Catalytic Generation and Use of Ketyl Radical from Unactivated Aliphatic Carbonyl Compounds

Article abstract of DOI:10.1021/acs.orglett.9b04235

Generation of a ketyl radical from unactivated aliphatic carbonyl compounds is an important strategy in organic synthesis. Herein, catalytic generation and use of a ketyl radical for the reductive coupling of aliphatic carbonyl compounds and styrenes by organic photoredox catalysis is described. The method is applicable to both aliphatic ketones and aldehydes to afford the corresponding tertiary and secondary alcohols in continuous flow and batch. Preliminary mechanistic investigation suggests the catalytic formation of a ketyl radical intermediate.

Full text of DOI:10.1021/acs.orglett.9b04235

This is an open access article published under a Creative Commons Attribution (CC-BY)
License, which permits unrestricted use, distribution and reproduction in any medium,
provided the author and source are cited.
Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Generation and Use of Ketyl Radical from Unactivated
Aliphatic Carbonyl Compounds
Hyowon Seo† and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139,
United States
S
* Supporting Information
ABSTRACT: Generation of a ketyl radical from unactivated
aliphatic carbonyl compounds is an important strategy in
organic synthesis. Herein, catalytic generation and use of a
ketyl radical for the reductive coupling of aliphatic carbonyl
compounds and styrenes by organic photoredox catalysis is
described. The method is applicable to both aliphatic ketones
and aldehydes to afford the corresponding tertiary and
secondary alcohols in continuous flow and batch. Preliminary
mechanistic investigation suggests the catalytic formation of a ketyl radical intermediate.
he formation of ketyl radicals from unactivated aliphatic
carbonyl compounds is an important strategy to generate
Scheme 1. Generation of Ketyl Radical and Reductive
Coupling of Unactivated Aliphatic Carbonyl Compounds
with Unsaturated Systems
T
carbon−carbon bonds between carbonyl carbons and unsatu-
rated systems.1 Classical protocols using either strongly
reducing agents, such as samarium diiodide (SmI2), or
dissolving metals, such as sodium and potassium in liquid
ammonia, allow access to ketyl radical species and thus enable
reductive coupling between unactivated aliphatic carbonyl
compounds and unsaturated systems (Scheme 1A).2−4
Although these methodologies have enabled invaluable trans-
formations, the reaction conditions necessitate rigorous
laboratory techniques for handling those air- and moisture-
sensitive metals. Green chemistry goals require catalytic and
inherently safer chemistry for accident prevention. Despite the
need for the development of catalytic, inexpensive, and metal-
free methods to replace such potentially dangerous or rare
earth metal requiring methods, recent methodologies are
mostly applicable to aromatic aldehydes5,6 including photo-
redox catalytic approaches.7−16 The major challenge to
reduction of unactivated carbonyl compounds is the standard
reduction potentials, which are typically lower than −2 V
versus SCE (e.g., cyclohexanone E1/2 = −2.78 V vs SCE and 3-
methylbutyraldehyde E1/2 = −2.63 V vs SCE calculated using
B3LYP)17 and the discrepancy in reduction potential between
aliphatic carbonyl compounds and established visible-light
photoredox catalysts (i.e., tris[2-phenylpyridinato-C2,N]-
iridium(III) [Ir(ppy)3] Ered
= −2.19 V vs SCE in
1/2
acetonitrile).18−20
Cossy21 and Hasegawa22 independently reported light-
mediated intramolecular cyclizations of unactivated ketones
and unsaturated systems. However, these methods are limited
to specific examples such as the fastest 5-exo intramolecular
cyclizations. In 2018, Nagib and co-workers reported the
photoredox catalyzed generation of ketyl radicals from
aliphatic aldehydes and their coupling with unsaturated
systems via in situ activation using acetyl iodide in the
presence of catalytic amounts of Zn(OTf)2 and Mn2(CO)10 as
a photoredox catalyst (Scheme 1B).23 They demonstrated
further application of their method to aliphatic ketones and
showed two coupling examples using trifluoroacetone.
