Linear β-amino alcohol catalyst anchored on functionalized magnetite nanoparticles for enantioselective addition of dialkylzinc to aromatic aldehydes

Article abstract of DOI:10.1039/d0ra04554c

A linear β-amino alcohol ligand, previously found to be a very efficient catalyst for enantioselective addition of dialkylzinc to aromatic aldehydes, has been anchored on differently functionalized superparamagnetic core-shell magnetite-silica nanoparticles (1a and 1b). Its catalytic activity in the addition of dialkylzinc to aldehydes has been evaluated, leading to promising results, especially in the case of 1b for which the recovery by simple magnetic decantation and reuse was successfully verified. This journal is

Full text of DOI:10.1039/d0ra04554c

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PAPER
Linear b-amino alcohol catalyst anchored on
functionalized magnetite nanoparticles for
enantioselective addition of dialkylzinc to aromatic
aldehydes†
Cite this: RSC Adv., 2020, 10, 29688
Carla Sappino, ‡a Ludovica Primitivo,‡ae Martina De Angelis,ae Francesco Righi,a
Federica Di Pietro,a Marika Iannoni,a Luciano Pilloni,b Stefano Vecchio Ciprioti,c
d
e
Alessandra Ricellie and Giuliana Righi
‡
*
Lorenza Suber,
A linear b-amino alcohol ligand, previously found to be a very efficient catalyst for enantioselective addition
of dialkylzinc to aromatic aldehydes, has been anchored on differently functionalized superparamagnetic
core–shell magnetite–silica nanoparticles (1a and 1b). Its catalytic activity in the addition of dialkylzinc to
aldehydes has been evaluated, leading to promising results, especially in the case of 1b for which the
recovery by simple magnetic decantation and reuse was successfully verified.
Received 22nd May 2020
Accepted 31st July 2020
DOI: 10.1039/d0ra04554c
rsc.li/rsc-advances
areas. For example, nanoparticles composed of a magnetite
(Fe3O4) core and a silica (SiO2) shell functionalized to anchor
Introduction
the molecular catalyst can overcome the problem of catalyst
recovery through simple magnetic decantation, i.e. attracting
the nanoparticles, with the attached catalyst molecules, by
a magnet applied to the external ask wall.2 Magnetite
nanoparticles, up to around 20 nm in size in fact, exhibit
a special form of magnetism called superparamagnetism,3
namely they become magnetic only in the presence of
a magnetic eld. This behavior has the great advantage that
in the absence of a magnetic eld the nanoparticles can be
well dispersed. For these reasons, there has been enormous
interest in the use of magnetic nanoparticles in asymmetric
catalysis and several chiral catalysts were immobilized onto
such supports.4 In light of the many opportunities and great
potential of these combined systems, the number of chiral
catalysts immobilized onto magnetic nanoparticles is
continuously growing.
Although in the last few decades several highly efficient chiral
catalysts, able to catalyze a variety of asymmetric trans-
formations in homogeneous catalysis, have been developed,
the large-scale use of this technique has not taken hold. It
has been calculated that homogeneous catalysis is used in
less than 20% of industrially relevant processes.1 The strin-
gent ecological and economical demands for sustainability,
embodied in the “green chemistry dictates”, have limited
their practical use. The main obstacles result from the diffi-
culty of separating the catalyst from the reaction mixture,
leading to expensive and polluting purication steps and to
limited possibilities of recovering and reusing the catalyst,
oen composed of precious chiral moieties. The ongoing
development of new asymmetric strategies has exploited
techniques belonging to materials chemistry. Indeed, that is
how asymmetric catalysis researchers started exploring
nanochemistry, a relatively young research eld that has
undergone an exponential growth in several application
a
`
Dipartimento di Chimica, Sapienza Universita di Roma, p.le A. Moro 5, 00185 Roma,
Italy. E-mail: carla.sappino@uniroma1.it; ludovica.primitivo@uniroma1.it
bSSPT-PROMAS-MATPRO, ENEA CR Casaccia, Via Anguillarese, 301-00123 Roma,
Italy
c
`
Dipartimento di Scienze di Base e Applicate per l'Ingegneria, Sapienza Universita di
Roma, Via del Castro Laurenziano 7, 00161 Roma, Italy
dCNR-ISM, Via Salaria km 29,300-00015 Monterotondo Scalo, Roma, Italy
e
`
CNR-IBPM, c/o Dipartimento Chimica, Sapienza Universita di Roma, p.le A. Moro 5,
00185 Roma, Italy. E-mail: giuliana.righi@cnr.it
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra04554c
Fig. 1 Structure of b-amino alcohol nanocatalysts 1a and 1b and
homogeneous b-amino alcohol ligand 9.
‡ These authors contributed equally to this work.
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of functionalized magnetic nanoparticles as catalysts for the
enantioselective Henry reaction. In this context, the nano-
catalyst 1b exhibited
a promising catalytic activity that
remained unchanged in the three catalytic cycles performed.7
Herein we report the results of the employment in the
asymmetric dialkylzinc addition to aldehydes both of the
homogeneous b-amino alcohol ligand 9 and of its immobilized
form, the magnetically recoverable b-amino alcohol nano-
catalysts 1a and 1b (Fig. 1).
Scheme 1 Asymmetric dialkylzinc addition to aldehydes catalysed by
ligand 2.
Results and discussions
We have recently reported the employment of the b-amino
alcohol catalyst 2 (Scheme 1) in the enantioselective addition of
diethylzinc to aromatic aldehydes,8 and in light of its broad
applicability as chiral catalyst we decided to investigate the
catalytic efficiency of its immobilized form.
