BPh3-Catalyzed [2+3] Cycloaddition of Ph3PCCO with Aldonitrones: Access to 5-Isoxazolidinones with Exocyclic Phosphonium Ylide Moieties

Article abstract of DOI:10.1021/acs.orglett.9b02192

A method for the generation of 5-isoxazolidinones with exocyclic phosphonium ylide functionalities via [2+3] cycloaddition of Ph₃PCCO and aldonitrones has been developed and applied in the synthesis of 4-alkylidene-5-isoxazolidinones via Wittig olefination. The reaction proceeds by BPh₃ catalysis under mild conditions and with a broad substrate scope. A reaction pathway involving the activation of the aldonitrone via interactions with the Lewis acid BPh₃ is proposed.

Full text of DOI:10.1021/acs.orglett.9b02192

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
BPh3‑Catalyzed [2+3] Cycloaddition of Ph3PCCO with Aldonitrones:
Access to 5‑Isoxazolidinones with Exocyclic Phosphonium Ylide
Moieties
Amandeep Brar, Daniel K. Unruh, Natalie Ling, and Clemens Krempner*
Department of Chemistry & Biochemistry, Texas Tech University, Box 41061, Lubbock, Texas 79409-1061, United States
S
* Supporting Information
ABSTRACT: A method for the generation of 5-isoxazolidi-
nones with exocyclic phosphonium ylide functionalities via
[2+3] cycloaddition of Ph3PCCO and aldonitrones has been
developed and applied in the synthesis of 4-alkylidene-5-
isoxazolidinones via Wittig olefination. The reaction proceeds
by BPh3 catalysis under mild conditions and with a broad
substrate scope. A reaction pathway involving the activation of
the aldonitrone via interactions with the Lewis acid BPh3 is proposed.
riphenylphosphoranylideneketene (Ph3PCCO), also
Tknown as Bestmann’s ylide, has attracted significant
interest over the past two decades not only due to its unusual
structure and bonding1 but also as a versatile reagent in organic
and organometallic synthesis.2−4 In addition to being utilized
as a precursor for amide- and ester-stabilized Wittig reagents,5
Ph3PCCO has found widespread applications as a linchpin
reagent for the synthesis of a wide variety of cyclic natural
products.6 These types of cyclization reactions proceed via a
tandem addition/Wittig reaction sequence, where a hydroxy-
aldehyde adds across the CO bond of Ph3PCCO to generate
the ester-stabilized phosphonium ylide, which subsequently
undergoes intramolecular Wittig olefination with elimination of
OPPh3.
stable and does not show signs of dissociation in solution
according to NMR spectroscopic investigations at various
temperatures.
Scheme 1. Stoichiometric and Catalytic Reactions of
Ph3PCCO (1) with Nitrone 3a in the Presence of BR3 (R =
C6F5)
Notably less is known about the ability of Ph3PCCO to
undergo cycloaddition reactions with polar organic substrates
to form heterocycles with intact exocyclic phosphonium ylide
moieties. Such ylides have the potential of being synthetically
useful for the “late-stage” introduction of exocyclic double
bonds via Wittig olefination. However, only a few unsaturated
molecules, including Ph2CCO, Ph-NCX,7 C3O2,8 XCHNCX
(X = CH2, O, or S),9,10 RN3,11 and R2CN2,12 have been
demonstrated to engage in such cyclization reactions with
Ph3PCCO. Note that reactions of the latter with organic
nitrones, 1,3-dipolar molecules of wide synthetic versatility, are
unknown, which is surprising given the efficiency by which
nitrones engage in selective [2+3] cycloadditions with various
alkynes and alkenes.13 Here, we report a highly efficient
protocol for the Lewis acid-catalyzed [2+3] cycloaddition of
Ph3PCCO (1) with various aldonitrones to previously
unknown 5-isoxazolidinone-substituted phosphonium ylides,
air- and moisture-stable precursors for the synthesis of
biologically active 4-alkylidene-5-isoxazolidinones.14
Despite its stability, a C6D6 solution of 2 reacted
immediately at room temperature with 1 equiv of aldonitrone
3a to give a crystalline precipitate, which was identified as the
product of a [2+3] cycloaddition, the O-borylated 5-
isoxazolidinone 5. The results of an X-ray analysis confirmed
the assumed connectivity of the heterocyclic ring and the
coordination of its carbonyl oxygen to B(C6F5)3 (Figure 1).
