Photoinduced Specific Acylation of Phenolic Hydroxy Groups with Aldehydes

Article abstract of DOI:10.1002/anie.202008897

A convenient method is reported to specifically acylate phenolic hydroxyl groups through a radical pathway. When a mixture of an aldehyde and a phenol in ethyl acetate is irradiated with blue light in the presence of iridium and nickel bromide catalysts at ambient temperature, phenoxyl and acyl radicals are transiently generated in situ and cross-couple to furnish an ester. Aliphatic hydroxy groups remain untouched under the reaction conditions.

Full text of DOI:10.1002/anie.202008897

A Journal of the Gesellschaft Deutscher Chemiker
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International Edition
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Accepted Article
Title: Photoinduced Specific Acylation of Phenolic Hydroxy Groups with
Aldehydes
Authors: Tairin Kawasaki, Naoki Ishida, and Masahiro Murakami
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202008897
Link to VoR: https://doi.org/10.1002/anie.202008897

10.1002/anie.202008897
Angewandte Chemie International Edition
COMMUNICATION
Photoinduced Specific Acylation of Phenolic Hydroxy Groups
with Aldehydes
Tairin Kawasaki, Naoki Ishida,* and Masahiro Murakami*
[a]
T. Kawasaki, Dr. N. Ishida, Prof. Dr. M. Murakami
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University
Katsura, Kyoto 615-8510, (Japan)
E-mail: naisida@sbchem.kyoto-u.ac.jp, murakami@sbchem.kyoto-u.ac.jp
Supporting information for this article is given via a link at the end of the document.
Abstract: We herein report a convenient method to specifically
acylate phenolic hydroxyl groups through a radical pathway. When a
mixture of an aldehyde and a phenol in ethyl acetate is irradiated with
blue light in the presence of iridium and nickel bromide catalysts at
ambient temperature, phenoxyl and acyl radicals are transiently
generated in situ, and cross-couple to furnish an ester. Aliphatic
hydroxy groups remain untouched under the present reaction
conditions.
benzylic and aldehydic radicals which cross-couple on nickel.
The bond dissociation energies (BDEs) of phenolic O–H bonds
(362-378 kJ/mol)[9] are only slightly smaller than those of benzylic
C–H bonds (369-381 kJ/mol),[9] and a phenoxyl radical is
isoelectronic to a benzylic radical. When p-cresol was used as
the alkylarene in our previous study, acylation of the phenolic O–
H bond was observed in addition to that of the benzylic C–H
bond.[8] This led us to investigate an acylation reaction of phenols
with aldehydes in more detail, and it was found that 4-tert-
butylphenol (1) was successfully acylated with valeraldehyde 2
under the slightly modified conditions to give the O-acylated
product in high yield; a solution of 1 (0.20 mmol), valeraldehyde
(2, 0.24 mmol, 1.2 equiv), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.004
mmol, 2 mol%), and NiBr2(dtbbpy) (0.01 mmol, 5 mol%) in ethyl
acetate (5.0 mL) was irradiated with blue LEDs (lmax = 467 nm) at
ambient temperatures for 24 h.[10] Purification of the reaction
mixture by preparative thin-layer chromatography afforded
analytically pure ester 3 in 96% yield based on 1. Generation of
dihydrogen gas was confirmed by a GC analysis of the headspace
of the reaction vessel. It was possible to perform the reaction on
a 2.0 mmol scale. It required 48 h irradiation for completion, and
subsequent purification using column chromatography on silica
gel afforded the ester 3 in 88% isolated yield. No significant
amounts of other by-product were observed.
Most organic radicals are short-lived, and have been rarely
observed directly. However, a number of reactions via radical
intermediates have been developed.[1]
They offer unique
synthetic maneuvers that are difficult to perform with closed-shell
intermediates. One of the challenges of current interest is to
develop cross-coupling reactions between two specific radical
species.[2] Since radical–radical coupling reactions generally
proceed in a diffusion-controlled manner, homo-coupling
reactions occur competitively.
