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Catalytic asymmetric Strecker hydrocyanation of imines using Yb(OTf)3–pybox catalystsw Babak Karimi* and Aziz Maleki Received (in Cambridge, UK) 5th May 2009, Accepted 26th June 2009 First published as an Advance Article on the web 22nd July 2009 DOI: 10.1039/b908854g We have explored the highly enantioselective Strecker hydrocyanation of a wide range of aromatic, a,b-unsaturated, heterocyclic, and aliphatic aldimines with good to excellent conversions and ees up to 98% in the presence of catalytic amounts of Yb(OTf)3–pybox complexes. The catalytic asymmetric Strecker reaction is one of the most important and useful C–C bond forming reactions. It represents a powerful and atom-economic approach for the synthesis of chiral a-aminonitriles, which are versatile building blocks for the preparation of both natural and un-natural a-amino acids and their derivatives.1 Consequently, there has been continuous research activity in this area in recent years, leading to the development of a diverse array of chiral catalysts, especially those based on chiral Lewis acid-catalyzed addition of cyanide transfer reagents to preformed imines.1,2 Most of these catalysts consist of chiral ligands attached to metals such as Al, Ti, Zr, Gd, Er, etc. Furthermore, in addition to metal-catalyzed asymmetric cyanation, several excellent versions of the Strecker process based on the use of organocatalysts have also been developed.1,3 Nevertheless, there is still a need for further efficient, and general methods in this field. To our knowledge, enantioselective cyanation of imines using chiral ytterbium(III) catalysts has been unexplored,4 although Yb(III) complexes have gained successful applications as chiral Lewis acid catalysts for various other synthetic transformations.5 The aim of this communication is to describe a procedure for the asymmetric synthesis of a-aminonitriles through the reaction of aldimines with TMSCN catalyzed by Yb(OTf)3–pybox complexes. The use of pybox complexes as catalysts for enantioselective synthetic transformations has been well documented6 since its first discovery by Nishiyama et al. in 1989.7 For initial optimization of the reaction conditions, the coupling of TMSCN and various types of N-substituted benzaldimines 1 was investigated as a model reaction system in the presence of a Yb(OTf)3–pybox as catalyst (Table 1).z8 Our initial attempts in applying the catalyst for the Strecker reaction revealed a significant effect of the substituent on the nitrogen and the highest enantioselectivity of 58% ee was achieved when a benzaldimine bearing an N-benzhydryl substituent was used as substrate at 40 1C (Table 1, entries 1–5). Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), PO Box 45195-1159, Gava Zang, Zanjan, Iran. E-mail:
[email protected]; Fax: +98-241-4214949; Tel: +98-241-4153225 w Electronic Supplementary Information (ESI) available: Experimental section, FT-IR, and 1H and 13C NMR spectra of the materials, HPLC chromatograms of the products. See DOI: 10.1039/b908854g
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Table 1 Effect of the N-substituent on enantioselective Strecker reaction of benzaldimine catalyzed by Yb(OTf)3–pybox complexesa
Run
PG
Time/ h
Solvent
Yb : pybox ratio
Yield (ee) [%]b,c
1 2 3 4 5
Ph PhCH2 PMP (Ph)2CH 2-(OH)Ph
24 24 24 24 24
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
1 : 1.2 1 : 1.2 1 : 1.2 1 : 1.2 1 : 1.2
90 (35) 93 (rac.) 95 (rac.) 95 (58) o5 (N.D)
a
Conditions: Yb(OTf)3 (5 mol%), TMSCN (2 equiv.), MeOH (2 equiv.). b Yields refer to isolated product unless stated otherwise. c Enantiomeric excesses were determined by HPLC analysis on a CHIRALPAK AD column.11
A further important observation was that upon addition of protic additives,2h,i,9 especially in a slow addition mode, a significant effect was observed in both the yields and the ees of the products. Among different protic additives that were used, such as 1,1,1-trifluoroethanol, PhOH, i-PrOH, and MeOH, it turned out that MeOH was the preferred additive for our purpose (Table 2). In the next stage, the reaction was further optimized for the reaction temperature, and we found that by decreasing the reaction temperature to 78 1C, the Strecker reaction of N-benzylidenediphenylmethanamine with TMSCN went to completion within 30 h affording the corresponding a-aminonitrile in 89% yield and with an ee value of 76% (Table 2, entry 1). We then turned our attention to the Yb(OTf)3 : pybox ligand ratios and we found that the best results were obtained using a ratio of 1 : 2. This ratio led to complete substrate conversion and afforded the corresponding a-aminonitrile in 97% ee and 95% isolated yield (Table 2, entry 3). Higher or lower ratios were found not to be beneficial for the ee values (Table 2, entries 1–4). The effects of solvent and additives were surveyed together using this new temperature and Yb(OTf)3 : pybox ratio. While the Strecker reaction in CH2Cl2 at 78 1C yielded an excellent enantiomeric excess of 97% (entry 3), the use of other solvents such as CH3CN, CHCl3, THF, and toluene led to much lower selectivities under the same reaction conditions (Table 2, entries 7–10). This journal is
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Table 2 Effect of various parameters on enantioselective Strecker reaction of N-benzylidenediphenylmethanamine catalyzed by Yb(OTf)3–pybox complexesa
Scheme 1 Lower enantioselectivity and chemical yields using a pybox ligand without the Br group.
