B(C6F5)3-Catalyzed Michael Reactions: Aromatic C-H as Nucleophiles

Article abstract of DOI:10.1021/acs.orglett.7b00720

The Michael reaction is a widely used reaction for the C-C coupling of electron-poor olefins and C(sp³)-H pronucleophiles. Herein we report the Michael reaction between alkenes and aromatic as well as heteroaromatic compounds as aromatic C(sp

Full text of DOI:10.1021/acs.orglett.7b00720

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Letter
pubs.acs.org/OrgLett
B(C6F5)3‑Catalyzed Michael Reactions: Aromatic C−H as Nucleophiles
Wu Li and Thomas Werner*
Leibniz Institute for Catalysis at the University of Rostock, Albert-Einstein-Straße 29a, 18059 Rostock, Germany
S
* Supporting Information
ABSTRACT: The Michael reaction is a widely used reaction for
the C−C coupling of electron-poor olefins and C(sp3)−H
pronucleophiles. Herein we report the Michael reaction between
alkenes and aromatic as well as heteroaromatic compounds as
aromatic C(sp2)−H nucleophiles under mild conditions. The reaction is catalyzed by readily available Lewis acidic B(C6F5)3 and
proceeds with high regioselectivity for a wide substrate scope.
he Michael reaction, namely the addition of an enolate to
an activated alkene such as an α,β-unsaturated carbonyl
deprotonation with a suitable base. (2) Substrates with a
hetero−H such as ROH, R2NH, RSH, and R2PH. Notably, only
a few examples were developed using more challenging
T
compound, is one of the most efficient and effective routes to
the formation of C−C bonds (Scheme 1, eq 1).1 Since its
aromatic C(sp2)−H as the nucleophile.13 Franzen
́
and Bah
reported a Michael reaction using N,N-dimethylaniline and
highly activated ethyl-4-oxo-2-butenoate as Michael acceptors
in the presence of a carbocation at room temperature.14
However, the substrate scope of this catalytic system is limited.
More recently, a cationic anti-Bredt di(amino)carbene gold(I)
complex catalyzed hydroarylation of enones with N,N-
dialkylanilines at 120 or 135 °C was reported by Bertrand
and co-workers.15
Scheme 1. Michael Reaction Utilizing Different
(Pro-)nucleophiles
Tris(pentafluorophenyl)-borane based catalytic systems have
been successfully employed in various important organic
transformations including hydrogenation reactions,16 hydro-
silylation17 of unsaturated organic functions, such as CO and
CC bonds, dehydrogenative coupling of alcohols,18 thiols,19
or amines,20 dehydrogenative oxidation,21 polymerizations,22
and other transformations.23 In addition, B(C6F5)3 also plays a
significant role as a component of frustrated Lewis pairs.24 Only
a few examples have been demonstrated for B(C6F5)3 catalyzed
C−C bond formation.25 In general, as a strong Lewis acid,
B(C6F5)3 can activate the carbonyl group via coordination to
one of the oxygen lone pairs. Accordingly, our design is to
employ B(C6F5)3 as a Lewis acid activating the α,β-unsaturated
carbonyl compound to facilitate the addition of electron-rich
aromatics. Herein, we report the first B(C6F5)3-catalyzed
Michael reaction with aromatic and heteroaromatic
C(sp2)−H as the nucleophiles (Scheme 1, eq 3).
