Synthesis of 4-Oxoisoxazoline N-Oxides via Pd-Catalyzed Cyclization of Propargylic Alcohols with tert-Butyl Nitrite

Article abstract of DOI:10.1021/acs.orglett.9b00811

A cyclization of propargylic alcohols with tert-butyl nitrite at room temperature in air was achieved using Pd(OAc)₂ as catalyst. The first reported 4-oxoisoxazoline N-oxides could be directly accessed from a range of multisubstituted propargylic alcohols in moderate to excellent yields under mild conditions. Density functional theory calculations indicated that the reaction proceeds through a palladium-catalyzed NO₂ addition that efficiently generates a ketoxime radical, which eventually produces 4-oxoisoxazoline N-oxide.

Full text of DOI:10.1021/acs.orglett.9b00811

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 4‑Oxoisoxazoline N‑Oxides via Pd-Catalyzed Cyclization
of Propargylic Alcohols with tert-Butyl Nitrite
Kai-Wen Feng, Yong-Liang Ban, Pan-Feng Yuan, Wen-Long Lei, Qiang Liu,* and Ran Fang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 South Tianshui Road, Lanzhou 730000, P.R. China
S
* Supporting Information
ABSTRACT: A cyclization of propargylic alcohols with tert-
butyl nitrite at room temperature in air was achieved using
Pd(OAc)2 as catalyst. The first reported 4-oxoisoxazoline N-
oxides could be directly accessed from a range of multi-
substituted propargylic alcohols in moderate to excellent
yields under mild conditions. Density functional theory calculations indicated that the reaction proceeds through a palladium-
catalyzed NO2 addition that efficiently generates a ketoxime radical, which eventually produces 4-oxoisoxazoline N-oxide.
a
Table 1. Optimization of Reaction Conditions
itrogenous organic molecules play a crucial role in
Nenriching the carbon-based natural world and are
Scheme 1. Protocol of the Synthesis of 4-Oxoisoxazoline N-
Oxides
b
time
(h)
TBN
(equiv)
yield
entry
cat. (mol %)
solvent
(%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(PPh3)4 (2)
CH3CN
THF
12
12
12
12
12
16
16
16
16
16
16
16
16
16
2.5
2.5
2.5
2.5
2.5
2.5
2.0
1.5
2.0
2.0
2.0
2.0
2.0
0
95
74
68
86
85
95
93
80
trace
16
67
0
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
13
14
Pd(PPh3)2Cl2 (2) CH3CN
PdCl2 (2)
CH3CN
CH3CN
CH3CN
CH3CN
c
Pd(OAc)2 (2)
Pd(OAc)2 (2)
75
37
d
a
Reaction conditions: 1a (0.2 mmol), TBN (0.4 mmol), solvent (2
b
mL), at room temperature under air in a closed bottle. Yields of
isolated products. Reaction exposed to the air. 2.0 equiv of NaNO2
c
d
prevalent in compounds investigated in the pharmaceutical
industry,1 the agriculture industry,2 organic synthesis,3 and
biological research.4 Moreover, aza-heterocyclic compounds, a
class of representative nitrogenous compounds, have drawn
extensive attention for their potential biological and
pharmaceutical activities.5 In particular, isoxazoline N-oxides
exhibit unique reactivity for the particular structure in this
family and are well-known to be versatile building blocks in
chemical synthesis.6
There are several methods for synthesizing isoxazoline N-
oxides on the basis of relevant literature. In general, isoxazoline
N-oxides can be prepared from functionalized aliphatic nitro
compounds via intramolecular O-alkylation.7 However, no
general strategy can be used to afford the functionalized nitro
and 2.0 equiv of CF3COOH instead of TBN.
precursors. Thus, intermolecular connection synthesis strat-
egies have been developed, and there are two main types: (1)
formal [3 + 2] cascade approaches8 and (2) formal [4 + 1]
annulation approaches.9 In addition, it is reported that β-
hydroxy ketoximes can be candidates to generate isoxazoline
N-oxides, which undergo an intramolecular N−O coupling
process by some additive oxidants.10 In this regard, although
Received: March 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00811
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Table 2. Reaction Scope
B
DOI: 10.1021/acs.orglett.9b00811
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. continued
a
Reaction conditions: 1 (0.2 mmol), TBN (0.4 mmol), and Pd(OAc)2 (2.0 mol %) in CH3CN (2.0 mL) were stirred at room temperature under
b
c
air in a closed bottle. Yields of isolated products. The amount of 1q is 0.1 mmol.
