Ruthenium-Catalyzed Heck-Type Alkenylation of Alkyl Bromides

Article abstract of DOI:10.1021/acs.joc.9b00898

The complex [CpRuCl(PPh₃)₂] displays a high catalytic activity for the Heck-type alkenylation of alkyl bromides in the first example using this metal under thermal conditions. The coupling reaction proceeds efficiently with a variety of functionalized tertiary, secondary, and primary alkyl bromides. The presence of Hünig's base has been revealed to be crucial for this transformation. Preliminary mechanistic studies support the participation of alkyl radicals in the reaction.

Full text of DOI:10.1021/acs.joc.9b00898

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Note
Ruthenium-Catalyzed Heck-Type Alkenylation of Alkyl Bromides
José María Muñoz-Molina, and Pedro J. Pérez
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00898 • Publication Date (Web): 27 May 2019
Downloaded from http://pubs.acs.org on May 28, 2019
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The Journal of Organic Chemistry
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Ruthenium-CatalyzedꢀHeck-TypeꢀAlkenylationꢀofꢀAlkylꢀBromidesꢀ
José María Muñoz-Molina* and Pedro J. Pérez*
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Laboratorio de Catálisis Homogénea, Unidad Asociada al CSIC, CIQSO-Centro de Investigación en Química Sostenible and
Departamento de Química, Universidad de Huelva, 21007 Huelva, Spain
3 2
ABSTRACT: The complex [Cp*RuCl(PPh ) ] displays a high catalytic activity for
the Heck-type alkenylation of alkyl bromides, in the first example using this
metal under thermal conditions. The coupling reaction proceeds efficiently with
a variety of functionalized tertiary, secondary, and primary alkyl bromides. The
presence of Hünig’s base has been revealed crucial for this transformation.
Preliminary mechanistic studies support the participation of alkyl radicals in the
reaction.
KEYWORDS : ruthenium catalysis, alkenylation, cross-coupling, single electron transfer, homogeneous catalysis.
The palladium-catalyzed Heck reaction has become
a
Scheme 1. (a) The Competing β-Hydride Elimination in
Palladium-Catalyzed Heck Reactions using Alkyl Hal-
ides; (b) Mechanistic Proposal for the Transition Met-
al-Catalyzed Radical Alkenylation of Alkyl Halides.
fundamental tool for carbon–carbon bond formation in organic
1
synthesis. Although a number of examples have been reported
for the alkenylation of aryl and vinyl halides and sulfonates,
the use of alkyl halides as the electrophile partner still remains
2
an important challenge. This limitation is mainly due to the
tendency of alkyl-palladium intermediates to undergo β-
hydride elimination competing with the olefin insertion step
(Scheme 1a). As an alternative strategy, transition metal-
catalyzed Heck-type radical reactions have emerged in recent
3
years, where the metal center triggers a single electron
transfer (SET) to an alkyl organic halide (RX) to generate a
carbon-centered radical I (Scheme1b, I). The addition of the
latter to an olefin generates a new carbon–carbon bond and
another radical (II), that undergoes a deactivation step in
which the metal is reduced to the initial oxidation state and the
addition product is formed (III). Next, the presence of a base
affords the formal Heck coupling product (IV), recovering the
alkenyl functionality. This mechanism resembles somehow
4
that of the atom transfer radical addition (ATRA) reactions.
In the past few years, several catalytic systems have been
5
described for radical Heck-type alkenylations. Among them,
6
Pd, Ni, Cu, and Fe have provided the best results, although
7
highly-efficient catalyst systems are yet scarce. In general,
reactions, their use in the radical Heck-type alkenylations is
limited to just two examples provided, independently, by Cho
large amounts of catalyst are need (10–30 mol%), thus
limiting potential practical applications. Surprisingly, in spite
8
9
10
and Lei, and operating under photolysis activation (Scheme
of the work from Severin, Demonceau and Stephenson
groups with ruthenium-based complexes toward ATRA
11
2
).
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The Journal of Organic Chemistry
Page 2 of 9
Scheme 2. Ruthenium-catalyzed alkenylation of alkyl
halides.
1
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6
Table 1. Ruthenium-catalyzed alkenylation of an alkyl
bromide: effect of reaction parameters.
a
b
entry
variation from the standard conditions
yield 3a [%]
1
2
3
4
5
6
none
no [Cp*RuCl(PPh
no base
>99
<1
17
86
12
6
3 2
) ]
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0
0.02% [Cp*RuCl(PPh
0.01% [Cp*RuCl(PPh
3
3
)
)
2
2
]
]
[RuCl
2
(p-cymene)]
2
,
instead
of
[
Cp*RuCl(PPh ) ]
3 2
st
7
Grubbs 1 catalyst, instead of [Cp*RuCl(PPh
Cs CO , instead of i-Pr EtN
CO , instead of i-Pr EtN
2,3,5-collidine, instead of i-Pr
CH CN instead of THF
3
)
2
]
11
0
8
2
3
2
During the past decade, we have been involved in the
development of highly efficient and selective catalyst systems
9
K
2
3
2
79
52
95
17
90
13
60
90
15
98
>99
0
12
10
2
EtN
for ATRA reactions and related processes. In view of the
aforementioned similarities with such transformation and the
lack of efficient ruthenium-based catalytic systems for the
alkenylation of alkyl halides, we have turned our attention into
a well-defined and commercially available ruthenium complex
as a potential catalyst. In particular, we have investigated the
coupling of styrenes and alkyl bromides in the presence of the
1
1
1
2
3
DMF instead of THF
toluene instead of THF
room temperature
50 ºC
13
1
1
1
4
5
6
14 h
complex [Cp*RuCl(PPh ) ], an ATRA catalyst previously
3 2
9
17
under air (capped ampoule)
reported by Demonceau and co-workers. Herein we report the
remarkable catalytic activity displayed by this complex in the
alkenylation of alkyl bromides, with broad substrate scope and
degrees of conversions much higher than the previously
1
8
0.5 equiv H
in the dark
2
O added
19
2
0
in the dark, using [Ru(bpy)
3 2
]Cl instead of
11
described Ru-based photocatalysts, which are at least
[Cp*RuCl(PPh
3 2
) ]
7
a
comparable to the best catalytic systems known to date.
