A Rhodium(II)-Catalyzed Formal [4+1]-Cycloaddition toward Spirooxindole Pyrrolone Construction Employing Vinyl Isocyanates as 1,4-Dipoles

Article abstract of DOI:10.1002/anie.201701147

A Rh^II-catalyzed, formal [4+1]-cycloaddition between diazooxindoles as electrophilic C₁ synthons and 1,3-heterodienes for the construction of spirooxindole pyrrolones is described. Employing vinyl isocyanates as 1,4-dipoles, the cycloannulation occurs under relatively mild conditions and provides the corresponding pyrrolones in good to excellent yields.

Full text of DOI:10.1002/anie.201701147

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201701147
German Edition: DOI: 10.1002/ange.201701147
Cycloadditions
A Rhodium(II)-Catalyzed Formal [4+1]-Cycloaddition toward
Spirooxindole Pyrrolone Construction Employing Vinyl Isocyanates as
1,4-Dipoles
Jennifer L. Meloche and Brandon L. Ashfeld*
Abstract:
A
RhII-catalyzed, formal [4+1]-cycloaddition
between diazooxindoles as electrophilic C1 synthons and 1,3-
heterodienes for the construction of spirooxindole pyrrolones
is described. Employing vinyl isocyanates as 1,4-dipoles, the
cycloannulation occurs under relatively mild conditions and
provides the corresponding pyrrolones in good to excellent
yields.
T
he strain-driven ring expansion of cyclopropanes has
emerged as a powerful design strategy for the assembly of
small and medium-sized carbocyclic frameworks.[1] Perhaps
two of the most common synthetic applications of this
approach include the [3,3]-rearrangement of divinyl cyclo-
propanes to yield 1,4-cycloheptadienes[2] and the assembly of
cyclopentenes from vinyl cyclopropanes in a formal [1,3]-
carbon migration.[3] However, despite accessibility of the
requisite starting materials, extensions of these rearrange-
ments to heterocyclic motifs are rare.[4] A notable exception is
the analogous rearrangement of N-cyclopropylimines to the
corresponding pyrrolines requiring high thermal or photo-
chemical conditions to generate a presumptive diradical
À
intermediate resulting from homolytic cyclopropyl C C
bond cleavage (Figure 1a).[5] Alternatively, Rigby demon-
strated in 2003 that the addition of thermally generated
nucleophilic carbenes to vinyl isocyanates initiates a 4p-
electrocyclization to yield the corresponding g-lactams (Fig-
ure 1b).[6] While elegant in their own rights, the forcing
conditions and indiscriminate nature of synthetic intermedi-
ates can limit their general utility. These complementary
approaches inspired us to develop a relatively mild, formal
[4+1]-cycloaddition[7] assembly of N-heterocycles that
exploits the chemoselectivity of electrophilic metallocarbenes
with the 1,4-dipole behavior of vinyl isocyanates.[1b,7d,8]
Given the prevalence of biologically active spirooxindole
alkaloids (i.e., mitraphylline,[9] voachalotine oxindole[10]) and
readily available oxindole derivatives, we chose to target
congeners of the core spirooxindole dihydropyrrole frame-
work (Figure 1c).[11] Employing diazooxindole 1 as a C1
synthon, we discovered that the RhII-catalyzed cyclopropa-
nation of vinyl isocyanate 2 generates a cyclopropyl isocya-
Figure 1. a) Ring expansion of iminocyclopropanes and cyclopropyl
carboxaldehydes; b) formal [4+1]-cycloaddition involving vinyl isocya-
nates; c) targeting spirooxindole natural products; d) this work.
nate 3 that then rapidly undergoes ring expansion in situ to
provide the target spirooxindole pyrrolone 4 (Figure 1d).[12]
This design exploits the electron deficient central carbon of
the isocyanate bearing an orthogonal p-bond and weakened
À
migrating C C cyclopropyl bond by virtue of the donating
potential of the isocyanate and withdrawing nature of the
oxindole amide to alleviate the high kinetic barrier to
a formal [1,3]-migration of the C3-oxindole quaternary
carbon.[12,13] Herein, we describe the successful implementa-
tion of this approach under milder conditions with improved
substrate scope and demonstrated synthetic utility.