Having extensively explored different anchoring strategies,
different functionalities necessary for the bond with the nano-
particle surface, and different suitable spacers, the nano-
structured catalyst 1 was designed (Fig. 2).§9
In the amide residue is thus introduced an aromatic and
a triazole ring through a CuI-catalyzed azide/alkyne cycloaddi-
tion (CuAAC)10 and a nanoparticle having a magnetite (Fe3O4)
core. The nanoparticle is coated with a thin silica (SiO2) layer to
protect the inner Fe3O4 from oxidation by air and to facilitate
the functionalization thanks to the many silanol groups
exposed on the surface (Fig. 2).11 Before testing the catalytic
efficiency of the nanostructured ligand 1, it was necessary to
verify that the introduced differences with respect to the ligand
2 would not affect the catalytic properties. The analogue 9 was
designed and obtained through a click reaction between the
alkyne 3 and the (3-azidopropyl)benzene 8.{ The alkyne 3 was
synthesized in three steps starting from the acid precursor 5
(Scheme 2).
Fig. 2 Immobilization strategy for catalyst 2.
b-Amino alcohols represent one of the most studied classes
of chiral ligands/auxiliaries. They have been used, both in
acyclic- and cyclic-derivative form, since the beginning of
asymmetric synthesis.5 Despite their wide use in asymmetric
catalysis, only a small number of b-amino alcohols have been
successfully immobilized on magnetic nanoparticles for cata-
lytic applications.6 We have recently reported the employment
Ligand 9 was then evaluated in the homogeneous phase
catalysis test. As shown in Table 1, the addition of Et2Zn to
different aldehydes catalyzed by ligand 9 gave results compa-
rable with those obtained with ligand 2.8
Considering the excellent results obtained in the asymmetric
catalysis of addition of diethylzinc to aldehydes, we decided also
to test the reaction with bulkier organozinc reagents. First,
catalyst 9 was tested in the addition of iPr2Zn to benzaldehyde.
Benzaldehyde was treated with iPr2Zn and 6 mol% catalyst 9, in
dry toluene for 12 h at room temperature. Differently from the
Et2Zn addition, the reduction side product benzyl alcohol 12a
was collected together with the desired alcohol 11a. However,
the use of 9 considerably enhanced the addition, as the mixture
ratio moved from substantially only the reduced product
collected in absence of the ligand, to 88 : 12 for the desired
§ A ligand derived from the immobilization on nanoparticles of a simpler
structure
[(4R,5S,E)-5-cyclohexyl-5-hydroxy-4-morpholino-N-(prop-2-yn-1-yl)
pent-2-enamide] instead of 3 had been previously tested leading to poorer
results in the catalytic reaction.
Scheme 2 (a) EDC/HOAt, DMF, rt, 12 h, 80%; (b) propargyl bromide,
K2CO3, CH3CN dry, reflux, 12 h, 83%; (c) morpholine, LiClO4, CH3CN
dry, reflux, 12 h, 75%; (d) 8, CuI, DIPEA, THF, rt, 12 h, 89%.
{ Not commercially available, synthesized from 3-phenyl-1-propanol in 2 steps:
(a) PBr3, CH2Cl2 dry, 0 ꢀC, 12 h; (b) NaN3, DMSO dry, 60 ꢀC, 12 h, 31% total etc.
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product in the presence of 9; moreover, in the presence of the resulting from slight oxidation of magnetite, that, being
catalyst, very high enantioselectivity was detected (95.5%) magnetic as well, does not appreciably inuence the super-
(Table 2).
Given the promising results, we evaluated the catalyst 9 in
paramagnetic character of the nanoparticles.
The superparamagnetic b-amino alcohol catalyst 1a was
the addition of iPr2Zn to a small selection of aromatic alde- initially evaluated in the usual reaction test. Benzaldehyde
hydes. As reported in Table 2, catalyst 9 still exhibits signicant and diethylzinc were added to a suspension, in toluene, of
catalytic activity, allowing the formation of the addition the magnetic catalyst, and the reaction was mechanically
product, completely absent without catalyst (entry 1), with good stirred at room temperature for 24 hours. Then the catalyst
yields and satisfactory enantioselectivities. The increased steric was easily recovered by magnetic decantation and the
hindrance appears to make the addition more difficult, as re- supernatant treated as usual. Unfortunately, the analysis of
ected in the signicant formation of the side reduction the supernatant revealed that almost no catalysis occurred:
product. This seems to be conrmed by the lower 11/12 ratio in the product was collected in 45% yield and with 15% ee
the case of 2-methylbenzaldehyde and 2-chlorobenzaldehyde (Table 3-entry 1). Considering the poor result observed, we
whose substituents on the ring are very close to the reaction site wondered if the vicinal hydroxyl groups exposed on the oxide
(entries 3 and 8).
surface could have interfered with the organometallic
Once we conrmed the retained catalytic activity, through reagent, ruining the reaction. Following a reported proce-
a CuI-catalyzed azide/alkyne cycloaddition (CuAAC), we immo- dure, we performed a second test adding BuLi to the reaction
bilized 3 onto azido-modied magnetic nanoparticles 4a and mixture which was supposed both to react with the vicinal
4b, the latter obtained aer treating 4a with hexamethyldisila- free silanols forming lithium silyloxides and to activate the
zane. The superparamagnetic catalysts 1a and 1b were thus Et2Zn forming a lithium amino alkoxide species, more reac-
obtained with 0.28 mmol gꢁ1 and 0.41 mmol gꢁ1 loading tive than the analogous zinc derivative.12 Once more, these
respectively (Scheme 3), as determined by C, H, N elemental conditions led, in both the concentrations tested, to the
analysis (see Experimental section). In fact, as N originates desired product in very low yield and mediocre enantiose-
exclusively from the functionalized catalyst, it is possible to lectivities, even if those values were slightly higher. In addi-
determine the mmol of the functionalized catalyst (1a or 1b)/g tion, a fair amount of 1-phenylpentan-1-ol, derived from the
by dividing the N weight% by its atomic weight, 14, then BuLi addition to the aldehyde (entries 2 and 3), was observed.
