Gold-catalyzed addition of β-ketoesters to alkenes: Influence of electronic and steric effects in the reaction outcome

Article abstract of DOI:10.3390/molecules23030629

The gold-catalyzed intermolecular hydroalkylation of olefins with β-ketoesters represents a conceptually attractive and useful synthetic tool; however, it has been scarcely applied, remaining a challenge for chemists. The aim of the current study was to i

Full text of DOI:10.3390/molecules23030629

molecules
Article
Gold-Catalyzed Addition of β-Ketoesters to Alkenes:
Influence of Electronic and Steric Effects in the
Reaction Outcome
ID
Agustina La-Venia, Mirta P. Mischne * and Ernesto G. Mata *
Instituto de Química Rosario, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de
Rosario-CONICET, Suipacha 531, Rosario S2002LRK, Argentina; lavenia@iquir-conicet.gov.ar
* Correspondence: mischne@iquir-conicet.gov.ar (M.P.M.); mata@iquir-conicet.gov.ar (E.G.M.);
Tel.: +54-9-341-4370477 (M.P.M. & E.G.M.)
Received: 7 February 2018; Accepted: 9 March 2018; Published: 10 March 2018
Abstract: The gold-catalyzed intermolecular hydroalkylation of olefins with β-ketoesters represents
a conceptually attractive and useful synthetic tool; however, it has been scarcely applied, remaining
a challenge for chemists. The aim of the current study was to investigate the addition of these
1,3-diketo-compounds to alkenes under gold catalysis conditions, in order to establish the electronic
and steric effects of the alkenyl substrates in the reaction outcome. The screening of different catalyst
systems and diverse olefins enabled defining the alkenyl requirements and the best reaction conditions
to efficiently achieve the coupled products.
Keywords: gold catalysis; hydroalkylation; β-ketoesters; olefins
1. Introduction
In recent years, the application of homogeneous gold catalysis has become a very active area
of research [1–13]. Gold is considered a “soft” metal, thus it is an excellent carbophilic activator
avoiding high oxophilicity, which is exhibited by most of the Lewis acids. Therefore, gold selectively
activates unsaturated carbon–carbon bonds (alkynes, alkenes, and allenes) towards nucleophilic attack,
catalyzing a large number of organic transformations with high efficiency under a broad scope of
reaction conditions (oxygen, water, and alcohols are usually tolerated) [14
nucleophilic additions onto alkynes and allenes have been widely explored for the generation of
both new C-heteroatom (N, S, O) bonds and new carbon–carbon bonds [20 26]. In the last few years,
gold-mediated activation of alkenes has been developed as well, but in less extension as expected,
due to their lower reactivity comparing with the alkynyl and allenyl counterparts [27 31]. In particular,
–19]. The gold-promoted
–
–
gold catalysis applied to unactivated olefins presents a limited scope of conditions and reagents, and is
mainly referred to heteroatom nucleophilic addition, which, in most of the cases, leads to the formation
of heterocyclic structures [32
catalysis from alkenyl systems remains scarcely investigated [39
hydroalkylation of olefins using 1,3-dicarbonyl systems, which represents an atom-economic alternative
to the classic nucleophilic alkylation, has been barely explored [43 46]. This conceptually attractive
–38]. Indeed, the formation of new carbon–carbon bonds achieved by gold
–42]. Specifically, the gold-mediated
–
synthetic approach presents only a few examples of intermolecular addition of 1,3-diketo-compounds
to alkenes, mainly limited to the use of electron-rich alkenes and Au(III) catalysts [43,45,47].
In this context, we decided to investigate the scope and limitations of gold catalysis for the
intermolecular addition of simple β-ketoesters onto diverse substituted alkenes, attempting to establish
the influence of steric and electronic factors on the course of this process.
Molecules 2018, 23, 629; doi:10.3390/molecules23030629
www.mdpi.com/journal/molecules

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2. Results and Discussion
As previously exposed, the reported examples of gold catalysis applied to the chemical
transformation under study refer to the coupling of 1,3-diketones either with aryl-conjugated
alkenes [45] or with electron-rich cyclic alkenes [43
Particularly interesting are the intramolecular versions of this process that enable the use of alternative
dicarbonyl systems, for instance -ene-1,3-diketoamides, which afford cyclic lactams (Scheme 1b) [46].
Moreover, in the presence of (R)-DTBM-SEGPHOS(AuCl)2 and Cu(OTf)2, the asymmetric version
of this ene- -ketoamide cyclization was achieved (Scheme 1c) [40]. The key modification in this
enantioselective hydroalkylation was the use of copper chloride scavengers [48,49].
,47] in the presence of cationic Au(III) (Scheme 1a).
β
β
Scheme 1.
Gold-catalyzed hydroalkylation of alkenes with 1,3-dicarbonyl compounds.
(a) Intermolecular version with 1,3-diketones. (b) and (c) Intramolecular version with β-ketoamides.
It is apparent from these reports that the use of
β-ketoesters as the dicarbonyl starting
material has been underexplored. In fact, both Li et al. [45] and Che et al. [46] specifically
highlighted that 1,3-dicarbonyl substrates incorporating ester functionalities failed to proceed to
the corresponding C–C bond formation under gold catalysis, probably due to decomposition of these
ester-functionalized starting materials in the presence of high Lewis acidic reagents [45]. In addition,
the intramolecular alternative using these kinds of diketo moieties has not been efficiently achieved
either. Recently, Gandon and coworkers reported a gold(I)-mediated cyclization via an intramolecular
hydroalkylation of an internal diene by a β-ketoester [44]. However, optimized reaction conditions
were accomplished using Bi(OTf)3/TfOH as an alternative catalytic system due to the fact that extensive
decomposition of starting material was observed using gold catalysts. Some other studies were carried
out trying to expand the hydroalkylation of olefins with
β-ketoesters mediated by auric cations;

Molecules 2018, 23, 629
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however, they were clearly unsuccessful [50]; furthermore, in some conditions, the gold catalysts
exhibited an unusual oxophilic behavior [51].
