Synthesis of Sterically Hindered α-Hydroxycarbonyls through Radical-Radical Coupling

Article abstract of DOI:10.1021/acs.orglett.1c01358

We describe a synthetic approach to sterically hindered α-hydroxy carbonyl compounds through radical-radical coupling. An organic photoredox catalysis reaction converts an aliphatic carboxylic acid and α-ketocarbonyl to a transient alkyl radical and a persistent ketyl radical, respectively, which couple selectively based on the persistent radical effect. This protocol allows the use of primary, secondary, and tertiary aliphatic carboxylic acids to introduce various alkyl substituents onto ketone moieties of α-ketocarbonyls under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.1c01358

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Letter
Synthesis of Sterically Hindered α‑Hydroxycarbonyls through
Radical−Radical Coupling
Kenji Ota, Kazunori Nagao,* and Hirohisa Ohmiya*
Cite This: Org. Lett. 2021, 23, 4420−4425
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ABSTRACT: We describe a synthetic approach to sterically
hindered α-hydroxy carbonyl compounds through radical−radical
coupling. An organic photoredox catalysis reaction converts an
aliphatic carboxylic acid and α-ketocarbonyl to a transient alkyl
radical and a persistent ketyl radical, respectively, which couple
selectively based on the persistent radical effect. This protocol
allows the use of primary, secondary, and tertiary aliphatic
carboxylic acids to introduce various alkyl substituents onto
ketone moieties of α-ketocarbonyls under mild reaction con-
ditions.
adical−radical coupling is a recently established powerful
R
bond formation process that enables the construction of
sterically hindered molecules by organic synthesis. To achieve
the selective coupling of two different radicals, the reaction was
designed based on the solvent cage effect1 or the persistent
radical effect (PRE).2 In particular, PRE enabled cross-coupling
between a transient (short-lived) radical and a persistent (long-
lived) radical when both radicals were generated at the same
rate. Visible-light photoredox catalysis can generate two
radicals in one catalytic turnover, allowing extensive inves-
tigation of unprecedented bond formation through radical−
radical coupling based on PRE.3 During such research,
sterically hindered alcohols were synthesized through
radical−radical coupling between an alkyl radical and a ketyl
radical.4 However, usable alkyl radicals have been limited to
stabilized radicals, such as allyl and α-heteroatom-substituted
alkyl radicals.
Earlier, our laboratory developed radical-mediated organo-
catalysis, leveraging PRE to synthesize sterically hindered
molecules.5 For example, we developed the N-heterocyclic
carbene (NHC)-catalyzed decarboxylative alkylation of
aldehydes with secondary and tertiary aliphatic carboxylic
acid-derived redox active esters to synthesize sterically
hindered ketones (Figure 1A).5 In this approach, a Breslow
intermediate-derived ketyl radical from a thiazolium type NHC
and aldehyde was found to be a persistent radical, which
coupled with a transient alkyl radical. We assumed that the
persistent nature of the ketyl radical originated from the
captodative effect6 due to an electron-donating oxyanion group
and an electron-withdrawing thiazolium ring. Recently, we
questioned whether this working principle could be applied to
the construction of sterically hindered tertiary alcohols.
Specifically, the substitution of a thiazolium ring of the ketyl
radical to an appropriate electron-withdrawing group would
Figure 1. Synthetic approaches to sterically hindered alcohols.
Received: April 20, 2021
Published: May 14, 2021
https://doi.org/10.1021/acs.orglett.1c01358
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4420−4425
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retain the persistent nature, allowing coupling with transient
alkyl radicals. We evaluated the persistent nature of the ketyl
radical in terms of its electronic features using radical
stabilization energy (RSE).7 Preliminary computational studies
indicated that the RSEs of ketyl radicals from α-ketocarbonyls
were comparable to that of a Breslow intermediate-derived
ketyl radical (Figure 1B, see Supporting Information),
prompting us to pursue the synthesis of sterically hindered
alcohols through radical−radical coupling.
