Ir(ppy)3-Catalyzed, Visible-Light-Mediated Reaction of α-Chloro Cinnamates with Enol Acetates: An Apparent Halogen Paradox

Article abstract of DOI:10.1021/acs.orglett.8b02484

The visible-light-mediated activation of vinyl chlorides derived from α-chloro ethyl cinnamates via oxidative quenching of excited photocatalyst fac-Ir(ppy)₃ is described. Upon photoelectron transfer and chloride extrusion, the corresponding vinyl radical can be efficiently trapped by enol acetates, giving rise to synthetically useful 1,4-dicarbonyl compounds in good to excellent yields. This transformation is distinguished by mild and environmentally benign reaction conditions and can be performed on a multigram scale, in sharp contrast to contrasting α-bromo ethyl cinnamates, which show low conversion under the various conditions applied.

Full text of DOI:10.1021/acs.orglett.8b02484

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ir(ppy)3‑Catalyzed, Visible-Light-Mediated Reaction of α‑Chloro
Cinnamates with Enol Acetates: An Apparent Halogen Paradox
̈
Thomas Foll, Julia Rehbein, and Oliver Reiser*
̈
Institute of Organic Chemistry, University of Regensburg, Universitatsstraße 31, 93053 Regensburg, Germany
S
* Supporting Information
ABSTRACT: The visible-light-mediated activation of vinyl chlorides derived from
α-chloro ethyl cinnamates via oxidative quenching of excited photocatalyst fac-
Ir(ppy)3 is described. Upon photoelectron transfer and chloride extrusion, the
corresponding vinyl radical can be efficiently trapped by enol acetates, giving rise to
synthetically useful 1,4-dicarbonyl compounds in good to excellent yields. This
transformation is distinguished by mild and environmentally benign reaction condi-
tions and can be performed on a multigram scale, in sharp contrast to contrasting
α-bromo ethyl cinnamates, which show low conversion under the various conditions applied.
ne key aspect of modern organic synthesis represents the
reducing fac-Ir(ppy)3 (E°Ir(IV)/Ir(III*) = −1.73 V vs SCE, ppy =
O
selective activation of C(sp2)−halogen bonds via transi-
2-phenylpyridine) as catalyst and chose enol acetates as trapping
tion metal catalysis. As a reliable approach, palladium-catalyzed
cross-coupling reactions proved to be a powerful method to
construct C−C bonds and have been well studied over the past
50 years.1 Reactivity strictly correlates with the dissociation
energies of the C−halogen bond. While oxidative addition to
C(sp2)−iodides and bromides is generally facile, unactivated
C(sp2)−chlorides are considered to be challenging substrates,
requiring specially designed catalysts and forcing reaction condi-
tions.2 Nevertheless, chloro-substituted compounds are greatly
preferred as substrates since they are readily available at a lower
cost compared to the bromides and iodides.
reagents (Scheme 1) because they are highly efficient in the
Scheme 1. Visible-Light-Mediated Activation of Vinyl
Halides
As an alternative approach, C(sp2)−halogen bonds can be
activated by an electron-induced bond cleavage to form a
carbon-centered radical and a halide anion. This principle was
first realized via electrochemical methods3 and more recently
via visible-light-mediated photoredox catalysis,4 which has
emerged as a versatile tool in organic synthesis.5 In this
context, our group reported the generation of vinyl radicals via
visible-light-mediated single electron transfer of vinyl bromides
with extended π-systems such as chalcones, which were shown
to be excellent precursors for the synthesis of 1,2-dihydro-
naphthalenes,4d polycyclic aromatic scaffolds,4e or indenones.4f
However, substrates with smaller π-systems such as α-bromo
ethyl cinnamate (1a-Br) show only poor conversion at best in
these transformations, which could be attributed to the
decrease in reduction potential in comparison to the corre-
reaction with radicals.7 However, only low yields at best of the
desired 1,4-dicarbonyl 3aa were observed (Table 1, entries 1, 2).
Further screening revealed that surprisingly α-chloro ethyl
cinnamate (1a-Cl), having an even more negative reduction
•−
potential (E°RX/RX = −1.64 V vs SCE) and a less favorable
leaving group based on bond dissociation energies (BDE C−Cl =
91.7 kcal/mol; C−Br = 79.4 kcal/mol), gave rise to 3aa in up to
98% yield (entry 5).