Taking into account this literature review, to achieve our objective, we decided firstly to test the
reaction between
β-ketoesters (1a and 1b) and p-methylstyrene (2a) to obtain the corresponding
coupling products 3a and 3b (Table 1). Different reaction conditions, mainly involving changes
in the catalyst mixture and temperature, were evaluated. For ethyl acetoacetate (1a), the use of a
AuCl3/AgSbF6 mixture (5 mol %/15 mol %) was the most efficient catalyst system, leading to 3a
in 75% yield (Entry 1). The product was obtained as an inseparable mixture of two diastereoisomers in
a 1:1 ratio, identified and quantified by 1H-NMR spectra and by HPLC. The use of AgOTf as co-catalyst
(Entry 2) provided similar results, whereas the use of Au(I) catalyst (Entry 3) caused a significant
decrease in yield. The addition of CuCl2 to avoid gold reduction resulted in a slight decrease in the
reaction yield (Entry 4) [52]. To evaluate the protic triflic acid (TfOH) effect, this acid was added as the
single promoter (Entry 5) [53]. The expected product 3a was obtained but with a notable decreased
yield (20%). Similarly, the use of AgOTf as the only catalyst was also tested, but the reaction did
not proceed at all, recovering the starting materials (Entry 6). These latter results proved that auric
triflate is the predominant catalytic specie involved in the hydroalkylation under study. On the other
hand, changing the dicarbonyl substrate by tert-butyl acetoacetate (1b) gave a complex mixture of
unidentified compounds, probably derived from self-condensation of the alkene and
hydrolysis in the acidic media (Entry 7).
β-ketoester
Table 1. Gold-catalyzed hydroalkylation of p-methylstyrene (2a) with β-ketoesters 1a and 1b.
1
R1
Et
Et
Catalyst System
T
rt
rt
Yield 1
75%
1
2
1a
1a
AuCl3 (5 mol %) AgSbF6 (15 mol %)
AuCl3 (5 mol %)
70%
AgOTf (15 mol %)
AuCl (5 mol %)
AgSbF6 (5 mol %)
AuCl3 (5 mol %)
AgSbF6 (15 mol %)
CuCl2 (10 mol %)
TfOH (2 mol %)
AgOTf (15 mol %)
AuCl3 (5 mol %)
3
4
1a
1a
Et
Et
rt
40%
60%
◦
0 C
◦
5
6
1a
1a
Et
Et
0 C
20%
NR 2
rt
NR 2
7
1b
tBu
rt
AgSbF6 (15 mol %)
The reaction was carried out by adding 2a (1.5 eq.) for 5 h with a syringe pump to the solution of the
β-ketoesters
1a or 1b (1.0 eq.) and catalyst in dichloromethane, then the reaction mixture was stirred overnight. The addition
1
products
No reaction.
3 were eventually isolated and purified by column chromatography. Yield after column chromatography.
2
With these optimized conditions in hand, we proceeded to investigate the scope and limitations
of the process testing different olefin partners. 1H-NMR spectroscopic analysis of the crude
reaction mixtures showed that, along with the presence of alkylated products
materials 1a and , signals corresponding to self-condensation olefin polymeric by-products [54
could be identified (Table 2).
3
and starting
2
,55]

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Table 2. Evaluation of olefin influence in the AuCl3/AgSbF6–promoted hydroalkylation.
Alkene
Product 1
Recovered Starting Material 2
Polymeric by-Products 3
2a, R2 = p-Me
2b, R2 = p-Et
2c, R2 = p-tBu
2d, R2 = p-CH2Cl
2e, R2 = p-OAc
2f, R2 = p-OMe
2g, R2 = p-OtBu
2h, R2 = p-CO2Me
2i, R2 = p-Br
2j, R2 = o-Br
2k, R2 = o-Me
2l
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3a, 75%
3b, 50%
3c, 20%
3d, 10% (35%) 4
3e, traces
3f, 7% (25%) 4
3g, traces
NP
1a
1a
1a
1a
1a
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
Yes
No
No
No
1a
1a
1a + 2h
1a + 2i
1a + 2j
1a + 2k
1a + 2l
1a 5
NP
NP
NP
NP
NP
NP
2m
2n
1a + 2n
1
Yields correspond to final products purified by flash column chromatography. The addition products
3 were
generated as inseparable mixtures of diastereoisomers in 1:1 ratio (see Supplementary Materials). NP: No addition
2
3
product 3 was observed. Starting material remained in the reaction mixtures. Signals attributed to polymeric
by-products were observed by 1H-NMR spectra of the reaction mixtures. Optimized conditions: AuCl3/AgOTf
4
(5/15 mol %), 0 ◦C. 5 1a was partially hydrolyzed, 2m was evaporated during the work up of the reaction.
A detailed examination of the results indicates that the reaction under study is very sensitive to
structural and electronic features of the alkene. In the case of para-substituted styrene derivatives (2a
the best results have been achieved for those substrates having both weak electron-donating such as
alkyl groups (2a , Entries 1–3) and weak electro-withdrawing substituents (2d, Entry 4), leading to the
adducts 3a
groups (2e
–i),
–c
–d
up to 75% yield. In the case of other aromatic substrates with stronger electron-donating
–g), the corresponding products were detected but with considerable decrease in the
yields and along with large amounts of polymeric material (Entries 5 and 6), except for 2g (Entry 7).
These results revealed an efficient gold-promoted alkene-activation, except for the most bulky
substituted styrene (R2 = OtBu); however, unfortunately, the polymerization process was predominant.
