Organophotoredox-Catalyzed Decarboxylative C(sp3)-O Bond Formation

Article abstract of DOI:10.1021/jacs.9b12335

This manuscript reports a visible-light-mediated organosulfide catalysis that enables the decarboxylative coupling between simple aliphatic alcohol and tertiary or secondary alkyl carboxylic acid-derived redox active esters to produce a C(sp³)-O-C(sp³) fragment. Results of the coupling using other heteroatom nucleophiles such as water, amides, and thiols are also described.

Full text of DOI:10.1021/jacs.9b12335

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Communication
Organophotoredox-Catalyzed Decarboxylative C(sp3)–O Bond Formation
Shotaro Shibutani, Taiga Kodo, Mitsutaka Takeda, Kazunori
Nagao, norihito tokunaga, Yusuke Sasaki, and Hirohisa Ohmiya
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 03 Jan 2020
Downloaded from pubs.acs.org on January 3, 2020
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Organophotoredox-Catalyzed Decarboxylative C(sp3)–O Bond
Formation
Shotaro Shibutani,†║ Taiga Kodo,†║ Mitsutaka Takeda,† Kazunori Nagao,*†, Norihito Tokunaga,‡ Yusuke
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Sasaki,‡ and Hirohisa Ohmiya*†§
†
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi,
Kanazawa 920-1192, Japan
‡Drug Discovery Chemistry Laboratories, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 2-
26-1, Muraoka-Higashi, Fujisawa, Kanagawa 251-8555, Japan
§JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
Supporting Information Placeholder
synthesis of sterically-hindered C(sp3)–O–C(sp3) fragments from
ABSTRACT: This manuscript reports a visible light-
mediated organosulfide catalysis that enables the
the corresponding aliphatic alcohols and alkylcarboxylic acids.7
We were interested in the radical-polar crossover (RPC) reaction
decarboxylative coupling between simple aliphatic alcohol
as an approach to non-acidic and catalytic generation of
and tertiary or secondary alkyl carboxylic acid-derived
carbocations for C(sp3)–heteroatom bond formation.8 RPC enables
redox active esters to produce a C(sp3)–O–C(sp3) fragment.
the generation of carbocations from carbon radicals in one pot.
Results of the coupling using other heteroatom nucleophiles
Specifically, tetrathiafulvalene (TTF), which has been used as a
such as water, amides and thiols are also described.
representative RPC catalyst, underwent a single electron transfer
event with carbon electrophiles to generate a persistent TTF radical
cation and the carbon radical (Scheme 1B).8 The reaction of these
radicals affords a sulfonium salt that can participate in the
The C(sp3)–X–C(sp3) (X = oxygen, nitrogen and sulfur)
subsequent substitution reaction with heteroatom nucleophiles.
fragment is essential in a wide array of pharmaceuticals.1 Among
This RPC catalysis prompted us to consider whether the
the diverse methods for accessing C(sp3)–X–C(sp3) fragments,
carbocation could be generated directly from a readily available
C(sp3)–heteroatom bond formation using alkylheteroatom
molecule under mild conditions, and exploited in C(sp3)–O bond
nucleophiles such as alcohols, amines or thiols and alkyl
formation, thereby providing a new strategy for C(sp3)–O–C(sp3)
electrophiles is one of the most straightforward and popular
fragment synthesis. On the other hand, the low reducing ability of
(Scheme 1A). For example, a simple SN2 nucleophilic substitution
TTF (Eox = –0.2 V vs. SCE in MeCN)8b,9 would limit the reaction
allows for the construction of C(sp3)–X–C(sp3) fragments.2
design based on RPC. Based on this knowledge, we envisioned that
However, the conventional methods have problems in functional
the excitation of organosulfide compounds by visible light could
group compatibility under the highly basic conditions required, and
create strong redox properties while retaining the characteristic
the intolerance toward sterically demanding substrates due to the
function of a RPC catalyst. After the RPC event, the resultant
nature of the SN2 mechanism. The SN1 reaction using alkyl halides
sulfonium salt would participate in the substitution reaction with
or alkenes is also known, however the reaction requires the highly
alcohol nucleophiles.
