First aromatic amine organocatalysed activation of α,β-unsaturated ketones

Article abstract of DOI:10.1039/c9nj02392e

This work provides an unprecedented example of a chiral aromatic amine used to activate α,β-unsaturated ketones in asymmetric aminocatalysis. Chiral aromatic diamine VII has been efficiently employed, as a proof of concept, in the Michael addition reaction between benzylideneacetones (1a-f) and coumarins (2a-d). The reaction gives rise to warfarin derivatives 3 with promising results using this family of catalysts for the first time. The additional studies performed supported the bifunctional mode of activation of the chiral catalyst VII and the covalent nature of the interactions between the catalyst VII and benzylideneacetones 1.

Full text of DOI:10.1039/c9nj02392e

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First aromatic amine organocatalysed activation
of a,b-unsaturated ketones†
Cite this:DOI: 10.1039/c9nj02392e
a
a
b
Isaac G. Sonsona,
and Raquel P. Herrera
Eugenia Marques-Lopez,
M. Concepcion Gimeno
´
´
´
a
*
This work provides an unprecedented example of a chiral aromatic amine used to activate a,b-unsaturated
ketones in asymmetric aminocatalysis. Chiral aromatic diamine VII has been efficiently employed, as a
proof of concept, in the Michael addition reaction between benzylideneacetones (1a–f) and coumarins
(2a–d). The reaction gives rise to warfarin derivatives 3 with promising results using this family of catalysts
for the first time. The additional studies performed supported the bifunctional mode of activation of the
chiral catalyst VII and the covalent nature of the interactions between the catalyst VII and benzylideneace-
tones 1.
Received 9th May 2019,
Accepted 13th June 2019
DOI: 10.1039/c9nj02392e
rsc.li/njc
procedures have been reported.6 Among the organocatalytic
approaches, the first example was reported by Jørgensen’s group
Introduction
After the tragic effects caused by the prescription of thalido- using a chiral imidazolidine organocatalyst following the Michael
mide to pregnant women at the beginning of the 1960s, more addition of cyclic 1,3-dicarbonyl compounds to a,b-unsaturated
efforts have been devoted to the synthesis and commercialisa- enones.7 After this pioneering example, other organocatalytic
tion of single enantiopure pharmaceuticals. The obtainment of procedures were reported with the main aim of obtaining better
a single enantiomer, as an optically active drug, is becoming results for the enantiopure products. Some of these organocatalytic
progressively more vital for the treatment of many diseases. approaches have been developed using aliphatic amines as
To achieve this pivotal goal, asymmetric catalysis has been catalysts.8 It is important to cite some of these pioneering examples
employed as a powerful tool to develop new reactions affording using aliphatic primary chiral amines such as those reported by
enantioenriched compounds.1 In this respect, one of the most Chin9 and Chen10 or more recently, by Zlotin’s group.11
important aims of organocatalysis has also been the prepara-
tion of new chiral biologically active compounds or natural organocatalytic reactions has been eclipsed by the corresponding
products.2
chiral aliphatic amines, mainly due to the conjugation between the
In contrast, the use of chiral aromatic amines to promote
Among the plethora of drug-based compounds, warfarin 3a nitrogen lone pair and the aromatic ring. Consequently, this con-
is one of the most widely used anticoagulants due to its jugation is responsible for their less nucleophilic behavior in
advantages such as oral administration, low price and perma- comparison with aliphatic amines.12 In fact, there are scarce organo-
nent effect. Like other pharmaceuticals, it is prescribed world- catalytic examples where a chiral aromatic amine promotes the
wide as a racemate. However, it is well-known that the reaction by itself.13,14 In addition to all reported examples for the
anticoagulant activity of the S enantiomer is about 5–8 times preparation of warfarin and its derivatives, to the best of our knowl-
higher than that of the R enantiomer.3 Different catalytic asym- edge there is not any example of a chiral aromatic amine used as an
metric approaches towards the synthesis of optically active organocatalyst for the synthesis of these interesting molecules.
warfarin by means of enzymatic,4 metal based5 or organocatalytic Moreover, none of these previous examples using aromatic amines
was involved in the activation of a,b-unsaturated ketones.
Hence, based on our continuous search for the discovery of
a
´
´
´
´
Departamento de Quımica Organica, Laboratorio de Organocatalisis Asimetrica,
new organocatalysts and catalytic reactions,15 we have studied
this alternative as a totally unexplored approach.
´
´
´
´
Instituto de Sıntesis Quımica y Catalisis Homogenea (ISQCH), (CSIC-Universidad
de Zaragoza), C/Pedro Cerbuna, No. 12, E-50009 Zaragoza, Spain.
