Platinum-catalyzed cyclizations via carbene intermediates: Syntheses of complementary positional isomers of isoxazoles

Article abstract of DOI:10.1039/c2sc21671j

A novel synthesis of regioisomeric isoxazoles is described. Using catalytic platinum, both propargylic N-hydroxycarbamates and N-alkoxycarbonyl amino ethers can be cyclized to form differentially substituted isoxazoles. Reaction conditions are developed that address specific aspects of the catalytic manifold. A unique mechanism involving a Pt-carbene intermediate is proposed, and deuterium labeling studies corroborate this hypothesis. This regiocomplementary approach to isoxazoles is highlighted in the syntheses of antirhinovirus analogues, illustrating the relevance of this science to medicinal chemistry.

Full text of DOI:10.1039/c2sc21671j

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Table of contents materials
Platinum-Catalyzed Cyclizations via Carbene Intermediates: Syntheses of
Complementary Positional Isomers of Isoxazoles
Paul Allegretti and Eric M. Ferreira*
A novel synthesis of regioisomeric isoxazoles is described. Via an interesting Pt-carbene
intermediate, substrates featuring oxygen- or nitrogen-based nucleophiles can be cyclized
to form differentially substituted isoxazoles.
Boc
OH
N
OMe
R1
O
N
OH
BocN
R1
R2
SO2Ph
[Pt]
R2
R2
regioisomeric
isoxazoles
51-96% yield
OMe
R1
OMe
R1
O
1.
N
O
NHBoc
O
[Pt]
R2
H
R1
2. conversion to
amino ether
R2
R2

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ARTICLE TYPE
Platinum-Catalyzed Cyclizations via Carbene Intermediates: Syntheses
of Complementary Positional Isomers of Isoxazoles
Paul A. Allegretti and Eric M. Ferreira*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A novel synthesis of regioisomeric isoxazoles is described. Using catalytic platinum, both propargylic Nꢀ
hydroxycarbamates and Nꢀalkoxycarbonyl amino ethers can be cyclized to form differentially substituted
isoxazoles. Reaction conditions are developed that address specific aspects of the catalytic manifold. A
unique mechanism involving a Ptꢀcarbene intermediate is proposed, and deuterium labeling studies
10 corroborate this hypothesis. This regiocomplementary approach to isoxazoles is highlighted in the
syntheses of antirhinovirus analogues, illustrating the relevance of this science to medicinal chemistry.
The prevalence of the heterocyclic structure in pharmaceutical
and materials chemistry is well established. Among heterocycles,
isoxazoles continue to prove highly valuable to interests both
regiocomplementarity.
15 synthetic1 and medicinal.2
Their importance necessitates
convenient synthetic methods to access their core structures.
There are several accepted methods for isoxazole synthesis,3
notably the [3+2] cycloaddition of nitrile oxides with C–C
multiple bonds4,5 or the combination of hydroxylamine with
20 various threeꢀcarbon components;6 each, however, has its
respective limitations (decreased regioselectivity, substrate
specificity, forcing conditions, etc.). More recent developments
have been aimed at addressing some of these drawbacks.7 One
such strategy is the metalꢀcatalyzed intramolecular cyclization of
25 a heteroatom nucleophile onto an unsaturation unit.8 An
attractive attribute within this approach would be the ability to
produce regioisomeric isoxazoles from a common advanced
intermediate. Herein we report the platinumꢀcatalyzed synthesis
of complementary 3,5ꢀdisubstituted isoxazoles from easily
30 accessed propargylic Nꢀhydroxycarbamates and propargylic
carbamoyl ethers.
Recently, we described the Ptꢀcatalyzed synthesis of furans
from homopropargylic alcohols, proposing a unique generation of
a carbene intermediate (Figure 1, A→C).9ꢀ11 We anticipated that
35 we could expand upon this reaction manifold to form alternative
heterocyclic compounds from the appropriate precursors.
Isoxazole syntheses via alkyne activation processes have seen
relatively limited exploration.8 With regard to this heterocyclic
structure, substrates bearing an N–O bond with either nitrogenꢀ or
40 oxygenꢀbased nucleophiles could be implemented in this context.
