β-Selective Aroylation of Activated Alkenes by Photoredox Catalysis

Article abstract of DOI:10.1002/anie.201901874

Late-stage synthesis of α,β-unsaturated aryl ketones remains an unmet challenge in organic synthesis. Reported herein is a photocatalytic non-chain-radical aroyl chlorination of alkenes by a 1,3-chlorine atom shift to form β-chloroketones as masked enones

Full text of DOI:10.1002/anie.201901874

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International Edition: DOI: 10.1002/anie.201901874
German Edition: DOI: 10.1002/ange.201901874
Photochemistry
b-Selective Aroylation of Activated Alkenes by Photoredox Catalysis
Zhen Lei+, Arghya Banerjee+, Elena Kusevska, Eric Rizzo, Peng Liu,* and Ming-Yu Ngai*
Abstract: Late-stage synthesis of a,b-unsaturated aryl ketones
remains an unmet challenge in organic synthesis. Reported
herein is a photocatalytic non-chain-radical aroyl chlorination
of alkenes by a 1,3-chlorine atom shift to form b-chloroketones
as masked enones that liberate the desired enones upon
workup. This strategy suppresses side reactions of the enone
products. The reaction tolerates a wide array of functional
groups and complex molecules including derivatives of
peptides, sugars, natural products, nucleosides, and marketed
drugs. Notably, addition of 2,6-di-tert-butyl-4-methyl-pyridine
enhances the quantum yield and efficiency of the cross-
coupling reaction. Experimental and computational studies
suggest a mechanism involving PCET, formation and reaction
of an a-chloro-a-hydroxy benzyl radical, and 1,3-chlorine
atom shift.
recent years.[10] Although these elegant approaches have
provided access to a range of simple a,b-unsaturated aryl
ketones, the development of mild and general catalytic
methods for late-stage synthesis of this important pharmaco-
phore remains a significant challenge in organic synthesis. To
address this unmet need, we examined photoredox-catalyzed
acyl radical chemistry,[11–13] in which photocatalytically gen-
2
À
erated aroyl radicals can react with olefins to form a C(sp )
C(sp3) bond and alkyl radical intermediates.[14] Direct oxida-
tion of these alkyl radicals by photoredox catalysts to the
corresponding cations followed by deprotonation to afford
a,b-unsaturated carbonyls is feasible in view of their electro-
chemical character.[15] However, both the efficiency and
generality of such an approach are limited because i) the
enone products, especially the b-monosubstituted enones, are
susceptible to a second radical addition of nucleophilic aroyl
radicals, forming doubly aroylated side products, and ii) the
a,b-unsaturated carbonyl products can undergo E/Z isomeri-
zation,[16] [2+2]-dimerization, and cross-[2+2] cycloaddition
with alkenes[17] by a photocatalytic energy-transfer mecha-
nism. We questioned whether these challenges could be
addressed by minimizing the amount of enones generated in
the reaction mixture through producing masked enones, for
example, b-chloroketones (Scheme 1).[18] We envisioned that
direct aroyl chlorination of alkenes using readily available
aroyl chlorides[19] should give the desired masked enones,
which then would undergo HCl elimination upon workup to
liberate a,b-unsaturated aryl ketone products.[20] This formal
À
L
ate-stage C H functionalization of biorelevant molecules
is a powerful strategy for the discovery of novel functional
molecules because it avoids laborious de novo synthesis of
new analogues, increases the efficiency of structure–activity
relationship studies, and produces promising new candidates
that might have never been evaluated otherwise.[1] Thus,
establishment of new methodologies that introduce useful
pharmacophores such as a,b-unsaturated aryl ketones at late
stages of a synthesis is highly desirable. Aryl vinyl ketones are
key components of synthetic building blocks, natural prod-
ucts, and pharmaceuticals and have important anticancer,
antimicrobial, anti-inflammatory, and immunosuppressive
activities.[2] Consequently, in addition to the conventional
stoichiometric reactions,[3] a range of catalytic intermolecular
strategies for the preparation of aryl enones, such as cross-
metathesis reactions,[4] transition metal catalyzed hydroacy-
lation of alkynes,[5] copper-catalyzed dehydrogenative cross-
coupling reactions,[6] palladium-catalyzed carbonylation reac-
tions,[7] NHC-catalyzed (NHC = N-heterocyclic carbene) ole-
fination of aldehydes using vinyliodonium salts,[8] and photo-
catalytic coupling reactions of a-keto-carboxylic acids and
styrenes in the presence of a stoichiometric amount of
SelectFluorTM, a strong oxidant,[9] have been developed in
À
b-selective alkenyl C H aroylation strategy is appealing
because it obviates the use of stoichiometric quantities of
strong oxidants such as SelectFluor[9] and eliminates the need
[*] Z. Lei,[+] A. Banerjee,[+] E. Rizzo, Prof. M.-Y. Ngai
Department of Chemistry and Institute of Chemical Biology and Drug
Discovery, The State University of New York at Stony Brook
Stony Brook, NY 11794 (USA)
E-mail: ming-yu.ngai@stonybrook.edu
E. Kusevska, Prof. P. Liu
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260 (USA)
E-mail: pengliu@pitt.edu
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201901874.
