Gold-Catalyzed Povarov-Type Reaction of Fluorinated Imino Esters and Furans

Article abstract of DOI:10.1021/acs.joc.6b01139

A gold-catalyzed Povarov-type reaction of fluorinated imino esters and furans is described. The process, which takes place in dichoromethane at room temperature, gives rise to novel fluorinated tetrahydrofuran-fused tetrahydroquinolines in good yields and moderate levels of diastereoselectivity in a very simple manner. The reported examples expand the versatility of the Povarov reaction to unprecedented fluorinated substrates, generating scaffolds that contain quaternary α-amino acid units.

Full text of DOI:10.1021/acs.joc.6b01139

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Article
Gold Catalyzed Povarov–Type Reaction
of Fluorinated Imino Esters and Furans
Alvaro Sanz-Vidal, Javier Miró, Maria Sanchez-Rosello, Carlos Del Pozo, and Santos Fustero
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01139 • Publication Date (Web): 08 Jul 2016
Downloaded from http://pubs.acs.org on July 9, 2016
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Gold Catalyzed Povarov–Type Reaction of Fluorinated Imino
Esters and Furans
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Álvaro Sanz-Vidal,† Javier Miró,† María Sánchez-Roselló,† Carlos del Pozo,*,† Santos
Fustero*,†,‡
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† Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain
‡ Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia,
Spain.
E-mail: santos.fustero@uv.es; carlos.pozo@uv.es
ABSTRACT:
A gold–catalyzed Povarov-type reaction of fluorinated imino esters and furans is described. The
process which takes place in dichoromethane at room temperature, gives rise to novel
fluorinated tetrahydrofuran-fused tetrahydroquinolines in good yields and moderate levels of
diastereoselectivity in a very simple manner. The reported examples expand the versatility of
the Povarov reaction to unprecedented fluorinated substrates, generating scaffolds that contain
quaternary α-amino acid units.
INTRODUCTION
The reaction of N-arylimines with electron-rich alkenes under Lewis or Brønsted acid catalysis,
the so-called Povarov reaction, leads to the formation of tetrahydroquinoline derivatives in a
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very simple and efficient manner.1 This family of compounds consists of extremely valuable
scaffolds, being widespread in Nature and having interesting biological properties.2 For that
reason, the Povarov reaction has gained a lot of interest and significant advances have been
made during the last decades. Among them, tetrahydrofuran-fused tetrahydroquinolines have
recently been disclosed as inhibitors of methionyl amino peptidase and as glucocorticoid
receptor modulators, being potential therapeutic agents for the treatment of liver disorders and
obesity (Figure 1).3
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Figure 1. Biologically active tetrahydrofurane-fused tetrahydroquinolines
On the other hand, it is well known that the introduction of fluorine atoms into organic
molecules is a powerful strategy to modify their physicochemical and biological properties.4
Specifically, the replacement of one or more hydrogen atoms by fluorine in the vicinity of an
amine function often results in a lower basicity, a higher metabolic stability and a decrease in
acute toxicity. For this reason, its introduction into potential drug candidates is a commonly
employed approach in drug discovery programs.5 Also, from an academic point of view, the
generation of new fluorinated chemical entities is always of high interest. Despite the
importance of tetrahydroquinolines in medicinal chemistry and the unquestionable utility of the
Povarov reaction for their construction, the examples reported in the literature involving
fluorinated substrates are quite limited.6
During an ongoing project in our laboratory directed towards the synthesis of new fluorinated
chemical entities, we decided to explore the reactivity of fluorinated imino esters with electron-
rich aromatic and heteroaromatic rings as nucleophilic partners in an aza-Friedel-Crafts
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reaction. This transformation would render valuable fluorinated quaternary α-amino acids. To
the best of our knowledge, only one example of the participation of fluorinated imino esters in
this type of process has been reported, employing indoles as nucleophiles.7,8
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Initial attempts were performed with trifluoropyruvate-derived imino esters and substituted
furans, in the presence of gold(I) complexes as Lewis acid catalysts. However, instead of the
expected addition to the imine functionality, a Povarov-type reaction occurred, thus generating
highly substituted fluorinated tetrahydrofurane-fused tetrahydroquinoline derivatives. As far as
we know, this is the first example of a Povarov-type reaction involving furanes as dienophiles.
Here, we present the results, scope and limitations, of this unprecedented transformation.
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RESULTS AND DISCUSSION
The reaction of trifluoromethyl imino ester 1a with 2-methyl furan 2a was selected as a model
reaction in order to find the optimal conditions to carry out the desired tandem process. Several
catalysts were tested and the results obtained are shown in Table 1.
Table 1. Optimization of the reaction conditions for the synthesis of tricycle 3a
Product (isolated
Entry
Catalyst
Solvent
Conversion
yield)a
1
2
3
4
AuCl3
AuCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
44
3a (37%)b
3a (81%)
3a (71%)
3a (75%)
>95
>95
>95
PPh3AuOTf
[Au(P(4-CF3C6H4)3)]OTf
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CH2Cl2
>95
3a (86%)
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AuCl3
AuCl3
AuCl3
6
7
8
Toluene
THF
<10
0
-
-
-
MeCN
0
AuCl3
9
MeOH
5a (82%)
3a (67%)
10
11
BF3·OEt2
CH2Cl2
CH2Cl2
>95
>95
TfOH
3a (20%)
12
13
TFA
CH2Cl2
CH2Cl2
>95
0
4a (86%)
-
14
CH2Cl2
0
-
a Reactions were performed with 1a (0.2 mmol) and 2 equiv of 2a (0.4 mmol) in the presence of
b
the corresponding catalyst (5 mol %) at rt for 12 h. In this case, only 1 equiv of furan 2a (0.2
mmol) was employed.
According to previous reports regarding the reaction of furans with highly electrophilic imines
in the presence of gold salts,9 and considering the activation of our imine carbon in 1a by the
presence of two electron-withdrawing substituents, the reaction was initially performed with
one equivalent of furan 2a and AuCl3 as the catalyst in dichloromethane at room temperature.
After 12 hours, together with some unreacted starting material, the formation of a new product
was observed (44% conversion). After isolating this product by flash chromatography, the
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tricyclic tetrahydroquinoline 3a was identified in 37% yield (Table 1, entry 1). The formation of
3a would entail a Povarov-type process between the N-aromatic imine functionality in 1a and
one of the double bonds in the furan ring 2a, followed by the addition of a second molecule of
furan 2a in a Friedel-Craft-type reaction.10
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In view of the incorporation of two molecules of furan to the final product, the reaction was
then performed with two equivalents of 2a, giving compound 3a in 81% isolated yield with
complete conversion (Table 1, entry 2).11 It is important to note that four stereocenters were
created in only one reaction step and final tetrahydroquinoline products were obtained as
mixtures of diastereoisomers, the major one being compound 3a with the stereochemistry
shown in the scheme in Table 1 (see below).
Other gold(I) complexes were also tested. Hence, PPh3AuOTf, in situ generated by combination
of PPh3AuCl and AgOTf, afforded tricycle 3a in slightly lower yield (Table 1, entry 3). The use
of electronically deficient phosphines such as P(4-CF3C6H4)3 in the starting gold salt did not
lead to better yields, giving rise to compound 3a in 75% yield (Table 1, entry 4) whereas the
NHC-derived gold(I) complex [1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene gold triflate,
SIPrAuOTf]12 provided the best results, leading to 3a in 86% yield (Table 1, entry 5).
When solvent screening was performed subsequently, the reaction in toluene resulted in very
poor conversion (<10%), when more polar solvents such as THF or CH3CN were used, the
reactions did not proceed at all (Table 1, entries 6-8). Finally, when the reaction was carried out
in MeOH fluorinated hemiaminal 5 arising from the addition of the solvent to the starting imino
ester, 1a was the only identified product (Table 1, entry 9).
.
The tandem protocol could also be carried out with BF3 OEt2 as the Lewis acid although in a
less efficient manner (Table 1, entry 10).13 Additionally, Brønsted acids were also evaluated as
catalysts in the synthesis of the tricyclic tetrahydroquinoline 3a. In this context, the use of triflic
acid led us to obtain compound 3a albeit in a low 20% yield (Table 1, entry 11), while TFA
rendered the aza-Friedel Craft product 4a in excellent yield (Table 1, entry 12). BINOL-derived
phosphoric acids were examined next, either the acid I itself or the more acidic triflimide II.
