Dendron-anchored organocatalysts: The asymmetric reduction of imines with trichlorosilane, catalysed by an amino acid-derived formamide appended to a dendron

Article abstract of DOI:10.1039/b916601g

Asymmetrie reduction of ketimines 1a-f with trichlorosilane can be catalysed by the Lewis-basic N-methylvaline-derived formamide anchored to a soluble dendron (lie) with good enan tio selectivity (≤94% ee) and low catalyst loading (typically 5 mol%) at ro

Full text of DOI:10.1039/b916601g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Dendron-anchored organocatalysts: the asymmetric reduction of imines with
trichlorosilane, catalysed by an amino acid-derived formamide appended to a
dendron†
Marek Figlus,a Stuart T. Caldwell,a Dawid Walas,a Gulen Yesilbag,b Graeme Cooke,*a Pavel Kocˇovsky´,*a
Andrei V. Malkov*a,c and Amitav Sanyal*b
Received 12th August 2009, Accepted 25th September 2009
First published as an Advance Article on the web 27th October 2009
DOI: 10.1039/b916601g
Asymmetric reduction of ketimines 1a–f with trichlorosilane can be catalysed by the Lewis-basic
N-methylvaline-derived formamide anchored to a soluble dendron (11c) with good enantioselectivity
(≤94% ee) and low catalyst loading (typically 5 mol%) at room temperature in toluene. This protocol
represents an improvement and simplification of the isolation procedure and recovery of the catalyst.
Introduction
There is an impressive portfolio of protocols for the enan-
tioselective transition metal-catalysed reduction of imines 1,1
which include hydrogenation,2 transfer hydrogenation3 and
hydrosilylation,4 etc.5 On the other hand, the organocatalytic
realm is currently confined to the reduction with Hantzsch
dihydropyridine catalysed by chiral Brønsted acids,6 and hydrosi-
lylation with Cl3SiH catalysed by chiral Lewis bases (Scheme 1).7–9
In the last few years Malkov, Kocˇovsky´ and co-workers have
developed a library of Lewis-basic formamides derived from
natural amino acids, and those originating from N-methyl valine,
such as 3–5 (Fig. 1), proved to be particularly efficient (≤97% ee).7
In order to improve the practicality of the isolation procedure,
these catalysts were then modified by appending a fluorous
ponytail (7),7c a solid resin (8),7e a gold nanoparticle (9)7i and
a soluble polymer (10).7j Herein, we report on an alternative
Fig. 1 Catalysts for the asymmetric reduction of imines. For R¢ see
Scheme 2.
approach, namely anchoring the catalyst to a dendron.
particular, the unique structural characteristics of these systems
offer advantages over traditional polymeric supports in terms of
providing: (i) a well-defined monodisperse structure; (ii) the ability
to tune the accessibility and microenvironment of the catalyst by
either attaching it to the terminal functionality, or by isolating
it within the dendrimer core; and (iii) the ability to augment
the rate and/or the selectivity of the reaction via the so-called
“dendrimer effect”.11 Unsurprisingly, these features have more
Scheme 1 Asymmetric reduction of selected ketimines. For structures a–f
recently inspired the development of dendrimer/dendron-based
catalysts for enantioselective transformations.12
see Table 1.
Dendron- and dendrimer-anchored catalysts provide an attrac-
tive architecture for performing a range of catalytic reactions.10 In
Results and discussion
Synthesis
aWestCHEM, Department of Chemistry, Joseph Black Building, Uni-
versity of Glasgow, Glasgow, UK G12 8QQ. E-mail: graemec@chem.
gla.ac.uk, pavelk@chem.gla.ac.uk
Dendrons with an appended catalytic moiety were synthesized
according to Scheme 2. 3,5-Dibenzyloxy benzyl alcohol 12a13
and the phenolic derivative (S)-(-)67e underwent the Mitsunobu
reaction with di-(4-chlorobenzyl)-azodicarboxylate (DCAD) and
triphenylphosphine (rt, 67 h) to afford the first-generation dendron
11a (17%). Similarly, the reaction of benzyl alcohol 12b13 with
phenol (S)-(-)67e (rt, 48 h) furnished the second-generation
bDepartment of Chemistry, Bogazici University, Bebek, Istanbul, 34342,
Turkey. E-mail: amitav.sanyal@boun.edu.tr
cDepartment of Chemistry, Loughborough University, Loughborough, LE11
3TU, UK. E-mail: A.Malkov@lboro.ac.uk
† Electronic supplementary information (ESI) available: General methods,
1
and H and 13C NMR spectra of the dendron-anchored catalysts 11a–c.
