Selective Monoarylation of Aromatic Ketones and Esters via Cleavage of Aromatic Carbon-Heteroatom Bonds by Trialkylphosphine Ruthenium Catalysts

Article abstract of DOI:10.1021/acs.orglett.6b03761

We report here the ruthenium-catalyzed selective monoarylation of aromatic ketones bearing two ortho carbon-heteroatom (O or N) bonds. Under the newly developed catalyst system consisting of RuHCl(CO)(PⁱPr₃)₂, CsF, and sty

Full text of DOI:10.1021/acs.orglett.6b03761

Letter
pubs.acs.org/OrgLett
Selective Monoarylation of Aromatic Ketones and Esters via
Cleavage of Aromatic Carbon−Heteroatom Bonds by
Trialkylphosphine Ruthenium Catalysts
Hikaru Kondo,† Takuya Kochi,† and Fumitoshi Kakiuchi*,†,‡
†Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa
223-8522, Japan
‡JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
S
* Supporting Information
ABSTRACT: We report here the ruthenium-catalyzed selective
monoarylation of aromatic ketones bearing two ortho carbon−
heteroatom (O or N) bonds. Under the newly developed catalyst
system consisting of RuHCl(CO)(PiPr3)2, CsF, and styrene, the C−
O arylation of 2′,6′-dimethoxyacetophenone with a phenylboronate
gave the C−O monoarylation product selectively. The selective C−
O monoarylation was applicable to a variety of arylboronates and
aromatic ketones and proceeds with high regio- and chemo-
selectivities. A formal synthesis of altertenuol was also achieved
using the C−O monoarylation of an aromatic ester as a key step.
Scheme 1. Product Selectivities on Ruthenium-Catalyzed
Direct Functionalizations of Unreactive Bonds
ransition-metal-catalyzed functionalization of unreactive
bonds such as C−H and C−Heteroatom bonds have been
T
extensively explored due to its great synthetic utility.1,2
Chelation-assisted control of the regioselectivity of the bond
cleavage has enabled the selective functionalization at the ortho
positions of the directing groups. However, there are still
limitations in selective monofunctionalizations of arenes
possessing multiple reaction sites.3 Our group has reported
ruthenium-catalyzed arylations of aromatic carbonyl compounds
with arylboronates via ortho-selective cleavage of carbon−
hydrogen or carbon−heteroatom bonds.1c,3b,4−8 In the reaction
of acetophenone derivatives having two ortho C−H or C−OMe
bonds, both ortho positions are smoothly arylated, and selective
monoarylation was hard to achieve even at low conversion of
substrates (Scheme 1A).5b,6a In the C−H arylation, the use of
styrene as an additive was found effective to some extent to form
monoarylation products mostly in moderate yields using 3 equiv
of acetophenones to arylboronates.3b In the corresponding
alkenylation reactions, it was possible to form monoalkenylation
products selectively, because coordination of the introduced
alkenyl group to the metal center may stabilize the catalytically
active low-valent ruthenium complex and may suppress the
second C−O bond cleavage. For example, we recently reported
selective C−O monoalkenylation of 2′,6′-dimethoxy-
acetophenone (1) with alkenylboronates using the catalyst
system consisting of RuH(OAc)(CO)(PPh3)2 and CsF (Scheme
1B).6c
aryl groups were introduced efficiently at the ortho position. The
C−O monoarylation of an aromatic ester was also applied to a
formal synthesis of altertenuol.
First, we investigated the ruthenium-catalyzed monophenyla-
tion of 1 with phenylboronate 2a (Table 1). When the reaction of
1 was conducted with 1.2 equiv of 2a in the presence of 2 mol %
of RuH2(CO)(PPh3)3 (5) at 120 °C for 30 min, diarylation
product 4a was obtained in 45% GC yield along with the desired
Herein we report the catalytic monoarylation of aromatic
ketones and esters possessing two unreactive C−O or C−N
bonds at ortho positions (Scheme 1C). A new catalyst system
consisting of RuHCl(CO)(PiPr3)2, CsF, and styrene was
established for the selective monoarylation, and a variety of
Received: December 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03761
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Letter
a
Table 1. Ruthenium-Catalyzed Selective C−O Monoarylation of an Acetophenone Derivative 1 with 2a
b
yields (%)
b
entry
Ru cat.
