Experimental and Computational Study of the (Z)-Selective Formation of Trisubstituted Olefins and Benzo-Fused Oxacycles from the Ruthenium-Catalyzed Dehydrative C-H Coupling of Phenols with Ketones

Article abstract of DOI:10.1021/jacs.8b05875

The cationic Ru-H complex was found to be an effective catalyst for the dehydrative C-H coupling of phenols with ketones to form the trisubstituted olefin products. The coupling of phenol with linear ketones led to highly stereoselective formation of the (Z)-olefin products. The dehydrative coupling of phenol with enones and diones efficiently formed the benzopyrene and related oxacyclic derivatives. The reaction of 3,5-dimethoxyphenol with cyclohexanone-2,2,6,6-d₄ showed a significant H/D exchange to both vinyl and α-CH₂ positions on the olefin product (72-75% D). A significant carbon isotope effect was observed on the ortho-arene carbon of the olefin product. The free energies of intermediate species for the entire catalytic cycle were successfully computed by using the DFT method. The DFT study revealed that the E/Z stereoselectivity is a result of the energy difference in the insertion step of ortho-metalated phenol to an enol form of the ketone substrate (Δ ΔE = 9.6 kcal/mol). The coupling method provides a direct catalytic C-H olefination method for ketones to form trisubstituted olefins without employing any reactive reagents or forming any wasteful byproducts.

Full text of DOI:10.1021/jacs.8b05875

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Article
Experimental and Computational Study of the (Z)-Selective Formation
of Trisubstituted Olefins and Benzo-Fused Oxacycles from the
Ruthenium-Catalyzed Dehydrative C–H Coupling of Phenols with Ketones
Hanbin Lee, Manoj V. Mane, Ho Ryu, Debashis Sahu, Mu-Hyun Baik, and Chae S. Yi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05875 • Publication Date (Web): 23 Jul 2018
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Experimental and Computational Study of the (Z)-Selective Formation of
Trisubstituted Olefins and Benzo-Fused Oxacycles from the Ruthenium-
Catalyzed Dehydrative C–H Coupling of Phenols with Ketones
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Hanbin Lee,† Manoj V. Mane,‡ Ho Ryu,§,‡ Debashis Sahu,‡ Mu-Hyun Baik‡,§,* and Chae S. Yi†,*
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†Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201-1881 United States
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141,
Republic of Korea
§Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141,
Republic of Korea
ABSTRACT. The cationic Ru–H complex was found to be an effective catalyst for the dehydrative C–H
coupling of phenols with ketones to form the trisubstituted olefin products. The coupling of phenol with linear
ketones led to highly stereoselective formation of the (Z)-olefin products. The dehydrative coupling of phenol
with enones and diones efficiently formed the benzopyrene and related oxacyclic derivatives. The reaction of
3,5-dimethoxyphenol with cyclohexanone-2,2,6,6-d4 showed a significant H/D exchange to both vinyl and ꢀ-
CH2 positions on the olefin product (72-75% D). A significant carbon isotope effect was observed on the ortho-
arene carbon of the olefin product. The free energies of intermediate species for the entire catalytic cycle were
successfully computed by using the DFT method. The DFT study revealed that the E/Z stereoselectivity is a
result of the energy difference in the insertion step of ortho-metalated phenol to an enol form of the ketone
substrate (ΔG = 9.6 kcal/mol). The coupling method provides a direct catalytic C–H olefination method for
ketones to form trisubstituted olefins without employing any reactive reagents or forming any wasteful
byproducts.