See SI for full details. 0.2 mmol of 4-methoxystyrene and 2 equiv of 2a
b 1
were employed. Yields were determined via H NMR analysis versus
diphenylmethane as internal standard.
We initiated our research by exploring the benchmarking
reaction of 4-methoxystyrene with ethyl 2-bromo-2-
methylpropionate toward the formation of the corresponding
3 2
styrene derivative 3a in the presence of [Cp*RuCl(PPh ) ] as
the catalyst. Optimization of the reaction conditions provided
us with a method that affords 3a in quantitative yield (Table 1,
entry 1). Control reactions established the importance of the
MeCN, DMF, or toluene were used as the solvent instead of
THF (entries 11–13). Experiments carried out at room
temperature (entry 14), 50 ºC (entry 15), with shorter reaction
times (entry 16), or in the presence of a small amount of air
entry 17) reduced the reaction outcome at different extent. On
the other hand, the addition of a small amount of water did not
alter the final yield (entry 18).
2
Ru complex and i-Pr EtN (Hünig’s base) for efficient coupling
under these conditions (entries 2–3): the reaction can be
accomplished in high yield with TONs up to 4300 (entry 4),
although the use of a very low catalyst loading resulted in
considerably less coupling product formation (entry 5, no
further reaction after 24 h). Remarkably, other Ru-based
(
Since previous work by Lei using Ru(bpy)
2
Cl
2
employed
11b
photochemical conditions
for this transformation, control
13
complexes, previously described as active ATRA or Heck
experiments have been carried out to assess the influence of
light in our system. When the probe reaction was carried out in
the dark, the same quantitative formation of 3a was observed
5
b
catalysts such as first generation Grubbs catalyst or
[RuCl (p-cymene)] were less effective than complex
Cp*RuCl(PPh ] for this transformation (entries 6–7). While
2
2
[
3 2
)
(Table 1,entry 19). At variance with that, [Ru(bpy)
not induce the catalytic reaction in the dark (entry 20). These
experiments evidence that [Cp*RuCl(PPh ] operates under
thermal conditions, with no effect of external light.
3 2
]Cl did
our standard reaction conditions employ the Hünig’s base, the
use of other organic or inorganic bases led to substantially less
product formation (entries 8–10). Regarding the effect of the
solvent, coupling reaction proceeds less efficiently when
3 2
)
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Page 3 of 9
The Journal of Organic Chemistry
Once established reaction conditions, we then examined
the substituent of the C=C bond. To test the practical
applicability of the protocol, we have run a gram scale
coupling reaction of 4-methoxystyrene with ethyl 2-bromo-2-
methylpropionate that proceeds in 97% yield (1.20 g of
product 3a).
With respect to the alkene, the scope of this method for the
alkenylation of alkyl halides is also broad (Scheme 4). Thus,
styrene derivatives bearing a variety of substitution patterns
serve as suitable coupling partners, including electron-rich and
electron-poor substrates with yields within the range 57-84%.
However, the reaction proceeds less efficiently when using a
sterically hindered styrene (Scheme 4, 3q). The reaction with
α–methylstyrene gave the corresponding alkenylation product
3r as a mixture of endo- and exo-isomers (85:15) in 72%
yield. Aliphatic olefins such as 1-hexene or those bearing
electron-withdrawing groups such as n-butyl acrylate do not
verify this transformation.
1
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the scope of this ruthenium-catalyzed method for alkenylation
by coupling a variety of tertiary, secondary and even primary
Scheme 3. Scope of ruthenium-catalyzed radical
a
alkenylation with respect to the alkyl halide.
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To gain insights on the reaction mechanism, we have used
radical scavengers to gather evidence for the presence of
radical intermediates. The standard reaction (Table 1, entry 1)
in the presence of 1.0 equiv of BHT (2,6-di-tert-butyl-4-
methylphenol) proceeds with quantitative yield. However, the
addition of 1.0 equiv TEMPO (2,2,6,6-tetramethylpiperidin-1-
yl)oxyl) at the beginning of a standard experiment induced the
complete inhibition of the catalytic reaction, and the isolation
of the alkylated TEMPO product 4 from the reaction mixture
1
4
in 24% yield (eq 1). This effect of TEMPO was verified in a
separate standard experiment that was treated with such
radical scavenger after 2 h of reaction, the formation of 3a
being inhibited at that precise moment. This is in agreement
with the involvement of C-centred radicals in this
transformation. In line with that, when a cumyl-containing α–
alkylstyrene (2,4-diphenyl-4-methyl-1-pentene) was employed
as reactant (eq 2), we observed a C-C bond-cleavage
a
0.5 mmol of alkene employed. Yields as average of two experiments.
1 mol % of 1 was used.
b
15
reaction, in which a stable cumyl radical is the leaving group,
alkyl bromides with 4-methoxystyrene (Scheme 3). The
reaction proceeds in good to excellent yields and is compatible
with a variety of functional groups, including ester, amide,
alcohol, and nitrile. Moreover, a difluoroalkyl bromide and a
perfluorinated benzyl bromide can be employed as reactants
with moderate to high yields. Derivative 3d has been
characterized by X-ray studies (CCDC 1899012) to
unambiguously demonstrate the structure of the compounds
obtained by this methodology, showing the trans geometry of
leading to the formation of 5 in 76% yield.
see Table 1
N
+
(1)
Br
2
CO Et
MeO
TEMPO (1.0 equiv.)
