Role of noncovalent interactions in the enantioselective reduction of aromatic ketimines with trichlorosilane

Article abstract of DOI:10.1021/ol049213+

Asymmetric reduction of ketimines 1 with trichlorosilane can be catalyzed by a new N-methyl L-valine derived Lewis basic organocatalyst, such as 4d, with high enantioselectivity. The structure-reactivity investigation suggests hydrogen bonding and arene-arene interactions between the catalyst and the incoming imine as the main factor determining the enantiofacial selectivity.

Full text of DOI:10.1021/ol049213+

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2253-2256
Role of Noncovalent Interactions in the
Enantioselective Reduction of Aromatic
Ketimines with Trichlorosilane
Andrei V. Malkov,* Andrea Mariani, Kenneth N. MacDougall, and Pavel Kocˇovsky´*
Department of Chemistry, UniVersity of Glasgow, Glasgow G12 8QQ, U.K.
amalkoV@chem.gla.ac.uk; paVelk@chem.gla.ac.uk
Received April 28, 2004
ABSTRACT
Asymmetric reduction of ketimines 1 with trichlorosilane can be catalyzed by a new N-methyl L-valine derived Lewis basic organocatalyst,
such as 4d, with high enantioselectivity. The structure−reactivity investigation suggests hydrogen bonding and arene−arene interactions
between the catalyst and the incoming imine as the main factor determining the enantiofacial selectivity.
The recipe for successful asymmetric catalysis includes a
delicate mix of various factors, such as catalyst structure and
loading, solvent, temperature, etc. Often, even minor changes
to any of these characteristics can produce a dramatic effect
on the stereochemical outcome of the reaction.1 Among the
methods designed to enhance enantioselectivity through
structural variations, chiral relay represents an emerging new
strategy where a conformationally flexible group, appropri-
ately placed, effectively conveys the chiral information to
the reaction center.2 We have recently developed new
N-methyl amino acid derived amidophoshine ligands and
demonstrated that the conformational bias, imposed by the
tertiary amide group, led to high enantioselectivity in the
Cu(I)-catalyzed conjugate addition of Et2Zn to R,â-enones.3
Our N-methyl valine derived ligands proved superior to those
prepared from proline, showing that the rigid cyclic frame-
work of proline may not always be an advantage.3
In search for an extension of this principle to other
applications, we turned our attention to imine reduction
(Scheme 1), which gives rise to chiral amines that are
Scheme 1. Asymmetric Reduction of Ketimines
(1) For recent overviews, see (a) Feringa, B. L.; van Delden, R. A. Angew.
Chem., Int. Ed. 1999, 38, 3418. (b) Mikami, K.; Terada, M.; Korenaga, T.;
Matsumoto, Y.; Ueki, M.; Angelaud, R. Angew. Chem., Int. Ed. 2000, 39,
3532. (c) Fagnow, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26.
(2) For a recent review on chiral relay effect, see: (a) Corminboeuf, O.;
Quaranta, L.; Renaud, P.; Liu, M.; Jasperse, C. P.; Sibi, M. P. Chem. Eur.
J. 2003, 9, 28. For a recent contribution, see: (b) Sibi, M. P.; Zhang, R.;
Manyem, S. J. Am. Chem. Soc. 2003, 125, 9306.
common intermediates in the synthesis of pharmaceutical
drugs and agrochemicals. Current methods for asymmetric
reduction of imines, such as transition-metal-catalyzed high-
pressure hydrogenation,4,5 hydrosilylation,4,6 or transfer
(3) Malkov, A. V.; Hand, J. B.; Kocˇovsky´, P. Chem. Commun. 2003,
1948.
10.1021/ol049213+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/27/2004

hydrogenation,7 are tainted by the problem of metal leaching,
so that development of an organocatalytic protocol appears
to be an attractive alternative. Because Cl3SiH can be
activated by Lewis bases (R3N, DMF, MeCN, etc.) to effect
hydrosilylation of imines,8 we set out to design a suitable
chiral Lewis basic catalyst.9,10 While this work was in
progress, Matsumura reported on the asymmetric reduction
of imines 1 with Cl3SiH, catalyzed by the L-proline-derived
formamides (S)-3a,b (10-20 mol %) with e66% ee (Scheme
1; Table 1, entries 1 and 2).11 This work represented a great
valine unit. To this end, diamides (S)-4,5 were synthesized,
which can be regarded as chiral analogues of DMF (Scheme
2).