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Unfortunately, the starting imino ester 1a remained unaltered in either case (Table 1, entries 13,
14).14
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At this point, the optimal reaction conditions were established when treating imino ester 1a and
2 equivalents of furan 2a with either AuCl3 or SIPrAuOTf as the catalysts, in dichloromethane
at room temperature. These conditions were applied to other fluorinated α-imino esters 1 and
furans 2. Thus, the evaluation of the scope of this tandem process produced the results displayed
in Table 2.15
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Table 2. Scope of the tandem Povarov-type/Friedel-Craft reaction
Product
Entry 1, 2
R
RF
R1
R2
R3
dr-(catalyst)a
Yield
1a,
3a, 81%
63:37 (A)
48:52 (A)
52:48 (A)
48:52 (A)c
- (A)
1
4-OMe
4-Me
H
CF3
CF3
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
2a
1b,
3b, 81%
3c, 82%
3d, 81%
2
2a
1c,
3
CF3
2a
1d,
4
-C4H4-b
4-CF3
4-OMe
CF3
2a
1e,
d
-
5
CF3
2a
1f,
3f, 84%
55:45 (B)
6
PhCF2
2a
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1g,
2a
3g, 79%
3h, 75%
3i, 78%
3j, 85%
3k, 82%
3l, 75%
3m, 85%
3n, 56%
3o, 51%
45:55 (A)
59:41 (B)
79:21 (B)
45:55 (A)
46:54 (A)
42:58 (A)
45:55 (B)e
71:29 (B)e,f
57:43 (B)g
- (A)
7
4-OMe PhCH=CHCF2 CO2Et
Me
Me
Me
Et
H
H
7
8
9
1h,
2a
8
4-OMe
4-OMe
4-OMe
4-Me
ClCF2
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CO2Et
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1i,
2a
5-Me-
furyl
9
H
1a,
2b
1b,
2b
1c,
2b
1a,
2c
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CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
Et
H
H
Et
H
4-OMe
4-OMe
4-OMe
4-OMe
Me
Ph
Me
H
1a,
2e
1a,
2f
2-
H
thienyl
1a,
2d
h
-
OMe
H
1a,
2e
(A)
(A)
17
18
4-OMe
4-OMe
CF3
CO2Et Benzyl
H
H
4b, 65%
4c, 86%
1j,
2a
CF3
H
Me
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a Diastereoisomeric ratio = major compound 3 / mixture of other diastereoisomers formed in the
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b
c
tandem process. Starting imino ester 1d contains a 1-naphthyl unit attached to the nitrogen.
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d
Compound 3d was isolated as a 3:1 mixture of unseparable diasteroisomers. A complex
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e
mixture of unidentified products was observed. Compound 3m was obtained as a 1:1 mixture
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f
g
of diastereoisomers at the stereocenter bearing R3. Conversion of the process was 65%.
Conversion of the process was 68%. h Starting material was recovered unaltered.
As indicated in Table 1, trifluoromethyl imino ester 1a reacted with furan 2a in the presence of
AuCl3 to render the corresponding tricyclic tetrahydroquinoline as a mixture of four
diastereoisomers in 81% overall yield (Table 2, entry 1). Fortunately, the major diastereoisomer
3a, which represented 63% of the products mixture, had a clearly different chromatographic
behavior and it could be isolated in 51% yield and fully characterized (see Supporting
Information). The rest of diastereoisomers (30% of the products mixture) appeared together
from the column and it was not possible to separate them. Analogous performance was observed
for other substrates 1.
The next step of our study was directed at the evaluation of the influence of the substituents on
the aromatic ring of the starting imino esters 1. Substrates 1b (with a p-tolyl), 1c (with a phenyl
ring) and 1d (with a 1-naphthyl) attached to the nitrogen underwent the tandem protocol
efficiently, affording final products in 81%, 82% and 81% overall yield, respectively (Table 2,
entries 2-4). Remarkably, substrate 1d gave access to a fluorinated steroid-type skeleton. On the
other hand, imino ester 1e bearing an electron-withdrawing group (CF3) yielded a complex
mixture of non-identified products (Table 2, entry 5). The reaction was also compatible with
other fluorinated moieties such as PhCF2, Ph-CH=CH-CF2 or CF2Cl. Tricycles 3f, 3g and 3h
were, therefore, obtained as the major diastereoisomers in good overall yields (Table 2, entries
6-8). Trifluoromethyl ketimine 1i was found to be a good partner in the tandem reaction with 2-
methyl furan 2a, giving rise to tetrahydroquinoline 3i as the major product from a mixture of
diastereoisomers with 78% overall yield (Table 2, entry 9).
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The scope of the furan counterpart 2 was also explored. Accordingly, 2-ethyl furan 2b took
efficiently part in the tandem process with trifluoromethyl imino esters 1a-c, leading to the
corresponding tricyclic derivatives 3j-l in good yields (Table 2, entries 10-12). The introduction
of a methyl substituent at position 3 of the furan–ring (R3) generated an additional stereocenter
in the final products. An equimolecular mixture of diastereoisomers at the tetrahydrofuran ring
in compound 3m was observed in this case (Table 2, entry 13). Aryl and heteroaryl substituents
were also suitable partners for the tandem protocol, although in those cases the conversion was
not complete and some starting material was recovered (Table 2, entries 14,15).
Surprisingly, the more activated furan 2d, bearing a methoxy group at position 2, did not react
with imino ester 1a under the reaction conditions (Table 2, entry 16), whereas other alkyl
substituents at that position, such as the benzyl group in furan 2e, gave the aza-Friedel Craft
product 4b in 65% yield (Table 2, entry 17).
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Finally, fluorinated aldimine 1j was also tested in its reaction with furan 2a. Trifluoromethyl
amine 4c, arising from the aza-Friedel Craft reaction, was isolated in 86% yield (Table 2, entry
18).
The relative stereochemistry of the major diastereoisomer 3 was determined by means of NMR
experiments on compound 3c. Specifically, the combination of HOESY and NOESY studies led
us to identify the arrangement of the protons and the trifluoromethyl group in the tricyclic
structure. Initially, the relative disposition of the trifluoromethyl group and the tetrahydrofuran
ring was elucidated by a HOESY experiment. The heteronuclear correlation between fluorine
nuclei and protons Ha and Hb (Figure 2) allowed us to assign the relative cis stereochemistry at
those positions. The cis relationship between those protons and the furan ring was determined
by means of a NOESY experiment, which showed the correlation between proton Ha and
protons Hc and Hd of the furan ring (Figure 2). The same stereochemical assignment was
assumed for all tetrahydroquinolines 3.
Figure 2. NMR experiments on compound 3a
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A plausible mechanistic rationale for the transformation presented herein is depicted in Scheme
1. In a first step, imino ester 1 would be activated by the gold salt (acting as a σ-Lewis acid) for
the attack of the furan–ring through its position 5. This attack would generate intermediate A,
which would evolve through the nucleophilic attack by the ortho position of the aromatic ring
giving rise to tricyclic intermediate B (aza-Diels Alder product in a Povarov reaction).16 Upon
[1,3]-proton shift and coordination of the gold salt with the enol ether moiety (intermediate C),
the nucleophilic addition of a second molecule of furan 2 would take place in a formal Friedel-
Craft type process, consequently releasing the final product 3 and regenerating the gold catalytic
species (Scheme 1). It is noteworthy to mention that this tandem protocol constitutes another
example of the dual σ- and π-Lewis role imparted by gold salts.17
Considering this reaction pathway, it is possible to rationalize the results shown in Table 2. On
the one hand, the introduction of electron–withdrawing substituents into the aromatic ring
(imino ester 1e; R = CF3) would decrease the nucleophilicity of the ortho position, avoiding the
formation of intermediate B and, therefore, the whole process. On the other hand, the formation
of intermediate D is most likely to play an important role in the success of the tandem protocol:
after the activation of the enol ether functionality in intermediate C by the gold salt, the addition
of the second molecule of furan would render final products 3 in an irreversible way. With more
activated furans such as 2d (R = CF3), intermediate B would contain an acetal functionality
instead of an enol ether. The activation of the acetal moiety would not take place in this case
and the equilibrium would be shifted to the starting material which indeed remained unaltered.
Alternatively, when steric hindrance at the 2-position of the furan increases, which is the case of
2-benzyl furan 2e, complexation of the gold salt is disfavored, thus rendering the aza-Friedel-
Craft products 4. More difficult to explain is the behavior observed with fluorinated aldimine 1j.
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Scheme 1. Mechanistic proposal for the synthesis of tricyclic tetrahydroquinolines 3
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SUMMARY
In summary, we have developed a new tandem protocol that involves a Povarov-type reaction
followed by a formal Friedel-Craft reaction, which rendered furoquinoline derivatives 3 in good
yields and moderate levels of diastereoselectivity. The process was efficiently catalyzed by gold
complexes, either AuCl3 or SIPrAuOTf, generating complex fluorinated scaffolds in a very
simple manner. Additionally, major diastereoisomers could be separated from the rest in most
cases, allowing their isolation and characterization. A wide variety of imino esters 1 were
compatible with the process, in the aromatic moiety as well as in the fluorinated alkyl chain.
However, the scope regarding the starting furans 2 is more limited. It is noteworthy that this is
the first reported Povarov-type protocol involving furans as dienophiles.
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EXPERIMENTAL SECTION
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Reactions were carried out under argon atmosphere unless otherwise indicated. The solvents
were purified prior to use: THF, diethyl ether and toluene were distilled from
sodium/benzophenone, dichloromethane and acetonitrile were distilled from calcium hydride.