Scheme 1. Photocatalytic b-aroylation of activated alkenes. BT=Bacca-
tin.
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Table 1: Selected examples of the coupling reaction between aroyl chlorides and alkenes.[a]
[a] Cited yields and E/Z ratios (within parentheses) are those of the isolated material. Ac=acetyl, Boc=tert-butyloxycarbonyl, B1 =2-trifluorobenzoyl,
B2 =4-chlorobenzoyl, Bz=benzoyl, DE=1,1-diphenylethylenyl, Py=pyridyl, TES=triethylsilyl, Pr=n-propyl, 2-6-ditBu-4-MePy=2,6-di-tert-butyl-4-
methyl-pyridine.
for prefunctionalization of the alkenes. As a result, it will
allow direct incorporation of the aroyl group at any time
during the target synthesis. Herein, we report i) the successful
development of a mild photocatalytic protocol that enables
late-stage synthesis of a,b-unsaturated aryl ketones from
aroyl chlorides and alkenes, ii) unprecedented effects of 2,6-
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di-tert-butyl-4-methyl-pyridine additive on the reaction effi-
sugars, natural products, nucleosides, and marketed drugs
ciency and quantum yield, and iii) a novel reaction mecha-
nism of aroyl chlorination of alkenes.
bearing functional groups such as free hydroxy groups,
tertiary amines, alkyl alkenes, acetal and triethylsilyl protect-
ing groups, oxetane, ketones, and heteroaromatics were
successfully aroylated to afford the desired products (4ae–
al) in 48–80% yields and with excellent levels of chemo-,
regio-, and diastereoselectivity. It is noteworthy that prepa-
ration of these complex aryl enones by the cross-metathesis
protocol is challenging because of i) the instability and limited
availability of aryl vinyl ketones and ii) the difficulty in
distinguishing between two different terminal alkenes (4ak).
Thus, our strategy is complementary to the cross-metathesis.
To illustrate the synthetic utility of the enone products for
preparation of useful molecular scaffolds, we derivatized the
products under various reaction conditions (Scheme 2).
After a systematic variation of different reaction param-
eters, such as additives, solvents, photoredox catalysts,
concentrations, and stoichiometries, we were pleased to
identify optimal reaction conditions in which a mixture of 4-
fluorobenzoyl chloride (1b, 1.50 equiv), 1,1-diphenyl-ethyl-
ene (2am, 1.00 equiv), fac-Ir(ppy)3 {fac-tris[2-phenylpyridi-
nato-C2,N]iridium(III), 1.00 mol%}, and 2,6-di-tert-butyl-4-
methyl-pyridine (1.20 equiv) in CHCl3 (0.100m) at 238C with
irradiation by a blue LED light for 16 hours afforded the
desired product 3b in 85% yield upon isolation (Table 1).[21]
Although aliphatic acyl chlorides failed to react under these
reaction conditions, a diverse set of aroyl chlorides was
successfully coupled to afford the desired enone products
(Table 1a). For example, electron-neutral (1a, 1r–s), elec-
tron-rich (1j–m), and electron-poor (1i, 1n–q) aroyl chlorides
reacted well under these reaction conditions, affording the
desired enones in 46–96% yields. Different halogen function-
alities (1b–h), in particular, Br and I, survived the reaction,
and provide synthetic handles for further structural elabo-
ration through metal-catalyzed coupling reactions. The reac-
tion tolerated o-, m-, and p-substituted aroyl chlorides (1d–f).