Interestingly, those substrates with strong electron-withdrawing substituents (2h, R2 = CO2Me and 2i
,
R2 = Br, Entries 8 and 9) did not provide the desired products and neither the possible products of
polymerization, recovering both starting materials, which could be justified by an ineffective olefin
coordination with the metal. A similar tendency was observed for ortho-substituted styrene derivatives 2j
and 2k, which did not generate the desired addition products, regardless of their electronic properties,
recovering in both cases the unreacted starting materials (Entries 10 and 11). Though, in the case of
alkene 2k (Entry 11), a small amount of polymerization product was observed, demonstrating a poor
activation of the olefin by the Au(III) [56,57], probably due to steric hindrance of the substituent in
ortho position in comparison to the para analogue 2a. As expected, the non-aromatic alkenes or alkenes
structurally different to styrene, remained unchanged under the optimized conditions (Entries 12–14),
which clearly indicated that the cationic gold failed to promote their activation.

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Taking into account these results, we can remark about two major difficulties for the broad
application of this synthetic tool. According to the most commonly proposed mechanism based on the
cationic gold activation of alkene species followed by methylene nucleophilic attack, the first difficulty
is related to the activation of alkenes by coordination with the active gold species. In order to achieve
such gold coordination, olefins must present sufficient electron density, restricting the type of alkene
able to participate in the hydroalkylation. This limitation becomes evident in those alkenes with low
electron density, which remained unreacted in the presence of the auric cation (2h–j and 2l–n).
The second drawback of the reaction arises from competition with the self-addition of the olefins.
Electron rich olefin can coordinate with the cationic gold, but the presence of free unactivated olefin in
the reaction medium can also efficiently act as a nucleophile. Thus, self-addition occurs between the
metal-coordinated olefin (electrophilic) and the free olefin (nucleophilic), generating the polymeric
by-product. There is a competition between both potential nucleophiles, high-electron density olefins
and the corresponding enol of 1,3-dicarbonyl compounds. The nucleophilic enolate can be generated
by the presence of metal co-catalyst, such as Cu or can be present directly in the dicarbonyl equilibrium.
In the case of
therefore, high electron density olefins are better nucleophiles, generating mainly polymerization
products during catalysis. In contrast, reactions involving diketones instead of -ketoesters are more
β-ketoesters, only a small proportion is present as the enol form (8% in DCM) [58];
β
efficient for the hydroalkylation of alkenes since these diketo compounds are mostly in their enol form
(81% in DCM).
Under these premises, we carried out further screening conditions to some promising substrates
(2e and 2f). It can be assumed that reduction of olefin self-addition would increase the efficiency of
the hydroalkylation reaction. To achieve the limitation of this undesired reaction, various strategies
were tested. The first attempts that involved the incorporation of base to the reaction mixture in order
to shift the keto/enol equilibrium did not proceed as expected. For instance, the addition of tBuOK
led to a slight increase of coupling while amine bases poisoned the catalyst. Fortunately, slow alkene
addition at low temperature showed promising effects. Moreover, when the decrease in temperature
was combined with a simple exchange of co-catalyst (AgOTf instead of AgSbF6), 3f was obtained with
a considerably higher yield (25%) (Entry 6, Table 2). Similar results were observed for substrate 2d
(R2 = CH2Cl), affording 3d with a 35% yield (Entry 4, Table 2).
3. Materials and Methods
3.1. General Information
Chemical reagents were purchased from commercial suppliers and used without further
purification, unless otherwise noted. Solvents were analytical grade or were purified by standard
procedures prior to use. Reactions requiring inert atmosphere were carried out under a high-purity dry
nitrogen atmosphere. Solvents from these reactions were transferred with syringe under high-purity
dry nitrogen pressure. Yields were calculated for material judged homogeneous by thin layer
chromatography (TLC) and nuclear magnetic resonance (1H-NMR). All reactions were monitored by
thin layer chromatography performed on silica gel 60 F254 pre-coated aluminum sheets, visualized
by a 254 nm UV lamp, and stained with an ethanolic solution of 4-anisaldehyde. Column flash
chromatography was performed using silica gel 60 (230–400 mesh).
3.2. Instrumental and Physical Data
1H-NMR spectra were recorded in a Bruker Avance spectrometer (Bruker Analytik GmbH,
Karlsruhe, Germany) at 300 MHz, in CDCl3 with tetramethylsilane (TMS) as internal standard (0 ppm).
13C-NMR spectra were recorded on the same apparatus at 75 MHz with CDCl3 as solvent and
reference (76.9 ppm). Chemical shifts (δ) are reported in ppm upfield from TMS and coupling constants
(J) are expressed in Hertz. The following abbreviations are used to indicate the multiplicities: s = singlet
,
d = doublet, t = triplet, q = quartet, m = multiplet, bs = broad singlet.

Molecules 2018, 23, 629
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IR spectra were obtained using a Shimadzu, Prestige–21 FT-IR spectrometer (Shimadzu, Kioto,
Japan), wavelengths are informed in cm−1, and only partial spectral data are listed.
High resolution mass spectra (HRMS) were recorded on a Bruker micrOTOF-Q II spectrometer
obtained on a Q-TOF mass spectrometer and detection of the ions was performed in electrospray
ionization, positive ion mode.
