Photo/N-Heterocyclic Carbene Co-catalyzed Ring Opening and γ-Alkylation of Cyclopropane Enal

Article abstract of DOI:10.1021/acs.orglett.9b04533

An unprecedented photo/NHC-co-catalyzed ring-opening C-C bond cleavage of cyclopropane enal and the following γ-alkylation with a halogenated compound via radicals were established, affording the corresponding γ-alkylated α,β-unsaturated esters in moderate to good yields.

Full text of DOI:10.1021/acs.orglett.9b04533

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Letter
Photo/N-Heterocyclic Carbene Co-catalyzed Ring Opening and
γ‑Alkylation of Cyclopropane Enal
Lei Dai and Song Ye*
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ABSTRACT: An unprecedented photo/NHC-co-catalyzed ring-opening
C−C bond cleavage of cyclopropane enal and the following γ-alkylation
with a halogenated compound via radicals were established, affording the
corresponding γ-alkylated α,β-unsaturated esters in moderate to good
yields.
s they are the fundamental structures of organic
Acompounds, the formation, cleavage, and transformation
of C−H and C−C bonds are of pivotal importance in synthetic
chemistry. Compared to the widely explored C−H function-
alization,1 C−C activation, which edits the molecular frame-
work, is still very limited.2 The ring opening of cyclopropane
provides an efficient strategy for C−C bond cleavage because
of the release of ring strain.3 For example, the ring opening of
donor−acceptor cyclopropane catalyzed by Lewis acid has
been well developed.4 However, the reaction usually goes well
with heteroatom nucleophiles or enolates, while the reaction
with a C(sp3) nucleophile is still a challenge (Scheme 1a).5
The C−C bond cleavage of cyclopropane by transition metal
catalysis and the following reactions with alkenes/alkynes were
also developed (Scheme 1b).6 Interestingly, the reaction with
electrophiles via the C−C bond cleavage of cyclopropane has
rarely been reported.
In the past few decades, organocatalysis of N-heterocyclic
carbenes (NHCs) has emerged as a useful strategy for the
umpolung of various substrates.7 The NHC-catalyzed redox
esterification of formylcyclopropanes via C−C bond cleavage
was pioneered by Bode et al. in 2006.8 The corresponding
reactions of the enolate/dienolate9 with carbonyl com-
pounds,10 fluorinated reagents,11 and azodicarboxylate esters11
have also been established via a two-electron pathway (Scheme
1c). However, NHC-catalyzed C−C bond cleavage with
C(sp3) electrophiles is still undocumented. As a continuation
of our efforts in merging photoredox catalysis12 with NHC
catalysis,13 we envision that the highly reactive alkyl radical,
generated under photocatalysis, may react with the dienolate
generated from cyclopropane enal via NHC-catalyzed ring
opening, which features C−C bond activation under organo-
catalysis and reaction with C(sp3) electrophiles (Scheme 1d).
Our investigation commenced with the reaction of cyclo-
propane enal 1a and diethyl 2-bromo-2-methylmalonate 2a in
the presence of methanol under photo/NHC catalysis (Table
1). Despite the fact that there is no desired ring-opening
alkylation product 3a observed for the reaction using
thiozolium A as the NHC precursor and 2 mol %
Ru(bpy)3(PF6)2 as the photocatalyst under blue light-emitting
diode (LED) irraditation (entry 1), It was found that the
corresponding reactions using imidazolium preNHC B and
triazolium preNHC C1 and C2 gave product 3a in 5−11%
yields with exclusive γ-regioselectivity (entries 2−4, respec-
tively). The triazolium preNHC C3 and C4 with an N-
electron-deficient aryl group failed to catalyze the reaction
(entries 5 and 6, respectively). Gratifyingly, the use of
tetracylic trizaolium preNHC D dramatically improved the
yield of the reaction to 83% with exclusive γ-regioselectivity
(entry 7). Decreasing the load of the photocatalyst to 1 mol %
led to decreased yields (entries 8 and 9), while a better yield
resulted with 2.5 mol % photocatalyst (entry 10). Finally, the
yield was maintained when the load of preNHC D was
decreased to 10 mol %. (entry 11).
After optimization of the reaction conditions, the scope of
alcohols for the reaction was then briefly explored (Scheme 2).
It was found that all of the primary alcohols with electron-
donating or electron-withdrawing groups worked well for the
reaction, furnishing the corresponding cross coupling products
(3a−3d) in good to excellent yields. Moderate to good yields
were also achieved for the reaction with secondary alcohols
when its load was increased (3e and 3f). It is noteworthy that
chloride and olefin were tolerated to furnish the desired
products (3g and 3h) in good to excellent yields. Furthermore,
the reaction could be scaled up with 3 mmol of 2a, giving 1.15
g of the corresponding ring-opening alkylation product 3a in
87% yield.
Received: December 17, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04533
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
Scheme 1. C−C Bond Cleavage of Cyclopropanes
Scheme 2. Substrate Scope of Nucleophiles
Scheme 3. Substrate Scope of Alkyl Electrophiles
a
Table 1. Optimization of Conditions
