the heteroarenes in moderate to good yields. Further, proper
functionalization of α-haloketoximes and a change of conditions allowed
the chemoselective synthesis of chromenone-oximes as well as rearranged
isoxazoles, thereby realizing a diversity-oriented synthesis.
yrazoles and isoxazoles belong to a prominent class of
nitrogen heterocycles exhibiting a wide range of potent
Scheme 1. Our Earlier Synthesis of Oxazoles (a) and Our
Design for Pyrazole, Isoxazole and Chromenone-oximes (b)
P
biological properties.1 In addition, they are also useful in the
field of agriculture apart from being frequently found in many
natural as well as synthetic products.2 Recently, chromenone-
oxime scaffolds have emerged as potent drugs for the treatment
of Parkinson’s disease.3 Owing to their attractive medicinal
properties (Figure 1), the development of new methods
Figure 1. Some potent drugs containing pyrazole, isoxazole, and
chromenone-oxime scaffolds.
soalkenes,7 and thus generated phosphonium salts could be
transformed into bioactive pyrazoles/isoxazoles via a tandem
acylation/Wittig reaction sequence (Scheme 1b). In this
context, we report a metal-free approach for the synthesis of
trisubstituted pyrazoles and disubstituted isoxazoles. In
addition, we have also explored the possibility of chemo-
selective intramolecular Wittig reaction that could result
rearranged isoxazoles and chromenone-oxime derivatives in a
diversity-oriented manner.8
Initially, the α-halohydrazone mixture E/Z-1a was selected
for our model reaction with PBu3 and PhCOCl (2a) in the
presence of Et3N in CH2Cl2. The desired pyrazole 3aa was
obtained in 61% yield (entry 1, Table 1). Other phosphines
such as PEt2Ph and PEtPh2 afforded 3aa in 39% and 34%
yields, respectively (entries 2 and 3). Delightfully, the reaction
was efficiently facilitated by PPh3, and 3aa was obtained in 80%
toward their synthesis have attracted great interest.4 Although
some elegant methods are available for the synthesis of each of
these heterocycles, the development of a single modular
method that could generate all of these heterocycles is still
desirable.
On the other hand, the Wittig reaction has recently
witnessed its multifaceted applications toward the synthesis
of diverse range of heterocycles.5 Our group has long been
devoted in the synthesis of various types of heteroarenes via a
three-component tandem phospha-Michael addition/O-acyla-
tion/Wittig reaction from a variety of α,β-unsaturated carbonyl
compounds.6 In 2014, we reported an efficient synthesis of
oxazoles from PBu3, N-acylimines, and acyl chlorides via the
Wittig reaction (Scheme 1a).6c To continue our effort toward
the development of novel intramolecular Wittig strategies, we
envisioned that the E/Z mixture of α-halohydrazones/
ketoximes when treated with phosphine generate Z-phospho-
nium salts exclusively via transient conjugated azo-/nitro-
Received: April 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01395
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. Optimization of the Reaction Conditions for 3aa
Scheme 3. Generation of Z-4a from (E/Z)-1a
b
b
b
entry
PR3
base
solvent (%) time (h) 3aa (4) (%)
formation of an equilibrating mixture of s-cis-I and s-trans-II
species. Preferential addition of PPh3 to s-cis-I furnishes
exclusively Z-4a because of its extra stability resulting from the
coordination between −NH and the phosphorus atom of PPh3
(see the Supporting Information for crystal data).
Having observed a similar phenomenon with α-chloroketox-
ime 5a, we turned our attention to generate isoxazole 6aa.
However, the standard conditions that worked for pyrazoles 3
resulted in a poor yield of 6aa. After extensive optimization
studies (see the Supporting Information), the optimal result
was obtained when 5a was treated with PBu3 in dry Et2O for 8
h, followed by evaporation of solvent, redissolving in THF, and
then sequential addition of MTBD and PhCOCl (2a) in THF
for 1 h at 30 °C in a one-pot synthesis (Scheme 4).
1
2
3
4
5
6
7
8
PBu3
PEt2Ph
PEtPh2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Et3N
Et3N
Et3N
Et3N
DIPEA
DBU
Et3N
Et3N
Et3N
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
1
3
3
5
5
1
3
3
5
61 (29)
39 (32)
34 (32)
80 (0)
71 (0)
0 (15)
26 (63)
34 (35)
81 (0)
CH3CN
CH2Cl2
c
9
a
Reactions were performed with 1a (0.3 mmol), PR3 (1.1 equiv), base
(3.0 equiv), and PhCOCl (2a) (1.2 equiv) in dry solvent (3 mL)
under argon at 30 °C. NMR yields. Et3N (2.5 equiv) was used.
b
c
yield (entry 4). To find the optimal conditions, several other
bases and solvents were screened (entries 5−8). In most of the
cases, the phosphonium salt 4 was observed in the reaction
mixture. The stoichiometry of base and the effect of
concentration was also examined. The optimal result was
obtained by treating 1a (1.0 equiv) and 2a (1.2 equiv) in the
presence of PPh3 (1.1 equiv) and Et3N (2.5 equiv) in
anhydrous CH2Cl2 at 30 °C for 5 h (entry 9).
a,b
Scheme 4. Substrate Scope of Disubstituted Isoxazoles 6
Having established the optimal conditions, the scope of the
substrates (Scheme 2) was investigated. The protocol worked
a,b
a
Scheme 2. Substrate Scope of Trisubstituted Pyrazoles 3
Reactions were performed with 5 (0.2 mmol), PBu3 (1.1 equiv),
MTBD (4.0 equiv), and R3COCl (1.2 equiv) in dry THF (2 mL)
b
c
under argon at 30 °C. Isolated yield. α-Bromohydrazone (5d) was
d
used. TFAA (2l, 1.5 equiv) was used.
