Carboxyl-Directed Conjugate Addition of C?H Bonds to α,β-Unsaturated Ketones in Air and Water

Article abstract of DOI:10.1002/adsc.201701468

A simple ruthenium-catalyzed conjugate addition of C?H bonds to α,β-unsaturated ketones directed by a removable carboxyl group was developed as an effective protocol to synthesize ortho-alkylated benzoic acids in a greener manner. Without any additives, s

Full text of DOI:10.1002/adsc.201701468

Title: Carboxyl-Directed Conjugate Addition of C‒H Bonds to α,ß-
Unsaturated Ketones in Air and Water
Authors: Wen-jing Han, Fan Pu, Chao-Jun Li, Zhong-Wen Liu, Juan
Fan, and Xian-Ying Shi
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10.1002/adsc.201701468
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Carboxyl-Directed Conjugate Addition of C‒H Bonds to α,ß-
Unsaturated Ketones in Air and Water
Wen-Jing Han,a Fan Pu,a Chao-Jun Li,b Zhong-Wen Liu,a Juan Fan,a and Xian-Ying
Shia,*
a
Key Laboratory for Macromolecular Science of Shaanxi Province, Key Laboratory of Applied Surface and Colloid
Chemistry (Ministry of Education), School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an
710062, People’s Republic of China
Fax: (86)-29-8153-0726; e-mail: shixy@snnu.edu.cn
Department of Chemistry, McGill University, Montreal, QC, H3A 0B8, Canada.
b
Received:((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
solvents. Moreover, additives and inert atmosphere
Abstract:
A simple ruthenium-catalyzed conjugate
are often required. Therefore, the development of a
simple catalytic system to accomplish these
transformations in a non-toxic solvent under aerobic
conditions is still highly desirable in terms of both
green chemistry and practicality.
addition of C‒H bonds to α,ß-unsaturated ketones directed
by a removable carboxyl group was developed as an
effective protocol to synthesize ortho-alkylated benzoic
acids in a greener manner. Without any additives,
satisfactory to excellent yields of the targeted products
were achieved in neat water, and the process characterizes
in mild reaction conditions (in air and water), simple
operations, and broad substrate scope. Noteworthy features
of this method include mild reaction conditions (in air and
water), operational simplicity and broad substrate scope.
The versatility and utility of the addition products were
demonstrated through further transformation into
commonly inaccessible but highly useful motifs of meta-
The carboxyl group has been regarded as a
fascinating directing group due to its advantages of
being installed and removed easily and convenient for
further transformation to other functional groups. In
addition, carboxylic acids are commercially available,
easy to store, and simple to handle.[7] However, to the
best of our knowledge, ortho-C‒H alkylation of
aromatic acids with carbonyl compounds has not
been reported so far. In 2016, Li’s group reported a
tandem dehydrogenative cyzclization of benzoic
acids and ethyl vinyl ketone utilizing Cu(OAc)2·H2O
as an oxidant, and the seven-membered cyclic
intermediate shown in Scheme 1 was proposed as the
likely intermediate.[8] Combining the structure of the
cyclic intermediate and our understanding on the
direct addition of C–H bonds to α,ß-unsaturated
ketones, we envisioned that ortho-alkylated benzoic
acids could be generated if the cyclic intermediate
was protonated. However, the high reactivity of
substituted
isochromanones.
Keywords: conjugate addition; C‒H activation; ruthenium
catalysis; carboxyl-directing; organic reaction in water
alkylbenzenes
and
3-substituted
As an alternative to the conjugate addition of
organometallic reagents to α,ß-unsaturated carbonyl
compounds, the direct addition of C‒H bonds to
unsaturated carbon-carbon bonds has been intensively
investigated because it offers a more straightforward
and economical route to form C–C bonds.[1] Such
processes proceed through aromatic C‒H activation
and subsequent unsaturated bond insertion, thus
avoiding the generation of stoichiometric amounts of
byproducts. After the pioneering work of Murai’s
group,[2] the chelation-assisted strategy is widely
applied to the direct addition of C–H bonds to α,ß-
unsaturated carbonyl compounds catalyzed by Pd,
Rh, Ir, Ru, Co or Mo complexes, and improved
selectivity has been achieved with the assistance of a
directing group such as carbonyl,[3] imine,[4] nitrogen
heterocycle,[5] and bidentate 8-aminoquinoline.[6]
Despite these remarkable advances, the addition
reactions were commonly carried out in organic
carboxyl,
e.g.
annulation
cyclization,
self
decarboxylation or decarboxylative cross-coupling,[9-
11]
makes the step of protonation particularly
challenging.