The C1−C2 distance of 5 was found to be 1.361(3) Å,
consistent with the formulation of the C1−C2 bond as a
We recently isolated and structurally characterized the Lewis
acid−base adduct 2 from the reaction of Ph3PCCO (1) with
B(C6F5)3 (Scheme 1 and Figure 1).15 Adduct 2 is thermally
Received: June 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02192
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. Solid-state structures of 2, 4, 5, and 6a (H atoms omitted for the sake of clarity; black for carbon, green for fluorine). Selected distances
(angstroms): 2, P1−C1 1.752(3), C1−C2 1.316(4), C2−O1 1.163(3), C1−B1, 1.705(1); 4, O2−N1 1.360(1), O2−B1 1.552(2), N1−C3
1.284(2); 5, P1−C1 1.740(2), O2−C2 1.355(2), O2−N1 1.481(2), O1−C2 1.286(2), O1−B1 1.525(2), C1−C3 1.521(3), C1−C2 1.361(3),
N1−C3 1.506(2); 6a, P1−C1 1.712(1), O1−C2 1.224(2), O2−C2 1.404(2), O2−N1 1.465(1), N1−C3 1.502(2), C1−C2 1.406(2), C1−C3
1.509(2).
double bond as shown in Scheme 1. Interestingly, when 3a was
treated with B(C6F5)3 prior to the addition of Ph3PCCO (1),
the crystalline Lewis acid base adduct 4 precipitated from
solution, which was isolated and characterized by NMR
spectroscopy and XRD (Figure 1). Note that the intermediate
formation of adduct 4 did not change the overall outcome of
the reaction as 4 reacted with Ph3PCCO (1) as selectively as
adduct 2 with nitrone 3a in quantitatively producing 5.
Encouraged by these results, we treated 1 and 3a with catalytic
amounts of B(C6F5)3 (5 mol %) in toluene as the solvent. In
fact, after ∼16 h at 80 °C, an air- and moisture-stable
crystalline material precipitated, which was isolated and
identified by NMR spectroscopy and X-ray crystallography
(Figure 1) as the 5-isoxazolidinone ylide 6a in ∼90% yield.
Compared to that of its B(C6F5)3 adduct 5, the C1−C2
distance [1.406(2) Å] of 6a is somewhat longer, suggesting
only partial double bond character.
essentially inactive (Table 1) even upon being heated to 80 °C.
The inability of B(OMe)3 and BEt3 to catalyze the reaction is
consistent with the observation that both compounds do not
form Lewis acid−base adducts with 1 or 3a or product 6a,
according to NMR spectroscopic studies. In striking contrast,
B(C6F5)3 forms stable and isolable adducts with 1, 3a, and 6a
(vide supra), while the catalytically most active BPh3 forms an
adduct only with nitrone 3a. This suggests that Lewis acid
activation of the nitrone is key to the catalytic process and that
competing Lewis acid−base interactions of the catalyst with
Ph3PCCO slow the reaction as is the case for B(C6F5)3. On the
basis of these findings, a mechanism shown in Scheme 2 is
Scheme 2. Proposed Mechanism of the Lewis Acid-
Catalyzed [2+3] Cycloaddition of 1 and 3a
Next, boranes of different Lewis acidities (defined by their
Gutmann acceptor number, AN)16 were screened as catalysts
for the [2+3] cycloaddition of 1 with 3a at various
temperatures in C6D6 as the solvent (Table 1). Despite its
lower Lewis acidity, BPh3 was found to be significantly more
active in catalyzing the reaction than B(C6F5)3. Even the
weaker Lewis acid B(OPh)3 performed somewhat better than
B(C6F5)3. However, boranes with Lewis acidities significantly
lower than those of BPh3, B(OPh)3, and B(C6F5)3 were
Table 1. Screening of Lewis Acid Catalysts for the [2+3]
a,b
Cycloaddition to 5-Isoxazolidinone Ylide 6a
c
catalyst
AN
temp (°C)
time (h)
6a (%)
none
−
77.6
−
71.4
−
68.7
−
30.3
16.4
13.8
13.2
100
25
80
25
65
25
65
65
80
80
80
24
4
16
40
20
8
0
8
d
e
f
B(C6F5)3
B(C6F5)3
B(OPh)3
B(OPh)3
BPh3
BPh3
BEt3
FBMes2
BMes3
B(OMe)3
95
88
90
99
99
<5
<5
<5
0
proposed. The borane catalyst increases the electron deficiency
of the imine carbon of the nitrone by adduct formation, which
facilitates the nucleophilic attack of the ylidic carbon of
Ph3PCCO (1). The thus formed intermediate I (not detected)
readily undergoes cyclization to the borane-5-isoxazolidinone
adduct. Interaction of the latter adduct with incoming nitrone
finally liberates the product, the 5-isoxazolidinone 6a, and
regenerates the borane−nitrone adduct.
After having identified BPh3 as the most efficient catalyst, we
investigated the substrate scope (Schemes 3). Various aromatic
and heteroaromatic aldonitrones, derived from reactions of the
respective aldehydes with [MeNH2OH]Cl and [BnNH2OH]-
d
2
e
e
e
e
20
24
24
24
a
Conditions: 0.10 mmol of 1, 0.10 mmol of 3, 0.005 mmol of catalyst,
b
c
0.5 mL of C6D6. The progress was monitored by 31P NMR. AN is
the acceptor number.16 From ref 17. From ref 18. Contains ∼5% of
d
e
f
5.