Received: November 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04235
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In the ketyl radical based strategies illustrated in Scheme 1A
and 1B, catalytic intermolecular coupling of aliphatic ketones
and unsaturated systems remained a considerable challenge
despite the similar reduction potentials of aliphatic aldehydes
and ketones.17 Herein, we overcome this challenge by using
strongly reducing organic photoredox catalysis under protic
conditions. In particular, we demonstrate the metal-free
reductive coupling of unactivated aliphatic ketones and
aldehydes with styrenes under continuous flow and batch
conditions (Scheme 1C).
Scheme 2. Scope of the Coupling Reaction Between
Aliphatic Ketones and Styrenes
a
As shown in Table 1, we began our studies by examining the
coupling of styrene (1) and tetrahydro-4H-pyran-4-one (2) in
Table 1. Reductive Coupling of Aliphatic Carbonyl
Compounds and Styrenes in Batch and Continuous Flow
a
b
entry
conditions
Standard conditions in flow
PMP in DMF/hexanes (2:1) instead of PMP-4-OH
in DMA
yield of 3 (%)
1
2
99
68
3
4
Standard conditions in batch, 35 min
Standard conditions in batch, 2 h
94
99
a
Reactions were carried out using a continuous-flow photochemical
system developed by Beeler.26 Calculated by gas chromatography
b
(GC) analysis using methyl benzoate as an internal standard.
the presence of p-terphenyl (20 mol %) as an organic
photoredox catalyst and 1,2,2,6,6-pentamethyl-4-piperidinol
(PMP-4-OH) in dimethylacetamide (DMA). The reaction was
performed in a continuous flow photochemistry system
(Figure S1) with a 2.7 mL reactor volume using 0.04 i.d.
perfluoroalkoxy (PFA) tubing equipped with a UV lamp and a
long-pass filter (λ > 280 nm). After a 35 min residence time,
GC analysis revealed quantitative formation of the desired
coupled product 3 (99%, Table 1, entry 1). Previously, we
reported β-selective hydrocarboxylation using carbon dioxide
via p-terphenyl photoredox catalysis in the presence of
1,2,2,6,6-pentamethylpiperidine (PMP) as a reductant in
dimethylformamide (DMF) and hexanes.24,25 Application of
those conditions to the coupling of 1 and 2 only provided 68%
of 3 (entry 2). Notably, use of conditions in entry 1 enables
the transformation to be carried out in a continuous flow
system without clogging in the absence of a nonpolar cosolvent
(i.e., hexanes) that was included to dissolve nonpolar
byproducts (e.g., dimer of PMP) under our previously
reported PMP/DMF condition.25 As shown in entries 3 and
4, we also conducted the coupling of 1 and 2 in batch (Figure
S2) but under otherwise identical conditions to entry 1 and
obtained a comparable yield of 3 after 35 min (94%, entry 3)
and quantitative yield after 2 h (entry 4).
a
b
c
Isolated yield of the coupling product. tR = 17 min. tR = 30 min.
flow (35 min) in moderate to excellent yields. Cyclic ketones
that were six-membered (3−5), four-membered (6), five-
membered (7), and seven-membered (8), as well as bicyclic
ring structures (9), were tolerated in moderate to excellent
yields. Notably, trans-product 5 from 4-tert-butyl cyclo-
hexanone and exo-product 9 from N-Boc-nortropinone were
obtained. Linear ketones provided coupled products in
moderate yields (10−13). Acetone could be coupled with
styrene derivatives in moderate to good yields (14−16).
Ketones containing γ,δ-unsaturation provided the desired
coupled products in moderate yield (17 and 18) without
observations of rearranged byproducts. Nabumetone, a
marketed nonsteroidal anti-inflammatory drug (NSAID), was
derivatized to provide 19 in 55% yield. We hypothesized that
subsequent ring closing would occur with 5-chloropent-2-one.
