Formation of β-Oxo- N-vinylimidates via Intermolecular Ester Incorporation in Huisgen Cyclization/Carbene Cascade Reactions

Article abstract of DOI:10.1021/acs.orglett.0c03619

Unusual intermolecular trapping of esters by carbenes generated via a Huisgen cyclization/retroelectrocyclization/dediazotization cascade reaction is presented. β-Oxo-N-vinylimidates could be obtained in one step from propargyl carbonazidates. Mechanistic control experiments suggested reversible dipole formation by ester addition to the carbene, and nitrogen attack to the ester carbonyl was irreversibly followed by stereoselective decarboxylative elimination to give the Z-vinyl imidate. The cross-conjugated enone, imidate, and enamine functional groups in the β-oxo-N-vinylimidates offer novel syntheses of functionalized oxazoles.

Full text of DOI:10.1021/acs.orglett.0c03619

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Letter
Formation of β‑Oxo‑N‑vinylimidates via Intermolecular Ester
Incorporation in Huisgen Cyclization/Carbene Cascade Reactions
Qinxuan Wang and Jeremy A. May*
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ABSTRACT: Unusual intermolecular trapping of esters by
carbenes generated via a Huisgen cyclization/retroelectro-
cyclization/dediazotization cascade reaction is presented. β-Oxo-
N-vinylimidates could be obtained in one step from propargyl
carbonazidates. Mechanistic control experiments suggested rever-
sible dipole formation by ester addition to the carbene, and
nitrogen attack to the ester carbonyl was irreversibly followed by stereoselective decarboxylative elimination to give the Z-vinyl
imidate. The cross-conjugated enone, imidate, and enamine functional groups in the β-oxo-N-vinylimidates offer novel syntheses of
functionalized oxazoles.
he considerable reactivity of carbenes1 promotes many
Scheme 2. Huisgen Cyclization/Carbene i-PrOAc Cascades
2
Tuseful synthetic transformations: C−H insertion, X−H
insertion,3−5 cyclopropanation,6 ylide formation,7 and cyclo-
addition.8 Electrophilic carbenes, often derived from diazo
compounds like 1 (Scheme 1a), engage in ylide formation with
oxygen-containing Lewis bases such as ketones (e.g., 2) and
ethers (e.g., 5) to form carbonyl ylides 37b,c,8 and oxonium
ylides 6,7d−g respectively. Highly reactive carbonyl yildes 3 can
undergo cycloaddition or cyclization to build oxacycles 4a7b,c
or epoxides 4b.7c,d,9 Allyl-substituted oxonium ylides 6 can
Scheme 1. Ylide Formation in Carbene Chemistry
undergo [2,3]-sigmatropic rearrangements to form homoallyl
ethers 7.7e,f Carbonyl ylide formation can be intermolecular or
intramolecular. Intermolecular reactions between carbenes and
ketones or aldehydes are well developed.7a−d,10 However,
intermolecular reactions between carbenes and esters are rare,9
despite many examples of intramolecular ester ylide
formation.7a−d,11 In fact, methyl benzoate was a stabilizing
additive in rhodium-catalyzed cyclopropanation.12 A similar
stabilizing interaction was seen in the cyclopropanation of
carbene 8 (Scheme 1b).13 The in situ formation of ylide 10 not
only facilitated the nucleophilic attack by the Rh−C bond on
the acrylate 9 (arrow a) but also prevented the self-
Received: November 2, 2020
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© XXXX American Chemical Society
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a
optimization, and the best conditions turned out to be the
same as those in our previous cascade reaction.15,16 The
reaction also occurred without rhodium catalysis, but in a
lower yield. In contrast, the cyclic substrate 17 gave a higher
yield of imidate 20 without Rh2(esp)2 (48%) than for the
catalyzed reaction (34%). This suggests that if there is
competing C−H insertion, more imidate may be formed
without rhodium catalysis. Different dirhodium and other
metal catalysts were examined, but the yield did not improve.16
Gratifyingly, a 47% yield was obtained at a 1 mmol scale with a
concentration of 0.02 M. We also tested comparable
conditions to Davies’ for intermolecular carbene-ester
reactions9 and other mixed solvent systems; however, the
yield was significantly lower.16
Scheme 3. Proposed Mechanism
A proposed mechanism is shown (Scheme 3). Carbonazi-
date 21 would first undergo Huisgen cyclization to form
triazole 24 as was the case in our previous studies.15,17 After
the subsequent triazole ring opening in the presence of a
dirhodium catalyst, α-diazoimine 25 and then rhodium α-
iminocarbene 26 would be generated. Although the precise
role of the rhodium catalyst is still unclear, we believe it
stabilizes the carbene intermediate to avoid detrimental
reactivity. Then, nucleophilic addition to rhodium carbene
26 by the carbonyl oxygen of i-PrOAc would occur to form
carbonyl ylide 27. We hypothesize that the formation of ylide
27 from rhodium carbene 26 and i-PrOAc is reversible, and the
highly reactive ylide 27, formed in situ, would generate oxazole
28 by cyclization. The alkoxy oxazole 28 would be unstable
and could undergo elimination and decarboxylation to
generate imidate 22. During the new CC π bond formation
from 28 to 29, the transient 1,3-allylic strain of the phenyl and
alkyl substituents would favor formation of Z-isomer 29.