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INTRODUCTION
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Carbonyl olefination methods have long been considered as one of the most versatile C–C coupling
protocols for the synthesis of complex organic molecules.1 Traditionally, phosphorous ylide and related main
group reagents have been widely used for the Wittig-type of coupling reactions, but early transition metal
reagents were also employed for McMurry2 and Tebbe-Petasis3 olefination reactions. Peterson olefination and
related nucleophilic addition-elimination methods for aldehydes and ketones have also been successfully
developed to form substituted olefins.1b,4 From the viewpoint of sustainable synthesis, these classical carbonyl
olefination methods pose inherent drawbacks in that the usage of stoichiometric amount of ylide or transition
metal reagents results in the formation of copious amount of toxic and wasteful byproducts. To overcome
shortcomings associated with classical olefination methods, a concerted research effort in the last few
decades has been devoted to the development of strategies for catalytic carbonyl olefination. In a seminal
work, Pd-catalyzed Negishi couplings of carbonyl derivatives with organozinc reagents have been extensively
used for the synthesis of highly functionalized olefins and related molecules.5 More recently, Schindler group
devised a remarkably effective intramolecular carbonyl-to-olefin metathesis reaction by using FeCl3 as a
catalyst.6 Milstein and co-workers utilized pincer-ligated Ru catalysts to promote a selective carbonyl
olefination via the coupling of alcohols with alkylsulfonates.7 Zhou and co-workers cleverly designed a Ni-
catalyzed olefination method from the coupling of arylketones with organoboron reagents.8 Li recently
reported a Ru catalyzed carbonyl olefination method via hydrazine promoted reductive coupling of carbonyl
compounds.9 Despite such remarkable advances in designing olefination methods, these coupling methods
still require reactive boron and sulfur reagents, which lead to the formation of salt byproducts. Additionally,
they exhibit tendencies of undergoing undesired side reactions such as dehydrogenation and aldol-type
condensation reactions. Catalytic C–H coupling methods have emerged as a step-efficient and direct
olefination protocol for arenes,10 although their synthetic utility has yet to be fully exploited in carbonyl
olefination reactions.
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One of the pertinent issues in carbonyl olefination methods has been concerned with controlling the
stereochemistry of olefin products. In particular, designing (Z)-selective olefination methods has been
considered the most challenging, since classical olefination methods generally favor the formation of (E)-
olefins. In this regard, Peterson4 and Horner-Wadsworth-Emmons11 olefination methods have been
extensively used for the synthesis of (Z)-olefin products, but the major issues on employing stoichiometric
reagents and the formation of toxic byproducts have not been resolved for these methods. In terms of catalytic
olefination methods, both Grubbs and Schrock-type metal-carbene catalysts have been successfully designed
and utilized for ring-closing metathesis reaction in forming biologically active (Z)-selective macrocyclic olefin
products.12 Pd-catalyzed Negishi-type coupling methods have also been successfully employed for the
synthesis of (Z)-selective trisubstituted olefins.5a
–
We previously discovered that the cationic ruthenium hydride complex [(C6H6)(PCy3)(CO)RuH]+BF4
(1) is a highly effective catalyst precursor for a number of dehydrative C–H coupling reactions of alkenes and
arenes with alcohols.13 Since these coupling reactions are driven by the formation of water, we reasoned that
the analogous dehydrative C–H coupling reactions with carbonyl compounds might be feasible in achieving
carbonyl olefination reactions. Herein, we report the scope and mechanistic study of ruthenium-catalyzed
dehydrative coupling reaction of phenols with ketones, which leads to a highly (Z)-selective synthesis of
trisubstituted olefin products. We combined experimental and computational analyses to establish a detailed
mechanism as well as to elucidate the origin of stereoselectivity for the olefination reaction. The catalytic
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method features a direct catalytic C–H olefination method of ketones with phenols without employing any
reactive reagents or forming any wasteful byproducts, while tolerating a number of common organic functional
groups.
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RESULTS AND DISCUSSION
Reaction Scope. In an effort to extend the scope of dehydrative C–H coupling method of arenes,13
we initially probed the feasibility of the coupling reaction of phenols with simple ketones by using the Ru–H
catalyst. Thus, the treatment of 3,5-dimethoxyphenol (0.5 mmol) with propiophenone (1.0 mmol) in the
presence of 1 (3 mol %) in 1,2-dichloroethane (2 mL) led to the formation of the alkenylated product (Z)-2a (eq
1). Among the screened catalysts, the Ru–H complex 1 exhibited distinctively high activity in forming the
coupling product, as analyzed by both GC and NMR spectroscopic methods (Table S1, Supporting
Information (SI)). Moreover, a highly stereoselective formation of (Z)-2a was observed, and its structure was
unambiguously established by NMR spectroscopic method (vide infra).
