Visible-Light Photoredox Enables Ketone Carbonyl Alkylation for Easy Access to Tertiary Alcohols

Article abstract of DOI:10.1021/acscatal.9b02401

Being a handle for synthesizing quaternary carbon centers and olefins, together with ubiquitous appearance in organic building blocks, makes tertiary alcohols valuable targets in synthesis. However, traditional syntheses of these alcohols have faced several challenges including the employment of functionalized reactive reagents, undesirable side reactions, and decomposition of the alcohol products under harsh conditions. The paucity of a synthetic approach to bulky tertiary alcohols prompts our interest to develop a benign catalytic protocol to tackle the current issues. Here, we have successfully demonstrated the use of ketyl radicals in intermolecular cross radical-radical coupling, which has opened a different door for accessing complex tertiary alcohols. On the other hand, by starting from feedstock and naturally derived chemicals without any pre-activation, it would be superior to traditional methodologies in the industrial context.

Full text of DOI:10.1021/acscatal.9b02401

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Article
Visible-light photoredox enables ketone carbonyl
alkylation for easy access to tertiary alcohols
Minh Duy Vu, Mrinmoy Das, Aoxin Guo, Zi-En Ang, Miloš #oki#, Han Sen Soo, and Xue-Wei Liu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02401 • Publication Date (Web): 22 Aug 2019
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Page 1 of 7
ACS Catalysis
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Visible-Light Photoredox Enables Ketone Carbonyl Alkylation for Easy
Access to Tertiary Alcohols
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Minh Duy Vu,† Mrinmoy Das,† Aoxin Guo, Zi-En Ang, Miloš Đokić, Han Sen Soo and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences Nanyang Technological
University 21 Nanyang Link, Singapore 637371
ABSTRACT: Being a handle for synthesizing quaternary carbon centers and olefins, together with ubiquitous appearance in
organic building blocks makes tertiary alcohols valuable targets in synthesis. However, traditional syntheses of these alcohols
have faced several challenges including the employment of functionalized reactive reagents, undesirable side reactions and
decomposition of the alcohol products under harsh conditions. The paucity of synthetic approach to bulky tertiary alcohols
prompts our interest to develop a benign catalytic protocol to tackle the current issues. Here, we have successfully
demonstrated the use of ketyl radicals in intermolecular cross radical-radical coupling, which has opened a different door for
accessing complex tertiary alcohols. On the other hand, by starting from feedstock and naturally derived chemicals without
any pre-activation, it would be superior to traditional methodologies in industrial context.
KEYWORDS photoredox catalysis, HAT catalyst, ketyl radical, tertiary alcohol, radical-radical cross coupling
The tertiary alcohol scaffold is prevalent in organic
molecules, ranging from pharmaceutical and agrochemical
compounds to natural products (Figure 1).1 Traditional
synthesis of alcohols, specifically tertiary alcohols, utilizes
the Barbier type carbonyl addition reactions developed in
the previous century.2 Nevertheless, the organometallic
reagents involved are pyrophoric and highly reactive. As a
consequence, they exhibit low functional group tolerance
which limits their applicability in complex alcohol
synthesis. Furthermore, the use of stoichiometric amounts
of metallic reagents is unsustainable and harmful to the
environment. Moreover, the nucleophilic addition of
organometallic reagents to ketones is sometimes not as
straightforward as compared to the reactions of aldehydes,
owing to the inherent steric congestion around the carbonyl
groups and the strong basicity of the reagents. Hence, these
Barbier reactions are often accompanied by undesirable
side reactions, including ketone reduction and aldol
condensation, which lead to a complex mixture of side-
products.3
also demonstrated by Buchwald and Liu through the
discovery of copper-catalyzed asymme-
R
Classical/ Modified
Barbier Reaction
M
R
R
R
steps
R
R
O
R
OH
Catalytic Reductive
Couplings
X
R1
R2
R1
R2
Less waste generated
by-product free
steps
R
H
Photoredox-Organocatalysis
(this work)
Allyl and
benzyl compounds
OH
Ph
Ph
OH
HO
N
N
MeO
N
R
R = -Me Terfenadine
R = -COOH Fexofenadine
Pharmaceuticals
Ancymidol
Plant growth regulators
In the last few years, a handful of new methodologies for
carbonyl addition were invented to overcome such
drawbacks. For example, milder organometallic reagents
were developed to eliminate the anhydrous property of the
reaction and many carbonyl additions can now be done in
aqueous solvent. However, stoichiometric usage of metallic
reagents is still necessary.4-6 These include nickel, copper
and palladium, which catalyzes the direct reductive
coupling between organic halides and carbonyl
derivatives.7 Moving beyond the traditional design of
carbonyl addition reactions, Krische presented the
reductive coupling between olefin-derived nucleophiles
and primary/secondary alcohols.8 The concept of using
unsaturated hydrocarbons as carbanion equivalent was
OH
O
OH
N
N
N
F
HO
HO CCl3
HO
OH
OH
O
F
Cl
Cl
OH
Flutriafol
Dicofol
Pesticide
Fungicide
Natural product
Figure 1. Overview of tertiary alcohol synthetic pathways and
examples of its occurrence in natural and artificial products.