E-mail: raquelph@unizar.es
b
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´
´
´
Departamento de Quımica Inorganica Instituto de Sıntesis Quımica y Catalisis
´
Homogenea (ISQCH) (CSIC-Universidad de Zaragoza), C/Pedro Cerbuna, No. 12,
Results and discussion
E-50009 Zaragoza, Spain
† Electronic supplementary information (ESI) available. CCDC 1913255. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9nj02392e
To test the model process depicted in Scheme 1, simple chiral
amine structures, non containing in their skeletons a proline,
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loading, afforded smooth variations in both the yield and
enantioselectivity of the reaction (Table S1, ESI†). In general,
the concentration of the reaction led to better reactivity without
impairing the enantioselectivity of the process (Table S1,
entries 9–12, ESI†). Variations in the amount of coumarin 2a
did not afford an appreciable improvement neither in the
reactivity nor in the enantioselectivity of the process. The
exploration of a vast number of different solvents did not afford
better results in comparison with those obtained with THF
(Table S2, ESI†). With the best reaction conditions in hand
(Table S1, entry 11), the scope of the reaction was explored
for different benzylideneacetones (1a–f) and coumarins (2a–d)
(Table 1).
In all cases, the Michael addition reaction took place
smoothly giving rise to the desired final products 3 with
moderate to good yields and with promising enantioselectivities.
This proof of concept is well accounted for a variety of coumarins
2a–d and benzylideneacetones 1a–f, and the crude products of
Scheme 1 Screening of catalysts in the Michael addition between
4-hydroxycoumarin (2a) and benzylideneacetone (1a).
an amino-cinchona or a DPEN moiety as is usual, were selected the reactions are very clean. Although the values of enantio-
as promising catalysts. Interestingly, these simple amines have selectivity did not show a clear correlation with the electronic
been overlooked so far in the literature for this process.
environment of the reagents, the reactivity suggests a depen-
To our delight, all catalysts, except II, promoted the Michael dence on the electronic environment in the aromatic ring of
addition reaction affording final desired product 3a (Scheme 1). coumarins 2 and benzylideneacetones 1. Therefore, deactivated
Primary amines exhibited higher reactivity in comparison with benzylideneacetones 1e, f (with electron-donating groups) led to
catalyst VII (as expected). Although catalyst VII was not the lower reactivities (entries 5, 10–12). Furthermore, coumarin 2d,
most reactive, it was surprisingly the most enantioselective. with a methyl group, seems to decrease the reactivity of the
To the best of our knowledge this is the first time that this process (entry 8). The absolute configuration was determined to
aromatic amine has been used to activate ketone electrophiles be R by comparison of the optical rotation of products 3a and 3b
in asymmetric aminocatalysis.16 Therefore, with these promis- with those reported in the literature.6b,17 Therefore, the same
ing results of enantioselectivity in hand, a deep exploration of stereochemical outcome was assumed for all products 3.
different parameters, in the previous model reaction, was
carried out using catalyst VII (Tables S1 and S2, ESI†).
Additionally, we have found some inconsistences regarding
the sign of the values previously reported for the optical
The study of the reaction conditions such as the amount of rotation of some of these products. In order to also support
solvent or equivalents of reagents 1a and 2a, and catalyst VII the absolute configuration of our products, single crystals were
Table 1 Scope of the Michael addition reactiona
Entry
R1
R2
Prod.
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
H (1a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
Cl (2b)
Br (2c)
Me (2d)
Br (2c)
Cl (2b)
Cl (2b)
Br (2c)
3a
3b
3c
3d
3e
3f
3g
3h
3i
68
76
85
92
62
57
53
25
25
20
52
40
64
64
66
50
58
67
67
61
62
62
54
54
4-Cl (1b)
4-Br (1c)
4-CN (1d)
4-Me (1e)
H (1a)
H (1a)
H (1a)
4-Cl (1b)
4-Me (1e)
4-OMe (1f)
4-OMe (1f)
9
10
11
12
3j
3k
3l
a
To a mixture of catalyst VII (20 mol%, 0.02 mmol) and coumarins 2a–d (0.2 mmol) in THF (100 ml), benzylideneacetones 1a–f (0.1 mmol) were
b
c
added at room temperature. After isolation by column chromatography. Determined by chiral HPLC analysis.
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Scheme 2 Study of the bifunctional role of the catalyst VII.
In the cationic ESI spectrum recorded directly from the
solution to the gas phase, several important mass peaks related
to some plausible intermediates of the reaction, such as the
imine between catalyst VII and benzylideneacetone 1a (m/z
413.2, Int. 1, and m/z 451.2, Int. 10) were found. The resulting
enamine intermediates (Int. 2 and Int. 3), generated after
Fig. 1 X-ray crystal structure of (R)-3c0.
grown from adduct 3c0 and the stereochemical outcome was coumarin 2a attacks Int. 1, were also found. From this observa-
determined to be also R for this product (Fig. 1).18 It is worth tion, it can be assumed that catalyst VII gives rise an imine with
noting that product 3c was crystallised as its pseudo- benzylideneacetone 1a before the attack of the nucleophile 2a.
diastereomeric hemiketal form 3c0.
