Alkyne Cycloadditions Mediated by Tetrabutylammonium Fluoride: A Unified and Diversifiable Route to Isoxazolines and Pyrazolines

Article abstract of DOI:10.1021/acs.orglett.7b01401

A versatile approach to isoxazolines and pyrazolines by the cyclization of alkyne substrates using tetrabutylammonium fluoride (TBAF) is described. The reported diheteroatom cycles were produced under mild reaction conditions and with broad product scope.

Full text of DOI:10.1021/acs.orglett.7b01401

Letter
pubs.acs.org/OrgLett
Alkyne Cycloadditions Mediated by Tetrabutylammonium Fluoride:
A Unified and Diversifiable Route to Isoxazolines and Pyrazolines
Edith Nagy and Salvatore D. Lepore*
Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431-0991, United States
S
* Supporting Information
ABSTRACT: A versatile approach to isoxazolines and pyrazolines by the cyclization of alkyne substrates using
tetrabutylammonium fluoride (TBAF) is described. The reported diheteroatom cycles were produced under mild reaction
conditions and with broad product scope. Evidence is also provided for a vinyl anion intermediate produced under unusually
mild conditions, which was trapped in situ as part of a tandem cyclization/aldehyde addition sequence. Finally, a deprotection/
functionalization method is described, leading to a substituted pyrazoline in good diastereoselectivity.
tudies involving partially unsaturated diheteroatom hetero-
cycles abound in medicinal chemistry literature. For
instance, isoxazolines have been exploited as inhibitors of
human macrophage migration inhibitory factor (MIF).1 This
same heterocyclic scaffold has also shown immunopotentiating
activity2 and antitumor properties (Figure 1).3 Pyrazolines have
have been efficiently converted to isoxazolines catalyzed by
palladium13 and copper.14 Mukherjee describes a mild
organocatalytic asymmetric approach to both isoxazolines and
S
pyrazolines involving a 5-exo-trig mechanism (Scheme 1).15
A
similar mechanistic approach was used by Kokotos;16 however,
in both cases, product scope is limited due to the presence of
the exocyclic fragment required to activate the system for ring
closure. List reported the development of an asymmetric
electrocyclization of α,β-unsaturated hydrazones catalyzed by a
chiral phosphoric acid.17 While the approach by List stands out
for its efficiency and enantioselectivity, it remains limited to
pyrazolines bearing two aryl substituents. Using a similar
Brønsted acid catalyst, Rueping developed an asymmetric
cycloaddition between alkenes and N-benzoylhydrazones to
afford fused bicyclic pyrazoline derivatives.18 Overall, the
aforementioned approaches to isoxazolines and pyrazolines
are either limited to the production of only one of these
heterocycles or suffer from limited product scope. Given the
growing importance of these heterocycles, the search for unified
and more general methods to their synthesis continues to be a
worthy goal.
Figure 1. Representative bioactive molecules.
also been at the center of numerous medicinal chemistry
investigations,4 including the development of selective inhib-
itors of B-Raf,5 carbonic anhydrase,6 and aurora kinases A and B
for antitumor therapy.7 This compound class also shows
promise as pesticides8 and antifungal agents.9
Not surprisingly, a variety of synthesis routes to these
heterocycles have emerged to enable further medicinal
discovery. Their synthesis is generally achieved through [3+2]
cycloadditions.10 While important headway with this reaction
has recently been made by Bharate11 and Kittakoop,12 these
mainly racemic approaches are largely limited to aryl-
substituted oximes to stabilize nitrile oxide formation. Intra-
molecular cyclizations leading to isoxazolines resolve the
problem of regioselectivity. Using this strategy, allyloximes
We previously reported a novel route to pyrazolines using
mild, nonmetal-mediated conditions.19 Our follow-up efforts
with this reaction were focused on elucidating the reaction
mechanism, which we have recently shown to involve a unique
cation-π interaction between a tetraalkylammonium ion and
carbon−carbon triple bond present in the substrate.20 During
these and subsequent studies, we discovered that our
Received: May 9, 2017
© XXXX American Chemical Society
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a
Scheme 1. Intramolecular Cyclization Approaches
Scheme 2. Isoxazoline and Pyrazoline Substrate Scope
a
All reactions were performed at 0.1 M concentration of propargyl
hydrazine or oxyamine and TBAF (1.5 equiv) with near-refluxing
b
temperatures (60−70 °C). Reaction proceeded very slowly at rt;
ammonium-mediated reaction could also be used to access
isoxazolines.
c
however, heating to 70 °C for 12 h led to full conversion. Reaction
required heating to 80 °C.