The scope of esters was then explored (Scheme 4). From
carbonazidate 21 with i-PrOAc, the Z-isomer of 22 was
isolated in 55% yield. The minor E-isomer was less stable than
the Z-isomer and was not isolable; it was only observed in the
crude NMR with a 4:1 Z/E ratio of isomers. With EtOAc, a
good combined yield of 30a and 30b (70%) was observed, and
each isomer could be isolated; however, the reduced steric
interactions also impacted the Z/E ratio and the selectivity
between 30a:30b was only 1.5:1. Further reducing the size of
the ester by using MeOAc gave imidates 31a and 31b as a
1.3:1 Z/E-isomer mixture after purification with a 76%
combined yield. Methyl propionate was also used to produce
imidates 32a and 32b with a 54% combined yield. In
comparison to EtOAc, the size of alkyl group connected to
the carbonyl has a greater impact than the size of the alkoxyl
on the yield (reduced to 54% from 70% for EtOAc), but the
configuration outcomes (Z/E ratio, 1.2:1 to 1.5:1) were
similar. Interestingly, the configuration of the imidate π bond
did not change, which indicates that the structure of the ester
does not impact the geometry of the imidate after
decarboxylation (from 29 to 22, Scheme 3). Methyl
isobutyrate gave 33 with a 5:1 Z/E ratio before purification
and a 25% isolated yield for the pure Z-isomer. Bulkier esters
like methyl pivalate gave product 34, which did not
decarboxylate, in 40% yield with 1:1 dr. Only a small amount
of the imidate 35 formed.
a
In those reactions without rhodium, a free carbene is assumed.
a
Scheme 4. Ester Scope
a
1
Isolated yields; Z/E ratio determined by H NMR analysis of peak
integration of crude material.
decomposition of carbene 8. Thus, esters have been efficiently
used as solvents in various rhodium-catalyzed carbene
reactions.14,15 To the best of our knowledge, the only
intermolecular carbene reaction with esters was reported in
2018 by Davies,9 where donor/acceptor carbenes 12 reacted
with esters to form tertiary alcohols 16 (Scheme 1c).
In a recent paper, we reported a Huisgen cyclization/
carbene cascade reaction to construct bridged azacycles and
propellanes.15 Investigations showed that the best solvent for
that transformation was isopropyl acetate (i-PrOAc). However,
an unexpected imidate 20 was found as a byproduct in 34%
yield (Scheme 2). Interestingly, the imidate 20 became the
favored product without Rh2(esp)2 (48% yield). Furthermore,
in the cascade reaction with acyclic carbonazidate 21, only
imidate 22 was isolated (55% yield), and no fused bicyclic
product 23 was detected. These results were inspiring, since
the reaction not only juxtaposes cross-conjugated enone,
imidate, and enamine functional groups in the product after a
single step, but it must also proceed through an unusual
mechanism. Moreover, Z/E-diastereoselectivity was observed
in this reaction, with only the Z-isomer of imidate 22 isolated.
