Organocatalysts immobilised onto gold nanoparticles: Application in the asymmetric reduction of imines with trichlorosilane

Article abstract of DOI:10.1039/b821391g

Gold nanoparticles functionalised with a valine-derived formamide have been developed as effective homogenous catalysts for the asymmetric reduction of ketimine 1 with trichlorosilane (≤84% ee) in toluene. This methodology both simplifies the recovery of

Full text of DOI:10.1039/b821391g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Organocatalysts immobilised onto gold nanoparticles: application in the
asymmetric reduction of imines with trichlorosilane†
Andrei V. Malkov,*‡ Marek Figlus, Graeme Cooke,* Stuart T. Caldwell, Gouher Rabani, Mark R. Prestly and
Pavel Kocˇovsky´*
Received 28th November 2008, Accepted 6th February 2009
First published as an Advance Article on the web 25th March 2009
DOI: 10.1039/b821391g
Gold nanoparticles functionalised with a valine-derived formamide have been developed as effective
homogenous catalysts for the asymmetric reduction of ketimine 1 with trichlorosilane (≤84% ee) in
toluene. This methodology both simplifies the recovery of the catalyst and its separation from the
product, as the nanoparticles can be readily removed and subsequently recycled by precipitation from
the reaction mixture.
Introduction
Organocatalysts, small organic molecules capable of promoting
enantioselective reactions, are rapidly gaining ground as viable al-
ternatives to their organometallic and bio-catalytic counterparts.1
However, typical organocatalytic procedures developed to date
generally require a relatively high catalyst loading, which cre-
ates problems in product isolation. To overcome the separation
difficulties, some of the successful organocatalysts have been
immobilised onto polymers.2 Most of these systems have utilised
commercially available polymers (e.g., polystyrenes); however, this
approach often produces catalysts that exhibit lower activity and
selectivity than the parent systems, presumably due to the impaired
accessibility of the catalytic site, problems associated with polymer
swelling, and/or thebackground reaction catalysed bythe polymer
itself.
Catalyst-functionalised nanoparticles3 offer an attractive al-
ternative for the development of new supported catalysts.4
In particular, the ability to functionalise monolayer-protected
nanoparticles via place-exchange reactions allows the synthesis
of soluble systems, whereby both the number and accessibility of
the catalyst molecules attached to the surface can be conveniently
controlled.5 Furthermore, the catalyst molecules immobilised onto
nanoparticles are located on the surface, which is in contrast with
polymer-supported catalysts, where a number of catalyst moieties
will be encapsulated inside the polymer.
The asymmetric reduction of prochiral ketimines (Scheme 1),
is one of the key reactions in synthetic organic chemistry
that provides precious building blocks for the fine-chemical
industry.6 The organocatalytic1 version is currently characterized
by two fundamentally different approaches: (i) hydrosilylation
with trichlorosilane, catalysed by chiral Lewis-bases, which ac-
tivate the nucleophilic hydride donor (Scheme 1),7,8 and (ii)
reduction with Hantzsch dihydropyridine, catalysed by chiral
Scheme 1 The asymmetric reduction of an imine with trichlorosilane.
Brønsted acids, which activate the electrophilic recipient (i.e., the
imine).9
During the last few years, Kocˇovsky´, Malkov and co-workers
have developed Lewis-basic organocatalysts for the reduction of
imines with Cl3SiH.7 In particular, the formamides 3a,b7b–d,10 based
on the N-methyl valine scaffold (Scheme 1), proved to be most
effective (Table 1, entries 1 and 2). The workup and isolation
procedures were then simplified by appending a fluorous tag
(e.g. 3c)7d or by anchoring the catalyst to an insoluble polymer
(e.g. 3d)7e (entries 3 and 4). However, the increased cost of the
former and reduced efficiency in the latter methodology has
hampered the further development of these systems. Herein, we
report on the immobilisation of a Lewis-basic amino acid-derived
formamide onto the monolayer-protected gold nanoparticles and
the application of this system as a catalyst for the asymmetric
reduction of ketimines with Cl3SiH. It was anticipated that the
solubility of these systems in organic solvents would restore
the benefits of working in a homogeneous solution, whilst the
relatively easy recovery of the inorganic support material would
reduce the cost implications.
Results and discussion
WestCHEM, Department of Chemistry, Joseph Black Building, University
of Glasgow, Glasgow, UK G12 8QQ. E-mail: A.Malkov@lboro.ac.uk,
graemec@chem.gla.ac.uk, pavelk@chem.gla.ac.uk
Synthesis
† Electronic supplementary information (ESI) available: TEM images of
6a and 7a. See DOI: 10.1039/b821391g
‡ Current address: Department of Chemistry, Loughborough University,
Loughborough, UK LE11 3TU
The synthesis of the catalyst-functionalised nanoparticles
(Scheme 2) commenced with the phenolic derivative 4.7d,e Ester-
ification with lipoic acid, using standard carbodiimide protocol,
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Table 1 Reduction of imine 1 with trichlorosilane, catalysed by 3, 5–7,
and 15a
(~8.14 ppm). FT- IR spectroscopy confirmed the ester and amide
1
carbonyls (at 1755 and 1655 cm-1). H NMR spectroscopy was
used to estimate the degree of catalyst loading on the butyl and
octyl protected nanoparticles. Based upon the integration of the
formamide proton(CONH)andthe terminal methylgroups (CH3)
of the butyl and octyl chains (in 7a and 7b), we estimate the average
ratio to be approximately 1 : ≥20 (CONH : CH3), suggesting a low
loading of the catalyst. Nanoparticles 7a and 7b exhibited good
solubility in non-polar solvents (e.g., CH2Cl2 and toluene) but
proved to be poorly soluble in more polar solvents (e.g., CH3OH).