Recently, Davies demonstrated that the treatment of a,b-
unsaturated ketones and aldehydes with RhII-stabilized
carbenoids led to epoxides resulting from addition of the
carbonyl to the electrophilic carbene carbon.[14] Based on
these findings, we were cognizant that the Lewis basic
heteroatoms of the isocyanate may hinder cyclopropanation
of the pendant olefin. Additionally, based on our previous
work and those of others, spirooxindole cyclopropanes are
surprisingly stable, and often require Lewis or Bronsted acid
activation to initiate ring expansion.[15] Despite these chal-
lenges, we began by examining the addition of diazooxindole
[*] J. L. Meloche, Dr. B. L. Ashfeld
Department of Chemistry and Biochemistry
University of Notre Dame
Notre Dame, IN 46556 (USA)
E-mail: bashfeld@nd.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201701147.
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1a to vinyl isocyanate 2a in the presence of Rh2(OAc)4
(Scheme 1). While a syringe pump addition of 1a in dry
PhMe at 0.01m minimized diazo dimerization, an intractable
mixture of products was observed. Speculating that this result
temperature to 508C without seeing an adverse effect on the
yield of 5a (entry 2). However, dimerization of diazooxindole
1a accounted for a 95% mass recover. Decreasing the
reaction concentration or extending the addition time of 1a
failed to mitigate this undesired side reaction. Increasing the
concentration of 2a enabled complete conversion of diazo-
oxindole 1a and improved the yield to 87% (entry 3).
Reducing the catalyst loading at temperatures ranging from
50–758C led to inferior yields of 5a (entries 4–6). Using the
optimized conditions in entry 3, we sought to evaluate this
formal [4+1]-cycloaddition approach toward the spirooxin-
dole lactam framework.
Our assessment of functional group compatibility began
by examining the effects of diazooxindole substitution on the
formal [4+1]-cycloaddition with vinyl isocyanate 2a
(Table 2). In general, good to excellent yields of cycloadducts
Scheme 1. Proof of concept.
Table 2: Structural variability in the diazooxindole 1.[a]
was due to the instability of pyrrolone 4a under the reaction
conditions, we sought to trap this intermediate with adven-
titious water as the hemiaminal by using wet PhMe. Gratify-
ingly, this seemingly minor modification led to a fortuitous
mixture of acyl enamine 5a and hemiaminal 6a in a 3.1:1 ratio
and combined yield of 44%. Cycloadduct 6a was obtained as
a single diastereomer and confirmed by X-ray crystallogra-
phy. Interestingly, the addition of water (1.0 equiv) led to
conversion of 1a to N-methyl isatin illustrating a delicate
balance in the concentration of trapping agent employed.
Owing to its synthetic potential and stability, we chose to
develop conditions that would optimize the formation of acyl
enamine 5a.
To drive the isomerization of 4a to spirooxindole 5a, we
discovered that by following the formal [4+1]-cycloaddition
of diazooxindole 1a and vinyl isocyanate 2a in dry PhMe with
t
the introduction of BuOK/tBuOH, provided spirooxindole
pyrrolone 5a in 83% yield (Table 1, entry 1). Illustrating the
comparatively mild conditions required for the spirocyclo-
propylisocyanate rearrangement, we could lower the reaction
Table 1: Optimization of 5a formation.[a]
[a] Conditions: slow addition of 1 (0.08 mmol) over 10 h to 2a
(0.24 mmol) and Rh2(OAc)4 (5 mol%) in PhMe (0.01m) at 508C,
followed by the introduction of tBuOK/tBuOH (50 mol%). See the
Supporting Information for detailed experimental procedures.
