Recyclable Hypervalent-Iodine-Mediated Dehydrogenative Cyclopropanation under Metal-Free Conditions

Article abstract of DOI:10.1021/acs.orglett.6b03209

A method is developed for the synthesis of cyclopropanes from the C(sp²)-C(sp³) single bonds of β-keto esters with activated methylene compounds under metal-free conditions in the presence of 5-trimethylammonio-1,3-dioxo-1,3-dihydro-1λ⁵-benzo[d][1,2]iodoxol-1-ol anion (AIBX), a recyclable water-soluble hypervalent iodine(V) reagent developed by our group. This mild, efficient method has a wide substrate scope and good functional group tolerance and is complementary to existing cyclopropanation strategies. The method can be used to construct polysubstituted ring-fused cyclopropanes and is amenable to further synthetic transformations for construction of complex biologically active molecules as well as asymmetric cyclopropanes (90% de) when a chiral ester auxiliary is used.

Full text of DOI:10.1021/acs.orglett.6b03209

Letter
pubs.acs.org/OrgLett
Recyclable Hypervalent-Iodine-Mediated Dehydrogenative
Cyclopropanation under Metal-Free Conditions
Ya-Nan Duan, Zhao Zhang, and Chi Zhang*
State Key Laboratory of Elemento-Organic Chemsitry, Collaborative Innovation Center of Chemical Science and Engineering
(Tianjin), Nankai University, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: A method is developed for the synthesis of
cyclopropanes from the C(sp2)−C(sp3) single bonds of β-keto
esters with activated methylene compounds under metal-free
conditions in the presence of 5-trimethylammonio-1,3-dioxo-
1,3-dihydro-1λ5-benzo[d][1,2]iodoxol-1-ol anion (AIBX), a
recyclable water-soluble hypervalent iodine(V) reagent
developed by our group. This mild, efficient method has a
wide substrate scope and good functional group tolerance and
is complementary to existing cyclopropanation strategies. The method can be used to construct polysubstituted ring-fused
cyclopropanes and is amenable to further synthetic transformations for construction of complex biologically active molecules as
well as asymmetric cyclopropanes (90% de) when a chiral ester auxiliary is used.
yclopropane moieties are present in a range of synthetic
compounds, bioactive natural products, and drugs.1
fused cyclopropane scaffold is a prevalent structural unit in
synthetic chemistry owing to its unique chemical reactivity
involving fragmentation and rearrangement.7 This scaffold is
typically constructed via intramolecular cyclization reactions
between olefins and tethered C1 synthons such as metal
carbenoids.8 Synthesis of its polysubstituted analogues is
challenging.
As part of our ongoing exploration of oxidative reactions
brought about by hypervalent iodine reagents,9 we herein
report the oxidative α,β′-cyclopropanation of saturated β-keto
esters under metal-free conditions, which constitutes a facile
method for the construction of polysubstituted bicyclo[3.1.0]
scaffolds via dehydrogenation-initiated Michael addition and
subsequent ring closure (Scheme 1b).
C
Cyclopropanes are also important synthetic building blocks
due to the highly strained ring. Release of ring strain by ring
opening, which occurs readily (particularly for donor−acceptor
cyclopropanes), provides the driving force for much of
cyclopropane chemistry.2 Numerous approaches to cyclo-
propane synthesis have been developed (Scheme 1a). Many
Scheme 1. Approaches to Cyclopropane Synthesis
We began our exploration by using tert-butyl 1-oxo-2,3-
dihydro-1H-indene-2-carboxylate (1a) to react with malononi-
trile (2.0 equiv) in the presence of 2.5 equiv of 5-
trimethylammonio-1,3-dioxo-1,3-dihydro-1λ5-benzo[d][1,2]-
iodoxol-1-ol anion (AIBX) in a solution of 3:1 (v/v) CH3CN/
water at 40 °C, affording cyclopropane 2a in 65% yield within
12.5 h, and the structure of 2a was confirmed by X-ray
crystallography (Figure 1).10 Further investigation of reaction
conditions for the dehydrogenative cyclopropanation revealed
that a system consisting of 2.0 equiv of malononitrile, 2.5 equiv
of AIBX, and 1.0 equiv of AcOH in 1:3 (v/v) CH3CN/water at
40 °C was optimal (for details, see the Supporting
Information).11
of the approaches, including Simmons−Smith reactions,3
transition-metal-catalyzed addition reactions of alkenes with
diazo compounds or iodonium ylides,4 Michael addition-
initiated ring-closure (MIRC) reactions,5 and others,6 start
from alkenes or unsaturated carbonyl compounds. Among
them, metal agents are not involved in MIRC reactions and
cyclopropanation initiated by hypervalent iodine reagents,6b−d
hyperiodite,6a and several other scattered examples.6e−h To our
knowledge, cyclopropanation of a C−C single bond, especially
under metal-free conditions, has never been achieved. The ring-
Using the optimal conditions, we carried out reactions of a
series of β-ketoesters to explore the generality of the reaction
(Scheme 2). Substrates bearing electron-donating substituents
Received: October 26, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03209
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Organic Letters
Letter
(−)-8-phenylmenthyl group as a chiral auxiliary underwent
efficient stereoselective cyclopropanation to furnish a product
bearing two contiguous stereogenic centers (2s, 93% yield, 90%
de).
