Decarboxylative Anti-Michael Addition to Olefins Mediated by Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.6b01712

Decarboxylative coupling of carboxylic acids with activated olefins has been accomplished using visible light photoredox catalysis. The strategic placement of a radical-stabilizing aromatic group at the β-position of the olefin component biases the regios

Full text of DOI:10.1021/acs.orglett.6b01712

Letter
pubs.acs.org/OrgLett
Decarboxylative Anti-Michael Addition to Olefins Mediated by
Photoredox Catalysis
Gabrielle H. Lovett and Brian A. Sparling*
Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States
S
* Supporting Information
ABSTRACT: Decarboxylative coupling of carboxylic acids
with activated olefins has been accomplished using visible light
photoredox catalysis. The strategic placement of a radical-
stabilizing aromatic group at the β-position of the olefin
component biases the regioselectivity of the addition, allowing
reliable, facile access to anti-Michael-type products from
readily available precursors. The scope of this methodology
was demonstrated with a range of carboxylic acids and appropriately substituted olefins and was applied toward a two-step
synthesis of the antiarrhythmic agent encainide.
adical-based transformations figure prominently in syn-
decarboxylative addition of carboxylic acids to aromatic and
styrenyl systems mediated by visible light photoredox catalysis,
providing products complementary to traditional Michael
methodology (Scheme 1).10−12
R
thetic chemistry, both for target-directed synthesis1 as well
as for the manufacture of plastics.2 The ability of radicals to add
to olefins has been a mainstay for the construction of C−C bonds
for over 40 years and has been strategically implemented in
natural product total synthesis.3 However, one drawback to this
chemistry is the limited pool of radical precursor functionality
that can be routinely employed (i.e., halides and alcohol-derived
groups such as xanthates) using traditional initiation method-
ology.
Scheme 1. Comparison of Traditional Michael Addition
Reactivity to This Work
Visible light photoredox catalysis has emerged in recent years
as a prodigious hotbed for the development of many new
chemical transformations.4 Activation of a catalyst such as
Ru(bpy)3Cl2 or [Ir(dFCF3ppy)2(dtbbpy)]PF6 (1) via visible
light-promoted metal-to-ligand charge transfer facilitates simul-
taneous one-electron reductant and oxidant behavior. These
activated catalysts may interact in a chemoselective manner with
organic substrates via single-electron transfer processes, thus
initiating synthetically useful reduction, oxidation, and C−C
bond-forming processes. Notably, MacMillan and co-workers
have utilized carboxylic acids as “traceless activating groups” in a
variety of photoredox bond-forming reactions, such as Michael
addition,5 alkyl fluorination,6 arylation,7 vinylation,8 and
anhydride decarboxylation9 reactions.
This decarboxylative coupling methodology is especially
powerful given the stability, variety, and commercial availability
of carboxylic acids, which would allow for the rapid generation of
chemically diverse libraries. In particular, we were intrigued with
MacMillan and co-workers’ report of photoredox-mediated
decarboxylative Michael additions.5 In their report, placement
of an aryl group on the α-position of the Michael acceptor
stabilized the intermediate acyl radical species directly following
conjugate addition. Inspired by this tactic, we hypothesized that
strategic placement of a radical stabilizing group at the β-position
of the acceptor would allow us to access products with opposite
regioselectivity (i.e., anti-Michael products). Herein, we explicate
our strategy, leading to a regioselective, intermolecular
We began our investigation with the decarboxylative coupling
of Boc-proline (2) and N-methyl-2-quinolinone (3) and were
delighted to find that this transformation selectively afforded
adduct 4 as the sole observable regioisomer in good yield across a
range of conditions (Table 1).13 Several bases were explored to
facilitate this transformation (entries 1−4), of which Cs2CO3
provided the highest yield. Akin to other reaction manifolds, the
use of cesium salts may be beneficial due to their increased
oxidative propensity, high solubility, and weak solvation, among
other properties.14 A screen of polar solvents revealed DMSO to
be optimal (entries 4−7).15 A study of reaction concentration
demonstrated increased dilution (i.e., 0.02 M vs 0.2 M of 3)
improved reaction efficiency (entries 4 vs 8). This concentration
effect may be due to greater light penetration into the reaction
solution at higher dilution, leading to greater photoredox
catalytic activity. To further test this hypothesis, we increased
the reaction opacity using 3 equiv of Cs2CO3 (entry 9) in
conditions otherwise identical to entry 4, which led to decreased
conversion and isolated yield of 4. Strongly oxidizing photo-
Received: June 13, 2016
Published: July 1, 2016
© 2016 American Chemical Society
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Letter
Table 1. Evaluation of Conditions for the Decarboxylative
Anti-Michael Addition
Scheme 2. Decarboxylative Additions to 3: Scope of the
a
Carboxylic Acid Component
a
entry
catalyst
base
solvent
yield (%)
1
1
K2HPO4
CsF
DMSO
DMSO
DMSO
DMSO
DMA
77
81
83
89
71
72
81
70
38
90
trace
0
2
1
3
1
CsOAc
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
4
1
5
1
a
6
1
DMF
All products are equimolar mixtures of racemic diastereomers unless
b
7
1
MeCN
stated otherwise. Product is a 2.3:1.3:1.1:1.0 mixture of diaster-
eomers. Product is approximately a 1.4:1.4:1.0:1.0 mixture of
diastereomers. Product is an inseparable 2:1 mixture of coupling
b
c
8
1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
d
c
9
1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
product and oxidized quinolinone. See Supporting Information for
details.
10
11
12
5
