Palladium-Catalyzed C-H Monoalkoxylation of α,β-Unsaturated Carbonyl Compounds

Article abstract of DOI:10.1021/acscatal.6b01084

An efficient method for the direct introduction of alkoxy groups into the β-position of alkene moieties of various α,β-unsaturated carbonyl compounds through the palladium-catalyzed C(sp²)-H monoalkoxylation using alcohols in the presence of sodium nitrite was developed; the corresponding enol ethers were selectively synthesized with minimal generation of acetals.

Full text of DOI:10.1021/acscatal.6b01084

Letter
pubs.acs.org/acscatalysis
Palladium-Catalyzed C−H Monoalkoxylation of α,β-Unsaturated
Carbonyl Compounds
Yasunari Monguchi,* Kouki Kunishima, Tomohiro Hattori, Tohru Takahashi, Yuko Shishido,
Yoshinari Sawama, and Hironao Sajiki*
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
S
* Supporting Information
ABSTRACT: An efficient method for the direct introduction of
alkoxy groups into the β-position of alkene moieties of various α,β-
unsaturated carbonyl compounds through the palladium-catalyzed
C(sp2)−H monoalkoxylation using alcohols in the presence of
sodium nitrite was developed; the corresponding enol ethers were
selectively synthesized with minimal generation of acetals.
KEYWORDS: monoalkoxylation, alkene, palladium catalysis, C−H functionalization, mild conditions
Scheme 1. Pd-Catalyzed Introduction of Hydroxy Groups
into Alkenes
nol ethers have been widely used as building blocks for the
Epreparation of heterocyclic compounds, such as iso-
xazoles,1 quinolines,2 furans,3 and pyridines,3 as well as for
the chemical modification of biologically active compounds,
such as nucleosides.4 Furthermore, the α,β-unsaturated ketone-
derived enol ethers could be good substrates for the
Danishefsky’s dienes5 and Rawal’s dienes,6 which could be
used for the Diels−Alder reaction. Recently, transition-metal-
catalyzed C−H functionalizations have been in the spotlight in
organic chemistry due to the elimination of the partial
preactivation of substrates, such as the introduction of a
leaving group.7 The palladium-catalyzed functionalization of a
terminal C−H bond of monosubstituted alkenes using
nucleophiles under oxidative conditions, which is the so-called
Wacker-type reaction, has been applied for C−N8 and C−
C9−11 bond formations. However, no general methods for the
mono C−O functionalization of α,β-unsaturated carbonyl
compounds generating β-monoalkoxylated α,β-unsaturated
carbonyl compounds have been developed in spite of their
valuable utilities, while acetals could be effectively prepared
through a further alkoxylation at the β-position (Scheme 1, eq
1).12,13 Recently, the Pd/Cu-catalyzed 1,2-diacetoxylation of
alkenes under aerobic oxidation conditions has been achieved
by the addition of the nitrite anion to the acetic acid-acetic
anhydride solution (Scheme 1, eq 2).14 Pd(MeCN)2ClNO2, a
Pd(II) nitrite salt, also mediated the oxidation of cyclic alkenes
to afford the corresponding cyclic epoxides, ketones, enols, and
enones.15 Furthermore, palladium acetate [Pd(OAc)2] gen-
erally exists as a trimer [Pd3(OAc)6], and it is also known that
the acetate ions of Pd3(OAc)6 could be partially substituted by
nitrite ions, such as Pd3(OAc)5NO.16
conditions to selectively afford the corresponding enol ethers
(Scheme 1, eq 3).
When a solution of benzyl acrylate (1) and Pd(OAc)2 (10
mol %) in MeOH was stirred at 110 °C under O2 atmosphere,
nearly no reaction took place (Table 1, entry 1), whereas the
desired benzyl (E)-β-methoxyacrylate (2)17 was obtained
together with dimethylacetal (3) and benzyl methyl malonate
In this paper, we demonstrate that Pd(OAc)2 would catalyze
the β-monoalkoxylation of α,β-unsaturated carbonyl com-
pounds in the presence of sodium nitrite under mild oxidative
Received: April 16, 2016
Revised: May 17, 2016
© XXXX American Chemical Society
3994
DOI: 10.1021/acscatal.6b01084
ACS Catal. 2016, 6, 3994−3997

