Silver-Catalyzed Asymmetric Insertion into Phenolic O?H Bonds using Aryl Diazoacetates and Theoretical Mechanistic Studies

Article abstract of DOI:10.1002/chem.201902126

An enantioselective insertion reaction of silver carbenes generated from donor–acceptor-substituted diazo compounds into the O?H bond of phenols was developed. A homobinuclear silver complex with a chiral phosphorous ligand was created in situ from AgNTf<

Full text of DOI:10.1002/chem.201902126

A Journal of
Accepted Article
Title: Silver-Catalyzed Asymmetric Insertion into Phenolic O–H Bonds
using Aryl Diazoacetates and Theoretical Mechanistic Studies
Authors: Shingo Harada, Koki Tanikawa, Haruka Homma, Chigaya
Sakai, Tsubasa Ito, and Tetsuhiro Nemoto
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10.1002/chem.201902126
Chemistry - A European Journal
COMMUNICATION
Silver-Catalyzed Asymmetric Insertion into Phenolic O–H Bonds
using Aryl Diazoacetates and Theoretical Mechanistic Studies
Shingo Harada,*,[a] Koki Tanikawa,[a] Haruka Homma,[a] Chigaya Sakai,[a] Tsubasa Ito,[a] and Tetsuhiro
Nemoto*[a,b]
Abstract: An enantioselective insertion reaction of silver carbenes
generated from donor-acceptor-substituted diazo compounds into the
O–H bond of phenols was developed. A homobinuclear silver complex
with a chiral phosphorous ligand was created in situ from AgNTf2 and
(S)-XylylBINAP (a 2-to-1 mole ratio). Detailed mechanistic studies
using combined experimental and computational techniques revealed
that one silver atom center of the catalyst forms a silver carbene and
another one works as a Lewis acid for the nucleophilic addition of a
phenol. Two counteranions, two water molecules, and two silver
atoms cooperatively mediate the subsequent protonation event to
lower the activation energy and control enantioselectivity, affording an
array of valuable α-aryl-α-aryloxy esters.
metal catalysis for synthesizing these molecules in an
enantioenriched form.[4-9] In 2006, Fu achieved a chiral copper
complex-catalyzed O–H insertion reaction of aliphatic alcohols,
but the insertion reaction into the phenolic hydroxy group
proceeded with only 11% enantiomeric excess (eq 3, Scheme
1).[6a] Although other attempts using copper catalysis with chiral
ligands continue to improve the enantioselectivity, the results
were unsatisfactory (7%[8b], 10% ee[8a]). In 2014, palladium
complexes with chiral spirobisoxazoline ligands were found to be
effective for a highly enantioselective O–H insertion of α-aryl-α-
diazo methyl ester into phenols reported by Zhu and Zhou
10
]
11 ]
group,[8d] while Lan, Shi[
and Liu, Zhang[
groups
independently reported that a gold catalyst chemoselectively
caused the C–H bond functionalization of phenols.[ 12 , 13 ] The
development of an insertion reaction into the O–H bond of
phenols with stereocontrol, however, remains a challenge.[6h]
Whereas chiral rhodium, copper, and palladium catalysts have
been employed for carbene-transfer reactions,[14] silver-carbene
α-Aryl-α-aryloxy-carbonyl functionalities are biologically
fascinating molecular structures and a useful platform in organic
synthesis. The class of molecules containing the functional group
system and their variants possess an array of bioactivities, as
represented by MBX and Cymbalta (duloxetine) shown in Figure
1.[1,2] Commonly applied approaches for the asymmetric synthesis
of these valuable scaffolds, however, require multistep processes
based on chiral pool synthesis or the utilization of chiral
auxiliaries.[ 3 ] Therefore, the development of efficient synthetic
methods for the molecular architecture is desirable.