The reactions were monitored with the aid of thin-layer chromatography (TLC) on 0.25 mm
precoated silica gel plates. Visualization was carried out with UV light and ethanolic
phosphomolybdic acid solution or potassium permanganate stain. Flash column
chromatography was performed with the indicated solvents on silica gel 60 (particle size 0.040-
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0.063 mm). H and 13C NMR spectra were recorded on 300 and 500 MHz spectrometers,
respectively. Chemical shifts are given in ppm (δ), with reference to the residual proton
resonances of the solvents. Coupling constants (J) are given in Hertz (Hz). The letters m, s, d, t,
and q stand for multiplet, singlet, doublet, triplet and quartet, respectively. The letters br
indicate that the signal is broad.
Preparation of the starting imines 1a-j
Procedure A: Ketone or ketoester condensation.
To a solution of the iminophosphorane 7 (5 mmol) in dry toluene (20 mL), the corresponding
fluorinated ketone (R1 = 5-methylfuryl) or keto ester (R1 = CO2Et) 6 (5 mmol) was added
dropwise and the reaction mixture was stirred at 80ºC for 18 hours. Then the reaction mixture
was cooled to room temperature and solvents were eliminated under reduced pressure. Et2O (20
mL) was added and cooled to 0ºC. The white precipitate was filtered through a pad of Celite and
washed with cold Et2O (3 x 10 mL). The filtrate was concentrated under reduced pressure and
purified by flash column chromatography.
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Procedure B: Aldehyde condensation. Synthesis of 1j
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To a solution of the trifluoroacetaldehyde ethyl hemiacetal 8 (5 mmol) and p-anisidine 9 (5
mmol) in dry toluene (15 mL), p-toluene sulfonic acid (5 mg) was added and the reaction
mixture was stirred at reflux under Ar atmosphere for 1.5 hours with a Dean-Stark trap. The
mixture was washed with a saturated solution of NaHCO3 (3 x 15 mL) and brine (20 mL). The
organic phase was then dried over Na2SO4 and solvents eliminated under reduced pressure. The
crude product was purified by Kugelrohr distillation.
Procedure C: Alkoxycarbonilation.
To a solution of triphenyl phosphine (33 mmol) and triethylamine (13.2 mmol) in CCl4 (20 mL)
the corresponding carboxylic acid 10 (11 mmol) was added and stirred for 5 minutes at room
temperature. Then, the aryl amine 11 (13.2 mmol) dissolved in more CCl4 (10 mL) was added
and the reaction mixture refluxed overnight. After cooling to room temperature and evaporation
of the solvents, triphenyl phosphine oxide precipitate was eliminated by filtration with hexane
and the crude product purified by column chromatography.
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NaI (11.6 mmol) was added to a solution of the corresponding imidoyl chloride 12 (7.1 mmol)
in dry acetone (20 mL) and the mixture was stirred at room temperature protected from light for
48 hours. The reaction mixture was then quenched with a saturated aqueous solution of Na2S2O3
and the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic
layers were washed with brine (3 x 15 mL) and dried over anhydrous Na2SO4. Filtration and
evaporation of solvents quantitatively gave the corresponding crude imidoyl iodides 13 as
yellow oils; these were subsequently used in the next step of the synthesis with no further
purification.
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Under CO atmosphere (1 atm), a solution of the previously obtained imidoyl iodide 13 in a
toluene/DMF mixture (10 mL:1 mL) and ethanol (8.5 mmol) were both added to a two-necked
flask containing K2CO3 (14.2 mmol) and palladium catalyst Pd2(dba)3·CHCl3 (0.28 mmol). The
reaction mixture was stirred at room temperature until the starting material was totally
consumed, as confirmed by means of TLC. The crude reaction mixture was then filtered
through a silica pad and washed with CH2Cl2. The solvents were eliminated under reduced
pressure and the mixture was purified by means of flash column chromatography.
Ethyl-3,3,3-trifluoro-2-[(4-methoxyphenyl)imino]propanoate (1a). Following general
procedure A, from 5 mmol of the corresponding iminophosphorane and 5 mmol of
trifluoropyruvate, 4.6 mmol (92%) of the desired imine were obtained after purification by
column chromatography Hex:EtOAc (10:1) as an orange oil.
Spectroscopic data for the titled compound are consistent with the literature.18
1H NMR (300 MHz, CDCl3) δ: 7.01 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 4.25 (q, J =
7.1 Hz, 2H), 3.82 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H).
Ethyl-3,3,3-trifluoro-2-(p-tolylimino)propanoate (1b). Following general procedure A, from
5 mmol of the corresponding iminophosphorane and 5 mmol of trifluoropyruvate, 4.55 mmol
(91%) of the desired imine were obtained after purification by column chromatography
Hex:EtOAc (10:1) as a pale yellow oil.
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Spectroscopic data for the titled compound are consistent with the literature.18
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1H NMR (300 MHz, CDCl3) δ: 7.09 (d, J = 7.9 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H), 4.13 (q, J =
7.1 Hz, 2H), 2.28 (s, 3H), 1.05 (t, J = 7.1 Hz, 3H).
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Ethyl-3,3,3-trifluoro-2-(phenylimino)propanoate (1c). Following general procedure A, from
5 mmol of the corresponding iminophosphorane and 5 mmol of trifluoropyruvate, 4.75 mmol
(95%) of the desired imine were obtained after purification by column chromatography
Hex:EtOAc (10:1) as a pale yellow oil.
Spectroscopic data for the titled compound are consistent with the literature.18
1H NMR (300 MHz, CDCl3) δ: 7.24-7.31 (m, 1H), 7.10-7.20 (m, 1H), 7.02-7.09 (m, 1H), 6.83-
6.89 (m, 2H), 4.08 (q, J = 7.2 Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H).
Ethyl (E)-3,3,3-trifluoro-2-[(2-methoxyphenyl)imino]propanoate (1d). Following general
procedure A, from 5 mmol of the corresponding iminophosphorane and 5 mmol of
trifluoropyruvate, 4.35 mmol (87%) of the desired imine were obtained after purification by
column chromatography Hex:EtOAc (10:1) as a brownish oil.
1H NMR (300 MHz, CDCl3) δ: 7.93 – 7.86 (m, 2H), 7.77 (d, J = 8.4 Hz, 1H), 7.61 – 7.54 (m,
2H), 7.41 (dd, J = 8.3, 7.3 Hz, 1H), 6.87 (dd, J = 7.3, 0.9 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 0.93
(t, J = 7.1 Hz, 3H).19F NMR (282 MHz, CDCl3) δ: -69.92 (s).13C NMR (75 MHz, CDCl3) δ:
159.8 (s), 149.8 (q, J = 36.9 Hz), 143.6 (s), 134.1 (s), 128.2 (s), 127.8 (s), 127.4 (s), 127.0 (s),
126.6 (s), 125.4 (s), 123.6 (s), 118.6 (q, J = 277.5 Hz), 113.1 (s), 63.1 (s), 13.8 (s). HRMS (ES)
calc. for (M+1) C15H12F3NO2F3: 296.0893; found: 296.0899.
Ethyl-3,3,3-trifluoro-2-{[4-(trifluoromethyl)phenyl]imino}propanoate
(1e).
Following
general procedure A, from 5 mmol of the corresponding iminophosphorane and 5 mmol of
trifluoropyruvate, 4.25 mmol (85%) of the desired imine were obtained after purification by
column chromatography Hex:EtOAc (10:1) as a pale yellow oil.
Spectroscopic data for the titled compound are consistent with the literature.19
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1H NMR (300 MHz, CDCl3) δ: 7.57 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 8.1 Hz, 2H), 4.11 (q, J =
7.1 Hz, 2H), 1.00 (t, J = 7.1 Hz, 3H).
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Ethyl (E)-3,3-difluoro-2-[(4-methoxyphenyl)imino]-3-phenylpropanoate (1f). Following
general procedure C, from 11 mmol of the corresponding carboxylic acid and 13.2 mmol of p-
anysidine, 8.91 mmol (81%) of the desired imine were obtained after purification by column
chromatography Hex:EtOAc (10:1) as an orange oil.
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1H NMR (300 MHz, CDCl3) δ: 7.68 – 7.65 (m, 2H), 7.50 – 7.46 (m, 3H), 6.91 (d, J = 9.1 Hz,
2H), 6.83 (d, J = 9.1 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H).19F
NMR (282 MHz, CDCl3) δ: -97.57 (s).13C NMR (75 MHz, CDCl3) δ: 162.7 (s), 158.9 (s), 140.9
(s), 135.2 (s), 131.0 (s), 130.9 (s), 129.4 (s), 128.8 (s), 126.4 (t, J = 6.0 Hz), 122.0 (s), 117.3 (t, J
= 246.4 Hz), 114.5 (s), 62.5 (s), 55.8 (s), 14.2 (s). HRMS (ES) calc. for (M+1) C18H17F2NO3:
334.1249; found: 334.1242.
Ethyl
(2E,4E)-3,3-difluoro-2-[(4-methoxyphenyl)imino]-5-phenylpent-4-enoate
(1g).
Following general procedure C, from 11 mmol of the corresponding carboxylic acid and 13.2
mmol of p-anysidine, 8.69 mmol (79%) of the desired imine were obtained after purification by
column chromatography Hex:EtOAc (10:1) as an orange oil.