The hydroarylation of methyl vinyl ketone (2a) with N,N-
dimethylaniline (1a) was chosen as a test reaction. Notably, no
product was detected in the absence of B(C6F5)3 (Table 1,
entry 1). However, in the presence of 5 mol % B(C6F5)3 as the
catalyst and CHCl3 as the solvent at 80 °C, the desired product
3a was obtained in 91% yield after a reaction time of 24 h
(entry 2). A lower reaction temperature resulted in a decrease
in yield, affording a yield of 52% for 3a (entry 3). CHCl3
sometimes contains traces of HCl. Thus, mesitylene was used
discovery by Arthur Michael in the late 1880s, the Michael
reaction has been extensively studied, and numerous variants of
this reaction have been developed.2 The hetero-Michael
addition including the oxa-,3 aza-,4 thia-,5 and phospha-Michael
reactions6 is the extension of this concept to heterocentered
anions (Scheme 1, eq 2). These reactions have been widely
implemented in organic synthesis and in material science.7 In
addition, the Michael reaction has been utilized in polymer
synthesis for biomedical applications such as gene transfection,8
cell scaffolds,9 tissue replacements,10 and biomaterials for pH-
sensitive drug delivery.11 Owing to the perfect atom economy,
the benefit from mild reaction conditions and high functional
group tolerance, the Michael and the hetero-Michael reaction
have become a comprehensive toolbox to prepare specific,
highly functionalized products.12 Over the past 130 years the
nucleophiles employed in the Michael reaction were mainly
based on the following: (1) Substrates containing C(sp3)−H
bonds with electron-withdrawing groups, such as acyl and
cyano, which increase the acidity of the methylene hydrogens.
This facilitates the formation of the respective carbanion by
Received: March 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00720
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Letter
Table 1. Hydroarylation of Methyl Vinyl Ketone (2a) with
N,N-Dimethylaniline (1a)
Scheme 2. Scope for the Conversion of Electron-Rich
a
Aromatic and Heteroaromatic Substrates 1 with Methyl
a
Vinyl Ketone (2a)
b
entry
catalyst
temp/°C
solvent
CHCl3
yield (%)
1
2
3
4
5
6
7
8
9
10
−
80
80
40
80
80
80
80
80
80
80
0
B(C6F6)3
B(C6F6)3
B(C6F6)3
Zn(OAc)2
ZnCl2
CHCl3
CHCl3
mesitylene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
91
52
c
82
0
19
27
0
FeCl3
TrBF4
PhCO2H
B(C6F6)3
0
d
76
a
Standard reaction conditions: 1a (2.0 mmol), 2a (4.0 mmol), cat.
b
(0.1 mmol), solvent (2.0 mL), 40 or 80 °C for 24 h. Determined by
c
d
1H NMR with mesitylene as internal standard. Isolated yield. 2.5 mol
% B(C6F6)3 was used.
as a solvent to study the influence of a trace amount HCl.
However, the yield only slightly decreased to 82% (entry 2 vs
4). Notably, in the presence of other common transition metal
Lewis acids such as Zn(OAc)2, ZnCl2, and FeCl3 as catalysts,
no product was detected or significantly lower yields were
obtained (entries 5−7). In the presence of TrBF4 (Triphe-
nylcarbenium tetrafluoroborate) as Lewis acidic organocatalyst
or benzoic acid as a Brønsted acidic catalyst, the formation of
3a was also not observed (entries 8 and 9). Lowering the
catalyst loading resulted in a 76% yield of the desired product
(entry 10).
With the optimized conditions in hand, we focused our
attention on the substrate scope. Thus, a range of electron-rich
aromatic substrates as well as aromatic heterocycles were
converted under the optimized conditions (Scheme 2). Overall,
all of the substrates were usually readily converted into the
corresponding Michael reaction products 3a−3t with high
regioselectivity, and good to excellent isolated yields. For
example, high yields were obtained when N,N-diethylaniline
(1b) and N,N-dibenzylaniline (1c) were coupled with methyl
vinyl ketone to give 3b and 3c, respectively. Aniline derivatives
with cyclic moieties could be smoothly transformed into the
desired products 3d and 3e with good yields. Moreover, 4-
phenylmorpholine (1f) reacted well with 2a and gave the
corresponding para-substituted product 3f in 70% yield.
