Photocatalytic α-Acylation of Ethers

Article abstract of DOI:10.1021/acs.orglett.7b01552

Direct coupling of ethers and acyl halides was promoted by a binary catalytic system comprising an Ir-based photocatalyst and a Ni complex under blue-light irradiation. Photocatalysts with high triplet energy directed the catalysis, and the reaction likely proceeded by triplet-triplet energy transfer from the excited photocatalysts. Chlorine radicals generated from an excited Ni complex bearing a Ni-Cl bond would be responsible for generating α-oxy radicals leading to the α-acylated ethers.

Full text of DOI:10.1021/acs.orglett.7b01552

Letter
pubs.acs.org/OrgLett
Photocatalytic α‑Acylation of Ethers
Zhongdong Sun, Naoya Kumagai,* and Masakatsu Shibasaki*
Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
*
S Supporting Information
ABSTRACT: Direct coupling of ethers and acyl halides was
promoted by a binary catalytic system comprising an Ir-based
photocatalyst and a Ni complex under blue-light irradiation.
Photocatalysts with high triplet energy directed the catalysis,
and the reaction likely proceeded by triplet−triplet energy
transfer from the excited photocatalysts. Chlorine radicals
generated from an excited Ni complex bearing a Ni−Cl bond
would be responsible for generating α-oxy radicals leading to
the α-acylated ethers.
isible-light photoredox catalysis has profoundly advanced
Scheme 1. Visible-Light-Mediated Acylation Reactions with
Ni/Ir
V
over the last several years, demonstrating the high
versatility of reaction manifolds harnessed with photoirradiation
in a wide variety of C−C and C−heteroatom bond-forming
1
reactions. Direct photoexcitation of organic substrates by
visible light is unlikely to be manifested, however, as organic
substrates only barely absorb visible light. On the other hand,
photosensitizers are amenable to converting the photoenergy of
visible light into chemical energy to activate organic molecules
via single-electron transfer (SET) or energy transfer, which is
attracting growing interest for the development of unprece-
dented chemical transformations. The broad compatibility of
photocatalytic cycles with organocatalysis and metal-based
catalysis further extends the scope of the synthetically versatile
reactions empowered by visible-light irradiation. These dual
2
3
catalytic systems allow for a diverse array of C(sp )−C(sp )
3
3
and C(sp )−C(sp ) bond-forming reactions using stable
2
3
4
pronucleophile carboxylates, trifluoroborates, and silicates
instead of organometallic nucleophiles, where photocatalytic
generation of an active nucleophile plays a critical role in
driving the catalysis.
The light-driven Ir/Ni catalysis strategy has been intensively
studied, and its particular utility in photocatalytic installation of
acyl units has been proven. MacMillan et al. documented a
decarboxylative coupling reaction of carboxylic acids and acy5l
chlorides via Ir photoredox and Ni catalysis (Scheme 1a).
Subsequently, the light-mediated direct α-acylation of amines
using anhydride as the acylation reagent has been achieved by
versatile α-oxygenated ketones. Herein, we report the direct α-
C(sp )−H acylation of ethers via Ir/Ni synergistic catalysis
(Scheme 1d).
3
At the outset, we selected benzoyl chloride 1a as an
archetypal acyl chloride in the reaction with THF. Based on the
proficiency of the precedent Ir/Ni binary catalytic system in α-
arylation of ethers using aryl halides reported independently by
6
Doyle et al. (Scheme 1b). Molander et al. recently developed a
protocol accessing dialkyl ketone from organotrifluoroborate
10,11
Molander and Doyle,
we examined a combined catalytic
and acyl chloride using synergistic photoredox/Ni catalysis
3
h
system comprising Ir[dF(CF )ppy] (dtbbpy)PF (dF(CF )ppy
(
Scheme 1c). However, photocatalytic α-acylation of ethers
3
2
6
3
=
2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine, dtbbpy =
has not been disclosed despite its potential synthetic utility.