In the present communication, we describe our expansion of
this unified approach to produce these diheteroatom hetero-
cycles with good product generality. We also put forward
additional evidence for a 5-endo-dig mechanism that proceeds
through a vinyl anion intermediate despite the exceptionally
mild conditions (Scheme 1). Finally, we reveal a one-pot
deprotection/functionalization approach to prepare highly
functionalized pyrazolines.
cyclization approaches for hydroamination of alkynes utilize
strong π-acids, which are incompatible with terminal alkynes.22
One limitation of the present method appears to be with
substrates bearing an aryl group as the only propargyl
substituent. These failed to give the expected product (such
as 13).
In our previous studies, we examined only hydrazine
substrates bearing both an alkyl and ester unit at the propargyl
position. These room temperature reactions gave pyrazoline
products in 5 min in the presence of tetrabutylammonium
fluoride (TBAF) in acetonitrile.20 To explore the role of alkyl-
only propargyl substituents on the rate of cyclization, we
prepared a series of hydrazine and oxamine derivatives without
the ester unit. We were delighted to discover that these
compounds were also converted to pyrazolines and isoxazolines
(products 2−12) with TBAF in acetonitrile (Scheme 2).
Without a propargyl ester group, the reactions were noticeably
slower; however, heating to 70 °C afforded good yields in 1 h.
On the basis of these results, we believe the rate enhancing
effect of the ester unit in the substrate used in our previous
studies to be due to inductive activation of the triple bond. We
considered an alternative explanation based on a Thorpe−
Ingold effect; however, substrate 4, bearing two alkyl
substituents at the propargyl position, was no more reactive
than other alkyl-only substrates.
To assess the importance of heteroatom substitution at the
propargyl position, substrates 14 and 15 were prepared
(Scheme 3). These substrates failed to cyclize even with
extended reaction times and increased temperatures. Com-
pounds 16 and 17 were of interest because they contain a
diheteroatom unit at the homopropargyl position, which we
Scheme 3. Role of the Propargyl Heteroatom
Besides being able to produce both pyrazolines and
isoxazolines under the same conditions, the scope of this
reaction is relatively broad, leading to all alkyl-substituted
heterocycles as well as those with aryl and alkyl groups. It is
important to note that, to our knowledge, this is only the
second21 example of the synthesis of 2,5-dihydroisoxazoles
from terminal alkynes (compounds 8 and 9). Traditional
a
Product 19 was isolated along with unreacted starting material.
B
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considered might be important for cyclization. Here again, no
cyclization was observed in the presence of TBAF even under
refluxing conditions in acetonitrile. In the presence of TBAF,
substrate 18 gave pyrazoline product 19, presumably after a
decarboxylation (Scheme 3). However, no cyclization product
resulting from the attack of the hydroxyl oxygen on the alkyne
was observed. This selectivity further suggested that a propargyl
diheteroatom plays an essential role in the present reaction.
Given these considerations, we believe that the observed 5-
endo-dig cyclization is likely promoted by the inductive
electron withdrawing effect of the propargyl heteroatom. In
their computational analysis, Alabugin and co-workers recently
showed that a 5-endo-dig-cyclization of a related system was
unusually favored due to an in-plane aromatic transition state.23
Cyclitive attack on nonconjugated carbon−carbon triple
bonds without the aid of a transition metal has rarely appeared
in the literature. One mechanistic consequence is that a vinyl
anion intermediate is formed. These are typically high-energy
species in the absence of stabilizing interactions with transition
metals. Vinyl anion intermediates have rarely been invoked
under similar conditions.24 We envisioned that, in our reaction,
the vinyl anion is immediately quenched by a proton source
especially since partial deuterium incorporation was observed in
the product of reactions performed in deuterated acetonitrile
(MeCN-d3). However, we sought further proof of a vinyl anion
intermediate by attempting to trap the putative anion with an
aldehyde. We were pleased to discover that cyclization followed
by vinyl anion trapping was successful in the presence of excess
p-Cl-benzaldehyde in nitrobenzene as solvent (Scheme 4). Due
Scheme 5. Synthesis of Nonracemic Pyrazolines
Transformations involving isoxazolines and pyrazolines have
usually focused on cleaving the N−N or N−O bonds. However,
in the present work, we sought to further elaborate these ring
systems in novel ways to build more complex frameworks.