Substrates bearing extended p-systems (1r, 1s) and hetero-
arenes such as thiophene (1t) and furan (1u) reacted
smoothly, providing the desired products in 55–89% yields.
We next directed our attention to examine the scope with
respect to the alkenes and found that a wide range of mono-
and disubstituted alkenes participate in this coupling reaction,
affording the desired enones in modest to good yields
(Table 1b). For example, various styrenes, regardless of
their electronics (2a–h, 2m–t, 2v, 2x, 2aa), were viable
substrates. Alkenes substituted with biologically important
heteroarenes such as thiophene (2i), thiazole (2j), quinoline
(2k), furan (2l), pyridine (2r–s), benzofuran (2r), and indole
(2s) were compatible under the optimized reaction condi-
tions. Both 1,2- and 1,1-disubstituted (hetero)aryl alkenes
(2m–t, 2v) reacted to give the desired trisubstituted enones in
yields of 51–82%. The E and Z diastereoselectivity of the
resulting enones is determined by the sterics of the alkene
substituents. While alkenes with sterically distinct substitu-
ents afforded one diastereomer (2n, 2t) exclusively, alkenes
with substituents of similar sizes gave a mixture of diastereo-
mers (1–1.3:1, 2o–s). Most of the monosubstituted alkenes
afforded the desired products as a single diastereomer.
Although aliphatic alkenes afforded only trace amounts of
the desired products, our method was successfully applied to
other alkene derivatives such as an enyne (2u), a diene (2v),
mono- and disubstituted a,b-unsaturated esters (2w–aa),
acyclic (2ab) and cyclic (2ac) enones, and acrylonitrile
(2ad) to furnish the corresponding products in 43–89%
yields. More importantly, the protocol allows straightforward
and selective syntheses of molecular scaffolds (e.g., 4m, 4n,
4t, 4v, 4ac) that are otherwise difficult to access.
Scheme 2. Synthetic utility of the enone products. M.S.=molecular
sieves, THF=tetrahydrofuran.
Treatment of 4t, an enone derivative that is difficult to
prepare otherwise, with the Febuxostat-derivative 5 under
Suzuki coupling reaction conditions afforded the desired
product 6 in 43% yield with 2:1 E/Z ratio. Under redox
annulation reaction conditions, the chalcone 4a’ coupled with
pyrrolidine and tetrahydroisoquinoline, forming the cyclic
amines 7 and 8, respectively, in modest yields.[22] The enone
4m underwent epoxidation smoothly to afford the desired
product 9 in 78% yield.
It is noteworthy that the 2,6-di-tert-butyl-4-methyl-pyri-
dine additive is critical for the success of the reaction. We
conducted a series of experiments to understand the role of
2,6-di-tert-butyl-4-methyl-pyridine additive. First, Stern–
Volmer experiments revealed that aroyl chlorides quench
excited fac-*Ir(ppy)3 photocatalysts but alkenes and 2,6-di-
tert-butyl-4-methyl-pyridine do not. Interestingly, the pres-
ence of 2,6-di-tert-butyl-4-methyl-pyridine enhanced the
quenching constant of aroyl chlorides from 9.89 ꢀ 108 mÀ1 sÀ1
To demonstrate the amenability of the photocatalytic
alkene aroylation process to late-stage synthetic applications,
drug-like molecules were subjected to the standard reaction
conditions (Table 1c). For example, derivatives of peptides,
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to 1.29 ꢀ 109 mÀ1 sÀ1 (see Figure S1 in the Supporting Informa-
tion). In addition, TEMPO [(2,2,6,6-Tetramethylpiperidin-1-
yl)oxyl] trapping experiments demonstrated that a 2,6-di-tert-
butyl-4-methyl-pyridine additive increased the yield of the
benzoyl-TEMPO adduct from 53 to 96%. These observations
suggested that the reaction proceeds through a radical
mechanism and the additive promotes the formation of the
aroyl radicals (Scheme 3a). We also noticed that the steric
bulk at the 2,6-position of pyridine is crucial in obtaining high
yields and no desired product was observed by using 4-
methylpyridine as the additive (Scheme 3b). 1H NMR studies
showed a significant downfield shift of 4-methylpyridine
protons after the addition of the aroyl chloride 1q, indicating
the formation of the aroyl pyridinium salt 10 (see Figure S3).