dividing by 5 as the functionalized catalyst molecule contains For the same reason, we decided to covalently block the free
ve N atoms, and by multiplyng by 10 in order to obtain silanol on the surface by treatment with hexamethyldisila-
the mmol in 1 g.
zane, which is able to transform the hydroxyl groups on the
TEM images showed the formation of nanoparticles with nanoparticle surface into trimethylsilyloxide.13 Aer the
diameters in the range 10–15 nm (Fig. 3). HR-TEM images treatment with HMDS, we obtained the silylated azido func-
showed lattice fringes attributable both to magnetite (Fe3O4) tionalized nanoparticles 4b, which immediately appeared to
and maghemite (g-Fe2O3) phases (Fig. 4), the latter possibly be much more dispersible in organic solvents. The
Table 1 Addition of Et2Zn to different aldehydes catalyzed by ligand 9a
Table 2 Addition of iPr2Zn to different aldehydes catalyzed by ligand
9a
Entry
Aldehyde
Yieldb (%)
ee (%)
Product
Yield 11 Yield 12
Entry Aldehyde
(%)
(%)
ee (%) Product
1
2
3
4
5
6
7
8
PhCHO
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
70
96
76
94
89
97
96
97
98
88
87
80
10a
10b
10c
10d
10e
10f
10g
10h
10i
4-CNPhCHO
4-BrPhCHO
2-ClPhCHO
2-MePhCHO
4-MePhCHO
2-MeOPhCHOc
3-MeOPhCHO
Cinnamaldehyde
PhCH2CH2CHO
cHexCHO
1
PhCHO (no ligand)
—
83
53
79
75
78
48
42
69
75
83
80
11
41
16
20
17
17
53
25
20
11
—
2
PhCHO
95.5
95
93
86
87
98
81
88
88
91
11a
11b
11c
11d
11e
11f
11g
11h
11i
3
4
5
6
7
8
9
10
11
2-MePhCHO
3-MePhCHO
4-MePhCHO
3-CNPhCHO
4-CNPhCHO
2-ClPhCHO
4-BrPhCHO
2-MeOPhCHO
3-MeOPhCHO
9
10
11
10j
10k
a
All the experiments were performed under identical conditions (6 h).
Chemical yields are referred to isolated compounds. The same
11j
b
c
a
results were obtained using CH2Cl2 as solvent.
All the experiments were performed under identical conditions (12 h).
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Scheme 3 (a) CuI, DIPEA, THF, r.t., 48 h, 0.28 mmol gꢁ1 loading (1a); 0.41 mmol gꢁ1 loading (1b).
immobilization of 3 on 4b furnished the nanostructured thermogravimetric analysis (Fig. 5) to eventually determine the
catalyst 1b that, tested in the usual reaction condition, gave fraction of water (by monitoring the mass loss that occurs
consistently improved results, especially regarding enantio- heating the sample at a constant rate). Actually, heating up to
selectivity, although not yet comparable with the homoge- 100 ꢀC it was possible to observe a mass loss of about 0.3% due
neous phase ones. However, noteworthy that the catalytic to adsorbed water, whereas a mass loss of about 1.5% observed
activity remained about unchanged in the tree catalytic cycles in the range 100–200 ꢀC can be attributed to chemically
performed.
bonded water. Unfortunately, the nanoparticles can't be sub-
We hypothesized that such a difference in activity between jected to a thermal treatment up to 175 ꢀC to eliminate water,
the homogeneous catalyst 9 and its anchored form 1 was due because of the resulting poor dispersibility in solvents caused
to small amounts of water on the nanoparticle surface by aggregation and agglomeration phenomena, probably due
incompatible with Et2Zn. To verify it, a sample of well-dried to incipient organic decomposition process on the nano-
nanostructured
catalyst
1b
was
subjected
to particle surface.
Fig. 3 TEM image of functionalized silica–coated magnetite nano- Fig.
4
HR-TEM image of functionalized silica–coated magnetite
particles 1b.
nanoparticles 1b.
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Table 3 Addition of R2Zn to different aldehydes catalyzed by nanocatalyst 1a
Entry
Aldehyde
Catalyst
Additive
R
Yieldb%
ee%
Product
1
2
3
4
5
6
7
8
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
4-Me-PhCHO
3-MeO-PhCHO
4-Br-PhCHO
PhCHO
1a
1a
1a
1b
—
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
iPr
iPr
45
25
27
50
48
47
48
59
48
77
46
49
15
25
28
50
50
48
48
53
58
47
50
47
10a
10a
10a
10a
10a
10a
10a
10f
10h
10c
11a
11d
BuLi 0.72 mmol gꢁ1
BuLi 0.35 mmol gꢁ1
—
—
—
—
—
—
—
—
—
1b I cycle
1b II cycle
1b III cycle
1b
1b
1b
1b
1b
9
10
11
12
4-Me-PhCHO
a
b
All the experiments were performed under identical conditions (24 h, r.t.) except for entry 2 and 3 performed at ꢁ15 ꢀC. Chemical yields are
referred to isolated compounds.
A study on the employment of 1b catalyst in different organic
reactions is in progress.