Again, fac-Ir(ppy)3 proved to be necessary for the reaction to
take place, while other catalysts tested (entries 7−10) were
unsuccessful in this transformation. Moreover, all attempts to
run the reaction in the presence of a sacrificial electron donor,
i.e., utilizing the reductive quenching cycle, only resulted in
undesired hydrodehalogenation.8 Control experiments proved
a photochemically driven process as no product was obtained
when neither a photocatalyst was used nor the reaction was
carried out in the dark (entries 11 and 12).
•−
sponding chalcones (E°RX/RX = −0.88 V vs SCE for (E)-α-
bromochalcone;4e E°RX/RX = −1.54 V vs SCE for 1a-Br).
•−
Established photocatalysts such as Ir(ppy)2(dtb-bpy)PF6
(dtb-bpy = 4,4′-di-tert-butyl-2,2′-bipyridine, Ir[dF(CF3)-
ppy]2(dtb-bpy)PF6 (dF(CF3)ppy = 2-(2,4-difluorophenyl)-
5-(trifluoromethyl)pyridine), Ru(bpy)3Cl2 (bpy = 2,2′-bipyridine),
and Cu(dap)2Cl (dap = 2,9-bis(p-anisyl)-1,10-phenanthroline)
led to no product formation, being in line with their more
+
positive reduction potential (E°M /M* = between −0.81 and
Received: August 3, 2018
−1.43 V vs SCE).6 We therefore considered the strongly
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02484
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Catalyst Screening and Reaction Optimization
b
+
entry
photocatalyst
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
Ir(ppy)2(dtb-bpy)PF6
Ir[dF(CF3)ppy]2(dtb-bpy)PF6
Ru(bpy)3Cl2
Cu(dap)2Cl
E°M /M* (V vs SCE)
−1.73
X
solvent
yield (%)
1
2
3
4
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
DMF
MeCN
DMF
16
8
43
58
98
15
-
-
-
-
-
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
c
5
d
6
7
8
9
10
11
−0.96
−0.89
−0.81
−1.43
e
f
-
g
12
fac-Ir(ppy)3
-
a
Standard reaction conditions: 1a-X (0.5 mmol, 1.0 equiv), 2a (2.5 mmol, 5.0 equiv), photocatalyst (1 mol %), solvent (c = 0.1 M),
b
N2 atmosphere, rt, 24 h, blue LED (λ = 455 nm). Isolated yield after purification via column chromatography. E/Z ratio of approximately 1:1 in all
cases. For details see SI. 2 mol % catalyst. Under O2 atmosphere. Green LED (λ = 530 nm) was used. No photocatalyst. No light.
c
d
e
f
g
a
Under the optimized reaction conditions (Table 1, entry 5)
we next established that ester substitution in 1-Cl is tolerated
well (Scheme 2, 3aa−3ca) with the exception of a sterically
Scheme 3. Scope of α-Chloro Cinnamates 1-Cl
Scheme 2. Scope of Enol Acetates 2 in the Coupling with
a
α-Chloro Cinnamates 1-Cl
a
Standard reaction conditions, see Scheme 2. Combined isolated
yields of separated E and Z isomer after purification via column
chromatography. E/Z ratio of approximately 1:1 to 2:1 in all cases.
For details see SI.
a
Standard reaction conditions: 1 (0.5 mmol, 1.0 equiv), 2 (2.5 mmol,
5.0 equiv), fac-Ir(ppy)3 (2 mol %) in 5 mL of MeCN. Combined
isolated yields of separated E and Z isomer after purification via
column chromatography. E/Z ratio of approximately 1:1 in all cases.
appreciable yields of the coupling products (3ah−3aj), and
no cross reactivity with halogen substituents in aromatic moie-
ties of the enol acetates was observed. The reaction is sensitive
to sterically more demanding enol acetates (3ag, 3ak), and also
alkyl substitution in the enol acetate was not tolerated well
(3al). Furthermore, heterocyclic coupling partners were not
amenable substrates (3am; also 3ra, 1s in Scheme 3) due to
the cross reactivity for direct addition of the vinyl radical to
such moieties.4e,9
b
For details see SI. 20 mmol scale, 0.5 mol % [Ir], 48 h.