Herein, we report the organic photoredox-catalyzed
decarboxylative alkylation of α-ketocarbonyls with carboxylic
acids as alkylation sources, producing sterically hindered α-
hydroxycarbonyls (Figure 1C).8−11 The reaction proceeds
through radical−radical coupling between a transient alkyl
radical and a persistent ketyl radical generated from aliphatic
carboxylic acid and α-ketocarbonyl, respectively. A broad array
of aliphatic carboxylic acids, α-ketoesters, and α-ketoamides
were amenable to this protocol.
We examined the reaction between 2-phenylisobutyric acid
(1a) and ethyl benzylformate (2a). Due to the persistent
nature of the radical anion form of the α-ketoester, 2a was
chosen as a substrate. By screening photoredox catalysts, bases,
and solvents, we found that 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-
dicyanobenzene (4Cz-IPN)12 as an organic photoredox
catalyst and a stoichiometric amount of Cs2CO3 in DMSO
promoted the desired alkylation product 3aa (Table 1, entry
1).
Table 1. Screening Results of Cross-Coupling between 1a
and 2a
a
yield (%) of yield (%) of
b
b
entry
change from standard conditions
none
Ir[dF(CF3)ppy]2(dtbbpy)PF6 instead
of 4Cz-IPN
3aa
4aa
1
2
96 (90)
92
2
3
3
4
5
6
7
8
9
10
11
12
13
Mes-AcrBF4 instead of 4Cz-IPN
Na2CO3 instead of Cs2CO3
K2CO3 instead of Cs2CO3
CsF instead of Cs2CO3
CsOAc instead of Cs2CO3
MeCN instead of DMSO
DMF instead of DMSO
DCM instead of DMSO
without Blue LED
0
75
77
68
70
53
62
11
0
0
12
11
16
15
4
19
10
0
without 4Cz-IPN
without Cs2CO3
0
11
0
0
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), 4Cz-IPN
(0.002 mmol), Cs2CO3 (0.4 mmol), DMSO (1.0 mL), 1 h under blue
b
LED irradiation. 1H NMR yield. Yield of the isolated product is
given in parentheses.
The effects of various photocatalysts and bases were
evaluated (Table 1, entries 2−7). Ir[dF(CF3)ppy]2(dtbbpy)-
PF6 has a redox potential comparable to that of 4Cz-IPN and
produced 3aa in high yield (entry 2). On the other hand, a
mesityl acridinium-type photoredox catalyst did not provide
the product (entry 3). Reactions using other alkali metal
carbonates or weaker cesium-based bases instead of Cs2CO3
resulted in significant formation of the dimer 4aa (entries 4−
7). Other polar aprotic solvents, such as MeCN and DMF,
exhibited lower reactivity than DMSO (entries 8 and 9). DCM
dramatically decreased the reaction efficiency due to the low
solubility of Cs2CO3 (entry 10). Control experiments revealed
that light irradiation, a photoredox catalyst, and base were
essential for promoting the desired reaction (entries 11−13).
With the optimized reaction conditions in hand, the scope of
the aliphatic carboxylic acids was investigated with 2a (Figure
2). A simple tertiary butyl group was efficiently introduced
onto an alcohol scaffold (3ba). A tertiary alkyl carboxylic acid
with a β-benzyloxy group was also a suitable substrate (3ca). 1-
Methylcyclohexylcarboxylic acid coupled with 2a to afford the
corresponding hindered alcohol (3da). The reactions with
heteroatom-fused cyclic tertiary alkyl fragments allowed access
to densely functionalized alcohols (3ea and 3fa). A 5-
membered alkyl group was tolerated (3ga).