Experimental
Unless otherwise stated, commercial reagents purchased from
Alfa Aesar, Acros and Aldrich chemical companies were used
without further purication. Purication of reaction products
was carried out by ash chromatography using Kieselgel F
Merck silica gel (230–400 mesh). Thin layer chromatography
(TLC) was performed on Kieselgel F 254 pre-coated silica gel
Fig. 5 TG curve of the nanostructured catalyst 1b.
plates and visualization was achieved by inspection under UV
light (Mineralight UVG 11 254 nm) followed by staining with
phosphomolybdic acid dip [polyphosphomolybdic acid (12 g),
Conclusions
ethanol (250 mL)] or 2,4-dinitrophenylhydrazine dip [2,4-
dinitrophenylhydrazine (4 g) ethanol (100 mL), water (20 mL),
The structure of the anchorable amino alcohol 3 was designed
starting from catalyst 2, whose efficiency had already been re-
sulfuric acid]. 1H NMR spectra were recorded using a Varian
Mercury 300 (300 MHz) or a Bruker Avance 400 (400 MHz).
ported in the well-established enantioselective amino alcohol-
1
Residual solvent peaks were used as internal references for H
promoted addition of diethylzinc to a variety of aldehydes in
NMR spectra: chloroform (d 7.26 ppm). Chemical shis (d) are
the homogeneous phase. We conrmed the retained catalytic
reported in parts per million (ppm) and coupling constants (J)
activity by employing its analogue 9, adding in particular a tri-
are reported in Hz. Splitting patterns are designated as s,
azole ring formed by anchoring the catalyst to the nanoparticles
singlet; bs, broad singlet; d, doublet; bd, broad doublet dd,
surface. Moreover, its broad applicability as a chiral catalyst was
doublet of doublets; ddd, doublet of doublet of doublets; t,
evaluated by carrying out the same reaction with the bulkier
triplet; dt, doublet of triplets; q, quartet; m, multiplet. 13C
diisopropylzinc, still leading to satisfactory results. Given the
spectra were recorded using a Varian Mercury 300 (75 MHz) or
interesting results obtained, we anchored this type of catalyst
a Bruker Avance 400 (100 MHz). Chemical shis (d) are reported
on superparamagnetic magnetite nanoparticles. Aer having
in parts per million (ppm) relative to the internal standard of
chosen a suitable spacer and different functionalized nano-
particle surfaces, the nanostructured catalysts 1a and 1b were
selected. Their catalytic activity was evaluated in the addition of
the residue solvent peak: chloroform (77.00 ppm). Optical
rotations were measured on a digital polarimeter Jasco DIP-370
with a cell path length of 1 cm; solution concentrations are
dialkylzinc to aldehydes leading to promising results, especially
reported in grams per 100 mL. Enantiomeric excesses were
in the case of 1b for which the recovery by simple magnetic
decantation and reuse was also successfully veried.
determined by way of a Agilent 1260 Innity HPLC system
equipped with a diode array detector (DAD) and chiral
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stationary phase; chiral columns used were Chiralpak IA, extracted with CH2Cl2. The combined organic extracts were
Chiralpak IB, Chiralpak IC. washed with brine, dried over Na2SO4 and concentrated in
Attenuated Total Reectance-Fourier Transform Infra Red vacuo. The crude product was puried by ash chromatography
(ATR-FTIR) spectra were recorded on a Shimadzu IR Prestige-21. (Hex/EtOAc 80 : 20) as eluent. The recovered nanoparticles were
Elemental analyses for C, H and N were performed on an EA repeatedly washed with CH2Cl2 and toluene and then they were
1110 CHNS–O Element Analyzer. Morphologic and structural stored in 3 mL of anhydrous toluene.
investigations were performed by way of a JEOL JEM 2010
Transmission Electron Microscopy (TEM).
(S)-1-Phenylpropan-1-ol (10a).14 130 mg, >95%. ee ¼ 96%
(HPLC: Chiralpak IB, hexane/i-PrOH ¼ 98 : 2, 0.9 mL minꢁ1
,
The thermal behavior of a powder sample of 1b was studied 258 nm, minor 12.1 min and major 12.4 min). 1H NMR (400
from room temperature to 180 ꢀC by a simultaneous Stanton MHz, CDCl3) d 7.40–7.23 (m, 5H, Ph), 4.60 (t, J ¼ 6.6 Hz, 1H,
Redcro Thermogravimetry/Heat Flux Differential Thermal CHOH), 1.90–1.67 (m, 3H, CH2, OH), 0.92 (t, J ¼ 7.4 Hz, 3H,
Analysis apparatus (STA625 model). The instrument is equip- CH3). 13C NMR (100 MHz, CDCl3) d 150.2, 132.3, 126.7, 119.0,
ped with two Al crucibles (one for the sample and one for the 111.0, 75.1, 32.1, 9.9.
reference, which was empty). Aer calibration with sapphire
(S)-4-(1-Hydroxypropyl)benzonitrile (10b).15 155 mg, >95%.
this instrument is able to provide heat ow data as a DSC unit ee ¼ 76% (HPLC: Chiralpak IA, hexane/i-PrOH ¼ 95/5, 0.8
1
(with lower sensitivity). So, the thermogravimetry (TG) experi- mL minꢁ1, 220 nm, minor 17.3 min and major 18.8 min). H
ments were carried out under purging inert Ar atmosphere of 50 NMR (400 MHz, CDCl3) d 7.60 (d, J ¼ 8.2 Hz, 2H, Ph), 7.44 (d, J ¼
mL minꢁ1 and heating rate of 10 ꢀC minꢁ1, providing the mass 8.3 Hz, 2H, Ph), 4.66 (t, J ¼ 6.4 Hz, 1H, CHOH), 2.39 (bs, 1H,
loss as a function of temperature. About 8 mg of the sample, OH), 1.81–1.69 (m, 2H, CH2), 0.90 (t, J ¼ 7.4 Hz, 3H, CH3). 13C
precisely weighed with an accuracy of ꢂ0.001 mg, was consid- NMR (100 MHz, CDCl3) d 150.2, 132.3, 126.7, 119.0, 111.0, 75.1,
ered. Calibration of temperature was performed by measuring 32.1, 9.9.
the onset melting temperature of high purity indium.