The discovery of novel enone-linked imidates like 20 and 22
prompted further investigation. To avoid competing C−H
insertion reactions, acyclic carbonazidate 21 was used for the
A carbonazidate with an isobutyl group (36, Table 1) can
react with esters as well, and a single isomer of imidate 37 was
isolated in 33% yield with i-PrOAc (entry 1). Bicyclic product
38, formed by C−H insertion, was also isolated in 39% yield.
As was seen above, EtOAc caused an increase in the combined
B
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a
Table 1. Carbonazidate Scope
a
b
c
1
Isolated yields; Z/E ratio determined by H NMR analysis of peak integration in crude material. EtOAc was used instead of i-PrOAc. Yield
d
determined by NMR. Reaction time 36 h.
yield of imidates 39a and 39b along with a decrease in
configurational selectivity (entry 2). Meanwhile, 35% of
bicyclic product 38 was also isolated. Surprisingly, carbo-
nazidate 40 did not produce any observable bicyclic C−H
insertion product 42. In this case, only the Z-isomer of imidate
41 was isolated in 35% yield (entry 3). This result is unusual
because C−H bond insertion next to ether oxygens is usually
regarded as being more facile.2a To avoid C−H insertion on
the isobutyl side chain, an isopropyl substituted carbonazidate,
43, was used. Imidate 44 was produced in 67% yield for the Z-
isomer with a Z/E ratio greater than 10:1 (entry 4). Another
reason for the increase of yield could be due to the Thorpe−
Ingold effect, with a larger substituent (isopropyl vs
methylene) facilitating Huisgen cyclization (i.e., 21 to 24,
Scheme 3). Methyl substituted carbonazidate 45 gave a higher
combined yield of Z and E imidates 46a and b (78%, entry 5)
than isopropyl carbonazidate 43. However, a lack of Z/E
selectivity (1.1:1) was observed indicating that stereoselectivity
is dependent on substituent size. Carbonazidate 47 produced
the carbamate-containing product 48a and b in 69% combined
yield with 3:1 dr along with a minor formation of imidate 49
with a Z/E ratio greater than 10:1 (entry 6), further supporting
that the substituent on the secondary carbon in the
carbonazidate plays an important role for the olefin stereo-
selectivity of the product. Extended heating increased the yield
of imidate 49, and the latter’s formation directly from purified
48a and b demonstrates that the bicyclic oxazoles are initially
formed and decarboxylation leads to the imidates, albeit slowly
for tert-butyl substitution. Both electron-donating and -with-
drawing groups on the phenyl ring caused a decrease of yield
(59%, entry 7, and 64%, entry 8). An electron-withdrawing
group on the alkynyl phenyl ring (−NO2, 52) did not impact
Z/E selectivity; however, with an electron-donating group
(−OMe, 50), a decrease of Z/E selectivity was observed.
C
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Scheme 5. Cyclic Substrate Scope
Scheme 7. exo- and endo-Oxazole Formation via Reduction
mediate, the rhodium catalyst was excluded. O-Ethyl imidate
60 was obtained in 50% yield from heterocycle 17 in EtOAc
(Scheme 5). From tetrahydrothiopyran carbonazidate 61, the
imidate 62 was obtained in 65% yield. As the ring
conformation of the carbonazidate substrates could impact
the outcome of the cascade, substituted rings were
investigated. With the carbonazidate tether trans to a phenyl
group at the cyclohexyl 4-position (63), bridged azacycle 65
was formed in 49% yield along with 25% of imidate 66.
However, when the same conditions were used with cis
substrate 67, imidate 66 was isolated in 71% yield. A possible
rationale for this divergent outcome is that intermediate 64,
generated from trans-carbonazidate 63, favored C−H insertion
to form bridged azacycle 65 because the equatorial phenyl
places the carbene carbon in an advantageous axial position for
transannular C−H bond insertion. On the other hand,
intermediate 68, generated from cis-carbonazidate 67,
disfavored C−H insertion by placing the carbene in an
equatorial position, favoring solvent addition.
Scheme 6. exo-Oxazole Formation via C−C Bond
Formation
The novel arrangement of multiple active functional groups,
π systems, and heteroatoms in the cascade products is
inspiring. To show one example of the combined reactivity, a
new synthetic pathway to heterocycles was demonstrated.