tric addition to ketones.9 Subsequently, aldehydes were
harnessed as latent alkyl carbanions for the ruthenium-
catalyzed addition to carbonyl compounds, as reported by
Li et al.10 The trend of reinventing the carbonyl addition
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reaction not only covered charge interaction mechanisms,
Page 2 of 7
mostly require a hetero atom adjacent to the radical center.
In contrast, our interest to find different coupling partners
to allylic and benzylic family of compounds, thus enlarge the
scope of the synthetic application.
1
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6
7
8
but also extended to the field of radical chemistry.
In 2016, Chi and co-workers demonstrated a metal-free
process using carbene catalyst to facilitate the addition of
benzyl halides to activated ketone substrates via a proposed
radical pathway.11 Glorius discovered rare examples of
intermolecular radical addition to carbonyl acceptors under
photoredox conditions earlier this year.12 On the other
hand, carbonyl substrates can be transformed into ketyl
radical intermediates, which undergo subsequent C-C bond
formation, via samarium (II) halides - the potent single
electron reductants.13-18
(a)
(b)
Rueping
H
H
R
R
O
R
HO
R
R
9
Inactivated Csp3-H substrates
Knowles
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R
OH
O
R
EWG
EWG
On the rise of photoredox chemistry over the last decade,
the radical pathways that involve ketyl radicals have been
developed extensively (Figure 2a). In 2013, Knowles and
co-workers reported the proton coupled electron transfer
(PCET) approach to generate challenging ketyl radicals.
These intermediates then underwent intramolecular
cyclization with olefin or imine functional groups.19-20 The
formation of ketyl radicals via photoredox catalysis was
Synergistic Photoredox &
Hydogen Atom Transfer
Catalysis
Zhu
OH
R
X
O
R
R
X
R
R
Xiao
R
R
O
X
Source of transient radicals
X
HO
R
R
developed
independently
by
Rueping
through
photoinduced electron transfer.21-23 It was revealed that
under in situ activation of a hole catalyst such as an
ammonium cation or an acid, the carbonyl reduction
potential significantly drops so that a wide array of
photoredox catalysts can be employed to achieve the ketyl
radicals. Under the reaction condition, these radicals were
found to dimerize22, couple with α-amino radicals21 and add
to olefins23. In 2016, Ngai et al. reported another utility of
ketyl radical - the intermolecular addition to electron
deficient styrene derivatives.24-25
Figure 2. Recent developments in ketyl radical chemistry via
photoredox catalysis.
Table 1. Optimization studies
O
H
1 mol% photocatalyst
10 mol% HAT catalyst
Solvent
HO
2
3
4
HAT Catalyst
SH
O
SK
SH
Si
HS
SO3Na
COOEt
HAT-1
SK
HAT-2
In comparison to olefin addition, cross radical-radical
coupling of ketyl radicals may show broader applications.