3.3. Synthetic Procedures
Gold-catalyzed hydroalkylation: A mixture of AuCl3 (15.2 mg, 0.05 mmol, 5 mol %) and AgSbF6
(51.5 mg, 0.15 mmol, 15 mol %) in anhydrous DCM (2 mL) under N2 atmosphere was stirred at room
temperature for 2 h. The
β-ketoester, ethyl acetoacetate 1a, (0.13 mL, 1 mmol) was then added to the
catalysts solution previously formed, followed by the addition of the solution of the corresponding
alkene
2
(1.5 mmol◦, 1.5 eq.) in anhydrous DCM (3 mL) with a syringe-pump during 5 h at room
temperature or at 0 C. The reaction mixture was further stirred at room temperature overnight under
N2 atmosphere. After that time, the solvent was evaporated and the reaction crude was purified
by column chromatography on silica gel (eluent: Hexane-AcOEt with increasing polarity) to afford
addition products
3 (1:1 diastereoisomeric mixture). Note: the AuCl3 catalyst must be weighed under
a nitrogen cone because of its high hygroscopicity.
3.4. Analytical Data of Individual Compounds
Ethyl 2-acetyl-3-(p-tolyl)butanoate 3a
.
Yield: 75% of colorless oil (inseparable mixture with
1
diastereoisomeric ratio 1:1). IR (Film) (cm−1): 2964, 2932, 1743 (
ν
CO), 1717 (
ν
CO), 1513, 1177. H-NMR
(CDCl3, 300 MHz):
δ
7.09 (8H, bs, ArH), 4.22 (2H, q, J = 7.2 Hz, -OCH2CH3), 3.90 (2H, q,0J = 7.1 Hz,
-OCH2CH3), 3.76 (1H, d, J = 11.0 Hz, H-2), 3.71 (1H, d, J = 10.9 Hz, H-2), 3.56–3.45 (2H, m, H-1 ), 2.30 (6H,
s, ArCH3)*, 2.29 (3H, s, H-4)*, 1.94 (3H, s, H-4)*, 1.31–1.27 (6H, m, H-20 and -OCH2CH3), 1.21 (3H,
d, J = 6.9 Hz, H-20), 0.97 (3H, t, J= 7.2 Hz, -OCH2CH3). 13C NMR (CDCl3, 75 MHz):
δ 202.5 (C, C-3),
202.4 (C, C-3), 168.6 (C, C-1), 168.1 (C, C-1), 140.1 (C, Ar), 139.9 (C, Ar), 136.4 (C, Ar), 136.2 (C, Ar),
129.3 (2 CH, Ar), 129.0 (2 CH, Ar), 127.2 (2 CH, Ar), 127.1 (2 CH, Ar), 67.6 (CH, C-2), 67.1 (CH, C-2),
61.3 (CH2, -OCH2CH3), 61.0 (CH2, -OCH2CH3), 39.6 (CH, C-10), 39.3 (CH, C-10), 29.7 (CH3, C-4),
29.4 (CH3, C-4), 20.9 (2 CH3, Ar-CH3), 20.6 (CH3, C-20), 20.3 (CH3, C-2), 14.0 (CH3, -OCH2CH3),
13.6 (CH3, -OCH2CH3). HRMS (ESI) m/z calcd. for C15H20NaO3 [M + Na]+ 271.1305, found 271.1302.
Ethyl 2-acetyl-3-(4-ethylphenyl)butanoate 3b. Yield: 50% of colorless oil (inseparable mixture with
diastereoisomeric ratio 1:1). IR (Film) (cm−1): 2965, 2932, 2873, 1744 (
ν
CO), 1716 (
νCO), 1513, 1176.
1H-NMR (CDCl3, 300 MHz):
δ 7.11 (8H, bs, ArH), 4.22 (2H, q, J = 7.2 Hz, -OCH2CH3), 3.89 (2H, q,
J = 7.1 Hz, -OCH2CH3), 3.77 (1H, d, J = 11.0 Hz, H-2), 3.71 (1H, d, J = 11.0 Hz, H-2), 3.59–30.46 (2H, m,
0
H-1 ), 2.60 (4H, q, J = 7.5 Hz, H-1”), 2.29 (3H, s, H-4), 1.93 (3H, s, H-4), 1.31-1.17 (15H, m, H-2 , H-2” and
-OCH2CH3)*, 0.94 (3H, t, J = 7.1 Hz, H-2”)*. 13C NMR (CDCl3, 75 MHz):
δ 202.5 (2 C, C-3), 168.5 (C, C-1),
168.1 (C, C-1), 142.6 (2 C, Ar), 140.2 (C, Ar), 140.1 (C, Ar), 128.0 (2 CH, Ar), 127.7 (2 CH, Ar), 127.2 (2 CH,
Ar), 127.1 (2 CH, Ar), 67.6 (CH, C-2), 67.0 (CH, C-2), 61.3 (CH2, -OCH2CH3), 60.9 (CH2, -OCH2CH3),
39.6 (CH, C-10), 39.3 (CH, C-10), 29.7 (CH3, C-4), 29.3 (CH3, C-4), 28.3 (CH2, C-1”), 28.2 (CH2, C-1”),
20.5 (CH3, C-20)*, 20.2 (CH3, C-20)*, 15.4 (CH3, C-2”)*, 15.3 (CH3, C-2”)*, 14.0 (CH3, -OCH2CH3),
13.6 (CH3, -OCH2CH3). HRMS (ESI) m/z calcd. for C16H23NaO3 [M + Na]+ 285.1461, found 285.1461.