Phenols are readily subject to hydrogen atom abstraction to
generate phenoxyl radicals, which undergo homo-coupling
reactions forming C–C and C–O bonds at the ortho/para carbons
as well as at the oxygen.[3] It is also a facile process for aldehydes
to generate acyl radicals by hydrogen atom abstraction.[4] There
has been reported only a single example for a C–O bond forming
cross-coupling reaction of a phenoxyl radical with an acyl
radical;[5] when 2 equiv of 2,4-di-t-butyl-6-phenylphenoxyl radical,
which is a persistent phenoxyl radical protected by steric shielding,
reacts with 1 equiv of benzaldehyde, one phenoxyl radical
abstracts the aldehydic hydrogen atom and the resulting acyl
radical undergoes radical/radical coupling with the other phenoxyl
radical to form the corresponding ester. The bulky substituents
located at the 2,4,6-positions sterically shield the phenoxyl radical
from undesired side-reactions on the benzene core.[6] Here we
report a photoinduced acylation reaction of phenols with
t-Bu
visible light
Ir[dF(CF3)ppy]2(dtbbpy)PF6
H
O
(2 mol%)
1
NiBr2(dtbbpy)
t-Bu
(5 mol%)
O
+
AcOEt, RT
O
n-Bu
O
3
- H2
96% (0.2 mmol scale, 24 h)
88% (2.0 mmol scale, 48 h)
H
n-Bu
2
(1.2 equiv)
CF3
F
F
aldehydes.
Phenoxyl radicals, including those sterically
t-Bu
t-Bu
t-Bu
N
Ir
unprotected ones, and acyl radicals cross-couple in an
intermolecular fashion. The present reaction is unique in that
phenolic hydroxyl groups are specifically acylated in the presence
of aliphatic ones, being contrast to the conventional acylation
reactions (vide infra).[7]
N
N
F
F
PF6
N
N
Ni
N
t-Bu
Br
Br
CF3
NiBr2(dtbbpy)
Ir[dF(CF3)ppy]2(dtbbpy)PF6
We recently reported that a cooperative action of
light/iridium/bromide anion/nickel induced a dehydrogenative C–
H/C–H cross-coupling reaction of alkylarenes with aldehydes to
furnish a-aryl ketones.[8] The mechanism we proposed involves
Scheme 1. Dehydrogenative Esterification of 1 with 2.
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1

10.1002/anie.202008897
Angewandte Chemie International Edition
COMMUNICATION
Mechanistic insights of the present reaction were obtained
from the following experiments. A nickel(II) salt lacking a bromide
ligand, i.e., Ni(OAc)2 and dtbbpy were used in place of
NiBr2(dtbbpy) in the reaction shown in Scheme 1, and no reaction
occurred.[11] Interestingly, addition of (n-Bu)4NBr to the mixture
restored the reactivity, suggesting that a bromide anion was
essential. It is known that photoirradiation of a mixture of
[Ir[dF(CF3)ppy]2(dtbbpy)]+ and a bromide anion induces single
electron transfer from the bromide anion to iridium(III) to produce
a bromine radical, which abstracts a hydrogen atom from aliphatic
aldehyde 2 gradually decomposed.[21] The ineligibility of the
aliphatic alcohol can be ascribed to its much larger BDE (436-443
kJ/mol)[8] than that of the phenol 1.
Step 1. Anion Exchange
Br
[Ir(III)]+ [PF6]-
+
+
[Ir(III)]+ [Br]-
[Ni(II) Br]+
[PF6]-
Ni(II)
Br
D
C
A
B
Step 2. Generation of Ir(II) and Br Radical
hν
[Ir(III)]+ [Br]-
[Ir(III)]+* [Br]-
Ir(II)
+
and aldehydic C–H bonds.[12]
We have observed that
Br
single
electron
transfer
E
C*
C
NiBr2(dtbbpy) reacts with Ir[dF(CF3)ppy]2(dtbbpy)PF6 to generate
an iridium complex to which a bromide anion binds.[8] It is likely
that the bromide anion binds to the 3- and 3’-positions of the
bipyridine ligand through hydrogen bonding.[13] Stern-Volmer
quenching experiments indicated that the photoexcited iridium(III)
complex was quenched by NiBr2(dtbbpy), but not by the phenol 1
or the aldehyde 2. We next carried out a radical trapping
experiment using TEMPO. Under the conditions that were
otherwise identical to those described in Scheme 1, an acylated
TEMPO was isolated,[11] being indicative of generation of an acyl
radical species. We observed that phenols became less reactive
as the BDEs of their O–H bonds increased by installation of
electron-withdrawing substituents on the benzene rings (vide
infra).[14] This electronic trend is suggestive of generation of a
phenoxyl radical from a phenol.