acidic and harsh conditions, resulting in low functional group
Here, we report C(sp3)–O bond formation enabled by
organophotoredox-catalyzed RPC. Decarboxylative coupling using
simple aliphatic alcohol nucleophiles and tertiary or secondary
alkyl carboxylic acid-derived redox active esters,10 through visible
light-mediated organosulfide catalysis occurred under mild
conditions (Scheme 1C).11,12
compatibility.3 Alternatively, transition-metal based catalysis has
become
a promising method for carbon–heteroatom bond
formation using heteroatom nucleophiles and alkyl electrophiles.4
Even with this method, however, C(sp3)–heteroatom bond
formation between alkylheteroatom nucleophiles and alkyl
electrophiles is quite difficult due to the slow oxidative addition of
the alkyl electrophile and reductive elimination from the in situ-
generated alkylmetal complex, which is prone to β-hydride
elimination.5 Additionally, the highly basic conditions due to the
pKa requirements of the nucleophiles complicate the reaction.5
Details of our working hypothesis are described in Scheme 1D.
We selected N-Ar-phenothiazine (PTH)13 as
a
suitable
organophotoredox catalyst due to three features: excitation in the
UV-visible area (λmax = 320 nm),13a high reduction potential (Ar =
Ph, E1/2* = –2.1 V vs. SCE)13b and potential persistent properties of
the corresponding radical cation.14 The catalytic cycle is initiated
by the excitation of phenothiazine irradiated by a light-emitting
diode (LED) to produce the high reducing excited state (A). The
excited catalyst (A) undergoes single electron transfer to redox
active ester 2 to generate the radical cation form of the catalyst (B)
and an alkyl radical C. Reaction between B and C through single
The electrochemical reaction using aliphatic alcohols and
alkylcarboxylic acids is a fundamental method for the synthesis of
the C(sp3)–O–C(sp3) fragment.6 Two consecutive single electron
oxidations convert a carboxylic acid to a carbocation under mild
and non-acidic conditions. The carbocation could then couple with
an alcohol nucleophile. More recently, Baran and co-workers
introduced an elegant and practical electrochemical method for the
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electron oxidation of C by B (right bottom) or radical–radical
organophotoredox catalyst and light were essential for this reaction
(data not shown). Without LiBF4, the reaction did not proceed
well.16
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coupling (left bottom) affords an alkylsulfonium intermediate D.
Finally, alcohol nucleophile 1 reacts with the carbocation liberated
from D to give 3 with deprotonation and regeneration of the ground
state of the organosulfide catalyst.
Table 1. Screening of catalysts and bases for reaction
between 1a and 2a.a
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Entry Change from standard conditions
Yield of
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3aa (%)b
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none
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PTH2 instead of PTH1
PTH3 instead of PTH1
PTH4 instead of PTH1
PTH5 instead of PTH1
PTH6 instead of PTH1
POX1 instead of PTH1
Ir(ppy)3 (2 mol%) instead of PTH1
Ru(bpy)3(PF6)2 (2 mol%) instead of PTH1 and
LiBF4
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Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol%) instead of
PTH1 and LiBF4
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a Reaction was carried out with 1a (0.6 mmol), 2a (0.2 mmol), PTH1 (0.02
mmol), and LiBF4 (0.02 mmol) in MeCN (0.6 mL) under blue LED
irradiation for 24 h. b 1H NMR yield based on 2a.
The screening of phenothiazine catalysts revealed that the
extension of -conjugation or the introduction of an electron
deficient group was important for the product yield (Table 1, entries
2–6). The reaction with simple N-phenyl-phenothiazine PTH2
resulted in low substrate conversion (entry 2). When PTH3
possessing an isomeric benzo[b]phenothiazine structure was used
instead of PTH1, the yield was significantly decreased (entry 3).
The reaction with N-3,5-dimethoxyphenyl-phenothiazine PTH4
did not improve the yield (entry 4). Although the use of a
trifluoromethyl-substituted phenothiazine PTH5 gave a result that
was comparable to that for PTH1, after a quick screening of
substrates, PTH1 was found to be the more versatile catalyst (entry
5). Additional introduction of electron-deficient groups into the N-
aromatic ring of PTH5 diminished the yield (entry 6). These
differences in catalyst performance were likely caused by the
efficiency of the catalyst excitation. The use of phenoxazine-type
POX117 resulted in moderate yield (entry 7). Other representative
photoredox catalysts based on Ir or Ru resulted in a complex
mixture with lower yields (entries 8–10).
