Aroyl Isocyanates as 1,4-Dipoles in a Formal [4 + 1]-Cycloaddition Approach toward Oxazolone Construction

Article abstract of DOI:10.1021/acs.orglett.8b00656

A formal phosphine-mediated [4 + 1]-cycloaddition between a 1,2-dicarbonyl and an aroyl isocyanate to provide oxazolones bearing a disubstituted C5 center is described. By exploiting the carbene-like reactivity of oxyphosphonium enolates as C1 synthons and aroyl isocyanates as formal 1,4-dipoles, oxazolones and spiroooxindole oxazolones are constructed in high yields (39-99%).

Full text of DOI:10.1021/acs.orglett.8b00656

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Aroyl Isocyanates as 1,4-Dipoles in a Formal [4 + 1]-Cycloaddition
Approach toward Oxazolone Construction
Kaitlyn E. Eckert and Brandon L. Ashfeld*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: A formal phosphine-mediated [4 + 1]-cycloaddition
between a 1,2-dicarbonyl and an aroyl isocyanate to provide
oxazolones bearing a disubstituted C5 center is described. By
exploiting the carbene-like reactivity of oxyphosphonium enolates
as C1 synthons and aroyl isocyanates as formal 1,4-dipoles,
oxazolones and spiroooxindole oxazolones are constructed in high
yields (39−99%).
+ 2]-cycloadditions, etc.).4a,b,5−7 In contrast, a [4 + 1]
hile five-membered heterocyclic frameworks have
Winspired synthetic and medicinal chemists alike for retrosynthetic disconnect of oxazolone 1 at C5 reveals a
disubstituted C1 synthon and an aroyl isocyanate 2 (Scheme
1b). Leveraging a recent resurgence in the literature of the
Kukhtin−Ramirez reaction, we envisioned exploiting the
biphilic reactivity of oxyphosphonium enolate 3 to assemble
this versatile heterocyclic framework.
While Ramirez first reported the feasibility of C−C and C−O
redox bond formations initiated by the addition of PL3 to 1,2-
dicarbonyls,8 Radosevich has pioneered a renaissance of this
disconnect, recently exemplified by the addition of α-ketoesters
to alkyl halides (Scheme 2a). Subsequently, we demonstrated
the feasibility of employing oxyphosphonium enolates as C1
synthons in a formal [4 + 1]-cycloaddition assembly of
decades, the selective and convergent assembly of biologically
active, highly substituted N- and N,O-mixed heterocycles
remains a challenge in pharmaceutical drug development.1
Notably, the 3-oxazolone subunit has recently drawn
considerable interest from industry and academia as a core
architecture prevalent across a diverse array of biologically
active natural products and designed small molecules. For
example, the oxazolone is a key architectural motif in a series of
β-hydroxysteroid dehydrogenase inhibitors used to treat
diabetes and obesity,2 the broad spectrum antibiotic,
Streptomyces albus-derived natural product indolmycin, and
the ergot alkaloids α- and β-ergocryptine (Scheme 1a).3 While
perhaps the most widely employed method for assembling the
oxazolone motif involves the intramolecular O-alkylation of α-
halo imides,4 more recent efforts have focused on establishing
quaternary substitution at the C5 position (e.g., alkylations, [3
Scheme 2. PL3-Mediated Annulations
Scheme 1. Biologically Active Oxazolones
Received: February 24, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00656
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Letter
dihydrobenzofurans from in situ generated ortho-quinone
methides (Scheme 2b). Additionally, He and co-workers
reported a similar strategy for the construction of isoxazoline
N-oxides from nitro alkenes and isatin derivatives (Scheme
2c).9−11 Inspired by these findings, and in continuation of our
work on the [4 + 1] assembly of heterocyclic scaffolds, herein,
we report the assembly of oxazolone 1, wherein conversion of
amide 4 to the corresponding aroyl isocyanate precedes
addition of 1,2-dicarbonyl 5 facilitated by trivalent phosphorus
(Scheme 2d). Subsequent O-alkylative redox cyclization of the
presumptive intermediate 6 yields the desired cycloadduct.
