In Situ Generation of Ruthenium Carbonyl Phosphine Complexes as a Versatile Method for the Development of Enantioselective C?O Bond Arylation

Article abstract of DOI:10.1002/chem.201905157

We report here a method for in situ generation of various ruthenium carbonyl phosphine catalysts for arylation via cleavage of inert aromatic carbon–oxygen bonds. The use of catalyst systems consisting of [RuCl₂(CO)(p-cymene)], CsF, styrene, an

Full text of DOI:10.1002/chem.201905157

A Journal of
Accepted Article
Title: In Situ Generation of Ruthenium Carbonyl Phosphine Complexes
as a Versatile Method for Development of Enantioselective C–O
Bond Arylation
Authors: Hikaru Kondo, Takuya Kochi, and Fumitoshi Kakiuchi
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To be cited as: Chem. Eur. J. 10.1002/chem.201905157
Link to VoR: http://dx.doi.org/10.1002/chem.201905157
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In Situ Generation of Ruthenium Carbonyl Phosphine Complexes
as a Versatile Method for Development of Enantioselective C–O
Bond Arylation
Hikaru Kondo, Takuya Kochi, and Fumitoshi Kakiuchi*
Dedication ((optional))
Abstract: We report here a method for in situ generation of various
ruthenium carbonyl phosphine catalysts for arylation via cleavage of
inert aromatic carbon–oxygen bonds. The use of catalyst systems
consisting of RuCl2(CO)(p-cymene), CsF, styrene, and phosphines
enabled facile screening of phosphine ligands. Asymmetric C–O
arylation was also achieved for atropo-enantioselective biaryl
synthesis using a chiral monodentate phosphine ligand.
lead to further development of novel methods for C–H/C–
heteroatom functionalization including asymmetric versions.
There have been several catalytic systems for unreactive bond
functionalizations involving in situ generated phosphine or NHC
catalysts of transition metals such as Pd, Ni, and Rh etc.[1,2]
A
ruthenium catalyst system was also reported by Darses and
Genet in 2006 and used for C–H/olefin coupling of aromatic
ketones. Ru(0) catalysts were generated in situ from RuCl2(p-
cymene)2 with various phosphines in the presence of HCO2Na
as a reducing reagent (Scheme 1b),[6a] but this catalyst has only
been used for C–H/olefin[6a-e] and C–H/alkyne[6f] couplings, and
no enantioselective functionalization was developed based on
this system.
Functionalization of unreactive C–H and C–heteroatom bonds
on aromatic rings using transition-metal catalyst has emerged as
a powerful tool for organic synthesis, because it enables
transformations difficult to achieve with conventional
methods.[1,2] Phosphine and NHC ligands have frequently been
used as ligands for metal catalysts and play crucial roles to
induce desired reactivities by their electronic and steric features.
Accordingly, convenient ligand screening methods based on a
reliable procedure for in situ generation of catalysts from a metal
catalyst precursor and various ligands have facilitated
development of novel functionalization reactions with desired
selectivity.[1,2]
A ruthenium phosphine complex, RuH2(CO)(PPh3)3 has been
recognized as a potent catalyst for regio- and chemoselective
C–H and C–heteroatom bond functionalizations.[3-5] Recently,
our group reported syntheses of series of RuHCl(CO)(PAr3)3-
and RuH2(CO)(PAr3)3-type complexes containing various
triarylphosphines and their use for direct C–H arylation of
aromatic ketones and nitriles (Scheme 1a).[4] Improvement of
both reactivity and selectivity in these reactions was achieved by
choosing an appropriate phosphine ligand for the preformed
ruthenium complexes. In addition, we also found that
(triarylphosphine)ruthenium
catalysts
such
as
i
RuHCl(CO)(P Pr3)2 are effective for selective C–O monoarylation
of aromatic ketones having multiple C–O bonds at the ortho
positions,[5a] while the arylation using RuH2(CO)(PPh3)3
selectively provides diarylation products.[5b] These results
essentially show that choice of appropriate phosphine ligands of
carbonyl phosphine ruthenium catalyst is important for reaction
development, but each of the screened phosphine complexes
needed to be prepared beforehand. Therefore, we envisioned
that establishment of a convenient procedure for in situ
generation of ruthenium carbonyl phosphine complexes would
[*]
H. Kondo, Dr. T. Kochi, Prof. Dr. F. Kakiuchi
Department of Chemistry, Faculty of Science and Technology, Keio
University
Scheme 1. Ruthenium phosphine catalyst for unreactive bond
functionalizations
3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522 (Japan)
E-mail: kakiuchi@chem.keio.ac.jp
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Herein we report a versatile method for in situ generation of
ruthenium carbonyl phosphine catalysts and its application to
facile ligand screening for C–O arylation (Scheme 1c).