It is remarkable that the formation of a diimine intermediate
In order to gain insights into the mode of activation by the with the catalyst (Int. 4) was not observed in the ESI-MS spectrum,
catalyst VII in this Michael reaction, additional experiments which could be due to the formation of an imine with each NH2
were performed. First, ESI-MS analysis was carried out (Fig. 2). group in the catalytic structure, as previously observed20 or
ESI-MS has been considered as an important technique for hypothesised9 by other authors, using primary aliphatic amines.
mechanistic studies of organic reactions.19 The presence of
Furthermore, some additional reactions were also performed
plausible intermediates in the solution of the reaction mixture in order to understand the role of the second NH2 group in the
was analysed directly (VII (20 mol%, 0.02 mmol), coumarin 2a catalyst (Scheme 2).
(0.15 mmol) and benzylideneacetone 1a (0.1 mmol), in THF
(100 ml) at room temperature) (Fig. 2).
Some conclusions could be made from the results shown in
Scheme 2: (1) first, the second NH2 group present in VII could
Fig. 2 Cationic ESI spectrum of the reaction mixture.
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a,b-unsaturated ketones in aminocatalysis. This Michael addi-
tion reaction is efficiently catalysed by the simple diamine
catalyst VII, which can be easily accessed in both enantiomeric
forms from commercially available sources. Final warfarin
derivatives 3 are obtained with good results, as a proof of
concept. The additional ESI-MS and experimental studies per-
formed supported a plausible bifunctional mode of activation
by catalyst VII. The detection of important and crucial inter-
mediates of the reaction strongly supports the role of the
diamine catalyst VII in the activation mechanism via amino-
catalysis. This work contributes to the scarcely developed field
of aromatic amines as organocatalysts and opens a door for
further studies in this area of research.
Fig. 3 Plausible TS to explain the bifunctional role of the catalyst.
not be involved in the generation of a second imine in agreement
with the results found in the ESI-MS analysis (Int. 1 and Int. 10,
Fig. 2). (2) Interestingly, the second NH2 group in catalyst VII could
play an important role in the enantioselection process, since when
catalyst VIII is used, the enantioselectivity dramatically collapses
and a racemic mixture is obtained. (3) The reaction seems to be
mainly activated by an aminocatalytic approach more than hydro-
gen bond activation alone, which agrees with the intermediates
(Int. 1–3) found in the ESI-MS spectra (Fig. 2). Hence, when
catalyst IX (which is more acidic than VII and VIII) was employed
the process did not work. (4) Moreover, the addition of an external
Brønsted acid did not enhance the reactivity of the process when
using VII. In the case of using catalyst VII alone, iminium ions
would be formed after deprotonation of the coumarin substrate
(Fig. 3). (5) A strange behaviour was observed with the low
reactivity displayed by catalyst VIII, just with one NH2 group in
its structure, since a higher reactivity could be initially expected.
Thus, it seems that the OH group is not involved in the enantio-
selection process and more importantly, it likely inhibits the
reaction. This finding could be explained by assuming an intra-
molecular hydrogen bonding between RO-HꢀꢀꢀNH2R. This would
make the NH2 group in VIII less nucleophilic than in catalyst VII,
avoiding the formation of the initial imine (Int. 1 and Int. 10,
Fig. 2) and therefore, obstructing the reaction. A similar intra-
molecular hydrogen bonding, although weaker, between RHN-Hꢀꢀꢀ
NH2R would also be possible.
Based on all these experiments, VII would act as a bifunc-
tional catalyst,21 activating at the same time the electrophile, by
the generation of an imine or iminium ion, and driving the
attack of the nucleophile (Fig. 3).
According to the above outcomes, a stereochemical model is
proposed in Fig. 3.22 The approach of the coumarin 2 to the in situ
generated imine (Int. 1) would be driven by an RHN–HꢀꢀꢀꢁOR0
bond, resulting in the addition to the re face (lower face) of the
imine (or iminium ion, Fig. 3). Moreover, we could not ignore
the possibility of an intramolecular hydrogen bond between the
second amino group and the iminium ion, giving rise to a more
rigid transition state. Hence, the enantiomer obtained would agree
with the absolute configuration (R) found in final products 3.
Experimental
General experimental methods and instrumentation
Starting materials 1a and 2a–d, as well as amine catalysts I–IX,
are commercially available and were employed as received
without further treatment or purification. In the case of
solvent, commercial tetrahydrofuran (THF, HPLC grade) was
transferred to a new recipient and molecular sieves (4 Å)
were added.