A series of secondary carboxylic acids were amenable to this
photoredox catalysis approach (Figure 2). It is noteworthy that
this reaction enabled access to various α-secondary alkyl-
substituted α-hydoxyesters, found in many muscarinic receptor
antagonists (3ha−3ka).9b Secondary benzylic and α-oxyalkyl
groups were tolerated (3la−3oa). Primary aliphatic acids also
underwent the reaction, although the product yields were low
to moderate (3pa−3ta). To demonstrate the high functional
group compatibility of this protocol, we conducted late-stage
functionalization of natural product and pharmaceutical drugs
containing carboxylic acid moieties (3ua−3ya).
Next, the scope of the α-ketoesters was explored using
benzylic 1a or nonbenzylic 1d (Figure 2). Electron-donating
and electron-withdrawing groups did not affect reaction
efficiency (3ab−3ae). Reactions with naphthalene or hetero-
aromatic ring-conjugated ketoesters gave the corresponding α-
hydroxyester products in moderate to high yields (3af−3ah).
In contrast to 1a, reactions with 1d decreased product yields
(3db−3dh).
Our investigation of the scope of α-ketocarbonyls revealed
that α-ketoamides are suitable substrates for this organic
photoredox catalysis approach.13 The lower RSE of α-
ketoamide compared to α-ketoester (Figure 2) resulted in
the reactions of 5a with 1a or 1d providing lower product
yields (3aa, 90% vs 6aa, 51%; 3da, 78% vs 6da, 36%). Since an
α-ketocarbonyl group can be installed on the terminal amine
moiety of α-amino acids or peptides,14 this protocol has
potential as a bioconjugation tool and thus we examined the
reactions of glycine-derived α-ketoamide 5a with α-amino
acids and peptides (Figure 2). A slight modification of reaction
conditions enabled coupling with proline, valine, and serine
derivatives, producing sterically hindered alcohols (6za−6Ba).
Dipeptides bearing a carboxylic moiety could also participate
in this reaction (6Ca and 6Da).
Other types of carbonyls were evaluated for this organic
photoredox catalysis approach. Reactions with acylcyanide
(7a), benzaldehyde (7b), acetophenone (7c), and benzophe-
none (7d) provided no product. In contrast, although the
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Figure 2. Substrate scope. aReaction conditions: 1 (0.2 mmol), 2, 5, 7 (0.2 mmol), 4Cz-IPN (0.002 mmol), Cs2CO3 (0.4 mmol) DMSO (1.0 mL),
1 h under blue LED irradiation. b1 (0.2 mmol), 2, 5, 7 (0.2 mmol), 4Cz-IPN (0.004 mmol), Cs2CO3 (0.4 mmol), DMSO (1.0 mL), 1 h under blue
LED irradiation. cReaction conditions: 1 (0.2 mmol), 5b (0.2 mmol), 4Cz-IPN (0.002 mmol), Cs2CO3 (0.1 mmol), H2O (1.0 mmol), DMSO (1.0
mL), 1 h under blue LED irradiation.
reaction efficiencies were low, trifluoroacetophenone (7e)
could couple with 1a.
from 2a would be slower than 5-exo radical cyclization. On the
basis of this result, the proposed mechanism is as outlined in
Figure 3C. Upon irradiation with a blue-emitting diode (LED),
the ground state of 4Cz-IPN becomes the excited state of
*4Cz-IPN. A base, such as Cs2CO3, converts the aliphatic
carboxylic acid 1 to the carboxylate (Ered,1/2 = +1.16 V vs SCE
for hexanonate),16 which is readily oxidized by *4Cz-IPN
[E1/2(*4Cz-IPN/4Cz-IPN−) = +1.35 V vs SCE],16 producing
the alkyl radical with decarboxylation. Then, a single electron
transfer from 4Cz-IPN− [E1/2(4Cz-IPN−/4Cz-IPN) = −1.21 V
vs SCE]17 to α-ketocarbonyl 2 [Ered,1/2 = −1.23 V vs SCE for
2a]18 occurs to form the ground state of 4Cz-IPN and a ketyl
radical, respectively. Finally, radical−radical coupling of the
transient alkyl radical and the persistent ketyl radical affords
the desired alcohol product 3 with protonation. The results of
screening of photoredox catalysts, shown in Table 1, support
this mechanism. Ir[dF(CF3)ppy]2(dtbbpy)PF6 [E1/2(*IrIII/
We took advantage of the characteristics of radical-mediated
transformation to examine a radical-relay type alkene
difunctionalization (Figure 3A). When styrene (9a) was simply
added to the standard conditions for two-component coupling
between 1d and 2a, the desired three-component coupling
product 10daa was obtained in excellent yield with a small
amount of 3da. p-Methoxystyrene and p-bromostyrene were
also applicable as alkene substrates (10dba and 10dca).