B
DOI: 10.1021/acs.orglett.9b02192
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Organic Letters
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Scheme 3. BPh3-Catalyzed [2+3] Cycloaddition of 1 with
Aromatic Aldonitrones 3a−q
Scheme 4. BPh3-Catalyzed [2+3] Cycloaddition of 1 with
Aldonitrones 9, 10, 13, and 14
nitrone 3a to furnish the respective 5-isoxazolethione ylide 18
in 70% yield as an air-stable crystalline material (Figure 2).
Figure 2. Synthesis and solid-state structure of 18 (H atoms omitted
for the sake of clarity). Selected distances (angstroms): S1−C2
1.669(2), P1−C1 1.728(2), O2−C2 1.390(2), O2−N1 1.483(2),
N1−C3 1.492(2), C1−C2 1.379(2), C1−C3 1.517(2).
Cl, were treated with Ph3PCCO in toluene at 65 °C for ∼24 h
(5 mol % BPh3). To our delight, the target products, the N-
methyl- and N-benzyl-substituted 5-isoxazolidinone ylides 6a−
q, were isolated as crystalline materials in excellent yields
ranging from 75 to 96%.
Note that in all cases, purification by column chromatog-
raphy was not necessary as most of the ylide products with the
exception of 6k and 6l precipitated from toluene as crystalline
materials in high purity during the course of the reaction. The
formation of the toluene and THF soluble ylides 6k and 6l was
evidenced by 31P NMR and their in situ conversion into their
4-methylidene derivatives 7 and 8, respectively, via Wittig
olefination with formaldehyde (see the Supporting Informa-
tion). To further extend the scope of this transformation,
reactions of Ph3PCCO with the endocyclic aldonitrones 9 and
10 were surveyed (Scheme 4). In the presence of 5 mol %
BPh3, the reactions proceeded smoothly in selectively
providing the crystalline [2+3] cycloaddition products 11
(92%) and 12 (91%). The reaction also seems to tolerate more
reactive functional groups as the ester- and acetal-function-
alized aldonitrones 13 and 14 upon treatment with Ph3PCCO
rapidly converted into the corresponding crystalline 5-
isoxazolidinone ylides 15 and 16, respectively, in very good
isolated yields within a few minutes at room temperature
(Scheme 4).19
The results of an X-ray analysis reveal the central C1−C2
distance [1.379(2) Å] of 18 to be somewhat shorter than that
of the 5-isoxazolidinone ylide 6a [C1−C2, 1.406(2) Å] but
longer than that of the B(C6F5)3 adduct 5 [C1−C2, 1.361(3)
Å].
To demonstrate the synthetic utility of this new [2+3]
cycloaddition reaction, ylide 6a was treated with ethyl
propynoate and various aldehydes (Scheme 5). As expected,
the reaction of 6a with formaldehyde proceeded smoothly at
room temperature in chloroform to generate 4-methylidene-5-
isoxazolidinone 19 in yields of 88%.20 19 can be hydrogenated
(Pd/H2) to give the corresponding β-amino acid 25
(Supporting Information). Excess acetaldehyde and elevated
temperatures were required to obtain 4-ethylidene-5-isoxazo-
lidinone 20 in 75% yield, while the activated aldehyde, ethyl
glyoxalate, readily reacted in chloroform with 6a to produce
the ester-functionalized 5-isoxazolidinone 21 in 86% yield.
Heating a toluene solution of 6a and ethyl propynoate (molar
ratio of 1:1) at 100 °C afforded after 2 days ylide 22 in 75%
yield as a crystalline material. The highly selective formation of
22 appears to be the result of an initial Michael-type addition
Astonishingly, also Ph3PCCS (17), the sulfur analogue of 1,
readily underwent a BPh3-catalyzed [2+3] cycloaddition with
C
DOI: 10.1021/acs.orglett.9b02192
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Scheme 5. Selected Transformations of 6a to 5-
Isoxazolidinones with Exocyclic CC Double Bonds
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02192.
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AUTHOR INFORMATION
Corresponding Author
■
*Department of Chemistry & Biochemistry, Texas Tech
University, Box 41061, Lubbock, TX 79409-1061. E-mail:
Clemens.krempner@ttu.edu.
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ORCID
Daniel K. Unruh: 0000-0002-2594-5786
Clemens Krempner: 0000-0003-2596-591X
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors gratefully acknowledge financial support by the
National Science Foundation (Grant 1407681; Project
SusChEM: IUPAC) as part of the IUPAC International
Funding Call on “Novel Molecular and Supramolecular
Theory and Synthesis Approaches for Sustainable Catalysis”.
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D
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(19) Note that even at higher temperatures these highly active
aldonitrones do not form the [2+3] cycloaddition products with
Ph3PCCO unless the borane catalyst is present.
(20) The ylides 6b and 12 could also be converted into the
corresponding 4-methylidene-5-isoxazolidinones 23 and 24, respec-
tively, via treatment with H2CO (see the Supporting Information
for more details).
́
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E
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