All reactions were performed at room temperature under
ambient conditions. The reactions were monitored by thin-
layer chromatography (TLC) using aluminum sheets recoated
with silica gel and a fluorescent indicator (60 F254, 0.2 mm).
Compounds were visualised at 254 nm by using UV light.
Products 3 were isolated by flash chromatography using silica
gel (0.06–0.2 nm) as the stationary phase and a mixture of
commercial dichloromethane and ethyl acetate as an eluent.
The chiral HPLC analysis of products 3 was performed using
a Waters 600 system, with a Daicel ChiralPak IC column as the
stationary phase and a mixture of commercial n-hexane and
isopropyl alcohol as an eluent. The specific rotation of products
3 was determined using a Jasco P-1020 polarimeter, in aceto-
nitrile of HPLC grade as the solvent. The absolute configuration
of products 3a and 3b was assigned comparing their specific
rotation with those reported in the literature.
The NMR spectra of the reagents and products were recorded
at 300 MHz (Bruker ARX300 spectrometer) or 400 MHz (Bruker
AV400 spectrometer), in chloroform-d (CDCl3) or dimethyl
sulfoxide-d6 ((CD3)2SO) as the deuterated solvent. The infrared
spectra of the starting materials and products were obtained
employing attenuated total reflection infrared (ATR-FTIR)
spectroscopy using a PerkinElmer FTIR spectrometer equipped
with a universal ATR sampling accessory. The HRMS analysis of
the reagents and products was performed using a MicroTof-Q
mass spectrometer and electrospray (ESI) as the ionisation
method. The melting point of the reagents and products was
determined using a Gallenkamp MPD 350 BM 2.5 device.
Materials. The spectroscopic data recorded for synthesised
starting materials 1b,23 1c,23 1d,23 1e,23 and 1f,23 and products
Conclusions
In conclusion, we have developed the first example of a obtained 3a,7 3b,7 3c,6b 3e,6b 3f,20 3g,6e 3h,10 3i6e and 3j6e are in
chiral aromatic amine used as an organocatalyst to activate agreement with the values previously reported by other authors.
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Synthesis of benzylideneacetone derivatives 1b–f
chromatography using a mixture of n-hexane and ethyl acetate
8 : 2 as an eluent. The mixture of isomers obtained was purified
by recrystallisation in methanol, affording 191 mg of com-
pound 1f (43% yield, (E)/(Z) 4 99 : 1).
The substrates 1b–f were synthesised from the corresponding
commercial aldehydes 4b–f and the phosphonium ylide 5,
which was previously prepared following the procedure
reported in the literature using commercially available reagents
(Scheme S1, ESI†).24 The respective yields after purification are
shown in Scheme S1 (ESI†). The ratio (E)/(Z) of products 1b–f
was determined by 1H-NMR spectroscopy, using DMSO-d6 as
the solvent.
General procedure for the enantioselective synthesis of
warfarin derivatives 3a–l catalysed by the chiral aromatic
diamine VII
To a mixture of benzylideneacetone derivative 1a–f (0.1 mmol)
and catalyst VII (5.74 mg, 0.02 mmol, 20 mol%) in THF (100 ml)
at room temperature, the corresponding 4-hydroxycoumarin
2a–d (0.2 mmol, 2 eq.) was added. The reaction mixture was
stirred at room temperature for three days, leading to the final
desired product with the lack of by-products. After this reaction
time, the residue obtained was purified by flash chromatogra-
phy using the gradient from CH2Cl2 : AcOEt, 99 : 1 to CH2Cl2 :
AcOEt, 94 : 6 as the eluent, affording the corresponding pure
product 3. The different yields and enantioselectivities obtained
are collected and compared in Table 1 of the manuscript.
(E)-4-(4-Chlorophenyl)-3-buten-2-one (1b)23. To a suspension
of phosphonium ylide 5 (955 mg, 3 mmol, 1.2 eq.) in toluene
(4 ml) at room temperature, 4-chlorobenzaldehyde (4b) (357 mg,
2.5 mmol) was added. The reaction mixture was stirred overnight
at reflux temperature. After cooling down the reaction to room
temperature, the corresponding residue was purified by flash
chromatography using a mixture of n-hexane and ethyl acetate
8 : 2 as an eluent. The mixture of isomers obtained was washed
with cold n-hexane, affording 320 mg of compound 1b (71% yield,
(E)/(Z) 4 99 : 1).