However, they are rarely reported in literature. The
previous success on intramolecular version was presented
by Zhu in 2016 in an attempt to synthesize multi-
substituted N-heterocycles.26 Another scarce example of
intermolecular cross radical coupling between α-
heteroatom (O, N) stabilized radicals and the ketyl radicals
was developed by Xiao and co-workers.27-28 An asymmetric
version of radical-radical cross coupling between electron
deficient ketone and N-methyl aryl amines was presented
by Meggers and coworkers.29 Ooi et al. reported
stereoselective cross coupling of N-arylaminomethanes
and aldimines using ionic Bronsted acid and
photosensitizer.30 Earlier this year, König also developed
photocatalytic Barbier reaction for allylation and
benzylation of carbonyls.31 To the best of our knowledge,
there has been no report on the use of simple transient
radicals derived from hydrocarbon feedstock or natural
sources in the analogous reaction.
HAT-3
HAT-4
HAT-5
Photocatalyst
(1 mol%)
HAT cat.
Additives
Entry
Results[a]
(10 mol%)
HAT-1
HAT-1
HAT-1
HAT-1
HAT-1
HAT-2
HAT-3
HAT-4
HAT-5
-
(10 mol%)
1
2
Ru(bpy)3(PF6)2
K2CO3
N.R.
N.R.
Ir(ppy)2(bpy)PF6
K2CO3
3
Ir(ppy)2(dtbbpy)PF6
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
-
K2CO3
Trace 4
40% 4
58% 4
90% 4
N.D.
4
K2CO3
5[b]
K2CO3
6
-
7
-
8
K2CO3
85% 4
N.D.
9
K2CO3
10
11
12[c]
13
-
-
-
-
N.R.
fac-Ir(ppy)3
fac-Ir(ppy)3
-
-
Only 7
N.R.
HAT-2
HAT-2
N.R.
The reactions were carried out under inert atmosphere (Ar
or N2) using 0.2 mmol benzophenone and 1.0 mmol
cyclohexene in 0.1 M acetone solution. The reaction vials were
irradiated by 34 W Kessil Blue LEDs for 12 hrs. [a] Isolated
yield. [b] Reaction in DMSO 0.1 M solution. [c] Reaction in the
dark. N.R. No reaction. N.D. Not determined, complex mixture
obtained.
In recent years, C-H activation is a promising and highly
favorable process for synthesis because of minimal pre-
functionalization required on the substrates.32-34 Being
intrigued by elegant approaches to transient radicals
demonstrated by MacMillan in various C-X and C-C bond
formation protocols (Figure 2b),35-40 we questioned
whether they can be applied in radical-radical cross
coupling with ketyl radicals, leading to a quick access of
bulkily substituted alcohols. In complement with the
reported radical-radical cross coupling methods which
The reaction would resemble hydrocarbonation of
ketones, which exhibits absolute atom economy and be of
great interest in sustainable chemistry.41 In this article, we
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report our design of such a reaction and show its potential
applications in tertiary alcohol synthesis.