Spectroscopic data for the titled compound are consistent with the literature.20
1H NMR (400 MHz, CDCl3) δ: 7.53 – 7.50 (m, 2H), 7.45 – 7.35 (m, 2H), 7.15 (dt, J = 4.5, 2.5
Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 6.56 (dt, J = 16.2, 11.5 Hz, 1H),
4.22 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H).
Ethyl (E)-3-chloro-3,3-difluoro-2-[(4-methoxyphenyl)imino]propanoate (1h). Following
general procedure C, from 11 mmol of the corresponding carboxylic acid and 13.2 mmol of p-
anysidine, 9.79 mmol (89%) of the desired imine were obtained after purification by column
chromatography Hex:EtOAc (10:1) as a brownish oil.
Spectroscopic data for the titled compound are consistent with the literature.18
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1H NMR (300 MHz, CDCl3) δ: 7.02 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 4.25 (q, J =
7.2 Hz, 2H), 3.82 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H).
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(E)-2,2,2-trifluoro-N-(4-methoxyphenyl)-1-(5-methylfuran-2-yl)ethan-1-imine
(1i).
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Following general procedure A, from 5 mmol of the corresponding iminophosphorane and 5
mmol of the corresponding ketone, 4.45 mmol (89%) of the desired imine were obtained after
purification by distillation under reduced pressure as an orange oil.
1H NMR (300 MHz, CDCl3) δ: 6.90 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 6.31 (d, J =
3.5 Hz, 1H), 5.99 (dd, J = 3.6, 0.9 Hz, 1H), 3.82 (s, 3H), 2.21 (s, 3H).19F NMR (282 MHz,
CDCl3) δ: -69.20 (d, J = 0.5 Hz).13C NMR (75 MHz, CDCl3) δ: 157.5 (s), 156.4 (s), 144.8 (s),
144.4 (s), 142.9 (s), 142.5 (s), 120.7 (s), 120.7 (s), 120.1 (q, J = 278.13), 119.9 (s), 114.8 (s),
108.9 (s), 55.9 (s), 14.0 (s). HRMS (ES) calc. for (M+1) C14H12F3NO2: 284.0893; found:
284.0898.
2,2,2-trifluoro-N-(4-methoxyphenyl)ethan-1-imine (1j). Following general procedure B, from
5 mmol of the corresponding amine 9 and 5 mmol of the corresponding hemiacetal 8, 3.75
mmol (75%) of the desired imine were obtained after purification by distillation under reduced
pressure as pale yellow oil.
Spectroscopic data for the titled compound are consistent with the literature.21
1H NMR (300 MHz, CDCl3) δ: 7.85 (q, J = 3.7 Hz, 1H), 7.31 (d, J = 9.0 Hz, 2H), 6.96 (d, J =
9.0 Hz, 2H), 3.86 (s, 3H).
General procedure for the gold catalysis. To a small vial fitted with a screw cap and a
magnet, 0.1 mmol of the corresponding imine was added with 1 mL of dry DCM and the vial
purged with nitrogen. Then 0.2 mmol of the corresponding furan was added and 5 mol% of
either gold trichloride A or carbene gold (I) catalyst B loaded and the reaction mixture was
stirred overnight at room temperature. Once the reaction time was completed, the mixture was
filtered through a silica pad and the product purified by flash column chromatography.
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Ethyl
(2R*,3aR*,4S*,9bR*)-8-methoxy-2-methyl-2-(5-methylfuran-2-yl)-4-
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(trifluoromethyl)-1,2,3a,4,5,9b-hexa hydrofuro [2,3-c]quinoline-4-carboxylate (3a).
Following the general procedure, from 28 mg of imine 1a, 18 µL of 2-methyl furan and 1.5 mg
of A, 35.5 mg (81%) of the desired product were obtained, after purification by column
chromatography using as eluent a mixture of Hex:DCM:EtOAc (9:0.5:0.1), as a mixture of
diastereoisomers 63:18:4:15. 3a was obtained (22 mg, 51%) as a yellowish oil while the rest of
diastereoisomers eluted together from the column.
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Major diastereoisomer:
1H NMR (300 MHz, CDCl3) δ: 6.69 – 6.68 (m, 3H), 6.01 (d, J = 3.1 Hz, 1H), 5.87 – 5.85 (m,
1H), 4.83 (d, J = 4.8 Hz, 1H), 4.43 (dq, J = 10.7, 7.1 Hz, 1H), 4.29 (dq, J = 10.7, 7.1 Hz, 1H),
3.76 (s, 3H), 3.58 – 3.54 (m, 1H), 2.97 (dd, J = 12.9, 7.5 Hz, 1H), 2.36 (dd, J = 12.9, 1.2 Hz,
1H), 2.28 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.16 (s, 3H). 19F NMR (282 MHz, CDCl3) δ: -74.96
(s). 13C NMR (75 MHz, CDCl3) δ: 166.3 (s), 157.3 (s), 153.2 (s), 151.6 (s), 133.8 (s), 124.1 (q, J
= 293.5 Hz), 123.1 (s), 116.8 (s), 113.8 (s), 113.4 (s), 105.8 (s), 105.1 (s), 79.5 (s), 74.7 (s), 64.4
(q, J = 26.8 Hz), 63.2 (s), 55.8 (s), 45.4 (s), 39.2 (s), 26.9 (s), 13.9 (s), 13.7 (s). HRMS (ES)
calc. for (M+1) C22H24F3NO5: 440.1679; found: 440.1694.
Ethyl
(2R*,3aR*,4S*,9bR*)-2,8-dimethyl-2-(5-methylfuran-2-yl)-4-(trifluoromethyl)-
1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-4-carboxylate (3b). Following the general
procedure, from 26 mg of imine 1b, 18 µL of 2-methyl furan and 1.5 mg of A, 34.3 mg (81%)
of the desired product were obtained, after purification by column chromatography using as
eluent a mixture of Hex:DCM:EtOAc (9:0.5:0.1), as a mixture of diastereoisomers 48:6:12:26:8.
3b was obtained (16 mg, 39%) as a yellowish oil, while the rest of diastereoisomers eluted
together from the column.
Major diastereoisomer:
1H NMR (300 MHz, CDCl3) δ: 6.90 – 6.86 (m, 2H), 6.63 (d, J = 8.0 Hz, 1H), 6.02 (d, J = 3.1
Hz, 1H), 5.87 (dq, J = 3.0, 1.0 Hz, 1H), 4.85 (sa, 1H), 4.83 (s, 1H), 4.44 (dq, J = 10.6, 7.1 Hz,
1H), 4.29 (dq, J = 10.7, 7.1 Hz, 1H), 3.58 – 3.54 (m, 1H), 2.96 (dd, J = 12.9, 7.4 Hz, 1H), 2.38
(dd, J = 12.9, 1.3 Hz, 1H), 2.28 (d, J = 0.9 Hz, 3H), 2.25 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.15
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(s, 3H). 19F NMR (282 MHz, CDCl3) δ: -75.03 (s). 13C NMR (75 MHz, CDCl3) δ: 166.3 (s),
157.5 (s), 151.5 (s), 137.4 (s), 128.9 (s), 128.4 (s), 128.1 (s), 124.2 (q, J = 290.1 Hz), 121.6 (s),
115.5 (s), 105.8 (s), 105.0 (s), 79.6 (s), 74.8 (s), 64.3 (q, J = 26.7 Hz), 63.1 (s), 45.4 (s), 38.9 (s),
26.9 (s), 20.8 (s), 13.9 (s), 13.7 (s). HRMS (ES) calc. for (M+1) C22H24F3NO4: 424.1730; found:
424.1746.
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Ethyl
(2R*,3aR*,4S*,9bR*)-2-methyl-2-(5-methylfuran-2-yl)-4-(trifluoromethyl)-
1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-4-carboxylate (3c). Following the general
procedure, from 25 mg of imine 1c, 18 µL of 2-methyl furan and 1.5 mg of A, 33.5 mg (82%) of
the desired product were obtained, after purification by column chromatography using as eluent
a mixture of Hex:DCM:EtOAc (9:0.5:0.1), as a mixture of diastereoisomers 52:9:28:5:6. 3c was
obtained (17 mg, 42%) as a yellowish oil, while the rest of diastereoisomers eluted together
from the column.