15
]
reactions[
are quite rare and there remains room for
improvement in terms of their stereoselectivities.[16] Our group has
developed a series of metal-carbene reactions[17] and recently
achieved an asymmetric intramolecular dearomatization reaction
of phenols with α-diazoamides using chiral silver phosphate.[18] In
the course of our studies, an intermolecular reaction of naphthols
with gold- or silver-carbenes chemoselectively provided C–H
19
]
functionalized products (eq 2),[
whereas silver-carbene
reactions with phenols gave O–H insertion products (eq 3). We
anticipated that an asymmetric O–H insertion reaction using a
silver complex could
Figure 1. Bioactive and useful compounds possessing α-aryl-α-aryloxy-
carbonyl group and their derivatives.
A transition metal-promoted O–H insertion reaction[4,5,6] into
phenols[ 7 , 8 ] with α-aryl-α-diazoacetates is a straightforward
method for asymmetric synthesis of α-aryl-α-aryloxyacetates. In
this field, much effort has been dedicated to developing chiral
Scheme 1. Reactions of naphthols and phenols with various metal-carbenes.
[a]
[b]
Dr. S. Harada, K. Tanikawa, T. Ito, H. Homma, C. Sakai, Prof. Dr. T.
Nemoto
Graduate School of Pharmaceutical Sciences, Chiba University
1-8-1, Inohana, Chuo-ku, Chiba 260-8675 (Japan)
E-mail: Sharada@chiba-u.jp, tnemoto@faculty.chiba-u.jp
Prof. Dr. T. Nemoto
be established if the chiral environment of the catalyst could be
appropriately designed and created. The conditions using a silver
catalyst would provide complementary functional group
compatibility with already-known methods. For instance, an aryl
iodide, a versatile synthetic fragment for carbon–carbon bond-
forming reactions in coupling chemistry, is potentially reactive
under transition metal catalysis. In fact, substrate examples with
these functionalities have not been described.[4-7] Another
concern is that O–H insertion products are easily racemizable
Molecular Chirality Research Center, Chiba University
1-33, Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201902126
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chiral methyl acetates under basic conditions, and thus harsh
acidic conditions (HCl in dioxane under reflux) are required for
hydrolysis of the ester to avoid the issue.[8d]
Herein, we describe the development of a carbene insertion
reaction into phenols with donor-acceptor-substituted diazo
compounds using a silver catalyst. Synthesized ester could be
transformed under mild conditions without any racemization.
Combined experimental and theoretical analyses were also
executed to clarify the reaction mechanism and the origin of
enantioinduction in chiral silver catalysis.
We commenced our experimental studies using phenol (2a)
and methyl 2-(4-bromophenyl)-2-diazoacetate (1a) as model
substrates in the presence of a [(S)-TRIPAg] dimer catalyst (Table
1).[18b] The attempted insertion reaction in dichloromethane
solvent at room temperature proceeded smoothly, affording the
desired O–H insertion product (3aa) in good yield with 71:29 er
(entry 1). A similar level of stereocontrol was observed when
the O–H insertion reaction (92:8 er, entry 13). Further
comprehensive examination of the reaction conditions revealed
that the addition of 20 mol% of water gave a satisfactory result
(entries 15-16).
With the optimal conditions for the Ag-catalyzed O–H insertion
reaction in hand (Table 1, entry 16), we evaluated the scope of
the method (Table 2). α-Aryl-α-diazoacetates 1b and 1c with
electron-donating substituents were applicable in this O–H
insertion, affording the corresponding products 3ba, 3ca in 81%
yields with high enantioselectivities (94:6, 91:9 er, respectively).