O
2
CO Et
4, 24%
1% [Cp*RuCl(PPh
3 2
) ]
i-Pr EtN (2.0 equiv)
2
Ph
EtO
2
C
EtO C
Ph
2
+
(2)
Ph
2
EtO C
Br
THF
100 ºC, 24h
2
EtO C
Scheme 4. Scope of ruthenium-catalyzed radical
a
5, 76%
alkenylation with respect to the alkene.
Tertiary amines have been proposed as reducing agents in
1
6
copper-catalyzed ATRP reactions and could be responsible
for the in situ constant regeneration of the active Ru(II)
catalyst in the event of radical recombination reactions. We
have monitored the reaction of the catalyst with the alkyl
3
1
1
bromide 2a at room temperature by P{ H} NMR. After 6 h,
the spectrum remained unmodified, only a small amount of
free PPh being detected along with the catalyst. The sample
3
was then heated at 100 ºC for 14 h, leading to the
disappearance of the resonance of the catalyst, and the
appearance of free PPh
typical range for similar Ru(III) complexes. Volatiles were
removed, the residue dissolved in tol-d , and amine was added
3
and a new species at 24.5 ppm, in the
17
8
(no alkyl bromide is present in the mixture at this stage). The
presence of the catalyst was inferred by NMR studies, where
the resonance of the initial Ru(II) complex was observed upon
heating a 100 ºC for 2 h (see Supporting Information). These
results demonstrate that the alkyl bromide induces the Ru(II)-
a
b
0
.5 mmol of alkene employed. Yields as average of two exApCerSimPeanrtsa.g1on Plus Environment
c
1
mol % of 1 was used. Yield determined via H NMR analysis versus
diphenylmethane as internal standard.

The Journal of Organic Chemistry
Page 4 of 9
Ru(III) oxidation whereas the amine originates the Ru(III)-
Ru(II) reduction. We have also looked after the generation of
nanoparticles that might be responsible for the catalytic
reaction. Toward that end we have monitored the reaction in
an effort to detect induction periods in which the nanoparticles
are formed (see Supporting Information). However, no such
periods have been observed, discarding the presence of Ru-
NPs in the reaction mixture.
purifications were carried out using silica gel (0.035-0.070 mm, 60
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6
Å). Organic solutions were concentrated under reduced pressure on a
Büchi rotary evaporator. NMR spectra were recorded at 298 K on an
Agilent 400 MR and Agilent 500 DD2 spectrometers. Chemical shift
1
13
values for H and C are reported as δ values (ppm) relative to the
deuterated solvent and coupling constants (J) in Hz. The
multiplicities are stated as follows: s = singlet, br = broad
singlet, d = doublet, t = triplet, q = quartet, m = multiplet.
Crystal structure determinations were carried out using a BRUKER
D8 FIXED-CHI diffractometer equipped with an Oxford Cryosystems
low-temperature device. Melting points were determined employing a
Dynalon-Stuart SMP10 instrument. Mass spectra were obtained on a
Orbitrap Elite mass spectrometer. Ionization method: ESI (positive or
negative).
With this information, and the related work in the
3,6
literature, a plausible mechanistic explanation is provided in
Scheme 5. The half-sandwich ruthenium(II) complex induces
the formation of carbon-centered radicals by a SET process.
The anti-Markovnikov addition of the radicals across the
olefin delivers another radical species capable of reducing the
ruthenium(III) center to the initial oxidation state, affording
ATRA product A. The based-induced elimination reaction
from the latter leads to the final, the formal Heck coupling
product. In an effort to detect the intermediate ATRA product
A, we run the reaction leading to product 3j (where the less
reactive primary site is involved) at 50 ºC. NMR spectra
showed a mixture of both ATRA and Heck products (see
Supporting Information). Additionally, in the event of the
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0
General Procedure: Heck-type Alkenylation of Alkyl
Bromides by Employing [Cp*RuCl(PPh
atmosphere of N , a glass ampoule equipped with a stir bar was
charged in turn with the corresponding amount of [Cp*RuCl(PPh
3 2
) ] Complex. Under an
2
3 2
) ]
(0.0005 mmol, 0.1%) from a THF stock solution, the olefin (0.5
mmol), the alkyl bromide (1 mmol), N,N-diisopropylethylamine (1
mmol), and dry THF to a total volume of 1.5 mL. The ampoule was
placed in an oil bath and the mixture was stirred for 24 h at 100 ºC.
Next, the mixture was passed through a short plug of silica gel and the
solvent was removed.
(E)-ethyl4-(4-methoxyphenyl)-2,2-dimethylbut-3-enoate (3a). The
title compound was synthesized according to the general procedure
Scheme 5. Mechanistic proposal for the thermal Ru-
catalyzed alkenylation of alkyl bromides.
from [Cp*RuCl(PPh
3
)
2
] (0.4 mg, 0.0005 mmol), 4-methoxystyrene
(
67.1 mg, 0.5 mmol), ethyl 2-bromo-2-methylpropionate (195.1 mg,
1
.0 mmol), N,N-diisopropylethylamine (129.2 mg, 1.0 mmol). The
reaction was purified by column chromatography on silica gel (5%
EtOAc/hexanes→10% EtOAc/hexanes). Colorless oil (120.0 mg,
9
1
7%). H NMR (500 MHz, CDCl
3
) δ 7.29 (d, J = 8.7 Hz, 2H), 6.83
(
d, J = 8.7 Hz, 2H), 6.36 (d, J = 16.2 Hz, 1H), 6.24 (d, J = 16.2 Hz,
1
7
H), 4.13 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 1.38 (s, 6H), 1.24 (t, J =
13 1
3
.1 Hz, 3H) ppm. C{ H} NMR (126 MHz, CDCl ) δ 176.4 (s),
159.0 (s), 132.4 (s), 129.9 (s), 127.4 (s), 127.3 (s), 113.9 (s), 60.7 (s),
5.3 (s), 44.3 (s), 25.1 (s), 14.2 (s) ppm. HRMS (ESI-TOF) m/z: [M +
5
+
Na] calcd for C15
were in accordance with those previously reported.