Major diastereoisomer:
1H NMR (300 MHz, CDCl3) δ: 7.12 – 7.04 (m, 2H), 6.79 (td, J = 7.5, 1.2 Hz, 1H), 6.71 (dd, J =
8.0, 1.0 Hz, 1H), 6.02 (d, J = 3.0 Hz, 1H), 5.87 (dd, J = 3.0, 1.0 Hz, 1H), 4.96 (s, 1H), 4.86 (dd,
J = 4.8, 1 Hz, 1H), 4.44 (dq, J = 10.8, 7.1 Hz, 1H), 4.30 (dq, J = 10.8, 7.1 Hz, 1H), 3.61 – 3.57
(m, 1H), 2.98 (dd, J = 12.9, 7.4 Hz, 1H), 2.39 (dd, J = 12.9, 1.1 Hz, 1H), 2.28 (d, J = 1 Hz, 3H),
1.27 (t, J = 7.1 Hz, 3H), 1.13 (s, 3H). 19F NMR (282 MHz, CDCl3) δ: -75.12 (s). 13C NMR (75
MHz, CDCl3) δ: 166.2 (s), 157.4 (s), 151.6 (s), 139.9 (s), 128.6 (s), 127.4 (s), 124.1 (q, J =
295.4 Hz), 121.6 (s), 119.3. (s), 115.4 (s), 105.8 (s), 105.0 (s), 79.6 (s), 74.7 (s), 64.1 (q, J =
26.5 Hz) 63.2 (s), 45.4 (s), 38.9 (s), 26.9 (s), 13.9 (s), 13.7 (s). HRMS (ES) calc. for (M+1)
C21H22F3NO4: 410.1574; found: 410.1585.
Ethyl
(3aR*,11S*,11aR*)-2-methyl-2-(5-methylfuran-2-yl)-11-(trifluoromethyl)-
2,3,3a,10,11,11a-hexahydrobenzo[h]furo[2,3-c]quinoline-11-carboxylate (3d). Following the
general procedure, from 29.5 mg of imine 1d, 18 µL of 2-methyl furan and 3 mg of B, 37.4 mg
(85%) of the desired product were obtained, after purification by column chromatography using
as eluent a mixture of Hex:DCM:EtOAc (9:0.5:0.1), as a mixture of diastereoisomers
48:21:13:3:15. 3d was obtained (18 mg, 40%) as a brownish oil together with other unseparable
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diastereoisomer in 3:1 ratio, while the rest of diastereoisomers eluted together from the column.
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Major diastereoisomers mixture (3:1):
1H NMR (300 MHz, CDCl3) δ: 8.04 (dd, J = 8.2, 0.9 Hz, 1H), 7.95 (dd, J = 8.2, 1.1 Hz, 0.3H),
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(d, J = 10.3 Hz, 1.3H), 7.13 (d, J = 8.5 Hz, 0.3H), 6.02 (d, J = 3.0 Hz, 1H), 5.87 (dq, J = 3.0, 1.0
Hz, 1H), 5.56 (s, 1H), 5.48 (d, J = 3.0 Hz, 0.3H), 5.44 (s, 0.3H), 5.24 (dq, J = 3.0, 1.0 Hz, 0.3H),
4.96 (d, J = 4.8 Hz, 1.3H), 4.55 – 4.31 (m, 2.6H), 3.77 – 3.73 (m, 1.3H), 3.05 (dd, J = 13.0, 7.5
Hz, 1H), 2.87 (dd, J = 13.0, 0.6 Hz, 0.3H), 2.58 (dd, J = 13.0, 7.5 Hz, 0.3H), 2.49 (dd, J = 13.0,
0.6 Hz, 1H), 2.29 (d, J = 0.9 Hz, 3H), 1.64 (d, J = 0.9 Hz, 1H), 1.55 (s, 1H), 1.40 (t, J = 7.1 Hz,
1H), 1.31 (t, J = 7.1 Hz, 3H), 1.05 (s, 3H).19F NMR (282 MHz, CDCl3) δ: -74.91 (s), -75.05
(s).13C NMR (126 MHz, CDCl3) δ: 166.3 (s), 166.3 (s), 157.3 (s), 155.6 (s), 151.4 (s), 150.1 (s),
134.6 (s), 134.3 (s), 133.0 (s), 132.9 (s), 128.3 (s), 128.1 (s), 126.3 (s), 126.2 (s), 125.7 (s),
125.5 (s), 125.3 (s), 125.1 (s),123.9 (q, J = 288.2 Hz), 123.8 (s), 120.6 (s), 120.4 (s), 119.7 (s),
119.2 (s), 116.2 (s), 116.0 (s), 105.7 (s), 105.4 (s), 104.9 (s), 104.7 (s), 79.8 (s), 79.6 (s), 74.4
(s), 64.1 (q, J = 27.1 Hz), 63.3 (s), 46.1 (s), 44.8 (s), 39.8 (s), 39.3 (s), 31.6 (s), 27.1 (s), 26.8 (s),
22.7 (s), 14.1 (s), 14.0 (s), 13.8 (s), 13.6 (s), 12.7 (s). HRMS (ES) calc. for (M+MeOH)
C25H24F3NO4: 492.1992; found: 492.1999.
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Ethyl
(2S*,3aS*,4R*,9bS*)-4-[difluoro(phenyl)methyl]-8-methoxy-2-methyl-2-(5-
(3f).
methylfuran-2-yl)-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-4-carboxylate
Following the general procedure, from 33 mg of imine 1f, 18 µL of 2-methyl furan and 3 mg of
B, 41.7 mg (84%) of the desired product were obtained, after purification by column
chromatography using as eluent a mixture of Hex:DCM:EtOAc (9:0.5:0.1), as a mixture of
diastereoisomers 55:4:27:14. 3f was obtained (23 mg, 46%) as a yellowish oil, while the rest of
diastereoisomers eluted together from the column.
Major diastereoisomer:
1H NMR (400 MHz, CDCl3) δ: 7.45 – 7.35 (m, 5H), 6.72 – 6.69 (m, 2H), 6.64 (d, J = 9.4 Hz,
1H), 6.04 (d, J = 3.0 Hz, 1H), 5.89 – 5.88 (m, 1H), 5.11 (d, J = 4.8 Hz, 1H), 4.50 (bs, 1H), 4.33
(dq, J = 10.7, 7.1 Hz, 1H), 4.12 (dq, J = 10.7, 7.1 Hz, 1H), 3.79 (s, 3H), 3.74 – 3.72 (m, 1H),
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3.01 (dd, J = 12.9, 7.6 Hz, 1H), 2.39 (dd, J = 12.9, 0.8 Hz, 1H), 2.30 (d, J = 0.7 Hz, 3H), 1.24 (t,
J = 7.1 Hz, 3H), 1.17 (s, 3H).19F NMR (282 MHz, CDCl3) δ: -103.19 (d, J = 37.2 Hz).13C NMR
(126 MHz, CDCl3) δ: 167.0 (s), 156.8 (s), 151.6 (s), 150.2 (s), 133.5 (s), 132.5 (t, J = 26.0 Hz),
129.2 (s), 126.8 (s), 125.4 (t, J = 6.3 Hz), 123.0 (s), 119.9 (t, J = 233.4 Hz), 115.2 (s), 112.8 (s),
111.9 (s), 104.6 (s), 103.6 (s), 77.9 (s), 74.1 (s), 65.4 (t, J = 26.8 Hz), 61.3 (s), 54.7 (s), 44.5 (s),
38.7 (s), 26.0 (s), 12.8 (s), 12.6 (s). HRMS (ES) calc. for (M+1) C28H29F2NO5: 498.2087; found:
498.2096.
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Ethyl
(2S*,3aS*,4R*,9bS*)-4-[(E)-1,1-difluoro-3-phenylallyl]-8-methoxy-2-methyl-2-(5-
(3g).
methylfuran-2-yl)-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-4-carboxylate
Following the general procedure, from 36 mg of imine 1g, 18 µL of 2-methyl furan and 1.5 mg
of A, 41.3 mg (79%) of the desired product were obtained, after purification by column
chromatography using as eluent a mixture of Hex:DCM:EtOAc (9:0.5:0.1), as a mixture of
diastereoisomers 45:17:15:4:19. 3g was obtained (23 mg, 36%) as a yellowish oil, while the rest
of diastereoisomers eluted together from the column.
Major diastereoisomer:
1H NMR (500 MHz, CDCl3) δ: 7.24 – 7.21 (m, 3H), 7.15 (dd, J = 6.9, 2.7 Hz, 2H), 6.83 (dd, J =
16.1, 2.2 Hz, 1H), 6.63 (d, J = 1.5 Hz, 2H), 6.55 (s, 1H), 6.11 (dt, J = 16.1, 12.1 Hz, 1H), 5.93
(d, J = 3.0 Hz, 1H), 5.78 – 5.77 (m, 1H), 4.79 (d, J = 4.8 Hz, 1H), 4.74 (s, 1H), 4.33 (dq, J =
10.7, 7.1 Hz, 1H), 4.19 (dq, J = 10.7, 7.1 Hz, 1H), 3.67 (s, 3H), 3.45 (dd, J = 6.3, 5.6 Hz, 1H),
2.85 (dd, J = 12.9, 7.6 Hz, 1H), 2.24 (dd, J = 12.9, 1.1 Hz, 1H), 2.19 (d, J = 0.8 Hz, 3H), 1.20 (t,
J = 7.1 Hz, 3H), 1.08 (s, 3H).19F NMR (282 MHz, CDCl3) δ: -103.00 (ddd, J = 246.1, 11.6, 2.3
Hz, 1F), -105.88 (dd, J = 242.1, 12.4 Hz, 1F).13C NMR (126 MHz, CDCl3) δ: 168.3 (s), 157.7
(s), 152.8 (s), 151.3 (s), 135.1 (t, J = 9.5 Hz), 134.9 (s), 134.8 (s), 129.1 (s), 128.7 (s), 127.3 (s),
123.6 (s), 120.3 (t, J = 254.4 Hz), 120.0 (t, J = 24.4 Hz), 116.6 (s), 113.7 (s), 113.4 (s), 105.6
(s), 104.6 (s), 78.9 (s), 75.2 (s), 66.4 (t, J = 26.2 Hz), 62.4 (s), 55.8 (s), 45.5 (s), 39.3 (s), 27.0
(s), 13.9 (s), 13.6 (s). HRMS (ES) calc. for (M+1) C30H31F2NO5: 524.2243; found: 524.2246.