The substrate scope of isoxazoles was further investigated. A
variety of α-haloketoximes 5 participated in the reaction with
different acyl chlorides 2 to afford the expected products 6 in
good yields. As in the case of hydrazones, the electronic nature
of R1 and R2 substituents in 1 and 2, respectively, has no
considerable effect on the course of the reaction. Gratifyingly,
aromatic acyl chlorides bearing ortho- and meta-substitutions
were also converted to isoxazoles in good yields. Similarly,
aliphatic acyl chlorides such as acetyl chloride (2n) and
anhydride such as TFAA (2l) were also applicable. In addition,
cinnamoyl chloride (2o) also furnished the isoxazole 6ao
although in moderate yield (45%).
After efficient synthesis of pyrazoles and isoxazoles, we also
envisioned that the presence of appropriately positioned
acyloxy functionality on ketoximes 8 could lead to bis-acylated
species 9 and open the doors for the possibility of a
chemoselective Wittig reaction that could subsequently lead
to either of the biologically important isoxazoles 10 or
chromenone-oxime scaffolds 11 (Scheme 5a). Accordingly,
the phosphonium salt 8a was treated with 4-ClPhCOCl (2e)
in the presence of the MTBD in THF at 30 °C (Scheme 5b).
Delightfully, isoxazole and chromenone-oxime were obtained
in 53% and 13% yields, respectively. The X-ray analysis,
however revealed the structure of isoxazole as 12ae instead of
10ae. After a series of control experiments, it was understood
that the isoxazole 12ae had resulted from 8a via an unexpected
intramolecular acyl-transfer from phenol to oxime/Wittig/O-
a
Reactions were performed with 1a (0.3 mmol), PPh3 (1.1 equiv),
Et3N (2.5 equiv), and R3COCl 2 (1.2 equiv) in dry CH2Cl2 (3 mL)
under argon at 30 °C. Isolated yield. α-Bromohydrazone (1d) was
used. Acetic anhydride (2k) was used. TFAA (2l) was used.
b
c
d
e
efficiently regardless of the electronic nature of substrates 1
and acyl chlorides 2. Interestingly, the less reactive hydrazone
1e (R1 = CH3) also participated smoothly to furnish 3ea in
54% yield. Hydrazones bearing tosyl and 2,4-dinitrophenyl
groups also generated products 3fa−3ha in high yields. It is
worth noting that although the electronic property of R3
substitutions in 2 did not affect the yields of 3, the steric
hindrance of R3 had a pronounced influence on the yield (3ah
and 3ai). Furthermore, it was encouraging to find that
perfluorobenzoyl chloride (2j), acetic anhydride (2k), and
TFAA (2l) were also able to provide the corresponding
products in good yields.
To investigate the formation of exclusive Z-4a in our
optimization studies, E/Z-1a was treated with PPh3 in CH2Cl2
at 30 °C. After 8 h, the phosphonium salt Z-4a was obtained in
94% yield (Scheme 3). This could be explained by the in situ
B
DOI: 10.1021/acs.orglett.9b01395
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Letter
transfer (R4CO) occurs irrespective of the solvent employed.
However, in the presence of a competing acyl chloride,
intramolecular acyl transfer is faster than intermolecular
acylation in THF, whereas CH2Cl2 as solvent facilitates
intermolecular acylation over intramolecular acyl migration
thus favoring 11.
Scheme 5. Our Design of the Chemoselective Wittig
Reaction (a) and Its Optimization (b)
The formation of product 11 from 8 can be explained in two
pathways, Wittig/O-acylation sequence, or an initial O-
acylation followed by chemoselective Wittig reaction. To rule
out the possibility of the former, bis-acylated oximes 13 were
prepared and treated with PBu3 in the presence of the MTBD
in CH2Cl2 at 30 °C (Scheme 7). Gratifyingly, the chromenone-
a,b
Scheme 7. Chemoselective Synthesis of 11
acylation sequence and the chromenone-oxime 11ae resulted
via a O-acylation/chemoselective Wittig reaction. The
formation of chromenone-oxime 11ae in minor amounts
hinted that chemoselective Wittig reaction could be achieved.
After extensive studies, it was found that switching the solvent
to CH2Cl2 could result in the predominant formation of 11ae
(Scheme 5b).