Scheme 2. Optimization of Catalyst Structure
Table 1. Reduction of Ketimines 1a-k with Trichlorosilane,
Catalyzed by (S)-3a,b and (S)-4aa
yield 2, % eec
cat. solvent (%)b (config)d
entry imine
R1, R2
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1b
1c
1d
1e
1e
1f
1g
1h
1i
1j
1k
1k
3a CH2Cl2
3b CH2Cl2
4a CH2Cl2
4a CHCl3
4a MeCN
91
52
68
79
65
62
57
43
30
69
50
80
96
36
50
60
97
46
55 (R)e
66 (R)e
79 (S)
86 (S)
30 (S)
76 (S)
80 (S)
87 (S)
85 (S)
80 (S)
87 (S)
37 (S)
85 (S)
22 (S)
<5
Ketimines 1a-k were reduced with Cl3SiH in the presence
of catalyst (S)-4a (10 mol %) (Table 1). Imine 1a afforded
2a in 79% ee (entry 3), and the product had the configuration
opposite to that reported by Matsumura,11 though the
configuration of the catalyst was identical! However, reduc-
tion of 1k, catalyzed by (S)-4a, gave nearly racemic product
(entry 18), while with (S)-3a the corresponding amine 2k
was obtained in 55% ee (entry 17; cf. entry 1). These results
suggest that the enantiodifferentiation mechanisms for pro-
line- and valine-derived catalysts are different. In the catalysis
by 3a, the emphasis in the proposed transition state,
accounting for the stereochemistry observed, was given to
the steric repulsion by placing the bulky anilide group of
the catalyst and the aromatic groups of the substrate away
from each other,11 which seemed to agree with the same level
of enantioselectivity obtained for the reduction of ketimines
1a and 1k. However, in the case of catalyst 4a, dramatic
difference in selectivities observed for 1a and 1k suggests
that electronic interactions between the catalyst and the
substrate may become a key factor.
4-MeOC6H4, Ph 4a CH2Cl2
4-MeOC6H4, Ph 4a CHCl3
4-CF3C6H4, Ph
4-NO2C6H4, Ph
2-naphth, Ph
2-naphth, Ph
c-C6H11, Ph
Ph, 4-MeOC6H4 4a CHCl3
Ph, 2-MeOC6H4 4a CH2Cl2
Ph, c-C6H11
Ph, n-Bu
4a CHCl3
4a CHCl3
4a CH2Cl2
4a CHCl3
4a CHCl3
9
10
11
12
13
14
15
16
17
18
4a CHCl3
4a CHCl3
3a CH2Cl2
4a CHCl3
<5
55 (R)e
8
Ph, CH2Ph
Ph, CH2Ph
a The reaction was carried out at 0.5 mmol scale with 1.5 equiv of Cl3SiH
and 10 mol % of the catalyst at room temperature for 16 h. b Isolated yield.
c Determined by chiral HPLC or GC. d Established from the optical rotation
(measured in CHCl3) by comparison with the literature data (see Supporting
Information) and/or by HPLC/GC via comparison with authentic samples;
configuration of 2d is assumed to be (S) in analogy with the rest of the
series. e Reference 11.
opportunity to test our chiral relay principle by replacing
Recently, we have shown that arene-arene interactions
can have a key impact on the reactivity and enantioselectivity
in organocatalysis,12 which prompted us to probe the extent
of noncovalent interactions involved in the reduction of
imines. First, the nature of the solvent was assessed.
Switching from CH2Cl2 to CHCl3 in the reduction of 1a
resulted in further increase of enantioselectivity (from 79%
the cyclic proline framework with the more flexible N-methyl
(4) (a) Morrison, J. D. Asymmetric Synthesis; Academic: New York,
1983; Vol 2. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley & Sons: New York, 1994. (c) Ojima, I. Catalytic Asymmetric
Synthesis, 2nd ed.; J. Wiley and Sons: New York, 2000. (d) James, B. R.
Catal. Today 1997, 37, 209. (e) Kobayashi, S.; Ishitani, H. Chem. ReV.
1999, 99, 1069.