Our initial investigation into the formal [4 + 1]-cycloaddition
of 1,2-dicarbonyls with acyl isocyanates revealed an intriguing
correlation between the nature of the trivalent phosphorus
reagent and product yield. Treatment of benzamide with oxalyl
chloride, followed by addition of α-ketoester 5a and P(OMe)3
at −78 °C to unpurified isocyanate 2a, led to formation of
oxazolone 1a in 67% yield (Scheme 3). However, employing N-
Scheme 4. Formal [4 + 1]-Cycloaddition Employing α-Keto
Esters
a
a
Conditions: 4 (0.24 mmol), 5 (0.20 mmol), P(NMe2)3 (0.20 mmol),
Scheme 3. Disparate Phosphorus Reactivity
in CH2Cl2 (0.2 M).
electron-rich aryl formates, which may be due to isocyanate
degradation resulting from slow oxyphosphonium enolate
formation.
Extending this strategy to the spirooxindole oxazolone
scaffold employing isatin derivatives revealed a broader
functional group tolerance than what was observed with the
complementary formates (Scheme 5). The formal [4 + 1]-
cycloaddition of N-acyl isatins with isocyanate 2a provided
spirooxindole oxazolones 8b and 8c in 92% and 72% yields
respectively, along with N-benzyl, -allyl, and -propargyl
a
Scheme 5. Construction of Spirooxazolone Oxindoles
methyl isatin (7a) in place of 5a led to only trace amounts of
spirooxazolone oxindole 8a. Interestingly, we noticed little
substrate dependence when P(OMe)3 was replaced with the
more electron-rich and sterically encumbered P(NMe2)3,
resulting in near-quantitative yields of oxazolones 1a and 8a
from α-ketoester 5a and isatin 7a, respectively. Consistent with
previous work on Kukhtin−Ramirez-like C−X bond forma-
tions, allowing the reaction to reach higher temperatures
resulted in significant self-condensation of the 1,2-dicarbonyl,
and aliphatic solvents (e.g., hexanes, toluene, etc.) led to
quantitative recovery of the starting materials.12
Based on the consistently high yields observed with
P(NMe2)3 in CH2Cl2 at −78 °C, we chose to employ this
optimal set of conditions to evaluate the formal [4 + 1]-
cycloaddition of aryl formates 5 with benzamide derivatives 4 in
the assembly of oxazolones 1 (Scheme 4). Electron-rich and
-poor aroyl isocyanates underwent cycloaddition with 5a to give
the corresponding oxazolones 1b−d in comparably good yields
(71−80%). Additionally, 4-fluoro- and 4-chloro-substituted aryl
formates provided oxazolones 1e and 1f in 74% and 70% yields,
respectively. Consistent with our earlier observation that
electron-deficient aryl formates were more reactive as [4 +
1]-cycloaddition C1 synthons than their electron-rich counter-
parts, the 3,5-bistrifluoromethyl phenyl-substituted α-ketoester
gave oxazolone 1g in 99% yield. It is noteworthy that this
method is limited by the need for an aryl 1,2-dicarbonyl, as
aliphatic formates failed to provide the desired cycloadducts. A
similarly intractable mixture of byproducts was observed with
a
Conditions: 4 (0.24 mmol), 7 (0.20 mmol), P(NMe2)3 (0.20 mmol),
b
in CH2Cl2 (0.2 M). Isolated as a mixture with N,N′-carbonyl-
dibenzamide in a 5:1 ratio; see Supporting Information.