This approach presents unique challenges, however. Specifically,
the substrates must be easily accessible and competent reactants
under the catalytic conditions, and the additional nitrogen
substituent (R3) must be cleavable, ideally in the same reaction
45 process. If these challenges could be overcome, then this method
would serve as an attractive and convenient protocol for the
syntheses of isoxazoles, with potential for access to
50
Figure 1. Development of Ptꢀcatalyzed isoxazole formations.
First, we needed an efficient synthetic route to precursors
containing the requisite N–O connectivity. Although the
additions of alkyne nucleophiles into nitrones has been
described,12 the N-hydroxylamine products generally featured
55 alkyl groups bound to nitrogen. We were concerned the presence
of a Lewis basic nitrogen would impede the proposed reaction or
that the alkyl groups (e.g., benzyl) would not easily cleave.13,14
An isolated report from Denis, however, described the use of Nꢀ
Boc nitrone surrogates as electrophiles in alkynylations by
60 generating the nitrone species in situ from corresponding
(phenylsulfonyl)alkylꢀNꢀhydroxycarbamates, and this method
appeared ideal for the syntheses of the targeted substrates.15
Using terminal alkyne 1, addition into the in situ generated
nitrone from hydroxycarbamate 2 proved effective, and the
65 resulting Nꢀhydroxycarbamate (3) was produced in good yield
overall (Scheme 1).
Scheme 1
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Table 1. Ligand and acid effects on isoxazole formation.
With hydroxycarbamate 3 in hand, we evaluated conditions to
induce cyclization (Scheme 2). The original conditions we had
developed in the furan chemistry ([(C2H4)PtCl2]2, THF, 23 °C)
displayed minimal reactivity, and even at elevated temperatures
in various solvents, the desired isoxazole (4) was produced in low
yield. Variation of catalyst species resulted in only marginal
changes to the reaction profile.16 Conspicuously, in most of the
PtCl2/olefin catalyst systems, the corresponding isoxazoline (5)
was observed in measurable quantities, a product arising from
5
10 simple intramolecular addition of the hydroxyl group across the
alkyne.17
45
Having established the optimized cyclization conditions, a
number of isoxazoles were synthesized using this method (Figure
3). An array of 3,5ꢀdisubstituted isoxazoles can be accessed from
their corresponding Nꢀhydroxycarbamates21 in good overall yield.
50 Particularly noteworthy is isoxazole 13, which features a separate
Boc carbamate. The stability of this functional group highlights
the process of how the Boc group on the isoxazole nitrogen is
removed; delocalization of the nitrogen lone pair in a putative
enamide intermediate likely facilitates selective ionization and
55 cleavage.22
Scheme 2
We saw the formation of isoxazoline 5 as a clue toward
15 explaining the problematic reactivity. In our experiences with the
aforementioned furan chemistry, the corresponding dihydrofuran
(e.g., 7, Figure 2) was seldom observed.18 A proton transfer
event to the methyl ether was believed to be required for the
generation of the productive carbene intermediate.
With
20 compound 3, we hypothesized that a potential hydrogen bonding
interaction between the cyclic oxonium and the carbamate
carbonyl was inhibiting proton transfer. Protodemetalation of
intermediate
8 therefore intervenes, leading to competitve
formation of isoxazoline 5.19
25
Figure 2. Isoxazoline formation related to proton transfer event.
From this hypothesis, we reasoned that an acidic additive
should facilitate ether ionization. Indeed, addition of AcOH to
the reaction mixture provided a noticeable improvement (Table 1,
30 entry 1). Our observation that olefin ligands could influence
reactivity in the furan chemistry then prompted us to examine the
addition of Lꢀtype monodentate ligands, and PPh3 did improve
the overall reaction (entry 2). A range of acids were then
evaluated in the reaction, and TFA was found to be the optimal
35 acid for cleanly affording isoxazole 4 while minimizing the
isoxazoline byproduct. Bases substantially inhibited the reaction
(entry 7). Phosphorus ligands were also screened. Systems
utilizing alkylphosphines were prohibitively slow, likely due to
the more electron rich metal center being less capable of
40 activating the alkyne for nucleophilic attack. Triarylphosphines
and phosphites were both quite effective (entries 8, 12), but
P(OPh)3 provided the most consistent behavior20 and we therefore
settled on that catalyst system.