E)-diethyl-2-(4-methoxystyryl)-2-methylmalonate (3b). The title
compound was synthesized according to the general procedure from
Cp*RuCl(PPh ] (0.4 mg, 0.0005 mmol), 4-methoxystyrene (67.1
H O Na 271.1305; found 271.1308. Data obtained
20 3
6b
(
[
3 2
)
mg, 0.5 mmol), diethyl 2-bromo-2-methylmalonate (253.1 mg, 1.0
mmol), N,N-diisopropylethylamine (129.2 mg, 1.0 mmol). The
reaction was purified by column chromatography on silica gel (5%
EtOAc/hexanes→20% EtOAc /hexanes). Colorless oil (149.0 mg,
97%). H NMR (500 MHz, CDCl
coupling of radical species, the amine acts as a reducing agent
which ensures the reduction of the Ru(III) species into the
Ru(II) catalyst to re-start the catalytic cycle. Thus, amine can
operate in two distintc parts of the catalytic cycle.
In conclusion, we have developed a new ruthenium-
catalyzed radical alkenylation protocol, in the first example
with this metal under thermal conditions. Well-defined and
1
3
) δ 7.32 (d, J = 8.7 Hz, 2H), 6.83
(
d, J = 8.4 Hz, 2H), 6.52 (d, J = 16.4 Hz, 1H), 6.42 (d, J = 16.4 Hz,
1
H), 4.25 – 4.11 (m, 4H), 3.77 (s, 3H), 1.63 (s, 3H), 1.24 (t, J = 6.9
13 1
Hz, 6H) ppm. C{ H} NMR (126 MHz, CDCl
3
) δ 171.2 (s), 159.4
(
s), 130.1 (s), 129.3 (s), 127.8 (s), 125.4 (s), 113.9 (s), 61.6 (s), 55.6
commercially available [Cp*RuCl(PPh
3
)
2
]
catalyzed the
+
(s), 55.3 (s), 20.4 (s), 14.0 (s) ppm. HRMS (ESI-TOF) m/z: [M + Na]
calcd for C17 Na 329.1359; found 329.1360. Data obtained were
in accordance with those previously reported.
reaction with high efficiency with the aid of Hünig’s base. The
reaction proceeds under simple reaction conditions, with broad
functional-group tolerance, and the substrate scope covers
tertiary, secondary, and even primary alkyl bromides. We have
found evidences supporting the dual role of the base,
promoting not only the elimination reaction of the ATRA
product but also avoiding the catalyst deactivation.
22 5
H O
6
a
(E)-ethyl-1-(4-methoxystyryl)cyclobutanecarboxylate (3c). The
title compound was synthesized according to the general procedure
from [Cp*RuCl(PPh ) ] (0.4 mg, 0.0005 mmol), 4-methoxystyrene
3 2
(67.1 mg, 0.5 mmol), ethyl 1-bromocyclobutanecarboxylate (207.1
mg, 1.0 mmol), N,N-diisopropylethylamine (129.2 mg, 1.0 mmol).
The reaction was purified by column chromatography on silica gel
(
5% EtOAc/hexanes→10% EtOAc /hexanes). Colorless oil (129.0
EXPERIMENTAL SECTION
1
3
mg, 99%). H NMR (500 MHz, CDCl ) δ 7.31 (d, J = 8.6 Hz, 2H),
6.84 (d, J = 8.8 Hz, 2H), 6.44 (d, J = 16.1 Hz, 1H), 6.30 (d, J = 16.0
Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 2.62 – 2.53 (m, 2H),
General Information. Unless otherwise stated, reactions
were carried out under nitrogen atmosphere with standard
Schlenck techniques or in a glovebox (MBRAUN UNILAB).
All solvents and reagents employed were purchased from
Aldrich, Acros, TCI, or dried in a solvent purification system
(MB SPS-800, MBRAUN). Analytical thin layer chromatography
was carried out using TLC-aluminium sheets with 0.2 mm of silica
gel (Merck 60 F254) and UV light as visualizing agent or
phosphomolybdic acid solution as developing agent. Chromatography
2
.27 – 2.18 (m, 2H), 1.97 – 1.85 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H)
13 1
3
ppm. C{ H} NMR (126 MHz, CDCl ) δ 175.7 (s), 159.0 (s), 129.7
(s), 129.2 (s), 128.2 (s), 127.4 (s), 113.9 (s), 60.7 (s), 55.2 (s), 49.9 (s),
30.9 (s), 15.9 (s), 14.2 (s) ppm. HRMS (ESI-TOF) m/z: [M + Na]
calcd for C16
+
H O Na 283.1305; found 283.1307. Data obtained were
20 3
6a
in accordance with those previously reported.
ACS Paragon Plus Environment

Page 5 of 9
The Journal of Organic Chemistry
(
E)-4-(4-methoxyphenyl)-2,2-dimethylbut-3-enamide (3d). The
title compound was synthesized according to the general procedure
from [Cp*RuCl(PPh ] (0.4 mg, 0.0005 mmol), 4-methoxystyrene
67.1 mg, 0.5 mmol), 2-bromo-2-methylpropionamide (166.0 mg, 1.0
(ESI-TOF) m/z: [M + Na]+ calcd for C13
14 3 2
H O F Na 279.0803; found
1
2
3
4
5
6
7
8
9
279.0805. Data obtained were in accordance with those previously
1
9
3
)
2
reported.