(5) For recent reports on catalytic hydrogenation (with Ir, Rh, and Ru),
see refs 4b-d and the following: (a) Xiao, D.; Zhang, X. Angew. Chem.,
Int. Ed. 2001, 40, 3425. (b) Jiang, X. B.; Minnaard, A. J.; Hessen, B.;
Feringa, B. L.; Duchateau, A. L. L.; Andrien, J. G. O.; Boogers, J. A. F.;
de Vries, J. G. Org. Lett. 2003, 5, 1503. (c) Cobley, C. J.; Henschke, J. P.
AdV. Synth. Catal. 2003, 345, 195. (d) Okuda, J.; Verch, S.; Stu¨rmer, R.;
Spaniol, T. S. J. Organomet. Chem. 2000, 605, 55. For Ru-catalyzed transfer
hydrogenation, see: (e) Samec, J. S. M.; Ba¨ckvall, J. E. Chem. Eur. J.
2002, 8, 2955.
(6) (a) Reding, M. T.; Buchwald, S. L. J. Org. Chem. 1998, 63, 6344.
(b) Verdaguer, X.; Lange, U. E. W.; Buchwald, S. L. Angew. Chem., Int.
Ed. 1998, 37, 1103. (c) Vedejs, E.; Trapencieris, P.; Suna, E. J. Org. Chem.
1999, 64. 6724. (d) Hansen, M. C.; Buchwald, S. L. Org. Lett. 2000, 2,
713. (e) Nishikori, H.; Yoshihara, R.; Hosomi, A. Synlett 2003, 561. (f)
Lipshutz, B. H.; Shimizu, H. Angew. Chem., Int. Ed. 2004, 43, 2228.
(7) Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003, 42, 5472.
(8) (a) Benkeser, R. A.; Snyder, D. J. Organomet. Chem. 1982, 225,
107. (b) Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 407.
(9) For an overview, see: (a) Denmark, S. E.; Fu, J. Chem. ReV. 2003,
103, 2763. For a recent contribution, see: (b) Malkov, A. V.; Bell, M.;
Orsini, M.; Pernazza, D.; Massa, A.; Herrmann, P.; Meghani, P.; Kocˇovsky´,
P. J. Org. Chem. 2003, 68, 9659 and references therein.
(10) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron 1999,
55, 977.
(11) (a) Iwasaki, F.; Omonura, O.; Mishima, K.; Kanematsu, T.; Maki,
T.; Matsumura, Y. Tetrahedron Lett. 2001, 42, 2525. For a related reduction
of ketones, see: (b) Iwasaki, F.; Onomura, O.; Mishima, K.; Maki, T.;
Matsumura, Y. Tetrahedron Lett. 1999, 40, 7507.
(12) Malkov, A. V., Dufkova´, L.; Farrugia, L.; Kocˇovsky´, P. Angew.
Chem., Int. Ed. 2003, 42, 3674.
2254
Org. Lett., Vol. 6, No. 13, 2004

to 86% ee; entries 3 and 4), whereas MeCN proved
unsuitable (entry 5).13 This behavior suggests π-π inter-
actions of the arene systems of the catalyst and the
substrate.14
Table 2. Reduction of Ketimines 1a-l with Trichlorosilane,
Catalyzed by 4a-f and 5a-ca
yield 2, % eec
The role of the individual aromatic nuclei both in the
ketimine 1 and in the catalyst 4 were then investigated to
find the scope of the reaction and shed light on the origin of
the asymmetric induction. The electron-rich imine 1b
exhibited enantioselectivity marginally lower than that of 1a
(entries 6 and 7), and electron-poor imines 1c,d showed
enhanced asymmetric induction (entries 8 and 9). 2-Naph-
thyl-imine 1e reacted in the same way as 1a (entries 10 and
11), but the cyclohexyl analogue 1f showed a significantly
reduced enantioselectivity, although in the latter case the
overall result was affected by rather fast, noncatalytic
background reaction (entry 12).