Step 3. Generation of Phenoxyl Radical
t-Bu
H
t-Bu
O
1
Br
+
HBr
O
Step 4. Addition of Phenoxyl Radical to Nickel(I)
t-Bu
t-Bu
Ni(I) Br
+
F
O
O Ni(Ⅱ) Br
G
Step 5. Generation of Acyl Radical
O
On these bases, we postulate the mechanistic pathway
depicted in Scheme 2, which is slightly different from that we
previously assumed for the dehydrogenative C–H/C–H coupling
reaction.[8] It consists of eight steps (Steps 1–8). Step 1; the
hexafluorophosphate anion of the cationic iridium(III) complex
exchanges with a bromide anion. Step 2; the iridium(III) bromide
complex C gets excited by light to induce single electron transfer
from the bromide anion to iridium(III). Thus, a bromine radical and
iridium(II) species E are generated.[12] Step 3; the bromine radical
takes away a hydrogen atom from the phenol 1 in preference to
the aldehyde 2.[15] Step 4; the resulting phenoxyl radical adds
onto the nickel(I) species F, which is generated by Step 6 (vide
infra), to form phenoxynickel(II) species G. Step 5; although
slower than the phenol 1, the aldehyde 2 also undergoes
hydrogen atom abstraction to generate an acyl radical, which
adds to the preformed phenoxynickel(II) species G.[16] Step 6; the
resulting nickel(III) species H undergoes reductive elimination to
form an ester linkage. Step 7; the nickel(I) species F reacts with
HBr to evolve dihydrogen and the Ni(II)Br2 species.[17] Step 8; the
iridium(II) E (E1/2[Ir(III)/Ir(II)] = -1.37 V vs SCE)[18] reacts with Ni(II)
species B (E1/2[Ni(II)/Ni(0)] = -1.2 V vs SCE)[19] to regenerate the
Ni(I) species F and the iridium(III) bromide C.[20]
O
2
H
R
+
Br
HBr
R
Step 6. Formation of Ester Linkage
t-Bu
t-Bu
O
+
R
O Ni(ⅡI) Br
O Ni(Ⅱ) Br
G
O
R
H
t-Bu
O
+
Ni(I) Br
F
O
R
3
Step 7. Hydrogen Evolution
Br
Ni(I) Br
+
+
+
1/2 H2
HBr
Ni(II)
Br
F
B
Step 8. Regeneration of Ir(III)
Br
Ir(II)
+
Ni(I) Br
[Ir(III)]+ [Br]-
Ni(II)
Br
F
E
C
A different mechanistic scenario is also conceivable;
nucleophilic addition of a phenol to an aldehyde gives rise to a
hemi-acetal, and the subsequent dehydrogenation affords an
ester.[7] Thus, we subjected the six-membered cyclic hemi-acetal
4 to the reaction conditions in order to see if dehydrogenation
B
Scheme 2. Possible Mechanistic Pathway.
occurred (Scheme 3).
However, no formation of the
visible light
Ir[dF(CF3)ppy]2(dtbbpy)PF6
(2 mol%)
NiBr2(dtbbpy)
(5 mol%)
dehydrogenated lactone 5 was observed and the starting material
remained intact, making the mechanism mentioned above
unlikely.
AcOEt, RT, 24 h
O
OH
O
O
We next used 1-octanol (6) instead of the phenol 1 in the
reaction with the aldehyde 2 to examine the eligibility of aliphatic
alcohols (Scheme 4). 1-Octanol (6) remained intact and the
5
4
not formed
(0.20 mmol)
2
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10.1002/anie.202008897
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COMMUNICATION
Scheme 3. Attempt of Dehydrogenation of Hemi-Acetal 4.