(
(E)-2-(3-(4-methoxyphenyl)allyl)benzonitrile (3i). The title
mmol), N,N-diisopropylethylamine (129.2 mg, 1.0 mmol). The
compound was synthesized according to the general procedure from
[Cp*RuCl(PPh ) ] (0.4 mg, 0.0005 mmol), 4-methoxystyrene (67.1
3 2
reaction was purified by column chromatography on silica gel
1
(Et
500 MHz, CDCl
2
O→20% EtOAc/Et
2
O). White solid (107.6 mg, 98%). H NMR
mg, 0.5 mmol), 2-(bromomethyl)benzonitrile (196.0 mg, 1.0 mmol),
N,N-diisopropylethylamine (129.2 mg, 1.0 mmol). The reaction was
purified by column chromatography on silica gel (5% EtOAc
(
3
) δ 7.31 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.8 Hz,
H), 6.48 (d, J = 16.3 Hz, 1H), 6.22 (d, J = 16.2 Hz, 1H), 3.80 (s,
2
3
1
13
1
1
H), 1.39 (s, 6H) ppm. C{ H} NMR (126 MHz, CDCl
3
) δ 179.0 (s),
/hexanes→10% EtOAc /hexanes). Colorless oil (106.0 mg, 85%). H
59.3 (s), 132.3 (s), 129.3 (s), 128.7 (s), 127.5 (s), 114.1 (s), 55.3 (s),
44.7 (s), 25.3 (s) ppm. HRMS (ESI-TOF) m/z: [M + Na] calcd for
3
NMR (500 MHz, CDCl ) δ 7.65 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 7.7
+
Hz, 1H), 7.43 – 7.37 (m, 1H), 7.36 – 7.22 (m, 3H), 6.85 (d, J = 8.1
Hz, 2H), 6.47 (d, J = 15.7 Hz, 1H), 6.26 – 6.13 (m, 1H), 3.81 (s, 3H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C
13
H
17
O
2
NNa 242.1152; found 242.1154. Mp: 151−152 °C.
1
3
1
(
E)-2-hydroxyethyl-4-(4-methoxyphenyl)-2,2-dimethylbut-3-
3
3.75 (d, J = 7.0 Hz, 2H) ppm. C{ H} NMR (126 MHz, CDCl ) δ
enoate (3e). The title compound was synthesized according to the
general procedure from [Cp*RuCl(PPh ] (4.0 mg, 0.005 mmol), 4-
159.1 (s), 144.3 (s), 132.9 (s), 131.9 (s), 129.7 (s), 127.4 (s), 126.7 (s),
3
)
2
124.2 (s), 118.0 (s), 113.9 (s), 112.4 (s), 55.3 (s), 37.7 (s) ppm. HRMS
+
methoxystyrene (67.1 mg, 0.5 mmol), 2-hydroxyethyl 2-
bromoisobutyrate (211.1 mg, 1.0 mmol), N,N-diisopropylethylamine
(ESI-TOF) m/z: [M + Na] calcd for C17
H
15ONNa 272.1046; found
272.1049. Data obtained were in accordance with those previously
6m
(
129.2 mg, 1.0 mmol). The reaction was purified by column
chromatography on silica gel (10% Et O/DCM→50% Et O/DCM).
Colorless oil (100.3 mg, 76%). H NMR (500 MHz, CDCl ) δ 7.29 (d,
reported.
2
2
(E)-1,2,3,4,5-pentafluoro-6-(3-(4-methoxyphenyl)allyl)benzene
(3j). The title compound was synthesized according to the general
procedure from [Cp*RuCl(PPh ) ] (0.4 mg, 0.0005 mmol), 4-
3 2
methoxystyrene (67.1 mg, 0.5 mmol), 2,3,4,5,6-pentafluorobenzyl
bromide (261.0 mg, 1.0 mmol), N,N-diisopropylethylamine (129.2
mg, 1.0 mmol). The reaction was purified by column chromatography
1
3
J = 8.5 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.38 (d, J = 16.2 Hz, 1H),
6.23 (d, J = 16.2 Hz, 1H), 4.25 – 4.17 (m, 2H), 3.81 (br, 2H), 3.78 (s,
1
3
1
3H), 1.87 (br, 1H), 1.40 (s, 6H) ppm. C{ H} NMR (126 MHz,
CDCl ) δ 176.9 (s), 159.1 (s), 131.8 (s), 129.7 (s), 127.7 (s), 127.5 (s),
14.0 (s), 66.5 (s), 61.4 (s), 55.3 (s), 44.5 (s), 25.2 (s) ppm. HRMS
3
1
on silica gel (hexanes→10% EtOAc /hexanes). White solid (121.0
+
1
(
ESI-TOF) m/z: [M + Na] calcd for C15
87.1258.
(E)-4-(4-methoxyphenyl)-2-methylbut-3-enenitrile (3f). The title
compound was synthesized according to the general procedure from
Cp*RuCl(PPh ] (0.4 mg, 0.0005 mmol), 4-methoxystyrene (67.1
H
20
O
4
Na 287.1254; found
mg, 77%). H NMR (500 MHz, CDCl
3
) δ 7.28 (d, J = 8.7 Hz, 2H),
2
6.85 (d, J = 8.8 Hz, 2H), 6.43 (d, J = 15.7 Hz, 1H), 6.09 (dt, J = 15.7,
13 1
6.8 Hz, 1H), 3.81 (s, 3H), 3.58 (dd, J = 6.8, 1.5 Hz, 2H) ppm. C{ H}
NMR (126 MHz, CDCl ) δ 159.2 (s), 144.9 (dm, J = 245.7 Hz), 139.5
3
[
3
)
2
(dm, J = 250.2 Hz), 137.5 (dm, J = 250.2 Hz), 131.8 (s), 129.3 (s),
mg, 0.5 mmol), 2-bromopropionitrile (134.0 mg, 1.0 mmol), N,N-
diisopropylethylamine (129.2 mg, 1.0 mmol). The reaction was
purified by column chromatography on silica gel (hexanes→5%
127.4 (s), 122.0 (s), 113.9 (s), 113.7 (m), 55.3 (s), 25.6 (s) ppm.