3
4,4′-di-tert-butyl-2,2′-bipyridine) and Ni complexes at room
Direct α-C(sp )−H functionalization of ethers has been a
temperature under visible-light irradiation (blue LED, 21 W).
sustained topic in photocatalytic systems, revealing that α-
arylation of ethers is feasible where radicals play a key role in
7
−11
activation.
We reasoned that this prior work could also be
Received: May 22, 2017
valid for the coupling with acyl chlorides to afford synthetically
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01552
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With readily available NiCl as the Ni source, a brief survey of
2
ligands and bases indicated that the reported combination of
the Ir photocatalyst and L2 was optimal with K PO , affording
3
4
2
a in 66% yield (Table 1, entries 1−9). Concentrated
conditions partially improved the yield (entry 6 vs 10).
a
Table 1. Conditions Screening of α-Benzoylation of THF
b
entry
ligand
concn (M)
base
yield (%)
1
2
3
4
5
6
7
8
9
L1
L1
L1
L1
L1
L2
L3
L4
L5
L2
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.2
K CO
31
<10
40
2
3
CS CO
2
3
K PO
3
4
DBU
<10
<10
66
Et N
3
K PO
3
4
4
4
4
4
K PO
3
50
K PO
3
28
K PO
3
29
10
K PO
3
77
Figure 1. Substrate generality of photocatalytic α-acylation of ethers.
Reactions were run using 0.4 mmol of acyl chloride 1 in the designated
ethereal solvent (0.2 M). Isolated yield is reported. (a) 69% yield was
obtained from a 1.0 mmol scale reaction. (b) dr = diastereomeric ratio.
(c) Regioisomer (acylation on Me group) was isolated in 21% yield.
a
b
1
Reactions were run using 0.2 mmol of 1a. Determined by H NMR
analysis of crude mixture using 1,3,5-trimethoxybenzene as an internal
standard.
III/II
initiated by excited *Ir[dF(CF )ppy] (dtbbpy)PF (E1/2*
=
3
2
6
14
1
.21 V vs SCE in MeCN) was unlikely. Consistent with the
recent independent reports of direct α-oxy C(sp )−H arylation
by Molander and Doyle, we reasoned that a chlorine radical
was responsible for the catalytic generation of the α-oxy C(sp )
radical from ethers (BDE of H−Cl: 102 kcal/mol, BDE of
THF: 92 kcal/mol). Chlorine radicals could be formed by
3
Having determined the optimized conditions, we evaluated
the scope of both the acyl chlorides and ethers (Figure 1). A
variety of benzoyl chloride derivatives bearing electron-
donating and -withdrawing groups were coupled with THF to
deliver the corresponding α-acylation products (2a−j). While
some cases had only moderate conversion, the reactions were
generally clean and only trace amounts, if any, of unidentified
products were detected. Halogen substitutions on the aromatic
ring were tolerated without undesired dehalogenation (2e−h).
Aliphatic acyl chlorides were accommodated in the present
catalytic system to engage in the coupling reaction with THF
10
11
3
15
homolysis of the Ni−Cl bond of Ni(II) complex 3 upon
excitation via triplet−triplet energy transfer from the excited Ir
16,17
photocatalyst (Figure 2).
To test this hypothesis, we performed the following set of
experiments. First, isolated Ni(II) acyl chloride complex 3,
prepared from Ni(cod)/L2 and 1a (eq 1), was subjected to
(2k−p). A cyclopropane derivative remained intact during the
reaction and provided the corresponding ketone product 2m in
high yield (85%). The successful coupling reactions using
sterically congested 1-adamantanecarbonyl chloride and (S)-
camphanic chloride showcased the robustness of this catalytic
system (2o,p). Notably, the present catalysis was not limited to
THF; cyclic (2q,r) and acyclic ethers (2s,t) were also
applicable, albeit generally resulting in only a moderate yield.