O–H bond becomes stronger as the electron density of the
benzene ring decreases upon introduction of the acyl group.[14]
n-Oct
H
visible light
Ir[dF(CF3)ppy]2(dtbbpy)PF6
(2 mol%)
NiBr2(dtbbpy)
(5 mol%)
O
H
H
visible light
O
O
6
(0.20 mmol)
Ir[dF(CF3)ppy]2(dtbbpy)PF6
(2 mol%)
NiBr2(dtbbpy)
(5 mol%)
11
O
(0.20 mmol)
+
n-Oct
O
O
O
n-Bu
+
AcOEt, RT, 24 h
H
AcOEt, RT, 24 h
O
O
n-Bu
7 not formed
O
H
n-Bu
2
(0.24 mmol)
12 63%
H
n-Bu
2
(0.24 mmol)
Scheme 4. Attempt to Acylate Aliphatic Alcohol 6 with 2.
Scheme 6. Reaction of m-Dihydroxybenzene (11).
This unique chemo-specificity of the present method is
noteworthy. Although a number of acylation reactions of hydroxy
groups with aldehydes have been developed,[7] they mostly
proceed through either (A) oxidation of the hemiacetal
intermediate or (B) oxidation of the Breslow intermediates
followed by nucleophilic addition of a hydroxy group. Those
methods would acylate both aliphatic and phenolic hydroxy
groups.
Various phenols underwent the dehydrogenative C–O bond
forming reaction with the aldehyde 2 (Table 1). Excellent yields
were obtained with phenols having electron-donating substituents
(13-16), 4-phenylphenol (17), and 2-naphthol (18). The BDE of
their O–H bonds are smaller than that of simple phenol.[14] In the
case of simple phenol (19), the initial hydrogen atom abstraction
step generating a phenoxyl radical was slower, and the
counterpart acyl radical gradually decomposed meanwhile to
lower the yield.[21] The yield was improved when the aldehyde 2
was added in five portions over 120 h. The reaction of phenols
having strongly electron-withdrawing groups such as a
methoxycarbonyl group was sluggish, and the corresponding
ester was produced in less than 20%. The substituent effect
observed with phenols is in accordance with the mechanism
involving generation of a phenoxyl radical from a phenol. Even
phenols whose hydroxy groups were sterically hindered by ortho
substituents were eligible substrates (20-22). Fluoro (23) and
chloro substituents (24) were tolerated on the benzene ring.
We next re-investigated the acylation reaction of p-cresol (8)
(Scheme 5). As described in the previous report,[8] a mixture of
the C–O bond forming product 9 and the C–C bond forming
product 10 was produced under the standard reaction conditions
(the ratio of 2/8 = 1/1). Interestingly, the C–O bond forming
product 9 was produced almost exclusively with 2/8 = 5/1. Albeit
uncertain, this unexpected shift in site-selectivity is possibly
explained by considering abundance of the radical species. A
bromine radical abstracts a hydrogen atom from the O–H bond in
preference to the benzylic and aldehydic C–H bonds, reflecting
their BDEs.[9] With the ratio of 2/8 = 1/1, the dominant generation
of the phenoxyl radical is probably moderately offset by its
sluggishness to couple with the acyl radical, resulting in the
production of similar amounts of 9 and 10. With the ratio of 2/8 =
5/1, however, the abundance of the aldehyde steers a bromine
radical to the aldehydic C–H bonds rather than to the benzylic C–
H bond. As a result, the generation of the benzylic radical is
minimized to produce 9 selectively.