+
HRMS (EI-magnetic sector) m/z: [M + H] calcd for C16
H
12OF
5
315.0803; found 315.0802. Mp: 68−69 °C. Data obtained were in
1
20
EtOAc /hexanes). Colorless oil (68.0 mg, 73%). H NMR (500 MHz,
accordance with those previously reported.
CDCl
3
) δ 7.29 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.63 (dd,
(E)-ethyl-2,2-dimethyl-4-(p-tolyl)but-3-enoate (3k). The title
compound was synthesized according to the general procedure from
[Cp*RuCl(PPh ) ] (0.4 mg, 0.0005 mmol), 4-methylstyrene (59.1 mg,
3 2
J = 15.8, 1.4 Hz, 1H), 5.90 (dd, J = 15.8, 6.2 Hz, 1H), 3.79 (s, 3H),
13
1
3
(
.49 – 3.43 (m, 1H), 1.47 (d, J = 7.1 Hz, 3H) ppm. C{ H} NMR
126 MHz, CDCl ) δ 159.7 (s), 131.9 (s), 128.4 (s), 127.8 (s), 122.1
(s), 121.1 (s), 114.1 (s), 55.3 (s), 28.4 (s), 19.2 (s) ppm. HRMS (ESI-
3
0.5 mmol), ethyl 2-bromo-2-methylpropionate (195.1 mg, 1.0 mmol),
N,N-diisopropylethylamine (129.2 mg, 1.0 mmol). The reaction was
purified by column chromatography on silica gel (hexanes→10%
+
TOF) m/z: [M + Na] calcd for C12
H
13ONNa 210.0889; found
1
2
10.0886. Data obtained were in accordance with those previously
EtOAc /hexanes). Colorless oil (97.3 mg, 84%). H NMR (500 MHz,
18
reported.
CDCl
3
) δ 7.26 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.39 (d, J
(
E)-methyl-4-(4-methoxyphenyl)-2-methylbut-3-enoate (3g). The
title compound was synthesized according to the general procedure
from [Cp*RuCl(PPh ] (0.4 mg, 0.0005 mmol), 4-methoxystyrene
67.1 mg, 0.5 mmol), methyl 2-bromopropionate (167.0 mg, 1.0
= 16.2 Hz, 1H), 6.33 (d, J = 16.2 Hz, 1H), 4.13 (q, J = 7.1 Hz, 1H),
1
3
1
2.31 (s, 2H), 1.38 (s, 3H), 1.24 (t, J = 7.1 Hz, 2H) ppm. C{ H}
NMR (126 MHz, CDCl ) δ 176.4 (s), 137.1 (s), 134.3 (s), 133.5 (s),
129.2 (s), 127.7 (s), 126.2 (s), 60.7 (s), 44.3 (s), 25.1 (s), 21.1 (s), 14.2
(s) ppm. Elemental analysis calculated for C15 C, 77.55; H,
8.68; N, 0.00. Found: C, 77.41; H, 9.66; N, <0.1. Data obtained were
3
)
2
3
(
mmol), N,N-diisopropylethylamine (129.2 mg, 1.0 mmol). The
reaction was purified by column chromatography on silica gel
20 2
H O
6
b
(
EtOAc) and purified by column chromatography on silica gel
in accordance with those previously reported.
1
(hexanes→5% EtOAc /hexanes). Colorless oil (102.0 mg, 93%). H
NMR (500 MHz, CDCl ) δ 7.28 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.8
Hz, 2H), 6.40 (d, J = 15.9 Hz, 1H), 6.11 (dd, J = 15.9, 8.1 Hz, 1H),
(E)-ethyl-4-(4-acetoxyphenyl)-2,2-dimethylbut-3-enoate (3l). The
title compound was synthesized according to the general procedure
from [Cp*RuCl(PPh ) ] (0.4 mg, 0.0005 mmol), 4-acetoxystyrene
3 2
(81.1 mg, 0.5 mmol), ethyl 2-bromo-2-methylpropionate (195.1 mg,
1.0 mmol), N,N-diisopropylethylamine (129.2 mg, 1.0 mmol). The
reaction was purified by column chromatography on silica gel (10%
3
3
3
.77 (s, 3H), 3.68 (s, 3H), 3.32 – 3.23 (m, 1H), 1.34 (d, J = 7.1 Hz,
H) ppm. C{ H} NMR (126 MHz, CDCl ) δ 175.0 (s), 159.1 (s),
3
13
1
130.5 (s), 129.5 (s), 127.4 (s), 126.4 (s), 113.8 (s), 55.2 (s), 51.8 (s),
+
43.0 (s), 17.4 (s) ppm. HRMS (ESI-TOF) m/z: [M + Na] calcd for
EtOAc /hexanes →30% EtOAc /hexanes). Colorless oil (138.2 mg,
1
C
13
H
16
O
3
Na 243.0992; found 243.0993. Data obtained were in
84%). H NMR (500 MHz, CDCl
3
) δ 7.35 (d, J = 8.5 Hz, 2H), 7.01
6
c
accordance with those previously reported.
E)-ethyl 2,2-difluoro-4-(4-methoxyphenyl)but-3-enoate (3h). The
title compound was synthesized according to the general procedure
from [Cp*RuCl(PPh ] (4.0 mg, 0.005 mmol), 4-methoxystyrene
67.1 mg, 0.5 mmol), ethyl bromodifluoroacetate (195.1 mg, 1.0
(d, J = 8.7 Hz, 2H), 6.39 (d, J = 16.2 Hz, 1H), 6.33 (d, J = 16.2 Hz,
1H), 4.13 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.38 (s, 6H), 1.23 (t, J =
(
1
3
1
3
7.1 Hz, 3H) ppm. C{ H} NMR (126 MHz, CDCl ) δ 176.1 (s),
3
)
2
169.4 (s), 149.8 (s), 135.0 (s), 134.8 (s), 127.2 (s), 126.9 (s), 121.6 (s),
(
60.8 (s), 44.3 (s), 25.0 (s), 21.1 (s), 14.1 (s) ppm. HRMS (ESI-TOF)
+
mmol), N,N-diisopropylethylamine (129.2 mg, 1.0 mmol). The
m/z: [M + Na] calcd for C16
H
20
O
4
Na 299.1254; found 299.1255.
reaction was purified by column chromatography on silica gel
(E)-ethyl-4-([1,1'-biphenyl]-4-yl)-2,2-dimethylbut-3-enoate (3m).