Since the linker unit between the catalyst and the support
often affects the activity quite dramatically, we prepared another
nanoparticle-immobilized catalyst 15 for comparison (Scheme 3).
Here, an undecanethiol unit was used to link the catalytic
moiety via an ether link, to the gold nanoparticle. Ether links
have proved to be an excellent choice in our previous work
(3c,d).7d,e Compound 10 was prepared from 11-bromoundecan-
1-ol 9 and phenolic derivative 8 via a Mitsunobu reaction. The
nitro group of compound 10 was then reduced to an amino group
to yield 11. Compound 11 was reacted with a BOC-protected
N-(Me)-Val derivative to afford 12, which was deprotected and
converted into the formamide derivative 13. The bromide in 13
was replaced by a thiol group upon reaction with (Me3Si)2S13 and
Bu4NF in THF at 0 ◦C for 2 h. The resulting thiol 14 (90%)
was immobilized by an exchange reaction with the butanethiol-
protected gold nanoparticles 6a to produce nanoparticles 15.
entry
run
catalyst
yieldb(%)
eec,d (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
—
—
—
—
—
—
—
1
2
3
4
—
—
3ae
3bf
3ce
3de,g
3ee
5e
85
95
90
81
90
80
51
90
92
92
89
88
86
91k
94k
91k
82k
91
89
—
84
82
80
68
70
79
6ah
7ah
7a
7a
7a
7bi
15j
a The reaction was carried out at 0.2 mmol scale with 2.0 equiv of
Cl3SiH in toluene at 20 ◦C overnight unless stated otherwise. b Isolated
yield. c Determined by chiral HPLC. d The absolute configuration of the
product was (S)-(-)-2 as shown by the optical rotation and by HPLC via
comparison with an authentic sample. e 10 mol%. f 5 mol%. g Chloroform
was used as solvent instead of toluene. h 100 mg. i 79 mg. j 20 mol%. k Ref.
7b–e.
1
Following integration of the broad H NMR resonances for the
formamide protons (CONH) and the terminal methyl groups
Scheme 2 Organocatalyst immobilisation on gold nanoparticles via a
lipoic acid linker.
afforded ester 5 (80%). In parallel, gold nanoparticles 6a and 6b
were prepared from HAuCl4·3H2O via reduction with NaBH4,
carried out in the presence of butane-thiol or octane-thiol and
tetraoctylammonium bromide as a phase-transfer catalyst, in
a toluene–water two-phase system.11,12 The resulting ~2 nm
nanoparticles 6a and 6b were then isolated by precipitation with
absolute ethanol, followed by filtration.11 The subsequent place-
exchange reactions between the latter nanoparticles and the lipoic
ester 5 afforded the catalyst-functionalised nanoparticles 7a and
7b, respectively, which were isolated again by precipitation with
ethanol. The 1H NMR spectra of 7a and 7b displayed broad
resonances for valine-derived catalytic moiety and in particular
revealed the presence of broad signals for the formamide protons
Scheme 3 Organocatalyst immobilisation on gold nanoparticles via a
thiol linker.
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(CH3) of the butyl chains, we estimate the average ratio to be
approximately 1 : 10 (CONH : CH3), suggesting a higher catalyst
loading compared to 7a.
separation from the product, as the nanoparticles can be readily
removed from the reaction mixture by precipitation and re-used.
Hence, this work may be viewed as a proof of concept, which can
be further extended to other, less expensive nanoparticle systems,
such as those based on Fe.16
Catalyst screening
The screening of the new catalyst candidates in the reduction of
imine 1, our bench-mark substrate,7 was carried out under the
conditions previously optimized for the non-supported catalysts
3a,b.7a–d Thus, Cl3SiH (0.40 mmol) was added to a solution of
1 (0.20 mmol) and 7a (100 mg) in dry toluene at 0 ◦C and
the mixture was stirred at room temperature overnight under
an argon atmosphere. After the reaction was complete, toluene
was evaporated and the residue was treated with methanol. The
resulting mixture was centrifuged, allowing the separation of the
solid catalyst from the product, which remained in the solution.
The methanolic solution was evaporated and the residue was
worked-up with aqueous NaHCO3 as previously described,7 to
afford amine (S)-(-)-2 (84% ee; Table 1, entry 8). The octanethiol-
coated nanoparticles 7b exhibited lower enantio-selectivity (70%
ee, entry 12), whereas 15 behaved in a similar manner as 7a (79%
ee, entry 13).14
The convenient recovery of 7a allowed us to probe the recycla-
bility of this system (entries 9–11), with the recovered catalyst
being re-used without further purification. While the 2nd and
3rd run gave essentially the same results as the fresh catalyst
(compare entry 8 with 9 and 10), considerable deterioration of
enantioselectivity was observed in the 4th run, although the
isolated yield remained practically unchanged (entry 11). Control
experiments showed that acetate 3e and the free lipoic acid ester 5
catalysed the reduction very effectively (91 and 89% ee, entries 5
and 6). Interestingly, the butanethiol-protected nanoparticles 6a,
lacking the organocatalyic moiety, were also found to catalyse
the reduction although at a lower rate, reflected in a reduced
conversion. Naturally, the resulting amine 2 was racemic (entry
7). The latter result suggests that the significant deterioration of
enantioselectivity in the 4th run (entry 11) may stem from partial
desorption of the immobilised organocatalyst from the nanopar-
ticle, and its gradual removal during the repeated workup, so that
the background reaction, catalysed by the stripped nanoparticles,
becomes competitive. Aggregation of the nanoparticles15 may also
be regarded as a contributing factor, as a decreased solubility of
the nanoparticles was observed after the 3rd run, thereby shifting
the clearly homogeneous system (1st run) to nearly heterogeneous
(4th run).