Variation of the imine N-substituent (R2) had a more
dramatic effect. Thus, whereas the p-methoxy imine 1g gave
high conversion and enantioselectivity (entry 13), its o-isomer
1h was much less efficient (entry 14), demonstrating the
steric effect. By contrast, imines 1i,j, derived from nonaro-
matic amines, afforded practically racemic products (entries
15 and 16), indicating the crucial role of the N-aryl moiety
of the ketimine for asymmetric induction.15
entry imine
R1, R2
Ph, Ph
c-C6H11, Ph
Ph, Ph
Ph, Ph
2-naphth, Ph
Ph, Ph
4-CF3C6H4, Ph
Ph, 4-MeOC6H4 4c CHCl3
Ph, Ph
Ph, Ph
4-MeOC6H4, Ph 4d CHCl3
4-CF3C6H4, Ph
4-CF3C6H4, Ph
Ph, 4-MeOC6H4 4d CHCl3
Ph, 4-MeOC6H4 4d CHCl3
Ph, Ph
4-MeOC6H4, Ph 4d Tol
4-CF3C6H4, Ph 4d Tol
Ph, 4-MeOC6H4 4d Tol
2-MeC6H4, Ph
Ph, Ph
4-CF3C6H4, Ph
Ph, Ph
Ph, Ph
Ph, Ph
cat solvent (%)b (config)d
1e
2e
3
4
5
6
7
8
9
10e
11
12
13e
14
15e
16
17
18
19
20
21
22
23
24
25
26
1a
1f
4a CHCl3
4a CHCl3
4b CH2Cl2
4b CHCl3
4b CH2Cl2
4c CHCl3
4c CHCl3
49
53
62
62
53
81
94
82
70
94
62
88
95
79
85
81
86
86
85
90
88
92
35
0
92 (S)
59 (S)
70 (S)
85 (S)
66 (S)
82 (S)
77 (S)
79 (S)
89 (S)
92 (S)
87 (S)
87 (S)
89 (S)
86 (S)
90 (S)
92 (S)
85 (S)
89 (S)
91 (S)
92 (S)
53 (S)
69 (S)
56 (S)
1a
1a
1e
1a
1c
1g
1a
1a
1b
1c
1c
1g
1g
1a
1b
1c
1g
1l
4d CHCl3
4d CHCl3
4d CHCl3
4d CHCl3
4d Tol
4d Tol
1a
1c
1a
1a
1a
1c
4e CHCl3
4e CHCl3
4f CHCl3
5a CHCl3
5b CHCl3
5c CHCl3
Lower temperature led to an increased enantioselectivity,
as shown for imines 1a and 1f and catalyst 4a (Table 2,
entries 1 and 2; cf. Table 1, entries 4 and 12), partly as a
result of suppressing the background reaction, which is
particularly strong for 1f.
23
84
7 (S)
35 (S)
4-CF3C6H4, Ph
a The reaction was carried out at 0.5 mmol scale with 1.5 equiv of Cl3SiH
and 10 mol % of the catalyst at room temperature unless stated otherwise,
16 h. b Isolated yield. c Determined by chiral HPLC or GC. d Established
from the optical rotation (measured in CHCl3) by comparison with the
literature data (see Supporting Information) and/or by HPLC/GC via
comparison with authentic samples; configuration of 2d and 2l is assumed
to be (S) in analogy with the rest of the series. e The reaction was carried
out at -20 °C.
The role of the amide functionality in the catalyst was
elucidated with the aid of amides 4a-f and 5a-c. No
reaction was observed with n-butyl amide 5a (Table 2, entry
24), confirming the importance of the aromatic system in
this position. Tertiary amide 5b, lacking the NH group,
proved to be a sluggish catalyst (entry 25), suggesting that
a hydrogen bonding between the NH group of the catalyst
and the imine nitrogen may also play a role in the transition
state. Furthermore, removing the N-Me group from the
formamide part, as in catalyst 5c, proved to be detrimental
to enantioselectivity (entry 26; cf. entry 7), showing the
importance of the N-Me for the chiral relay.3
A set of anilides 4a-f was employed to shed light on the
nature of the aromatic interactions between the anilide part
of the catalyst and the substrate.16 Catalyst 4b with a donor
group was found to be slightly less efficient with imines 1a,e,
compared to 4a (Table 2, entries 3-5). An additional
methoxy substituent (4c) led to a further decrease in
selectivity (entries 6-8). 3,5-Dimethylphenylamide 4d gen-
erally gave higher yields and slightly better selectivity than
the parent phenylamide 4a (entries 9-15). By contrast, a
significantly reduced efficacy was observed for the electron-
poor 3,5-bis(trifluoromethyl)- and 3,5-dichloroanalogues 4e
and 4f (entries 21-23).