See DOI: 10.1039/b916601g
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reduction of imine 1a proceeded uneventfully in the presence of
each of the three dendron-supported catalysts 11a–c (Table 1,
entries 1–3) and, when complete, as indicated by TLC, the mixture
was added dropwise to vigorously stirred methanol, which was
expected to precipitate the catalyst. However, in the case of the
first-generation catalyst (11a), this operation was unsuccessful as
no precipitation was observed, leaving a homogeneous solution.
Aqueous workup of the latter solution, followed by evaporation
and classical chromatography of the residue, afforded amine 2a
(89% ee; entry 1). With the second-generation catalyst (11b),
the addition of the organic phase to methanol resulted in the
formation of a biphasic system with white droplets of the catalyst
(at the bottom) surrounded by a “milky” solution, which was
separated and centrifuged. This process removed ca. 60% of the
catalyst. The supernatant was worked up and evaporated, and
the product 2a was purified by chromatography. The precipitation
procedure applied to the reaction catalysed by the third-generation
catalyst (11c) was more successful: ca. 90% of the catalyst was
recovered from the mixture by centrifugation so that the product
(2a) thus obtained (after the aqueous workup) was contaminated
with only ≤1% of the catalyst (as revealed by HPLC) and was
purified by chromatography.
These experiments demonstrated that only the third-generation
catalyst 11c offered the advantages expected for a dendron.
Therefore, this catalyst was employed to establish the scope
of this method using our standard set of model imines 1b–f
(Table 1, entries 4–9). The yields and enantioselectivities proved
to be similar to those obtained with homogeneous, non-supported
catalysts, reaching a maximum of 94% ee for imine 1e (entry 8). For
comparison, Sigamide 5,7c,g one of the most successful catalysts for
this transformation known to date,7,8 produced amine 2e in 96%
ee.7d Little variation was observed as a function of the substitution
pattern. As with Sigamide,7c,d,f toluene was identified as the
solvent-of-choice for the dendron-supported catalysts, whereas
the less environmentally friendly dichloromethane proved to be
inferior (compare entries 5 and 6).
Scheme 2 Synthesis of dendron-anchored catalysts 11a–c.
dendron 11b (23%), and the benzyl alcohol 12c13 (using diethyl
azodicarboxylate DEAD) produced the third-generation dendron
11c (26%; rt, 24 h).
Catalyst screening
When the regenerated catalyst 11c (10 mol%) was reused for
the reduction of imine 1a, the corresponding amine 2a was
obtained in the same yield as with the fresh catalysts (90%) but
the enantioselectivity dropped to 81% ee (compare with 89% ee,
Table 1, entry 3).
The reduction of a substantial portfolio of imines, catalysed by
3–5 and 7–10, was investigated by us earlier.7 Since relatively
little variation was observed as a function of the imine structure,
the present study was confined to a selected set of representative
examples of aromatic imines 1a–f (Scheme 1 and Table 1). The
Table 1 Reduction of ketimines 1a–f with trichlorosilane, catalysed by the valine-derived N-methyl formamides anchored to dendrons (S)-11a–ca
Catalyst (mol%)
1a–f
R1
R2
Yield (%)b
2 ee (%)c
1
2
3
4
5
6
7
8
9
11a (10)
11b (10)
11c (10)
11c (5)
11c (5)d
11c (5)e
11c (5)
11c (5)
11c (5)
1a
1a
1a
1b
1c
1c
1d
1e
1ff
Ph
Ph
Ph
4-CF3Ph
2-Naphth
2-Naphth
4-MeOPh
Ph
Me
Me
Me
Me
Me
Me
Me
CH2Cl
CH2CO2Et
88
90
89
81
68
23
78
69
89
89
87
89
91
85
70
79
94
82
Ph
a The reaction was carried out at a 0.2 mmol scale with 2.0 equiv. of Cl3SiH in toluene. Trichlorosilane was added at 0 ◦C, and the mixture was allowed
to warm up to room temperature and stirred for 16 h. b Yields of isolated products. c The absolute configuration of the resulting amines was found to be
(S)-2 by comparison of their optical rotation and their HPLC behaviour with those of the authentic samples (ref. 7). d Trichlorosilane was added at room
temperature instead of 0 ◦C as 1c was not soluble in toluene at 0 ◦C. e The reaction was carried out in CH2Cl2. f Ref. 14.