t
bulky Bu-ester, which disrupts conjugation of the system
sufficiently to prevent the photocoupling (3da). Focusing on
1a-Cl, various enol acetates were subsequently subjected to this
visible-light-mediated transformation. Excellent results were
obtained using electron-rich enol acetates (3ab−3af), reflecting
the electrophilic nature of the vinyl radical intermediate. Never-
theless, moderately electron-deficient substituents still gave
The reaction could also be run on a 20 mmol scale: using a
setup with 30 high power LEDs and internal water cooling to
B
DOI: 10.1021/acs.orglett.8b02484
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
maintain ambient temperature, 61% of 3aa could be readily
prepared in 48 h. It is important to note that in this experiment
the catalyst loading was greatly reduced to 0.5 mol % com-
pared to the original 2 mol % (see Supporting Information
(SI) for details). In all cases, we observed an E/Z distribution
of close to 1:1 for the products 3; control experiments (see SI)
showed that both starting materials 1 as well as products 3
undergo rapid photoisomerization; moreover, vinyl radicals are
known to have a very low barrier of rotation.10
Electron-deficient cinnamates (Scheme 3) were also proven
to be excellent coupling partners given that electron-with-
drawing groups make the single electron reduction more
feasible (3ea−3ja). Notably, chemoselectivity prevailed as
both bromide (3fa, 3ja) as well as chloride substituents (3ea,
3ha, 3ia) attached on the aromatic ring showed no cross
reactivity.4c As observed in related processes before,4d,e nitro-
substitution (3ka) was not possible, presumably due to efficient
quenching of excited states by this moiety. The limitation of this
coupling process was found for electron-donating substituents,
resulting in a sharp decrease in yield (3la−3pa). Again, hetero-
cyclic substrates were not amenable due to side reactions
occurring directly on the aromatic core (3ra, 1s). Finally, conju-
gation of the vinyl chloride with an arene substituent is neces-
sary as can be seen from the unsuccessful activation of 1t or 1u.
1,4-Dicarbonyl compounds including those of type 3 have
been broadly applied for the synthesis of furans and pyrrols.11
A different application of products 3 is demonstrated with the
CBS reduction12 of 3aa to enantioenriched α-alkylidene-γ-aryl-
γ-butyrolactone 5 (Scheme 4), a class of substrates being of
Table 2. Comparison of α-Halo Cinnamates
c
BDE vinyl−X
conv (%) /yield
•−b
c
entry
X
(kcal mol−1
)
E°RX/RX
(%)
1
2
3
4
F
123.7
91.7
79.4
61.9
−1.93 V
−1.64 V
−1.54 V
n.d.
0/0
Cl
Br
I
100/98
23/23
-
a
Reactions were performed using optimized reaction conditions
b
(Table 1, entry 5). Reduction potentials were measured in MeCN vs
c
1
SCE. Conversion and yield were determined by H NMR analysis
using 1,3,5-trimethoxybenzene as internal standard.
the BDE of the vinyl halide is approximately 12 kcal/mol
higher for the chloride than for the bromide. Still, 1a-Br gave
rise to significantly lower yield of 3aa under the optimized reac-
tion conditions for 1a-Cl (Table 2, entries 2 and 3). By compu-
ting the driving forces and relative stabilites of key intermediates
in the two elemental steps (Table 3) we tried to elucidate if
Table 3. Computed Enthalpies and Gibbs Free Energies
Associated with the Two Key Elemental Steps of Radical
a
Anion Formation and Fragmentation
Scheme 4. Synthesis of Enantioenriched α-Alkylidene-γ-
a
aryl-γ-butyrolactone 5
gas phase
PCM (MeCN)
X
ΔH (kcal/mol) ΔG (kcal/mol) ΔH (kcal/mol) ΔG (kcal/mol)
•−
Step 1: ΔE
−26.2
− ΔE1b−X
[1b−X]
Br
Cl
−25.2
−24.4
−66.0
−68.1
−65.4
−25.1
−66.6
Step 2: {ΔE6 + ΔE−X} − ΔE
•−
[1b−X]
Br
Cl
13.3
21.8
4.5
12.4
−8.9
−4.5
−18.5
−15.8
a
Standard reaction conditions: 3aa (1.0 mmol, 1.0 equiv), BH3·Me2S
(1.3 mmol, 1.3 equiv), (S)-4 (0.1 mmol, 10 mol %), toluene, −15 °C,
23 h. Isolated yield after purification via column chromatography.