The title compound was synthesized according to the general
procedure from [Cp*RuCl(PPh ) ] (0.4 mg, 0.0005 mmol), 4-
3 2
vinylbiphenyl (90.1 mg, 0.5 mmol), ethyl 2-bromo-2-
methylpropionate (195.1 mg, 1.0 mmol), N,N-diisopropylethylamine
(129.2 mg, 1.0 mmol). The reaction was purified by column
1
(
dichloromethane). Colorless oil (116.1 mg, 91%). H NMR (500
MHz, CDCl
H), 6.87 (d, J = 8.8 Hz, 1H), 6.14 (dt, J = 16.2, 11.5 Hz, 1H), 4.33
q, J = 7.1 Hz, 1H), 3.81 (s, 1H), 1.34 (t, J = 7.1 Hz, 1H) ppm.
3
) δ 7.37 (d, J = 8.8 Hz, 1H), 7.00 (dt, J = 16.2, 2.6 Hz,
1
(
1
3
1
C{ H} NMR (126 MHz, CDCl
36.3 (t, J = 9.5 Hz), 128.9 (s), 126.8 (s), 116.3 (t, J = 25.0 Hz), 114.2
(s), 112.9 (t, J = 248.2 Hz), 63.0 (s), 55.3 (s), 13.9 (s) ppm. HRMS
3
) δ 164.1 (t, J = 35.2 Hz), 160.7 (s),
1
chromatography on silica gel (hexanes→10% EtOAc /hexanes).
1
White solid (115.2 mg, 78%). H NMR (500 MHz, CDCl
3
) δ 7.58 (d,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 9
J = 7.4 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.46 – 7.39 (m, 4H), 7.32 (t,
J = 7.4 Hz, 1H), 6.55 – 6.28 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.41 (s,
(129.2 mg, 1.0 mmol). The ampoule was placed in an oil bath and the
mixture was stirred for 24 h at 100 ºC. Next, the reaction mixture was
filtered through a short plug of silica gel (EtOAc) and purified by
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
6
H), 1.26 (t, J = 7.1 Hz, 3H) ppm. C{ H} NMR (126 MHz, CDCl
δ 176.3 (s), 140.7 (s), 140.1 (s), 136.2 (s), 134.6 (s), 128.8 (s), 127.5
s), 127.3 (s), 127.2 (s), 126.9 (s), 126.8 (s), 60.8 (s), 44.5 (s), 25.1 (s),
3
)
column chromatography on silica gel (hexanes→10% EtOAc
1
(
1
C
/hexanes). Colorless oil (32.0 mg, 24%). H NMR (500 MHz, CDCl
3
)
+
4.2 (s) ppm. HRMS (ESI-TOF) m/z: [M + Na] calcd for
Na 317.1512; found 317.1511. Mp: 50−51 °C. Data obtained
4.15 (q, J = 7.1 Hz, 2H), 1.53 – 1.38 (m, 10H), 1.33 – 1.21 (m, 5H),
13 1
20
H
22
O
2
3
1.12 (s, 6H), 0.98 (s, 6H) ppm. C{ H} NMR (126 MHz, CDCl ) δ
6
c
were in accordance with those previously reported.
E)-ethyl-4-(4-fluorophenyl)-2,2-dimethylbut-3-enoate (3n). The
title compound was synthesized according to the general procedure
from [Cp*RuCl(PPh ] (4.0 mg, 0.005 mmol), 4-fluorostyrene (61.1
176.0 (s), 81.0 (s), 60.5 (s), 59.5 (s), 40.5 (s), 33.4 (s), 24.4 (s), 20.4
+
(
(s), 17.0 (s), 14.1 (s) ppm. HRMS (EI-magnetic sector) m/z: [M + H]
calcd for C15H O N 272.2220; found 272.2221. Data obtained were
30 3
6c
3
)
2
in accordance with those previously reported.
mg, 0.5 mmol), ethyl 2-bromo-2-methylpropionate (195.1 mg, 1.0
mmol), N,N-diisopropylethylamine (129.2 mg, 1.0 mmol). The
Diethyl-2-methyl-2-(2-phenylallyl)malonate (5). Under an
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
atmosphere of N
charged in turn with [Cp*RuCl(PPh )
2
, a glass ampoule equipped with a stir bar was
] (4.0 mg, 0.005 mmol), 2,4-
reaction was purified by column chromatography on silica gel
3 2
1
(
dichloromethane). Colorless oil (80.2 mg, 68%). H NMR (500
diphenyl-4-methyl-1-pentene (118.2 mg, 0.5 mmol), THF (1 mL),
diethyl 2-bromo-2-methylmalonate (253.1 mg, 1.0 mmol), N,N-
diisopropylethylamine (129.2 mg, 1.0 mmol). The ampoule was
placed in an oil bath and the mixture was stirred for 24 h at 100 ºC.
Next, the reaction mixture was filtered through a short plug of silica
MHz, CDCl
3
) δ 7.34 – 7.28 (m, 2H), 7.00 – 6.95 (m, 2H), 6.37 (d, J =
1
6.2 Hz, 1H), 6.30 (d, J = 16.2 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 1.38
1
3
1
(s, 6H), 1.24 (t, J = 7.1 Hz, 3H) ppm. C{ H} NMR (126 MHz,
CDCl ) (126 MHz, CDCl ) δ 176.2 (s), 162.2 (d, J = 246.5 Hz), 134.2
d, J = 2.2 Hz), 133.3 (d, J = 3.3 Hz), 127.8 (d, J = 7.9 Hz), 126.7 (s),
3
3
(
gel (hexanes→10% EtOAc /hexanes). Colorless oil (110.3 mg, 76%).
