Light/Palladium-Promoted Benzylic C?H Acylation Using a Benzoyl Group as the Photo-Directing Group

Article abstract of DOI:10.1002/asia.201801881

2-Methylphenyl ketones undergo site-selective acylation at the benzylic position when treated with acid anhydride under UV irradiation in the presence of a palladium catalyst. The benzoyl carbonyl group serves as the photo-directing group so that the ortho benzylic C?H bond is activated site-selectively.

Full text of DOI:10.1002/asia.201801881

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Light/Palladium-Promoted Benzylic C–H Acylation Using a
Benzoyl Group as the Photo-Directing Group
Authors: Yusuke Masuda, Naoki Ishida, and Masahiro Murakami
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To be cited as: Chem. Asian J. 10.1002/asia.201801881
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Light/Palladium-Promoted Benzylic C–H Acylation Using a
Benzoyl Group as the Photo-Directing Group
Yusuke Masuda, Naoki Ishida, and Masahiro Murakami*
Abstract: 2-Methylphenyl ketones undergo site-selective acylation
at the benzylic position when treated with acid anhydride under UV
irradiation in the presence of a palladium catalyst. The benzoyl
carbonyl group serves as the photo-directing group so that the ortho
benzylic C–H bond is activated site-selectively.
carried out without photo-irradiation to confirm that no reaction
occurred.[7]
The C–H functionalization protocol presents a straightforward
and efficient method to manipulate organic molecules in an
atom- and step-economical manner.[1] It is one of the major
issues how to target a specific C–H bond among a multitude of
C–H bonds existing in a molecule. It was shown in the seminal
report by Murai that an acyl group on a benzene ring directs a
metal to activate its ortho C(sp2)–H bond.[2] This work has
triggered a numerous number of studies on utilization of
directing groups which bring a metal into close proximity to a
targeted C–H bond and site-selectively activate it (Figure 1a).[3,4]
We now report that a carbonyl group on a benzene ring acts as
the photo-directing group to site-selectively activate a C(sp3)–H
bond at an ortho benzylic position.[5] A palladium catalyst
subsequently acylates the activated intermediate with acid
anhydride to afford a 1,5-diketone (Figure 1b).[6] This is the first
Among various mechanistic possibilities conceivable for the
formation of 3a from 2-methylbenzophenone 1a and acetic
anhydride 2a under photo-irradiation, Scheme 1 shows one of
the plausible pathways. Initially, the o-quinodimethane A is
generated from 1a upon photo-excitation.[8,9] This process
mechanistically consists of three steps; (i) photoexcitation of the
carbonyl group, (ii) 1,5-hydrogen shift, which is the most facile
mode for hydrogen shift,[10] to the excited carbonyl oxygen
generating 1,4-biradical B, and (iii) isomerization of B to o-
quinodimethane A which has a closed-shell structure.[11] On the
other hand, acetic anhydride 2a undergoes oxidative addition
example
in
which
photo-generated
o-quinodimethane
intermediates are combined with transition-metal catalysis.
Figure 1. Directing groups for transition-metal catalyzed C–H activations.
When 2-methylbenzophenone 1a was treated with acetic
anhydride 2a in the presence of a Pd(OAc)2/P(Oi-Pr)3 catalyst
under photo-irradiation for 2 h, 1,5-diketone 3a was produced in
95% yield [Eq. (1)]. For comparison, a same reaction was
[*]
Dr. Y. Masuda, Dr. N. Ishida, Prof. Dr. M. Murakami
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University, Katsura, Kyoto 615-8510 (Japan)
E-mail: murakami@sbchem.kyoto-u.ac.jp
Supporting information and the ORCID identification numbers for the
authors of this article can be found under:
Scheme 1. Proposed mechanism.
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onto palladium(0) to form acetyl(acetato)palladium(II) C.[12] The
photo-generated enol A coordinates onto palladium to form the
intermediate D followed by elimination of acetate acid.[13] The
2
51%
72%
75%
73%
62%
72%
resulting acetyl(enolato)palladium(II)
E
tautomerizes into
acetyl(benzyl)palladium(II) F, thereby regaining aromatization
energy. Finally, a carbon–carbon bond is formed by reductive
elimination to furnish the 1,5-diketone 3a with regeneration of
Pd(0).[14,15]
3
The directing effect of the carbonyl group was corroborated
by the reaction using 2,5-dimethylbenzophenone 1b, which had
two methyl groups at different positions, i.e., ortho and meta
positions on the benzene ring [Eq. (2)]. Acetylation took place
site-selectively at the methyl group ortho to the carbonyl group
to form the product 3b. No acetylation occurred at the meta
methyl group. It is also notable that the ortho C(sp2)–H bond on
the benzene ring, which is often activated with the aid of
directing groups based on coordination, remained intact. This
unique site-selectivity originates from the privileged mode of 1,5-
hydrogen shift at the photo-excited state.