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OH Ph
OH
O
H
BF4
1 (3 mol %)
Ru
+
+
H2O (1)
Ph
H
PCy3
CH2ClCH2Cl
125 oC
MeO
OMe
(Z)-2a
MeO
OMe
OC
1
(0.5 mmol)
(1.0 mmol)
The substrate scope of the olefination reaction was explored using the catalyst 1, as summarized in
Table 1. An electron-rich 3,5-dimethoxyphenol was found to be a suitable substrate for the coupling with aryl-
substituted linear ketones to form ortho-alkenylated phenol products 2a-2n (entries 1-14). For these aryl-
substituted ketones, highly (Z)-selective olefin products 2a-2i were formed in the crude mixture, as analyzed
by GC-MS (entries 1-9). In contrast, the coupling with aliphatic linear ketones resulted in a mixture of (E)/(Z)-
olefins, with the (Z)-isomer being the major products for 2k-2n (entries 11-14). The analogous treatment of
3,5-dimethoxyphenol with cyclic ketones led to the clean formation of 2q-2s (entries 17-19), while the coupling
with 2-indanone yielded the indenyl-substituted product 2t (entry 20). The coupling of 1-naphthol with linear
and cyclic ketones led to the formation of the coupling products 2o and 2v, respectively (entries 15 and 22).
The coupling reaction of phenols with electron-withdrawing group was quite sluggish leading to low olefin
product yields.
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Table 1. Dehydrative C–H Olefination of Phenols with Ketonesa
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entry
phenol
OH
ketone
O
product(s)
OH Ar
yield (%)
R
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9
Ar
R
OMe
2a
MeO
R = Me
R = Ph
R = H
R = n-Pr
R = Me
R = H
R = Me
R = Me
R = Me
MeO
OMe
95
96
55
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72
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Ar = Ph
Ar = Ph
Ar = Ph
Ar = Ph
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2b
2c
2d
2e
2f
2g
2h
2i
Ar = p-Cl-C6H4
Ar = p-Cl-C6H4
Ar = p-OMe-C6H4
Ar = p-Me-C6H4
Ar = p-F-C6H4
OH
R
OH
O
R'
R
R'
OMe
MeO
MeO
OMe
2j (Z:E >95:5)
2k (Z:E = 4:1)
2l (Z:E = 3:1)
2m (Z:E = 1.4:1)
2n (Z:E = 3.4:1)
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72
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77
77
R = Me
R = Me
R = Me
R = Me
R = Et
R' = Ph
R' = Bn
R' = Et
R' = Me
R' = Me
OH
OH
OH Ph
O
O
15
70
58
Ph
Ph
2o
OH Ph
16
MeO
OMe
MeO
MeO
OMe
2p
OMe
OH
OMe
OH
O
n
n
OMe
MeO
OMe
92b
83b
63b
17
18
19
2q
2r
n = 1
n = 2
n = 4
2s
OH
O
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21
22
78
MeO
MeO
OMe
2t
OH
OH
O
O
OH
55b
MeO
2u
OH
62b
2v
a Reaction conditions: phenol (0.5 mmol), ketone (1.0 mmol), 1,2-dichloroethane (2 mL), 1 (3 mol %), 125 °C,
16 h. b 1.5 mmol of ketone was used.
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To further demonstrate its synthetic utility, we next surveyed the substrate scope of the catalytic
carbonyl olefination method by employing a number of biologically active ketone substrates (Table 2). Thus,
the coupling of 3,5-dimethoxyphenol with 4-hydroxycoumarin yielded the coupling product 2w, while the
reaction with (+)-nootkatone led to the alkenylated product 2x in a single step. The treatment with an anti-
inflammatory agent nabumetone also readily afforded a 5:1 Z/E mixture of alkenylated product 2y. The
treatment with (+)-4-cholesten-3-one and adrenosterone predictively yielded the corresponding diene products
2z and 2aa, respectively.
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Table 2. Dehydrative Coupling of 3,5-Dimethoxyphenol with Functionalized Ketonesa
O
OH
OH
OH
O
MeO
OMe
MeO
OMe
MeO
OMe
OMe
2y (Z:E = 5:1, 43%)
2w (69%)
2x (35%)
130 oC, 72 h
135 oC, 16 h
140 oC, 24 h
O
H
O
OH
OH
H
H
H
H
2z (29%)
2aa (25%)
130 oC, 72 h
130 oC, 72 h
MeO
OMe
MeO
OMe
a Reaction conditions: phenol (0.5 mmol), ketone (1.0 mmol), 1,2-dichloroethane (2 mL), 1 (3 mol %).
The (Z)-stereochemistry of these olefin products was established by NMR spectroscopic methods.