The reaction showed a wide scope also with regard to
aldehydes. Simple aliphatic aldehydes (25-29) and those having
carbamate (30), ester (31), acetal (32), and hydroxy (33) groups
all reacted well with the phenol 1. The reaction of aromatic
aldehydes was slower,[22] and necessitated irradiation with more
intense light for a longer period of time in order to attain
reasonable yields (34-37). The lower reactivity of aromatic
aldehydes is possibly ascribed to the inductive effect of the
aromatic group which would make the aldehydic hydrogen less
electron-rich. Since the bromine radical is electrophilic, the
process of hydrogen atom abstraction from aromatic aldehydes
would be slower. This postulation accords with the results that
the higher yields were observed with p-tolualdehyde and p-
anisaldehyde than with benzaldehyde.[23]
H
H3C
visible light
Ir[dF(CF3)ppy]2(dtbbpy)PF6
(2 mol%)
NiBr2(dtbbpy)
(5 mol%)
O
H
O
O
n-Bu
8
(0.20 mmol)
9
+
+
AcOEt, RT, 24 h
O
n-Bu
H
n-Bu
O
OH
The synthetic utility of the present method was highlighted by
the reaction of naturally-occurring phenols (Scheme 7). a-
Tocopherol (38) successfully engaged in the reaction with the use
of 5.0 equiv of the aldehyde 2 in spite of the fact that its hydroxy
group was significantly encumbered by the two ortho methyl
groups. Optically pure a-amino acid 40 efficiently reacted with 1.2
equiv of aldehyde 2 with the stereochemical integrity of the a-
carbon retained. Of particular note was that phenolic glycoside
42 (b-arbutin) was acylated selectively at the phenolic hydroxy
group with the other aliphatic ones in the glycosyl unit remaining
untouched. No epimerization occurred at the anomeric center nor
at other chiral centers. A conventional synthesis of O-acylated
2
(x mmol)
10
x
2/8
9
10
0.20
1.0
1
5
38% 33%
87% 0%
Scheme 5. Site-selectivity Experiment.
The reaction of m-dihydroxybenzene (11) with 2 (1.2 equiv)
afforded mono-ester 12 selectively, and the corresponding di-
ester was not formed (Scheme 6). This is because the phenolic
3
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10.1002/anie.202008897
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COMMUNICATION
Table 1. Substrate Scope.
visible light
Ir[dF(CF3)ppy]2(dtbbpy)PF6
(2 mol%)
NiBr2(dtbbpy)
(5 mol%)
O
O
Ar
H
+
O
Ar
H
(1.2 equiv)
R
AcOEt, RT, 24 h
O
R
Scope of Phenols
O
MeO
n-BuO
Ph
O
O
O
O
O
O
n-Bu
MeO
O
n-Bu
O
n-Bu
n-Bu
O
n-Bu
O
n-Bu
O
n-Bu
OMe
15 89%[c)
16 71%[c]
18 99%[c]
14 84%
17 93%
13 88%[b]
t-Bu
Me
Me
O
O
O
F
Cl
O
O
O
O
O
O
n-Bu
O
n-Bu
O
n-Bu
O
n-Bu
n-Bu
Ph
t-Bu
Me
22 62%[e]
19 54%[d]
23 76%[d]
24 66%[d]
20 64%
21 71%
Scope of Aldehydes (Ar = 4-t-butylphenyl)
O
O
O
O
O
O
O
Ar
Ar
Ar
CO2Me
Ar
Et
Ar
Me
10
O
O
O
Ar
O
Ar
O
O
Me
O
Ph
NBoc
NBoc2
31 46%
Me
25 80%[e]
26 94%
28 90%
29 64%
27 77%
30 72%
O
O
O
O
O
Me
MeMe
OH
O
Ar
Ar
Ar
Ar
O
O
O
O
O
O
Ar
Ar
O
O
Ph
3
Me
Me
OMe
NHAc
33 97%
34 59%[f]
35 68%[f]
36 78%[f]
37 49%[f]
32 62%
[a] Reaction conditions: phenol derivatives (0.20 mmol, 1.0 equiv), aldehydes (0.24 mmol, 1.2 equiv), NiBr2(dtbbpy) (0.01 mmol, 5 mol%), Ir[dF(CF3)ppy]2(dtbbpy)PF6
(0.004 mmol, 2 mol%), AcOEt (5 mL), blue LEDs (23 W, λmax = 467 nm), ambient temperature, 24 hours otherwise noted. [b] 72 h. [c] 120 h. [d] Aldehydes were
added in five portions (0.20 mmol each) over 120 h. [e] 5.0 Equiv of aldehydes. [f] 72 h. High power blue LEDs (40 W, λmax = 463 nm).
visible light
2 (1.0 mmol)
Ir[dF(CF3)ppy]2(dtbbpy)PF6
(2 mol%)
phenolic glycosides necessitates protection/deprotection of
aliphatic hydroxy groups.[24] The present acylating method
Me
Me
Me
Me
Me
Me
provides a synthetic advantage that they can be synthesized
starting from plant-origin phenolic glycosides without the need for
protection/deprotection of the glycosyl unit.