Scheme 4. Chemical Transformations
b
entry
preNHC
X (mol %)
Y (mol %)
yield (%)
1
2
3
4
5
6
7
8
A
B
2
2
2
2
2
2
2
1
20
20
20
20
20
20
20
10
15
15
10
0
11
8
5
0
C1
C2
C3
C4
D
D
D
D
D
0
Scheme 5. Promising Enantioselective Reaction
83
70
69
92
95
9
10
11
1
2.5
2.5
a
General conditions: 1a (0.75 mmol), 2a (0.30 mmol), Ru-
(bpy)3(PF6)2 (1−2.5 mol %), preNHCs (10−20 mol %), CsOAc
(200 mol %), MeOH (5.0 equiv), DCE (3 mL), 18 × 1 W household
b
blue LED, 12 h, 25 °C. Isolated yields.
A variety of brominated compounds were then explored as
the radical precursors (Scheme 3). It was found that a series of
B
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of malonate derivative 3a with Pd(OH)2/C under H2 provided
product 4a in 91% yield. Bromination of compound 3a by NBS
afforded the corresponding α-bromo malonate 4b in 71% yield
(Scheme 4).
Scheme 6. Preliminary Mechanistic Studies
A promising enantioselectivity was achieved when chiral
NHC precursor E was used for the reaction (Scheme 5).
A series of control experiments were conducted to illustrate
the reaction mechanism (Scheme 6). The reaction without
light, photocatalyst, or NHC afforded no desired product. The
reaction was completely prohibited when TEMPO was added
as the radical scavenger, while radical coupling adduct 5a of the
α-methylmalonate radical and TEMPO was detected by high-
resolution mass spectrometry.
A plausible mechanism for the reaction is shown in Scheme
7. Alkyl radical I is generated from alkyl halide via photoredox
catalysis. Radical I reacts with dienolate intermediate II, which
is generated from γ-cyclopropane enals via NHC-catalyzed C−
C bond cleavage, to give homoenolate radical III. The
subsequent single-electron transfer oxidation of homoenolate
radical III by RuIII photocatalyst IV furnishes unsaturated acyl
azolium intermediate V and completes the photoredox
catalytic cycle. Acyl azolium intermediate V is trapped by
alcohol to give the final γ-alkylated α,β-unsaturated ester and
regenerates the NHC catalyst.
In summary, an unprecedented NHC-catalyzed C−C bond
cleavage of γ-cyclopropane enals and the following γ-alkylation
via radicals under photoredox conditions were developed. A
variety of halogenated alkylation reagents, such as α-alkyl-α-
bromomalonates, methyl 2-(bromomethyl)-5-nitrobenzoate,
and iodoacetonitrile, worked well for the reaction, providing
the desired γ-alkylated α,β-unsaturated esters in moderate to
good yields. The reaction features exclusive γ-regioselectivity,
tolerance of functional groups, and mild reaction conditions.
Further investigation of NHC/photo-co-catalyzed reactions is
underway in our laboratory.
α-alkyl-α-bromomalonates bearing linear and branched
aliphatic chains worked well to afford the corresponding
products (3i−3k) in good yields with exclusive γ-regioselec-
tivity. The reaction with α-benzyl-α-bromomalonate with
electron-donating and electron-withdrawing groups went
smoothly, giving the corresponding products 3l−3o in good
to excellent yields. The aryl group with an ortho substituent, a
meta substituent, or a β-naphthyl did not affect the reaction
(3p−3r). More importantly, the brominated compounds with
additional functional groups, such as boronic ester, olefin, and
α,β-unsaturated ester, were all well tolerated (3s−3u).
Interestingly, the reaction with methyl 2-(bromomethyl)-5-
nitrobenzoate afforded the product in reasonable yield (3v).
Furthermore, a simple alkylation reagent, α-iodoacetonitrile,
worked well to give the product in 64% yield (3w).
Unfortunately, 2-bromo-2-nitropropane did not work under
our current reaction conditions (3x). Attempts to expand the
scope of the enals, such as epoxy enals and several other
cyclopropane enals, failed to give desired products under the
current conditions (see the Supporting Information for
details).
The multifunctional ring-opening alkylation product allows
many possible further derivations. For instance, hydrogenation
Scheme 7. Proposed Mechanism
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04533.
■
sı
Experimental procedures, full spectroscopic data for all
new compounds, and copies of H, 13C, and 19F NMR
1
spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Song Ye − Institute of Chemistry, Chinese Academy of
Sciences, Beijing, China, and University of Chinese
Academy of Sciences, Beijing, China; orcid.org/0000-
0002-3962-7738; Email: songye@iccas.ac.cn
Other Author
Lei Dai − Institute of Chemistry, Chinese Academy of
Sciences, Beijing, China, and University of Chinese
Academy of Sciences, Beijing, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04533
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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(c) Cavitt, M. A.; Phun, L. H.; France, S. Intramolecular donor−
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Financial support from the National Natural Science
Foundation of China (21425207, 21672216, and 21831008)
and the Beijing National Laboratory for Molecular Sciences
(BNLMS-CXXM-202003) is gratefully acknowledged.
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