Reactions of α -diazoacetates 1e-1h possessing electron-
deficient aryl substituents also proceeded with a high level of
enantiocontrol (3ea-3ha, 93:7 to 95:5 er). In addition, electron-
abundant and deficient phenols were usable in the O–H insertion,
furnishing the functionalized methyl esters (3ab-3af). Other
enantioenriched esters such as benzyl, tert-butyl, 2-methoxyethyl,
and allyl ester variants were obtained in moderate to good yields
(3ia-3la, 66-76% yield, 90:10 to 95:5 er). Although the method
under palladium catalysis produced decent results (74% yield,
86:14 er) when using aliphatic alcohol such as butanol,[8d] this
silver catalysis furnished 3ah in high yield with high selectivity
(91% yield, 91:9 er).[21]
Table 1: Optimization of reaction conditions for the O–H insertion.[a]
Catalyst
Ligand
Ph
N2
O
H
OH
OMe
+
OMe
(p-Br)-C6H4
(p-Br)-C6H4
3aa
CH2Cl2 (0.05 M)
rt, 5 h
2a
(1.5 equiv.)
O
O
1a
Table 2: Substrate scope of asymmetric insertions into O–H bond of phenols
and aliphatic alcohols.
i-Pr
i-Pr
AgNTf2 (20 mol%), H2O (20 mol%)
(S)-Xylyl-BINAP (10 mol%)
Ph
Ph
P
Ar
O
Ph
Ph
Ph
Ph
i-Pr
Ar
Ar
O
O
Me
Me
P
P
PPh2
PPh2
O
1
+
2
NMe
2
O
O
O
O
P
3
P
P
P
P
Ag
(1.5 equiv.)
CH2Cl2 (0.02 M), rt, 5 h
Ar
Ph
Ph
i-Pr
1g Ar = p-ClC6H4, R = Me
1h Ar = m-IC6H4, R = Me
1i Ar = C6H5, R = Bn
1b Ar = p-MeOC6H4, R = Me
1c Ar = m-MeC6H4, R = Me
N2
i-Pr
(S)-BINAP: Ar = Ph
(S)-Xylyl-BINAP:
Ar = 3,5-Me2-C6H3
(―)-DIOP
(S)-SDP
(R)-MonoPhos
(S)-BINAPO
i-Pr
2
OR
1d Ar = C6H5, R = Me
[(S)-TRIPAg]2
Ar
1j Ar = C6H5, R = t-Bu
1e Ar = p-FC6H4, R = Me
1f Ar = m-BrC6H4, R = Me
1k Ar = C6H5, R = CH2CH2OMe
1l Ar = C6H5, R = allyl
O
3ba-ha
3ab-af
3ia-la
3ag
entry
Catalyst/Ligand (mol%)
Yield (%)
er (R:S)
71:29
69:31
85:15
91:9
2b R’ = p-MeOC6H4
2c R’ = p-MeC6H4
2d R’ = p-t-BuC6H4
2e R’ = p-FC6H4
R’O
H
2f R’ = p-Br-C6H4
2g R’ = CH2CH2Ph
2h R’ = Bu
OR
1
2
3
4
5
[(S)-TRIPAg]2/none(10/0)
AgNTf2/(S)-BINAP (20/20)
AgNTf2/(S)-BINAP(20/15)
AgNTf2/(S)-BINAP(20/10)
AgNTf2/(S)-BINAP(20/7.5)
AgNTf2/(S)-BINAP(10/20)
CuOTf/(S)-BINAP(20/10)
[AllylPdCl]2/(S)-BINAP(10/10)
AgNTf2/(–)-DIOP(20/10)
80
22
37
62
65
13
25
35
52
37
50
58
72
74
69
81
R’ OH
Ar
O
3ah
Ph
Ph
Ph
Ph
O
H
O
H
O
H
O
H
OMe
OMe
OMe
OMe
67:33
55:45
64:36
50:50
44:56
50:50
50:50
42:58
92:8
O
O
O
O
6[b]
MeO
F
Me
3ba
3ca
85% yield, 91:9 er
3da
82% yield, 93:7 er
3ea
7
82% yield, 91:9 er
79% yield, 93:7 er
8
OMe
9
10
AgNTf2/(S)-SDP(20/10)
O
H
O
H
O
H
11
AgNTf2/(R)-MonoPhos(10/10)
AgNTf2/(S)-BINAPO(20/10)
AgNTf2/(S)-XylylBINAP(20/10)
AgNTf2/(S)-XylylBINAP(20/10)
AgNTf2/(S)-XylylBINAP(20/10)
AgNTf2/(S)-XylylBINAP(20/10)
O
H
OMe
Br
OMe
I
OMe
OMe
12
O
O
O
Cl
O
13
Br
3fa[a]
3ga[a]
3ha[a]
3ab
14[c]
15[c,d]
16[c,e]
93:7
68% yield, 96:4 er
62% yield, 94:6 er
69% yield, 93:7 er
81% yield, 91:9 er
84:16
95:5
Me
t-Bu
F
Br
[a] The diazo compound 1a, dissolved in CH2Cl2, was added drop-wise over
90 min. [b] 1a recovered (36%). [c] Reaction was performed in 0.02 M
solvent. [d] MS 5A (1 g/mmol) was used. [e] 20 mol% of water was used.