Ethyl
(2S*,3aS*,4R*,9bS*)-4-(chlorodifluoromethyl)-8-methoxy-2-methyl-2-(5-
methylfuran-2-yl)-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-4-carboxylate
(3h).
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Following the general procedure, from 29 mg of imine 1h, 18 µL of 2-methyl furan and 3 mg of
B, 34.1 mg (75%) of the desired product were obtained, after purification by column
chromatography using as eluent a mixture of Hex:DCM:EtOAc (9:0.5:0.2), as a mixture of
diastereoisomers 59:22:5:14. 3h was obtained (20 mg, 44%) as a brownish oil, while the rest of
diastereoisomers eluted together from the column.
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Major diastereoisomer:
1H NMR (300 MHz, CDCl3) δ: 6.71 – 6.69 (m, 3H), 6.03 (d, J = 3.0 Hz, 1H), 5.88 (dd, J = 3.0,
1.0 Hz, 1H), 4.92 (d, J = 3.8 Hz, 2H), 4.45 (dq, J = 10.7, 7.1 Hz, 1H), 4.31 (dq, J = 10.7, 7.1 Hz,
1H), 3.78 (s, 3H), 3.64 – 3.57 (m, 1H), 2.99 (dd, J = 12.9, 7.5 Hz, 1H), 2.39 (dd, J = 12.9, 0.9
Hz, 1H), 2.30 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.18 (s, 3H).19F NMR (282 MHz, CDCl3) δ: -
58.98 (d, J = 158.8 Hz, 1F), -60.78 (dd, J = 158.8, 2.1 Hz, 1F).13C NMR (126 MHz, CDCl3) δ:
166.5 (s), 157.3 (s), 152.9 (s), 151.4 (s), 133.7 (s), 129.3 (dd, J = 311.1, 305.5 Hz), 122.9 (s),
116.4 (s), 113.7 (s), 113.2 (s), 105.7 (s), 104.9 (s), 79.3 (s), 74.7 (s), 68.5 (t, J = 22.6 Hz), 63.0
(s), 55.7 (s), 45.3 (s), 39.2 (s), 26.8 (s), 13.8 (s), 13.6 (s). HRMS (ES) calc. for (M+1)
C22H24ClF2NO5: 456.1384; found: 456.1390.
(2R*,3aR*,4S*,9bR*)-8-methoxy-2-methyl-2,4-bis(5-methylfuran-2-yl)-4-
(trifluoromethyl)-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline (3i). Following the general
procedure, from 28 mg of imine 1k, 21 µL of 2-ethyl furan and 1.5 mg of B, 34.9 mg (78%) of
the desired product were obtained, after purification by column chromatography using as eluent
a mixture of Hex:DCM:EtOAc (9:0.5:0.2), as a mixture of diastereoisomers 79:4:11:3:3. 3i was
obtained (28 mg, 61%) as a yellowish oil, while the rest of diastereoisomers eluted together
from the column.
Major diastereoisomer:
1H NMR (500 MHz, CDCl3) δ: 6.67 (d, J = 8.7 Hz, 1H), 6.59 (dd, J = 8.7, 2.4 Hz, 1H), 6.47 (d,
J = 2.4 Hz, 1H), 6.10 (d, J = 3.2 Hz, 1H), 6.05 (d, J = 3.0 Hz, 1H), 5.83 (dd, J = 3.0, 1.0 Hz,
1H), 5.78 (dd, J = 3.2, 1.0 Hz, 1H), 4.90 (d, J = 5.8 Hz, 1H), 4.20 (bs, 1H), 3.66 (s, 3H), 3.32 –
3.28 (m, 1H), 2.85 (dd, J = 12.8, 8.2 Hz, 1H), 2.23 (d, J = 0.8 Hz, 3H), 2.15 (d, J = 0.7 Hz, 3H),
2.07 (dd, J = 12.8, 3.3 Hz, 1H), 1.29 (s, 3H).19F NMR (282 MHz, CDCl3) δ: -74.13 (s).13C NMR
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(126 MHz, CDCl3) δ: 156.2 (s), 152.8 (s), 151.9 (s), 150.4 (s), 147.0 (s), 133.1 (s), 125.3 (s),
123.5 (q, J = 286.4 Hz), 116.7 (s), 112.7 (s), 111.9 (s), 109.9 (s), 105.5 (s), 104.9 (s), 104.1 (s),
80.0 (s), 60.6 (q, J = 27.7 Hz), 54.5 (s), 43.6 (s), 39.2 (s), 29.9 (s), 25.8 (s), 12.7 (s), 12.6 (s).
HRMS (ES) calc. for (M+1) C24H24F3NO4: 448.1730; found: 448.1740.
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Ethyl (2R*,3aR*,4S*,9bR*)-2-ethyl-2-(5-ethylfuran-2-yl)-8-methoxy-4-(trifluoromethyl)-
1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-4-carboxylate (3j). Following the general
procedure, from 28 mg of imine 1a, 21 µL of 2-ethyl furan and 1.5 mg of A, 39.7 mg (85%) of
the desired product were obtained, after purification by column chromatography using as eluent
a mixture of Hex:DCM:EtOAc (9:0.5:0.2), as a mixture of diastereoisomers 45:24:10:12:9. 3j
was obtained (18 mg, 38%) as a yellowish oil, while the rest of diastereoisomers eluted together
from the column.
Major diastereoisomer:
1H NMR (300 MHz, CDCl3) δ: 6.67 – 6.62 (m, 3H), 6.06 (d, J = 3.1 Hz, 1H), 5.89 (dt, J = 3.1,
1.0 Hz, 1H), 4.74 (sa, 1H), 4.73 (s, 1H), 4.42 (ddd, J = 12.6, 8.1, 4.5 Hz, 1H), 4.38 – 4.30 (m,
1H), 3.75 (s, 3H), 3.55 – 3.51 (m, 1H), 2.90 (dd, J = 13.0, 8.0 Hz, 1H), 2.62 (q, J = 7.6 Hz, 2H),
2.35 (dd, J = 13.0, 1.7 Hz, 1H), 1.48 (q, J = 7.4 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.6
Hz, 3H), 0.52 (t, J = 7.4 Hz, 3H). 19F NMR (282 MHz, CDCl3) δ: -74.92 (s). 13C NMR (75
MHz, CDCl3) δ: 166.3 (s), 157.3 (s), 155.8 (s), 153.3 (s), 133.7 (s),124.2 (q, J = 290.1 Hz),
123.6 (s), 116.8 (s), 113.8 (s), 113.4 (s), 105.7 (s), 104.1 (s), 83.5 (s), 74.2 (s),64.5 (q, J = 26.7
Hz), 63.2 (s), 55.8 (s), 44.0 (s), 38.9 (s), 32.8 (s), 21.6 (s), 14.0 (s), 12.3 (s), 8.7 (s). HRMS (ES)
calc. for (M+1) C24H28F3NO5: 468.1992; found: 468.2017.
Ethyl
(2R*,3aR*,4S*,9bR*)-2-ethyl-2-(5-ethylfuran-2-yl)-8-methyl-4-(trifluoromethyl)-
1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-4-carboxylate (3k). Following the general
procedure, from 26 mg of imine 1b, 21 µL of 2-ethyl furan and 1.5 mg of A, 37.0 mg (82%) of
the desired product were obtained, after purification by column chromatography using as eluent
a mixture of Hex:DCM:EtOAc (9:0.5:0.2), as a mixture of diastereoisomers 46:7:21:10:5:11. 3k
was obtained (17 mg, 38%) as a yellowish oil, while the rest of diastereoisomers eluted together
from the column.