Experimental section
General Methods
Melting points were determined on a Kofler block and are
uncorrected. Optical rotations were recorded in CHCl3 at 25 C
◦
unless otherwise indicated, with an error of ≤ 0.1. The [a]D values
are given in 10-1deg cm3 g-1. The NMR spectra were recorded as
1
CDCl3 solutions, H at 400 MHz and 13C at 100.6 MHz, with
chloroform-d1 (d 7.26, 1H; d 77.0, 13C) as internal standard
unless otherwise indicated. Various 2D-techniques and DEPT
experiments were used to establish the structures and to assign
the signals. The IR spectra were recorded for KBr discs or for
a thin film between NaCl plates. The mass spectra (EI and/or
CI) were measured on a dual sector mass spectrometer using
direct inlet and the lowest temperature enabling evaporation.
All reactions were performed under an atmosphere of dry,
oxygen-free nitrogen in oven-dried glassware, twice evacuated
and filled with inert gas. Solvents and solutions were transferred
by syringe-septum and cannula techniques. All solvents for the
reactions were of reagent grade and were dried and distilled
under nitrogen immediately before use as follows: toluene from
sodium/benzophenone, dichloromethane from calcium hydride,
triethylamine from calcium hydride. Petroleum ether refers to
the fraction boiling in the range of 60–80◦C. Yields are given
for isolated products showing one spot on a TLC plate and
no impurities detectable in the NMR spectrum. The identity
of the products prepared by different methods was checked by
comparison of their NMR, IR, and MS data and by the TLC
behaviour. The chiral HPLC methods were calibrated with the
corresponding racemates.
Synthesis of 5. Phenolic derivative 47e (200 mg, 0.72 mmol)
and 4-(dimethylamino)-pyridine (DMAP, 28 mg, 0.23 mmol) were
consecutively added to a solution of (3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI; 344 mg, 1.79 mmol) and
( )-lipoic acid (296 mg, 1.43 mmol) in CH2Cl2 (10 mL) and the
◦
reaction mixture was stirred at 25 C for 20 h. The mixture was
then diluted with ethyl acetate (30 mL) and washed consecutively
with water (2 ¥ 40 mL), 0.5M HCl (40 mL), saturated NaHCO3
(2 ¥ 40 mL), water (40 mL), and brine (40 mL) and dried over
MgSO4, filtered and evaporated. The residue (357 mg) was purified
by chromatography on a column of silica gel (25 g) eluting with a
mixture of CH2Cl2 and MeOH (100 : 1), to afford pure formamide
(-)-5 (280 mg, 80%) as a yellow oil: Rf = 0.44 and 0.26 (two spots;
Conclusions
In conclusion, we have synthesised gold nanoparticles 7a,b and 15
functionalised with a valine-derived formamide and demonstrated
their propensity to catalyse the asymmetric reduction of imine 1
with Cl3SiH at room temperature in the environmetally benign
toluene as solvent. The highest level of catalytic activity and
enantioselectivity (≤84% ee) was attained with 7a. This result
can be extrapolated to a number of derivatives of imine 1, since
we have previously demonstrated little variation of the yield and
enantioselectivty as a function of the substitution pattern in
the imine structure for catalysts 3a–d.7 This new homogenous
methodology simplifies the recovery of the catalyst and its
1
CH2Cl2–MeOH, 49 : 1); [a]D -89.20 (c 0.65, CHCl3); H NMR
(400 Hz, CDCl3, a mixture of rotamers in ca. 4 : 1 ratio; the signals
for the minor rotamer are marked with an *) d 0.91 (d, J = 6.6 Hz,
3H), 1.03 (d, J = 6.5 Hz, 3H), 1.48–1.64 (m, 2H), 1.66–1.77 (m,
2H), 1.78–1.85 (m, 2H), 1.88–1.96 (m, 1H), 2.10 (s, 6H), 2.36–
2.51 (m, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.91 (s, 0.37H*), 2.99 (s,
2.63H)* 3.09–3.22 (m, 2H), 3.50 (d, J = 10.4 Hz, 0.14H*), 3.54–
3.62 (m, 1H), 4.39 (d, J = 11.3, 0.89H), 7.23 (s, 0.31 H*), 7.27 (s,
1.63H), 7.99 (s, br. 0.11H*), 8.13 (s, 0.89H), 8.19 (s, 0.77H), 8.22
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(s, 0.18H*); 13C NMR d 16.49 (CH3), 18.53 (CH3), 19.52 (CH3),
24.81 (CH2), 25.20 (CH), 28.85 (CH2), 31.60 (CH3), 33.74 (CH2),
34.59 (CH2), 38.42 (CH2), 40.21 (CH2), 56.26 (CH), 63.26 (CH),
119.83 (CH), 130.74 (C), 135.10 (C), 144.52 (C), 163.98 (CHO),
167.06 (CO), 171.26 (CO); IR (KBr) n 3434, 2926, 1753, 1656,
1556, 1485, 1411, 1372, 1187 1124 cm-1; MS (FAB) m/z (%) 467
([MH]∑+, 14), 278 (22), 189 (16), 1432 (94), 115 (100), 88 (30), 79
(23); HRMS (FAB) 467.2043 (C23H35N2O4S2 requires 467.2038).