We obtained information on the underlying mechanism of
this approach by conducting a radical clock experiment with
citronellic acid 1E (Figure 3B). The reaction produced only 5-
exo cyclized product 3Ea′, indicating the intermediacy of an
alkyl radical from the aliphatic carboxylic acid in this organic
photoredox catalysis approach.15 Additionally, radical−radical
coupling between a primary alkyl radical and a ketyl radical
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corresponding aliphatic carboxylic acid and α-ketocarbonyl,
respectively. The reaction is applicable to three-component
coupling with alkenes and to the modification of pharmaceut-
ical drugs and biomolecules. Further applications of this
protocol to macromolecules are under investigation.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01358.
Experimental details and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Kazunori Nagao − Division of Pharmaceutical Sciences,
Graduate School of Medical Sciences, Kanazawa University,
Kanazawa 920-1192, Japan; orcid.org/0000-0003-
3141-5279; Email: nkazunori@p.kanazawa-u.ac.jp
Hirohisa Ohmiya − Division of Pharmaceutical Sciences,
Graduate School of Medical Sciences, Kanazawa University,
Kanazawa 920-1192, Japan; JST, PRESTO, Saitama 332-
0012, Japan; orcid.org/0000-0002-1374-1137;
Email: ohmiya@p.kanazawa-u.ac.jp
Author
Kenji Ota − Division of Pharmaceutical Sciences, Graduate
School of Medical Sciences, Kanazawa University, Kanazawa
920-1192, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01358
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
a
b
This work was supported by The Uehara Memorial
Foundation, JSPS KAKENHI Grant Number JP21H04681 to
Scientific Research (A), JSPS KAKENHI Grant Number
JP17H06449 (Hybrid Catalysis), Kanazawa University SAKI-
GAKE project 2020 and JST, PRESTO Grant Number
JPMJPR19T2.
Figure 3. Mechanistic studies. R = 2-phenethyl. The reaction with
c
1a under standard conditions. R = ethyl.
IrII) = +1.21 V vs SCE and E1/2(IrII/IrIII) = −1.37 V vs SCE]19
possessing redox potentials comparable to that of 4Cz-IPN
showed similar reactivity. On the other hand, Mes-AcrBF4
[E1/2(*Mes-Acr/Mes-Acr−) = +2.06 V vs SCE and E1/2(Mes-
Acr−/Mes-Acr) = −0.57 V vs SCE]20 did not show catalytic
activity due to insufficient reduction ability.
While investigating the scope of α-ketocarbonyls, we also
examined aliphatic α-ketoesters (Figure 3D). The reaction of
1a and methyl-substituted ketoester B gave no coupling
product. In contrast to B, tert-butyl-substituted ketoester C
underwent decarboxylative alkylation to produce the desired
highly hindered alcohol. Although C is disadvantageous from
the viewpoint of reduction potential and lower RSE, the steric
bulkiness of a tertiary butyl group stabilizes the corresponding
ketyl radical sufficiently to participate in radical−radical
coupling.
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(18) See the Supporting Information.
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Organic Letters
pubs.acs.org/OrgLett
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