Our model reactions between benzophenone (2) and
cyclohexene (3) were examined under various photoredox
conditions (Table 1). Photocatalysts that have relatively low
1
2
3
4
5
6
Table 2. (a) Substrate scope evaluation for various ketones. (b) Substrate scope evaluation for various
allylic/benzylic Csp3-H
7
8
9
1
(a)
1 mol% Ir(ppy)3
(
)
(b)
O
R
OH
R3
R3
O
1
( )
1 mol% Ir(ppy)3
Acetone (0.1 M)
Thiol and additives
R3
R2
R4
Acetone (0.1 M)
R1
R4
Ph
R1
R4
R
Thiol and additives
R1
R2
R2
HO
Ph
Ph
Blue LED, 30 o
C
Blue LED, 30 o
C
HO
Ph
R
R
1-4 = Aryl, Alkyl
= Aryl, Heteroaryl, Alkyl
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O
OH
OH
OH
OH
OH
a
OH
OH
OH
F
OMe
a
a
a
a
10
11
12
13
(50%)
(90%)
(78%)
(85%)
a‡
a‡
a†
30
31
32
33
(80%)
(61%)
(63%)
(85%, 3:1)
OH
gram scale: 78%
O
O
OH
OH
HO
OH
OH
OH
OH
OH
OH
CF3
NH2
b†
b
a
a
b
a
34
35 (30%)a
36
(37%)
37 (51%, 3.5:1)b†
(56%, 1.8:1)
15
16
17
(48%)
(22%)
(52%)
14
(71%)
O
OH
OH
OH
OH
N
OH
OH
OH
b
OH
CF3
Cl
Cl
b*
a
a
a
b†‡
18
22
26
19
20
21
(54%)
(27%)
(57%)
(61%)
b†
‡
b
38
(58%, 1:1)
39
(44%, 2:1)
40
41
(40%)
(69%)
Br
OH
S
OH
O
OH
S
OH
O
OH
b
OH
b
OH
OH
N
N
b
a
b
b
23
24
25
(59%)
(85%)
(68%)
(67%)
b
b
42
43
44
45
(28%)
(82%)
(50%)
(61%)
OH
OH
OH
OH
b*
b*
b*
b*
27
28
29
(70%)
(58%)
(52%)
(51%)
All reactions were carried out under inert atmosphere of Argon, with 0.2 mmol ketone and 1.0 mmol cyclohexene for 12-16 hours
(a), or with 0.2 mmol benzophenone and 0.6 mmol olefin/alkyl benzene for 12-16 hours (b) unless otherwise indicated. Yields given
in parentheses are isolated yields. a, condition A using KSAc (10 mol%). b, condition B using tri-isopropylsilanethiol (10 mol%) and
K2CO3 (10 mol%). Diastereoisomers were obtained without selectivity (dr ≈ 1:1) for all the cases using unsymmetrical ketones. *
Reactions were carried out for 72 hours. † Regioisomers were obtained, the main isomers are depicted in all cases. ‡ Additional
loading of olefin required (see Supplementary Information for more details)
reduction potential could not facilitate the transformation
(Entry 1-3). The initial use of acid additives (ie. benzoic
acid)20-21 to facilitate ketone single electron reduction gave
detrimental results while base additives such as carbonate
salts increased the reaction efficiency, possibly by
accelerating thiolate formation (Entry 4 & 5). In addition,
the reaction works on polar aprotic solvents such as DMSO
but the reaction system that contains protic solvents
including alcohols or trace water gave rise to a pinacol
dimerization product (7). The choice of thiol catalyst is a
decisive factor in this protocol. From our screening results
(Table 1), we have concluded two optimized conditions, in
which, both gave good yields of product in the model
reaction (>85%). (Entry 6 & 8).
potassium carbonate, all in 10 mol% loading. Although the
triplet state benzophenone has been known as a hydrogen
atom transfer catalyst that provides trace coupling product
with cyclohexene, our control experiments ruled out this
pathway, reaffirming the necessity of all parameters.42
(Entry 11-13).
A plausible mechanism for the ketone hydrocarbonation
is delineated in figure 3. After initial excitation by blue light
(455 nm), the photosensitizer (1) transforms into its long-
lived triplet excited-state (lifetime 1900 ns).43-44 Owing to
great reducing ability (E = -1.73 V vs SCE),45 the excited
photocatalyst undergoes oxidative quenching by aryl
ketone (Ebenzophenone = -1.87 V vs SCE)46-47 to generate semi-
persistent ketyl radical
and higher oxidation state
photocatalyst (Ir4+) with good oxidizing ability (E = +0.77 V
vs SCE)45. Consequently, single electron oxidation of in situ
generated thiolate gives thiyl radical. We anticipate that the
electrophilic thiyl radical can serve as a powerful hydrogen
Condition A features the direct use of inexpensive
potassium thioacetate without additional base, while
condition B employs tri-isopropylsilanethiol together with
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Page 4 of 7
atom transfer catalyst which abstracts the allylic/benzylic
products were obtained in a diastereoisomeric mixture (dr
≈ 1:1 in all the cases).