One of the most diagnostic feature of the (Z)-olefin products is that allylic CH2 protons of (Z)-2 exhibited an
ABX type of second-order pattern in the 1H NMR spectrum due to a diastereotopic environment resulted from
restricted rotation of the phenol group. In contrast, allylic CH2 protons of (E)-2 showed a simple first order
pattern. The stereochemistry of (Z)-2a was also definitively established by X-ray crystallography (Figure S3,
SI). From both synthetic and environmental points of view, the salient features of the catalytic method are that
it facilitates a direct C–H coupling of readily available phenol and ketone substrates in a highly regio- and
stereoselective fashion and that it forms synthetically valuable trisubstituted olefin products 2 without using
any reactive reagents or forming wasteful byproducts.
Computational Study. Inspired by related ruthenium catalyzed dehydrative C–H coupling reactions,
we initially compiled a plausible mechanistic pathway for the olefination reaction, which involves an initial
ortho-C–H metalation of phenol, migratory insertion of the ketone substrate and the subsequent dehydration
and elimination steps (Scheme 1).13a However, despite our best efforts, we have not been able to detect or
trap any catalytically relevant intermediate species, which made it difficult to establish a detailed mechanism
of the coupling reaction experimentally. Thus, to attain deeper insights into the reaction mechanism and to
elucidate the origin of (E)/(Z) selectivity, we turned to the DFT calculations. We have successfully computed
the entire catalytic cycle for the coupling reaction of 3,5-dimethoxyphenol with 1,2-diphenylethanone
substrates, and the free energy profile diagram has been constructed, as shown in Figure 1. The catalytic
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cycle begins with the Ru–H complex 1 forming a loosely bound transient adduct 4 with the phenol substrate,
which can readily extrude the originally η6-bound benzene ligand and proceed with the ortho-C–H metalation
mediated by the phenolic OH directing group. The ortho-metalation step is associated with a barrier of 23.7
kcal/mol to generate the key intermediate complex 5, which is only 5.1 kcal/mol uphill energetically, driven by
the release of hydrogen gas (Figure S5, SI). As supporting experimental evidence for the benzene ligand
dissociation, we previously observed a facile arene exchange reaction and the formation of free benzene from
the coupling reactions mediated by the Ru–H catalyst 1.14
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Scheme 1. Proposed Catalytic Cycle for the Coupling of 3,5-Dimethoxyphenol with 1,2-Diphenylethanone.
The intermediate 5 initiates the catalytic cycle by binding (E)- and (Z)-enol form of the ketone
substrate to form the adducts 6’ and 6, respectively. Interestingly, the adduct 6’ made by coordinating the (Z)-
enol substrate is lower in energy by ~7 kcal/mol than the analogue formed from (E)-enol substrate 6.
Subsequent migratory insertion affords intermediate 7’ and 7 traversing via the transition state 6’-TS and 6-
TS, where the relative energy between two stereoisomers is inverted during the migratory insertion step. At
the transition state, the 6-TS formed from the (E)-enol substrate is nearly 6.5 kcal/mol lower in energy than 6’-
TS, which contains the (Z)-enol substrate. This energy difference is notably diminished to ~1.5 kcal/mol, but
the relative ordering is maintained in the transient, high-energy intermediate 7 and 7’. Rotation around the C–
C bond leads to the much more stable intermediates 8 and 8’, where the alkoxide group is appropriately
positioned to act as a Lewis base and coordinated to the metal. The two diastereoisomers are predicted to be
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nearly isoenergetic at this intermediate state. To push the reaction forward, the hydroxyl group originating
from the enol substrate must be eliminated via a dehydration step, as mentioned above. We explored several
possible ways of accomplishing this task, and found that the heterolytic cleavage of the C–OH bond
accompanied by hydroxyl-transfer to the Ru-center and reconstitution of the olefinic double bond of the
substrate is energetically the most favorable pathway to give complex 9 and 9’. Release of the product 2b or
2b’ and addition of a new equivalent of phenol gives the ruthenahydroxyl-complex 10, which can restart the
catalytic cycle by activating the phenolic ortho-C–H bond and extruding an equivalent of water to generate
intermediate 5.