To gain additional insight into the present α-C−H
functionalization of ethers, a series of control experiments
were conducted to probe the mechanistic aspects. A
reactions of THF and 1a with various photosensitizers under
visible-light irradiation (Table 2). The reaction proceeded with
photosensitizers with high triplet energy (E ), e.g., Ir[dF-
T
18
(CF )ppy] (dtbbpy)PF (60.1 kcal/mol) (entries 1). In
3
2
6
competition experiment using a mixture of THF/THF-d (1/
contrast, photosensitizers with lower triplet energy failed to
facilitate the reactions efficiently and produced only trace
amounts of product (entries 2 and 4). Particularly noteworthy
is the poor yield obtained from the reaction using [9-
8
1
, v/v) as the substrate gave a higher fraction of THF-derived
12
3
product 2a (k /k = 2.4), indicating that α-C(sp )−H bond
cleavage was at least partly involved in the rate-determining
step. Given that ethers possess relatively high oxidation
H
D
MesAcr]ClO , which has a much higher oxidation potential
4
13
PS/PS
potentials (for THF, E = 1.75 V vs SCE), cleavage of the
(E *
= 2.06 V vs SCE in MeCN) than Ir[dF(CF )-
3
19
1
/2
3
α-oxy C(sp )−H bond through a SET/deprotonation process
ppy] (dtbbpy)PF , suggesting that oxidation of Ni(II) to
2 6
B
DOI: 10.1021/acs.orglett.7b01552
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. α-Benzoylation of THF under UV (254 nm)
Irradiation
state of 3; however, photoreduction to Ni(I) and the
9
involvement of a Ni(I)/Ni(III) cycle cannot be ruled out.
On the basis of the above experiments, a plausible catalytic
cycle is delineated in Figure 2. The Ir photosensitizer with high
ET serves as an energy shuttle, passing energy from its long-
lived triplet excited state to Ni(II) complex 3 generated by
oxidative addition of acyl chlorides 1, engaging triplet−triplet
energy transfer to produce an excited triplet state of Ni(II)
complex 4. This pivotal intermediate presumably undergoes
Ni−Cl homolysis to generate a chlorine radical, which is
responsible for the abstraction of α-hydrogen from ethers.
3
Subsequent capture of the thus-formed α-oxy C(sp ) radical by
the Ni catalyst gives 5. Reductive elimination of 5 delivers the
corresponding α-acylated product 2 and thereby regenerates
the Ni(0) complex to drive the subsequent catalytic cycles. In
addition to acyl chlorides, we found that acyl anhydride 6 and
mixed anhydride 8 could be exploited in the present catalytic
Figure 2. Plausible catalytic cycle.
a
Table 2. Reactions Using Ni(II) Complex 3
acylation protocol using NiCl as the Ni source, albeit in
2
somewhat lower yield (Scheme 3a). Ni(OAc) was a competent
2
Scheme 3. Reactions Underscore the Importance of the
Chloride Anion
b
E *M/M
(V)
λmax
ET
yield
entry
1
photosensitizer
(nm) (kcal/mol)
(%)
Ir[dF(CF3)
1.21
470
60.1
65
ppy] (dtbbpy)PF
2
6
2
3
4
5
Ir(ppy)3
0.31
2.05
0.77
−
518
590
615
55.2
−
46.5
trace
trace
trace
trace
[9-MesAcr]ClO4
Ru(bpy) Cl2
3
−
−
−
a
b
1
Reactions were run using 0.2 mmol of 1a. Determined by H NMR
analysis of crude mixture using 1,3,5-trimethoxybenzene as an internal
standard.