In this vein, we envisioned that the tert-butyloxycarbonyl
(Boc) group on the enamine nitrogen in each heterocycle could
be removed under acidic conditions. Accordingly, we attempted
a selective removal of this group and were pleased to observe
the formation of 2-pyrazoline products 24 and 25 (Scheme 6).
Scheme 6. Selective Deprotection and Aldehyde Addition
Scheme 4. Tandem Cyclization and Vinyl Anion Trapping
We note that compound 25 is a novel azaproline derivative and
contains an orthogonally protected carboxylic acid and amine
group, which can be conveniently exploited in peptide
synthesis. These reactions worked best with trifluoracetic acid
(TFA) in the presence of activated molecular sieves. Under the
same conditions, isoxazoline 26 was also produced in excellent
yields. Intrigued by this result, we explored the use of a Lewis
acid27 to promote the addition of an aldehyde to the C4-carbon
of 6a together with selective Boc removal. To our delight, the
functionalization attempt yielded addition product 27 in good
yield and reasonable diastereoselectivity (6:1). Others have
deprotected enamine-type systems using hydroxide28 or
palladium29 with concomitant addition. However, similar
transformations under Lewis acidic conditions leading to
products such as 27 is unprecedented.30
The relative stereochemistry between centers C3 and C4 of
product 27 was determined to be exclusively trans. Crystallog-
raphy studies indicate that the configurational variability is at
the exocyclic position (C6). The trans selectivity between C3
and C4 can be understood as resulting from the steric hindrance
offered by the alkyl substituent at C3 that favors a Re face attack
(Figure 2). Importantly, this substituent also constrains the Boc
group on the adjacent nitrogen to assume a relative trans
orientation (N2 to C3). On the basis of this N2 configuration,
to the presence of water in TBAF,25 the reaction was performed
with TBAB and sodium phenoxide as base, leading to product
21 in modest isolated yield (50%). We note that the added base
(NaOPh) was entirely soluble in this reaction, and thus, TBAB
was not required as a phase transfer agent in this reaction. As
we highlighted in our previous mechanistic investigation, the
ammonium cation engages the carbon−carbon triple bond in a
cation-π interaction, which seems connected with its rate
enhancing effect on this reaction.20 The vinyl anion was also
successfully trapped by other electron deficient aromatic
aldehydes, though in lower yields.
One of the benefits of the present route to pyrazolines and
isoxazolines is that the starting propargyl substrates are readily
accessible in nonracemic form. We previously produced these
materials through the catalytic asymmetric addition of silyl
allenes to an azidodicarboxylates.19 However, these starting
materials can also be prepared by taking advantage of the
extensive literature on catalytic asymmetric alkyne additions to
aldehydes.26 To demonstrate this accessibility to nonracemic
heterocyclic products, we converted commercially available (S)-
1-octyn-3-ol (99% ee) to propargyl hydrazine 22 in one step
(Scheme 5). A subsequent cyclization afforded the correspond-
ing pyrazoline 23 with no erosion of enantiomeric purity.
C
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: slepore@fau.edu
ORCID
Salvatore D. Lepore: 0000-0002-8824-6114
Notes
The authors declare no competing financial interest.
(25) Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050−
2051.
ACKNOWLEDGMENTS
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We wish to acknowledge the NIH (GM110651) for financial
support. This material is also based upon work supported by
the National Science Foundation Graduate Research Fellow-
ship (to E.N.) under Grant 1257290.
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