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3
4
5
6
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9
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Ph
Ph
Ph
Ph
Ph
Ph
[Ru]
HO
HO
[Ru]
HO
[Ru]
HO
[Ru]
H
[Ru]
HO
Ph
HO
HO
OH
HO
Ph
R
HO
ΔGsol
[kcal/mol]
R
R
R
5-TS/5'-TS
6-TS/6'-TS
R
10-TS
7-TS/7'-TS
8-TS/8’-TS
6'-TS
40
30
20
(36.74)
7'-TS
(33.61)
6-TS
(33.29)
8-TS
(29.42)
8'-TS
Z-selective path
E-selective path
7-TS
(31.13)
10-TS
(24.77)
7'
(30.36)
7
(27.42)
(28.78)
Ph
5-TS
5'-TS
(9.75)
5
[Ru]
HO
HO
(14.51)
8'
(13.73)
Ph
E-enol
(8.66)
8
10
0
9'
(9.63)
(12.50)
6
10
(9.72)
(8.70)
7/7'
9
5
5
R
Ph
(6.77)
[Ru]
(5.06)
6'
Z-enol
(6.21)
Ph
OH
(1.52)
3
Ph
Ph
5
Ph
Ph
HO
O
(–1.34)
R
HO
[Ru]
Ph
[Ru]
Ph
–10
HO
[Ru]
HO
Ph
H2O
Ph
2b/2b'
HO
HO
HO
8/8'
R
HO
HO [Ru]
R
6/6'
R
10
5
R
9/9'
R
Enol Addition
Migratory Insertion
Catalyst Regeneration
Figure 1. The free energy profile for the formation of (E)-2b (red) and (Z)-2b (black) with water as the
byproduct.
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O
C
ΔE(SCF)
(kcal/mol)
Ph
Cy3P Ru
O
C
Ph
HO
Cy3P Ru
5
OH
Ph
60
HO
6
7
8
9
R
6'-TS
Ph OH
50.83
R
6-TS
ΔEint
(–13.86)
42.52
40
20
0
Olefin
(26.08)
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ΔEint
(–15.19)
Olefin
(25.32)
36.96
RuL
(24.74)
RuL
(17.20)
27.33
O
O
Ph
Ph
C
Cy3P Ru
HO
C
Cy3P Ru
HO
Ph
OH
Ph
OH
6'
R
6
R
Figure 2. The fragment energy analysis of the migratory insertion step for the formation of (Z)-2b vs (E)-2b.
To understand the stereoselectivity described above, we performed a detailed fragment energy
analysis on the migratory insertion step for both stereoisomers. In this analysis, we first fragment the
intermediates 6/6’ and the transition states 6-TS/6’-TS into chemically meaningful fragments, namely, the
olefin substrate marked in blue and the ruthenium-fragment carrying the ligands as ‘RuL’ shown in red in
Figure 2. Then, the energies of these fragments are calculated independently, which allows for evaluating how
much energy is required to distort each of the fragments to the geometry found in the transition state.15 Figure
2 summarizes the fragment and interaction energies, which can be computed by subtracting the sum of
fragment energies from the total molecular energy. Interestingly, the majority of the energy difference between
the two transition states is caused by the RuL fragment distortions. The RuL fragments in 6 must invest 17.2
kcal/mol to reach the structure found in 6-TS, whereas 24.7 kcal/mol must be invested to distort the structure
of RuL in 6’ to what is found in 6’-TS. This difference of 7.5 kcal/mol is by far the largest contributor to the
electronic transition state energy difference of 9.6 kcal/mol. The olefin fragments require 25.3 and 26.1
kcal/mol energy, which is mostly invested into lengthening the C–C double bond in preparation of the
migratory insertion. These distorted fragments interact with each other allowing to recover 15.2 and 13.9
kcal/mol to afford the final transition state energies of 27.3 and 37.0 kcal/mol, as illustrated in Figure 2. It is
curious that the interaction energy in 6-TS is 1.3 kcal/mol greater although the fragment distortions are more
severe in 6’-TS. The degree of fragment distortions are generally related to the transition state being late,
which means that both the bond breaking and bond forming processes should have progressed further. And
that is typically reflected in greater fragment distortion, but also in greater interaction energies.
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Figure 3. Optimized structures of the transition state (a) 6-TS and (b) 6’-TS. Oxygen atoms are shown in grey
color. Non-essential atoms, such as the cyclohexyl-groups on the phosphine ligand and non-essential
hydrogen atoms, are not shown. Bond lengths are given in Å.