To investigate the mechanism of this transformation, we
carried out several control experiments (Scheme 3). First, cyclic
Scheme 3. Control Experiments
Figure 1. Single-crystal X-ray structure of 2a.
Scheme 2. Substrate Scope
enone 3a was prepared14 by means of a reported method with
PhSeCl/pyridine and subsequent oxidation with hydrogen
peroxide. When 3a was cyclopropanated under the standard
conditions, except that 1.5 equiv of AIBX was used, the reaction
smoothly gave the desired product (74%, Scheme 3a),
confirming the intermediacy of an enone. When substrate 1t,
a 1a analogue bearing a β′-phenyl group, was allowed to react
with 1.5 equiv of AIBX in the absence of malononitrile, enone
3t was obtained in 52% yield (Scheme 3b), a result that
provides direct evidence for the dehydrogenative reactivity
involved in the cyclopropanation mechanism.
On the basis of our previous work on AIBX-initiated
reactions9 and the results of the above-described experiments,
we propose the mechanism shown in Scheme 4. First, enone 3a
Scheme 4. Plausible Reaction Mechanism
a
b
Reaction carried out in 1:1 (v/v) CH3CN/H2O. Reaction carried
c
out in 1:1:3 CH3CN/THF/H2O. Camphorsulfonic acid was used as
additive instead of AcOH. Reactions in 2:3 CH3CN/H2O. The de
value was determined by H NMR spectroscopy.
d
e
1
(Me, OMe) on the phenyl ring were smoothly converted to the
desired cyclopropane products in good to high yields (2b−2e),
and it was notable that substrates bearing one or two methyl
groups on the phenyl ring yielded the desired products without
undergoing benzylic oxidation. A substrate with a readily
oxidizable naphthalene ring tolerated the oxidative conditions,
giving the desired product (2f) in excellent yield. The allyloxy
group in substrate 1g remained intact under the cyclo-
propanation conditions, affording 2g in 94% yield. We also
obtained excellent yields of halogen-substituted cyclopropanes
(2h−2l), which contain reactive handles for construction of
more complex molecules. Substrates bearing benzyl and
(adamantan-1yl)methyl ester moieties smoothly afforded the
corresponding cyclopropanated products (80% and 87%,
respectively). Furthermore, cyclopropanation could be accom-
plished even with fully saturated substrates: specifically, 2p and
2q were obtained in 65% and 77% yields, respectively, in the
presence of camphorsulfonic acid as an additive.12 Methyl α-
cyanoacetate was also a suitable nucleophile, affording a single
regioisomer (2r) under the optimal conditions (for structural
information obtained by crystallographic analysis, see the
Supporting Information, Section VI).13 A substrate with an
is produced via AIBX-mediated dehydrogenation, as confirmed
by the control experiment shown in Scheme 3a. Under the
acidic conditions, Michael addition of malononitrile to 3a can
be expected to occur readily. The nucleophilic hydroxyl group
of the resulting adduct attacks the iodine center of another
molecule of AIBX to give a reactive iodine(V) complex. Finally,
after elimination of a molecule of water, intramolecular
oxidative cyclization driven by the release of one AIBA
molecule gives 2a.