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Ethyl 2-acetyl-3-(4-(tert-butyl)phenyl)butanoate 3c Yield: 20% of colorless oil (inseparable mixture with
1
diastereoisomeric ratio 1:1). H-NMR (CDCl3, 300 MHz):
δ 7.29 (4H, d, J = 8.5 Hz, ArH), 7.15–7.10 (4H,
m, ArH), 4.22 (2H, q, J = 7.1 Hz, -OCH2CH3), 3.93–3.83 0(2H, m, -OCH2CH3), 3.77 (1H, d, J = 10.9 Hz
(27H, m, H-20, -C(CH3)3 and -OCH2CH3)*, 0.88 (3H, t, J = 7,1 Hz, -OCH2CH3)*. 13C NMR (CDCl3,
,
H-2), 3.70 (1H, d, J = 11.0 Hz, H-2), 3.57–3.48 (2H, m, H-1 ), 2.30 (3H, s, H-4), 1.93 (3H, s, H-4), 1.34–1.22
75 MHz):
δ 202.5 (2 C, C-3), 168.6 (C, C-1), 168.5 (C, C-1); 149.6 (C, Ar); 149.5 (C, Ar); 139.9 (C, Ar);
139.8 (C, Ar); 127.0 (2 CH, Ar); 126.8 (2 CH, Ar); 125.4 (2 CH, Ar); 125.1 (2 CH, Ar); 67.70(CH, C-2);
0
67.0 (CH, C-2); 61.3 (CH2, -OCH2CH3); 60.9 (CH2, -OCH2CH3); 39.5 (CH, C-1 ); 39.3 (CH, C-1 ); 34.3 (2 C,
-C(CH3)3); 31.2 (6 CH3, -C(CH3)3); 29.7 (CH3, C-4); 29.3 (CH3, C-4); 20.5 (CH3, C-20); 20.1 (CH3, C-2’);
14.0 (CH3, -OCH2CH3); 13.5 (CH3, -OCH2CH3). HRMS (ESI) m/z calcd. for C18H30NO3 [M + NH4]+
308.2226, found 308.2218.
Ethyl 2-acetyl-3-(4-(chloromethyl)phenyl)butanoate 3d Yield: 35% of colorless oil (inseparable mixture with
1
diastereoisomeric ratio 1:1). H-NMR (CDCl3, 300 MHz):
δ 7.31 (4H, d, J = 7.5 Hz, ArH), 7.23–7.18 (4H,
m, ArH), 4.55 (4H, bs, -CH2Cl), 4.23 (2H, q, J = 7.1 Hz, -OCH2CH3), 3.89 (2H, q, J = 7.1 Hz, -OCH2CH3),
3.78 (1H, d, J = 10.8 Hz, H-2), 3.73 (1H, d, J = 10.9 Hz, H-2), 3.61–3.50 (2H, m, H-10), 2.30 (3H, s, H-4),
1.96 (3H, s, H-4), 1.31–1.27 (6H, m, H-20 and -OCH2CH3), 1.23 (3H, d, J = 6.9 Hz, H-20), 0.95 (3H, t,
J = 7,1 Hz, -OCH2CH3). 13C NMR (CDCl3, 75 MHz):
δ 202.0 (C, C-3), 201.9 (C, C-3), 168.3 (C, C-1),
167.9 (C, C-1), 143.5 (C, Ar), 143.4 (C, Ar), 135.9 (2 C, Ar), 128.8 (2 CH, Ar), 128.6 (2 CH, Ar), 127.7 (2 CH,
Ar), 127.6 (2 CH, Ar), 67.2 (CH, C-2), 66.8 (CH, C-2), 61.4 (CH2, -OCH2CH3), 61.1 (CH2, -OCH2CH3),
45.8 (CH2, -CH2Cl), 45.7 (CH2, -CH2Cl), 39.4 (CH, C-10), 39.3 (CH, C-10), 29.7 (CH3, C-4), 29.4 (CH3,
C-4), 20.3 (CH3, C-20), 20.2 (CH3, C-20), 14.0 (CH3, -OCH2CH3), 13.6 (CH3, -OCH2CH3). HRMS (ESI)
m/z calcd. for C15H23ClNO3 [M + NH4]+ 300.1366, found 300.1358.
Ethyl 2-acetyl-3-(4-methoxyphenyl)butanoate 3f Yield: 25% of colorless oil (inseparable mixture with
1
diastereoisomeric ratio 1:1). H-NMR (CDCl3, 300 MHz):
δ 7.14 (2H, d, J = 6.0 Hz, ArH), 7.11 (2H, d,
J = 6.0 Hz, ArH), 6.82 (4H, dd, J = 8.7, 0.9 Hz, ArH), 4.21 (2H, q, J = 7.2 Hz, -OCH2CH3), 3.90 (2H, q,
J = 7.2 Hz, -OCH2CH3), 3.77 (6H, s, -OCH3), 3.74 (1H, d, J = 11.1 Hz, H-2), 3.68 (10H, d, J = 11.1 Hz,
0
H-2), 3.55-3.44 (2H, m, H-1 ), 2.29 (3H, s, H-4), 1.93 (3H, s, H-4), 1.31–1.26 (6H, m, H-2 and -OCH2CH3),
0
1.21 (3H, d, J = 6.9 Hz, H-2 ), 0.98 (3H, t, J = 7.2 Hz, -OCH2CH3). 13C NMR (CDCl3, 75 MHz):
δ 202.5 (C,
C-3), 202.4 (C, C-3), 168.6 (C, C-1), 168.1 (C, C-1), 158.2 (2 C, Ar), 135.2 (C, Ar), 134.9 (C, Ar), 128.2 (4 CH,
Ar), 113.9 (2 CH, Ar), 113.6 (2 CH, Ar), 67.7 (CH, C-2), 67.1 (CH, C-2), 61.3 (CH2, -OCH2CH3), 61.0 (CH2,
-OCH2CH3), 55.1 (CH3, -OCH3), 55.0 (CH3, -OCH3), 39.2 (CH, C-10), 38.9 (CH, C-10), 29.7 (CH3, C-4),

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29.3 (CH3, C-4), 20.6 (CH3, C-20), 20.3 (CH3, C-20), 14.0 (CH3, -OCH2CH3), 13.6 (CH3, -OCH2CH3).