B
DOI: 10.1021/acs.orglett.8b00656
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Letter
oxazolones 8d−f produced in comparable yields. Interestingly,
unlike their aryl formate counterparts, the presence of electron-
donating groups at the C5 position of N-methyl isatin did not
hinder oxazolone formation as evidenced by the excellent yields
observed in the assembly of 8g and 8h. The presence of a
bromide at C5 or C6 led to comparable yields of oxazolones 8i
and 8j in 67% and 81%, respectively. These results seem to
indicate that the reactivity of isatins is more impervious to
electronic perturbations relative to the corresponding aryl
formates.
As we observed in the formate-derived series of oxazolones,
cycloadducts were obtained in generally good yields in the
formal [4 + 1]-cycloaddition regardless of electron-donating or
-withdrawing groups on the aroyl isocyanate. For example,
electron-rich and electron-deficient benzamides provided
oxazolones 8k and 8l in 55% and 64% yields, respectively. It
is worth noting that while benzamide meta- and para-
substitution did not significantly hinder the cycloaddition
event, ortho-substitution led to trace oxazolone formation,
presumably due to increased steric encumbrance in either the
isocyanate addition or cyclization steps.
derivatives. In 2010, Radosevich first reported the use of
stoichiometric chiral phosphoramine 11 in the enantioselective
construction of α-hydroxy and α-amino esters proceeding via a
Kukhtin−Ramirez-like redox condensation.14 Although interest
in redox phosphorus-catalyzed reactions has increased in recent
years, identifying conditions to facilitate catalyst turnover that
are compatible with electrophilic functionality present is often
an impediment to the development of these methods.
However, we anticipated gaining valuable mechanistic insight
into oxazolone formation through the use of a stoichiometric
chiral phosphoramine. Thus, conversion of benzamide 4a to the
corresponding aroyl isocyanate followed by treatment with
formate 5a and phosphoramine 11 provided oxazolone 1a in
36% yield and 36% ee (Scheme 7). The relatively low yield of
Scheme 7. Stereoinduction with a Chiral Phosphorus
Reagent
Based on our previous work on the development of formal [4
+ 1]-cycloadditions employing diazo compounds as C1
synthons, we sought to evaluate the utility of these versatile
reagents in the presence of a Rh(II) catalyst toward enabling
oxazolone construction.13 However, we discovered that despite
the biphilic similarities of oxyphosphonium enolates and
metallocarbenes, these presumptive reaction intermediates led
to significantly different outcomes when exposed to aroyl
isocyanates. Treatment of aroyl isocyanate 2a, derived from
benzamide (4a), with diazooxindole 9 in the presence of 5 mol
% Rh2(OAc)4 failed to provide spirooxindole 8a, but instead led
to formation of 3-amido oxindole 10 in 94% yield (Scheme 6).
1a in comparison to those described in Schemes 4 and 5
illustrates the delicate balance between the phosphorus ligation
structure and product yield commensurate with our compar-
ison of P(OMe)3 and P(NMe2)3 (Scheme 3). Despite the low
yield and enantiomeric excess, the stereoinduction observed in
the assembly of 1a would indicate that the phosphoramine was
present in the enantiodetermining step, leading to oxazolone
formation.
A series of control experiments provided additional
mechanistic evidence of this P(NMe2)3-mediated, formal [4 +
1]-cycloaddition approach toward oxazolone construction. For
example, when P(NMe2)3 was omitted from the addition of α-
ketoester 5a to isocyanate 2a, reversion to benzamide 4a and
quantitative recovery of 5a were observed. Interestingly, when
benzamide 4b was treated with oxalyl chloride followed by the
addition of P(NMe2)3 at room temperature in the absence of
either an aryl formate or isatin derivative, N-acyl urea 12 was
obtained in 76% yield (Scheme 8). The structure of 12 was
Scheme 6. Amidation of Diazooxindoles
Scheme 8. Ligand Transfer from P(NMe2)3
Exposure of 4a directly to diazooxindole 9 under comparable
reaction conditions likewise provided oxindole 10. While
speculative at this stage, a mechanism that involves reversion
of isocyanate 2a to amide 4a, mediated by residual HCl that is
generated upon conversion to the corresponding isocyanate,
may rationalize formation of oxindole 10. Support for this
hypothesis was obtained from the observation that vigorous
extrusion of HCl from the conversion of 4a to 2a, by placing
the crude reaction mixture under reduced pressure for 2 h, led
to dimerization of diazooxindole 9 and degradation of 2a in the
presence of Rh2(OAc)4.