Figure 3. Ptꢀcatalyzed synthesis of isoxazoles from propargylic Nꢀ
hydroxycarbamates.
Given the success of the isoxazole syntheses from the
60 propargylic NꢀhydroxyꢀNꢀalkoxycarbonylamines, we speculated
that we could access the regioisomeric isoxazole by reversing the
positions of the nitrogen and oxygen atoms. Illustrated in Figure
4, a nitrogenꢀbased nucleophile would attack the activated alkyne,
and leaving group extrusion followed by a 1,2ꢀshift would lead to
65 an analogous enamide intermediate. Again, cleavage of the
carbamate and aromatization would afford the isoxazole.
2
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Figure 4. Regioisomeric isoxazole formation using nitrogenꢀbased
nucleophiles.
The syntheses of these substrates can be accomplished by two
5
straightforward methods.
Addition of alkyne
1
into
propionaldehyde affords propargylic alcohol 17 (Scheme 3).
From this compound,
a
Mitsunobu reaction using Nꢀ
hydroxyphthalimide23 followed by aminolysis and Boc
installation affords the carbamoyl ether (18). Alternatively, a
10 oneꢀpot Mitsunobu reaction using Boc2NOH and cleavage of one
of the two butoxycarbonyl groups afforded the identical substrate
in comparable yield.
Scheme 3
Figure 5. Ptꢀcatalyzed synthesis of isoxazoles from propargylic NꢀBoc
15
We were delighted to discover that under the aforementioned
catalytic platinum conditions the amino ethers cyclized to form
the regioisomeric isoxazoles (Figure 5). A number of these
isoxazole products (19ꢀ24) are the direct complements of the
heterocycles formed from the Nꢀhydroxycarbamates (Figure 4, 4,
30
amino ethers.
Toward further understanding the mechanism of this process,
we started by considering our work in furan formation (see
above, Scheme 1). Based on our observations in that chemistry,
we proposed that a formal [1,2] hydrogen shift onto the platinum
20 9ꢀ13), each pair originating from the same propargylic ether
starting material. These reactions proceeded more efficiently
than the ones utilizing the oxygenꢀnucleophile counterparts; the
yields were uniformly higher and the reaction times were
shorter.24 As before, a variety of 3,5ꢀdisubstituted isoxazoles
25 were accessed in generally excellent yields, also showing notable
functional group compatibility, tolerating carbamates (24),
carboxylic acids (30), thioethers (31), and sulfoxides (32).
35 carbene (B) was a pivotal step, leading to an enol that
subsequently isomerized to the aromatic furan. We believed that
a related mechanistic pathway was operative here, where an enol
ether or enamide intermediate protonates at the exocyclic
position, and loss of the Boc group generates the isoxazole
40 product. Deuterium labeling studies proved consistent with this
mechanistic proposal (Scheme 4). Compound 33, bearing a
deuterium at the propargylic site that is presumably involved in
the [1,2]ꢀshift, was subjected to the standard catalytic cyclization
conditions with protic TFA. Indeed, deuteriumꢀlabeled isoxazole
45 34 was produced with essentially complete incorporation.
Conversely, when the analogous protic substrate (35) was
subjected to the same conditions using TFAꢀd1, deuterium atoms
were incorporated at two different positions in measurable
amounts.25
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Scheme 4
Figure 6 illustrates our rationale for the production of
isoxazole 36. Incorporation at the methine position is readily
explained via the intermediacy of enamine 37; protonation by
TFAꢀd1 and Boc cleavage produces the isoxazole.26 Although the
secondary incorporation at the homobenzylic position appears
unusual, it can be rationalized by a stepwise migratory process
leading to enamine 43. The hydride migrates to the electronꢀ
5
10 deficient carbene of intermediate 40, affording oxocarbenium 41.
If this species is sufficiently long lived prior to demetalation,
deuterium can exchange α to the oxocarbenium, ultimately
producing deuterated isoxazole 44.