4
5[c]
6[c]
7
The acetylation reaction was examined using various 2-
methylphenyl ketones (Table 1). Both electron-rich and electron-
deficient benzene rings were suitable as the core aromatics
(entries 1 and 2). Functional groups such as fluoro, chloro, and
methoxycarbonyl groups were all tolerated on the aromatic rings
(entries 3-6). The reaction of those having electron-withdrawing
substituents was slower than that of electron-rich substrates.[16]
Bis(o-tolyl) ketone underwent the acylation only once to produce
the diketone 3i, and no bis-acetylated product was formed (entry
7).[17] 2-Ethylbenzophenone failed to participate in the acylation
reaction.[18]
[a] Reaction conditions: 2-methylphenyl ketone (0.20 mmol), acetic anhydride
(0.40 mmol), Pd(OAc)2 (0.01 mmol), P(Oi-Pr)3 (0.04 mmol), t-BuOH (1.0 mL),
UV light (365 nm, LED lamp), room temperature, 2 h. [b] Isolated yield. [c] 0.02
mmol of P(Oi-Pr)3, 1 h.
Table 1. Scope of 2-methyl benzophenones.[a]
The substrate scope was investigated also using various
carboxylic anhydrides (Table 2). Propanoic anhydride 2b and
isobutylic anhydride 2c successfully participated in the reaction
as the acylating reagent (entries 1 and 2), whereas pivalic
anhydride failed to give the acylated ketone, presumably due to
the steric reasons. Levulinic anhydride 2d was a suitable
substrate to give triketone 3m in 48% yield (entry 4).
Entry
1
Substrate 1
Product 3
yield[b]
83%
O
H
Table 2. Scope of acid anhydrides.[a]
Ph
MeO
1c
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Entry
1
Acid anhydride 2
Product 3
yield[b]
80%
2
3
4
59%
63%
48%
Scheme 2. Sequential transformations from 2-methylbenzophenone 1a to 2,3-
benzodiazepine 4, isoquinoline 5, and 2-naphthol 6 in one-pot..
In conclusion, we disclosed that a benzylic C–H bond of 2-
methylbenzophenone is activated under photo-irradiation to be
acylated with carboxylic anhydrides in the presence of a
palladium catalyst. A benzoyl carbonyl group acts as the photo-
directing group to activate the benzylic C–H bond site-selectively.
A number of reactions of 2-methyl benzophenones forming C–C
bond at the benzylic position has been reported.[5,20] However, o-
quinodimethane A has never been used in combination with
transition-metal catalysis. We demonstrated that the cooperation
of light and transition-metal catalysts gives rise to the powerful
methods for site-selective C–C bond formations of 2-methyl
benzophenones.
[a] Reaction conditions: 2-methylphenyl ketone (0.20 mmol), acetic anhydride
(0.40 mmol), Pd(OAc)2 (0.01 mmol), P(Oi-Pr)3 (0.04 mmol), t-BuOH (1.0 mL),
UV light (365 nm, LED lamp), room temperature, 2 h. [b] Isolated yield.
The present reaction was driven only by light and a catalytic
amount of palladium, and no stoichiometric amounts of other
reagents were employed. Consequently, it was possible to
dispense with a work-up and isolation procedure before carrying
out further derivatization of the produced 1,5-dicarbonyl
compounds. Instead, reagents were directly added to the
reaction mixture containing the diketone 3a to successfully
prompt subsequent reactions (Scheme 2). For example,
hydrazine was added to a same reaction flask after 1a was
reacted with 2a, and the resulting mixture was heated at 80 C
for 16 h. An aqueous work-up followed by chromatographic
purification afforded 2,3-benzodiazepine 4. In general, 2,3-
benzodiazepine is a versatile pharmacophore, often constituting
psychotropic drugs such as Tofisopam and Girisopam.[19] When
the in-situ generated 3a was treated with an aqueous ammonia
solution, isoquinoline 5 was obtained in 83% yield. Diketone 3a
underwent also an intramolecular aldol condensation reaction
upon treatment with potassium hydroxide to form 2-naphthol 6 in
90% yield.