Accordingly, the substituted tetrahydrofuran 20 was obtained
as a single product in 53% yield. Although higher frequencies
of light (λ > 280 nm) were removed by an optical filter,
Norrish type fragmentations27,28 were unavoidable with certain
substrates. As exemplified in compound 21, a ketone
We subsequently examined the scope of the coupling
reaction between aliphatic ketones and styrenes under batch
and continuous flow conditions as illustrated in Scheme 2. The
reaction provided the desired tertiary alcohol products with
complete linear selectivity in both batch (2 h) and continuous
B
DOI: 10.1021/acs.orglett.9b04235
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
containing a tertiary γ-hydrogen underwent the coupling to
provide the desired product 21a in 38% yield with α,β-cleaved
product 21b (18% yield) that was produced by Norrish type II
fragmentation. Norrish type I fragmentation was also observed
when using an α-tertiary carbonyl. Utilizing 3-methyl-2-
butanone, the desired coupled product 22a was obtained in
16% yield along with α-carbon cleavage product 22b in 31%
yield. Unfortunately, α-quaternary carbonyl and α-phenyl
carbonyl compounds did not provide any product under the
current optimized conditions. Selected batch reactions were
also performed to compare yields. Batch yields were lower (5,
8, 11, 14, and 17) or comparable (3 and 7) to those in flow.
A range of electron-rich and electron-neutral substituents on
styrene were tolerated including protected amines (15),
protected alcohols (6, 8, 12, and 16), fluorine (17), and
alkyl chains (5 and 7) (Scheme 2). Styrenes with extended
conjugation (e.g., 4-vinyl biphenyl) or electron-withdrawing
substituents did not provide the desired coupled products. We
observed reduced styrene as the major byproducts in these
reactions which suggests that the reduction of styrene
derivatives under photoredox catalysis may not induce the
desired coupling (vide infra).
ketone and amine under UV irradiation is not likely (Scheme
4A). Second, in the absence of PMP-4-OH under otherwise
optimized conditions, no product was observed, highlighting
its crucial role in the net reductive reaction.
Scheme 4. Preliminary Mechanistic Investigations
We next evaluated unactivated aliphatic aldehydes to afford
secondary alcohol products (Scheme 3). The corresponding
Scheme 3. Scope of the Coupling Reaction Between
a
Aliphatic Aldehydes and Styrenes
Considering the reduction potentials of styrene derivatives
(e.g., styrene E1/2 = −2.58 V vs SCE in DMF)29 and aliphatic
ketones (e.g., cyclohexanone E1/2 = −2.78 V vs SCE),17 both
species can be reduced under the p-terphenyl catalytic system
(E0 = −2.63 V vs SCE in DMF).30 To probe the formation of a
ketyl radical intermediate in the reaction, we conducted a
radical clock experiment using cyclopropyl methyl ketone
(31), although its reduction potential (E0 = −3.38 V vs SCE
derived from Marcus theory)31 is out of the range of the p-
terphenyl catalytic system (Scheme 4B). Nevertheless, we
obtained the rearranged product 32 in 34% yield, while the
closed cyclopropyl ring product was not detected by GCMS.
This result suggests that the ketyl radical intermediate is
involved in the mechanism. The discrepancy between the
reduction potentials of certain unactivated carbonyl com-
pounds and the p-terphenyl catalyst can be attributed to the
protic conditions of our protocol. Based on literature
reports,11,32 the reduction of carbonyl compounds in protic
media occurs at less negative potentials than in aprotic solvents
due to protonation, leading to the protonation of the primary
carbonyl radical anion and a σ-radical located at the carbon
atom in slightly protic organic solvents. We hypothesize that
a
b
Isolated yield of the coupling product. 4 equiv of acetaldehyde were
used.
linear coupled products 23−25 with 4-vinylanisole were
produced in 17 min of residence time. Acetaldehyde also
underwent the desired coupling to provide 26 in 65% yield. 10-
Undecenal containing a distal double bond was tolerated to
provide 27 in 56% yield without detection of rearranged
products under radical conditions. Hex-5-ynal provided a
moderate yield of the desired product 28. 2-Methylbutanal also
underwent the desired transformation to give 29 in 38% yield.