Ni(III) via SET might not be operative in the reaction (entry
3
). The UV−vis spectrum of complex 3 showed no detectable
20
absorption in the visible-light region (400−600 nm),
consistent with the failed reaction when no photosensitizer
was used under visible-light irradiation (entry 5). An intense
absorption band in the UV region for complex 3 suggested that
UV irradiation resulted in excitation of complex 3 into an
excited singlet state that led to the excited triplet state through
intersystem crossing and relaxation. Indeed, the catalysis
proceeded without a photosensitizer to deliver product 2a in
Ni source for the reaction of acyl chloride 1a, but this was not
the case for acyl anhydride 6 (Scheme 3b). The observed
n
reaction with 6 using a chloride additive ( Bu NCl) confirmed
4
41% yield after 8 h of UV (254 nm) irradiation (Scheme 2a),
that Ni complex 7, which was initially generated after oxidative
addition of 6, underwent a ligand exchange to give chloride
complex 3, entering into the productive catalytic cycle
mentioned above (Figure 2).
whereas the reaction did not proceed with UV (254 nm)
irradiation alone in the absence of complex 3 (Scheme 2b).
This observation supports the involvement of the excited triplet
C
DOI: 10.1021/acs.orglett.7b01552
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
In summary, we developed a direct α-C(sp )−H acylation of
ethers using an Ir and Ni binary catalytic system under visible-
light irradiation. Cyclic and acyclic ethers, as well as acyl
chlorides and anhydrides, were compatible to produce α-
acylated ethers. The corresponding control experiments
suggested that triplet−triplet energy transfer was key to
generating the chlorine radicals, which would be responsible
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3
for the α-C(sp )−H activation of ethers. Our ongoing research
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ASSOCIATED CONTENT
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Chem. 2017, 6, 669.
■
*
S
(10) Heitz, D. R.; Tellis, J. C.; Molander, G. A. J. Am. Chem. Soc.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01552.
2
016, 138, 12715.
(11) Shields, B. J.; Doyle, A. G. J. Am. Chem. Soc. 2016, 138, 12719.
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Experimental details and characterization data (PDF)
(
AUTHOR INFORMATION
Corresponding Authors
■
*
*
(
E-mail: nkumagai@bikaken.or.jp.
E-mail: mshibasa@bikaken.or.jp.
ORCID
(
excited photosensitizer to organic molecules, see: (a) Demas, J. N.;
Addington, J. W. J. Am. Chem. Soc. 1976, 98, 5800. (b) Juris, A.;
Gandolfi, M. T.; Manfrin, M. F.; Balzani, V. J. Am. Chem. Soc. 1976, 98,
Naoya Kumagai: 0000-0003-1843-2592
Masakatsu Shibasaki: 0000-0001-8862-582X
Notes
1
047. (c) Juris, A.; Manfrin, M. F.; Maestri, M.; Serpone, N. Inorg.
Chem. 1978, 17, 2258. (d) Marciniak, B.; Buonocore, G. E. Spectrosc.
Lett. 1990, 23, 149.
(
17) For triplet−triplet energy transfer from a photosensitizer to an
The authors declare no competing financial interest.
organometallic complex with detailed mechanistic study, see: Welin, E.
R.; Le, C.; Arias-Rotondo, D. M.; McCusker, J. K.; MacMillan, D. W.
C. Science 2017, 355, 380.
ACKNOWLEDGMENTS
This work was financially supported by ACT-C
JPMJCR12YO) from JST and KAKENHI (25713002,
7H03025, and JP16H01043 in Precisely Designed Catalysts
■
(
(18) Teegardin, K.; Day, J. I.; Chan, J.; Weaver, J. Org. Process Res.
Dev. 2016, 20, 1156.
(19) Ohkubo, K.; Mizushima, K.; Iwata, R.; Souma, K.; Suzuki, N.;
Fukuzumi, S. Chem. Commun. 2010, 46, 601.
1
with Customized Scaffolding) from JSPS.
(20) See the Supporting Information.
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DOI: 10.1021/acs.orglett.7b01552
Org. Lett. XXXX, XXX, XXX−XXX