Experimental Section
A typical procedure for synthesis of diketones: Pd(OAc)2 (2.2 mg, 0.01
mmol, 5 mol%) was placed in a Pyrex flask, which was subsequently
filled with an argon by vacuum-refill cycles. 2-Methylbenzophenone 1a
(39 mg, 0.20 mmol), acetic anhydride 2 (41 mg, 0.40 mmol, 2.0 equiv),
P(Oi-Pr)3 (8.4 mg, 0.04 mmol, 20 mol%), and t-BuOH (1.0 mL) were
added into the flask, which was pre-stirred for 5 minutes at room
temperature.21 After irradiated with LED lamp (365 nm) for 2 h at ambient
temperature, the resulting mixture was passed through a pad of Florisil®
and eluted with diethyl ether. Volatiles were removed under reduced
pressure. The residue was purified by preparative thin-layer
chromatography (hexane/ethyl acetate = 3/1) to give the acylated product
3a (46.0 mg, 0.19 mmol, 96% yield, colorless oil).
Acknowledgements
This work was supported by JSPS KAKENHI Grants Numbers
JP15H05756 (M.M.) and 18H04648 (N.I.) (Hybrid Catalysis).
Y.M. acknowledged JSPS fellowship for young scientists
(14J03286).
Keywords: photoreaction • palladium • acylation • C–H
activation • directing group
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[1]
Selected reviews and perspectives: a) W. R. Gutekunst, P. S. Baran,
[19] E. J. Horváth, K. Horváth, T. Hámori, M. I. Fekete, S. Sólyom, M.
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[3]
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[21] The reaction mixture was melted by heating when the temperature was
below
the
melting
point
of
t-BuOH
(25
C)
For selected reviews of directing group-assisted C–H bond activations,
see: a) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev. 2010,
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Asaumi, T. Ikeda, S. Yorimitsu, Y. Ishii, F. Kakiuchi, S. Murai, J. Am.
Chem. Soc. 2000, 122, 12882; b) S. Yu, Y. Li, L. Kong, X. Zhou, G.
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Tetrahedron Lett. 1970, 11, 145; b) D. M. Findlay, M. F. Tchir, J. Chem.
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[6]
For direct C–H acylations by photoredox catalysis, see: a) D. A.
DiRocco, T. Rovis, J. Am. Chem. Soc. 2012, 134, 8094; b) C. L. Joe, A.
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See supporting information for the details.
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[9]
The generation of A under UV irradiation was confirmed by a separate
reaction of 1a with methyl vinyl ketone. See supporting information for
the mechanistic investigations.
[10] For selected reviews, see: a) G. Majetich, K. Wheless, Tetrahedron
1995, 51, 7095; b) J. Robertson, J. Pillai, R. K. Lush, Chem. Soc. Rev.
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[11] Stereoisomeric o-quinodimethane having inward-oriented hydroxy
group would revert to 1a without participating in the palladium-catalyzed
process.
[12] a) K. Nagayama, F. Kawataka, M. Sakamoto, I. Shimizu, A. Yamamoto,
Chem. Lett. 1995, 24, 367; b) A. Jutand, S. Négri, J. G. De Vries, Eur. J.
Inorg. Chem. 2002, 2002, 1711.
[13] The replacement of the acetate ligand with A might be initiated by π-
coordination of the diene moiety of A rather than anionic displacement.
[14] All experiments to detect the intermediate E or F failed, probably
because tautomerization and reductive elimination steps were fast.
[15] Single electron transfer from the palladium complex to acetic anhydride
forming acetyl radical species is also conceivable. For recent examples
of the palladium-catalyzed coupling reactions through single electron
transfer, see: a) D. Kurandina, M. Parasram, V. Gevorgyan, Angew.
Chem. Int. Ed. 2017, 56, 14212; Angew. Chem. 2017, 129, 14400; b)
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[16] Whereas the reaction of 1d was slow, the product 3d gradually
decomposed upon irradiation for a long period of time.
[17]
A deuterium experiment using the mono-acetylated product 3i
suggested that it fails to generate an o-quinodimethane intermediate
with the remaining o-methylbenzoyl moiety; see supporting information
for details.
[18] No styrene derivatives, possibly generated through -hydride
elimination, was formed. We assumed that the generation of a benzyl
palladium species corresponding to F would be hampered by sterics.
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