HRMS (ESI) m/z calcd. for C15H24NO4 [M + NH4]+ 282.1705, found 282.1694.
4. Conclusions
In conclusion, this study demonstrates that the intermolecular hydroalkylation of alkenes
with
β-ketoesters catalyzed by cationic gold species can be achieved efficiently by selecting the
substrate patterns. It is worthwhile to highlight that, in most of the cases, the
β-ketoester substrate
(ethylacetoacetate 1a) exhibited a significant stability to gold catalysis conditions, and only under
certain conditions (high temperature, addition of extra acid to the reaction mixture) did its hydrolysis
took place. Regarding the alkene requirements, it is concluded that the coupling reaction proceeds
efficiently only with those olefinic structures whose electron density is enough to coordinate with the
cationic gold species but not too elevated to exhibit predominant nucleophilic character that would
lead to the self-addition as the main reaction and, therefore, prevent the reaction with the nucleophilic
1,3-dicarbonyl moiety of the β-ketoester. These requirements limit the scope of suitable alkenes for this
synthetic tool. In order to improve yields, low temperature during a very slow addition of the olefin
was successfully carried out.
1
Supplementary Materials: The following are available online, Figures S1–4: H, 13C, HSQC, and HMBC NMR
1
spectra of compound 3a in CDCl3, Figures S5–8: H, 13C, HSQC, and HMBC NMR spectra of compound 3b in
1
1
CDCl3, Figures S9–12: H, 13C, HSQC, and HMBC NMR spectra of compound 3c in CDCl3, Figures S13–16: H,
13C, HSQC, and HMBC NMR spectra of compound 3d in CDCl3, Figures S17–20: H, 13C, HSQC, and HMBC
NMR spectra of compound 3f in CDCl3.
1
Acknowledgments: Support from CONICET, ANPCyT and Universidad Nacional de Rosario from Argentina
(UNR) is gratefully acknowledged.
Author Contributions: Mirta P. Mischne and Ernesto G. Mata conceived and designed the experiments;
Agustina La-Venia performed the experiments and analyzed the data; Agustina La-Venia, Mirta P. Mischne,
and Ernesto G. Mata wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest. The funding sponsors had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the
decision to publish the results.
References
1.
2.
3.
4.
5.
6.
Arcadi, A. Alternative Synthetic Methods through New Developments in Catalysis by Gold. Chem. Rev.
2008, 108, 3266–3325. [CrossRef] [PubMed]
Furstner, A.; Davies, P.W. Catalytic Carbophilic Activation: Catalysis by Platinum and Gold pi-Acids.
Angew. Chem. Int. Ed. 2007, 46, 3410–3449. [CrossRef] [PubMed]
Furstner, A. Gold and platinum catalysis-a convenient tool for generating molecular complexity.
Chem. Soc. Rev. 2009, 38, 3208–3221. [CrossRef] [PubMed]
Hashmi, A.S.; Rudolph, M. Gold catalysis in total synthesis. Chem. Soc. Rev. 2008, 37, 1766–1775. [CrossRef]
[PubMed]
Rudolph, M.; Hashmi, A.S. Gold catalysis in total synthesis-an update. Chem. Soc. Rev. 2012, 41, 2448–2462.
[CrossRef] [PubMed]
Shen, H.C. Recent advances in syntheses of heterocycles and carbocycles via homogeneous gold catalysis.
Part 1: Heteroatom addition and hydroarylation reactions of alkynes, allenes, and alkenes. Tetrahedron 2008
64, 3885–3903. [CrossRef]
,

Molecules 2018, 23, 629
9 of 11
7.
8.
9.
Shen, H.C. Recent advances in syntheses of carbocycles and heterocycles via homogeneous gold catalysis.
Part 2: Cyclizations and cycloadditions. Tetrahedron 2008, 64, 7847–7870. [CrossRef]
Gorin, D.J.; Sherry, B.D.; Toste, F.D. Ligand Effects in Homogeneous Au Catalysis. Chem. Rev. 2008, 108,
3351–3378. [CrossRef] [PubMed]
Pflasterer, D.; Hashmi, A.S. Gold catalysis in total synthesis - recent achievements. Chem. Soc. Rev. 2016, 45,
1331–1367. [CrossRef] [PubMed]
10. Shahzad, S.A.; Sajid, M.A.; Khan, Z.A.; Canseco-Gonzalez, D. Gold catalysis in organic transformations:
A review. Synth. Commun. 2017, 47, 735–755. [CrossRef]
11. Echavarren, A.M.; Hashmi, A.S.; Toste, F.D. Gold Catalysis—Steadily Increasing in Importance.
Adv. Synth. Catal. 2016, 358, 1347. [CrossRef]
12. Dyker, G. An Eldorado for Homogeneous Catalysis? Angew. Chem. Int. Ed. 2000, 39, 4237–4239. [CrossRef]
13. Hashmi, A.S. Gold-Catalyzed Organic Reactions. Chem. Rev. 2007, 107, 3180–3211. [CrossRef] [PubMed]
14. Hashmi, A.S. Homogeneous Gold Catalysis Beyond Assumptions and Proposals—Characterized
Intermediates. Angew. Chem. Int. Ed. 2010, 49, 5232–5241. [CrossRef] [PubMed]
15. Hashmi, A.S. Dual Gold Catalysis. Acc. Chem. Res. 2014, 47, 864–876. [CrossRef] [PubMed]
16. Huang, H.; Zhou, Y.; Liu, H. Recent advances in the gold-catalyzed additions to C-C multiple bonds.
Beilstein J. Organ. Chem. 2011, 7, 897–936. [CrossRef] [PubMed]