Run T/1C 1 2 3 4 5 6 7 8 9 10 11 12 13
78 78 78 78 0 60 78 78 78 78 78 78 78
Yb : pybox ratio 1 : 1.2 1 : 1.5 1:2 1 : 2.5 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2
Solvent/activator
Time/h
Yield (ee) [%]b,c
CH2Cl2/MeOH CH2Cl2/MeOH CH2Cl2/MeOH CH2Cl2/MeOH CH2Cl2/MeOH CH2Cl2/MeOH CH3CN/MeOH CHCl3/MeOH THF/MeOH Toluene/MeOH CH2Cl2/PhOH CH2Cl2/i-PrOH CH2Cl2/ CF3CH2OH
30 30 30 30 24 24 30 30 30 30 30 30 30
89 (76) 90 (85) 95 (97) 95 (93) 95 (30) 92 (75) 5 (N.D)d 10 (25) NRd NRd —d 90 (97) 90 (83)
a Conditions: Yb(OTf)3 (5 mol%), TMSCN (2 equiv.), activator (2 equiv.). b Isolated yields unless stated otherwise. c Enantiomeric excesses were determined by HPLC analysis on a CHIRALPAK AD column.11 d A heterogeneous mixture was formed.
We also screened a number of other well-known metal triflates and observed that the products were obtained in lower yields and enantioselectivities (Table 3). It is worth mentioning that decreasing the catalyst loading from 5 mol% to lower ratios resulted in significantly lower yields and enantioselectivities (Table 3, entry 5). It was also noted that the reaction of N-benzylidenediphenylmethanamine, in the presence of Yb(OTf)3 as catalyst using a pybox ligand that does not bear the bromine substituent could Table 3 Effect of various metal triflates and catalyst loading on the enantioselective Strecker reaction of N-benzylidenediphenylmethanaminea
Run
M(OTf)n
M : pybox ratio (loading)
Time/h
Yield (ee) [%]b,c
1 2 3 4 5 6
Mg(OTf)2 Sc(OTf)3 Cu(OTf)2 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3
1:2 1:2 1:2 1:2 1:2 1:2
30 30 30 30 48 24
5 (N.D)d 70 (54) NR 95 (97) 85 (78) 96 (95)
(5) (5) (5) (5) (3) (8)
a Conditions: TMSCN (2 equiv.), MeOH (2 equiv.). b Isolated yields unless stated otherwise. c Enantiomeric excesses were determined by HPLC analysis on a CHIRALPAK AD column.11 d The reaction was carried out at 40 1C.
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only reach a maximum yield of 85% and enantioselectivity of 72% ee under the same reaction conditions (Scheme 1).10 This observation suggests that the Br group in the 4-position of the pyridine moiety has a significant effect especially on product enantioselectivities. With the optimal reaction conditions established, we then proceeded to investigate the scope of this new catalytic asymmetric Strecker reaction. As shown in Table 4, various types of aldimine, including aromatic, a,b-unsaturated, and aliphatic aldimines furnished the corresponding a-aminonitriles in excellent yields (85–97%) and moderate to excellent enantioselectivities (61–97%).w It is noteworthy that hindered 2-substituted aromatic imines gave the corresponding Table 4 Enantioselective Strecker reaction of aldimines catalyzed by Yb(OTf)3–pybox Complexesa
Run
R
Time/h
Yield (%)b
ee (%)c,d
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
C6H5 2-Me-C6H4 3-Me-C6H4 4-Me-C6H4 2-Cl-C6H4 3-Cl-C6H4 4-Cl-C6H4 2-Br-C6H4 3-Br-C6H4 4-Br-C6H4 2-Naphthyl 2-Thenyl 3-Pyridyl 2-Furyl 3-TBDMSO-C6H4 2,4-Me2-C6H3 Ph–CHQCH Ph–CH2CH2 CH3(CH2)5 (CH3)3C
32 24 36 36 72 72 72 72 72 72 72 48 72 36 72 24 36 24 24 24
95 97 95 93 97 93 91 97 92 90 90 85 57 50 96 97 98 86 95 91
97 94 82 96 92 91 83 97 91e 84 80 92f 65 45 87 96 98 74g 62g 76g
a Conditions: Yb(OTf)3 (5 mol%), TMSCN (2 equiv.), MeOH (2 equiv.). b Isolated yields unless stated otherwise. c Enantiomeric excesses were determined by HPLC analysis on a CHIRALPAK AD column.11 d The configurations were determined by the comparison with known samples reported in the literature. e The reaction was initiated at 78 1C and then the temperature was gradually increased to 65 1C. f The reaction was initiated at 78 1C and then the temperature was gradually increased to 40 1C. g The reaction was performed using one-pot procedure in the presence of 4 A˚ MS.