Scheme 1. Organophotoredox-catalyzed C(sp3)–O bond formation
After screening of the reaction conditions based on our working
hypothesis, we found that the reaction between secondary alcohol
1a (0.6 mmol) and pivalic acid-derived redox active ester 2a (0.2
mmol) occurred in the presence of PTH1 (10 mol %)13a possessing
a benzo[b]phenothiazine scaffold and LiBF4 (10 mol %) as an
additive under irradiation with a blue LED to give 3aa in 81% yield
(Table 1, entry 1).15 Control experiments revealed that the
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Table 2. Substrate scopea
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a Reaction was carried out with 1a (0.6 mmol), 2a (0.2 mmol), PTH1 (0.02 mmol), and LiBF4 (0.02 mmol) in MeCN (0.6 mL) under blue LED irradiation for
24 h. b PTH4 (0.02 mmol) was used instead of PTH1. c The color of light was changed. d PTH6 (0.02 mmol) was used instead of PTH1. e PTH3 (0.02 mmol)
was used instead of PTH1. f 12 h. g Reaction was carried out with 2 (0.2 mmol), PTH1 (0.02 mmol), water (10 l) and LiBF4 (0.02 mmol) in acetone (0.8 mL)
under blue LED irradiation for 24 h.
With the optimized conditions in hand, we investigated the scope
of redox active esters (Table 2, top). Various acyclic tertiary carbon
fragments were introduced to the oxygen atom of the alcohol (3aa–
3ad). The low yield of 3ad is due to the competing formation of
styrene derivative caused by instability of the generated
carbocation. Tertiary benzyl groups could couple with the alcohol
to give the corresponding benzyl ethers in high yield due to the
stabilization of the cation by the aromatic ring (3ae and 3af). This
protocol was not limited to acyclic systems. 5- or 6-Membered
aliphatic rings could be utilized as coupling partners to furnish the
attractive and sterically hindered ether compounds (3ag–3ai). In
the case of the 5-membered ring, a significant amount of alkene
stemming from the elimination reaction of the redox ester alone
was observed as a side product (3ag). The adamantyl group could
be incorporated to the ether moiety by the use of PTH4 catalyst
(3aj). In addition to tertiary alkyl groups, secondary benzyl groups
successfully engaged with the alcohol (3ak and 3al). This reaction
also enabled access to the acetal and hemiaminal ether scaffolds by
use of -heteroatom-substituted carboxylic acid derivatives (3am
and 3an). Gemfibrozil- and Loxoprofen-derived redox active esters
underwent the decarboxylative etherification in moderate to good
yields (3ao and 3ap).
We next explored the scope of the alcohols in the C(sp3)–O bond
formation using tertiary benzylic carboxylic acid (Table 2, middle).
A variety of functional groups were tolerated in the primary alcohol
substrates. An alkyl halide and olefin, which might be eroded by
basic or transition-metal catalyzed reaction conditions, were
compatible (3ce and 3de). A primary alcohol substrate having a
thiazole group gave 3ee. Aliphatic heterocycle-substituted
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methanol substrates underwent the C–O bond formation (3fe–3je).
types of mechanisms are conceivable. One involves a radical–
radical coupling, and the other is an oxidation of C to a carbocation
by B. The latter mechanism may be more plausible for the
following two reasons. First, the organophotoredox catalysts
without a sulfur atom functioned in the reaction, albeit with low
yields (Table 1, entries 7–10). Secondly, the series of
phenothiazine-derived radical cations has sufficient redox potential
(E1/2 = 0.42–1.02 V vs SCE)21 to oxidize a tertiary alkyl radical to
a carbocation (tert-butyl, E1/2ox = 0.09 V vs SCE)22 based on cyclic
voltammetry measurements. Although the oxidation of a transient
alkyl radical is known as a challenging process,22 the persistent
radical effect of B might allow the oxidation by increasing the
concentration of the radical cations.23
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While the acetonide- and Boc-protecting groups would be removed
under the representative SN1 reaction conditions, our reaction
system was tolerant to such acid-sensitive protecting groups (3he–
3je). This is benefit of using the present method. Non-benzylic
tertiary redox active ester was also coupled with primary alcohol
albeit with a low yield (3gc). The significant reduction of the yield
would be due to the instability of the carbocation species (3gc v.s.