(S)-1-(4-Bromophenyl)propan-1-ol (10c). 206 mg, >95%. ee ¼
The synthesis and characterization of compounds 3, 6, 7, 8, 97% (HPLC: Chiralpak IC, hexane/i-PrOH ¼ 99/1, 1.5 mL minꢁ1
,
9, the preparation of magnetite/silica core–shell nanoparticles 220 nm, minor 7.4 min and major 8.6 min). 1H NMR (400 MHz,
(4a and 4b) and the nanostructured catalysts (1a and 1b) have CDCl3) d 7.45 (d, J ¼ 8.4 Hz, 2H, Ph), 7.18 (d, J ¼ 8.5 Hz, 2H, Ph),
been reported in our previous publication.7
4.52 (t, J ¼ 6.5 Hz, 1H, CHOH), 2.20 (bs, 1H, OH), 1.82–1.63 (m,
2H, CH2), 0.88 (t, J ¼ 7.4 Hz, 3H, CH3). 13C NMR (100 MHz,
CDCl3) d 143.6, 131.5, 127.8, 121.2, 75.3, 32.0, 10.1.
General procedure for the addition of dialkylzinc to aldehydes
catalyzed by free ligand in homogeneous phase
(S)-1-(2-Chlorophenyl)propan-1-ol (10d). 162 mg, >95% ee ¼
89% (HPLC: Chiralpak IA, hexane/i-PrOH
¼
99.5/0.5, 1
To a solution of the chiral amino alcohol (0.06 mmol, 6 mol%)
in toluene dry (2 mL) the aldehyde (1 mmol) was added under
argon atmosphere at room temperature. The mixture was then
cooled to 0 ꢀC. 2.2 mmol of dialkylzinc (2.2 mL of a 1.0 M hexane
solution of Et2Zn or 2.2 mL of a 1.0 M toluene solution of
iPr2Zn) were added dropwise. Then the reaction mixture was
allowed to reach the room temperature and stirred for 6 hours.
The reaction was quenched by the addition of a saturated NH4Cl
solution (10 mL). The mixture was then extracted with CH2Cl2.
The combined organic extracts were washed with brine, dried
over Na2SO4 and concentrated in vacuo. The crude product was
puried by ash chromatography (Hex/EtOAc 80 : 20).
mL minꢁ1, 225 nm, minor 29.6 min and major 32.4 min). H
NMR (400 MHz, CDCl3) d 7.51 (dd, J ¼ 7.7, 1.7 Hz, 1H, Ph), 7.36–
7.24 (m, 2H, Ph), 7.21–7.14 (m, 1H, Ph), 5.04 (dd, J ¼ 7.6, 4.9 Hz,
1H, CHOH), 2.43 (bs, 1H, OH), 1.87–1.63 (m, 2H, CH2), 0.97 (t, J
¼ 7.4 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) d 142.1, 132.0,
129.4, 128.4, 127.3, 127.1, 72.0, 30.5, 10.1.
1
(S)-1-(o-Tolyl)propan-1-ol (10e). 143 mg, >95%. ee ¼ 97%
(HPLC: Chiralpak IA, hexane/i-PrOH ¼ 95 : 5, 0.8 mL minꢁ1
,
220 nm, minor 7.6 min and major 8.3 min). 1H NMR (400 MHz,
CDCl3) d 7.46 (d, J ¼ 7.4 Hz, 1H, Ph), 7.27–7.12 (m, 3H, Ph), 4.87
(t, J ¼ 6.4 Hz, 1H, CHOH), 2.34 (s, 3H), 1.82–1.70 (m, 3H, CH2,
OH), 0.99 (t, J ¼ 7.4 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3)
d 142.9, 142.3, 134.7, 130.5, 127.3, 126.4, 125.3, 72.2, 31.0, 19.2,
10.5.
General procedure for the addition of dialkylzinc to aldehydes
catalyzed by functionalized nanoparticles
(S)-1-(p-Tolyl)propan-1-ol (10f). 144 mg, >95%. ee ¼ 97%
0.25 mmol of aldehyde was added, under argon atmosphere and (HPLC: Chiralpak IA, hexane/i-PrOH ¼ 98/2, 1 mL minꢁ1
,
at room temperature, to a dispersion of the catalyst-loaded 262 nm, minor 13.9 min and major 15.6 min). 1H NMR (400
nanoparticles (6 mol%) in 3 mL of dry toluene. The mixture MHz, CDCl3) d 7.23 (d, J ¼ 8.1 Hz, 2H, Ph), 7.17 (d, J ¼ 7.9 Hz,
ꢀ
was mechanically agitated for 20 min and then cooled to 0 C. 2H, Ph), 4.53 (t, J ¼ 6.6 Hz, 1H, CHOH), 2.37 (s, 3H, CH3), 2.24
0.8 mmol of dialkylzinc (0.8 mL of a 1.0 M hexane solution of (bs, 1H, OH), 1.89–1.67 (m, 2H, CH2), 0.92 (t, J ¼ 7.4 Hz, 3H,
Et2Zn or 0.8 mL of a 1.0 M toluene solution of iPr2Zn) was added CH2CH3). 13C NMR (100 MHz, CDCl3) d 141.7, 137.1, 129.1,
dropwise. Then the reaction mixture was allowed to reach the 126.0, 75.9, 31.8, 21.2, 10.23.
room temperature and mechanically agitated for 24 hours. The
(S)-1-(2-Methoxyphenyl)propan-1-ol (10g). 160 mg, >95%. ee
reaction vessel was placed over an external magnet until the ¼ 97% (HPLC: Chiralpak IB, hexane/i-PrOH ¼ 97 : 3, 0.8
1
reaction mixture became transparent, and the solution was mL minꢁ1, 280 nm, major 10.9 min and minor 11.7 min). H
separated from the nanoparticles. The reaction was quenched NMR (400 MHz, CDCl3) d 7.33–7.21 (m, 2H), 6.99–6.85 (m, 2H),
by the addition of a saturated NH4Cl solution (3 mL) and then 4.80 (t, J ¼ 6.6 Hz, 1H, CHOH), 3.84 (s, 3H, OCH3), 2.61 (bs, 1H,
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OH), 1.87–1.76 (m, 2H, CH2CH3), 0.96 (t, J ¼ 7.4 Hz, 3H, CH3). 6.8 Hz, CH3). 13C NMR (100 MHz, CDCl3) d 143.8, 137.9, 128.3,
13C NMR (100 MHz, CDCl3) d 156.7, 132.5, 128.2, 127.1, 120.8, 128.2, 127.4, 123.8, 80.2, 35.3, 21.6, 19.2, 18.4.