Csp3-H bonds (BDE for cyclohexene C-Hallylic = 83.2 kcal·mol-
1, BDE for toluene C-Hbenzylic = 89.9 kcal·mol-1).48-49 In fact, the
presence of cyclohexenyl radical 6 was confirmed by the
isolation of the TEMPO trapping product 8. The transient
allylic/benzylic radicals can undergo cross radical-radical
coupling with the ketyl radical to afford the desired tertiary
alcohols.
1
2
3
4
5
6
7
8
To our delight, aryl-alkyl ketones can undergo the cross-
radical coupling reaction efficiently, although extended
reaction times are required. This significantly broadens the
range of tertiary alcohols that can be synthesized using our
benign protocol. Ketones with cyclic alkyl (26) and linear
alkyl (29) worked equally well. Moreover, benzylic ketone
(18), branched primary and secondary alkyl ketones (27
and 28) also furnished tertiary alcohols with synthetically
useful yields (>50%). Additionally, trifluoro substituted
acetophenone reacted, albeit slowly, to form
trifluoromethyl tertiary alcohol (19). Even though
significant effort has been made to optimize the reaction
conditions for the alkylation of dialkyl ketones and
aldehydes, no desirable outcome has been achieved so far.
It is presumably due to the high reduction potential of the
dialkyl ketones and the short lifetime of the aldehyde
derived ketyl radicals. The Stern- Volmer quenching plot
shows that the aromatic ketones are good quenchers of the
excited state [fac-Ir(ppy)3]*, while the aliphatic ketones and
alkenes are not (See supplementary information). This
explains the limitation of our scope towards the aliphatic
ketones.
With the optimized conditions in hand, initially we
evaluated the scope of carbonyl alkylation on a wide range
of ketones (Table 2a). Diaryl ketones generally provided
good
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21
22
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25
26
27
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46
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60
O
H
1
( )
1 mol% fac-Ir(ppy)3
10 mol% thiol
Acetone
N
N
HO
Ir
N
2
3
4
1
( )
fac-Ir(ppy)3
O
R
S
[Ir3+]*
[Ir3+
]
H
Photoredox
Catalysis
HAT
Catalysis
SET
SET
HAT
O
R
SH
R
S
[Ir4+
]
We next sought to expand this reaction from the model
substrate - cyclohexene to other allylic/benzylic systems
(Table 2b). Conjugated alkene - cycloheptatriene provided
a good yield of 80% (30), owing to greater stability of the
transient radical. Apart from that, cycloalkenes in various
ring sizes, both cycloheptene (31) and cis-cyclooctene (32),
gave reasonably good results (>60%). Heterocyclic alkenes
with a polarized double bond, for example, dihydropyran
and dihydrofuran, furnished regioisomeric product
mixtures due to the 1,3-allylic rearrangement. Notably, free-
hydroxyl containing olefins can be viable substrates for the
reaction as well, although a lower yield was observed. It has
been challenging to synthesize a carbanion equivalent with
such unprotected hydroxyl presenting. Further successful
examples with acyclic linear terminal (39), internal olefins
(38) and branched olefin (37) reaffirmed the broad
applicability of our method, from natural feedstock to latent
alkyl carbanion equivalents.
5
6
OH
Ph
Ph
Radical Cross Coupling
Ph
Ph
O
N
OH
7
8
HO
4
Figure 3. Proposed mechanism for carbonyl alkylation of
ketones using photoredox catalysis.
coupling efficiency, in spite of steric hindrance. However,
ortho-substituted aryl ketone (16) gave significantly lower
yield compared with the para- and meta- counterpart (12
and 14). It is interesting that the benzylic Csp3-H bond on the
ketone substrate was not activated by the thiyl radical,
hence, the selective cross-coupling with cyclohexene was
observed. Strong electron donating substituents such as -
OMe (13) or –NH2 (15) present on the ketone substrates
imposes negative impact to the reaction outcome. Although
these substituents can stabilize the ketyl radical
intermediates, they raise the energy barrier for single
electron reduction process. The conversion of the ketone
substrates in these cases was not completed even after 48
hours. A cyclic diaryl ketone gave a moderate yield of 48%
(17), possibly because of a reduced steric shield which
helps to stabilize the ketyl radical intermediate. A gram-
scale reaction was performed with the use of minimal
amount of catalysts over prolonged reaction times and gave
very good yield (0.1 mol% [Ir], 2 mol% KSAc; 10).