Scheme 1. Ruthenium-catalyzed direct addition of C‒H
bonds to α,β-unsaturated ketones in air and water
1
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10.1002/adsc.201701468
Advanced Synthesis & Catalysis
As part of our continuous interest in carboxyl-
Table 1. Selected results for optimizing reaction
directed C‒H functionalizations,[12] we demonstrate
herein an efficient ruthenium-catalyzed conjugate
addition of C‒H bonds to α,β-unsaturated ketones
directed by carboxyl to afford a variety of ortho-
alkylated benzoic acids in neat water (Scheme 1),
which complements conventional alkylation reactions
such as the Friedel-Crafts reaction and cross-coupling
between aryl (or alkyl) halides and alkyl (or aryl)
metal reagents. Noteworthy features of the proposed
method include commercially available and cheap
substrates, additive-free catalytic system, benign
solvent, mild aerobic atmospheric conditions,
operational simplicity, and broad substrate scope. The
facile manipulation of the ortho-alkylated benzoic
acids as an additional synthetic opportunity was
demonstrated to synthesize commonly inaccessible
but highly valuable motifs of meta-substituted
alkylbenzenes and 3-substituted isochromanones.
To validate our hypothesis, o-toluic acid (1a) and
ethyl vinyl ketone (2a) were chosen as representative
starting materials. In accordance with our previous
work,[12c] the reaction was firstly performed in 1,4-
dioxane with a [RuCl2(p-cymene)]2 catalyst under an
atmosphere of N2. Unfortunately, neither the cyclized
nor the alkylated product was detected (Table 1, entry
1). Given the proton–transfer as an important step to
initiate the addition reaction, NaOAc (0.5 equiv) was
added as a basic additive. Delightfully, 3a in a yield
of 50% was obtained accompanied by 16% yield of
3a’ (Table 1, entry 2). The basic NaOAc may
neutralize the generated proton in the step of C–H
activation and facilitate the arene metalation. A
further experiment showed surprisingly that this
transformation could be easily performed under air
without the protection of an inert atmosphere (Table
1, entry 3). However, when NaOAc was replaced by
acidic additives such as acetic acid, pivalic acid, and
2,4,6-trimethylbenzoic acid, no conjugation addition
product was detected. Under similar conditions,
commonly used catalysts such as Cp*RuCl(PPh3)2,
RuCl2(COD), RuCl2(PPh3)3, [Cp*RhCl2]2, Pd(TFA)2,
Pd(OAc)2, were all found to be ineffective for this
reaction (Table 1, entries 4-9). Moderate to good
yields of 3a were observed when the reaction was run
in toluene, DCE, DME, THF, CH3CN, PhCl, or H2O
(entries 10-16).
conditions.[a]
Yield(%)b
Entry
Catalyst
Solvent
3a
--
3a’
--
1[c,d] [RuCl2(p-cymene)]2 dioxane
2[c]
3
4
5
6
7
8
9
[RuCl2(p-cymene)]2 dioxane
[RuCl2(p-cymene)]2 dioxane
50
55
3
16
21
10
3
Cp*RuCl(PPh3)2
RuCl2(COD)
RuCl2(PPh3)3
[Cp*RhCl2]2
Pd(TFA)2
Pd(OAc)2
[RuCl2(p-cymene)]2 toluene
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
dioxane
dioxane NDe
dioxane
dioxane
dioxane
dioxane
ND
ND
ND
ND
50
47
50
66
40
ND
81
4
ND
13
ND
26
13
8
10
11
12
13
14
15
16
17d
18f
DCE
DME
THF
[RuCl2(p-cymene)]2 CH3CN
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
PhCl
H2O
H2O
H2O
42
54
11
4
52
5
79
ND
[a]
[b]
Reactions were carried out with 1a (0.1 mmol), 2a (0.2
mmol), [RuCl2(p-cymene)]2 (5 mol%), NaOAc (0.5
equiv), solvent (0.6 mL) at 130 °C for 24 h, under air in
pressure tubes.
Determined by H NMR analysis of the crude reaction
mixture using 1,3,5-trimethoxybenzene as an internal
standard.
1
[c] Protected by N2.
[d] Without NaOAc.
[e] ND = not detected.
[f] [RuCl2(p-cymene)]2 (1.5 mol%), run at 95 °C without
NaOAc for 12 h under air.
aromatic acids bearing ortho-substituted electron-
donating groups reacted efficiently with good yields
of the desired products (3b-3g, 42%-69%). Halogens
(Cl, Br, and I) were also compatible with the catalytic
conditions and afforded 57-78% yields (3h-3j), which
further demonstrates the synthetic potential to highly
functionalized targets by a stepwise coupling. The
reactions of di-substituted aromatic acids bearing one
substituent at the ortho position of carboxyl gave the
desired products in good to excellent yields (3k-3u,
51%-83%) and 3-methoxy-2-methylbenzoic acid
delivered the highest yield of the addition product (3l,
83%). Importantly, 1 mmol and 5 mmol scale
transformations of 3-methoxy-2-methylbenzoic acid
by the Ru-catalyzed protocol afforded 3l in 80% and
74% isolated yields, respectively (see Supporting
Information).