the corresponding *Py-HCl salt.[23] This salt may act as
a Brønsted acid catalyst and facilitate the generation of the a-
chloro-a-hydroxybenzyl radical by a proton-coupled elec-
tron-transfer (PCET) mechanism.[24] Indeed, the addition of
0.05 equivalents of *Py-HCl salt and a mixture of *Py/*Py-
HCl (1.15/0.05 equiv) improved the product yield from 42 to
70 and 94% (Scheme 3c, entries 1, 3, and 4), respectively,[25]
demonstrating the feasibility of the PCET reaction pathway.
Furthermore, the quantum yield of the reaction was increased
from 0.19 to 0.66 by the addition of the 2,6-di-tert-butyl-4-
methyl-pyridine additive (Scheme 3d).[11d,26] Since the quan-
tum yield is lower than 1, an extended radical-chain reaction
mechanism is unlikely, and correlates with light ON/OFF
experiments (see Figure S6).
1
Once 10 was formed, the H NMR of the reaction mixture
Detailed DFT calculations provided additional insights
into the reaction mechanism (Scheme 3e). First of all, the
proposed PCET step to form the a-chloro-a-hydroxybenzyl
radical Ib is thermodynamically favorable.[27] Notably, instead
of undergoing HCl elimination to give the benzoyl radical Ic’,
the radical Ib reacts with styrene to form the benzyl radical Ic.
In addition, while an intermolecular oxidation of Ic by
remained unchanged even after irradiation with blue LEDs
for 16 hours. Thus, these results rule out the aroyl chloride
activation by the formation of aroyl pyridinium salts. Notably,
the addition of 2,6-di-tert-butyl-4-methyl-pyridine increased
both the product yield (4d’ and 4d) and the ratio of the
product distribution (Scheme 3c, entries 1 and 2), favoring
the formation of the chloro product 4d’. These observations
implied that the 2,6-di-tert-butyl-4-methyl-pyridine (*Py)
additive serves as more than just a base. Although the exact
role of the 2,6-di-tert-butyl-4-methyl-pyridine requires further
studies, we speculated that a small amount of HCl formed in
the reaction mixture protonates the pyridine additive to give
+
Ir(ppy)3 to form the benzylic cation Id’ is an endergonic
process, an intramolecular 1,3-chlorine atom shift[28] to
produce Id is an exergonic reaction. Subsequent single-
electron oxidation of Id by Ir(ppy)3+ and deprotonation of Ie
are both highly exothermic.
Scheme 3. Mechanistic studies. All energies are Gibbs free energies in kcalmolÀ1 computed at the M06-2X/6–311+G(d,p)/SMD(CHCl3)//M06-
2X/6–31+G(d)/SMD(CHCl3) level of theory using benzoyl chloride and styrene as substrates. [a] Yields within the parentheses are those of the
corresponding enone formed in the reaction mixture. See the Supporting Information for details.
4
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Based on these experimental and computational studies,
comments and suggestions provided by the referees. Calcu-
a plausible reaction mechanism is depicted in Scheme 4.
Photoexcitation of the photocatalyst Ir(ppy)3 produces the
long-lived excited *Ir(ppy)3 (t1/2 = 1.9 ms, E1/2IV/III* = À1.73 V
lations were performed at the Center for Research Comput-
ing at the University of Pittsburgh.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkenes · aroylation · photochemistry · radicals ·
synthetic methods
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Scheme 4. Proposed reaction mechanism.
vs. SCE).[29] In the presence of 2,6-di-tert-butyl-4-methyl-
pyridinium species, the aroyl chloride IIa (Ep of benzoyl
chloride = À1.02 V vs. SCE)[19b] undergoes a PCET process
with *Ir(ppy)3 to liberate 2,6-di-tert-butyl-4-methyl-pyridine
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+
radical IId. Single-electron oxidation of IId by Ir(ppy)3
followed by deprotonation regenerates the ground state
Ir(ppy)3 and affords the desired b-chloro-ketone IIe, which
delivers the final enone upon workup.