Increasing the reaction temperature from 80 to 100 °C led to
a slightly improved yield of 76%. Importantly, in the case of
substrate 1g which contains a valuable cyano group, this
functional group remained untouched under the reaction
conditions. Furthermore, when we investigated the N,N-
dimethylanilines 1h−1m bearing either electron-donating or
-withdrawing groups on the phenyl ring, the corresponding
β‑(aryl)ketones 3h−3m were isolated in excellent yields (88%−
93%) and regioselectivities. 3-Methoxy-N,N-dimethylaniline
(1k) gave mixtures of mono- and dialkylated products in
95% overall yield. The reaction of N,N-dimethyl-1-naphthyl-
amine (1m) gave the C4-substituted product 3m in 85% yield
under the standard reaction conditions. A low yield was isolated
when 1-methyl-1,2,3,4-tetrahydroquinoline (1n) was employed
as the substrate. The reaction of julolidine (1o) with 2a gave
the corresponding alkylated product 3o in 13% yield. The yield
a
Standard reaction conditions: 1 (2.0 mmol), 2a (4.0 mmol),
B(C6F5)3 (0.1 mmol), CHCl3 (2.0 mL), 80 °C for 24 h, unless
otherwise noted. Isolated yields are shown. 100 °C. The reaction was
carried out in mesitylene (2.0 mL) at 130 °C. The reaction was
carried out at room temperature.
b
c
d
was improved to 57% in mesitylene as the solvent at a higher
reaction temperature of 130 °C.
Notably, if the para-position was blocked, no ortho-
substitution was observed, e.g., when N,N-dimethyl-p-toluidine
(1p) was used as a substrate. The five-membered aromatic
heterocycle 2-methylfuran (1q) proved to be a suitable
substrate, and the corresponding product 3q was obtained in
57% yield. Similarly, 1-methylindole (1r) underwent the
reaction to generate a 1:1 mixture of mono- and dialkylated
products in 86% overall yield, while 1,2-dimethyl-indole (1t)
afforded 3t in 62% yield.
In addition to further illustrate the scope of this reaction with
respect to the Michael acceptor, several α,β-unsaturated
carbonyl compounds 2 were converted with N,N-dimethylani-
line (1a) (Scheme 3). The reaction of oct-1-en-3-one (2b) with
B
DOI: 10.1021/acs.orglett.7b00720
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Letter
aromatic C(sp2)−H as the nucleophiles and various α,β-
unsaturated carbonyl compounds as electrophiles. The reaction
proceeds for a wide range of substrates with high
regioselectivity, and the desired products were usually obtained
in good to excellent isolated yields. This B(C6F5)3-catalyzed
transformation complements the scope of Michael donors to a
wide range of C(sp2)−H nucleophiles. Studies on the
mechanism of this reaction as well as other B(C6F5)3-catalyzed
transformations will be reported in due course.
Scheme 3. Substrate Scope of Various α,β-Unsaturated
Carbonyl Compounds
a
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00720.
Experimental details, characterization data of all com-
1
pounds, and copies of H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
a
Corresponding Author
*E-mail: thomas.werner@catalysis.de.
ORCID
Standard reaction conditions: 1a (2.0 mmol), 2 (4.0 mmol),
B(C6F5)3 (0.1 mmol), CHCl3 (2.0 mL), 80 °C for 24 h, unless
b
otherwise noted. Isolated yields are shown. The reaction was carried
out in mesitylene (2.0 mL) at 130 °C, 1a (4.0 mmol) and
c
cinnamaldehyde (2d, 2.0 mmol). 1a (4.0 mmol) and (E)-1,4-
Thomas Werner: 0000-0001-9025-3244
Notes
diphenylbut-2-ene-1,4-dione (2f, 2.0 mmol).
The authors declare no competing financial interest.
1a led to the desired product 3u in 90% yield. Notably, the
conversion of α,β-unsaturated aldehydes such as acrylaldehyde
(2c), cinnamaldehyde (2d), and methacrylaldehyde (2e) gave
the desired products 3v−3w in moderate yields between 43%
and 60%. In contrast, the reaction of (E)-1,4-diphenylbut-2-
ene-1,4-dione (2f) with N,N-dimethylaniline (1a) gave the
corresponding adduct 3y in 88% yield.
ACKNOWLEDGMENTS
We wish to thank Prof. M. Beller from the Leibniz Institute for
Catalysis for his support and advice.
■
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