O
H
O
H
O
H
O
H
OMe
OMe
OMe
OMe
O
O
O
O
Br
Br
Br
Br
3ac
3ad
3ae
3af
83% yield, 96:4 er
78% yield, 93:7 er
69% yield, 93:7 er
59% yield, 90:10 er
Ph
Ph
Ph
Ph
OMe
O
H
O
H
O
H
O
H
O
O
O
O
using 20 mol% of AgNTf2 and (S)-BINAP, giving 3aa, albeit in
lower yield (22%, entry 2). The mole ratio of Ag salt to the ligand
significantly affected the yield and enantioselectivity, and a 2-to-1
ratio was determined to be optimal (entries 2-6).[20] Although other
metal salts such as Cu or Pd catalyst and chiral phosphorous
ligands or phosphine oxide did not improve the enantiomeric ratio
of 3aa (entries 7-12), the use of (S)-XylylBINAP was effective for
O
O
Ph
O
O
3ia
3ja
76% yield, 95:5 er
3ka
66% yield, 92:8 er
Me
3la[b]
76% yield, 90:10 er
75% yield, 92:8 er
O
H
O
H
OMe
OMe
O
O
Br
Br
3ah
3ag
77% yield, 90:10 er
91% yield, 91:9 er
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[a] 3 equivalent of PhOH was used. [b] Reaction was performed in 0.012 M
solvent.
functionality as a ligand in the in situ-generated catalyst
complex.[20] Because computational analyses of the generation of
Ag-carbene from diazo compounds were previously performed,[28]
we initiated our calculation from Ag-carbene RT, where carbonyl
oxygen coordinated to the other cationic Ag atom, making the
carbene more electrophilic. Nucleophilic attack of a phenol
oxygen on the Ag-carbene proceeded smoothly with a low
activation energy of +4.4 kcal/mol via TS1O, generating a formally
C-bound and O-bound Ag2-enolate CP1O. On the other hand,
reaction at the para-position of phenol was kinetically and
thermodynamically unfavorable, likely due to the steric repulsion
and/or dearomatization[29] of phenol, contrary to the Au-carbene
reaction.[10,11,19,26] Enol formation to CP2 from CP1O also occurred
with a reasonably low energy barrier, but the following key
tautomerization of CP2 to the final product (PRO) was calculated
to be an impractical process with excessive activation energy
(ΔΔG‡ = +54.8 kcal/mol, TS3). PRO was also found to be
accessible with ΔΔG‡ = +13.7 kcal/mol via CP2’’-2H2O and TS3’’-
2H2O, where two water molecules assist in the proton transfer. A
proton shuttle catalysis through hydrogen-bonding network would
be operative,[30] accounting for the water-sensitivity of the Ag-
catalysed reaction.