Me
O
O
R
Me
O
R
NiBr2(dtbbpy) (5 mol%)
O
AcOEt, RT, 120 h
n-Bu
HO
In summary, we have developed a dehydrogenative acylation
reaction of phenols with aldehydes forming the corresponding
esters. It presents a unique example in which phenoxyl radicals
lacking steric shielding are intermolecularly trapped by acyl
radicals. It is noteworthy that only phenolic O–H bonds are
acylated and aliphatic ones remain intact. This feature stands in
contrast to the results of a standard reaction to acylate a
nucleophilic hydroxy group with activated acylating agents such
as acyl chlorides. The present method provides a general and
straightforward method to synthesize esters even from naturally-
occurring phenol derivatives.
Me
3
Me
R =
38 (0.20 mmol)
39 53%
O
O
visible light
2 (0.24 mmol)
Ir[dF(CF3)ppy]2(dtbbpy)PF6
(2 mol%)
NiBr2(dtbbpy) (5 mol%)
OH
n-Bu
CO2Me
AcOEt, RT, 24 h
CO2Me
Boc
HN
Boc
HN
40 (0.20 mmol)
41 62%, >99% ee
>99% ee
O
Acknowledgements
visible light
2 (0.24 mmol)
n-Bu
O
O
OH
Ir[dF(CF3)ppy]2(dtbbpy)PF6
(2 mol%)
NiBr2(dtbbpy) (5 mol%)
This work was supported by JSPS KAKENHI Grant Numbers
15H05756 (M.M.), 18H04648 (Hybrid Catalysis) (N.I.), and
20H04810 (Hybrid Catalysis) (N.I.). We thank Prof. Kenji
Matsuda, Prof. Kenji Higashiguchi, and Mr. Yusuke Nakakuki
(Kyoto Univ.) for their assistance with photophysical analysis, and
Prof. Ryu Abe and Prof. Masanobu Higashi, Prof. Osamu Tomita
OH
OH
O
O
HO
HO
HO
HO
O
AcOEt, RT, 24 h
OH
OH
42 (0.20 mmol)
43 60%
Scheme 7. Esterification Reactions of Natural Product Derivatives.
4
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10.1002/anie.202008897
Angewandte Chemie International Edition
COMMUNICATION
[17] D. C. Powers, B. L. Anderson, D. G. Nocera, J. Am. Chem. Soc. 2013,
135, 18876-18883.
(Kyoto Univ.) for their assistance with analysis of the evolved
hydrogen gas.
[18] M. S. Lowry, J. I. Goldsmith, J. D. Slinker, R. Rohl, R. A. Pascal, G. G.
Malliaras, S. Bernhard, Chem. Mater. 2005, 17, 5712-5719.
[19] M. Durandetti, M. Devaud, J. Perichon, New J. Chem. 1996, 20, 659-667.
[20] For the detailed mechanistic studies on the iridium/nickel-catalyzed
cross-coupling reactions, see: a) B. J. Shields, G. D. Scholes, A. G.
Doyle, J. Am. Chem. Soc. 2018, 140, 3035-3039; b) R. Sun, Y. Qin. S.
Ruccolo, C. Schnedermann, C. Costentin, D. G. Nocera, J. Am. Chem.
Soc. 2019, 141, 89-93.
Keywords: Cross-coupling • Photocatalysis • Nickel • Phenols •
Aldehydes
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[10] Control experiments confirmed that visible light, iridium, and nickel
catalysts were all essential.
[11] See SI for details.
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[15] DFT calculation at M06-2x/6-311G+(d,p) level of theory indicated that the
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H bond of acetaldehyde by 6.4 kJ/mol.
[16] Diphenoxylnickel(III) species would be reversibly formed from the
nickel(II) species G and the phenoxyl radical. However, reductive
elimination producing a peroxide would be unfavorable.
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10.1002/anie.202008897
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
O
H
O
visible
n-Bu
O
O
light
O
OH
+
OH
n-Bu
H
Ir + NiBr2 cat.
O
O
HO
HO
O
HO
HO
OH
OH
Esters are synthesized from phenols and aldehydes through coupling of phenoxyl and acyl radicals that are transiently generated.
The present reaction offers a convenient method to specifically acylate phenolic hydroxyl groups in the presence of aliphatic ones.
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