Selected batch reactions to afford 24, 26, and 28 provided
lower yields (18−23%) compared to the corresponding
continuous flow reactions.
Preliminary investigations have provided some insight into
the mechanism of the reaction. First, control experiments
conducted in the absence of p-terphenyl did not provide any
product, indicating that the direct charge transfer between
C
DOI: 10.1021/acs.orglett.9b04235
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the reduction of unactivated carbonyl compounds by p-
terphenyl catalysis is modulated by the presence of both PMP-
4-OH and water in the reaction medium.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04235.
Next, we tested the more conjugated 4-vinyl biphenyl (33,
E
p/2 = −2.26 V vs SCE in DMF, Figure S3) which should lead
to the reduction of 4-vinyl biphenyl (33) over the cyclo-
hexanone (34, E1/2 = −2.78 V vs SCE calculated using
B3LYP)17 under photoredox catalysis (Scheme 4C). Since the
product we observed was 4-ethyl biphenyl (35) in 15% yield,
the single-electron reduction of styrene followed by
nucleophilic attack at the carbonyl appears less likely.
Lastly, we investigated the competition experiment between
the intermolecular addition to styrene and 5-exo cyclization
using hex-5-enal (36) (Scheme 4D). The exclusive formation
of the rearranged product 37 indicates that 5-exo cyclization
outcompetes the intermolecular addition to styrene. This
rearranged product provides indirect evidence of the formation
of a radical intermediate derived from the carbonyl group.
Although further mechanistic studies are warranted, we
propose the catalytic mechanism summarized in Scheme 5.
Experimental details and compound characterizations
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tfj@mit.edu.
ORCID
Hyowon Seo: 0000-0002-9569-1902
Timothy F. Jamison: 0000-0002-8601-7799
Present Address
†Department of Chemical Engineering, Massachusetts Institute
of Technology, 77 Massachusetts Ave., Cambridge, MA 02139
(USA)
Scheme 5. Proposed Mechanism
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Bill and Melinda Gates
Foundation. H.S. thanks Amgen Graduate Fellowship in
Synthetic Chemistry. We thank Rachel L Beingessner (MIT)
for her advice and support.
REFERENCES
■
(1) Hart, D. J. Free-Radical Carbon-Carbon Bond Formation in
Organic Synthesis. Science 1984, 223, 883−887.
(2) Kahn, B. E.; Rieke, R. D. Carbonyl Coupling Reactions Using
Transition Metals, Lanthanides, and Actinides. Chem. Rev. 1988, 88,
733−745.
(3) McMurry, J. E. Carbonyl-Coupling Reactions Using Low-Valent
Titanium. Chem. Rev. 1989, 89, 1513−1524.
Photoexcitation of the organic photoredox catalyst, p-terphenyl
(PTP), produces the excited singlet state of p-terphenyl
(PTP*),30 which undergoes single-electron transfer (SET)
with the reductant, PMP-4-OH, to generate the strong
reducing p-terphenyl radical anion (PTP•−) and the PMP-4-
OH radical cation (Photoredox catalytic cycle A). The p-
terphenyl radical anion (PTP•−) would reduce carbonyl to a
ketyl radical in protic media. The ketyl radical then adds to the
β-position of styrene and produces a stable benzylic radical
intermediate which is further reduced to a benzylic anion by
photoredox catalytic cycle B.25 Finally, the styrene-carbonyl
coupled product is formed by a protonation of the benzylic
anion. The reactive PMP-4-OH radical cation is quenched by
dimerization after the deprotonation (compounds S2; see
Supporting Information).