(E)-4-(4-Bromophenyl)-3-buten-2-one (1c)23. To a suspension
of phosphonium ylide 5 (955 mg, 3 mmol, 1.2 eq.) in toluene
(4 ml) at room temperature, 4-bromobenzaldehyde (4c) (467 mg,
2.5 mmol) was added. The reaction mixture was stirred overnight
at reflux temperature. After cooling down the reaction to room
temperature, the corresponding residue was purified by flash
chromatography using a mixture of n-hexane/ethyl acetate 8 : 2
as an eluent. The mixture of isomers obtained was further purified
by recrystallisation in methanol, affording 203 mg of compound
1c (36% yield, (E)/(Z) 4 99 : 1).
(R)-4-Hydroxy-3-(3-oxo-1-phenylbutyl)chromen-2-one (3a)
(warfarin)7. Starting from benzylideneacetone 1a (14.92 mg,
0.1 mmol) and coumarin 2a (33.09 mg, 0.2 mmol, 2 eq.),
following the general procedure described above, 20.94 mg of
compound 3a was obtained (68% yield). The corresponding ee
(64%) was determined by chiral HPLC analysis of the product
(Daicel Chiralpak IC column, n-hexane/isopropyl alcohol
80 : 20, flow rate 1 ml minꢁ1, l = 282.5 nm): tmajor = 16.7 min;
t
minor = 24.3 min. [a]2D3 = +8.7 ꢂ 0.1 (c 0.75, acetonitrile, 64% ee).
{lit.,6b [a]2D3 = ꢁ9.4 (c 0.4, acetonitrile, 83% ee, S-3a)}.
(E)-4-(4-Cyanophenyl)-3-buten-2-one (1d)23. To a suspension
of phosphonium ylide 5 (955 mg, 3 mmol, 1.2 eq.) in toluene
(4 ml) at room temperature, 4-bromobenzaldehyde (4d) (345.1 mg,
2.5 mmol) was added. The reaction mixture was stirred overnight
at the reflux temperature. After cooling to room temperature, the
corresponding residue was purified by flash chromatography
using a mixture of n-hexane and ethyl acetate 8 : 2 as an eluent.
The mixture of isomers obtained was purified by recrystallisa-
tion in methanol, affording 230 mg of compound 1d (54% yield,
(E)/(Z) 4 99 : 1).
(R)-3-[1-(4-Chlorophenyl)-3-oxobutyl]-4-hydroxychromen-2-one
(3b) (coumachlor)7. Starting from benzylideneacetone 1b
(18.06 mg, 0.1 mmol) and coumarin 2a (33.09 mg, 0.2 mmol,
2 eq.), following the general procedure described above, 26.03 mg
of compound 3b was obtained (76% yield). The corresponding ee
(64%) was determined by chiral HPLC analysis of the product
(Daicel Chiralpak IC column, n-hexane/isopropyl alcohol 80 : 20,
flow rate 1 ml minꢁ1, l = 279.4 nm): tmajor = 10.5 min; tminor
=
21.3 min. [a]2D5 = ꢁ6.1 ꢂ 0.1 (c 0.60, acetonitrile, 64% ee). {lit.,17
[a]2D5 = ꢁ8.8 (c 0.27, acetonitrile, 79% ee, R-3b)}.
(E)-4-(4-Methylphenyl)-3-buten-2-one (1e)23. To a suspension
of phosphonium ylide 5 (955 mg, 3 mmol, 1.2 eq.) in toluene
(4 ml) at room temperature, 4-methylbenzaldehyde (4e) (304 ml,
2.5 mmol) was added. The reaction mixture was stirred over-
night at reflux temperature. After cooling down the reaction to
room temperature, the corresponding residue was purified by
flash chromatography using a mixture of n-hexane and ethyl
acetate 8 : 2 as an eluent. The mixture of isomers obtained was
purified by flash chromatography using n-hexane/diethyl ether
9 : 1 as an eluent, affording 205 mg of compound 1e (51% yield,
(E)/(Z) 4 99 : 1).
(R)-3-[1-(4-Bromophenyl)-3-oxobutyl]-4-hydroxychromen-2-one
(3c)6b. Starting from benzylideneacetone 1c (22.50 mg, 0.1 mmol)
and coumarin 2a (33.09 mg, 0.2 mmol, 2 eq.), following the
general procedure described above, 33.04 mg of compound 3c
was obtained (85% yield). The corresponding ee (66%) was
determined by chiral HPLC analysis of the product (Daicel
Chiralpak IC column, n-hexane/isopropyl alcohol 80 : 20, flow rate
1 ml minꢁ1, l = 279.4 nm): tmajor = 11.7 min; tminor = 23.0 min.
[a]2D3 = ꢁ10.0 ꢂ 0.1 (c 0.60, acetonitrile, 66% ee).