1
1
15.4 (d, J = 21.6 Hz), 60.8 (s), 44.3 (s), 25.1 (s), 14.2 (s) ppm.
3
H NMR (400 MHz, CDCl ) δ 7.31 – 7.11 (m, 5H), 5.22 (d, J = 1.7
+
HRMS (EI-magnetic sector) m/z: [M + H] calcd for C14
H
18
O
2
F
Hz, 1H), 5.07 (s, 1H), 3.98 – 3.87 (m, 2H), 3.82 (ddt, J = 12.4, 10.8,
7.1 Hz, 2H), 3.12 (s, 2H), 1.25 (s, 3H), 1.11 (t, J = 7.1 Hz, 6H) ppm.
237.1285; found 237.1288. Data obtained were in accordance with
6
b
13
1
those previously reported.
E)-ethyl-2,2-dimethyl-4-(m-tolyl)but-3-enoate (3o). The title
compound was synthesized according to the general procedure from
Cp*RuCl(PPh ] (0.4 mg, 0.0005 mmol), 3-methylstyrene (59.1 mg,
.5 mmol), ethyl 2-bromo-2-methylpropionate (195.1 mg, 1.0 mmol),
3
C{ H} NMR (101 MHz, CDCl ) δ 171.8 (s), 144.5 (s), 141.7 (s),
(
128.0 (s), 127.4 (s), 126.8 (s), 118.2 (s), 61.1 (s), 53.4 (s), 40.4 (s),
+
19.8 (s), 13.9 (s) ppm. HRMS (ESI-TOF) m/z: [M + Na] calcd for
[
3
)
2
C H O Na 313.1410; found 313.1408. Data obtained were in
15 20 2
21
0
accordance with those previously reported.
N,N-diisopropylethylamine (129.2 mg, 1.0 mmol). The reaction was
purified by column chromatography on silica gel (hexanes→10%
Supporting Information.
The Supporting Information is available free of charge on the ACS
Publications website at DOI: ------------.
Mechanistic study results, X-ray crystallographic data, copies of
NMR spectra (PDF).
Crystal structure data for compound 2d (CIF).
1
EtOAc /hexanes). Colorless oil (66.5 mg, 57%). H NMR (500 MHz,
CDCl
3
) δ 7.22 – 7.13 (m, 3H), 7.03 (dtd, J = 6.9, 1.7, 0.7 Hz, 1H),
6
.42 – 6.34 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 2.33 (s, 3H), 1.39 (s,
1
3
1
6H), 1.24 (t, J = 7.1 Hz, 3H) ppm. C{ H} NMR (126 MHz, CDCl
δ 176.3 (s), 138.1 (s), 137.1 (s), 134.3 (s), 128.4 (s), 128.2 (s), 128.0
s), 127.0 (s), 123.5 (s), 60.8 (s), 44.4 (s), 25.1 (s), 21.4 (s), 14.2 (s)
3
)
(
+
AUTHOR INFORMATION
Corresponding Authors
jose.molina@dqcm.uhu.es
perez@dqcm.uhu.es
ppm. HRMS (ESI-TOF) m/z: [M + Na] calcd for C15
55.1356; found 255.1357.
E)-ethyl-2,2-dimethyl-4-(o-tolyl)but-3-enoate (3p). The title
compound was synthesized according to the general procedure from
Cp*RuCl(PPh ] (0.4 mg, 0.0005 mmol), 2-methylstyrene (59.1 mg,
.5 mmol), ethyl 2-bromo-2-methylpropionate (195.1 mg, 1.0 mmol),
20 2
H O Na
2
(
ORCID
[
0
3 2
)
J. M. Muñoz Molina: 0000-0002-7458-1472
Pedro J. Pérez: 0000-0002-6899-4641
N,N-diisopropylethylamine (129.2 mg, 1.0 mmol). The reaction was
purified by column chromatography on silica gel (hexanes →10%
1
Notes
EtOAc /hexanes). Colorless oil (77.9 mg, 67%). H NMR (500 MHz,
The authors declare no competing financial interest.
CDCl
3
) δ 7.41 – 7.36 (m, 1H), 7.18 – 7.09 (m, 3H), 6.62 (d, J = 16.1
Hz, 1H), 6.24 (d, J = 16.0 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 2.31 (s,
1
3
1
3
H), 1.40 (s, 6H), 1.25 (t, J = 7.1 Hz, 3H) ppm. C{ H} NMR (126
MHz, CDCl ) δ 176.3 (s), 136.4 (s), 136.1 (s), 135.3 (s), 130.2 (s),
27.3 (s), 126.0 (s), 125.8 (s), 125.7 (s), 60.8 (s), 44.6 (s), 25.2 (s),
ACKNOWLEDGMENTS
We thank MINECO for Grant CTQ2017-82893-C2-1-R. We also
thank Francisco Molina for X-ray structure determination.
3
1
+
19.7 (s), 14.2 (s) ppm. HRMS (ESI-TOF) m/z: [M + Na] calcd for
Na 255.1356; found 255.1359.
Ethyl-2,2-dimethyl-4-phenylpent-4-enoate
compound was synthesized according to the general procedure from
Cp*RuCl(PPh ] (0.4 mg, 0.0005 mmol), α-methylstyrene (59.1 mg,
15 20 2
C H O
(3r).
The
title
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purified by column chromatography on silica gel (hexanes→10%
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28.0 (s), 127.2 (s), 126.7 (s), 116.9 (s), 60.1 (s), 45.8 (s), 42.4 (s),
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.5 mmol), [Cp*RuCl(PPh
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