Figure 3 illustrates the structural difference between 6-TS and 6’-TS, which offers an explanation for
the aforementioned energy components. In order to promote the insertion, the double bond between C2 and
C3 must be broken, in conjuction with the formation of a new single bond between C1 and C2. The most
relaxed geometry for this transition state features a square-planar metallacyclobutane-like structure. The 6-TS
adopts a fairly planar structure with the dihedral angle ∠Ru–C1–C2–C3 being ~5°, as shown in Figure 3a. In
contrast, 6’-TS has an unfavorable steric interaction between the phenyl group of the enol and the carbonyl
group of the Ru-catalyst, which leads to a significant departure from planarity with the ∠Ru–C1–C2–C3
dihedral angle of ~26°, as illustrated in Figure 3b. The four bond lengths in the four-membered metallacycle
directly report on how far the transition state has progressed away from the reactant state. The Ru–C1 bonds
are 2.11 and 2.23 Å in 6-TS and 6’-TS, respectively, which is consistent with 6’-TS being more distorted than
6-TS, as discussed above. The C1–C2 bond is much longer at 2.17 Å in 6-TS compared to 1.94 Å in 6’-TS,
again consistent with 6-TS being an “earlier” transition state. The sterically induced deviation from planarity
also explains why the interaction energy computed in the fragment energy analysis is notably diminished in 6’-
TS. As the π-orbitals from the olefin substrates and the in-plane d-orbitals on Ru cannot be optimally arranged
due to the steric demand of the enol in 6’-TS, the interaction remains weak despite the larger structural
distortion of each fragments, which is also a consequence of the steric clash between the carbonyl and the
aromatic substituent on the enol.
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(75% D)
OH
OH
O
(44% D)
D
D
1 (3 mol %)
(2)
+
(72% D)
D
D ClCH2CH2Cl
125 oC
MeO
OMe
2r-d
MeO
OMe
(50% D)
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Experimental Support for the Mechanism. Several kinetic experiments were performed to assess
the validity of the DFT computed mechanism. First, the H/D exchange pattern was examined from the reaction
of 3,5-dimethoxyphenol with cyclohexanone-2,2,6,6-d4 (93% D) (eq 2). The isolated product 2r-d showed a
significant amount of H/D exchange to both vinyl and ꢀ-CH2 positions (72-75% D) as well as to the arene
positions (Figure S1, SI). This H/D exchange pattern indicates a facile keto-enol tautomerization of the
substrate under the reaction conditions. The extensive H/D exchange on the arene positions can readily be
explained via the chelate assisted ortho-arene C–H metalation process; such process has been well known to
occur rapidly and reversibly in metal-mediated coupling reactions via arene C–H activation.16 To confirm the
facile nature of the arene C–H activation step, the reaction rate was measured separately from the reaction of
3,5-dimethoxyphenol with cyclohexanone and cyclohexanone-2,2,6,6-d4. A negligibly small deuterium isotope
effect of kH/kD = 1.1 ± 0.1 was obtained from the first order rate plot (Figure S2, SI), again supporting the
notion of a rapid and reversible arene C–H activation step for the coupling reaction.
1.019
1.001
1.000 (ref)
OH
1.002
OH
O
1 (3 mol %)
+
(3)
Ph
ClCH2CH2Cl
125 oC
MeO
OMe
(Z)-2a
MeO
OMe
As discussed above, our DFT calculations indicate that the migratory insertion of ketone substrate is
the most likely rate-determining step. To confirm this computational result, we measured the carbon isotope
effect from the coupling reaction of 3,5-dimethoxyphenol with propiophenone by employing Singleton’s high-
precision NMR technique (eq 3).17 The most significant carbon isotope effect was observed on the ortho-
arene carbon of the product (Z)-2a when the 13C ratio of the product from a high conversion was compared
with the sample obtained from a low conversion (13C(avg 96% conversion)/13C(avg 19% conversion) at Cortho
=
1.019; average of two runs) (Table S2, SI). No significant carbon isotope effect was observed on the carbonyl
carbon, and this can be rationalized via an early asynchronous transition state of the multi-insertion steps as
depicted in Figure 1.18 Overall, the results are in good agreement with the calculated reaction energy profile
as shown in Figure 1, further reinforcing that the C–C bond forming migratory insertion of the ketone substrate
is the turnover-limiting step of the coupling reaction.