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Major diastereoisomer:
1H NMR (300 MHz, CDCl3) δ: 6.80 – 6.77 (m, 2H), 6.53 (d, J = 8.7 Hz, 1H), 5.98 (d, J = 3.1
Hz, 1H), 5.81 (dt, J = 3.1, 1.0 Hz, 1H), 4.73 (sa, 1H), 4.67 (d, J = 5.2 Hz, 1H), 4.36 (dq, J =
10.7, 7.1 Hz, 1H), 4.26 (dq, J = 10.7, 7.1 Hz, 1H), 3.47 – 3.43 (m, 1H), 2.81 (dd, J = 13.0, 8.0
Hz, 1H), 2.54 (qd, J = 7.5, 0.9 Hz, 1H), 2.28 (dd, J = 13.0, 1.7 Hz, 1H), 2.17 (s, 3H), 1.40 (q, J
= 7.4 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.6 Hz, 3H), 0.44 (t, J = 7.4 Hz, 3H). 19F
NMR (282 MHz, CDCl3) δ: -74.99 (s). 13C NMR (75 MHz, CDCl3) δ: 166.3 (s), 157.3 (s), 155.9
(s), 137.3 (s), 128.9 (s), 128.5 (s), 128.0 (s), 124.2 (q, J = 290.3 Hz), 122.2 (s), 115.5 (s), 105.6
(s), 104.1 (s), 83.5 (s), 74.2 (s), 64.4 (q, J = 26.86 Hz), 63.2 (s), 44.0 (s), 38.5 (s), 32.8 (s), 21.6
(s), 20.8 (s), 14.0 (s), 12.3 (s), 8.7 (s). HRMS (ES) calc. for (M+1) C24H28F3NO4: 452.2043;
found: 452.2067.
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Ethyl (2R*,3aR*,4S*,9bR*)-2-ethyl-2-(5-ethylfuran-2-yl)-4-(trifluoromethyl)-1,2,3a,4,5,9b-
hexahydrofuro[2,3-c]quinoline-4-carboxylate (3l). Following the general procedure, from 25
mg of imine 1c, 21 µL of 2-ethyl furan and 1.5 mg of A, 32.7 mg (75%) of the desired product
were obtained, after purification by column chromatography using as eluent a mixture of
Hex:DCM:EtOAc (9:0.5:0.2), as a mixture of diastereoisomers 42:6:13:26:4:9. 3l was obtained
(14 mg, 32%) as a yellowish oil, while the rest of diastereoisomers eluted together from the
column.
Major diastereoisomer:
1H NMR (300 MHz, CDCl3) δ: 7.08 – 7.03 (m, 2H), 6.78 (td, J = 7.5, 1.1 Hz, 1H), 6.69 (d, J =
8.0 Hz, 1H), 6.06 (d, J = 3.1 Hz, 1H), 5.89 (dt, J = 3.1, 0.9 Hz, 1H), 4.92 (s, 1H), 4.76 (d, J =
4.9 Hz, 1H), 4.44 (dq, J = 10.7, 7.1 Hz, 1H), 4.34 (dq, J = 10.7, 7.1 Hz, 1H), 3.58 – 3.54 (m,
1H), 2.90 (dd, J = 13.0, 7.9 Hz, 1H), 2.62 (qd, J = 7.5, 0.6 Hz, 2H), 2.38 (dd, J = 13.0, 1.5 Hz,
1H), 1.46 (q, J = 7.3 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.5 Hz, 3H), 0.50 (t, J = 7.5
Hz, 3H). 19F NMR (282 MHz, CDCl3) δ: -75.11 (s). 13C NMR (75 MHz, CDCl3) δ: 166.3 (s),
157.3 (s), 155.9 (s), 139.7 (s), 128.6 (s), 127.3 (s), 124.1 (q, J = 290.0 Hz), 121.1 (s), 119.3 (s),
115.3 (s), 105.7 (s), 104.1 (s), 83.5 (s), 74.1 (s), 64.2 (q, J = 27.68 Hz), 63.2 (s), 43.8 (s), 38.5
(s), 32.8 (s), 21.6 (s), 14.0 (s), 12.3 (s), 8.7 (s). HRMS (ES) calc. for (M+1) C23H26F3NO4:
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438.1887; found: 438.1906.
Ethyl (2R*,3aR*,4S*,9bS*)-2-(4,5-dimethylfuran-2-yl)-8-methoxy-1,2-dimethyl-4-
(trifluoromethyl)-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-4-carboxylate (3m).
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mg of B, 38.3 mg (82%) of the desired product were obtained, after purification by column
chromatography using as eluent a mixture of Hex:DCM:EtOAc (9:0.5:0.1), as a mixture of
diastereoisomers 46:25:14:12:3. 3m was obtained (17 mg, 37%) as a brownish oil together with
other unseparable diastereoisomer in 3:1 ratio, while the rest of diastereoisomers eluted together
from the column.
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Major diastereoisomers mixture (3:1):
1H NMR (300 MHz, CDCl3) δ: 6.73 – 6.56 (m, 2.6H), 6.53 (d, J = 2.5 Hz, 1H), 6.49 (d, J = 2.6
Hz, 0.3H), 5.94 (sa, 0.3H), 5.93 (sa, 1H), 5.21 (d, J = 8.4 Hz, 0.3H), 5.16 (d, J = 6.2 Hz, 1H),
4.12 – 3.92 (m, 2.6H), 3.68 (s, 3H), 3.67 (s, 1H), 3.49 – 3.40 (m, 1.3H), 3.11 – 2.95 (m, 1.3H),
2.12 (s, 3H), 2.02 (s, 1H), 1.83 (s, 3H), 1.76 (s, 1H), 1.20 – 0.90 (m, 13.3H). 19F NMR (282
MHz, CDCl3) δ: -70.73 (s, 1F), -71.99 (s, 3F). 13C NMR (126 MHz, CDCl3) δ: 168.2 (s), 168.0
(s), 155.3 (s), 154.2 (s), 153.8 (s), 153.3 (s), 146.8 (s), 146.4 (s), 136.5 (s), 135.8 (s), 125.6 (q, J
= 245.3 Hz), 122.3 (s), 121.2 (q, J = 268.9 Hz), 118.6 (s), 118.4 (s), 115.5 (s), 114.4 (s), 113.6
(s), 113.6 (s), 112.9 (s), 109.1 (s), 108.7 (s), 83.4 (s), 83.2 (s), 70.2 (q, J = 26.3 Hz), 68.7 (q, J =
27.0 Hz), 62.8 (s), 62.7 (s), 55.7 (s), 55.7 (s), 50.2 (s), 47.9 (s), 44.9 (s), 43.4 (s), 31.7 (s), 31.1
(s), 21.2 (s), 19.1 (s), 14.3 (s), 13.9 (s), 13.9 (s), 13.7 (s), 12.4 (s), 11.6 (s), 11.4 (s), 10.0 (s),
10.0 (s). HRMS (ES) calc. for (M+1) C24H28 F3NO5: 468.1992; found: 468.1991.
Ethyl
(2S*,3aR*,4S*,9bR*)-8-methoxy-2-phenyl-2-(5-phenylfuran-2-yl)-4-
(3n).
(trifluoromethyl)-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-4-carboxylate
Following the general procedure, from 28 mg of imine 1a, 24 µL of 2-phenyl furan22 and 3 mg
of B, 28.4 mg (56%) of the desired product were obtained, after purification by column
chromatography using as eluent a mixture of Hex:DCM:EtOAc (9:0.5:0.2), as a mixture of
diastereoisomers 71:22:7. 3n was obtained (20.2 mg, 40%) as a colorless oil together with other
unseparable diastereoisomer in 1:0.8 ratio, while the rest of diastereoisomers eluted together
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Major diastereoisomers mixture (1:0.8):
1H NMR (500 MHz, CDCl3) δ: 7.69 – 7.66 (m, 1.8H), 7.52 – 7.50 (m, 1.8H), 7.43 – 7.38 (m,
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3.6H), 7.35 – 7.30 (m, 1.6H), 7.27 – 7.16 (m, 5.6H), 7.11 – 7.06 (m, 2.6H), 6.74 – 6.64 (m,
3.6H), 6.59 – 6.47 (m, 3.6H), 6.25 (d, J = 3.3 Hz, 1H), 6.09 (d, J = 3.3 Hz, 0.8H), 5.71 (d, J =
3.4 Hz, 1H), 5.09 (d, J = 5.3 Hz, 0.8H), 4.92 (d, J = 4.8 Hz, 1H), 4.82 (br s, 0.8H), 4.80 (br s,
1H), 4.56 – 4.33 (m, 3.6H), 3.75 – 3.69 (m, 1.8H), 3.64 (s, 3H), 3.63 (s, 2.6H), 3.52 (dd, J =
12.9, 7.4 Hz, 0.8H), 3.45 (dd, J = 13.0, 0.9 Hz, 1H), 3.07 (dd, J = 13.0, 7.5 Hz, 1H), 2.86 (dd, J
= 12.9, 2.1 Hz, 0.8H), 1.49 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 2.6H).19F NMR (282 MHz,
CDCl3) δ: -74.68 (s), -74.98 (s).13C NMR (126 MHz, CDCl3) δ: 166.4 (s), 166.2 (s), 157.1 (s),
155.8 (s), 154.0 (s), 153.4 (s), 153.3 (s), 153.1 (s), 144.9 (s), 143.2 (s), 133.9 (s), 133.8 (s),
130.9 (s), 130.8 (s), 128.9 (s), 128.8 (s), 128.5 (s), 128.4 (s), 127.6 (s), 127.6 (s), 127.5 (s),
127.1 (s), 127.0 (s), 126.3 (q, J = 226.8 Hz), 125.6 (s), 125.3 (s), 124.2 (q, J = 239.4 Hz), 124.2
(s), 123.8 (s), 123.7 (s), 122.4 (s), 122.1 (s), 116.9 (s), 116.6 (s), 113.9 (s), 113.7 (s), 113.6 (s),
109.7 (s), 109.7 (s), 105.6 (s), 105.4 (s), 83.5 (s), 83.5 (s), 75.4 (s), 75.1 (s), 64.6 (q, J = 27.4
Hz), 64.4 (q, J = 25.9 Hz), 63.5 (s), 63.4 (s), 56.0 (s), 55.7 (s), 47.6 (s), 47.0 (s), 39.9 (s), 39.1
(s), 31.7 (s), 29.9 (s), 22.8 (s), 14.3 (s), 14.2 (s), 14.0 (s). HRMS (ES) calc. for (M+1)
C32H28F3NO5: 564.1920; found: 564.1901.