The activation of trichlorosilane is likely to proceed via a
bidentate coordination with the catalyst through the forma-
mide and anilide carbonyls.17 In the series of catalysts 4a-
f, the Lewis basicity of the formamide moiety remained
constant, while the substituents in the arylamide part should
affect its donor properties. Apparently, catalysts 4e,f, with
electron-withdrawing groups in the aromatic ring, are less
efficient in chelation to the weakly Lewis acidic trichloro-
silane. Therefore, despite their increased capability of
π-stacking,18 moderate enantioselectivity was obtained. In
the electron-rich anilides 4b,c, the chelating ability is not
compromised but in this case the π-π interactions with the
(13) In the absence of the catalyst, the conversion after 24 h at room
temperature in CH2Cl2 and CHCl3 was <5%, and ∼10% in MeCN.
(14) Note that chloroform has been shown to be the solvent that most
strongly stabilizes the arene-arene interactions: Breault, G. A.; Hunter,
C. A.; Mayers, P. C. J. Am. Chem. Soc. 1998, 120, 3402.
(15) While imines 1a-e,g,h,j,k all exists as pure (E)-isomers, NMR
spectra of 1f,i,l indicate 11:1, 14:1, and 3:1 (E/Z)-mixtures, respectively.
(16) This strategy is commonly used in design of chiral selectors in chiral
chromatography: Pirkle, W. H.; Koscho, M. E. J. Chromatogr. A 1999,
840, 151.
(17) In the 13C NMR spectrum of a 1:1 mixture of 4d and HSiCl3, shifts
of ∼0.1 and 0.2 ppm were observed for the corresponding signals of
formamide and anilide carbonyls relative to free 4d. The methyl groups in
the aromatic ring became nonequivalent, indicating a weak bidentate
coordination. Furthermore, replacing the formamide unit proved fruitless:
Thus, no reaction was observed for the -N(Me)CO2CF3 and -N(Me)CO2-
(t-Bu) analogues of 4a and for the acetamide congener of 3a.11b
Org. Lett., Vol. 6, No. 13, 2004
2255

substrate are weaker.19 Finally, 3,5-dimethylphenylamide 4d
represents a perfect balance of electronic properties, which
results in good reactivity and enantioselectivity.
On the basis of the available experimental data we suggest
structure A (Figure 1) as a transition state in the reduction
A possible involvement of hydrogen bonding prompted
us to employ toluene as an environmentally friendly replace-
ment for chlorinated solvents. Although toluene is not
regarded as an ideal solvent when π-π interactions are
involved, the results presented in Table 2 (entries 16-20)
show that, in this reaction, it is actually the solvent of
choice: the level of selectivity attained in toluene at room
temperature matched those in chloroform at -20 °C.
In conclusion, we have designed new L-valine-derived
catalysts 4, which effect reduction of N-aryl ketimines 1 with
Cl3SiH to afford secondary amines 2. The observed enan-
tioselectivity (e92% ee) of this organocatalytic protocol
matches the level of the transition-metal-catalyzed methods,5
with 4d being the champion catalyst and toluene the solvent
of choice. Arene-arene interactions and hydrogen bonding
between the catalyst and the substrate appear to be the key
factors in the enantiodifferentiation process.
Figure 1. Proposed transition state.
Acknowledgment. We thank the University of Rome “La
Sapienza” for a fellowship to A.M. and the University of
Glasgow for a fellowship to K.N.McD. and additional
support.
of N-arylimines, which incorporates both hydrogen bonding
and π-stacking as key elements.
(18) (a) Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc. 1990, 112,
5525. (b) Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem.
Soc., Perkin Trans. 1 2001, 651. (c) Waters, M. L. Curr. Opin. Chem. Biol.
2002, 6, 736. (d) Castellano, R. K.; Diederich, F.; Meyer, E. A. Angew.
Chem., Int. Ed. 2003, 42, 1210.
(19) The alternative edge-to-face C-H/π interactions, which are normally
favored by electron-rich aromatic donors,18 would dictate the formation of
a different transition state, which may result in lower enantioselectivity.
Supporting Information Available: General experimen-
1
tal methods, synthesis of ligands 4 and 5, and H and 13C
NMR spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL049213+
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Org. Lett., Vol. 6, No. 13, 2004