J = 7.6 Hz), 2.97 (s), 4.33 (d, J = 10.3 Hz), 8.00 (broad signal),
8.13 (broad signal); IR (KBr) n 3440, 2951, 2927, 2869, 1760, 1649,
1560, 1460, 1418, 1375, 1266, 1211, 1094 cm-1.
Synthesis of 10. Triphenylphosphine (1.96 g, 7.47 mmol),
11-bromo-1-undecanol (1.86 g, 7.40 mmol), and 97% diethyl
azodicarboxylate (1.17 mL, 7.46 mmol) were added consecutively
to a stirred solution of 2,6-dim◦ethyl-4-nitrophenol 8 (1.0 g,
5.98 mmol) in THF (14 mL) at 0 C. The resulting mixture was
stirred at 25 ◦C for 18 h and the solvent was then evaporated.
The residue (6.12 g) was purified by chromatography on a column
of silica gel (80 g) eluting with a mixture of petroleum ether and
CH2Cl2 (4 : 1), to give 10 (1.96 g, 82%) as a yellowish oil: Rf =
0.42 (petroleum ether–CH2Cl2, 4 : 1); 1H NMR (400 Hz, CDCl3) d
1.30–1.56 (m, 14H), 1.82 (pent, J = 6.6 Hz, 2H), overlapped with
1.85 (pent, J = 6.9 Hz, 2H), 2.34 (s, 6H), 3.41 (t, 2H, J = 6.8 Hz),
3.81 (t, J = 6.6 Hz, 2H), 7.91 (s, 2H); 13C NMR d 16.60 (CH3),
26.00 (CH2), 28.13 (CH2), 28.73 (CH2), 29.38 (CH2), 29.43 (CH2),
29.50 (CH2), 30.32 (CH2), 32.79 (CH2), 34.06 (CH2), 72.75 (CH2),
124.19 (CH), 132.32 (C), 143.28 (C), 161.66 (C); MS (EI) m/z (%)
401 and 399 (M∑+, 14), 167 (100), 137 (33), 97 (30), 55 (62); HRMS
(EI) 399.1415 (C19H30BrNO3 requires 399.1409).
Synthesis of gold nanoparticles 6a. A solution of hydrogen
tetrachloroaurate hydrate HAuCl4·3H2O (2.0 g, ~49% Au metal
basis, 5.0 mmol) in deionised water (150 mL) was added to a stirred
solution of tetraoctyl ammonium bromide (6.80 g, 12.44 mmol,
2.5 equiv) in toluene (480 mL). The mixture was stirred for
10 min, the organic layer was separated and butanethiol (132 mL,
1.24 mmol, 0.25 equiv) was added. The solution was stirred for
10 min and then a solution of NaBH4 (1.88 g, 49.8 mmol, 10 eq.)
in deionised water (150 ml) was added over ~10 s.12 The resulting
black solution was stirred at room temperature for 3.5 h after
which time the layers were separated and the toluene layer was
concentrated to near dryness under vacuum. Ethanol (70 mL) was
then added and the precipitate was isolated by gravity filtration,
and then washed with ethanol (300 mL) and acetone (450 mL)
Synthesis of 11. Tin(II) chloride dihydrate (4.50 g,
19.94 mmol) was added to a solution of the nitro ether 10 (2.00 g,
5.00 mmol) in EtOH (25 mL) and the resulting solution was stirred
1
to afford nanoparticles 6a as a black powder (1.07 g): H NMR
(400 Hz, CDCl3) d 0.95 (broad signal), 1.27 (broad signal), 1.54
(broad signal), 1.68 (broad signal), 3.38 (broad signal).
◦
at 40 C for 25 h. The mixture was then cooled and a saturated
aqueous solution of NaHCO3 (80 mL) was added to reach pH 10.
The product was extracted with ether (3 ¥ 150 mL) and the organic
phase was dried over MgSO4. The filtrate was concentrated to
~250 mL and aqueous 1M HCl (20 mL) was added. The mixture
was stirred for 10 min, the precipitated white solid was collected
by filtration and washed with ether (3 ¥ 100 mL). Drying in the
air afforded the aniline salt 11 (1.05 g, 52%) as a white powder:
mp 188–192 ◦C (dec); 1H NMR (400 Hz, CDCl3) d 1.30–1.52(m,
14H), 1.78 (pent, J = 6.7, Hz 2H), 1.85 (pent, J = 7.3 Hz, 2H),
2.27 (s, 6H), 3.41 (t, J = 6.9 Hz, 2H), 3.71 (t, J = 6.5 Hz, 2H),
7.16 (s, 2H), 10.33 (br s, 2.65H); 13C NMR d 16.26 (CH3), 26.08
(CH2), 28.16 (CH2), 28.74 (CH2), 29.40 (CH2), 29.45 (CH2), 29.48
(CH2), 29.51 (CH2), 30.31 (CH2), 32.83 (CH2), 34.02 (CH2), 72.56
(CH2), 123.12 (CH), 124.50 (C), 133.23 (C), 156.55 (C); MS (CI)
m/z 372 and 370 (M+, 100), 369 (22), 290 (13), 138 (78), 137 (21),
69 (48); HRMS (CI) 370.1752 (C19H33BrNO3 requires 370.1746).