In summary, metal-free reductive coupling of aliphatic
carbonyl compounds and styrenes was developed using p-
terphenyl photoredox catalysis in both batch and continuous
flow. This method has been shown to be compatible with a
range of ketone and aldehyde derivatives with electron-rich
and -neutral styrenes. Preliminary mechanistic investigations
suggest the catalytic formation of a ketyl radical to enable the
desired coupling.
(4) Szostak, M.; Fazakerley, N. J.; Parmar, D.; Procter, D. J. Cross-
Coupling Reactions Using Samarium(II) Iodide. Chem. Rev. 2014,
114, 5959−6039.
(5) Nguyen, K. D.; Park, B. Y.; Luong, T.; Sato, H.; Garza, V. J.;
Krische, M. J. Metal-Catalyzed Reductive Coupling of Olefin-Derived
Nucleophiles: Reinventing Carbonyl Addition. Science 2016, 354,
aah5133.
(6) Zheng, Y.-L.; Liu, Y.-Y.; Wu, Y.-M.; Wang, Y.-X.; Lin, Y.-T.; Ye,
M. Iron-Catalyzed Regioselective Transfer Hydrogenative Couplings
of Unactivated Aldehydes with Simple Alkenes. Angew. Chem., Int. Ed.
2016, 55, 6315−6318.
(7) Ischay, M. A.; Anzovino, M. E.; Du, J.; Yoon, T. P. Efficient
Visible Light Photocatalysis of [2 + 2] Enone Cycloadditions. J. Am.
Chem. Soc. 2008, 130, 12886−12887.
(8) Tarantino, K. T.; Liu, P.; Knowles, R. R. Catalytic Ketyl-Olefin
Cyclizations Enabled by Proton-Coupled Electron Transfer. J. Am.
Chem. Soc. 2013, 135, 10022−10025.
(9) Du, J.; Skubi, K. L.; Schultz, D. M.; Yoon, T. P. A Dual-Catalysis
Approach to Enantioselective [2 + 2] Photocycloadditions Using
Visible Light. Science 2014, 344, 392−396.
(10) Lee, K. N.; Ngai, M.-Y. Recent Developments in Transition-
Metal Photoredox-Catalysed Reactions of Carbonyl Derivatives.
Chem. Commun. 2017, 53, 13093−13112.
(11) Nakajima, M.; Fava, E.; Loescher, S.; Jiang, Z.; Rueping, M.
Photoredox-Catalyzed Reductive Coupling of Aldehydes, Ketones,
and Imines with Visible Light. Angew. Chem., Int. Ed. 2015, 54, 8828−
8832.
D
DOI: 10.1021/acs.orglett.9b04235
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
̈
(12) Berger, A. L.; Donabauer, K.; Konig, B. Photocatalytic Barbier
Reaction − Visible-Light Induced Allylation and Benzylation of
Aldehydes and Ketones. Chem. Sci. 2018, 9, 7230−7235.
̈
̈
(13) Schwarz, J. L.; Schafers, F.; Tlahuext-Aca, A.; Luckemeier, L.;
Glorius, F. Diastereoselective Allylation of Aldehydes by Dual
Photoredox and Chromium Catalysis. J. Am. Chem. Soc. 2018, 140,
12705−12709.
(14) Lee, K. N.; Lei, Z.; Ngai, M.-Y. β-Selective Reductive Coupling
of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis
Acid/Photoredox Catalysis. J. Am. Chem. Soc. 2017, 139, 5003−5006.
(15) Fava, E.; Nakajima, M.; Nguyen, A. L. P.; Rueping, M.
Photoredox-Catalyzed Ketyl−Olefin Coupling for the Synthesis of
Substituted Chromanols. J. Org. Chem. 2016, 81, 6959−6964.
(16) Xia, Q.; Dong, J.; Song, H.; Wang, Q. Visible-Light
Photocatalysis of the Ketyl Radical Coupling Reaction. Chem. - Eur.
