Ruthenium-catalyzed carbon-carbon bond formation via the cleavage of an unreactive aryl carbon-nitrogen bond in aniline derivatives with organoboronates

Article abstract of DOI:10.1021/ja0713431

The RuH₂(CO)(PPh₃)₃-catalyzed reaction of 2-amino-6-methylacetophenone with phenylboronic acid 2,2-dimethyl-1,3-propanediol ester in refluxing toluene gave the corresponding phenylation product in 83% yield via aryl carbon

Full text of DOI:10.1021/ja0713431

Published on Web 04/20/2007
Ruthenium-Catalyzed Carbon-Carbon Bond Formation via the Cleavage of an
Unreactive Aryl Carbon-Nitrogen Bond in Aniline Derivatives with
Organoboronates
Satoshi Ueno,‡ Naoto Chatani,‡ and Fumitoshi Kakiuchi*,†
Department of Chemistry, Faculty of Science and Technology, Keio UniVersity, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama, Kanagawa 223-8522, Japan, and Department of Applied Chemistry, Faculty of Engineering, Osaka
UniVersity, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Received February 26, 2007; E-mail: kakiuchi@chem.keio.ac.jp
Scheme 1. The Phenylation of a Variety of C-N Bondsa
The catalytic functionalization of unreactive bonds such as
carbon-hydrogen,1 carbon-carbon,2 carbon-fluorine,3 and carbon-
oxygen4 bonds has become an interesting research subject in modern
organic synthesis. In addition to these reactions, the functionalization
of aryl carbon-nitrogen bonds in aniline derivatives is also
challenging because, to date, only one example of the oxidative
addition of an aryl C-N bond in anilines to a transition metal has
been reported.5,6 For the functionalization of aryl C-N bonds, the
bonds are usually activated by conversion to diazonium salts (Ar-
N2X),7 ammonium salts,8 triazenes,9 and imidazoles.10 However,
to the best of our knowledge, the catalytic functionalization of
unreactive aryl C-N bonds in aniline derivatives has not yet been
achieved. Herein, we describe the first example of catalytic C-C
bond formation via the cleavage of aryl C-N bonds in anilines.
In our continuous studies of the catalytic functionalization of
unreactive carbon bonds such as C-H and C-O bonds, we found
that RuH2(CO)(PPh3)3 (1) can function as an excellent catalyst, and
the use of a chelation assistance protocol is highly efficient for
attaining the cleavage of these bonds.1a,4b,d,11 Therefore, the reaction
of 2′-N,N-dimethylamino-6′-methylacetophenone (2) with 5,5-
dimethyl-2-phenyl[1,3,2]dioxaborinane (3) was examined using 1
as a catalyst (eq 1). We were pleased to find that the expected
ortho phenylation via aryl C-N bond cleavage took place to give
2′-methyl-6′-phenylacetophenone (4) in 84% yield.12 This result
provides the following notable features: (1) this is the first example
of the catalytic functionalization of aryl C-N bonds in anilines
via an oxidative addition of a C-N bond to a low-valent transition
metal; (2) this coupling reaction proceeds through a transmetalation
between a ruthenium-amide complex and an organoboron com-
pound.
a Isolated yields. b Phenylboronate 3 (1.0 mmol) and catalyst 1 (0.04mmol).
c Phenylboronate 3 (1.5 mmol) and catalyst 1 (0.06 mmol).
Table 1. The Coupling Reaction of
N,N-Dimethylaminopivalophenone (5) with Various
Organoboronatesa
When this coupling reaction was carried out using 2′-N,N-
dimethylaminoacetophenone, the phenylation took place at both
C-NMe2 and C-H bonds. To suppress this undesired phenylation
at the C-H bond, pivalophenone derivatives were employed.
Several amino groups such as -NMe2, -N(CH2)4, -NMe(allyl),
-NHMe, and -NH2 are applicable to this aryl C-N/RB(OR′)2
coupling (Scheme 1). The substituent on the nitrogen atom does
not have a significant effect on the yields of the coupling products
except for the -NMeAc group. Interestingly, a free N-H group
(NHMe and NH2) does not disturb this coupling reaction. In the
case of the reaction of an NMeAc derivative, the reactivity of the
a Conditions: RuH2(CO)(PPh3)3 1 (0.02 mmol), toluene (0.5 mL),
arylamine 5 (0.5 mmol), organoboronate (0.6 mmol), reflux, 20 h.
b Conditions: 1 (0.04 mmol), organoboronate (1.0 mmol). c Conditions: 1
(0.06 mmol), organoboronates (1.5 mmol).
ketone was decreased. Coupling product 6 was obtained in 51%
yield under conditions of 12 mol % of catalyst loading.
Several organoboronates involving aryl, heteroaryl, alkenyl, and
alkylboronates can be used in this reaction. Some selected results
are listed in Table 1. In the case of 4-styrylboronate, the yield was