5 were obtained from oxindoles with various N- and arene-
substitution patterns. Common N-acyl and N-alkyl diazo-
oxindole substitution were well tolerated, as demonstrated by
the formation of 5b–f in 77–88% yields. Notably, the presence
of N-allyl and N-propargyl groups underwent cycloaddition in
good yields without competitive alkene/alkyne cyclopropa-
Entry
2a
(equiv)
Rh2(OAc)4
(mol%)
T [8C]
Yield [%]
1
2
3
4
5
6
2.0
2.0
3.0
2.0
2.0
3.0
5.0
5.0
5.0
1.0
1.0
1.0
100
50
50
50
65
75
83
83 (95)[b]
87
50
66
72
À
nation observed, and the presence of an acetylenic C H did
not adversely affect the yield of adduct 5g. As a result of its
poor solubility in PhMe, the formal cycloaddition of diazo-
oxindole (R1 = R2 = H) proceeded in significantly lower yield
[a] Conditions: slow addition of 1a (0.09 mmol) over 10 h to 2a and
Rh2(OAc)4 (5 mol%) in PhMe (0.01m) at 508C, followed by the
introduction of tBuOK/tBuOH (50 mol%). See the Supporting Informa-
tion for detailed experimental procedures. [b] Yield based on recovered
1a dimer.
1
( ꢀ 35% by H NMR).
While the formal [4+1]-cycloaddition tolerated a variety
of diazooxindole arene substitution, the presence of an
2
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electron withdrawing bromide generally led to higher yields
applicable to the alleviation of diabetic complications.[17] For
of the cycloadducts than alkyl or electron donating methoxy
groups.[16] For example, methyl and bromide substitution at
the C5 provided adducts 5h and 5i in 60% and 76% yield,
respectively, while 5-methoxy diazooxindole gave 5j in 54%.
Similarly, C6-Br substitution led to formation of 5k in 76%,
whereas the 6- and 7-methoxy spirooxindoles 5l and 5m were
obtained in 59% and 53% yield, respectively. These results
are consistent with an electrophilic metallocarbene cyclo-
propanation of 2a.
example, spirooxindole succinimide ADN-138 is a potent
aldose reductase inhibitor that improves cataract and neuro-
pathy in diabetic mice.[18]
Varying olefin substitution on isocyanate 2 exhibited
a similar, albeit inverse trend of electronic influence on the
yield of formal [4+1]-cycloadducts 5 with diazooxindole 1a
(Table 3). While the vinyl isocyanate bearing a p-F-C6H4
Furthermore, we examined alternative methods of manip-
ulating the olefin present in pyrrolone intermediate 4. Access
to the saturated lactam was readily achieved by an in situ
reduction of the acyl enamine functionality. Treatment of
diazooxindole 1a with vinyl isocyanate 2a in the presence of
Rh2(OAc)4 (5 mol%) at 508C for 17 h followed by the
addition of NaBH3CN and AcOH in THF (0.02m) for 2 h, in
Table 3: Assessment of vinyl isocyanate 2 substitution.[a]
t
place of BuOK/tBuOH, led to formation of spirooxindole
lactam 8 in 80% yield as a 1.2:1 mixture of diastereomers
[Eq. (2)]. Likewise, catalytic hydrogenation of 4 afforded
lactam 8 by transferring the reaction mixture to a flask
containing Pd/C under 1 atm of H2 in EtOAc (0.01m),
following consumption of vinyl isocyanate 2a, in comparable
yield and diastereoselectivity.
[a] Conditions: slow addition of 1a (0.08 mmol) over 10 h to 2
(0.24 mmol) and Rh2(OAc)4 (5 mol%) in PhMe (0.01m) at 508C,
followed by the introduction of tBuOK/tBuOH (50 mol%). See the
Supporting Information for detailed experimental procedures.
substituent at the a-position gave adduct 5n in 64% yield,
p-tolyl or p-anisol substitution yielded 5o and 5p in 85% and
82% yield, respectively. Employing m-tolyl-substituted vinyl
isocyanate led to formation of cycloadduct 5q in comparable
yield (89%). Despite the potential for endo/exocyclic olefin
formation, employing an a-benzyl vinyl isocyanate provided
exclusively the exocyclic acyl enamine 5r, favoring aryl
conjugation, as a mixture of E/Z isomers. Tri- and tetra-
substituted vinyl isocyanates failed to provide the corre-
sponding cycloadduct 5 in greater than trace quantities,
leading to primarily dimerization of 1a, even at elevated
temperatures (ꢁ 1008C). These results are consistent with an
initial cyclopropanation of the vinyl isocyanate prior to
pyrrolone formation.