110.6, 72.4, 55.3, 30.2, 10.5.
2-Methyl-1-(p-tolyl)propan-1-ol (11d). 128.4 mg, 78%. ee ¼
(S)-1-((3-Methoxyphenyl))propan-1-ol (10h). 160 mg, >95%, 86.1% (HPLC: Chiralpak IB, hexane/i-PrOH
¼
98 : 2, 1
ee ¼ 98% (HPLC: Chiralpak IA, hexane/i-PrOH ¼ 95 : 5, 1 mL minꢁ1, 220 nm, T ¼ 30 C, major 6.8 min and minor 7.3
mL minꢁ1, 220 nm, minor 9.9 min and major 10.5 min). 1H min).1H NMR (300 MHz, CDCl3) d 7.32–7.09 (m, 4H, Phe), 4.32
NMR (400 MHz, CDCl3) d 7.25 (t, J ¼ 8.1 Hz, 1H, Ph), 6.92–6.89 (d, 1H, J ¼ 7.0 Hz, CHOH), 2.35 (s, 3H, CH3–Phe), 2.02–1.88 (m,
(m, 2H, Ph), 6.81 (ddd, J ¼ 8.3, 2.5, 1.0 Hz, 1H, Ph), 4.55 (t, J ¼ 1H, CH(CH3)2), 1.85 (bs, 1H, OH), 1.01 (d, 3H, J ¼ 6.7 Hz, CH3),
6.6 Hz, 1H, CHOH), 3.80 (s, 3H, OCH3), 2.03 (bs, 1H, OH), 1.85– 0.79 (d, 3H, J ¼ 6.8 Hz, CH3). 13C NMR (100 MHz, CDCl3) d 140.8,
1.68 (m, 2H, CH2), 0.92 (t, J ¼ 7.4 Hz, 3H, CH3). 13C NMR (100 137.1, 129.0, 126.6, 80.1, 35.3, 21.2, 19.1, 18.5.
ꢀ
MHz, CDCl3) d 159.8, 146.5, 129.5, 118.4, 113.0, 111.5, 76.0,
(ꢁ)-3-(1-Hydroxy-2-methylpropyl)benzonitrile (11e). 144 mg,
55.3, 31.9, 10.2.
82%, [a]2D5 ¼ ꢁ15.6 (c 1.5, CHCl3), ee ¼ 86.6% (HPLC: Chiralpak
(S,E)-1-Phenylpent-1-en-3-ol (10i). 154 mg, >95%. ee ¼ 88% IB, hexane/i-PrOH ¼ 98 : 2, 1 mL minꢁ1, 220 nm, T ¼ 30 ꢀC,
(HPLC: Chiralpak IC, hexane/i-PrOH ¼ 98 : 2, 1 mL minꢁ1
,
major 19.8 min and minor 22.4 min). 1H-NMR (300 MHz,
254 nm, minor 13.0 min and major 14.9 min). 1H NMR (400 CDCl3) d: 7.63 (t, 1H, J ¼ 1.7 Hz, Phe), 7.58–7.53 (m, 2H, Phe),
MHz, CDCl3) d 7.41–7.37 (m, 2H, Ph), 7.35–7.29 (m, 2H, Ph), 7.47–7.41 (m, 1H, Phe) 4.46 (d, 1H, J ¼ 6.2 Hz, CHOH) 2.01–1.83
7.27–7.22 (m, 1H, Ph), 6.58 (d, J ¼ 15.9 Hz, 1H, PhCH), 6.20 (dd, (m, 1H, CH(CH3)2); 1.60 (bs, 1H, OH); 0.95 (d, 3H, J ¼ 6.7 Hz,
1H, J ¼ 15.9, 6.7 Hz, CHCHOH), 4.22 (dd, 1H, J ¼ 12.3, 6.2 Hz, CH3); 0.84 (d, 3H, J ¼ 6.8 Hz, CH3). 13C NMR (100 MHz, CDCl3)
CHOH), 1.72–1.61 (m, 3H, CH2CH3 + OH), 0.98 (t, J ¼ 7.5 Hz, 3H, d 145.1, 131.2, 131.1, 130.3, 129.1, 119.1, 112.4, 78.8, 35.5, 18.9,
CH3). 13C NMR (100 MHz, CDCl3) d 136.9, 132.4, 130.6, 128.7, 17.7.
127.8, 126.6, 74.6, 30.4, 9.9.
(ꢁ)-4-(1-Hydroxy-2-methylpropyl)benzonitrile (11f). 84 mg,
(S)-1-Phenylpentan-3-ol (10j). 155 mg, >95%. ee ¼ 87% 48%. ee ¼ 97.7% (HPLC: Chiralpak IB, hexane/i-PrOH ¼ 98 : 2,
[a]2D5: +16.9 (CHCl3, c ¼ 3.2). 1H NMR (300 MHz, CDCl3) d: 7.36– 1 mL minꢁ1, 220 nm, T ¼ 30 ꢀC, major 20.8 min and minor 22.2
7.15 (m, 5H, CHarom), 3.64–3.50 (m, 1H, CHOH), 2.91–2.59 (m, min). 1H NMR (400 MHz, CDCl3) d 7.24 (d, 2H, J ¼ 8.2 Hz, Phe),
2H, CH2Ph), 1.89–1.68 (m, 4H, CH2CHCH2), 1.28 (bs, 1H, OH), 7.19 (d, 2H, J ¼ 8.2 Hz, Phe), 4.33 (d, 1H, J ¼ 7.0 Hz, CHOH),
0.96 (t, J ¼ 7.4 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3) d: 142.3; 2.96–2.84 (m, 1H, CH(CH3)2), 1.01 (d, 3H, J ¼ 6.7 Hz, CH3), 0.79
128.5; 128.5; 125.9; 72.8; 38.7; 32.2; 30.4; 10.0.