Scheme 2. Scaled-up Reaction of 1a and Reduction of 2a
to air.11 Propargylic alcohols are widely researched for the
excellent reactivity and abundant functional group trans-
formations.12 In recent years, many combinations of
propargylic alcohols and CO2 have been developed, which
ordinarily generate five-membered ring lactones.13 As a
consequence, we envisioned that NO2 and propargylic alcohols
can build isoxazoline N-oxide analogues. Herein, we report the
first synthesis of 4-oxoisoxazoline N-oxides from propargylic
alcohols and tert-butyl nitrite using Pd(OAc)2 as catalyst
(Scheme 1).
We initiated our investigations with cyclic propargylic
alcohol 1a as the model substrate to react with TBN (Table
1). Considering both that TBN can release NO2 smoothly in
air and the volatility of NO2, an acetonitrile solution dissolving
1a (1.0 equiv), TBN (2.5 equiv), and Pd(OAc)2 (0.1 equiv) in
an air atmosphere vessel with a plug was designed. After 12 h
of stirring under room temperature, 4-oxoisoxazoline N-oxide
2a was obtained in 95% yield. THF and CH2Cl2 were
evaluated in this reaction (entries 2 and 3), which indicated
CH3CN is the best candidate solvent. When Pd(OAc)2 was
employed in a smaller amount (entries 4 and 5), the yields
reduced by almost 10%. To our delight, a longer reaction time
can improve the efficiency (entry 6). In addition, the amount
of TBN could be decreased to 2.0 equiv with a negligible
influence on the yields (entries 7 and 8). Several typical
palladium catalysts were also studied for their efficiency
(entries 9−11), and Pd(OAc)2 is still the best catalyst for the
cyclization. Not surprisingly, no desired product could be
obtained when Pd(OAc)2 was absent (entry 12) and the
reaction in a bottle exposed in air gave lower yield than that in
a closed bottle containing air (entry 13). We also used NaNO2
and CF3COOH instead of TBN to react with 1a and obtained
2a in a lower yield, which proved NO2 was the actual reagent
(entry 14).
Scheme 3. Biologically Active Compound 4 and Synthesis of
Compound 9
With the optimized conditions in hand, we next investigated
the substrate scope of this Pd-catalyzed synthesis of 4-
oxoisoxazoline N-oxides (Table 2). First, we tested six-
membered ring propargylic alcohols with different substitu-
tions on the alkynyl moiety. In the case of n-butyl- and
benzyloxymethyl-substituted alkynylcyclohexanols 1b and 1c,
the system performed well and the corresponding products 2b
and 2c were obtained in 84% and 43% yields, respectively. For
phenyl-substituted alkynyl cyclohexanols, cyclizations with
TBN afforded the desired products 2d−f in 65−96% yields.
We were glad to see that the thienyl group had excellent
compatibility in this approach, and 2g was isolated in 93%
yield. While spiro-ring propargylic alcohol 1h is also an
excellent substrate for this reaction, bridged-ring propargylic
alcohol 1i reluctantly reacted with TBN under the standard
conditions. Moreover, heterocyclic propargylic alcohol 1j and
other sizes of cyclic propargylic alcohols 1k,l performed well,
and the corresponding products were obtained in moderate to
high yields. We also examined the scope of propargylic
alcohols with phenyl and alkyl chain substitutions instead of
the cycloalkyl moiety. As expected, annulations with TBN took
place smoothly and delivered 4-oxoisoxazoline N-oxides 2m−o
in good to high yields. In addition, heteroaromatics were
tolerated well in the transformations, and cyclic products 2p
Figure 1. Calculated reaction pathway for the cyclization.
various substituted isoxazoline N-oxides can be delivered, there
is no report about 4-oxoisoxazoline N-oxide synthesis.