In conclusion, we have developed a photocatalytic b-
selective alkene aroylation using readily available aroyl
chlorides and activated alkenes. The synthetic utility of the
reaction is highlighted by its broad functional-group compat-
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reaction is amenable to late-stage functionalization of com-
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natural products, nucleosides, and commercially available
drugs. Notably, 2,6-di-tert-butyl-4-methyl-pyridine additive
serves more than a base, it also promotes electron transfer,
increases quantum yields, and enhances the reaction effi-
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involving PCET, formation and reaction of an a-chloro-a-
hydroxy benzyl radical, and 1,3-chlorine atom shift is
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Xu, J.-Q. Chen, D. Liu, Y. Bao, Y.-M. Liang, P.-F. Xu, Org. Chem.
Front. 2017, 4, 1331; c) Y. Liu, Q.-L. Wang, C.-S. Zhou, B.-Q.
Xiong, P.-L. Zhang, C.-a. Yang, K.-W. Tang, J. Org. Chem. 2018,
83, 2210; d) C. M. Wang, D. Song, P. J. Xia, J. Wang, H. Y. Xiang,
H. Yang, Chem. Asian J. 2018, 13, 271.
[20] Noncatalyzed coupling of aroyl chlorides and activated alkenes
is feasible at about 2008C, but it suffers from limited substrate
scope and low product yield. F. Bergmann, S. Israelashvili, D.
Gottlieb, J. Chem. Soc. 1952, 2522.
[27] DFT calculations showed that DG of the direct SET and the
PCET pathways are À0.4 kcalmolÀ1 and À10.1 kcalmolÀ1
,
respectively. These data suggest the favorability of the PCET
mechanism as compared to the direct SET pathway.
[28] a) B. J. Walker, P. J. Wrobel, J. Chem. Soc. Chem. Commun.
1980, 462; b) J. L. Adcock, H. Luo, J. Org. Chem. 1993, 58, 1704;
c) S.-C. Lu, W.-X. Wang, P.-L. Gao, W. Zhang, Z.-F. Tu, Org.
Biomol. Chem. 2012, 10, 232.
[29] L. Flamigni, A. Barbieri, C. Sabatini, B. Ventura, F. Barigelletti,
Top. Curr. Chem. 2007, 281, 143.
[21] See the Supporting Information for detailed optimization tables.
[22] Y. Kang, M. T. Richers, C. H. Sawicki, D. Seidel, Chem.
Commun. 2015, 51, 10648.
[23] There are several potential pathways of generating HCl in the
reaction mixture that lead to formation of pyridinium HCl salts.
First, the CHCl3 solvent contains ethanol (0.33 wt%) as
a stabilizer, which may react with benzoyl chloride to form
Manuscript received: February 12, 2019
Revised manuscript received: March 18, 2019
Version of record online: && &&, &&&&
6
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ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2019, 58, 1 – 7
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Angewandte
Communications
Chemie
Communications
Photochemistry
Z. Lei, A. Banerjee, E. Kusevska, E. Rizzo,
P. Liu,* M.-Y. Ngai*
&&&& — &&&&
b-Selective Aroylation of Activated
Alkenes by Photoredox Catalysis
Compatible: A photocatalytic b-selective
alkene aroylation, using readily available
aroyl chlorides and activated alkenes, was
developed. The synthetic utility of the
reaction is highlighted by its broad func-
tional-group compatibility and high levels
of chemo- and regioselectivity. The reac-
tion is amenable to late-stage function-
alization of complex molecules including
derivatives of sugars, peptides, natural
products, nucleosides, and commercially
available drugs.
Angew. Chem. Int. Ed. 2019, 58, 1 – 7
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!