J. 2018, DOI: 10.1002/chem.201804873.
(17) Roth, H.; Romero, N.; Nicewicz, D. Experimental and
Calculated Electrochemical Potentials of Common Organic Molecules
for Applications to Single-Electron Redox Chemistry. Synlett 2016,
27, 714−723.
(18) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light
Photoredox Catalysis with Transition Metal Complexes: Applications
in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363.
(19) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis.
Chem. Rev. 2016, 116, 10075−10166.
(20) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. Photoredox
Catalysis in Organic Chemistry. J. Org. Chem. 2016, 81, 6898−6926.
(21) Belotti, D.; Cossy, J.; Pete, J. P.; Portella, C. Synthesis of
Bicyclic Cyclopentanols by Photoreductive Cyclization of.Delta.,.Ep-
silon.-Unsaturated Ketones. J. Org. Chem. 1986, 51, 4196−4200.
(22) Hasegawa, E.; Takizawa, S.; Seida, T.; Yamaguchi, A.;
Yamaguchi, N.; Chiba, N.; Takahashi, T.; Ikeda, H.; Akiyama, K.
Photoinduced Electron-Transfer Systems Consisting of Electron-
Donating Pyrenes or Anthracenes and Benzimidazolines for Reductive
Transformation of Carbonyl Compounds. Tetrahedron 2006, 62,
6581−6588.
(23) Wang, L.; Lear, J. M.; Rafferty, S. M.; Fosu, S. C.; Nagib, D. A.
Ketyl Radical Reactivity via Atom Transfer Catalysis. Science 2018,
362, 225−229.
(24) Seo, H.; Katcher, M. H.; Jamison, T. F. Photoredox Activation
of Carbon Dioxide for Amino Acid Synthesis in Continuous Flow.
Nat. Chem. 2017, 9, 453−456.
(25) Seo, H.; Liu, A.; Jamison, T. F. Direct β-Selective Hydro-
carboxylation of Styrenes with CO 2 Enabled by Continuous Flow
Photoredox Catalysis. J. Am. Chem. Soc. 2017, 139, 13969−13972.
(26) Telmesani, R.; Park, S. H.; Lynch-Colameta, T.; Beeler, A. B. [2
+ 2] Photocycloaddition of Cinnamates in Flow and Development of
a Thiourea Catalyst. Angew. Chem., Int. Ed. 2015, 54, 11521−1125.
(27) Norrish Type I Reaction: (Norrish Type I Process, Norrish
Type I Cleavage). Comprehensive Organic Name Reactions and
Reagents; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2010.
(28) Norrish Type II Reaction: (Norrish Type II Process, Norrish
Type II Photoreaction, Yang Cyclization). Comprehensive Organic
Name Reactions and Reagents; John Wiley & Sons, Inc.: Hoboken, NJ,
USA, 2010.
(29) Filardo, G.; Gambino, S.; Silvestri, G.; Gennaro, A.; Vianello, E.
Electrocarboxylation of Styrene through Homogeneous Redox
Catalysis. J. Electroanal. Chem. Interfacial Electrochem. 1984, 177,
303−309.
(30) Matsuoka, S.; Kohzuki, T.; Pac, C.; Ishida, A.; Takamuku, S.;
Kusaba, M.; Nakashima, N.; Yanagida, S. Photocatalysis of Oligo(p-
Phenylenes): Photochemical Reduction of Carbon Dioxide with
Triethylamine. J. Phys. Chem. 1992, 96, 4437−4442.
(31) Phillips, J. P. PhD. Dissertation, Virginia Polytechnic Institute
and State University, 1998.
(32) Organic Electrochemistry: Revised and Expanded, 5th ed.;
Hammerich, O., Speiser, B., Eds.; CRC Press: 2015.
E
DOI: 10.1021/acs.orglett.9b04235
Org. Lett. XXXX, XXX, XXX−XXX