(R)-3-[1-(4-Cyanophenyl)-3-oxobutyl]-4-hydroxychromen-2-one
(3d). Starting from benzylideneacetone 1d (17.12 mg, 0.1 mmol)
and coumarin 2a (33.09 mg, 0.2 mmol, 2 eq.), following the
general procedure described above, 30.65 mg of compound 3d
was obtained (92% yield). The corresponding ee (50%) was
determined by chiral HPLC analysis of the product (Daicel
(E)-4-(4-Methoxyphenyl)-3-buten-2-one (1f)23. To a suspen-
sion of phosphonium ylide 5 (955 mg, 3 mmol, 1.2 eq.) in
toluene (4 ml) at room temperature, 4-methoxybenzaldehyde
(4f) (304 ml, 2.5 mmol) was added. The reaction mixture was
stirred overnight at reflux temperature. After cooling to room Chiralpak IC column, n-hexane/isopropyl alcohol 80 : 20, flow rate
temperature, the corresponding residue was purified by flash 1 ml minꢁ1, l = 250.0 nm): tmajor = 20.8 min; tminor = 26.5 min.
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[a]2D3 = ꢁ10.9 ꢂ 0.1 (c 1.37, acetonitrile, 50% ee). M.p. 105–107 1C. IC column, n-hexane/isopropyl alcohol 80 : 20, flow rate 1 ml minꢁ1
,
IR (cmꢁ1) 3353 (OH), 2226 (CN), 1680 (CQO), 1608 (CQO), 1381, l = 271.0 nm): tmajor = 20.0 min; tminor = 30.7 min. [a]2D3 = ꢁ4.9 ꢂ 0.1
1068, 759, 727, 563. In CDCl3, the product was found to exist in a (c 0.31, acetonitrile, 61% ee).
fast equilibrium between its open chain form 3d (E10 mol%) and
(R)-6-Bromo-3-[1-(4-chlorophenyl)-3-oxobutyl]-4-hydroxychromen-
both pseudo-diastereomeric hemiketals 3d0 (E30 mol% and 2-one (3i)6e. Starting from benzylideneacetone 1b (16.06 mg,
E60 mol%). 1H-NMR (300 MHz, CDCl3) d 1.72 (s, 0.9H3d [a]
,
0.1 mmol) and coumarin 2c (49.19 mg, 0.2 mmol, 2 eq.),
following the general procedure described above, 10.54 mg of
0
RCH3), 1.77 (s, 1.8H3d [b], RCH3), 1.92 (dd, J1 = 10.4 Hz, J2
=
0
8.9 Hz, 0.6H3d [a], RCH2R0), 2.32 (s, 0.3H3d, RCH3), 2.37–2.49 compound 3i was obtained (25% yield). The corresponding ee
0
(m, 1.2H3d [b], RCH2R0), 3.01 (br s, 0.3H3d [a], ROH), 3.23–3.33 (62%) was determined by chiral HPLC analysis of the product
0
0
(m, 0.1H3d, RCH2R0), 3.33 (br s, 0.6H3d [b], ROH), 3.86 (dd, J1 = (Daicel Chiralpak IC column, n-hexane/isopropyl alcohol
0
2
14.5 Hz, J = 8.0 Hz, 0.1H3d, RCH2R0), 4.19–4.24 (m, 0.6H3d [b]
+
80 : 20, flow rate 1 ml minꢁ1, l = 272.2 nm): tmajor = 8.2 min;
0
0.3H3d [a], RCHR0R00), 4.68–4.71 (m, 0.1H3d, RCHR0R00), 7.22–7.24 tminor = 13.6 min. [a]2D4 = ꢁ35.2 ꢂ 0.1 (c 0.34, acetonitrile,
0
0
0
(m, 0.1H3d, Ar-H), 7.27–7.37 (m, 2.4H3d [b] + 1.2H3f [a], Ar-H), 7.41– 62% ee).
0
0
7.43 (m, 0.2H3d, Ar-H), 7.50–7.60 (m, 1.8H3d [b] + 0.9H3d [a]
+
(R)-6-Chloro-4-hydroxy-3-(3-oxo-1-p-tolylbutyl)-2H-chromen-2-
0
0.4H3d, Ar-H), 7.81–7.83 (m, 0.6H3d [b]
,
Ar-H), 7.86–7.88 one (3j)6e. Starting from benzylideneacetone 1e (16.32 mg,
0
(m, 0.3H3d [b], Ar-H), 7.95–7.98 (m, 0.1H3d, Ar-H), 9.64 (br s, 0.1 mmol) and coumarin 2b (40.53 mg, 0.2 mmol, 2 eq.),
0.1H3d, ROH). 13C-NMR (75 MHz, CDCl3) d 28.2, 28.4, 35.1, 35.2, following the general procedure described above, 7.14 mg of
35.8, 39.6, 42.0, 44.9, 98.9, 100.0, 101.0, 103.3, 110.4, 110.5, 115.5, compound 3j was obtained (20% yield). The corresponding ee
115.8, 116.5, 116.8, 116.9, 119.1, 122.9, 123.0, 124.0, 124.2, 128.1, (62%) was determined by chiral HPLC analysis of the product
128.5, 129.1, 132.0, 132.1, 132.3, 132.4, 132.7, 148.4, 149.3, 153.1, (Daicel Chiralpak IC column, n-hexane/isopropyl alcohol 80 : 20,
159.4, 161.3. HRMS (ESI+) calcd for [NaC20H15NO4]+ ([M + Na]+) flow rate 1 ml minꢁ1, l = 272.2 nm): tmajor = 12.2 min; tminor
356.0899; found 356.0893.