Synthesis of gold nanoparticles 6b. Synthesised on a 1.0 g scale
from HAuCl4·3H2O (1.0 g, 2.5 mmol) in an identical manner to
that shown above but using octanethiol (91 mg, 0.62 mmol) instead
of butanethiol. 1H NMR (400 Hz, CDCl3) d 0.88 (broad signal),
1.27 (broad signal), 1.55 (broad signal), 1.66 (broad signal), 3.37
(broad signal).
Synthesis of gold nanoparticles 7a. Disulfide (-)-5 (538 mg,
1.15 mmol) was added to a solution of butylthiolate-stabilised
gold nanoparticles 6a (538 mg, 0.63 mmol) in toluene (70 mL) and
the resulting solution was stirred at room temperature for 3 days.
The solution was then concentrated under vacuum and EtOH
(50 mL) was added. The resulting precipitate was filtered by gravity
filtration and washed with EtOH (150 mL) and acetone (150 mL)
to furnish nanoparticles 7a (493 mg) as a black powder: 1H NMR
(400 Hz, CDCl3) d 0.89 (broad signal), 1.55 (broad signal), 2.97
(broad signal), 3.54 (broad signal), 4.33 (broad signal), 8.14 (broad
signal); IR (KBr) n 3446, 2954, 2923, 2869, 1757, 1655, 1560,
1456, 1416, 1375, 1261, 1210, 1094 cm-1. Anal. found: C, 7.14; H,
1.15. The filtrate was concentrated under vacuum and then passed
quickly through a plug of silica gel, eluting with a CH2Cl2–Me2CO
mixture (3 : 1) to give unreacted lipoic ester 5 (371 mg).
Synthesis of 12. The aniline hydrochloride 11 (1.00 g,
2.46 mmol) was added to a stirred mixture of CH2Cl2 (50 mL),
H2O (10 mL), and sat. NaHCO3 (10 mL) and the stirring
was continued for 10 min. The organic phase was separated,
dried over MgSO4, and concentrated to ~10 mL by evaporation,
to furnish solution A. To a stirred solution of (S)-BOC-N-
methyl-valine (0.69 g, 2.98 mmol) in CH2Cl2 (7 mL) were
successively added at 0 ◦C: solution A, triethylamine (0.46 mL,
3.30 mmol), 1-hydroxy-benzotriazole (HOBt; 0.46 g, 3.41 mmol),
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (EDCI; 0.61 g, 3.19 mmol). The reaction mixture was stirred
at 0 ◦C for 1 h and then at room temperature for 22 h. The
mixture was then diluted with ethyl acetate (100 mL) and washed
successively with water (60 mL), cold 0.5M HCl (2 ¥ 55 mL),
saturated NaHCO3 (2 ¥ 55 mL), and brine (55 mL) and dried
over MgSO4 and evaporated. The residue (0.95 g) was purified by
Synthesis of gold nanoparticles 7b. Disulfide (-)-5 (59 mg,
0.13 mmol) was added to a solution of octylthiolate-stabilised
gold nanoparticles 6b (100 mg, 0.10 mmol) in DCM (20 mL)
and the resulting solution was stirred at room temperature for
2 days. The solution was then concentrated under vacuum and
EtOH (50 mL) was added. The resulting precipitate was filtered
by gravity filtration and washed with EtOH (100 mL) and acetone
(100 mL) to furnish nanoparticles 7b (88 mg) as a black powder:
1H NMR (400 Hz, CDCl3) d 0.93 (broad signal), 1.12 (s), 1.61
(broad signal), 1.79 (broad signal), 2.10 (s), 2.42–2.51 (m), 2.60 (t,
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chromatography on a column of silica gel (100 g) eluting with a
mixture of petroleum ether and ethyl acetate (12 : 1), to afford pure
amide (S)-(-)-12 (741 mg, 51%) as a pale orange oil: Rf = 0.52
(petroleum ether–ethyl acetate, 8 : 1); [a]D -55.0 (c 1.0, CHCl3);
1H NMR (400 Hz, CDCl3) d 0.90 (d, J = 6.6 Hz, 3H), 1.00 (d,
J = 6.4 Hz, 3H), 1.48 (s, 9H), as a part of 1.25–1.52 (m, 23H),
1.77 (pent, J = 7.3 Hz, 2H), 1.85 (pent, J = 7.3 Hz, 2H), 2.24 (s,
6H), 2.30–2.40 (m, 1H), 2.82 (s, 3H), 3.40 (t, J = 6.9 Hz, 2H), 3.69
(t, J = 6.6 Hz, 2H), 4.09 (d, J = 11.0 Hz, 1H), 7.16 (s, 2H), 8.03
(br s, 0.74 H); 13C NMR d 16.36 (CH3), 18.55 (CH3), 19.84 (CH3),
25.88 (CH), 26.12 (CH2), 28.14 (CH2), 28.34 (CH3), 28.73 (CH2),
29.38 (CH2), 29.45 (CH2), 29.52 (CH2), 30.34 (CH2), 32.80 (CH2),
34.08 (CH2), 65.85 (CH), 72.45 (CH2), 80.54 (C), 120.04 (CH),
131.46 (C), 133.28 (C), 152.49 (C), 157.33 (CO), 168.56 (CO); MS
(EI) m/z (%) 584 and 582 (M∑+, 8), 368 (37), 157 (52), 129 (95),
86 (100), 57 (48); HRMS (EI) 582.3038 (C30H51BrN2O4 requires
582.3032).