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Ethyl (2R*,3aR*,4S*,9bR*)-8-methoxy-2-(thiophen-2-yl)-2-[5-(thiophen-2-yl)furan-2-yl]-4-
(trifluoromethyl)-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-4-carboxylate
(3o).
Following the general procedure, from 28 mg of imine 1a, 24 µL of 2-(2-thienyl) furan and 3
mg of B, 26.4 mg (51%) of the desired product were obtained, after purification by column
chromatography using as eluent a mixture of Hex:DCM:EtOAc (9:0.5:0.2), as a mixture of
diastereoisomers 57:18:11:14. 3o was obtained (15 mg, 29%) as a yellowish oil, while the rest
of diastereoisomers eluted together from the column
Major diastereoisomer:
1H NMR (300 MHz, CDCl3) δ: 7.25 – 7.23 (m, 1H), 7.13 (dd, J = 4.9, 1.3 Hz, 1H), 6.97 – 6.90
(m, 4H), 6.60 (br s, 1H), 6.56 (d, J = 1.6 Hz, 2H), 6.05 (d, J = 3.4 Hz, 1H), 5.86 (d, J = 3.4 Hz,
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1H), 5.04 (d, J = 5.1 Hz, 1H), 4.75 (br s, 1H), 4.46 (qd, J = 7.1, 0.9 Hz, 1H), 3.71 (t, J = 5.8 Hz,
1H), 3.58 (s, 3H), 3.35 (dd, J = 12.9, 1.2 Hz, 1H), 3.09 (dd, J = 12.9, 7.1 Hz, 1H), 1.41 (t, J =
7.1 Hz, 3H).19F NMR (282 MHz, CDCl3) δ: -74.89 (s).13C NMR (75 MHz, CDCl3) δ: 166.1 (s),
154.4 (s), 153.3 (s), 149.2 (s), 148.6 (s), 133.8 (s), 133.7 (s), 127.5 (s), 127.0 (s), 124.7 (s),
124.3 (s), 124.1 (q, J = 290.5 Hz), 123.9 (s), 122.6 (s), 121.6 (s), 116.7 (s), 113.9 (s), 113.4 (s),
108.8 (s), 105.7 (s), 82.1 (s), 75.7 (s), 64.4 (q, J = 26.9 Hz), 63.5 (s), 55.7 (s), 48.1 (s), 39.7 (s),
14.2 (s). HRMS (ES) calc. for (M+1) C28H24F3NO5S2: 576.1121; found: 576.1096.
Ethyl 3,3,3-trifluoro-2-[(4-methoxyphenyl)amino]-2-(5-methylfuran-2-yl)propanoate (4a).
Following the general procedure, from 28 mg of imine 1a, 18 µL of 2-methyl furan and 2 µL of
trifuoroacetic acid, 31.1 mg (86%) of the monoaddition product were obtained, after purification
by column chromatography using as eluent a mixture of Hex:DCM:EtOAc (9:0.5:0.2) as a
yellowish oil.
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1H NMR (300 MHz, CDCl3) δ: 6.60 – 6.55 (m, 2H), 6.52 – 6.47 (m, 2H), 6.37 (dd, J = 3.0, 0.9
Hz, 1H), 5.87 (dq, J = 3.1, 0.9 Hz, 1H), 4.77 (br s, 1H), 4.30 – 4.19 (m, 2H), 3.63 (s, 3H), 2.13
(d, J = 0.7 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H).19F NMR (282 MHz, CDCl3) δ: -71.88 (s).13C NMR
(75 MHz, CDCl3) δ: 166.9 (s), 154.9 (s), 153.6 (s), 143.4 (s), 137.1 (s), 124.0 (q, J = 288.4 Hz),
121.3 (s), 121.3 (s), 114.3 (s), 113.2 (s), 113.2 (s), 107.0 (s), 68.8 (q, J = 28.5 Hz), 64.0 (s), 55.8
(s), 14.2 (s), 13.8 (s). HRMS (ES) calc. for (M+1) C17H18F3NO4: 358.1261; found: 358.1270.
Ethyl 2-(5-benzylfuran-2-yl)-3,3,3-trifluoro-2-[(4-methoxyphenyl)amino]propanoate (4b).
Following the general procedure, from 28 mg of imine 1a, 29 µL of 2-benzyl furan and 1.5 mg
of SIPrAuOTf, 26.4 mg (61%) of the monoaddition product were obtained, after purification by
column chromatography using as eluent a mixture of Hex:DCM:EtOAc (9:0.5:0.2) as a
brownwish oil.
1H NMR (300 MHz, CDCl3) δ: 7.25 – 7.18 (m, 3H), 7.04 – 7.01 (m, 2H), 6.63 – 6.55 (m, 4H),
6.49 (dd, J = 3.2, 1.2 Hz, 1H), 5.98 (dt, J = 3.3, 0.8 Hz, 1H), 4.90 (bs, 1H), 4.34 – 4.22 (m, 2H),
3.85 (s, 2H), 3.71 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H).19F NMR (282 MHz, CDCl3) δ: -71.99 (s).13C
NMR (126 MHz, CDCl3) δ: 166.5 (s), 155.5 (s), 154.6 (s), 143.6 (s), 137.7 (s), 136.6 (s), 128.4
(s), 126.4 (s), 123.6 (q, J = 288.0 Hz), 121.1 (s), 113.9 (s), 113.0 (s), 107.3 (s), 68.5 (q, J = 28.7
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Hz), 63.7 (s), 55.4 (s), 34.2 (s), 13.7 (s). HRMS (ES) calc. for (M+1) C23H22F3NO4: 434.1574;
found: 434.1580.
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4-methoxy-N-[2,2,2-trifluoro-1-(5-methylfuran-2-yl)ethyl]aniline (4c). Following the general
procedure, from 20 mg of imine 1j, 18 µL of 2-methyl furan and 1.5 mg of gold (III)
tetrachloride, 24.5 mg (86%) of the monoaddition product were obtained, after purification by
column chromatography using as eluent a mixture of Hex:DCM:EtOAc (9:0.5:0.2) as a
colourless oil.
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1H NMR (300 MHz, CDCl3) δ: 6.74 – 6.68 (m, 2H), 6.64 – 6.58 (m, 2H), 6.21 (d, J = 3.2 Hz,
1H), 5.88 – 5.86 (m, 1H), 4.77 (q, J = 7.0 Hz, 1H), 3.67 (s, 3H), 2.21 (s, 3H).19F NMR (282
MHz, CDCl3) δ: -74.99 (d, J = 7.0 Hz).13C NMR (75 MHz, CDCl3) δ: 154.0 (s), 153.5 (s), 145.6
(s), 139.8 (s), 124.8 (q, J = 282.6 Hz), 116.4 (s), 116.4 (s), 115.2 (s), 110.7 (s), 107.0 (s), 56.7
(q, J = 32.1 Hz), 56.0 (s), 13.9 (s). HRMS (ES) calc. for (M+1) C14H14F3NO2: 286.1049; found:
286.1054.
Ethyl 3,3,3-trifluoro-2-methoxy-2-[(4-methoxyphenyl)amino]propanoate (5a). Following
the general procedure, from 28 mg of imine 1a, 18 µL of 2-methyl furan and 1.5 mg of gold
(III) tetrachloride, 25 mg (82%) of the methanol addition product were obtained, after
purification by column chromatography using as eluent a mixture of Hex:DCM:EtOAc
(9:0.5:0.2).
Spectroscopic data for the titled compound are consistent with the literature.23
1H NMR (300 MHz, CDCl3) δ: 6.91 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 9.1 Hz, 2H), 5.02 (bs, 1H),
4.38 (q, J = 7.1 Hz, 2H), 3.76 (s, 3H), 3.40 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Experimental procedures, characterization of all new compounds, and NMR spectra (1H, 13C,
and 19F) (PDF)
AUTHOR INFORMATION
Corresponding Authors
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*E-mail: santos.fustero@uv.es
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*E-mail: carlos.pozo@uv.es
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully thank the Spanish Ministerio de Economía y Competitividad (CTQ-2013-43310-
P), and Generalitat Valenciana (GV/PrometeoII/2014/073), for financial support. J. M. and A. S.
thank University of Valencia and the Spanish Ministerio de Economía y Competitividad for a
predoctoral fellowship.
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