=
19.4 min. [a]2D4 = ꢁ25.8 ꢂ 0.2 (c 0.20, acetonitrile, 62% ee).
(R)-4-Hydroxy-3-[1-(4-methylphenyl)-3-oxobutyl]-chromen-2-
(R)-6-Chloro-4-hydroxy-3-[1-(4-methoxyphenyl)-3-oxobutyl]-
one (3e)6b. Starting from benzylideneacetone 1e (16.32 mg, chromen-2-one (3k). Starting from benzylideneacetone 1f (17.62
0.1 mmol) and coumarin 2a (33.09 mg, 0.2 mmol, 2 eq.), mg, 0.1 mmol) and coumarin 2b (40.53 mg, 0.2 mmol, 2 eq.),
following the general procedure described above, 20.10 mg of following the general procedure described above, 15.62 mg of
compound 3e was obtained (62% yield). The corresponding ee compound 3k was obtained (42% yield). The corresponding ee
(58%) was determined by chiral HPLC analysis of the product (54%) was determined by chiral HPLC analysis of the product
(Daicel Chiralpak IC column, n-hexane/isopropyl alcohol (Daicel Chiralpak IC column, n-hexane/isopropyl alcohol
80 : 20, flow rate 1 ml minꢁ1, l = 279.4 nm): tmajor = 17.3 min; 80 : 20, flow rate 1 ml minꢁ1, l = 272.2 nm): tmajor = 17.3 min;
t
minor = 33.2 min. [a]2D3 = +3.3 ꢂ 0.2 (c 0.37, acetonitrile, 58% ee).
t
minor = 31.6 min. [a]2D3 = ꢁ27.9 ꢂ 0.1 (c 0.77, acetonitrile, 54% ee).
{lit.,6a [a]2D5 = +16.6 (c 1.0, dichloromethane, 96% ee, (R)-3e)}.
IR (cmꢁ1) 3353 (OH), 1694 (CQO), 1614 (CQO), 1510, 1241, 824,
(R)-6-Chloro-4-hydroxy-3-(3-oxo-1-phenylbutyl)chromen-2-one 730, 535. In CDCl3, the product was found to exist in a fast
(3f)20. Starting from benzylideneacetone 1a (14.92 mg, 0.1 mmol) equilibrium between its open chain form 3k (E20 mol%)
and coumarin 2b (40.53 mg, 0.2 mmol, 2 eq.), following the and both pseudo-diastereomeric hemiketals 3k0 (E40 mol%).
general procedure described above, 19.41 mg of compound 3f 1H-NMR (400 MHz, CDCl3) d 1.68 (s, 1.2H3k , RCH3), 1.74
0
1
was obtained (57% yield). The corresponding ee (67%) was (s, 1.2H3k , RCH3), 2.00 (dd, J = 14.0 Hz, J2 = 11.5 Hz,
0
determined by chiral HPLC analysis of the product (Daicel 0.4H3k [a], RCH2R0), 2.04 (s, 0.2H3k, RCH3), 2.29 (s, 0.4H3k
,
0
Chiralpak IC column, n-hexane/isopropyl alcohol 80: 20, flow RCH3), 2.38 (dd, J1 = 14.2 Hz, J2 = 6.8 Hz, 0.4H3k [b], RCH2R0),
0
rate 1 ml minꢁ1, l = 272.2 nm): tmajor = 13.1 min; tminor = 18.3 min. 2.47 (dd, J1 = 14.1 Hz, J2 = 6.9 Hz, 0.4H3k [b], RCH2R0), 2.54 (dd,
0
[a]2D3 = ꢁ22.1 ꢂ 0.1 (c 0.69, acetonitrile, 67% ee).