Asymmetric C–O arylation was also achieved for atropo-
enantioselective biaryl synthesis via the cleavage of sterically-
congested C–O bonds by newly-identified ruthenium chiral
phosphine catalyst (Scheme 1d).
9), as observed for our previously-reported C–O arylation of 1
using RuHX(CO)(PR3)2-type complexes (X = Cl, OAc) as
catalysts.[5a] The use of PtBu3 or PnBu3, whose
RuHX(CO)(PR3)2-type complexes have not been reported, was
also examined but resulted in the formation of 3 in no more than
7% yield (entries 10 and 11). These results essentially showed
the high practicality of the in situ catalyst generation method
described here not only by mostly reproducing the
characteristics of the ligands in the C–O arylation of 1[5a] but also
by identifying a new ligand applicable to the arylation. It is also
shown that the in situ catalyst generation system can be used to
switch the mono-/diarylation selectivity conveniently by choosing
an appropriate ligand.
In order to establish a convenient method for in situ generation
of ruthenium-phosphine catalysts, we first examined the
arylation of 2’,6’-dimethoxyacetophonone (1) with phenyl
boronate 2 using various combinations of ruthenium complexes,
PPh3, and additives (Scheme 2). Under the catalytic condition
consisting of [RuCl2(p-cymene)]2, PPh3, and HCO2Na which was
reported by Darses and Genet,[6a] only a trace amount of
diarylation product 4 was obtained. Screening of additives
showed that a combination of [RuCl2(p-cymene)]2, PPh3, CsF
and styrene[7] provides diphenylation product 4 in 13% yield
along with 3% of monoarylation product 3. Because ruthenium
catalysts we have used for ortho-selective functionalization of
aromatic ketones generally possessed a carbonyl ligand,[3,4]
RuCl2(CO)(p-cymene) (5) was examined as a catalyst precursor
and found to dramatically improve the yields of arylation
products 3 and 4 (7 and 53% yields, respectively).
Table 1. Screening of External Phosphine Ligands on Ruthenium-
Catalyzed C–O Arylation of Acetophenone Derivative 1 with 2
Entry
Phosphine
Conv. [%][b]
Yields [%][b]
3
4
1
none
2
2
nd[c]
53
2
PPh3
62
<1
79
42
78
81
90
96
13
<1
7
3
P(2-MeC6H4)3
P(3-MeC6H4)3
P(4-MeC6H4)3
P(4-F3CC6H4)3
PCy3
trace
8
nd[c]
63
4
5
7
35
6
17
66
76
78
7
61
7
9
Scheme 2. Initial Attempts on In-Situ Generation of Ru-Phosphine Catalyst for
C–O Arylation of 2’,6’-Dimethoxyacetophenone (1)
8
PtBu2Me
PiPr3
13
9
17
10
11
PtBu3
nd[c]
nd[c]
With the newly developed catalyst system in hand, we then
investigated the arylation of 1 with 2 using various phosphines to
see the reliability of the in-situ-generation method. When the
reaction was conducted in the absence of phosphine,
monoarylation product was obtained in 2% yield (Table 1, entry
1). In the presence of PPh3, the arylation of 1 proceeded and
gave diarylation product 4 as a major product (entry 2). Other
triarylphosphines were also examined using the same protocol
(entries 3-6). While the arylation did not proceed by using P(2-
MeC6H4)3, whose RuHCl(CO)(PAr3)n- or RuH2(CO)(PAr3)n-type
complex has been neither reported nor prepared in our group
(entry 3),[4a] the reaction in the presence of P(3-MeC6H4)3 or P(4-
MeC6H4)3 afforded 4 as a major product (entries 4 and 5). The
arylation also proceeded using P(4-F3CC6H4)3 as a ligand to give
3 and 4 in 17 and 61% yields, respectively with excellent
material balance (entry 6). It is important to note that the
RuHCl(CO)(PAr3)3- and RuH2(CO)(PAr3)3-type complexes could
not be prepared from P(4-F3CC6H4)3 by our previously-reported
method[4a,8] and its applicability as a ligand has not been
evaluated for the C–O arylation.[9] In contrast, the reactions
using trialkylphosphines such as PCy3, PtBu2Me, and PiPr3
provided monoarylation product 3 as a major product (entries 7-
PnBu3
trace
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), 5 (0.01 mmol), CsF
(0.04 mmol), styrene (0.2 mmol), 100 ºC, 1 h. [b] Determined by GC
analysis. [c] Not detected.