CsF (mol %)
styrene (equiv)
conversion (%)
3a
4a
1
2
3
4
5
6
RuH2(CO)(PPh3)3 (5)
−
−
4
−
1
1
1
1
1
1
1
−
47
73
70
72
92
98
96
<1
3
2
10
19
61
77
75
84
45
53
50
9
5
RuH(OAc)(CO)(PPh3)2
RuH(OAc)(CO)(PCy3)2
4
RuH(OAc)(CO)(PiPr3)2
4
15
22
12
RuHCl(CO)(PiPr3)2 (6)
4
c
7
6
6
6
4
c
d
d
8
c
−
4
nd
2
nd
d
9
nd
a
b
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), Ru cat. (0.01 mmol), CsF (0.02 mmol), styrene (0.5 mmol), 120 °C, 30 min. Determined by
GC analysis. Performed at 80 °C for 15 min. Not detected.
c
d
monophenylation product 3a in 2% yield (entry 1). Under these
reaction conditions, it is clearly shown that the subsequent
second phenylation occurs fast even at low conversion. The use
of styrene as an additive led to higher reactivity, and the yield of
3a was slightly improved to 10% (entry 2).9 The screening of the
ruthenium catalyst was then examined. A combination of
RuH(OAc)(CO)(PPh3)2 with CsF, an effective catalyst system
for the C−O monoalkenylation,6c gave monoarylation product
3a with higher selectivity but still in low yield (entry 3).
Screening of a series of RuH(OAc)(CO)(PR3)2-type complexes
containing various phosphines revealed that those with
trialkylphosphines such as PCy3 and PiPr3 serve as good
catalysts10 for the selective monophenylation reaction (entries
4 and 5), and the reaction using RuH(OAc)(CO)(PiPr3)2 gave
3a in 77% yield. The use of RuHCl(CO)(PiPr3)2 (6) gave 3a in
high yield with greater catalytic activity (98% conversion) (entry
6). Optimization of the reaction conditions using catalyst 6
further improved the yield of 3a and the selectivity toward
monoarylation over diarylation, and the reaction at 80 °C for 15
min provided 3a in 84% yield (entry 7). The reactions in the
absence of either CsF or styrene were not successful, indicating
that both of them are essential for generation of a catalytically
active species (entries 8 and 9).
Scheme 2. Ruthenium-Catalyzed Selective C−O
a
Monoarylation of 1 with Arylboronates 2
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), 6 (0.01 mmol),
CsF (0.02 mmol), styrene (0.5 mmol), toluene (0.5 mL), 80 °C, 15
b
min. Isolated yields are shown. Used 4 mol % of 6, 8 mol % of CsF,
c
and 2 equiv of styrene. Performed at 60 °C and used 10 mol % of 6,
20 mol % of CsF, and 5 equiv of styrene.
With the optimized reaction conditions in hand, we examined
the scope of arylboronates 2 for the C−O monoarylation
(Scheme 2). In addition to phenylboronate 2a, arylboronates
bearing various para-substituents can be used for the
monoarylation. The reaction of 1 proceeded with arylboronates
possessing electron-donating (dimethylamino, methoxy, and
methyl) and electron-withdrawing (trifluoromethyl, fluoro, and
chloro) groups (2b−g), and the corresponding monoarylation
products 3b−g were obtained in 73−81% isolated yields.11 The
coupling with arylboronates having bromo, iodo, and vinyl
groups (2h−j) required higher catalyst loadings, but the
corresponding monoarylation products 3h−j were isolated in
76−81% yields. Meta-substituted arylboronates 2k−m also
provided 3k−m in high yields. The reactions with 2-
naphthylboronate 2n and 3,4-dibenzyloxyphenylboronate 2o
also afforded the corresponding products 3n and 3o in 81% and
76% yields, respectively. The monoarylation with ortho-
methoxyphenylboronate 2p occurred smoothly without sacrific-
ing the methoxy group on the introduced aryl group. The
reactions with heteroarylboronates 2q−t also proceeded using 4
mol % of 6 for 1−2 h to afford 3q−t in good to excellent yields.