Because AIBX is highly water-soluble (0.38 M), it can be
regenerated (above 90%) after the reaction by (1) removal of
the organic components by extraction with EtOAc, (2)
B
DOI: 10.1021/acs.orglett.6b03209
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Organic Letters
Letter
evaporation of the aqueous phase to give reduced form of
AIBX, and (3) oxidation of the reduced AIBX with dimethyl
dioxirane.
Next we explored the reactivity of the polysubstituted
bicyclo[3.1.0] scaffold obtained from the cyclopropanation
reaction. When 2a was treated with tBuOK in toluene (Scheme
5a), fission of the C−C bonds in both the cyclopentanone and
was treated with methanol in the presence of catalytic Bu2SnO,
ring opening occurred at the less-strained cyclopentanone
moiety rather than at the more-strained cyclopropane moiety,
efficiently affording indole carboxylic methyl ester 8u, which
has a 2,2-dicyano-3-methoxycarbonylcyclopropyl group at C-2.
It is well-known that ring cleavage, a typical reaction pathway
for compounds with small rings, especially cyclopropane and
cyclobutane rings, is driven by the release of ring strain.19
However, methods for cleavage of cyclopentanone derivatives
under mild conditions are elusive.20 The 2,2-dicyano
substituted cyclopropane moiety in 8u contains potentially
reactive sites for further synthetic elaboration of this indole-
based molecule.6a,21
Scheme 5. Ring Opening of the Bicyclo[3.1.0] Scaffold and
Synthesis of Compounds 7
In conclusion, we developed a method for cyclopropanation
that is mediated by the water-soluble hypervalent iodine(V)
reagent AIBX and that involves dehydrogenation-initiated
Michael addition and ring-closure reactions of C(sp2)−C(sp3)
single bonds in saturated β-ketoesters. This method provides a
straightforward, step-economical alternative to the previously
reported cyclopropanation strategies, which require substrates
bearing at least one C−C double bond. Introducing a chiral
ester auxiliary into the substrate led to the efficient synthesis of
a cyclopropane bearing two contiguous chiral centers with a
high de value. Moreover, this method and further trans-
formation of the products obtained can be expected to facilitate
the synthesis of libraries of potentially biologically active
compounds. Further scope broadening of this particular
cyclopropanation and applying it to modifying complex
bioactive molecules are of great significance. Efforts toward
these goals are currently ongoing in our lab.
the cyclopropane moieties produced tetrasubstituted alkene 4a
(70%), which bears geminal cyano groups at the terminal end
of the alkene and an ester at the other end. This type of alkene
can serve as a key component in the preparation of
polyfunctionalized indolines, quinoxalin-2-ones, pyrazolopyr-
idines, and pyridazines.15 In addition, it is the key intermediate
in the synthesis of compounds 7 (Scheme 5b), which can
activate soluble guanylate cyclases and thus are valuable for the
prevention and treatment of cardiovascular disease.16 The
smooth formation of 4a suggests that a series of dicyanoalkene
analogues 4 could be produced by treatment of the compounds
shown in Scheme 2 with tBuOK. We surmise that the synthetic
route shown in Scheme 5b could be used to transform
dicyanoalkenes 4 into a library of active analogues of 7.
Indole motifs are common in natural products, pharmaceut-
icals, and agrochemicals, and more than 200 indole-based
compounds are currently marketed as drugs or are undergoing
clinical trials.17 Because of the importance of these motifs, we
used our method to derivatize indole-based substrates.
Compound 1u was synthesized from 3,4-dihydrocyclopenta-
[b]indol-1(2H)-one (NC001-8), a drug candidate for treatment
of spinocerebellar ataxia type 3 and other polyglutamine-
mediated diseases,18 after sequential N-protection and methox-
ycarbonylation (Scheme 6). When 1u was subjected to the
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.6b03209.
Full experimental details; optimization of reaction
conditions; characterization data; ORTEP drawing and
crystallographic data for compounds 2a and 2r (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhangchi@nankai.edu.cn.
ORCID
Chi Zhang: 0000-0001-9050-076X
Notes
Scheme 6. Indole Derivatization
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by The National Natural
Science Foundation of China (21172110, 21472094, and
21421062). We thank Mr. L.-H. Zuo and Ms. Y.-L. Guo both
in Nankai University for preparing several substrates.
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