Isocyano Enones: Addition-Cyclization Cascade to Oxazoles

Article abstract of DOI:10.1021/acs.orglett.6b01147

Copper iodide catalyzes the conjugate addition of organometallic and heteroatom nucleophiles to isocyano enones to afford oxazoles. A range of enolates, metalated nitriles, amines, and thiols undergo catalyzed conjugate addition to cyclic and acyclic oxoalkene isocyanides. Mechanistic studies suggest that copper complexation facilitates the nucleophilic attack on the isocyano enone to generate an enolate that cyclizes onto the isocyanide leading to a variety of substituted acyclic or ring-fused oxazoles.

Full text of DOI:10.1021/acs.orglett.6b01147

Letter
pubs.acs.org/OrgLett
Isocyano Enones: Addition−Cyclization Cascade to Oxazoles
Allen Chao,† J. Armando Lujan-Montelongo,‡ and Fraser F. Fleming*,§
†Department of Chemistry, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States
‡Departmento de Química, Centro de Investigacion
Ciudad de Mexico 07360, Mexico
́ ́
y de Estudios Avanzados (Cinvestav), Av Instituto Politecnico Nacional 2508,
́
́
§Department of Chemistry, Drexel University, 32 South 32nd Street, Philadelphia, Pennsylvania 19104-2875, United States
S
* Supporting Information
ABSTRACT: Copper iodide catalyzes the conjugate addition of
organometallic and heteroatom nucleophiles to isocyano enones
to afford oxazoles. A range of enolates, metalated nitriles, amines,
and thiols undergo catalyzed conjugate addition to cyclic and
acyclic oxoalkene isocyanides. Mechanistic studies suggest that
copper complexation facilitates the nucleophilic attack on the
isocyano enone to generate an enolate that cyclizes onto the
isocyanide leading to a variety of substituted acyclic or ring-fused oxazoles.
socyanides are exceptionally versatile precursors with unique
microwave irradiation (100 °C, 1−2 h) of 5- and 6-membered
epoxyketones 2, generated from the corresponding enones 1,10
provided a direct method for promoting the ring opening and
dehydration to the corresponding ene formamides 3.11 Sub-
sequent dehydration of the formamide functionality afforded
the corresponding isocyanides 4.12
Although the ring opening−dehydration route rapidly provided
5- and 6-membered isocyano enones 4a−4c, the strategy was not
amenable to the synthesis of 7-membered or acyclic isocyanides.13
Consquently, a complementary sequence was developed to both
cyclic and acyclic isocyano enones (Scheme 2). The strategy
1
and biological activity.2 The formal
Ichemical reactivity
divalent character of isocyanides3 permits an array of reactivity
not commonly observed with other functionality; isocyanides
react with electrophiles, nucleophiles, radicals, and transition
metals.1,4 In many cases, the resulting intermediates have been
harnessed in multicomponent reaction sequences where the
isocyanide serves as a central connection point.5
Conspicuously lacking among the reactions of isocyanides are
bond constructions at sites other than the isocyanide carbon.1 Iso-
cyano enones appeared to be attractive candidates to address this
void because they incorporate orthogonal ketone, olefin, and
isocyanide functionalities primed for sequential reactions. Acti-
vation of the olefin by both ketone and isocyanide groups was
anticipated to promote conjugate addition reactions,6 a funda-
mental bond construction that is largely unexplored for isocyano-
alkenes.7 Primary amines and H2S are among the few nucleophiles
that react with isocyanoalkenes, first by conjugate addition and
then by reaction with the isocyanide.8 Described below is a
copper-catalyzed addition of carbon and heteroatom nucleophiles
to isocyano enones that generates a diverse array of oxazoles.