Synthetic Applications. These experimental and computational studies provided
a new
mechanistically driven rationale for designing stereoselective carbonyl olefination methods to construct
biologically relevant structural motifs. In an effort to further extend its synthetic utility, we have begun to
explore the dehydrative coupling method with enones and related carbonyl compounds (Scheme 2). For
example, the coupling of 3,5-dimethoxyphenol with a linear enone 4-phenyl-3-buten-3-one led to the direct
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formation of chromene core structure 11. In contrast, the coupling with a cyclic enone 2-cyclohexenone
selectively yielded a bicyclic hemiketal product 12 with >95% diastereoselectivity. The molecular structure of
12 was definitively established by X-ray crystallography (Figure S4, SI). The couplings with 2-norbornanone
and 2,5-hexanedione smoothly formed the bicyclic products 13 and 14, respectively. These exploratory
examples clearly demonstrate the synthetic power of dehydrative C–H coupling strategy in constructing
oxygen heterocycle core structures without using any reactive reagents or forming toxic byproducts. We are
currently pursing to establish the scope of the coupling reactions between electron-rich arene substrates with
these carbonyl compounds, and the results will be published in a separate article.
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Scheme 2. Dehydrative Coupling of 3,5-Dimethoxyphenol with Ketones
OH
MeO
O
MeO
O
OH
OMe
OMe Ph
11 (72%)
125 oC, 16 h
12 (79%)
125 oC, 16 h
MeO
OMe
MeO
O
O
MeO
O
OMe
14 (75%)
OMe
13 (61%)
140 oC, 16 h
130 oC, 16 h
CONCLUSIONS
In summary, we have successfully developed a highly chemo- and stereoselective dehydrative C–H
olefination method of phenols with ketones to form trisubstituted olefins. The well-defined ruthenium-hydride
catalyst was found to exhibit uniquely high activity and selectivity for promoting (Z)-olefin products. The
experimental and computational studies provide a detailed mechanistic picture for the catalytic cycle, which
consists of the ortho-metalation of phenol, migratory insertion of the carbonyl substrate and dehydration steps
in forming the olefin products. The DFT computational analysis revealed that the stereoselective formation of
(Z)-olefins results from an unfavorable steric interaction between the substrate substituents and the axial
carbonyl ligand of the Ru-catalyst during the migratory insertion step. The analogous C–H coupling reactions
of enones and diones directly led to the formation of synthetically useful benzo-fused oxacyclic derivatives.
Studies towards expanding the arene substrate scope as well as for exploiting mechanistic insights to
increase synthetic applicability for this catalytic method are underway in our laboratories.
EXPERIMENTAL SECTION
General Information. All operations were carried out in a nitrogen-filled glove box or by using
standard high vacuum and Schlenk techniques unless otherwise noted. Solvents were freshly distilled over
appropriate drying reagents. Benzene, toluene, and hexanes were distilled from purple solutions of sodium
and benzophenone, and dichloromethane was dried over calcium hydride prior to use. All organic substrates
were received from commercial sources and were used without further purification. Column chromatography
was performed on Dynamic Absorbents silica gel 60A (32-63 μm particle size), and thin layer chromatography
was performed on Agela TLC plates pre-coated with silica gel MF254. The NMR spectra were recorded on a
Varian 300 or 400 MHz FT-NMR spectrometer, and the data are reported in parts per million (ppm) relative to
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TMS. Mass spectra were recorded from Agilent 6850 GC-MS spectrometer with a HP-5 (5%
phenylmethylpolysiloxane) column (30 m, 0.32 mm, 0.25 μm). High-resolution mass spectra (HRMS) were
obtained at the Mass Spectrometry/ICP Lab, Department of Chemistry and Biochemistry, University of
Wisconsin-Milwaukee, Milwaukee, WI. Elemental analyses were performed at the Midwest Microlab,
Indianapolis, IN.