In an effort to gain insight into the participation of PL3
throughout the course of heterocycle formation, we chose to
evaluate the potential for optical enrichment of the
corresponding C5-disubstituted oxazolone through the use of
a chiral trivalent phosphorus reagent. The enantioselective
assembly of fully substituted carbon centers remains a nontrivial
endeavor in synthesis, and optically enriched oxazolones are
synthetically viable precursors to α-hydroxy carboxylic acid
verified by X-ray crystallography and represents a rather
unusual ligand transfer event from P(NMe2)3 to the
corresponding aroyl isocyanate. This result, when coupled
with the absence of comparable N-acyl urea formation when a
formate or isatin derivative is present, would seem to indicate
that the addition of P(NMe2)3 to the 1,2-dicarbonyl
component is kinetically favored despite the inherent electro-
philicity of isocyanates.
Based on our current and previous findings, and in
consideration of those reported by Radosevich, Ramirez, and
others, a possible mechanism for oxazolone formation is
illustrated in Scheme 9. Addition of P(NMe2)3 to α-ketoester 5
C
DOI: 10.1021/acs.orglett.8b00656
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Letter
Scheme 9. Possible Reaction Mechanism
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CAREER CHE-1056242 and 1665440). We thank Kevin X.
Rodriguez and Dr. Allen G. Oliver at the University of Notre
Dame for assistance in collecting X-ray crystallographic data.
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establishes an equilibrium between dioxaphospholene 3′ and
oxyphosphonium enolate 3. Conversion of amide 4 to aroyl
isocyanate 2 employing (COCl2)2 sets the stage for the
addition of 3 to generate oxyphosphonium 6. Subsequent ring
closure via displacement of OP(NMe2)3 by the imide anion
ultimately provides oxazolone 1. While dissociation of the
phosphoramide generates a stabilized, quaternary carbocation,
the formation of optically enriched oxazolone 1a employing 11
suggests the presence of phosphoramide in the transition state
of ring closure from 6 to 1. However, the modest level of
enantiomeric excess observed would indicate the possibility of
competing associative and dissociative mechanisms.
In conclusion, we have developed a formal trivalent
phosphorus-mediated [4 + 1]-cycloaddition strategy for the
assembly of C5-disubstituted oxazolones employing aroyl
isocyanates as 1,4-dipoles and α-aryl 1,2-dicarbonyls as C1
synthons. Employing α-ketoesters and isatins provided the
corresponding formate-derived and spirooxindole oxazolones in
good to excellent yields, respectively. The optimized reaction
conditions proved exceptionally mild and amenable to scale up.
Studies aimed at exploiting this formal [4 + 1]-cycloaddition
approach to construct heterocyclic motifs of pharmaceutical
and materials significance are currently underway and will be
reported in due course.
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.8b00656.
Experimental procedures, spectroscopic data, and
crystallographic data (PDF)
Accession Codes
CCDC 1814365 contains 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: bashfeld@nd.edu.
ORCID
(10) (a) Zhou, R.; Zhang, K.; Han, L.; Chen, Y. S.; Li, R. F.; He, Z. J.
Chem. - Eur. J. 2016, 22, 5883. (b) Zhou, R.; Zhang, K.; Chen, Y. S.;
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2015, 17, 4750. (d) Xu, S. L.; Zhou, L. L.; Ma, R. Q.; Song, H. B.; He,
Brandon L. Ashfeld: 0000-0002-4552-2705
Notes
The authors declare no competing financial interest.
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