(d, J ¼ 6.8 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) d 149.4,
(S)-1-Cyclohexylpropan-1-ol (10k).16 125.2 mg, 70%. ee ¼ 80% 132.3, 127.6, 119.2, 111.2, 79.1, 35.6, 19.2, 17.8.
(HPLC on the o-bromo benzoyl ester derivative: Chiralpak IA,
1-(2-Chlorophenyl)-2-methylpropan-1-ol (11g). 82 mg, 44%.
hexane/EtOH ¼ 99 : 1, 0.8 mL minꢁ1, 220 nm, minor 5.5 min ee ¼ 81.2% (HPLC: Chiralpak IF, hexane/i-PrOH ¼ 98 : 2, 1
and major 5.9 min). 1H NMR (400 MHz, CDCl3) d 3.27 (ddd, J ¼ mL minꢁ1, 220 nm, r.t., minor 7.3 min and major 8.5 min). 1H
8.9, 5.4, 3.9 Hz, 1H, CHOH), 1.86–0.91 (m, 17H, c-Hex, CH2CH3, NMR (400 MHz, CDCl3) d 7.51 (dd, 1H, J ¼ 7.7, 1.7 Hz, Ph), 7.35–
OH), 0.94 (t, 3H, J ¼ 7.4 Hz, CH3). 13C NMR (100 MHz, CDCl3) 7.26 (m, 2H, Ph), 7.22–7.16 (m, 1H, Ph), 4.91 (d, 1H, J ¼ 6.0 Hz,
d 77.8, 43.3, 29.5, 27.9, 27.0, 26.7, 26.5, 26.4, 10.4.
CHOH), 2.12–1.99 (m, 1H, CH(CH3)2), 1.84 (bs, 1H, OH), 0.97 (d,
(S)-2-Methyl-1-phenylpropan-1-ol (11a).17 132 mg, 88%. 3H, J ¼ 6.7 Hz, CH3), 0.93 (d, 3H, J ¼ 6.9 Hz, CH3). 13C NMR (100
[a]2D5 ¼ ꢁ26.1 (c 3.3, CHCl3). ee ¼ 95.5% (HPLC: Chiralpak IB, MHz, CDCl3) d 141.4, 130.8, 129.5, 128.4, 128.2, 126.9, 75.6,
hexane/i-PrOH ¼ 99 : 1, 1 mL minꢁ1, 220 nm, T ¼ 30 ꢀC, major 34.2, 19.5, 17.2.
8.0 min and minor 8.6 min).1H NMR (300 MHz, CDCl3) d 7.40–
1-(4-Bromophenyl)-2-methylpropan-1-ol (11h). 167 mg, 73%.
7.20 (m, 5H, Phe), 4.36 (d, 1H J ¼ 6.9 Hz, CHOH), 2.10 (bs, 1H, [a]2D5 ¼ ꢁ24.8 (c 2.1, CHCl3), ee ¼ 88.2% (HPLC: Chiralpak IB,
OH), 2.03–1.87 (m, 1H, CH(CH3)2), 1.01 (d, 3H, J ¼ 6.7 Hz, CH3), hexane/i-PrOH ¼ 99 : 1, 1 mL minꢁ1, 220 nm, T ¼ 30 ꢀC, major
0.80 (d, 3H, J ¼ 6.8 Hz, CH3). 13C NMR (75 MHz, CDCl3) d 143.8, 8.8 min and minor 9.2 min). H NMR (300 MHz, CDCl3) d 7.44
1
128.3, 127.5, 126.7, 80.2, 35.4, 19.1, 18.3.
(d, J ¼ 8.3 Hz, 2H), 7.16 (d, J ¼ 8.3 Hz, 2H), 4.31 (d, J ¼ 6.6 Hz,
(S)-2-Methyl-1-(o-tolyl)propan-1-ol (11b).18 92 mg, 56%. 1H), 2.11 (bs, 1H), 1.95–1.83 (m, 1H), 0.95 (d, J ¼ 6.7 Hz, 3H),
[a]D25 ¼ ꢁ28.6 (c 2.5, CHCl3). ee ¼ 95.3% (HPLC: Chiralpak IB, 0.78 (d, J ¼ 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 142.6,
hexane/i-PrOH ¼ 98 : 2, 1 mL minꢁ1, 220 nm, T ¼ 30 ꢀC, major 131.3, 128.4, 121.2, 79.3, 35.3, 18.9, 18.1.
6.8 min and minor 7.1 min).1H-NMR (300 MHz, CDCl3) d: 7.49–
1-(2-Methoxyphenyl)-2-methylpropan-1-ol (11i). 142 mg,
7.35 (m, 1H, Phe); 7.31–7.06 (m, 4H, Phe); 4.63 (d, 1H, J ¼ 79%. ee ¼ 88.2% (HPLC: Chiralpak IB, hexane/i-PrOH ¼ 98 : 2,
6.7 Hz, CHOH); 2.34 (s, 3H, CH3–Phe); 2.02–1.91 (m, 1H, 1 mL minꢁ1, 220 nm, T ¼ 30 C, major 7.8 min and minor 8.4
ꢀ
1
CH(CH3)2); 1.74 (bs, 1H, OH); 1.04 (d, 3H, J ¼ 6.67 Hz, CH3); 0.85 min). H NMR (400 MHz, CDCl3) d 7.32–7.18 (m, 2H, Ph), 6.95
(d, 3H, J ¼ 6.67 Hz, CH3). 13C NMR (100 MHz, CDCl3) d 142.3, (td, 1H, J ¼ 7.4, 1.1 Hz, Ph), 6.88 (d, 1H, J ¼ 8.2 Hz, Ph), 4.51 (d,
135.1, 130.4, 127.2, 126.2, 126.2, 75.9, 34.7, 19.6, 19.5, 18.0.