of silica gel (70 g) eluting with a mixture of CH2Cl2 and MeOH
(70 : 1), to afford pure formamide (S)-(-)-14 (461 mg, 90%) as
a yellowish oil: Rf = 0.42 and 0.30 (two spots; CH2Cl2–MeOH,
1
70 : 1); [a]D -77.0 (c 1.0, CHCl3); H NMR (400 Hz, CDCl3; a
mixture of rotamers in ca. 4 : 1 ratio; the signals for the minor
rotamer are marked with an *) d 0.91 (d, J = 6.6 Hz, 3H), 1.04
(d, J = 6.5 Hz, 3H), 1.29–1.41 (m, 13H), 1.44–1.51 (m, 2H), 1.61
(pent, J = 7.2 Hz, 2H), 1.77 (pent, J = 7.3 Hz, 2H), 2.24 (s, 4.94H),
2.25 (s, 0.75H*) 2.39–2.48 (m, 1H), 2.52 (q, J = 7.5 Hz, 2H), 2.93
(s, 0.53H*), 2.98 (s, 2.48H), 3.46 (d, J = 10.3 Hz, 0.13H*), 3.53
(t, J = 6.6 Hz, 0.11H), 3.69 (t, J = 6.6 Hz, 1.90H), 4.35 (d, J =
11.3 Hz, 0.85H), 7.14 (s, 0.24H*), 7.16 (s, 1.64H), 7.88 (s, 0.82H),
8.14 (s, 0.83H), 8.22 (s, 0.11H*); 13C NMR d 16.35 (CH3), 18.53
(CH3), 19.56 (CH3), 24.66 (CH2), 25.14 (CH), 26.13 (CH2), 28.36
(CH2), 29.05 (CH2), 29.47 (CH2), 29.50 (CH2), 29.52 (CH2), 29.55
(CH2), 30.35 (CH2), 31.55 (CH3), 34.04 (CH2), 63.10 (CH), 72.48
(CH2), 120.25 (CH), 131.54 (C), 132.84 (C), 152.77 (C), 163.94
(CO), 166.91 (CO); IR (KBr) n 3433, 2962, 2925, 2853, 1656,
1612, 1552, 1485, 1409, 1261, 1215, 1069, 1024, 802; MS (EI) m/z
(%) 464 (M∑+, 48), 323 (83), 142 (58), 114 (100), 86 (25), 55 (12);
HRMS (EI) 464.3076 (C26H44N2O3S requires 464.3073).
Synthesis of 13. Trifluoroacetic acid (13.5 mL) was added
dropwise to a solution of◦the BOC derivative 12 (1.54 g, 2.64 mmol)
in CH2Cl2 (20 mL) at 0 C and the stirring was continued at the
same temperature for 1 h. The acid was removed under reduced
pressure and the residue was co-evaporated with toluene (2 ¥
20 mL) to afford a TFA salt of the deprotected amine as a
brownish oil, which was used in the following step without further
purification. The crude ammonium salt was dissolved in formic
acid (15.2 mL) and the resulting solution was cooled to 0 ◦C. Acetic
anhydride (11.5 mL) was then added dropwise and the mixture
was allowed to stir at room temperature for 15 h. The volatiles
were then evaporated and the residue (1.42 g) was purified by
chromatography on a column of silica gel (140 g) eluting with
a mixture of CH2Cl2 and MeOH (70 : 1), to afford formamide
(S)-(-)-13 (1.19 g; 88%) as a yellow oil: Rf = 0.42 and 0.30 (two
spots; CH2Cl2–MeOH, 70 : 1); [a]D -78.0 (c 1.0, CHCl3); 1H NMR
(400 Hz, CDCl3 a mixture of rotamers in ca. 4 : 1 ratio; the signals
for the minor rotamer are marked with an *) d 0.90 (d, J = 6.6 Hz,
3H), 1.03 (d, J = 6.3 Hz, 3H), 1.29–1.47 (m, 14H), 1.76 (pent, J =
7.2 Hz, 2H), 1.84 (pent, J = 7.1 Hz, 2H), 2.22 (s, 6H), 2.38–2.51
(m, 1H), 2.91 (s, 0.47H*), 3.00 (s, 2.49H), 3.40 (t, J = 6.9 Hz,
2H), 3.55 (d, J = 10.6 Hz, 0.18H*), 3.68 (t, J = 6.5 Hz, 2H),
4.42 (d, J = 11.2 Hz, 0.82H), 7.14 (s, 0.32H*), 7.18 (s, 1.64H),
8.13 (s, 0.82H), 8.22 (s, 0.77H), 8.25 (s, 0.22H*), 8.34 (s, 0.17H*);
13C NMR d 16.32 (CH3), 18.56 (CH3), 19.48 (CH3), 25.32 (CH),
26.09 (CH2), 28.11 (CH2), 28.70 (CH2), 29.35 (CH2), 29.42 (CH2),
29.49 (CH2), 30.31 (CH2), 31.53 (CH3), 32.77 (CH2), 34.05 (CH2),
62.86 (CH), 72.40 (CH2), 120.27 (CH), 131.43 (C), 132.90 (C),
152.70 (C), 163.85 (CO), 167.02 (CO); MS (EI) m/z (%) 512 and
510 (M∑+, 22), 369 (36), 114 (100), 86 (25), 55 (12); HRMS (EI)
510.2455 (C26H43BrN2O3 requires 510.2457).