Development of catalytic asymmetric reactions is an area
where in situ catalyst generation methods are particularly useful,
because precious chiral ligands can be rapidly screened for the
reactions and do not have to be wasted for sometimes inefficient
syntheses of the corresponding metal complexes. Having
established the in situ generation method of the ruthenium
catalysts described above, therefore, we explored the
asymmetric C–O arylation of axially chiral biaryl compounds
using optically-active phosphine ligands.[10] There have been
only a few methods reported for catalytic atropo-enantioselective
biaryl synthesis of by cross coupling of arenes via cleavage of
inert C–H [11, 12] or C–O [13] bonds, and further developments of
these reactions are still desired.
The reaction of 1-methoxy-2-acetonaphthone (6a) and 1-
naphthyl boronates 7 was first examined in the presence of 10
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mol % of 5 and (R)-MOP (L1) in toluene at 100 ºC for 24 h and
1,1’-binaphthyl derivative 8aa was obtained in 49% yield and
46% ee (Table 2, entry 1).[14] The use of 1,4-dioxane as a
solvent slightly increased the yield and the enantiomeric excess
(entry 2). Similar yield and enentioselectivity were observed for
the reaction with pinacol ester 7b instead of neopentyl glycol
ester 7a, but the material balance between substrate 6a and
product 8aa was improved (entry 3). Screening of the ligands
were then investigated using various chiral phosphines. While
MOP-type ligands L2-4 did not lead to considerable
improvement (entries 4-6), the reaction using MOP-alkene
ligand L5 provided 8aa in higher yield (63%) with greater
enantioselectivity (61% ee) (entry 7).[15] Because L5 contains an
alkene moiety at C2’ position, the reaction in the absence of
styrene was also conducted and gave 8aa in 71% yield with
62% ee (entry 8). Lowering the reaction temperature to 80 ºC
enhanced the enantiomeric excess to 66% (entry 9). Additional
modification of the ligand was examined at the aryl group on the
phosphorus atom, and introduction of bulky aryl groups such as
3,5-Me2C6H3 and 3,5-tBu2C6H3 improved the enantiomeric
excess to 81 and 88% ee, respectively (entries 10 and 11).
Further optimization of the reaction conditions including the
solvent, the catalyst loading, and the reaction time revealed that
the reaction in THF with 20 mol % of 5 for 48 h gave 8aa in 58%
NMR yield with 90% ee (entry 12).
The scope of the atropo-enantioselective C–O arylation was
explored using various acetophenone derivatives and
arylboronates (Scheme 3). The reaction of 6a proceeded with
arylboronates possessing electron-donating (methoxy and
methyl) and -withdrawing (fluoro) groups (7b-7d), and the
corresponding arylation products 8ab-8ad were obtained. While
excellent enantioselectivity was observed for reactions with
methyl- (7c) and fluoro-substituted (7d) arylboronates, methoxy-
substituted arylboronate 7b showed low reactivity in the reaction
with using L7 and the use of L5 led to the formation of arylation
product 8ab in 50% yield but with 68% ee. The reaction of 3,5-
dimethyl-2-methoxyacetophenone 6b with 7a showed higher
reactivity than that of 6a and gave the corresponding arylation
product 8ba in 73% yield with 93% ee. The reaction of 6b with
various naphthyboronates 7b-e also afforded 8bb-be in 65-96%
ee. The molecular structure of the product 8be including the
absolute configuration was confirmed by single-crystal X-ray
diffraction analysis.[17] Introduction of 9-phenanthlene group to
6a was also possible using L5 and L7 as a ligand and gave
arylation product 8af in 44-54% yield with 67-71% ee. The
pinacol ester of ortho-tolylboronic acid was not applicable to this
reaction, but the neopentyl glycol ester was found as an
effective coupling partner and gave the corresponding product
8ag in 51% yield with 80% ee.