1H, J ¼ 7.4 Hz, CHOH), 3.84 (s, 3H, OCH3), 2.23 (bs, 1H, OH),
2-Methyl-1-(m-tolyl)propan-1-ol (11c). 136 mg, 83%, ee ¼ 2.13–1.97 (m, 1H, CH(CH3)2), 1.03 (d, 3H, J ¼ 6.7 Hz, CH3), 0.80
93.4% (HPLC: Chiralpak IB, hexane/i-PrOH
¼
98 : 2,
1
(d, 3H, J ¼ 6.8 Hz, CH3). 13C NMR (100 MHz, CDCl3) d 156.7,
mL minꢁ1, 220 nm, T ¼ 30 C, major 6.9 min and minor 7.2 131.7, 128.2, 128.1, 120.6, 110.6, 76.8, 55.3, 34.2, 19.6, 18.5.
ꢀ
min) 1H NMR (300 MHz, CDCl3) d 7.40–6.96 (m, 4H, Phe), 4.31
1-(3-Methoxyphenyl)-2-methylpropan-1-ol (11j). 158 mg,
(d, 1H, J ¼ 6.9 Hz, CHOH), 2.36 (s, 3H, CH3–Phe), 2.04–1.86 (m, 88%. ee ¼ 91.1% (HPLC: Chiralpak IB, hexane/i-PrOH ¼ 98 : 2,
1H, CH(CH3)2), 1.01 (d, 3H, J ¼ 6.7 Hz, CH3), 0.80 (d, 3H, J ¼ 1 mL minꢁ1, 220 nm, T ¼ 30 ꢀC, major 13.4 min and minor 17
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min). 1H NMR (400 MHz, CDCl3) d 7.28–7.22 (m, 1H, Ph), 6.91–
6.87 (m, 2H, Ph), 6.84–6.79 (m, 1H, Ph), 4.34 (d, 1H, J ¼ 6.9 Hz,
CHOH), 3.81 (s, 3H, OCH3), 2.00–1.89 (m, 1H, CH(CH3)2), 1.77
(bs, 1H, J ¼ 9.7 Hz, OH), 1.00 (d, CH3, J ¼ 6.7 Hz, 3H), 0.81 (d,
3H, J ¼ 6.8 Hz, CH3). 13C NMR (100 MHz, CDCl3) d 159.7, 145.6,
129.3, 119.1, 112.9, 112.2, 80.1, 55.3, 35.4, 19.2, 18.3.
7 C. Sappino, L. Primitivo, M. De Angelis, M. Oneto Domenici,
A. Mastrodonato, I. Ben Romdan, C. Tatangelo, L. Suber,
L. Pilloni, A. Ricelli and G. Righi, ACS Omega, 2019, 4,
21809–21817.
8 C. Sappino, A. Mari, A. Mantineo, M. Moliterno, M. Palagri,
C. Tatangelo, L. Suber, P. Bovicelli, A. Ricelli and G. Righi,
Org. Biomol. Chem., 2018, 16, 1860–1870.
9 C. Sappino, Design and synthesis of new nanostructured
chiral catalyst, PhD thesis, Sapienza University of Rome,
2017.
Conflicts of interest
There are no conicts to declare.
10 L. Liang and D. Astruc, Coord. Chem. Rev., 2011, 255, 2933–
2945.
11 C. Sun, J. S. H. Lee and M. Zhang, Adv. Drug Delivery Rev.,
2008, 60, 1252–1265.
Acknowledgements
We would like to thank Dott. Daniele Mirabile Gattia (ENEA) for
XRD measurement.
`
`
12 J. Fraile, J. A. Mayoral, J. Serrano, M. A. Pericas, L. Sola and
D. Castellnou, Org. Lett., 2003, 5, 4333–4335.
13 V. Slavov, A. R. Sanger and K. T. Chuang, J. Phys. Chem. B,
2000, 104, 983–989.
Notes and references
1 R. A. Sheldon, Chem. Commun., 2008, 3352–3365.
2 L. M. Rossi, N. J. S. Costa, F. P. Silvia and R. Wojcieszak,
Green Chem., 2014, 16, 2906–2933.
14 M. Asami and S. Inoue, Bull. Chem. Soc. Jpn., 1997, 70, 1687–
1690.
15 Y. S. Shih, R. Boobalan, C. Chen and G.-H. Lee, Tetrahedron:
Asymmetry, 2014, 25, 327–333.
16 Z.-L. Wu, H.-L. Wu, P.-Y. Wu and B.-J. Uang, Tetrahedron:
Asymmetry, 2009, 20, 1556–1560.
17 W. Wu, S. Liu, M. Duan, X. Tan, C. Chen, Y. Xien, Y. Lan,
X. Dong and X. Zhang, Org. Lett., 2016, 18, 2938–2941.
18 W. K. Yang and B. T. Cho, Tetrahedron: Asymmetry, 2000, 11,
2947–2952.
¨
3 S. Shylesh, V. Schunemann and W. R. Thiel, Angew. Chem.,
Int. Ed., 2010, 49, 3428–3459.
4 (a) R. Dalpozzo, Green Chem., 2015, 17, 3671–3686; (b)
J. Safaei-Ghomi and S. Zahedi, Appl. Organomet. Chem.,
2015, 29, 566–571.
5 D. J. Ager, I. Prakash and D. R. Schaad, Chem. Rev., 1996, 96,
835–875.
6 F. Michalek, A. Lagunas, C. Jimeno and M. A. Pericas, J.
Mater. Chem., 2008, 18, 4692.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 29688–29695 | 29695