Further
optimization
showed
that
this
transformation could successfully proceed in neat
water, giving a 52% yield of 3a without any additives
(Table 1, entry 17). Subsequently, the amount of the
catalyst and reaction time were examined to optimize
the reaction conditions with H2O as a solvent. The
yield of 3a could be enhanced to 79% by reducing the
amount of the catalyst loading to 1.5 mol%,
shortening the reaction time to 12 h, and lowering the
temperature to 95 °C (Table 1, entry 18).
After investigating the model reaction, the scope of
this new protocol in/on water with various aromatic
acids was studied in detail. As shown in Table 2, the
substituents on the phenyl ring had less influence on
the yields of the desired product. For example,
Aromatic acids with two possible sites for the C‒H
bond activation, such as meta- or para-substituted
benzoic acids, were also easily converted into
alkylated products under the optimal conditions.
2
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10.1002/adsc.201701468
Advanced Synthesis & Catalysis
Table 2. Substrate scope for the conjugate addition of
aromatic acids with α,ß-unsaturated ketones.[a]
Table 3． Conjugate addition of benzoic acids and para-
substituted benzoic acids with ethyl vinyl ketone.[a]
[a]
Reactions were carried out with acids (0.2 mmol), ethyl vinyl
ketone (0.4 mmol), [RuCl2(p-cymene)]2 (1.5mol%), H2O (1.0
mL) at 95 °C for 12 h, under air in pressure tubes, isolated
yield.
carboxylic acid (3z and3aa).
To further explore the substrate scope and
limitations of this process, the reactions between 3-
methoxy-2-methylbenzoic acid and various α,ß-
unsaturated ketones were tested (Table 2, 3ab- 3af).
Under the optimized reaction conditions, aliphatic
α,ß-unsaturated ketones could be converted into the
desired products smoothly. The long chain aliphatic
ketones showed slightly lower reactivity compared to
that of the short chain aliphatic ketones (3ae and 3af).
However, no targeted product was detected using (E)-
hex-4-en-3-one as a substrate probably due to the
steric hindrance. Moreover, aryl substituted α,ß-
unsaturated ketones displayed poor activity in this
transformation. For example, 1-phenylprop-2-en-1-
one failed to afford the desired product, and 5-
phenylpent-1-en-3-one generated much lower yield of
the addition product (18% 1H NMR yield).
To understand the reaction mechanism, different
experiments were conducted. The H/D exchange
experiment with isotopically labeled solvent was
firstly carried out (Scheme 2). When the benzoic
acid was treated with D2O in the absence of ketone,
87% deuterium incorporation was observed at the two
ortho positions of the carboxyl (Scheme 2a). If the
reaction was performed in D2O, the desired product
with 18% deuterium incorporation was obtained at
the ortho of the carboxyl and carbonyl, respectively,
(Scheme 2b). The formation of D5-3ag underwent the
[a]
Reactions were carried out with acids (0.2 mmol), α,ß-
unsaturated ketones (0.4 mmol), [RuCl2(p-cymene)]2 (1.5
mol%), H2O (1.0 mL) at 95 °C for 12 h, under air in pressure
tubes, isolated yield.
Meta-substituted benzoic acids could undergo
selective alkylation at less sterically hindered
position (3v-3y), suggesting that the reaction is
mainly under steric control rather than electronic
control. Noteworthy, the meta-nitrobenzoic acid
bearing
a strongly electron-withdrawing group
reacted smoothly with an ethyl vinyl ketone to give
the alkylation product in a 40% yield. This result was
different from previous reports using the carboxyl as
a directing group,[8,12] where nitrobenzoic acid is
inactive. However, employing meta-isophthalic acid
as a substrate, no targeted product was detected.
Benzoic acid, para-substituted benzoic acids and
piperonylic acid affored a mixture of dialkylated and
monoalkylated products, and dialkylated compounds
were isolated as the main products even if excessive
acids were used (See supporting information, Table
S1). The reaction was also extendable to
heteroaromatic carboxylic acids such as 1-methyl-
1H-indole-2-carboxylic acid and thiophene-2-
Scheme 2. Probing the reversibility of the C‒H activation
step.
3
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10.1002/adsc.201701468
Advanced Synthesis & Catalysis
deuterolysis of ruthenacycle intermediate and H/D
exchange with D2O through
a
keto-enol
tautomerization at a high temperature (see Supporting
Information).[13] These results imply that a reversible
cyclometalation mode exist in the reaction.[14]
The kinetics isotope effects (KIE) were determined
within 10 min at a low conversion. Parallel
experiments utilizing equimolar D5-benzoic acid and
benzoic acid were conducted independently to assess
the reaction rates for ortho-C‒H vs C‒D (Scheme 3a),
and a KH/KD ratio of 3.7 was obtained. The competing
reaction of D5-benzoic acid and benzoic acid with the
ethyl vinyl ketone (2a) were carried out in the same
reaction tube giving a KH/KD ratio of 6.0 (Scheme 3b).