Alkylboronates such as benzyl-, neopentyl-, and β-phenethylbor-
onates were also examined for this reaction but failed to give the
corresponding alkylation products.
Sequential ortho C−O arylation of 1 using two types of
arylboronates may provide acetophenone derivatives bearing two
different aryl groups at the ortho positions. Therefore, the C−O
arylation of monophenylation product 3a was then investigated.
As shown in Scheme 3, when the reaction was conducted using
Scheme 3. Sequential Ortho C−O Arylation
B
DOI: 10.1021/acs.orglett.6b03761
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ruthenium catalyst 5, which is prone to afford the diarylation
product, at 120 °C for 4 h, introduction of methoxyphenyl and
trifluoromethylphenyl groups proceeded efficiently via cleavage
of the remaining ortho C−O bond to afford the unsymmetric
diarylation products 7c and 7e in excellent yields.
We next investigated the scope of aromatic ketones for the C−
O monoarylation (Table 2). The arylation of 2′,4′,6′-trimethoxy-
catalyzed alkenylation of aromatic ketone derivatives via cleavage
of C−O or C−N bonds.6c
It is unclear why the new catalyst system provides
monoarylation products selectively over diarylation products,
but the subsequent second arylation can be avoided by stabilizing
the ruthenium(0) species formed after the reductive elimination.
Coordination of styrene as a π-acid may facilitate the reductive
elimination to form the ruthenium(0) species and retard the
second oxidative addition of the C−O bond, as suggested for our
previously reported C−H monoarylation (Figure 1).3b The use
Table 2. Selective Monoarylation of Various Aromatic
a
Ketones
Figure 1. A possible explanation of the mono-/diarylation selectivity.
of highly electron-donating trialkylphosphines may increase the
electron density on the ruthenium center and may strengthen the
coordination of styrene to prevent the second cleavage of the C−
O bond.
The utility of the ruthenium-catalyzed C−O monoarylation
reaction was demonstrated further by the reaction of aromatic
esters (Scheme 4). Snieckus and Zhao recently reported the
Scheme 4. C−O Monoarylation of Benzoate Derivatives 10
a
Reaction conditions: 8 (0.5 mmol), 2a (0.6 mmol), 6 (0.01 mmol),
CsF (0.02 mmol), styrene (0.5 mmol), toluene (0.5 mL), 80 °C, 15
b
min. Isolated yields are shown. Performed at 120 °C for 30 min.
ester-directed C−O arylation of naphthoate derivatives using
catalyst 5, but it was not applicable to simple benzoate
derivatives.13 When our new catalyst system was employed for
the phenylation of isopropyl benzoate derivative 10a at 100 °C
for 12 h, monophenylation product 11a was obtained in 54%
yield. The reaction of tert-butyl ester 10b required a higher
catalyst loading but gave 11b in 47% yield.
Finally, we applied the C−O monoarylation to the formal
synthesis of altertenuol, a toxin produced by Alternaria tenuis
(Scheme 5).14 The reaction of tert-butyl 2′,4′,6′-trimethoxy-
benzoate (12), prepared from the commercially available
carboxylic acid in 91% yield, with arylboronate 2o provided
monoarylation product 13 in 57% yield. Treatment of 13 with
formic acid removed the tert-butyl group to deliver carboxylic
c
d
e
Performed for 1 h. Performed at 120 °C for 1 h. 1 equiv of 2a was
used.
acetophenone (8a) selectively took place at the ortho position
and furnished monophenylation product 9a in 74% yield (entry
1). The reaction of benzophenone derivative 8b, which has two
C−O bonds and two C−H bonds at the positions ortho to the
carbonyl group, gave the corresponding C−O monophenylation
product 9b in 69% yield without coupling at the ortho C−H
bonds (entry 2). The reaction of 2′,6′-diethoxyacetophenone 8c
also proceeded via cleavage of the C−OEt bond to provide
monoarylation product 9c in 80% yield (entry 3).12
The reaction of acetophenones possessing two different
functional groups at the ortho positions was then examined.