3ge).
Secondary alcohols were found to be competent coupling
partners (Table 2, middle). For example, the use of 4-
hydroxypiperidine, 4-hydroxyproline or nortropine derivatives was
possible with amide or ester moieties remaining untouched (3ke–
3me). 2-Oxetanol was also a suitable substrate (3ne). Testosterone
was tertiary-alkylated (3oe). When 1,2-hexanediol was subjected to
the reaction conditions, the alkylation occurred at the primary
alcohol over the secondary one (3pe). A primary alcohol was also
given preference over a secondary amide group (3qe). These
preferences were explained by the steric hindrance. Tertiary
alcohol substrates were also tested as a coupling partner, however,
no desired products were obtained (data not shown).
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In summary, the visible light-mediated organosulfide catalysis
enabled the decarboxylative coupling between simple aliphatic
alcohol, amide or thiol nucleophiles and tertiary or secondary alkyl
carboxylic acid-derived redox active esters to construct C(sp3)–X–
C(sp3) fragments. Mild conditions and the applicability to various
heteroatom nucleophiles are benefits of this protocol. The
organophotoredox catalysis involved the RPC
process, which enables the generation of a carbocation
from a carbon radical.24
Water could be utilized as a heteroatom nucleophile to realize
the formal decarbonylation of carboxylic acids (Table 2, bottom).18
Changing the reaction solvent from acetonitrile to acetone was of
great importance. Various tertiary carboxylic acids were easily
converted to the corresponding tertiary alcohols (4f, 4o and 4q).
ASSOCIATED CONTENT
Supporting Information. Experimental details
and characterization data for all new
compounds (PDF). This material is available
free of charge via the Internet at
http://pubs.acs.org.
Notably, the extension to other alkylheteroatom nucleophiles
could access the valuable C(sp3)–X–C(sp3) fragments (Table 2,
bottom). Specifically, Boc-protected primary amines could
participate in the reaction with tertiary benzylic redox ester 2e to
afford the sterically hindered secondary amides (6ae and 6be),
which are difficult to be accessed by SN1 type reactions.
Furthermore, this protocol provided a synthetic approach to dialkyl
thioethers. The conventional approach has relied on Williamson
ether synthesis-type reactions under highly basic conditions.19
Primary alkyl thiols were efficiently tertiary-alkylated with 2e (8ae
and 8be). The secondary alkyl thiol was also tolerated (8ce).
However, these C(sp3)–N and C(sp3)–S bond formations using
tertiary non-benzylic redox active esters were unsuccessful.
AUTHOR INFORMATION
Corresponding Authors
Kazunori Nagao: nkazunori@p.kanazawa-u.ac.jp
Hirohisa Ohmiya: ohmiya@p.kanazawa-u.ac.jp
ORCID
Kazunori Nagao: 0000-0003-3141-5279
Hirohisa Ohmiya: 0000-0002-1374-1137
We conducted mechanistic experiments to understand the details
of the present catalysis. The reaction with 2r under the optimal
conditions was examined (Scheme 2A). Only 3ar was obtained as
the sole product. This product formation indicated the generation
of an -oxycarbocation by a 1,2-hydride shift in the alkylsulfonium
or free carbocation. When 2s bearing a hydroxy group at the -
position was employed with the optimized conditions, the ring
expansion occurred to produce the mixture of 9s and 9s’ (Scheme
2B).20 This result also supported the intermediacy of the
carbocation in the organophotoredox reaction.
Author Contributions
║S.S. and T.K. contributed equally.
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI Grant
Number JP18H01971 to Scientific Research (B),
JSPS KAKENHI Grant Number JP17H06449 (Hybrid
Catalysis), Kanazawa University SAKIGAKE
project 2018, Takeda Pharmaceutical Company Limited and
JST, PRESTO Grant Number JPMJPR19T2 (to H.O.). We
also thank Dr. Taniyuki Furuyama at Kanazawa
University for his valuable assistance for
running CV and UV/Vis absorption experiments.
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