Synthesis of gold nanoparticles 15. Thiol (-)-14 (6.7 mL of
a ~60 mg/mL solution in CH2Cl2, ~0.87 mmol) was added to a
solution of butylthiolate-stabilized gold nanoparticles 6a (400 mg)
in CH2Cl2 (60 mL) (~2 : 1 14 : butanethiol mol ratio) and the
resulting solution was stirred at room temperature overnight.
The solution was concentrated under vacuum to near dryness
and petroleum ether (70 mL) was added. The resulting solid was
isolated by filtration and washed with petroleum ether (300 mL)
to give the functionalised nanoparticles 15 (521 mg) as a black
powder, soluble in most solvents except petroleum ether: 1H
NMR (400 Hz, CDCl3) d 0.92 (broad signal), 1.03 (broad signal),
1.28 (broad signal), 1.60 (broad signal), 2.00 (broad signal),
2.24 (broad signal), 2.44 (broad signal), 2.97 (broad signal), 3.06
(broad signal), 3.51 (broad signal), 4.51 (broad signal), 7.00 (broad
signal), 8.14 (broad signal), 8.29 (broad signal); IR (KBr) n 3465,
3286, 2921, 2851, 1655, 1611, 1551, 1484, 1409, 1214, 1062. Anal.
found: C, 24.97; H, 3.40; N, 2.15.
General Procedure for the Asymmetric Reduction of Imine 1
Catalysed by 7a,b. The imine 1 (50 mg, 0.22 mmol) was added
to a suspension of catalyst 7a (100 mg) or 7b (79 mg) in toluene
(1.5 mL), followed by the addition of trichlorosilane (50 mL) at
0 ◦C and the mixture was stirred at room temperature overnight.
The solvent was evaporated and the residue was treated with
methanol (25 mL) to form a dispersion, which was centrifuged.
The black solid was separated from the solution and dispersed
again in MeOH (25 mL). Repeated centrifugation of the latter
dispersion afforded a regenerated catalyst,17 which was dried
under high vacuum prior to the next use. Methanolic solutions
were combined, the solvent was evaporated, and the residue
was dissolved in chloroform (30 mL), followed by washing with
NaHCO3 (10 mL). The aqueous phase was additionally extracted
with chloroform (30 mL) and the combined organic extracts were
dried over MgSO4 and the solvent was evaporated. The crude
product was purified by chromatography on a column of silica gel
(10 g) eluting with a mixture of petroleum ether and ethyl acetate
(15 : 1), to give pure amine 2. The results are summarized in the
Table 1.
Synthesis of 14. Tetrabutyl-ammonium fluoride (TBAF, 1M
soln in THF; 1.22 mL, 1.22 mmol) was slowly added to a
solution of formamide (S)-(-)-13 (571 mg, 1.12 mmol) and
hexamethyldisilathiane (0.28 mL, 1.35 mmol) in THF (6 mL) at
0 ◦C and the mixture was stirred at this temperature for 100 min.
Sat. NH4Cl (35 mL) was added and the stirring was continued for
an additional 5 min. The mixture was then extracted with CH2Cl2
(2 ¥ 100 mL) and the organic extract was dried, and evaporated.
The residue (623 mg) was purified by chromatography on a column
1882 | Org. Biomol. Chem., 2009, 7, 1878–1883
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8 (a) F. Iwasaki, O. Onomura, K. Mishima, T. Kanematsu, T. Mak and
Y. Matsumura, Tetrahedron Lett., 2001, 42, 2525; (b) O. Onomura, Y.
Kouchi, F. Iwasaki and Y. Matsumura, Tetrahedron Lett., 2006, 47,
3751; (c) Z. Wang, X. Ye, S. Wei, P. Wu, A. Zhang and J. Sun, Org.
Lett., 2006, 8, 999; (d) Z. Wang, M. Cheng, P. Wu, S. Wei and J. Sun,
Org. Lett., 2006, 8, 3045; (e) Z. Wang, S. Wei, C. Wang and J. Sun,
Tetrahedron: Asymmetry, 2007, 18, 705; (f) D. Pei, Z. Wang, S. Wei, Y.
Zhang and J. Sun, Org. Lett., 2006, 8, 5913; (g) C. Wang, X. Wu, L.
Zhou and J. Sun, Chem. Eur. J., 2008, 14, 8789; (h) D. Pei, Y. Zhang,
S. Wei, M. Wang and J. Sun, Adv. Synth. Catal., 2008, 350, 619; (i) H.
Zheng, J. Deng, W. Lin and X. Zhang, Tetrahedron Lett., 2007, 48,
7934; (j) H.-J. Zheng, W. B. Chen, Z.-J. Wu, J.-G. Deng, W.-Q. Lin,
W.-C. Yuan and X.-M. Zhang, Chem. Eur. J., 2008, 14, 9864; (k) S.
Guizzetti, M. Benaglia, F. Cozzi, S. Rossi and G. Celentano, Chirality,
2009, 21, 233.
9 (a) M. Rueping, E. Sugiono, C. Azap, T. Theissmann and M. Bolte,
Org. Lett., 2005, 7, 3781; (b) M. Rueping, A. P. Antonchick and T.
Theissmann, Angew. Chem. Int. Ed., 2006, 45, 3683; (c) M. Rueping,
A. P. Antonchick and T. Theissmann, Angew. Chem., Int. Ed., 2006,
45, 6751; (d) M. Rueping and A. P. Antonchick, Angew. Chem., Int.
Ed., 2007, 46, 4562; (e) S. Hoffman, A. M. Seayad and B. List, Angew.
Chem., Int. Ed., 2005, 44, 7424; (f) S. Hoffmann, M. Nicoletti and B.