decreased slightly due to the polymerization of some of the
4-styrylboronate during the reaction. The reaction using sterically
demanding arylboronates such as 2-tolyl- and 1-naphthylboronates
† Keio University.
‡ Osaka University.
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C O M M U N I C A T I O N S
afforded the coupling products in 87 and 99% isolated yields,
respectively. When the coupling reaction with heteroarylboronates
was carried out in the presence of 8 mol % of catalyst, the
corresponding coupling products were obtained in 45-77% yields.
The reaction using 1-propenylboronate (E:Z ) 5:95) afforded 2′-
(1-E-propenyl)pivalophenone as a major product (E:Z ) 94:6).
When (Z)-1-propenylboronate was heated at 60 °C for 30 min in
the presence of RuH2(CO)(PPh3)3 catalyst, isomerization of (Z)-1-
propenylboronate (E:Z ) 5:95) to the corresponding E-isomer (E:Z
) 95:5) occurred. This suggests that the E-propenylation product
was formed after the isomerization of the propenylboronate.
Alkylboronates, such as benzyl, trimethylsilylmethyl, â-phenethyl,
and cyclopropylboronates, can be used in this reaction. It is
noteworthy that, in the case of the reaction of â-phenethylboronate,
the R-phenethyl product, which could be formed via â-hydride
elimination from the â-phenethylruthenium intermediate followed
by the re-insertion of the double bond in styrene into the Ru-H
bond, was not formed, and that the cyclopropyl group can be
introduced on the aromatic ring without ring opening of the
cyclopropyl ring, which is usually reactive toward low-valent
transition metals.
To obtain information with respect to the transmetalation process,
we carried out a competitive reaction using 2′-aminopivalophenone
5, 4-N,N-dimethylaminophenylboronate 7, and 4-trifluorometh-
ylphenylboronate 8 (eq 2). After heating for 20 h, the coupling
product 10 derived from 8 was obtained as the major product. This
indicates that an electron-withdrawing group improves the reactivity
of the arylboronate. These electronic effects of the arylboron
compounds are consistent with the results of the palladium-catalyzed
cross-coupling reaction of propargylic carbonates with arylboron
compounds.13 In their study of this reaction, these workers reported
that transmetalation between the palladium-alkoxy species and
arylboron compounds proceeded through the coordination of the
alkoxy oxygen to the boron atom. We propose, on the basis of
their studies, that the transmetalation between the Ru-NMe2 species
and Ar-B(OR)2 takes place via the coordination of the amino group
to the boron atom. The low reactivity of N-methyl-N-(2-
pivaloylphenyl)acetamide, in which the electron density on the
nitrogen atom is slightly lower than those of other amino groups
(Scheme 1), is consistent with this proposed mechanism of the
transmetalation step.
The ruthenium-catalyzed chemoselective sequential C-C bond
formation using 2′-N,N-dimethylaminoacetophenone (13) with 3
and trimethylvinylsilane (14) gave 15 as the sole product (eq 4).15
Phenylation at the C-N bond with 3 and alkylation at the C-H
bond with 14 took place to give product 15 in 99% isolated yield.
In summary, we discovered the ruthenium-catalyzed C-C bond
formation via the unreactive aryl C-N bond cleavage in aniline
derivatives with organoboronates. This reaction includes two
important elementary steps: one is oxidative addition of an
unreactive aryl C-N bond to the late transition-metal complex and
the other is transmetalation between the Ru-NR2 species and
organoboronates. Further studies to address the scope and limitation
of this reaction and the reaction pathway are currently in progress.
Acknowledgment. This work was supported, in part, by a
Grant-in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the Ministry
of Education, Culture, Sports, Science and Technology, Japan, and
by the Cooperative Research with Sumitomo Chemical Co., Ltd.
F.K. thanks Tokuyama Science Foundation, and S.U. acknowledges
Research Fellowships of J.S.P.S. for Young Scientist.
Supporting Information Available: Experimental procedures and
spectral analyses of all products (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
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In place of aromatic ketones, aromatic esters 11 can also be used
in this reaction. The phenylation occurred efficiently at the C-N
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