Moreover, 2-naphthamides 9 were found applicable to the
atropo-enantioselective C–O arylation using L5 (Scheme 4).[18,19]
The reaction of naphthamides 9a with naphthylboronate 7a and
ortho-tolylboronate 7g gave the corresponding arylation
products 10aa and 10ag in moderate yields with 44-67% ee.
Pyrrolidine amide 10b and morpholide amide 10c were also
reacted with 7a to give the corresponding binaphthyl products
10ba and 10ca in moderate yields with 54-73% ee.
In summary, we developed an in situ generation method of
ruthenium phosphine catalyst for selective ortho C–O arylation
of aromatic carbonyl compounds. A novel catalyst system
consisting of RuCl2(CO)(p-cymene) (5), phosphine, CsF, and
styrene was found as a suitable catalyst system, and efficient
screening of the phosphine ligand for the C–O arylation reaction
of 1 was demonstrated. The practicality of the catalyst system
was further illustrated by the development of atropo-
enantioselective biaryl synthesis, and the use of MOP-alkene
ligands L5 and L7 for C–O arylation at the sterically-congested
site led to the formation of axially chiral biaryls with up to 96%
ee. We believe that the in situ generation method of ruthenium
catalysts will be a valuable tool for further developments of
functionalization reactions via inert bond cleavage and their
asymmetric variants.
Table 2. Optimization of Asymmetric C–O Arylation of an Acetonaphthone
Derivative 6a with 1-Naphthylboronate 7
Conv.[%][b]
Yield [%][b]
Ee[c]
46
Entry
7
L
Temp
1[d]
2
7a
7a
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
L1
L1
L1
L2
L3
L4
L5
L5
L5
L6
L7
L7
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
80 ºC
64
83
71
56
40
25
49
59
56
47
32
18
53
53
3
57
4
42
5
-30
6
77
80
63
71
-61
-62
7
8[e]
9[e]
10[e]
11[e]
12[e,f]
41
54
14
36
49
10
-66
-81
-88
80 ºC
80 ºC
80 ºC
68
58 (52)[g]
-90
[a] Reaction conditions: 6a (0.2 mmol), 7a (0.3 mmol), 5 (0.02 mmol), CsF
(0.08 mmol), styrene (0.2 mmol), 100 ºC, 24 h. [b] Determined by 1H NMR
analysis. [c] Determined by HPLC analysis (OJ-H, flow rate 1 mL/ min,
hexane:IPA = 95:5). [d] Toluene was used as a solvent. [e] The reaction was
conducted in the absence of styrene. [f] Reaction was conducted in THF
with 20 mol % of 5, 20 mol % of L, 80 mol % of CsF for 48 h. [g] Isolated
yield was shown in parentheses.
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Acknowledgements
F.K. thanks to financial support, in part, by the Promotion of
Science (JSPS) KAKENHI Grant Number JP15H05839 in Middle
Molecular Strategy, Japan. H.K. is grateful to JSPS for a
Research Fellowship for Young Scienetists (JP16J02904). We
thank Mr. Issei Suzuki at Keio University for experimental
assistance. We are grateful to Professor Yukari Fujimoto (Keio
University) for her assistance with correcting the specific
rotations.