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colourless oil: Rf 0.40/0.23 (petroleum ether–ethyl acetate, 1 : 1);
[a]D -47.9 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, a mixture
of amide rotamers in ca. 4 : 1 ratio; only the data for the major
rotamer are given) d 0.93 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.5 Hz,
3H), 2.28 (s, 6H), 2.44–2.53 (m, 1H), 3.01 (s, 3H), 4.42 (d, J =
11.2 Hz, 1H), 4.70 (s, 2H), 5.00 (s, 4H), 5.04 (s, 8H), 6.59 (s, 3H),
6.71 (s, 4H), 6.73 (s, 2H) 7.23 (s, 2H), 7.33–7.44 (m, 20H), 8.15 (s,
1H), 8.18 (s, 1H); 13C NMR d 16.47 (CH3), 18.51 (CH3), 19.50
(CH3), 25.24 (CH), 31.53 (CH3), 62.99 (CH), 69.95 (CH2), 70.04
(CH2), 73.90 (CH2), 101.50 (CH), 106.32 (CH), 106.54 (CH),
120.36 (CH), 127.52 (CH), 127.96 (CH), 128.55 (CH), 131.63 (C),
133.32 (C), 136.69 (C), 139.19 (C), 139.87 (C), 152.31 (C), 159.93
(C), 160.10 (C), 163.93 (CHO), 167.01 (CO); IR (film) n 3315,
3032, 2928, 1656, 1595 cm-1; m/z (FAB) 1006 [(M + H)+, 2%], 531
(95), 303 (30), 219 (100); HRMS 1005.4672 [C64H65O9N2 requires
(M + H)+ 1005.4690].
Conclusions
In conclusion, three generations of dendron-supported
N-methylvaline derivatives 11a–c were prepared as organo-
catalysts for the enantioselective reduction of imines 1a–f with
trichlorosilane, a convenient, non-expensive reducing agent.
Application of the third-generation catalyst 11c resulted in a
substantial simplification of the isolation procedure, as most
of the catalyst (≥90%) can be removed by precipitation and
centrifugation.15 Toluene was again identified as the reaction
medium-of-choice and the enantioselectivities (≤94% ee) mirrored
those attained with Sigamide (5)7 and its congeners.