Oxazoles are present in many natural products and
pharmaceuticals due to their Lewis basicity and hydrogen
bonding abilities.19 The enone motif in 22 could undergo 1,2-
nucleophilic addition with methyllithium to form tertiary
alkoxide 69, followed by eliminative cyclization to generate the
alkylidene oxazole 70 (Scheme 6). Grignard reagents
functioned just as well with oxazole formation, providing
alkyl-, alkynyl-, and aryl-substituted oxazoles 70, 71, and 72 in
good to excellent yields.
Alternatively, Luche reduction of imidate 22 gave the
unusual exo-unsaturated nonaromatic oxazole 73 in 78% yield
(Scheme 7). Similarly, imidates 44 and 37 could also undergo
reduction to generate exo-unsaturated oxazoles 74 and 76 in
76% and 77% yield, respectively. exo-Unsaturated oxazoles 74
and 76 could tautomerize to endo-oxazoles 75 and 77 with t-
Brominated carbonazidates 54 and 56 were also utilized for
imidate formation, and they gave 55 and 57 in moderate yields,
respectively (entries 9 and 10). Furthermore, 4-bromopheny-
lalkynyl carbonazidate 56 increased the Z/E selectivity to
greater than 10:1, which could be due to the ring’s more
electron-deficient nature. Carbonazidate 58 can yield thio-
phene-containing18 imidate 59 in 69% yield (Z-isomer) with
high Z/E selectivity (entry 11).
Cyclic carbonazidates were also used for the formation of
imidates. To avoid C−H insertion by the carbene inter-
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Chiral Guanidine Derivatives. Angew. Chem., Int. Ed. 2014, 53, 1636−
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BuOK in quantitative yields. Both Z- and E- imidates 46a and
46b were subjected to reduction. Only the Z-imidate 46a was
effective, and tautomerization formed endo-oxazole 79 in 74%
yield with >95% purity for the two steps without any
chromatographic purification after either step.
In conclusion, a Huisgen cyclization/carbene cascade
reaction with intermolecular trapping of the in situ carbene
intermediate by esters proved to be quite robust. Z-Isomer
selectivity was demonstrated in many transformations. A
proposed mechanism hypothesizes that decarboxylation was
the key driving force in the reaction and provided the
stereoselectivity. The major competing reactivity was C−H
bond insertion, which could be avoided by exclusion of the
Rh(II) catalyst. The novel reaction provided imidate products
with cross-conjugated imidate, enamine, and ketone motifs
that were used successfully in heterocycle synthesis.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03619.
Experimental procedures, compound characterization,
optimization tables, and copies of spectra (PDF)
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Catalyzed Carbenoid Cyclopropanations. Org. React. 2001, 57, 1−
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Stereoselective Cyclopropanation Reactions. Chem. Rev. 2003, 103,
977−1050.
AUTHOR INFORMATION
Corresponding Author
■
Jeremy A. May − Department of Chemistry, University of
Houston, Houston, Texas 77204-5003, United States;
orcid.org/0000-0003-3319-0077; Email: jmay@uh.edu
(7) (a) Padwa, A.; Hornbuckle, S. F. Ylide Formation from the
Reaction of Carbenes and Carbenoids with Heteroatom Lone Pairs.
Chem. Rev. 1991, 91, 263−309. (b) Padwa, A.; Zou, Y.; Cheng, B.; Li,
H.; Downer-Riley, N.; Straub, C. S. Intramolecular Cycloaddition
Reactions of Furo[3,4-b]indoles for Alkaloid Synthesis. J. Org. Chem.
2014, 79, 3173−3184. (c) Toda, Y.; Kaku, W.; Tsuruoka, M.;
Shinogaki, S.; Abe, T.; Kamiya, H.; Kikuchi, A.; Itoh, K.; Suga, H.
Three-Component Reactions of Diazoesters, Aldehydes, and Imines
Using a Dual Catalytic System Consisting of a Rhodium(II) Complex
and a Lewis Acid. Org. Lett. 2018, 20, 2659−2662. (d) Doyle, M. P.;
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Diaryl Alkynes: Synthesis of Polycyclic Fused Indole and Spiroox-
Author
Qinxuan Wang − Department of Chemistry, University of
Houston, Houston, Texas 77204-5003, United States
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the NSF
(Grant CHE-1352439) and the Welch Foundation (Grant E-
1744).
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