Generation of the Methoxycarbonyl Radical by Visible-Light Photoredox Catalysis and Its Conjugate Addition with Electron-Deficient Olefins

Article abstract of DOI:10.1021/acs.orglett.6b00895

Visible-light photoredox-catalyzed fragmentation of methyl N-phthalimidoyl oxalate allows the direct construction of a 1,4-dicarbonyl structural motif by a conjugate addition of the methoxycarbonyl radical to reactive Michael acceptors. The regioselectivity of the addition of this alkoxyacyl radical species to electron-deficient olefins is heavily influenced by the electronic nature of the acceptor, behavior similar to that exhibited by nucleophilic alkyl radicals.

Full text of DOI:10.1021/acs.orglett.6b00895

Letter
pubs.acs.org/OrgLett
Generation of the Methoxycarbonyl Radical by Visible-Light
Photoredox Catalysis and Its Conjugate Addition with Electron-
Deficient Olefins
Yuriy Slutskyy and Larry E. Overman*
Department of Chemistry, University of California, Irvine, California 92697−2025, United States
S
* Supporting Information
ABSTRACT: Visible-light photoredox-catalyzed fragmentation of methyl N-
phthalimidoyl oxalate allows the direct construction of a 1,4-dicarbonyl
structural motif by a conjugate addition of the methoxycarbonyl radical to
reactive Michael acceptors. The regioselectivity of the addition of this alkoxyacyl
radical species to electron-deficient olefins is heavily influenced by the
electronic nature of the acceptor, behavior similar to that exhibited by
nucleophilic alkyl radicals.
he normal reactivity of carbonyl compounds renders 1,3-
or 1,5-dicarbonyl functionality much easier to incorporate
T
into organic molecules than 1,4-dicarbonyl functionality.1 The
1,4-addition of acyl-anion equivalents to α,β-unsaturated
carbonyl compounds is a general approach for constructing
1,4-dicarbonyl products. However, several steps are needed to
introduce an alkoxycarbonyl group in this way.1 Transition-
metal-catalyzed alkoxycarbonylation is a widely practiced and
immensely important method to incorporate carbonyl
functionality into alkenes;2 however, the use of this chemistry
to alkoxycarbonylate electron-deficient alkenes has not been
widely developed.3 A potentially attractive approach for
preparing γ-ketoesters would be the direct 1,4-addition of an
alkoxycarbonyl radical to α,β-unsaturated carbonyl com-
pounds.4 Although intramolecular additions of alkoxycarbonyl
radicals to alkenes are well-known and used productively to
construct 5- and 6-membered lactones,5 there are only a few
examples of synthetically useful bimolecular coupling reactions
of alkoxycarbonyl radicals with alkenes.6 In these cases, the
alkoxycarbonyl radical is generated by Fe- or Pd-catalyzed
oxidation of carbazate precursors.
for producing alkoxycarbonyl radicals by visible-light photo-
redox catalysis would be alkyl N-phthalimidoyl oxalates8 or a
salt of an alkyl hemioxalate (Scheme 1).10,11 For this method to
Scheme 1. Two Potential Precursors of Alkoxycarbonyl
Radicals
Computational studies suggest that alkoxycarbonyl radicals
are less nucleophilic than acyl radicals, leading them to be
termed as either ambiphilic or in some contexts electrophilic
radicals.7 These studies raise some concern about whether an
alkoxycarbonyl radical would be sufficiently nucleophilic to add
efficiently to an electron-deficient C−C π-bond. However, in
our recent investigations on the generation of tertiary radicals
from tertiary alkyl N-phthalimidoyl oxalate precursors, we
observed that the intermediate alkoxycarbonyl radical formed
from adamantanol precursor 1 reacted efficiently with methyl
vinyl ketone to give γ-ketoester 2 (eq 1).8,9 As a result, we
became interested in the possibility of using an oxalate
precursor and visible-light photoredox catalysis to conveniently
generate alkoxycarbonyl radicals in the context of their
conjugate addition to α,β-unsaturated carbonyl compounds
and related electron-deficient alkenes. Two potential precursors
be successful, β-scission of the alkoxycarbonyl radical B to give
an alkyl radical must be slower than its reaction with the radical
acceptor.12 The rate of decarboxylation of alkoxycarbonyl
radicals is known to reflect the stability of the forming alkyl
radical with the rate of decarboxylation of the tert-
butoxycarbonyl radical estimated to be ∼500 times faster
than that of a primary alkoxycarbonyl radical.13 As the
methoxycarbonyl radical would be expected to decarboxylate
even more slowly, our studies focused on developing a
Received: March 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00895
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
convenient method to generate this carbon radical and
surveying its reactivity with alkenes.