The synthesis of oxoalkene isocyanides is challenging.9
Scouting experiments identified a short route to cyclic 5- and
6-membered isocyano enones predicated on a formamide ring-
opening dehydration of epoxy ketones (Scheme 1). In practice,
Scheme 2. Alternate Isocyano Enone Synthesis
Scheme 1. Isocyano Enone Synthesis
builds on the chemistry of vinyl azides14 that are readily accessed
from the corresponding enones by sequential bromination and
treatment with azide.15 Conversion of the vinyl azides 5d and 5e
to the corresponding isocyanides was achieved by treatment
with PPh3 to generate an azophosphorane that was intercepted
with acetic formic anhydride to afford the ene formamides 3d
Received: April 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01147
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
and 3e.11,16 Subsequent dehydration provided the isocyano
enones 4d and 4e (Scheme 2).17
presumably because of the greater steric compression during
C−C bond formation. Conjugate additions of diethyl malonate
and malononitrile to the 7-membered and acyclic isocyano
enones 4c and 4d, respectively, afforded the corresponding
oxazoles 6o−r (Table 1, entries 15, 16 and 17, 18, respectively).
Rapid access to the fused 7-membered oxazoles 6o and 6p is
particularly significant given the bioactivity of several structurally
related marine-derived oxazolones.23
Isocyano enones 4 were anticipated to be particularly reactive
toward nucleophilic conjugate addition because the correspond-
ing oxoalkene nitriles are excellent Michael acceptors.6
Attempted conjugate additions to 4a with a variety of
organometallics (RLi, RMgX, R3MgLi, RZnX, R2Zn, R3ZnLi)
produced complex mixtures,18 whereas the enolate derived from
diethyl malonate afforded oxazole 6a in 10% yield (Table 1,
Efforts to extend the oxazole reaction to the 5-membered
isocyano enone 4e were not successful but provided insight
into the reaction mechanism (eq 1). Exposure of 4e to the
a
Table 1. Malonate Conjugate Addition to 4a
standard conditions with diethyl malonate afforded a low yield
of the isocyano enone 6s rather than the expected oxazole.
Presumably, the intermediate enolate generated from the malonate
addition is unable to attack the isocyanide because of the larger
bond angles enforced by the 5-membered ring.
Further mechanistic insight was gained from deuterium-
labeling experiments. Addition of D2O at the end of the reaction
did not result in deuterium incorporation (eq 2, conditions A),
suggesting that oxazole protonation occurred during the
catalytic cycle.24 The proton source was identified through the
reaction of 4a with λ-D2-diethyl malonate, which afforded
the deuterated oxazole 6t (eq 2, condition B, 96% deuteration in
the oxazole).25
a
Reaction conditions: 4a (0.18 mmol), diethyl malonate (0.18 mmol),
LDA (0.18 mmol) catalyst (3 mol %), THF (5.0 mL), 1 h, 0 °C.
b
Performed in the absence of LDA.
entry 1). Screening potential catalysts identified several copper
complexes as competent catalysts (Table 1, entries 7−11).4
Further optimization of solvent (CH2Cl2, H2O, DMSO, DMF,
Et2O, and THF) and base (NaH, LDA, K2CO3, i-Pr2NEt, and
KHMDS) led to an optimized procedure with catalytic CuI and
either LDA or NaH in THF (Table 1, entry 11).19
The reaction scope was explored through the addition of
diverse carbon and heteroatom nucleophiles to a series of
isocyano enones 4 (Table 2).20 Dicarbonyl nucleophiles such as
metalated malonates, ethyl acetoacetate, and 2,4-pentanedione
smoothly reacted with 4a (Table 2, entries 1−4). Addition
of diethyl 2-methylmalonate afforded 6b with contiguous
tertiary−quaternary centers (entry 2). Conjugate additions with
2-coumaranone and nitromethane (Table 2, entries 5 and 6)
efficiently afforded substituted oxazoles; with malonitrile, the
use of NaH proved to be more efficient than LDA (Table 2,
entry 7).21 The heteroatom nucleophiles benzylamine and
4-methylbenzenethiol readily form the corresponding oxazoles
(entries 8 and 9) with p-TolSH undergoing conjugate addition
even in the absence of base.