The ruthenium-catalyzed monophenylation of an acetophenone
derivative with methoxy and phenoxy groups delivered mono-
phenylation product 9d, formed via cleavage of the C−OMe
bond, in 77% yield as a major product along with 9% of C−OPh
bond cleavage product 3a (entry 4). The reaction of an
acetophenone derivative possessing a methoxy and dimethyla-
mino group with 1 equiv of 2a proceeded efficiently via C−N
bond cleavage to give 3a in 89% yield without generating C−O
monophenylation product 9e (entry 5). The observed chemo-
selectivity to favor cleavage of more electron-donating groups is
opposite to that of the conventional bond cleavage process via
oxidative addition but is similar to that of our ruthenium-
Scheme 5. Formal Synthesis of Altertenuol
C
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Letter
J.; Lee, Y.; Ryu, J.; Kim, J.; Lee, Y.; Jung, Y.; Chang, S. J. Am. Chem. Soc.
2014, 136, 1132. (e) Zhang, S.-Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G.
J. Am. Chem. Soc. 2015, 137, 531. (f) Dastbaravardeh, N.; Toba, T.;
Farmer, M. E.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 9877. (g) Sarkar,
D.; Gulevich, A. V.; Melkonyan, F. S.; Gevorgyan, V. ACS Catal. 2015, 5,
6792.
(4) Kakiuchi, F.; Kochi, T.; Murai, S. Synlett 2014, 25, 2390.
(5) Selected recent examples of our ruthenium-catalyzed C−H
functionalization: (a) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai,
S. J. Am. Chem. Soc. 2003, 125, 1698. (b) Kakiuchi, F.; Matsuura, Y.; Kan,
S.; Chatani, N. J. Am. Chem. Soc. 2005, 127, 5936. (c) Kitazawa, K.;
Kochi, T.; Sato, M.; Kakiuchi, F. Org. Lett. 2009, 11, 1951. (d) Kitazawa,
K.; Kotani, M.; Kochi, T.; Langeloth, M.; Kakiuchi, F. J. Organomet.
Chem. 2010, 695, 1163. (e) Kitazawa, K.; Kochi, T.; Nitani, M.; Ie, Y.;
Aso, Y.; Kakiuchi, F. Chem. Lett. 2011, 40, 300. (f) Ogiwara, Y.; Miyake,
M.; Kochi, T.; Kakiuchi, F. Organometallics 2017, 36, 159. See also ref
3b.
acid 14 in 93% yield. Subsequent oxidative cyclization by
K2S2O8 provided biaryl lactone 15 in 72% yield as a single
15
regioisomer. The total synthesis of altertenuol by Abe and co-
workers was achieved in one step from compound 15.14e
In summary, we developed the ruthenium-catalyzed selective
monoarylation of aromatic ketones and esters via cleavage of
unreactive C−O or C−N bonds. The new catalyst system
consisting of 6, CsF, and styrene was particularly effective in the
selective monoarylation. Various arylboronates can be used as
coupling partners for the reaction, and aromatic ketones bearing
two different aryl groups at the ortho positions was synthesized
by further C−O arylation of a monoarylation product. The
catalytic ortho C−O arylation of simple benzoate derivatives was
also achieved for the first time using this catalyst system and
applied to the formal synthesis of altertenuol.
(6) C−O functionalization: (a) Kakiuchi, F.; Usui, M.; Ueno, S.;
Chatani, N.; Murai, S. J. Am. Chem. Soc. 2004, 126, 2706. (b) Ueno, S.;
Mizushima, E.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2006, 128,
16516. (c) Kondo, H.; Akiba, N.; Kochi, T.; Kakiuchi, F. Angew. Chem.,
Int. Ed. 2015, 54, 9293.