Table 1. Initial Studies and Reaction Optimization
Methyl N-phthalimidoyl oxalate (4) was obtained by
acylation of methanol with N-phthalimidoyl chlorooxalate (3)
using a modification of a procedure developed previously in our
laboratory for the preparation of tertiary alkyl N-phthalimidoyl
oxalates (Scheme 2).8 The reaction was carried out in the
b
radical precursor
(equiv)
temp
(°C)
7
yield
a
entry
solvent (M)
(equiv)
(%)
c
Scheme 2. Preparation of Methyl N-Phthalimidoyl Oxalate
(4) and Cesium Methyl Oxalate 6
1
4 (1.5)
1:1 CH2Cl2/THF
(0.1)
23
1.5
50
2
6 (1.5)
3:1 DME/DMF
(0.1)
40
2
c
3
4 (1.5)
4 (1.5)
4 (3.0)
4 (3.0)
4 (3.0)
4 (2.0)
4 (2.0)
4 (2.0)
4 (2.0)
CH2Cl2 (0.1)
benzene (0.1)
CH2Cl2 (0.1)
CH2Cl2 (0.1)
CH2Cl2 (0.1)
CH2Cl2 (0.6)
CH2Cl2 (0.6)
CH2Cl2 (0.6)
CH2Cl2 (0.6)
23
23
23
80
23
23
23
23
23
1.5
1.5
3.0
3.0
3.0
2.0
2.0
2.0
2.0
55
38
90
50
c
4
c
5
c
6
d
7
94
d
8
94
e
9
0
16
56
f
10
g
11
a
Reaction conditions for radical precursor 4: 1 equiv of 8a, 1.5 mol %
absence of DMAP at 0 °C to prevent formation of dimethyl
oxalate. Additionally, the use of pyridine in place of Et3N led to
more reproducible results. Phthalimidoyl oxalate 4 was not
stable to silica gel chromatography; however, upon careful
trituration it was isolated on a multigram scale as a colorless
solid in high yield and acceptable purity. Reagent 4 is stable to
light and can be stored in a −20 °C freezer for prolonged
periods of time without decomposition. Cesium methyl oxalate
6 was generated from commercially available methyl hemi-
oxalate 5 upon reaction with 0.5 equiv of Cs2CO3 in water,
followed by concentration to give 6 as a colorless solid.
of [Ru(bpy)3](PF6)2, low-intensity blue LEDs, 18 h. Reaction
conditions for radical precursor 6: 1 equiv of 8a, 2 mol % of
b
Ir[dF(CF3)ppy]2(dtbbpy)PF6, 35 W blue LEDs, 18 h. Yield
1
determined by H NMR analysis of the crude reaction mixture using
c
1,4-dimethoxybenzene as an internal standard. Reaction was
performed in the presence of i-Pr2NEt·HBF4 (1 equiv) as an additive.
d
e
Isolated yield after silica gel chromatography. Reaction performed in
f
the absence of visible light. Reaction performed in the absence of
photocatalyst. Reaction was stopped after 6 h.
g
of the reaction proved to be detrimental (entry 6), whereas
omission of the ammonium additive resulted in a slight increase
in yield (entry 7). Finally, by varying the concentration of the
reaction mixture, we were able to reduce the excess of the
radical precursor 4 and the Hantzsch ester 7 from 3 to 2 equiv
without compromising the isolated yield of 9a (entry 8). In the
absence of visible light, no product was formed (entry 9),
whereas reactions carried out in absence of the photocatalyst or
for 6 h instead of 18 h led to greatly reduced formation of
coupled product 9a (entries 10 and 11).17
With optimal reaction conditions identified, the scope of the
conjugate addition of the methoxycarbonyl radical to a range of
alkene coupling partners was investigated (Table 2). Acceptors
containing a terminal double bond and activated by sulfone,
ketone, ester, amide, nitrile, or phosphonate functional groups
performed best in the reaction, furnishing the corresponding
products in moderate to high yields (entries 1−6). However,
introduction of either an α methyl or α phenyl substituent to
methyl vinyl ketone resulted in no detectable formation of the
coupled product, as did incorporation of such substituents into
benzyl acrylate.18 Cyclopent-2-en-1-one was a poor coupling
partner, yielding the desired product in 27% yield, whereas 5-
oxocyclopent-1-ene-1-carbonitrile underwent conjugate hydride
reduction by the Hantzsch ester 7.19 However, acyclic enones
containing a second electron-withdrawing substituent at the β-
carbon, such as dimethyl fumarate or trans-3-cyanoacrylate, did
react in high yield (entries 7 and 8). The outcome of the latter
reaction is noteworthy, as acceptor 8h possessing two electron-
withdrawing groups of different steric and electronic properties
underwent exclusive addition α to methyl ester substituent.
This sense of regioselectivity, which was attributed by Giese to
larger LUMO coefficient at C-2,4a has been observed
Using conditions optimized earlier for the coupling of
tertiary radicals generated from related precursors with
electron-deficient alkenes,8,10 the reaction of radical precursors
4 and 6 with phenyl vinyl sulfone (8a) was examined (Table 1).