We next sought to expand the synthetic potential of the
formal [4+1]-cycloadducts by examining a-siloxy vinyl iso-
cyanates as a means of incorporating an additional functional
handle into the newly formed heterocycle. Treatment of vinyl
isocyanate 2b bearing a TBS ether at the a-position led to
formation of silylated and protiodesilylated spirosuccinimides
7a and 7b in a combined quantitative yield [Eq. (1)]. It bears
noting that N-silyl succinimide 7a is readily converted to 7b
under mildly acidic conditions and that exogenous base was
not required to facilitate O-to-N silyl migration. The spiro-
oxindole succinimide framework is a relevant pharmacophore
present in a number of biologically active compounds
To gain mechanistic insight into this formal [4+1]-cyclo-
addition, we explored the intermediacy of presumptive
spirooxindole cyclopropyl isocyanate 3. Performing the
RhII-catalyzed cyclopropanation of diazooxindole 1a and
vinyl isocyanate 2a at room temperature sufficiently slowed
the ring expansion event [Eq. (3)]. This enabled isolation of
cyclopropane 3a as a single diasteromer in a 1:1 mixture
consisting of ketone 9 in 92% combined yield. However,
1H NMR of the mixture prior to chromatographic purification
revealed an 81% yield of 3a. Thus, ketone 9 likely arises from
exposure of cyclopropane 3a to adventitious water, which
when combined with the mildly acidic conditions of chroma-
tographic purification, results in a reaction cascade involving
carbamic acid generation, decarboxylation, and hydrolysis of
the resulting imine. Heating a solution of 3a in PhMe at 508C
led to smooth conversion to cycloadduct 5a, supporting our
hypothesis that the cyclopropyl isocyanate is a viable inter-
mediate en route to the formal [4+1]-cycloaddition products.
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In summary, we have demonstrated the use of diazo-
oxindoles as C1 synthons in a RhII-catalyzed, formal [4+1]-
cycloaddition toward the construction of spirooxindole pyr-
rolones effectively employing vinyl isocyanates as 1,3-hetero-
diene surrogates. The method exhibits good tolerance to
a diverse array of functional groups and substitution patterns
across each component, and the unsaturated spiro-g-lactams
are amenable to further synthetic manipulations pertinent to
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isocyanate enables ring expansion to the corresponding 5-
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and the development of an enantioselective protocol are
currently under investigation, and will be reported in due
course.
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This work was supported by the National Science Foundation
(CAREER CHE-1056242) and Walther Cancer Foundation
Advancing Basic Cancer Research Program. We thank Dr.
Allen G. Oliver and Kevin X. Rodriguez for assistance with
the X-ray crystallography.
Conflict of interest
The authors declare no conflict of interest.
Keywords: [4+1]-cycloadditions ·
cyclopropane rearrangements · diazooxindoles ·
spirooxindole alkaloids · vinyl isocyanates
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Manuscript received: February 1, 2017
Revised: March 17, 2017
Final Article published: && &&, &&&&
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Communications
Cycloadditions
J. L. Meloche,
B. L. Ashfeld*
&&&& — &&&&
A Rhodium(II)-Catalyzed Formal [4+1]-
Cycloaddition toward Spirooxindole
Pyrrolone Construction Employing Vinyl
Isocyanates as 1,4-Dipoles
Put a ring on it: The title reaction between
diazooxindoles as electrophilic C1 syn-
thons and 1,3-heterodienes enables the
construction of spirooxindole pyrrolones.
Employing vinyl isocyanates as 1,4-
dipoles, the cycloannulation occurs under
relatively mild conditions and provides
the corresponding pyrrolones in good to
excellent yields.
6
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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