ee determined via chiral HPLC.
a
E: Either being enthalpy, H, or Gibbs free energy, G. See SI for
further details.
interest due to its biologically active properties including anti-
inflammatory, phytotoxic, or cytotoxic activities.13 The abso-
lute stereochemistry of (R,Z)-5 was confirmed by X-ray crystal-
lography and is in line with the predictive model for CBS
reductions.12
The overall mechanism of the coupling reaction developed
here follows the established modes discussed before;4d,e,7 however,
the trend in reactivity observed for the α-halo cinnamates is
puzzling. Nevertheless, the reversal for the ease in C−X (X =
Cl, Br) bond dissociation moving from benzyl halides to their
corresponding radical anions has been suggested.14
In agreement with reduction potentials and bond dissocia-
tion energies (BDEs), the α-fluoro cinnamate 1a-F does not
allow vinyl radical formation to take place (Table 2). In turn,
we have been unable to synthesize 1a-I, for which vinyl radical
formation should have been most facile. While the reduction
potential of 1a-Cl is only slightly more negative than for 1a-Br,
indeed the different overall reactivity in the catalyzed
transformation is only due to differences in the fragmentation
of the radical anions.
In the gas phase, the radical anion formation (Step 1) is
favorable, independently of X. The dissociation into carbon
radical and the halide anion (Step 2) however is unfavorable in
both cases. The latter reflects that gas phase structures with
evolving or fully established charges cannot be stabilized. Using a
simple polarizable continuum model (PCM, solvent = MeCN,
for other solvents see SI) to mimic the dielectric effects of the
solvent, now both elemental steps become exergonic. While the
driving force for the release of the bromide is still favored over
the chloride, the free energies become more convergent (ΔΔG =
3 kcal/mol), whereas in the gas phase there was a more than
3-fold higher driving force to cleave the C−Br bond. Interest-
ingly, the computed reaction enthalpies indicated that MeCN
is likely to be the most suitable solvent. And indeed, further
C
DOI: 10.1021/acs.orglett.8b02484
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
screening of different solvents for the reaction did not bring
further improvement: while unipolar solvents did not allow a
conversion neither with 1a-Cl nor with 1a-Br, more polar
solvents (DMF, DMSO, MeCN/water, see SI for details)
allowed significantly better conversions of the former, but
overall the yield decreased for both substrates compared to
pure acetonitrile. While these calculations suggest that in polar
solvents the photochemical activation of vinyl-C−Cl becomes
more feasible, nevertheless, the vinyl bromides should be more
reactive. Conducting an experiment in which 1a-Br and 1a-Cl
were employed in a 1:1 ratio confirmed this: while the conver-
sion and the yield of coupling product 3aa were now low,
analysis of the crude reaction mixture revealed an approx-
imately 3 times faster conversion of 1a-Br compared to 1a-Cl
(see SI for details). Thus, we concluded that AcBr, being
formed upon reaction of 1a-Br and enol acetates might be an
efficient catalyst poison for fac-Ir(ppy)3, while the correspond-
ing AcCl formed in the reaction of 1a-Cl is not. Indeed, adding
AcBr (0.5 equiv, reflecting 50% conversion) to the reaction
mixture under conditions used to convert 1a-Cl (Table 1, entry
5) gave rise to 3aa only in a strongly diminished yield of 22%.
All attempts to reverse this process by adding various inor-
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: oliver.reiser@chemie.uni-regensburg.de.
ORCID
Julia Rehbein: 0000-0001-9241-0637
Oliver Reiser: 0000-0003-1430-573X
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
GRK 1626 (“Photocatalysis”) of the German Research
Foundation (DFG) is gratefully acknowledged for funding.
■
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02484.
Experimental details, characterization data, NMR spectra
of all compounds, HPLC chromatograms, X-ray data,
and computational details (PDF)
Accession Codes
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E
DOI: 10.1021/acs.orglett.8b02484
Org. Lett. XXXX, XXX, XXX−XXX