It is well-known that tert-butyl nitrite (TBN) is used to serve
as a NO source in various synthesis reactions. In fact, TBN can
also release NO2 in reaction systems, especially when exposed
C
DOI: 10.1021/acs.orglett.9b00811
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
and 2q were isolated in high yields. Last but not least, it should
be mentioned that some special propargylic alcohols, such as
terminal alkynes 1r−t, primary alcohol 1u, and secondary
alcohol 1v, were incompatible with the reaction conditions.
A gram-scale reaction of propargylic alcohol 1a (10 mmol)
with TBN (25 mmol) was designed to demonstrate the
inherent value of this transformation, and the desired product
2a was obtained in 71% yield. Additionally, 4-oxoisoxazoline
N-oxide 2a could be readily converted into the corresponding
isoxazoline 3a in good yield (Scheme 2). It is notable that 4-
oxoisoxazoline compounds derived from the present trans-
formations are not only potentially bioactive but also excellent
precursors to bioactive compounds. For instance, 4-oxoisox-
azoline 9 could be easily transformed to compound 4, a CRAC
(calcium release-activated calcium channels) modulator.14 To
further extend the utility of this annulation reaction, we chose
commercially available aniline 5 as the raw material to
synthesize compound 9 in four steps (Scheme 3). After a
diazotization, iodination, and Sonogashira cross-coupling
sequence, aniline 5 was transformed to aromatic propargylic
alcohol 7 in 76% yield. Subsequently, cyclization of the
resulting alcohol 7 with TBN under standard conditions
afforded 4-oxoisoxazoline N-oxide 8 in 80% yield. Finally,
reduction of 8 with triethyl phosphite gave the desired 4-
oxoisoxazoline 9 in 50% yield.
Experimental procedures and detailed characterization
data of all products (PDF)
Accession Codes
CCDC 1898980−1898981 contain the supplementary crys-
tallographic 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 Authors
■
*E-mail: liuqiang@lzu.edu.cn.
*E-mail: fangr@lzu.edu.cn.
ORCID
Qiang Liu: 0000-0001-8845-1874
Ran Fang: 0000-0001-6804-6572
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the NSFC (No.
21871123).
■
To gain some insight into the mechanism, density functional
theory (DFT) calculations were implemented (Figure 1).15
First, propargylic alcohol 1a is activated by Pd(OAc)2 to form
intermediate 10, and TBN releases NO2 into the vessel. Then,
DFT calculations indicated that intermediate 10 undergoes an
addition reaction to deliver intermediate 11 through TSa1,
where C−N bond formation resulted from the N atom
connecting with the methyl side alkyne C atom. That the
activation energy of this process was lower than the energy of
the other addition paths favored this view, and a value up to
20.8 kcal/mol revealed that this conversion was the rate-
determining step. Immediately, the generated nitro alkene
intermediate 11 transformed to ketoxime radical 12 through a
cyclic four-membered TS2, and Pd(OAc)2 was recovered at
the same time. The O-centered ketoxime radical 12 behaves as
N-centered radical 13,16 which could be nucleophilically
attacked by the adjacent hydroxyl group. With the N−O
bond-forming cyclization of radical 13 and the aid of t-BuO•,
the desired product 2a was eventually obtained.
In summary, we have developed a convenient strategy for
the construction of 4-oxoisoxazoline N-oxides from propargylic
alcohols and TBN mediated by Pd(OAc)2 catalysis. The
system achieves cyclization of various propargylic alcohols with
TBN in moderate to excellent yields under mild conditions.
The resulting 4-oxoisoxazoline N-oxides can be easily trans-
formed to 4-oxoisoxazolines which are found in a variety of
biologically active molecules. As little known compounds, 4-
oxoisoxazoline N-oxides have unexplored potential in bio-
logically active research, application of organic synthesis, and
industry.
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ACS Publications website at DOI: 10.1021/acs.or-
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