Scheme 7
35
To summarize, we have developed the platinumꢀcatalyzed
cyclizations of both propargylic Nꢀhydroxylamines and
propargylic aminoethers to form regioisomeric isoxazoles. Initial
reactivity insights allowed the formulation of new catalytic
condtions, and the transformations proceed in good to excellent
40 yields overall. Importantly, both regioisomeric isoxazoles can be
readily accessed using the same propargylic ether starting
material. By simply selecting the appropriate electrophile in the
acetylide addition (either nitrone or aldehyde), the connectivity of
the downstream isoxazole can be established. This accessibility
45 is highlighted in the direct syntheses of medicinallyꢀrelevant
isoxazoles 48 and 50. Deuterium labeling experiments further
support our mechanistic hypothesis of a unique platinum carbene
intermediate and offer insights toward its reactivity. The
continued exploration of new transformations utilizing this
50 method of carbene generation, as well as further developments in
this area of catalysis, will be reported in due course.
15
Figure 6. Mechanistic rationale for deuterium incorporation in 36.
We believe the development of this methodology for
complementary isoxazole syntheses will have particularly useful
implications in medicinal chemistry. A demonstration of this
utility is depicted in Scheme 7. Isoxazole 48 has been previously
20 evaluated for its promising antirhinovirus activity.27 One key
facet demonstrated in studies on this family of compounds was
that the positioning of the nitrogen and oxygen atoms in the
isoxazole heterocycle was highly relevant to its activity.28,29
Propargylic ether 45 can serve as a direct and convenient
25 branchpoint for the formation of regioisomeric isoxazoles, simply
by using the appropriate nitrone or aldehyde electrophiles. Both
isoxazoles are easily formed, with the Ptꢀcatalyzed cyclizations
proceeding in excellent yields. One could also envision simple
molecular diversification via the introduction of alternative
30 nitrones and aldehydes. We anticipate the convenience of this
heterocycle synthesis will render this a highly enabling tool for
medicinal chemists.
Acknowledgment
Colorado State University is acknowledged for the support of our
55 program.
Notes and references
a Colorado State University, Department of Chemistry, Fort Collins, CO,
80523, USA. Tel: 1-970-491-6379; E-mail: emferr@mail.colostate.edu
† Electronic Supplementary Information (ESI) available: Experimental
60 details, compound characterization data, and spectra. See
DOI: 10.1039/b000000x/
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15
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25
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35
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75
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3
4
18 The hydroalkoxylation product was observed in two cases: 1) When
gold catalysts were employed, consistent with the notion that gold is
less effective at electron donation to generate the carbene species in
our proposed mechanism, regardless of a proton transfer event; 2) At
very low temperatures (ꢀ60 °C), the hydroalkoxylation product could
be observed in small quantities under platinum conditions. At
slightly higher temperatures (ꢀ40 °C), the product was never
observed.
19 Isoxazoline 5 does not convert to the corresponding isoxazole
product when subjected to the reaction conditions.
20 With PPh3, we observed yield variations in up to 5%. This variation
did not occur with P(OPh)3.
5
6
21 The Nꢀhydroxycarbamate substrates were each synthesized from the
appropriate alkyne and nitrone precursors. See the Supporting
Information for experimental details.
22 (a) Susbtrates based on other Nꢀalkoxycarbonyl groups, such as
methyl and allyl, could also be cyclized to form the same isoxazoles.
The unsubstituted (NH) hydroxylamine afforded trace product. The
tꢀbutoxycarbonyl group was found to be the optimal substituent for
this transformation. See the Supporting Information for details. (b)
In Wada’s related oxidative iodocyclization (ref 7d), he found that an
Nꢀisopropyloxycarbonyl group provided the highest yields of
isoxazoles.
23 E. Grochowski and J. Jurczak, Synthesis, 1976, 682ꢀ684.
24 The higher reactivity of these substrates relative to the Nꢀ
hydroxycarbamates could be attributed to the nature of the
heteroatom nucleophile. Differential conformational preferences
arising from allylic strain effects of the carbamate functional group
may also play a role in the relative reactivity.
7
8
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25 As a control, isoxazole 26 was exposed to the reaction conditions
using TFAꢀd1. After 24 h no deuterium incorporation was observed.
6418ꢀ6421; (f) Z. She, D. Niu, L. Chen, M. A. Gunawan, X. Shanja, 110 26 The nitrogenꢀbound proton accounts for a source of hydrogen atoms,
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14 Dealkylative processes have been observed in the presence of
nucleophilic species in similar reactions. See refs 8d,f.
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5150.
70 16 See Supporting Information for the complete optimization studies.
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