Keywords: Ruthenium • Synthetic methods • Cleavage
reactions • Asymmetric synthesis • Homogeneous catalysis
[1]
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[2]
Representative
reviews
and
accounts
for
catalytic
C–O
Scheme 3. Ruthenium-catalyzed atropo-enantioselective C–O arylation of
aromatic ketone 6 with various boronate 7. Reaction conditions: 6 (0.2 mmol),
7 (0.3 mmol), 5 (0.04 mmol), L7 (0.04 mmol), CsF (0.16 mmol), THF (0.2 mL),
80 ºC, 48 h. [a] The absolute configuration of 8aa was determined by
comparing its optical rotation value with that in the literature.[16] The
configurations of other biaryl compounds were assigned by analogy. [b]
Reaction conditions: 6 (0.2 mmol), 7 (0.3 mmol), 5 (0.03 mmol), L5 (0.03
mmol), CsF (0.12 mmol), 1,4-dioxane (0.2 mL), 70 ºC, 96 h. [c] O-tolylB(nep)
functionalizations: a) B. Su, Z.-C. Cao, Z.-J. Shi, Acc. Chem. Res. 2015,
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C.-J. Li, ACS Catal. 2017, 7, 510.
(7g') was used instead of o-tolylB(pin) (7g).
[3]
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[7]
[8]
According to our previous studies, CsF and styrene are effective
additives for generation of catalytically active species from
RuHX(CO)(PAr3)n and RuHX(CO)(Palkyl3)2 . See refs. 3a, 4b and 4c.
It was reported that RuH2(CO){P(4-F3CC6H4)3}3 can be prepared as a
side product in the synthesis of Ru(CO)3{P(4-F3CC6H4)3}2: J. Jeschke,
M. Korb, T. Ruffer, C. Gabler, H. Lang, Adv. Synth. Catal. 2015, 357,
4069.
Scheme 4. Ruthenium-catalyzed atropo-enantioselective C–O arylation of
Aromatic Amide 9 with various boronate 7. Reaction conditions: 9 (0.2 mmol),
7 (0.3 mmol), 5 (0.03 mmol), L5 (0.03 mmol), CsF (0.12 mmol), 1,4-dioxane
(0.2 mL), 70 ºC, 48 h. [a] The absolute configuration of 10aa was determined
by comparing its optical rotation value with that in the literature.[20] The
configurations of other biaryl compounds were assigned by analogy. [b] O-
tolylB(nep) was used instead of o-tolylB(pin).
[9]
Higher catalytic activities of P(4-F3CC6H4)3 than PPh3 were shown in
the ruthenium-catalyzed C–H/olefin coupling using in situ catalyst
generation method by Darses and Genet. See refs. 6c and 6d.
[10] Representative reviews of atropselective biaryl syntheses: a) M. C.
Kozlowski, B. J. Morgan, E. C. Linton, Chem. Soc. Rev. 2009, 38,
3193; b) G. Bringmann, T. Gulder, T. A. M. Gulder, M. Breuning, Chem.
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Rev. 2011, 111, 563; c) G. Bringmann, A. J. Price Mortimer, P. A. Keller,
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Chem. Int. Ed. 2018, 57, 11040; Angew. Chem. 2018, 130, 11206.
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[14] See the Supporting Information for more details on the optimization of
the reaction conditions.
[15] Du and coworkers developed L4 and L5 for Pd-catalyzed asymmetric
allylic alkylation, see: Z. Cao, Y. Liu, Z. Liu, X. Feng, M. Zhuang, H. Du,
Org. Lett. 2011, 13, 2164.
[16] J. Liu, K.-F. Hu, J.-P. Qu, Y.-B. Kang, Org. Lett. 2017, 19, 5593.
[17] CCDC 1952511 (8be) contains the supplementary crystallographic data
for this paper. The data can be obtained free of charge from the
Cambridge Crystallographic Data Centre.
[18] The use of L7 for the reaction of aromatic amide 9 gave arylation
product 10 less than 10% yield. Thus, we used L5 instead of L7.
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10.1002/chem.201905157
Chemistry - A European Journal
COMMUNICATION
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COMMUNICATION
A convenient method for in situ
generation of ruthenium phosphine
catalysts for direct C–O arylation of
aromatic compounds was
Hikaru Kondo, Takuya Kochi, and
Fumitoshi Kakiuchi*
Page No. – Page No.
developed. Atropo-enantioselective
C–O arylation of aromatic ketones
and amides was also achieved using
the in situ catalyst generation
method through efficient screening
of chiral phosphines.
In Situ Generation of Ruthenium
Carbonyl Phosphine Complexes as
a Versatile Method for Development
of Enantioselective C–O Bond
Arylation
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