Experimental
Imines 1a–f and amines 2a–f are known compounds, previously
prepared in this laboratory;7 synthesis of the phenolic derivative
6 was reported by us recently.7c,e Dendrons 12a–c were prepared
using the previously reported methodology.13
Formamide (S)-(-)-11c
Diethyl azodicarboxylate (DEAD) (0.13 mL, 0.81 mmol) was
added to a solution of phenol (S)-67c,e (151 mg, 0.54 mmol),
alcohol 12c13 (1.04 g, 0.65 mmol) and triphenylphosphine (212 mg,
0.81 mmol) in dry THF (10 mL). The mixture was stirred
at room temperature for 24 h, after which time the solution
was concentrated under vacuum. The residue was purified by
chromatography on a column of silica gel (130 g) with a petroleum
ether–ethyl acetate mixture (2 : 3) to afford a crude product, which
was further purified by washing with MeOH (2 ¥ 40 mL) and
then ether (2 ¥ 40 mL). Drying of the residue afforded pure
formamide (S)-(-)-11c (263 mg, 26%) as a solid foam: Rf 0.49/0.37
(petroleum ether–ethyl acetate, 2 : 3); [a]D 24.9 (c 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3, a mixture of amide rotamers in ca. 4 : 1
ratio; only the data for the major rotamer are given) d 0.91 (d, J =
6.6 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H), 2.25 (s, 6H), 2.41–2.50 (m,
1H), 2.96 (s, 3H), 4.32 (d, J = 11.2 Hz, 1H), 4.67 (s, 2H), 4.96 (s,
8H), 4.97 (s, 4H), 5.01 (s, 16H), 6.53 (t, J = 2.2 Hz, 2H), 6.56 (t,
J = 2.2 Hz, 4H), 6.59 (t, J = 2.2 Hz, 1H), 6.66 (d, J = 2.2 Hz,
12H), 6.72 (d, J = 2.2 Hz, 2H), 7.18 (s, 2H), 7.27–7.41 (m, 40H),
7.82 (s, 1H), 8.12 (s, 1H); 13C NMR d 16.47 (CH3), 18.49 (CH3),
19.49 (CH3), 25.18 (CH), 31.49 (CH3), 63.00 (CH), 69.90 (CH2),
70.00 (CH2), 73.87 (CH2), 101.37 (CH), 101.50 (CH), 106.30 (CH),
106.39 (CH), 106.54 (CH), 120.34 (CH), 127.50 (CH), 127.93
(CH), 128.51 (CH), 131.62 (C), 133.28 (C), 136.68 (C), 139.13
(C), 139.91 (C), 152.30 (C), 159.99 (C), 160.10 (C), 163.92 (CHO),
166.96 (CO); IR (film) n 3312, 3032, 2930, 2873, 1658, 1594 cm-1;
MS (FAB) m/z 1855 [(M + H)+, 8%), 846 (10), 606 (13), 423 (45),
303 (100)]; HRMS 1853.8033 [C120H113O17N2 requires (M + H)+
1853.8039].
Formamide (S)-(-)-11a
Di-(4-chlorobenzyl)-azodicarboxylate (DCAD) (436 mg,
1.19 mmol, 1.2 equiv.) was added to a solution of phenol (S)-67c,e
(305 mg, 1.09 mmol, 1.1 equiv.), alcohol 12a13 (319 mg, 0.99 mmol)
and triphenylphosphine (313 mg, 1.19 mmol, 1.2 equiv.) in dry
CH2Cl2 (10 ml). The mixture was stirred at room temperature for
67 h, after which time the resulting precipitate was filtered off and
washed with CH2Cl2 (10 mL). The combined organic fractions
were concentrated under vacuum and purified by chromatography
on a column of silica gel (70 g) with a petroleum ether–ethyl
acetate mixture (1 : 1) to afford pure formamide (S)-(-)-11a
(96 mg, 17%) as a viscous colourless oil: Rf 0.38/0.25 (petroleum
1
ether–ethyl acetate, 1 : 1); [a]D -58.3 (c 1.0, CHCl3); H NMR
(400 MHz, CDCl3, a mixture of amide rotamers in ca. 4 : 1 ratio;
only the data for the major rotamer are given) d 0.93 (d, J =
6.6 Hz, 3H), 1.07 (d, J = 6.5 Hz, 3H), 2.26 (s, 6H), 2.41–2.54 (m,
1H), 3.02 (s, 3H), 4.47 (d, J = 11.2 Hz, 1H), 4.59 (s, 2H), 5.06 (s,
4H), 6.61 (t, J = 2.2 Hz, 1H), 6.74 (d, J = 2.2 Hz, 2H), 7.24 (s,
2H), 7.31–7.45 (m, 10H), 8.15 (s, 1H), 8.38 (s, 1H); 13C NMR d
16.44 (CH3), 18.55 (CH3), 19.45 (CH3), 25.37 (CH), 31.53 (CH3),
62.86 (CH), 70.03 (CH2), 73.90 (CH2), 101.48 (CH), 106.55 (CH),
122.37 (CH), 127.46 (CH), 127.93 (CH), 128.51 (CH), 131.58
(C), 133.34 (C), 136.73 (C), 139.83 (C), 152.28 (C), 160.01 (C),
163.87 (CHO), 167.11 (CO); IR (film) n 3317, 2964, 2929, 1656,
1596 cm-1; MS (FAB) m/z (%) 581 ([M + H]+, 10), 303 (20), 142
(100), 92 (65); HRMS 580.3017 [C36H41O5N2 requires (M + H)+].