ACS Catalysis
Letter
a
A variety of alcohols was applicable for the β-monoalkox-
ylation of benzyl acrylate, although i-PrOH and t-BuOH
indicated somewhat lower reactivities due to possible steric
hindrance (Table 2, 2a−2e). The methoxylation of the benzyl
Table 1. Optimization of Reaction Conditions
a
Table 2. C−H Alkoxylation of Alkenes Using Alcohols
b
ratio
temp
(°C)
entry
Ag
additive
gas
1/2/3/4
1
2
3
4
5
6
−
Ag2O
−
−
−
−
110
110
110
110
110
110
110
80
O2
O2
O2
O2
O2
O2
O2
O2
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
94/5/1/0
58/28/8/6
AgOCOCF3
AgOAc
AgOAc
−
42/24/32/2
22/59/2/17
4/80/2/14
92/8/0/0
NaNO2
NaNO2
NaNO2
NaNO2
NaNO2
KNO2
NaNO3
NaOAc
NaNO2
NaNO2
NaNO2
NaNO2
NaNO2
NaNO2
c
7
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
100/0/0/0
5/80/2/13
1/76/2/21
4/75/3/18
15/61/2/22
36/43/0/21
4/81/3/12
45/50/5/0
15/75/10/0
8
9
80
10
11
12
80
80
80
d
13
80
14
25
e
15
25
e
e
e
,
,
,
f
g
16
17
18
25
11/79 (70%) /9/1
h
25
6/82/11/1
1/77/20/2
f,i
25
a
Reaction conditions: 1 (0.25 mmol), Pd(OAc) (10 mol %), Ag
reagent (2.2 equiv), additive (0 or 20 mol %) in MeOH (1 mL) at 110,
a
b
c
1
Reaction conditions: 1 (0.25 mmol), Pd(OAc) (20 mol %), Ag
80, or 25 °C for 6 h. Determined by H NMR analysis Without
Pd(OAc)2. Freshly distilled MeOH was used. 20 mol % of
Pd(OAc)2 was used. 8 h. Isolated yield. 12 h. MeOH (0.5 mL)
d
e
reagent (2.2 equiv), NaNO2 (20 mol %) in alcohol (1 mL) at 25 °C.
Isolated yields are shown.
f
g
h
i
was used.
acrylate derivatives and 2-naphthylmethyl acrylate smoothly
proceeded regardless of the kinds and substitution pattern of
the substituents on the aromatic ring (2f−2k). Aliphatic and
aryl esters of acrylic acid as well as vinyl alkyl ketone also
underwent the β-monomethoxylation to afford the desired
methyl enol ethers (2l−2p). Furthermore, the methoxy group
was successfully introduced to the β-position of the β-methyl
acrylate derivative, benzyl crotonate, in a completely stereo-
selective manner (2q),18 while benzyl metacrylate possessing a
methyl substituent at the α-position was not suitable as a
substrate for the present reaction (2r).
(4) by the addition of a silver(I) salt (2.2 equiv) as an oxidant
(entries 2−4); AgOAc was the most effective for the
consumption of 1 (entry 4) among the silver(I) salts that we
investigated. The production of 2 significantly increased by the
addition of NaNO2 (entry 5), and Pd(OAc)2 (entry 7) was
found to be essential for the β-monomethoxylation of 1. The
reaction proceeded with a similar product distribution at 80 °C
(entry 8) and even under Ar atmosphere (entry 9). It was
found out that only the nitrite anion showed a positive effect
regardless of the metal cation elements by comparison with the
alternative salts of NaNO2 (entries 9 and 10 vs 11 and 12).
Although the formation ratio of benzyl methyl acrylate (4) was
only slightly decreased by the use of freshly distilled MeOH as
the solvent, a further study was performed using commercial
MeOH without any purification from a practical point of view
(entries 13 vs 8 and 9). The decrease in the reaction
temperature from 80 to 25 °C led to a low conversion of 1
(entry 14), whereas the reaction efficiency was significantly
enhanced with a low level of the byproduct formation by
increasing the catalyst use to 20 mol % (entry 15) and the
extension of the reaction time to 8 h (entry 16) to give the
desired 2 in 70% isolated yield; however, the product balance
was not virtually improved by further extension of the reaction
time (entry 17). The decrease in the use of MeOH from 1 to
0.5 mL caused a significant increase in the formation ratio of
the acetal 3 possibly due to the Pd-mediated further addition of
MeOH based on the high concentration of Pd(OAc)2 (entry
18).12g
The present oxidative conditions for the C(sp2)−H β-
monoalkoxylation of α,β-unsaturated carbonyl compounds
could be applied to the C−H β-amination8a and β-arylation9
of benzyl acrylate. When 3 equiv of benzyl acrylate was used for
the reaction with diphenylamine in 1,2-dichloroethane in the
presence of Pd(OAc)2, AgOAc, and NaNO2, the desired
enamine was obtained in 84% yield (Scheme 2, eq 1). The
phenylation of benzyl acrylate could be achieved by the use of
PhB(OH)2 as a nucleophile to give the corresponding benzyl
cinnamate in 89% yield (Scheme 2, eq 2).
Benzyl methyl malonate (4) could be obtained under
elevated temperature conditions at 80 °C in 60% yield from
benzyl (E)-β-methoxyacrylate (2), the major product of the
present C−H β-monomethoxylation reaction (Scheme 3, eq 1),
whereas no reaction took place in the case of the acetal (3) as
the starting material (Scheme 3, eq 2).19 Therefore, there is no
doubt that 2 is an intermediate for the formation of the
byproduct (4) of the C−H β-methoxylation.
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DOI: 10.1021/acscatal.6b01084
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ACS Catalysis
Letter
In conclusion, we have developed an effective and selective
C(sp2)−H monoalkoxylation at the β-position of α,β-
unsaturated carbonyl compounds in the presence of NaNO2
under Pd-catalyzed oxidative conditions. A wide variety of enol
ethers could be synthesized from acrylates and α,β-unsaturated
ketones in good yields. Furthermore, the protocol could be
applied to the C−N and C−C bond-forming reactions using
amine and arylboronic acid derivatives as nucleophiles. One of
the distinctive features of the present reaction is the mild
conditions (25 °C) and no need of the special purification of
reagents. Further study for the application of the present
conditions to the novel C(sp2)−H monofunctionalization of
terminal alkenes is ongoing in our laboratory.
Scheme 2. Application of Other Nucleophiles
Scheme 3. Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.6b01084.
■
S
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: monguchi@gifu-pu.ac.jp.
*E-mail: sajiki@gifu-pu.ac.jp.
■
The proposed reaction mechanism of the C(sp2)−H
monoalkoxylation at the β-position of the α,β-unsaturated
carbonyl compounds is depicted in Scheme 4. Palladium salts
Notes
Scheme 4. Proposed Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We sincerely thank the N.E. Chemcat Co. for the kind gift of
Pd(OAc)2.
■
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DOI: 10.1021/acscatal.6b01084
ACS Catal. 2016, 6, 3994−3997