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a-aminonitriles with high yields and excellent enantioselectivities in most cases (Table 4, entries 2, 5, 8). In addition, aromatic heterocyclic aldimines, as well as aliphatic aldimines can be converted into chiral Strecker products in moderate to good yields and with moderate to excellent enantioselectivities (Table 4, entries 12–14, 18–20). Even, in the case of the most challenging a-unbranched aldehydes, the corresponding Strecker products were obtained in excellent yields and high enantioselectivities through a modified three-component procedure (Table 4, entries 18, 19). However, this protocol as its present form is not suitable for the enantioselective Strecker reaction of ketimines. In conclusion, a highly enantioselective Strecker hydrocyanation of a wide range of aromatic, a,b-unsaturated, heterocyclic, and aliphatic aldimines was introduced with good to excellent conversions and ee values up to 98% in the presence of catalytic amounts of Yb(OTf)3–pybox complexes. Mild reaction conditions, and good to excellent enantioselectivities, especially for highly challenging aliphatic, and heterocyclic aldehydes render this method as an alternative approach for the preparation of chiral a-aminonitriles. Further investigations are currently under way in this group to rationalize mechanisms, extend the substrate scope, and to design and prepare a new supported version of this catalytic system.
3
4 5
Notes and references z General Catalytic Procedure: A 2-dram oven-dried vial was charged with a stirbar, Yb(OTf)3 (30 mg, 0.048 mmol), and the pybox ligand (44 mg , 0.098 mmol) in a dry box. The vial was capped with a septum and removed from the dry box. Dichloromethane (1.0 mL) was added to the vial under an atmosphere of dry Ar. The resulting mixture was stirred vigorously at rt for 1 h until the reaction became homogeneous. To the resulting complex solution 1 mmol of imine and 4 mL dichloromethane were added under argon and the resulting reaction mixture were cooled to the desired temperature. After 20 min, TMSCN (2 mmol) were added to the flask in one portion and then methanol (2 mmol) was injected drop wise via the septum. The reaction was maintained at the desired temperature until consumption of imine was complete as monitored by thin layer chromatography. The excess TMSCN and solvent were removed in the cold in vacuo and then products were purified by flash chromatography on silica gel. 1 (a) S. J. Connon, Angew. Chem., Int. Ed., 2008, 47, 1176; (b) C. Spino, Angew. Chem., Int. Ed., 2004, 43, 1764; (c) H. Gro¨ger, Chem. Rev., 2003, 103, 2795; (d) M. Shibasaki, M. Kanai and T. Mita, Org. React., 2008, 70, 1–119. 2 For some selected examples of the Strecker reaction using chiral metal catalysts see: (a) J. Wang, X. Hu, J. Jiang, S. Gou, X. Huang, X. Liu and X. Feng, Angew. Chem., Int. Ed., 2007, 46, 8468; (b) N. Kato, T. Mita, M. Kanai, B. Therrien, M. Kawano, K. Yamaguchi, H. Danjo, Y. Sei, A. Sato, S. Furusho and M. Shibazaki, J. Am. Chem. Soc., 2006, 128, 6768; (c) J. Blacker, L. A. Clutterbuck, M. R. Crampton, C. Grosjean and M. North, Tetrahedron: Asymmetry, 2006, 17, 1449; (d) S. Lundgren, E. Wingstrand, M. Penhoat and C. Moberg, J. Am. Chem. Soc., 2005, 127, 11592; (e) N. Kato, M. Suzuki, M. Kanai and M. Shibazaki, Tetrahedron Lett., 2004, 45, 3147; (f) S. Nakamura, N. Sato, M. Sugimoto and T. Toru, Tetrahedron: Asymmetry, 2004, 15, 1513; (g) S. Masumoto, H. Usuda, M. Suzuki, M. Kanai and M. Shibazaki, J. Am. Chem. Soc., 2003, 125, 5634; (h) M. Takamura, Y. Hamashima, H. Usuda,
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