Formamide (S)-(-)-11b
Di-(4-chlorobenzyl)-azodicarboxylate
(DCAD)
(60
mg,
General procedure for the asymmetric reduction of 1a catalysed by
11a,b
0.15 mmol) was added to a solution of phenol (S)-67c,e
(43 mg, 0.15 mmol), alcohol 12b13 (108 mg, 0.14 mmol) and
triphenylphosphine (41 mg, 0.15 mmol) in dry CH2Cl2 (3 ml). The
mixture was stirred at room temperature for 48 h, after which time
the resulting precipitate was filtered off and washed with CH2Cl2
(10 mL). The combined organic fractions were concentrated
under vacuum and purified by chromatography on a column of
silica gel (30 g) with a petroleum ether–ethyl acetate mixture (1 : 1)
to afford pure formamide (S)-(-)-11b (33 mg, 23%) as a viscous
Trichlorosilane (50 mL) was added to a solution of imine 1a
(0.22 mmol) and catalyst 11a or 11b (10 mol%) in toluene (1.5 mL)
at 0 ◦C, and the mixture was stirred at room temperature overnight.
Chloroform (30 mL) was then added and the solution was washed
with aqueous saturated NaHCO3 (10 mL). The aqueous phase
was extracted with chloroform (30 mL) and the combined organic
solutions were dried over MgSO4. Chloroform was partially
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˚
evaporated, silica gel (1 g) was added to the residue, and the
rest of the solvent was evaporated to dryness. The latter silica
gel-adsorbed mixture was loaded onto a column of dry silica gel
(15 g) and eluted with a mixture of petroleum ether and ethyl
acetate (24 : 1 or 9 : 1) to afford pure amine 2a. For yields and
enantioselectivity, see Table 1.
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General Procedure for the Asymmetric Reduction of 1a–f
Catalysed by 11c
Trichlorosilane (50 mL) was added to a solution of imine 1
(0.22 mmol) and catalyst 11c (0.022 mmol) in toluene (1.5 mL) at
0 ◦C and the mixture was stirred at room temperature overnight.
The mixture was then poured into rapidly stirred methanol
(50 mL), the resulting cloudy mixture was centrifuged, and the
clear supernatant was evaporated. The residue was treated with
chloroform (30 mL) and the resulting solution was washed with
aqueous saturated NaHCO3 (10 mL). The aqueous phase was
extracted with chloroform (30 mL), and the combined organic
solutions were dried over MgSO4 and evaporated. The crude
product was purified by chromatography on a column of silica gel
(10 g) using a mixture of petroleum ether and ethyl acetate (15 : 1)
to give the pure amine 2 (89%). For yields and enantioselectivity,
see Table 1. The amines thus obtained were identical to the
authentic samples prepared earlier by us.7
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Acknowledgements
This work was supported by the EPSRC (grant Nos.
GR/S87294/01 and EP/E018211/1), the Royal Society of
Edinburgh, and AstraZeneca. We thank the University of Glasgow
for a graduate fellowship to M.F. A.S thanks TUBITAK (105S353)
and TUBA-GEBIP for financial support.
Notes and references
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14 Imine 1f exists in its enamine form. However, the enamine–imine
equilibration can be facilitated, e.g., by addition of AcOH (≤1 equiv.).
The resulting imine concentration is sufficient for an effective reduction,
as demonstrated by us for Sigamide 5 as catalyst7f ,g
.
15 At 5 mol% catalyst loading, the product after centrifugation is
contaminated by less than 0.5% of the catalyst and can be further
purified by chromatography or crystallization.
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