J1 = 14.2 Hz, J2 = 3.0Hz, 0.4H3k [a], RCH2R0), 3.11 (br s, 0.4H3k
,
0
0
(R)-6-Bromo-4-hydroxy-3-(3-oxo-1-phenylbutyl)chromen-2-one ROH), 3.25–3.30 (m, 0.4H3k + 0.2H3k, ROH + RCH2R0), 3.75–3.86
0
(3g)6e. Starting from benzylideneacetone 1a (14.92 mg, 0.1 mmol) (m, 1.2H3k [a] + 1.2H3k [b] + 0.6H3k, ROCH3), 4.09–4.15 (m, 0.4H3k
+
0
0
0
and coumarin 2c (49.19 mg, 0.2 mmol, 2 eq.), following the 0.2H3k, RCHR0R00 + RCH2R0), 4.24 (dd, J1 = 6.6 Hz, J2 = 2.8 Hz,
general procedure described above, 20.69 mg of compound 3g 0.4H3k , RCHR R ), 4.63 (dd, J = 10.4 Hz, J2 = 2.1 Hz, 0.2H3k,
1
0
00
0
was obtained (53% yield). The corresponding ee (67%) was RCHR0R00), 7.12–7.31 (m, 2H, Ar-H), 7.12–7.31 (m, 3H, Ar-H), 7.41–
determined by chiral HPLC analysis of the product (Daicel 7.44 (m, 0.4H3k + 0.2H3k, Ar-H), 7.51 (dd, J1 = 8.8 Hz, J2 = 2.5 Hz,
0
1
1
0
0
Chiralpak IC column, n-hexane/isopropyl alcohol 80: 20, flow 0.4H3k , Ar-H), 7.78 (d, J = 2.5 Hz, 0.4H3k , Ar-H), 7.86 (d, J = 2.5
rate 1 ml minꢁ1, l = 272.2 nm): tmajor = 13.7 min; tminor = 18.9 min. Hz, 0.4H3k , Ar-H), 7.91 (d, J = 2.5 Hz, 0.2H3k, Ar-H), 9.56 (br s,
1
0
[a]2D3 = ꢁ24.3 ꢂ 0.1 (c 1.00, acetonitrile, 67% ee).
0.2H3k, ROH). 13C-NMR (100 MHz, CDCl3) d 28.0, 28.5, 33.4, 34.7,
(R)-4-Hydroxy-6-methyl-3-(3-oxo-1-phenylbutyl)chromen-2-one 40.7, 42.6, 55.4, 55.4, 99.5, 101.0, 102.4, 113.8, 114.3, 114.9, 117.8,
(3h)10. Starting from benzylideneacetone 1a (14.92 mg, 0.1 mmol) 118.2, 118.3, 122.5, 122.8, 123.7, 128.1, 128.2, 129.3, 129.3, 129.7,
and coumarin 2d (35.95 mg, 0.2 mmol, 2 eq.), following the 131.6, 131.8, 132.1, 132.8, 134.8, 157.5. HRMS (ESI+) calcd for
general procedure described above, 8.04 mg of compound 3h was [NaC20H17ClO5]+ ([M + Na]+) 395.0662; found 395.0657.
obtained (25% yield). The corresponding ee (61%) was deter-
(R)-6-Bromo-4-hydroxy-3-[1-(4-methoxyphenyl)-3-oxobutyl]-
mined by chiral HPLC analysis of the product (Daicel Chiralpak chromen-2-one (3l)6e. Starting from benzylideneacetone 1f
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Paper
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2 eq.), following the general procedure described above, 13.22 mg
of compound 3l was obtained (32% yield). The corresponding ee
(54%) was determined by chiral HPLC analysis of the product
(Daicel Chiralpak IC column, n-hexane/isopropyl alcohol 80 : 20,
flow rate 1 ml minꢁ1, l = 272.2 nm): tmajor = 19.5 min; tminor
36.9 min. [a]2D4 = ꢁ34.3 ꢂ 0.1 (c 0.61, acetonitrile, 54% ee).
=
˙
1124–1134; (d) M. Is-ik, H. U. Akkoca, I. M. Akhmedov and
Conflicts of interest
C. Tanyeli, Tetrahedron: Asymmetry, 2016, 27, 384–388;
´
´
ˇ
´
(e) V. Modrocka, E. Veverkova, M. Meciorava and
There are no conflicts to declare.
ˇ
R. Sebesta, J. Org. Chem., 2018, 83, 13111–13120; ( f )
R.-Q. Mei, X.-Y. Xu, Y.-C. Li, J.-Y. Fu, Q.-C. Huang and
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Acknowledgements
This work was supported by a 2018 Leonardo Grant for Researchers
and Cultural Creators, BBVA Foundation. The authors also thank
´
Ministerio de Economıa, Industria y Competitividad (MINECO-
FEDER CTQ2016-75816-C2-1-P and CTQ2017-88091-P), Universidad
de Zaragoza (JIUZ-2017-CIE-05) and Gobierno de Aragon-Fondo
Social Europeo (Research Group E07_17R) for financial support
of their research. We acknowledge support of the publication fee by
the CSIC Open Access Publication Support Initiative through its
Unit of Information Resources for Research (URICI).
´
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New J. Chem.
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