Following our previous success in aldehyde Csp2-H
activation,50 we have tested and achieved benzoin
condensation type product (40) in the cross-radical
coupling between an acyl radical and a ketyl radical.
Moreover, a series of benzylic Csp3-H substrates were
successfully employed in the carbonyl alkylation. Tertiary
(41) and secondary (both cyclic - 42 and acyclic - 43, 44)
benzylic substrates gave moderate to good yields (50-82%).
However, a primary benzylic substrate provided a low yield
(45), attributed to the short-lived primary radical
intermediate. In addition, it is of considerable value for the
tolerance of a bromo substituent, which will allow multi-
functionalization of the substrate. It has been problematic
for the classical organometallic reagents in this aspect.
In addition, heterocyclic aryl ketones are viable
substrates that produced bulky tertiary alcohols in
moderate to good yields (59%-85%). Electron deficient
heterocycles (pyridine in 21, benzothiazole in 24) and
electron enriched heterocycles (furan in 23, indole in 25)
did not show any substantial effect in the reactivity. When
these non-symmetrical ketones were employed, the alcohol
Finally, mild reaction condition, a central advantage of
this protocol, has been demonstrated in late-stage
diversification of advanced, highly functionalized synthetic
intermediates and natural products. As illustrated in Table
3, fenofibrate, a top-selling pharmaceutical for treatment of
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* xuewei@ntu.edu.sg
hypercholesterolemia, successfully underwent the cross-
1
2
3
4
5
6
7
8
radical coupling reaction, forming alcohol 46 in a moderate
yield of 64%. The reaction is chemoselective at the carbonyl
group, leaving the ester group intact. Furthermore, the
potential pharmaceutical precursors (47 and 48) were
smoothly synthesized in one step from inexpensive and
commercially available substrates.
Author Contributions
† These authors contributed equally.
Notes
The authors declare no competing financial interests.
ASSOCIATED CONTENT
Supporting Information includes experimental procedures and
full characterization of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
More beneficially, alkene-containing natural products
and derivatives may likewise be employed directly as
carbanion equivalent for the carbonyl alkylation. Citronellyl
acetate reacted with benzophenone with complete
conversion, giving a mixture of regio-isomers, from which,
the main isomer (49) was isolated and characterized.
Naturally
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10
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13
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19
20
21
22
23
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25
26
27
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29
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35
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39
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43
44
45
46
47
48
49
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57
58
59
60
ACKNOWLEDGMENT
We gratefully acknowledge National Research Foundation
(NRF2016NRF-NSFC002-005) and the Ministry of Education
(MOE 2013-T3-1-002), Singapore for financial support of this
research.
Table 3. Application of visible-light photoredox
mediated carbonyl alkylation.
Boc
N
ABBREVIATIONS
ppy, 2-phenylpyridine; dtbbpy, 4,4′-Di-tert-butyl-2,2′-
dipyridyl; bpy, 2,2′-bipyridyl
OH
OH
O
Cl
O
OH
O
Cl
b†
b
†
a
46
47
48
(58%)
(64%; dr = 1:1)
(63%)
*
Fenofibrate late-stage modification
Tamoxifen precursor synthesis
Fexofenadine precursor synthesis
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title, should give the reader a representative idea of one of the following: A key structure, reaction, equation, concept,
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specifications.
1
2
3
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6
7
8
R3
R2
9
R3
R1
O
HO
R1
10
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R2
R'
R
Ir
RSH
H
R' = Alkyl, Aryl,
Heteroaryl
100% atom economy
No stoichiometric activator
>40 examples
7
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