Coupling of N-phthalimidoyl oxalate 4 (1.5 equiv) with phenyl
vinyl sulfone in the presence of 1.5 mol % of [Ru(bpy)3](PF6)2,
1.5 equiv of diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicar-
boxylate (7), and 1 equiv of i-Pr2NEt·HBF4 in 1:1 THF/
CH2Cl2 with irradiation at room temperature with low-intensity
blue LEDs gave product 9a in 50% yield (Table 1, entry 1). In
contrast, the reaction of methyl cesium oxalate 6 (1.5 equiv)
with phenyl vinyl sulfone in the presence of 2 mol % of
Ir[dF(CF3)ppy]2(dtbbpy)PF6 and 10 equiv of water in 3:1
DME/DMF irradiated with 35 W blue LEDs provided adduct
9a in only 2% yield (Table 1, entry 2). As low yields were also
obtained in further screening of the reaction of oxalate salt 6
with benzyl acrylate,14 we chose to focus on optimizing the
coupling of phthalimidoyl oxalate 4 with acceptor 8a. The
major byproduct of the reaction of entry 1 was identified as the
product of addition of the 2-tetrahydrofuryl radical to phenyl
vinyl sulfone (∼30%). To suppress this unwanted reactivity, a
solvent screen was performed that identified CH2Cl2 as the
optimal solvent (entry 3). The choice of a polar aprotic solvent
was important, as reactions run in nonpolar solvents such as
benzene led to lower yields, likely because of the low solubility
of Hantzsch ester 7 (entry 4). Employing alternative reductive
quenchers such as 1,3-dimethyl-2-arylbenzimidazolines,15 or 2-
phenylbenzothiazoline,16 led to greatly diminished yields of
addition product 9a. The yield of 9a was improved substantially
by increasing the amounts of phthalimidoyl oxalate 4 and
Hantzsch ester 7 to 3 equiv (entry 5). Raising the temperature
B
DOI: 10.1021/acs.orglett.6b00895
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
allylic substitution product 9j in 47% yield. To our surprise,
methyl 2-(bromomethyl)acrylate was unreactive.18
Table 2. Acceptor Scope with N-Phthalimidoyl Oxalate 4
As alkoxycarbonyl radicals had been suggested to be
ambiphilic or electrophilic, we examined the reactivity of the
methoxycarbonyl radical generated from N-phthalimidoyl
oxalate 4 with electron-rich alkenes and styrenes (Scheme
3).18 For example, performing the reaction in the presence of a
Scheme 3. Coupling of N-Phthalimidoyl Oxalate with
Electron-Rich Alkenes and Styrenes
prototypical electron-rich alkene, butyl vinyl ether (8k), led to
no detectable coupled product. Reactions carried out in the
presence of styrene derivatives 8l−n led to broad peaks in the
1H NMR spectra of crude reaction mixtures, indicating likely
polymerization of the intermediate stabilized benzylic radicals
formed upon addition of the methoxycarbonyl radical.
In summary, methyl N-phthalimidoyl oxalate (4) was shown
to be a convenient precursor of the methoxycarbonyl radical
under visible-light photoredox conditions. It reacts in good
yield with terminal alkenes harboring a variety of electron-
withdrawing substituents, thus providing a convenient method
for the direct construction of γ-ketoesters and related products.
It also reacts in high yield with 1,2-disubstituted alkenes
activated by two electron-withdrawing substituents and in one
relevant case with regioselectivity higher than that of alkyl
radicals. We attribute the somewhat limited scope of reactivity
of the methoxycarbonyl radical to it being less nucleophilic than
alkyl carbon radicals. No indication that the methoxycarbonyl
radical shows ambiphilic reactivity was observed.
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.6b00895.
Experimental procedures, characterization data of new
1
compounds, and copies of H and 13C NMR spectra
(PDF)
a
Reaction performed using the optimized conditions (see the
AUTHOR INFORMATION
Corresponding Author
■
Supporting Information). All yields are yields of pure products
isolated after silica gel chromatography.
*Email: leoverma@uci.edu.
Notes
The authors declare no competing financial interest.
previously; however, in the previous cases the magnitude of
regioselection was much lower: 5−6:1.20 4-Methoxybutenolide
(8i), which was shown previously to react in good yield with a
nucleophilic tertiary carbon radical,8,10 coupled in low yield
with the methoxycarbonyl radical (entry 9). Coupling of the
methoxycarbonyl radical with 2-phenylallyl bromide (8j) gave
ACKNOWLEDGMENTS
■
This research was supported by the National Science
Foundation (CHE1265964), an F. S. and Joan Rowland
Fellowship to Y.S., and a graduate fellowship award to Y.S.
C
DOI: 10.1021/acs.orglett.6b00895
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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NSF and NIH Shared Instrumentation grants.
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