Ir(ppy)3
none
d
Scheme 3. Decarboxylative Additions of Boc-Proline (2):
Scope of the Radical Acceptor Component
13
1
0
a
a
b
c
Isolated yield. Reaction run at 0.2 M concentration. 3 equiv
d
Cs2CO3 was used. Reaction run in the absence of light.
catalysts 1 and closely related [Ir(ppy)2(dtbbpy)]PF6 (5) were
more efficient than the strongly reducing photocatalyst Ir(ppy)3,
which failed to induce decarboxylation (entries 4 vs 10−11). We
utilized 1 in subsequent studies given its stronger oxidizing
properties (E*1/I2II/II = +1.21 V for 1 and E*1/I2II/II = +0.66 V for 5 vs
saturated calomel electrode in MeCN).16 In the absence of
catalyst (entry 12) or light (entry 13), no product was observed.
Without active cooling, the reactions reached thermal equili-
brium at 45 °C; yields were not adversely affected when run at
this temperature when compared to room temperature.
Additionally, yields were not significantly different when the
reaction was conducted open to the atmosphere or under the
rigorous exclusion of oxygen.
Having found optimal conditions for the synthesis of 4, we
surveyed a variety of carboxylic acid radical precursors (6a−g) in
coupling reactions with quinolone 3 (Scheme 2). Acids bearing
an α-heteroatom substituent gave good yields for this trans-
formation, including 5- and 6-membered heterocyclic rings (7a−
f).17 Proline derivatives bearing a small 3-substituent provided
only modest levels of diastereoselection in products 7b and 7c.
Alicyclic carboxylic acids may also be utilized in this method-
ology, such as adamantoic acid (6g) to afford 7g.
We next examined the scope of radical acceptors with N-Boc
proline 2 as the nucleophile (Scheme 3). Quinolinones 8a,b and
indole 8c provided coupling products 9a−c in good yields. The
reactivity of exocyclic olefin acceptors was also explored.
Coupling with anti-Markovnikov selectivity was achieved using
styrene and styrenyl derivatives (8d−i). Substitution at the
styrenyl α- and β-positions was tolerated to afford 9e and 9f. It is
interesting to note that the anti-Michael product 9g predomi-
a
All products are equimolar mixtures of racemic diastereomers unless
b
stated otherwise. Reaction provided a 5.7:1 mixture of regioisomers.
The minor regioisomer is the Michael-type product resulting from
addition to the β-position. See Supporting Information for details.
nated in the reaction with methyl cinnamate (8g) over the
traditional Michael-type product. 2-Vinylpyridine (8h) was also a
competent coupling partner in this reaction to give 9h. The
efficiency of coupling reactions producing 9i as well as 9a and 9c
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Letter
illustrate the orthogonality of this reaction to traditional cross-
coupling methodology.
A mechanism illustrating our rationale for anti-Michael
regioselectivity is depicted in Scheme 4, involving the reaction
the reported manufacturing route21 of this drug are devoted to
coupling and modification of similar fragments (i.e., aldol
condensation, dehydration, and reduction), this photoredox
coupling methodology is superior both in terms of step- and
redox-economy.22 Further, this chemistry may be utilized to
quickly generate a library of encainide analogues.
In summary, photoredox catalysis was utilized to facilitate
decarboxylative coupling of cyclic carboxylic acids and a wide
range of radical acceptors with anti-Michael selectivity. For
styrenyl substrates, anti-Markovnikov addition products were
reliably obtained. Among other functionality, highly substituted
β-alkoxy- or β-aminocarbonyl motifs may be accessed using this
methodology. The reaction is operationally facile to execute, and
its mild reaction conditions tolerate a wide variety of
functionality. Given its orthogonality to traditional carbon−
carbon bond-forming processes, such as Pd-catalyzed cross-
coupling and Michael additions, this methodology may be
particularly useful for the parallel synthesis of compound libraries
and generally useful to the synthetic community as a whole.
Scheme 4. Proposed Mechanism for the Photoredox-
Catalyzed Anti-Michael Addition
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01712.
Experimental procedures and spectral data (PDF)
of Boc-protected proline (2) with an olefin 10 to form adduct 11
using photoredox catalyst 1. Upon activation of 1 with blue LED
light to excited-state species 12, base-mediated decarboxylative
single-electron oxidation affords radical 13 and reduced Ir species
14. Reversible addition18,19 of radical 13 to acceptor 10 gives rise
to two possible regioisomers, 15 or 16. Formation of the α-
coupled product 15 should be thermodynamically preferred
owing to benzylic radical stabilization, which cannot occur in
regioisomer 16. This radical stabilization biases against addition
of the nucleophilic radical species to the more electrophilic
position of the olefin. Single-electron reduction and protonation
of 15 affords product 11 and regenerates the ground-state Ir
catalyst 1, completing the photoredox cycle.
To further illustrate the value of this methodology, we
performed a 2-step synthesis of encainide (17), a discontinued
class Ic antiarrhythmic agent (Scheme 5).20 Acylation of 2-
vinylaniline (18) with 4-anisoyl chloride (19) gave radical
addition precursor 20. Without any modifications to our
photoredox coupling protocol, we obtained encainide in 70%
yield through the coupling of N-methyl DL-pipecolic acid (21)
with 20. Considering that three steps of the four total utilized in
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: brian.sparling@amgen.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge support from the Amgen Internship Program.
We thank Paul Krolikowski (Amgen) and Lincoln Ombelets
(Amgen) for assistance with NMR spectroscopic studies. We
thank Justin Malinowski (Amgen), Erin DiMauro (Amgen), Ben
Milgram (Amgen), and James Harvey (Amgen) for insightful
discussions.
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