Collectively, the deuteration and addition experiments
suggest a catalytic cycle featuring a conjugate addition−enolate
cyclization (Scheme 3). The propensity of copper(I) to complex
isocyanides suggests that the active catalyst may be ligated to
multiple isocyanides. Complexation of the active catalyst 8 with
the oxonitrile likely facilitates the conjugate addition of the
nucleophile via 9 leading to the oxazole enolate 7. Cyclization of
the alkoxide onto the copper-complexed isocyanide (7 → 10)
parallels several similar reactions of isocyanides with pendant
nucleophiles. Protonation of the resultant complex 10 releases
the oxazole 6 and regenerates the active copper catalyst.
Copper iodide catalyzes a facile conjugate addition−cyclization
to isocyano enones that affords oxazoles. The requisite isocyano
enones are readily synthesized through two complementary
routes that provide access to acyclic and 5−7-membered isocyano
enones. A diverse range of carbon and heteroatom nucleophiles
efficiently react with these isocyano enones to afford substituted
oxazoles ideally functionalized for elaboration into synthetic
targets. Mechanistic analysis indicates that the reaction proceeds
via a conjugate addition to a copper-activated isocyanide that
triggers an enolate cyclization onto the isocyanide to generate the
Conjugate addition of a representative suite of nucleophiles
to the gem-dimethyl-substituted isocyanide 4b afforded the
corresponding oxazoles 6j−n (Table 1, entries 10−14). The
reactions with 4b were less efficient and required longer reaction
times (Table 2, note f) than for the des-methyl isocyanide 4a22
B
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a
Table 2. Isocyano Enone Addition−Cyclizations
a
b
Reaction conditions: 4a (1 equiv), nucleophile (1.5 equiv), CuI (3 mol %), THF (5.0 mL), LDA (1.1 equiv), 1 h, 0 °C. Yield for a larger scale
c
d
reaction performed on 0.8 mmol of 4a. A 7:1 ratio of diastereomers was obtained (determined by 1H NMR). NaH was used in place of LDA.
e
f
Performed in the absence of base; with NaH, the yield was 62%. The reaction required 3 h to proceed to completion.
oxazole. The synthesis is modular, rapid, and provides a versatile
route into a valuable class of heterocycles.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fleming@drexel.edu. Fax: +1 215 895 1265. Tel:
ASSOCIATED CONTENT
■
+1 215 895 2644.
S
* Supporting Information
Notes
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01147.
The authors declare no competing financial interest.
1H and 13C NMR FIDs (ZIP)
ACKNOWLEDGMENTS
■
Experimental procedures and physical characterizations of
the products; 1H and 13C NMR spectra of new compounds
(PDF)
Financial support from the National Institutes of Health
(2R15AI051352-04) is gratefully acknowledged.
C
DOI: 10.1021/acs.orglett.6b01147
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(15) Nair, V.; Panicker, S. B.; Augustine, A.; George, T. G.; Thomas,
S.; Vairamani, M. Tetrahedron 2001, 57, 7417−7422.
(16) Kosiova, I.; Janicova, A.; Kois, P. Beilstein J. Org. Chem. 2006, 2,
No. 23. DOI: 10.1186/1860-5397-2-23.
Scheme 3. Cu-Catalyzed Oxazole Formation
(17) (a) The isocyano enone was used without purification because
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Chem. Lett. 1998, 8, 257. (b) Kotha, S.; Brahmachary, E.;
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the isocyanide.
(19) Use of catalytic or substoichiometric base led to incomplete
conversion accompanied by unidentified materials. The optimal
procedure employed 1.1 equiv of base and 1.5 equiv of nucleophile
(see Table 2); the excess nucleophile may provide an adventitious
proton source.
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oxazole formation.
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(23) (a) Dattelbaum, J. D.; Singh, A. J.; Field, J. J.; Miller, J. H.;
Northcote, P. T. J. Org. Chem. 2015, 80, 304−312. (b) Robinson, P. J.;
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malonate in 6t that leads, upon workup, to a mixture of mono- and
dideuterated oxazoles. Correspondingly, attempts to trap the cuprated
oxazole with benzoyl chloride, TMSCl, and iodomethane before
protonation were unsuccessful.
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