Hydrogenation of 3ia with Pd/C at room temperature
quantitatively furnished the corresponding carboxylic acid with no
loss of enantiopurity relative to the starting material.[22]
While detailed mechanisms of the asymmetric carbene
insertion into O–H bond of water have been investigated,[23] the
reaction process of an asymmetric insertion into phenol has not
been studied.[ 24 ] Therefore, the following experiments were
performed to obtain mechanistic information. Reaction in the
presence of alkyne 4, instead of using phenol, gave a
cyclopropene 5 (eq 5), which generated the Ag-carbene species
in situ.[ 25 ] No nonlinear effect between the enantioselectivity
values of 3aa and catalyst was observed (figure 2), indicating an
involvement of a single catalyst in the enantiodetermining process.
In addition, water molecule(s) would participate in the
enantiodetermining step, in view of the results of entries 12, 14
and 15 in Table 1 and some previous studies of metal-carbene
mediated insertion reactions. [23,26] This reaction exhibited a kinetic
isotope effect (kH/kD=3.17, eq 6)[27], thereby supporting the notion
that O–H bond cleavage or C–H bond formation is the rate-
determining step.
To shed light on the origin of the asymmetric induction, the
protonation process was studied in more detail by depicting a
chiral ligand in CH2Cl2 solvent. In the TSR-2H2O model, providing
(R)-product, cooperative attractive interactions[31] were working
between two Ag centers, counteranions, and the substrate, as
well as two water molecules in the chiral environment. Notably,
the dual Ag···O interactions would generate the reactive proton
donor to the enolate (bond length of the O–H (violet): 1.24 Å),
positively affecting the total Gibbs Energy of the asymmetric
protonation. On the other hand, a single and longer Ag···O
interaction (2.5 Å) and analogous kind of hydrogen network were
working in TSS-2H2O. These factors would make a critical
difference to the activation energy (ΔΔΔG‡ = 1.78 kcal/mol) for the
enantiodiscrimination of the enols, which corresponds to 95:5
selectivity, supporting the experimental results.
Figure 2. No chiral amplification.
To further elucidate the reaction mechanism, we performed
computational studies based on quantum chemical calculations
(Scheme 2).[22] A structurally simplified achiral ligand was used to
clear the whole course of the reaction. The fact that the mole ratio
of Ag salt/ligand (1/2) was quite critical for the reaction efficiency
suggests that each Ag atom center could have a single phosphine
‒
L
+
F3C
O
TS3
‒
Ag
P
P
‒
L
L
OMe
S
TS1’C
‒
O1.8 Å
H
+
Tf
P
O
+
N
Ag
P
P
Ag
O
OMe
Ph
Ag
P
P
O
+10
OMe
Ph
-7.7
-3.9
+
‒
+
H
O
Ph
+
Ag
δ+
L
Ag
1.4 Å
O
H
Ag
H
OH
1.1 Å
+
O
P
H1.7 Å
O
+13.9
‒
Ag
CP1’C
δ+
L
O
TS3’-1H2O
‒
L
Ph
Ph
‒
F3C
TS1O
OMe
L
Ph
TS3
+4.3
Ph
S
O
O 1.8 Å
H
TS2
‒
Tf
N
TS3’-1H2O
CP1O
RT
+4.4
+
0
2.4 ÅO
H 1.0 Å
‒
Ag
P
L
H
O
(0.0)
-56.2
+
O
+
Ag
Ag
Ag
P
P
P
O
OMe
H
+54.8
F3C
OMe
H 1.9 Å
-89.8
‒
a
S
O
+
‒
Ph
O
L
O 1.7 Å
H
‒
Ph
O
H
N
Tf
Tf
Ph
N
Ph
-22.2
+43.8
F3C
S
‒
O
S
CP2’’-2H2O
2.4 ÅO
O
N
+
H 1.4 Å
O
1.6 Å
O
O
Ag
Tf
P
‒
+
H
- 10
PAg
2.4 ÅO
NTf2
+
CF3
CP1O
+
P
Ag
Ag
‒
P
O
H
OMe
2.5 Å
2.6 Å
OMe
+
F3C
H
NTf2
PAg
2.2 Å
+
O
‒
Ph
L
P
Ag
S
O
O 1.8 Å
H
‒
Ph
Tf
nH2O
N
Ph
O
TS3’’-2H2O
‒ O
S
HOPh
CP2
N
+
O
H
O
P
P
Ag
Tf
P
P
-13.3
OMe
Ph
CF3
+
+13.7
- 20
O
OMe
Ag
CP2’’-2H2O
-35.4
Ph
Ph
OPh
‒
-22.9
L
RT
PRO
CP2
DGGas
(kcal/mol)
CP2’-1H2O
Attack of Phenol
Enol Formation
Tautomerization
Scheme 2. Reaction coordinate diagram and calculated key structures for the O–H insertion reaction (L=NTf2). Optimal geometries and frequencies were
computed at the rB3LYP/6-31G* (for H, C, N, O) and LanL2DZ (Ag) levels of theory. a Hydrogen atoms have been omitted for the sake of clarity.