The KIE observed under these conditions indicate
that the C‒H bond cleavage is likely the rate-limiting
step.[15]
Scheme 4. Proposed mechanism.
complex C. Subsequently, the insertion of the C=C
bond into the C–Ru bond afforded the seven-
membered ruthenacycle D. The protonation of D by
the HCl afforded the final product and regenerated
the active ruthenium catalyst to continue the catalytic
cycle.
Facile manipulation of the alkyl aromatic acids
offers an additional synthetic opportunity. For
example, the carboxyl can be removed by Ag2CO3-
promoted decarboxylation protocol in a traceless
fashion to furnish meta-substituted alkylbenzene,[17]
which is difficult to prepare via the traditional
Friedel–Crafts reaction (Scheme 5). Moreover, the
intramolecular oxidative cyclization of the obtained
ortho-alkylated benzoic acid 3a delivered avaluable
3-substituted isochromanone (Scheme 6), which not
only appears in a number of natural products with
therapeutic potentials, but also serves as a useful and
significant precursor for synthesizing pharmaceutical
and agrochemical products.[18]
Scheme 3. The experiments to determine the kinetics
isotopic effects.
To confirm whether the catalyst is intact after the
reaction, the additional experiment using o-toluic acid
and ethyl vinyl ketone as substrates was performed
(see Supporting Information). By comparing the
HRMS spectra of the fresh and used catalysts, the p-
cymene was very probably linked to the ruthenium
after the reaction. Based on our mechanistic studies
and the understanding on the carboxyl-assisted C–H
bond activation reactions catalyzed by ruthenium,[16]
a plausible alkylation process was proposed in
Scheme 4. The catalytic addition reaction was
initiated by the dissociation of the dimeric precatalyst
Scheme 5. Decarboxylation of 3i.
[RuCl2(p-cymene)]2, affording
a
coordinatively
Scheme 6. Synthesis of 3-substituted isochromanone.
unsaturated monomer A. Then, the species A would
experience a cyclometalation reaction with the
aromatic acids via a Ru(II)-catalyzed C‒H activation
under the assistance of the carboxyl to generate the
intermediate B, releasing two equivalents of protons
simultaneously. The coordination of Ru with the
double bond of α,ß-unsaturated ketones produced the
In summary, an efficient ruthenium-catalyzed
conjugate addition of C‒H bonds to α,ß-unsaturated
ketones directed by carboxyl group was developed
for the synthesis of a wide range of ortho-alkylated
4
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10.1002/adsc.201701468
Advanced Synthesis & Catalysis
benzoic acids in good to excellent yields. Employing
water as a singular solvent, this protocol was
successfully realized free of any additives under air
atmospheres, which makes it a greener synthesis and
easier practical operation. Additional notable features
of the new method were commercially available and
cheap starting materials, broad substrate scope,
relatively cheaper ruthenium catalysts, and easy scale
up. Moreover, the simple and efficient transformation
of the addition products into highly valuable motifs
makes this method more important in practical
syntheses. This finding provides useful insights for an
environmentally friendly direct addition of C−H
bonds to unsaturated double bonds. Further studies on
the applications of this methodology are currently
under way in our laboratory.
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Experimental Section
A typical experimental procedure: An oven-dried reaction
vessel was charged with [RuCl2(p-cymene)]2 (Ru*,1.8 mg,
1.5 mol%, 0.003 mmol), aromatic acids (0.2 mmol), α,ß-
unsaturated ketones (0.4 mmol), and deionized water (1.0
mL).The vial was sealed under air and heated at 95 °C (oil
bath temperature) for 12 h. When the reaction was
complete, the resulting mixture was cooled to room
temperature, and filtered through a short silica gel pad.
Then, the mixture was concentrated in vacuo to give a
residue, which is purified by the preparative thin-layer
chromatography (TLC) on silica gel to afford the
corresponding products.
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Acknowledgements
The authors are grateful to the National Science Foundation of
China (Grant No. 21572122, 21636006 and 21776171), the
Fundamental Research Funds for the Central Universities (Grant
GK 201703019 and GK 201601005) for providing financial
supports.
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10.1002/adsc.201701468
Advanced Synthesis & Catalysis
COMMUNICATION
Carboxyl-Directed Conjugate Addition of C‒H
Bonds to α,ß-Unsaturated Ketones in Air and
Water
Adv. Synth. Catal.Year, Volume, Page – Page
Wen-Jing Han, Fan Pu, Chao-Jun Li, Zhong-Wen
Liu, Juan Fan, and Xian-Ying Shi*
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