17. Li, Z.; Brouwer, C.; He, C. Gold-Catalyzed Organic Transformations. Chem. Rev. 2008, 108, 3239–3265.
[CrossRef] [PubMed]
18. Skouta, R.; Li, C.J. Gold-catalyzed reactions of C-H bonds. Tetrahedron 2008, 64, 4917–4938. [CrossRef]
19. Gorin, D.J.; Toste, F.D. Relativistic effects in homogeneous gold catalysis. Nature 2007, 446, 395–403.
[CrossRef] [PubMed]
20. Corma, A.; Leyva-Perez, A.; Sabater, M.J. Gold-Catalyzed Carbon-Heteroatom Bond-Forming Reactions.
Chem. Rev. 2011, 111, 1657–1712. [CrossRef] [PubMed]
21. Hashmi, A.S. Homogeneous gold catalysts and alkynes: A successful liaison. Gold Bull. 2003, 36, 3–9.
[CrossRef]
22. Jimenez-Nunez, E.; Echavarren, A.M. Molecular diversity through gold catalysis with alkynes.
Chem. Commun. 2007, 43, 333–346. [CrossRef] [PubMed]
23. Jimenez-Nuñez, E.; Echavarren, A.M. Gold-Catalyzed Cycloisomerizations of Enynes: A Mechanistic
Perspective. Chem. Rev. 2008, 108, 3326–3350. [CrossRef] [PubMed]
24. Kennedy-Smith, J.J.; Staben, S.T.; Toste, F.D. Gold(I)-Catalyzed Conia-Ene Reaction of beta-Ketoesters with
Alkynes. J. Am. Chem. Soc. 2004, 126, 4526–4527. [CrossRef] [PubMed]
25. Muzart, J. Gold-catalysed reactions of alcohols: Isomerisation, inter- and intramolecular reactions leading to
C-C and C-heteroatom bonds. Tetrahedron 2008, 64, 5815–5849. [CrossRef]
26. Dorel, R.; Echavarren, A.M. Gold(I)-Catalyzed Activation of Alkynes for the Construction of Molecular
Complexity. Chem. Rev. 2015, 115, 9028–9072. [CrossRef] [PubMed]
27. Chiarucci, M.; Bandini, M. New developments in gold-catalyzed manipulation of inactivated alkenes.
Beilstein J. Organ. Chem. 2013, 9, 2586–2614. [CrossRef] [PubMed]
28. Zhu, Y.; Zhou, W.; Petryna, E.M.; Rogers, B.R.; Day, C.S.; Jones, A.C. Insights into Alkene Activation by Gold:
Nucleophile Activation with Base as a Trigger for Generation of Lewis Acidic Gold. ACS Catal. 2016, 6,
7357–7362. [CrossRef]
29. Bay, S.; Englert, A.; Nalivela, K.S.; Hashmi, A.S.; Larsen, M.H. Gold catalysis: Experimental mechanistic
insights into the anellation of phenols with 1,3-dienes. J. Organomet. Chem. 2015, 795, 58–62. [CrossRef]
30. Hashmi, A.S.; Ramamurthi, T.D.; Rominger, F. Synthesis, structure and reactivity of organogold compounds
of relevance to homogeneous gold catalysis. J. Organomet. Chem. 2009, 694, 592–597. [CrossRef]
31. Klatt, G.; Xu, R.; Pernpointner, M.; Molinari, L.; Quang-Hung, T.; Rominger, F.; Hashmi, A.S.; Koppel, H.
Are beta-H-Eliminations or Alkene Insertions Feasible Elementary Steps in Catalytic Cycles Involving Gold(I)
Alkyl Species or Gold(I) Hydrides? Chem. A Eur. J. 2013, 19, 3954–3961. [CrossRef] [PubMed]
32. Bandini, M.; Monari, M.; Romaniello, A.; Tragni, M. Gold-Catalyzed Direct Activation of Allylic Alcohols in
the Stereoselective Synthesis of Functionalized 2-Vinyl-Morpholines. Chem. A Eur. J. 2010, 16, 14272–14277.
[CrossRef] [PubMed]

Molecules 2018, 23, 629
10 of 11
33. Han, X.; Widenhoefer, R.A. Gold(I)-Catalyzed Intramolecular Hydroamination of Alkenyl Carbamates.
Angew. Chem. Int. Ed. 2006, 45, 1747–1749. [CrossRef] [PubMed]
34. Hirai, T.; Hamasaki, A.; Nakamura, A.; Tokunaga, M. Enhancement of Reaction Efficiency by Functionalized
Alcohols on Gold(I)-Catalyzed Intermolecular Hydroalkoxylation of Unactivated Olefins. Org. Lett. 2009, 11,
5510–5513. [CrossRef] [PubMed]
35. Iglesias, A.; Muñiz, K. Oxidative Interception of the Hydroamination Pathway: A Gold-Catalyzed
Diamination of Alkenes. Chem. A Eur. J. 2009, 15, 10563–10569. [CrossRef] [PubMed]
36. Yang, C.G.; He, C. Gold(I)-Catalyzed Intermolecular Addition of Phenols and Carboxylic Acids to Olefins.
J. Am. Chem. Soc. 2005, 127, 6966–6967. [CrossRef] [PubMed]
37. Zhang, G.;
Cui, L.;
Wang, Y.;
Zhang, L. Homogeneous Gold-Catalyzed Oxidative
Carboheterofunctionalization of Alkenes. J. Am. Chem. Soc. 2010, 132, 1474–1475. [CrossRef]
[PubMed]
38. Zhang, J.; Yang, C.G.; He, C. Gold(I)-Catalyzed Intra- and Intermolecular Hydroamination of Unactivated
Olefins. J. Am. Chem. Soc. 2006, 128, 1798–1799. [CrossRef] [PubMed]
39. Denes, F.; Perez-Luna, A.; Chemla, F. Addition of Metal Enolate Derivatives to Unactivated Carbon-Carbon
Multiple Bonds. Chem. Rev. 2010, 110, 2366–2447. [CrossRef] [PubMed]
40. Fang, W.; Presset, M.; Guerinot, A.; Bour, C.; Bezzenine-Lafollee, S.; Gandon, V. Cationic gold(I)-catalyzed
enantioselective hydroalkylation of unactivated alkenes: Influence of the chloride scavenger on the
stereoselectivity. Org. Chem. Front. 2014, 1, 608–613. [CrossRef]