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10.1002/chem.201902126
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COMMUNICATION
In conclusion, we developed a silver-catalyzed asymmetric
insertion reaction into the O–H bond of phenols and aliphatic
alcohols with donor-acceptor-substituted diazo compounds. The
reaction proceeded under mild conditions at room temperature,
furnishing α-aryl-α-aryloxy esters in enantioenriched form. We
proposed water- and counter anion-mediated asymmetric
protonation of silver-enol complex based on computational
argumentations. Further methodology development using a chiral
homobinuclear silver catalyst is ongoing in our laboratory.
Acknowledgements
This work was supported by Futaba Electronics Memorial
Foundation, Toray Science Foundation, The Naito Foundation,
JSPS KAKENHI Grant Numbers JP18K05098 and 18H02550.
Numerical calculations were carried out on SR24000 at Institute
of Management and Information Technologies, Chiba University
of Japan.
Keywords: bimetallic • carbenes • silver • insertion • density
functional calculations
Figure 3. Enantiodetermining transition state structures in CH2Cl2 calculated at
the rB3LYP/6-31G** and LANL2DZ level of theory (G: in kcal/mol).
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Entry for the Table of Contents
COMMUNICATION
Shingo Harada, Koki Tanikawa, Haruka
Homma, Chigaya Sakai, Tsubasa Ito,
and Tetsuhiro Nemoto*
Lewis Acid
AgNTf2 (20 mol%)
PhOH
‒
Ph
+
NTf2
OR
‒
(S)-Xylyl-BINAP (10 mol%)
O
P
P
Ag
+
O
H
H2O (20 mol%)
OR
+
N2
Ag
Ar
NTf2
CH2Cl2 (0.02 M)
rt, 5 h
OR
Ar
Page No. – Page No.
O
Ar
A
g
-
C
a
r
b
e
n
e
O
∆∆G‡ = 14.6 kcal/mol (RB3LYP/6-311G*/LANL2DZ (Ag), IEFPCM-DCM)
Silver-Catalyzed Asymmetric
Insertion into Phenolic O–H Bonds
using Aryl Diazoacetates and
Theoretical Mechanistic Studies
A chiral homobinuclear silver complex-catalyzed carbene insertion into O-H bonds
of phenols was developed. The catalyst was created in situ from AgNTf2 and (S)-
XylylBINAP (a 2-to-1 mole ratio). Theoretical studies revealed that water- and
counter anion-mediated asymmetric protonation of silver-enol complex is the
enantiodetermining step for the synthesis of α-aryl-α-aryloxy esters in an
enantioenriched form.
This article is protected by copyright. All rights reserved.
[a]
Dr. S. Harada, K. Tanikawa, T. Ito, H. Homma, C. Sakai, P