(7) C−N functionalization: (a) Ueno, S.; Chatani, N.; Kakiuchi, F. J.
Am. Chem. Soc. 2007, 129, 6098. (b) Koreeda, T.; Kochi, T.; Kakiuchi, F.
J. Am. Chem. Soc. 2009, 131, 7238. (c) Koreeda, T.; Kochi, T.; Kakiuchi,
F. Organometallics 2013, 32, 682. (d) Koreeda, T.; Kochi, T.; Kakiuchi,
F. J. Organomet. Chem. 2013, 741−742, 148. See also ref 6c.
(8) C−F functionalization: Kawamoto, K.; Kochi, T.; Sato, M.;
Mizushima, E.; Kakiuchi, F. Tetrahedron Lett. 2011, 52, 5888.
(9) No coupling reaction between substrates with styrene was
observed in any reaction described in this paper.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03761.
■
S
Full experimental details and characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kakiuchi@chem.keio.ac.jp.
ORCID
(10) Selected examples of direct C−H functionalizations by
trialkylphosphine ruthenium catalysts: (a) Guari, Y.; Sabo-Etienne, S.;
Chaudret, B. J. Am. Chem. Soc. 1998, 120, 4228. (b) Guari, Y.;
Castellanos, A.; Sabo-Etienne, S.; Chaudret, B. J. Mol. Catal. A: Chem.
2004, 212, 77. (c) Grellier, M.; Vendier, L.; Chaudret, B.; Albinati, A.;
Rizzato, S.; Mason, S.; Sabo-Etienne, S. J. Am. Chem. Soc. 2005, 127,
17592. (d) Yi, C. S.; Lee, D. W. Organometallics 2010, 29, 1883.
(e) Kwon, K.-H.; Lee, D. W.; Yi, C. S. Organometallics 2010, 29, 5748.
(f) Walton, J. W.; Williams, J. M. J. Angew. Chem., Int. Ed. 2012, 51,
12166.
(11) A competition experiment of 1 with equimolar of 2c and 2e gave
3c in lower yield than 3e. Similar electronic effects of organoboron
compounds were also observed in ref 7a, c. See the Supporting
Information for details.
Fumitoshi Kakiuchi: 0000-0003-2605-4675
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
F.K. is thankful for financial support, in part, by JSPS KAKENHI
Grant Number JP15H05839 in Middle Molecular Strategy and
ACT-C from the Japan Science and Technology Agency (JST),
Japan. H.K. is grateful to the Japan Society for the Promotion of
Science (JSPS) for a Research Fellowship for Young Scienetists
(JP16J02904).
(12) The reaction of 2,6-dimethoxy-3-methylbenzophenone with 2a
was examined but provided a complex mixture, and the regioselectivity
of the C−O arylation could not be determined. The reaction of 4-
methoxy-4-methyl-2-pentanone was also attempted but did not give any
arylation product.
(13) Recently, Snieckus and Zhao reported amide- or ester-directed
C−O functionalizations using our ruthenium catalyst systems: (a) Zhao,
Y.; Snieckus, V. J. Am. Chem. Soc. 2014, 136, 11224. (b) Zhao, Y.;
Snieckus, V. Org. Lett. 2015, 17, 4674. (c) Zhao, Y.; Snieckus, V. Chem.
Commun. 2016, 52, 1681.
(14) (a) Rosett, T.; Sankhala, R. H.; Stickings, C. E.; Taylor, M. E. U.;
Thomas, R. Biochem. J. 1957, 67, 390. (b) Thomas, R. Biochem. J. 1961,
80, 234. (c) Nemecek, G.; Cudaj, J.; Podlech, J. Eur. J. Org. Chem. 2012,
2012, 3863. (d) Thomas, R.; Nemecek, G.; Podlech, J. Nat. Prod. Res.
2013, 27, 2053. (e) Matsukihira, T.; Saga, S.; Horino, Y.; Abe, H.
Heterocycles 2014, 89, 59.
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