41. Porcel, S.; López-Carrillo, V.; García-Yebra, C.; Echavarren, A.M. Gold-Catalyzed Allyl-Allyl Coupling.
Angew. Chem. Int. Ed. 2008, 47, 1883–1886. [CrossRef] [PubMed]
42. Xiao, Y.P.; Liu, X.Y.; Che, C.M. Efficient Gold(I)-Catalyzed Direct Intramolecular Hydroalkylation of
Unactivated Alkenes with alpha-Ketones. Angew. Chem. Int. Ed. 2011, 50, 4937–4941. [CrossRef] [PubMed]
43. Nguyen, R.V.; Yao, X.Q.; Bohle, D.S.; Li, C.J. Gold- and Silver-Catalyzed Highly Regioselective Addition
of Active Methylenes to Dienes, Triene, and Cyclic Enol Ethers. Org. Lett. 2005, 7, 673–675. [CrossRef]
[PubMed]
44. Vayer, M.; Fang, W.; Guillot, R.; Bezzenine-Lafollee, S.; Bour, C.; Gandon, V. Acid-catalysed intramolecular
addition of beta-ketoesters to 1,3-dienes. Org. Biomol. Chem. 2017, 15, 584–588. [CrossRef] [PubMed]
45. Yao, X.; Li, C.J. Highly Efficient Addition of Activated Methylene Compounds to Alkenes Catalyzed by Gold
and Silver. J. Am. Chem. Soc. 2004, 126, 6884–6885. [CrossRef] [PubMed]
46. Zhou, C.Y.; Che, C.M. Highly Efficient Au(I)-Catalyzed Intramolecular Addition of beta-Ketoamide to
Unactivated Alkenes. J. Am. Chem. Soc. 2007, 129, 5828–5829. [CrossRef] [PubMed]
47. Balamurugan, R.; Koppolu, S.R. Scope of AuCl3 in the activation of per-O-acetylglycals. Tetrahedron 2009, 65,
8139–8142. [CrossRef]
48. Fang, W.; Presset, M.; Guerinot, A.; Bour, C.; Bezzenine-Lafollee, S.; Gandon, V. Silver-Free Two-Component
Approach in Gold Catalysis: Activation of [LAuCl] Complexes with Derivatives of Copper, Zinc, Indium,
Bismuth, and Other Lewis Acids. Chem. Eur. J. 2014, 20, 5439–5446. [CrossRef] [PubMed]
49. Guerinot, A.; Fang, W.; Sircoglou, M.; Bour, C.; Bezzenine-Lafollee, S.; Gandon, V. Copper Salts as Additives
in Gold(I)-Catalyzed Reactions. Angew. Chem. Int. Ed. 2013, 52, 5848–5852. [CrossRef] [PubMed]
50. Nguyen, R.V.; Li, C.J. An Annulation toward Fused Bicyclolactones. J. Am. Chem. Soc. 2005, 127, 17184–17185.
[CrossRef] [PubMed]
51. Jagdale, A.R.; Youn, S.W. AuI-Catalyzed Intramolecular Cyclization of 2-Alkenylphenyl Carbonyl
Compounds: Exploring the Oxophilic Lewis Acidity of AuI Species. Eur. J. Org. Chem. 2011, 2011,
3904–3910. [CrossRef]
52. Zhang, X.; Corma, A. Effective Au(III)-CuCl2-catalyzed addition of alcohols to alkenes. Chem. Commun.
2007, 43, 3080–3082. [CrossRef] [PubMed]
53. Rosenfeld, D.C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.; Hartwig, J.F. Hydroamination and
Hydroalkoxylation Catalyzed by Triflic Acid. Parallels to Reactions Initiated with Metal Triflates. Org. Lett.
2006, 8, 4179–4182. [CrossRef] [PubMed]
54. Hashmi, A.S.; Schafer, S.; Goker, V.; Eisenbach, C.D.; Dirnberger, K.; Zhao-Karger, Z.; Crewdson, P.
Gold Catalysis: AuCl-induced Polymerization of Styrene and n-Butylvinylether. Aust. J. Chem. 2014
67, 500–506. [CrossRef]
,

Molecules 2018, 23, 629
11 of 11
55. Urbano, J.; Hormigo, A.J.; de Fremont, P.; Nolan, S.P.; Diaz-Requejo, M.M.; Perez, P.J. Gold-promoted styrene
polymerization. Chem. Commun. 2008, 759–761. [CrossRef]
56. Hashmi, A.S.; Frost, T.M.; Bats, J.W. Highly Selective Gold-Catalyzed Arene Synthesis. J. Am. Chem. Soc.
2000, 122, 11553–11554. [CrossRef]
57. Hashmi, A.S.; Schwarz, L.; Choi, J.H.; Frost, T.M. A New Gold-Catalyzed C-C Bond Formation. Angew. Chem.
Int. Ed. 2000, 39, 2285–2288. [CrossRef]
58. Reichardt, C.; Welton, T. Solvents and Solvent Effects in Organic Chemistry, 4th ed.; Wiley-VCH Verlag & Co.
KGaA: Weinheim, Germany, 2011; ISBN 978-3-527-32473-6.
Sample Availability: Samples of the compounds are available from the authors.
©
2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).