Further, different acyl chlorides were tested under the
reaction conditions, and the desired isoxazoles 12aa−ap could
be obtained in 40−54% yields as major products. Notably,
when TFAA was employed, the isoxazole 12a (59%) obtained
was devoid of trifluoroacetate ester. However, the acyl chloride
2c bearing a p-MeOPh group resulted in poor selectivity
(Scheme 6). The X-ray analysis of 12ac as well as EIMS of all
a
Reactions were performed with 13 (0.2 mmol), MTBD (1.5 equiv),
b
in dry CH2Cl2 (2 mL) under argon at 30 °C. Isolated yield.
oxime derivatives 11 were obtained exclusively in yields of up
to 83% within 4 h. This further demonstrates that
chromenone-oximes 11 were indeed obtained from 8a via a
chemoselective intramolecular Wittig reaction of bis-acylated
species and not from an initial Wittig reaction followed by O-
acylation.
Scheme 6. Synthesis of Isoxazoles and Chromenone-
a,b
oximes
A tentative mechanism is outlined in Scheme 8. First, the
reaction of phosphine (PPh3 or PBu3) with 1 or 5 generates
Scheme 8. Plausible Mechanism for Diverse Heteroarenes
a
Reactions were performed with 8 (0.2 mmol), MTBD (2.5 equiv),
and R3COCl (1.2 equiv) in dry THF (2 mL)/ CH2Cl2 (2 mL) under
b
c
d
argon at 30 °C. Isolated yield. TFAA (2l) was used. Without
e
R3COCl in THF. Without R3COCl in CH2Cl2.
the products unambiguously demonstrated an initial acyl group
(R4CO) transfer from phenol to oxime followed by a Wittig
reaction generating isoxazoles and a subsequent O-acylation
(R3CO) of phenols to finally afford rearranged isoxazole 12.
Additionally, the reactions were also conducted in CH2Cl2
to test the chemoselective generation of chromenone-oximes
11. Gratifyingly, in all cases, the desired chromenone-oximes
11aa−ap were predominantly obtained in up to 61% yields.
The selectivity was again disturbed when 2c was employed. To
understand the effect of solvent on the selective formation of
11 and 12, we carried out an experiment with 8a and MTBD
in THF in the absence of R3COCl. The rearranged isoxazole
12a resulting from an acyl transfer/Wittig sequence was
obtained in 55% yield in 3 h. Surprisingly, the same isoxazole
12a was also obtained in similar yield (55%) when the reaction
was conducted in CH2Cl2 (Scheme 6).
the phosphonium salt Z-4/7 via the in situ generated s-cis-I and
s-trans-II isomers of azo-/nitroso-alkene intermediates. In
presence of the base, the salt undergoes acylation with acyl
chloride 2 to afford intermediate A. Deprotonation of A by
another equivalent of base generates reactive phosphorus ylide
B, which upon Wittig reaction affords pyrazoles 3 or isoxazoles
6. The phosphonium salt 8 in the presence of MTBD in THF
as solvent would form the intermediate C, which then
undergoes intramolecular acyl group (R4CO) transfer and
generates D. Wittig reaction and a subsequent O-acylation with
R3COCl affords isoxazole 12. On the other hand, the
phosphonium salt 8 in CH2Cl2 as solvent undergoes acylation
Although inconclusive, these results indicate that in the
absence of a competing acyl chloride the intramolecular acyl
C
DOI: 10.1021/acs.orglett.9b01395
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with R3COCl to form the bis-acylated phosphonium salt 9,
which further provides the ylide E in the presence of the base.
The ylide E then undergoes a chemoselective intramolecular
Wittig reaction at the ester carbonyl (phenolic site) to afford
the chromenone-oxime 11.
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In summary, an efficient strategy for the synthesis of
substituted pyrazoles and isoxazoles is developed via a
phosphine-mediated Wittig reaction of α-halohydrazones or
ketoximes under mild and metal-free conditions. Further a
chemoselective Wittig reaction was also realized by appropriate
functionalization of ketoximes, which subsequently led to
biologically relevant chromenenone-oxime scaffolds. Further
investigations to construct diverse heteroarenes utilizing this
protocol are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
(3) Charvin, D.; Pomel, V.; Ortiz, M.; Frauli, M.; Scheffler, S.;
Steinberg, E.; Baron, L.; Deshons, L.; Rudigier, R.; Thiarc, D.; Morice,
C.; Manteau, B.; Mayer, S.; Graham, D.; Giethlen, B.; Brugger, N.;
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01395.
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Relationship, and Antiparkinsonian Effect of a Potent and Brain-
Penetrant Chemical Series of Positive Allosteric Modulators of
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Optimization data, experimental procedures, character-
ization data and spectra of all compounds (PDF)
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CCDC 1588092−1588093, 1839883, 1845897, 1882452,
1893511−1893512, and 1904919 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wenweilin@ntnu.edu.tw.
ORCID
Praneeth Karanam: 0000-0003-3982-3525
Wenwei Lin: 0000-0002-1121-072X
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of the
Republic of China (MOST 107-2628-M-003-001-MY3) for
financial support..
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