General Procedure for the Coupling Reaction of Phenol with Ketone. In a glove box, a phenol
(0.5 mmol), a ketone (1.0-1.5 mmol), and complex 1 (9 mg, 3 mol %) were dissolved in 1,2-dichloroethane (2
mL) in a 25 mL Schlenk tube equipped with a Teflon stopcock and a magnetic stirring bar. The tube was
brought out of the glove box, and was stirred in an oil bath preset at 125-140 °C for 16-72 h. The reaction tube
was taken out of the oil bath, and was cooled to room temperature. After the tube was open to air, the solution
was filtered through a short silica gel column by eluting with CH2Cl2 (10 mL), and the filtrate was analyzed by
GC-MS. Analytically pure product was isolated by column chromatography on silica gel (230-460 mesh,
hexanes/EtOAc). The product was completely characterized by NMR and GC-MS spectroscopic methods.
Computational Details. All calculations were carried out using DFT19 as implemented in the Jaguar
9.1 suite20 of ab initio quantum chemistry programs. Geometry optimizations were performed with B3LYP21
functional including Grimme’s D3 dispersion correction22 and the 6-31G** basis set. Ruthenium was
represented using the Los Alamos LACVP basis23 that includes effective core potentials. The energies of the
optimized structures were reevaluated by additional single point calculations on each optimized geometry
using Dunning’s correlation consistent triple-ζ basis set cc-pVTZ(-f)24 that includes a double set of polarization
functions. For ruthenium, we used a modified version of LACVP, designated as LACV3P, in which the
exponents were decontracted to match the effective core potential with triple-ζ quality. Solvation energies
were evaluated by a self-consistent reaction field (SCRF)25 approach based on accurate numerical solutions
of the Poisson-Boltzmann equation. In the results reported, solvation calculations were carried out with the 6-
31G**/LACVP basis at the optimized gas phase geometry employing the dielectric constant of ε = 10.36 for
dichloroethane. As is the case for all continuum models, the solvation energies are subject to empirical
parametrization of the atomic radii that are used to generate the solute surface. We employed26 the standard
set of optimized radii in Jaguar for H (1.150 Å), C (1.900 Å), N (1.600Å), P (2.074 Å) and Ru (1.481 Å).
Analytical vibrational frequencies within the harmonic approximation were computed with the 6-31G**/LACVP
basis to confirm proper convergence to well-defined minima or saddle points on the potential energy surface.
The energy components have been computed with the following protocol. The free energy in solution
phase G(sol) has been calculated as follows:
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G(Sol) = G(gas) + G(solv)
(1)
(2)
(3)
(4)
(5)
G(gas) = H(gas) - TS(gas)
H(gas) = E(SCF) + ZPE
ΔE(SCF) = ΣE(SCF) for products - ΣE(SCF) for reactants
ΔG(Sol) = ΣG(Sol) for products - ΣG(Sol) for reactants
G(gas) is the free energy in gas phase; G(solv) is the free energy of solvation as computed using the
continuum solvation model; H(gas) is the enthalpy in gas phase; T is the temperature (298.00K); S(gas) is the
entropy in gas phase; E(SCF) is the self-consistent field energy, i.e. “raw” electronic energy as computed from
the SCF procedure and ZPE is the zero-point energy. Note that by entropy here we refer specifically to the
vibrational/rotational/translational entropy of the solute(s); the entropy of the solvent is incorporated implicitly
in the continuum solvation model.
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To locate transition states, the potential energy surface was first explored approximately using the
linear synchronous transit (LST)27 method, followed by a quadratic synchronous transit (QST)28 search using
the LST geometry as an initial guess.
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Supporting Information. The Supporting Information is available free of charge on the ACS Publications
website. Experimental procedures, characterization data for organic products (PDF) and Cartesian
coordinates of all computed structures and energy components.
AUTHOR INFORMATION
Corresponding Author
E-mail: chae.yi@marquette.edu
E-mail: mbaik2805@kaist.ac.kr
ORCID
Mu-Hyun Baik: 0000-0002-8832-8187
Chae S. Yi: 0000-0002-4504-1151
Manoj V. Mane: 0000-0001-8236-3638
Ho Ryu: 0000-0001-8450-991X
Debashis Sahu: 0000-0002-0352-4753
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the National Science of Foundation (CHE-1358439, CHE-1664652) and the National
Institute of Health General Medical Science (R15 GM109273) is gratefully acknowledged. This research was
supported in part by the Institute for Basic Science (IBS-R010-D1) in Korea.
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Graphic Entry for the Table of Contents
4
O
OH Ar
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R
Ar
OH
[Ru] -H2O
R
BF4
H
O
Ru
H
PCy3
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O
R
R'
R
R'
OC
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[Ru] -H2O
[Ru]
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