List, J. Am. Chem. Soc., 2006, 128, 13074; (g) J. Zhou and B. List,
J. Am. Chem. Soc., 2007, 129, 7498; (h) R. I. Storer, D. E. Carrera, Y.
Ni and D. W. C. MacMillan, J. Am. Chem. Soc., 2006, 128, 84; (i) S. G.
Ouellet, A. M. Walji and D. W. C. MacMillan, Acc. Chem. Res., 2007,
40, 1327; (j) T. Marcelli, P. Hammar and F. Himo, Chem. Eur. J., 2008,
14, 8562.
Acknowledgements
This work was supported by the EPSRC (grant Nos.
GR/S87294/01 and EP/E018211/1), the Royal Society of Ed-
inburgh, and AstraZeneca. We thank the University of Glasgow
for a graduate fellowship to M. F. We thank Colin How and Jim
Gallagher for help with the electron microscopy studies.
Notes and references
1 (a) Asymmetric Organocatalysts ed. A. Berkessel and H. Gro¨ger, Wiley-
VCH, Weinheim, 2005; (b) J. Seayad and B. List, Org. Biomol. Chem.,
2005, 3, 719; (c) Enantioselective Organocatalysis, ed. P. I. Dalko, Wiley-
VCH, 2007.
2 (a) For recent examples, see, e.g.: C. A. McNamara, M. J. Dixon and
M. Bradley, Chem. Rev., 2002, 102, 3275; (b) M. Heitbaum, F. Glorius
and I. Escher, Angew. Chem., Int. Ed., 2006, 45, 4732; (c) F. Cozzi, Adv.
Synth. Catal., 2006, 348, 1367.
3 Nanoparticles and Catalysis, ed. D. Astruc, Wiley-VCH, Weinheim,
2008.
4 For a recent example of chiral organocatalytic nanoparticles see:
S. Luo, X. Zheng and J.-P. Cheng, Chem. Commun., 2008,
5719.
5 A. C. Templeton, M. J. Hostetler, E. K. Warmoth, S. W. Chen, C. M.
Hartshorn, V. M. Krishnamurthy, M. D. E. Forbes and R. W. Murray,
J. Am. Chem. Soc., 1998, 120, 4845.
6 (a) For reviews on the reduction of imines, see: Asymmetric Synthesis,
ed. J. D. Morrison, Academic, New York, 1983, vol. 2; (b) R. Noyori,
Asymmetric Catalysis in Organic Synthesis, Wiley and Sons, New York,
1994; (c) I. Ojima, Catalytic Asymmetric Synthesis, J. Wiley, and Sons,
New York, 2nd edn, 2000; (d) B. R. James, Catal. Today, 1997, 37,
209; (e) S. Kobayashi and H. Ishitani, Chem. Rev., 1999, 99, 1069;
(f) B. T. Cho, Tetrahedron, 2006, 62, 7621; (g) For an overview of
metal-catalysed reductions, seeJ. S. M. Samec, J.-E. Ba¨ckvall, P. G.
Andersson and P. Brandt, Chem. Soc. Rev., 2006, 35, 237; (h) For
enzymatic approaches to chiral amines via reduction, see, e.g. C. J.
Dunsmore, R. Carr, T. Fleming and N. J. Turner, J. Am. Chem. Soc.,
2006, 128, 2224 and refs cited therein.
7 (a) A. V. Malkov, A. Mariani, K. N. MacDougall and P. Kocˇovsky´, Org.
Lett., 2004, 6, 2253; (b) A. V. Malkov, S. Stoncˇius, K. N. MacDougall,
A. Mariani, G. D. McGeoch and P. Kocˇovsky´, Tetrahedron, 2006, 62,
264; (c) A. V. Malkov, S. Stoncˇius and P. Kocˇovsky´, Angew. Chem., Int.
Ed., 2007, 46, 3722; (d) A. V. Malkov, M. Figlus, S. Stoncˇius and P.
Kocˇovsky´, J. Org. Chem., 2007, 72, 1315; (e) A. V. Malkov, M. Figlus
and P. Kocˇovsky´, J. Org. Chem., 2008, 73, 3985.
10 Catalysts 3a,b are now commercially available as Kenamide and
Sigamide.
11 (a) For the method, see: M. Brust, M. Walker, D. Bethel, D. J. Schiffrin
and R. J. Whyman, J. Chem. Soc., Chem. Commun., 1994, 801; (b) M. J.
Hostetler, J. E. Wingate, C.-J. Zhong, J. E. Harris, R. W. Vachet, M. R.
Clark, J. D. Londono, S. J. Green, J. J. Stokes, G. D. Wignall, G. L.
Glish, M. D. Porter, N. D. Evans and R. W. Murray, Langmuir, 1998,
14, 17.
12 The speed of addition of the solution of NaBH4 (≤10 s) proved to be
crucial for obtaining reproducible results.
13 For the method, see: J. Zhu, A. Kell and M. S. Workentin, Org. Lett.,
2006, 8, 4993.
14 An analogue of 15 with a 1,3-propane-spacer (instead of the 1,11-
undecane) proved ineffective as a catalyst.
15 B. S. Lee, S. K. Namgoong and S. Lee, Tetrahedron Lett., 2005, 46,
4501.
´
16 C. O. Da´laigh, S. A. Corr, Y. Gun’ko and S. J. Connon, Angew. Chem.
Int. Ed., 2007, 46, 4329.
17 Catalyst 7b was recovered only in 32% and was not used again.
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The Royal Society of Chemistry 2009
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