Catalytic, enantioselective synthesis of α-aminonitriles with a novel zirconium catalyst

Article abstract of DOI:10.1002/(SICI)1521-3773(19981204)37:22<3186::AID-ANIE3186>3.0.CO;2-E

Strecker reactions of aldimines with Bu₃SnCN in the presence of the novel chiral zirconium binuclear catalyst 1 provide α-aminonitriles in good yields and with high enantioselectivities. The reaction can be applied to a wide range of substrates. Since both enantiomers of the choral sources are readily available, both enantiomers of the α-aminonitriles are easily prepared according to this method. L = N-methylimidazole.

Full text of DOI:10.1002/(SICI)1521-3773(19981204)37:22<3186::AID-ANIE3186>3.0.CO;2-E

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[9] D. J. Williams, D. E. Partin, F. J. Lincoln, J. Kouvetakis, M. O'Keeffe, J.
Solid State Chem. 1997, 134, 164 ± 169.
[10] M. A. Omary, T. R. Webb, Z. Assefa, G. E. Shankle, H. H. Patterson,
Inorg. Chem. 1998, 37, 1380 ± 1386.
[11] I. G. Dance, L. J. Fitzpatrick, A. D. Rae, M. L. Scudder, Inorg. Chem.
1983, 22, 3785 ± 3788.
[12] H. Schmidbaur, Chem. Soc. Rev. 1995, 391 ± 400.
[13] K. Nakamoto, Infrared and Raman Spectra of Inorganic and
Coordination Compounds, 4th ed., Wiley, New York, 1986, p. 272;
I. G. Dance, L. J. Fitzpatrick, A. D. Rae, M. L. Scudder, Inorg. Chem.
1983, 22, 3785 ± 3788.
asymmetric Strecker reactions. In the presence of a zirconium
catalyst (10 mol%) that was prepared from Zr(OtBu)4, (R)-
6,6'-dibromo-1,1'-bi-2-naphthol ((R)-6-Br-BINOL, 2 equiv),[9]
and N-methylimidazole (NMI, 3 equiv), aldimine 1a was
treated with Bu3SnCN[10] in dichloromethane at 458C. The
reaction proceeded smoothly to afford the corresponding a-
aminonitrile in 70% yield with 55% ee. After several reaction
conditions were examined, the best results (92% yield,
91% ee) were obtained when the reaction was carried out in
benzene/toluene (1/1) with use of a chiral zirconium catalyst
prepared from Zr(OtBu)4 (1 equiv), (R)-6-Br-BINOL
(1 equiv), (R)-3,3'-dibromo-1,1'-bi-2-naphthol ((R)-3-Br-
BINOL),[11] and NMI (3 equiv; Table 1). Use of other solvents
resulted in a slight decrease in selectivity. The free hydroxyl
group of the aldimine was important for obtaining both high
yield and high selectivity.[7] When the aldimine prepared from
Catalytic, Enantioselective Synthesis of
a-Aminonitriles with a Novel Zirconium
Catalyst**
Haruro Ishitani, Susumu Komiyama, and
ShuÅ Kobayashi*
Table 1. Influence of ligands and solvents.
a-Aminonitriles are useful intermediates for the synthesis
of amino acids[1] and nitrogen heterocycles such as thiadia-
zoles and imidazoles.[2] The Strecker reactions of aldimines
with cyanides provide one of the most efficient methods for
the preparation of a-aminonitriles,[3] and several diastereose-
lective approaches for the synthesis of optically active a-
aminonitriles have been reported.[4] In 1996 Lipton et al.
reported the first catalytic enantioselective Strecker-type
reactions with use of a dipeptide ligand as catalyst.[5] Although
efficient catalytic reactions provide a-aminonitriles derived
from benzaldehyde derivatives in high enantioselectivities,
low selectivities were observed in the reactions of aldimines
derived from aliphatic and heterocyclic aldehydes.[6] Here we
report chiral zirconium-catalyzed Strecker reactions of ald-
imines with tributyltin cyanide (Bu3SnCN), which provide
various types of a-aminonitriles in high yields and with high
enantioselectivities.
Ligand (equiv)
Solvent
CH2Cl2
Yield [%] ee [%]
(R)-6-Br-BINOL (0.2)
(R)-6-Br-BINOL (0.2)
70
55
69
91
toluene/benzene (1/1) 72
toluene/benzene (1/1) 92
(R)-6-Br-BINOL (0.1)
‡ (R)-3-Br-BINOL (0.1)
(R)-6-Br-BINOL (0.1)
‡ (R)-3-Br-BINOL (0.1)
(R)-6-Br-BINOL (0.1)
‡ (R)-3-Br-BINOL (0.1)
(R)-6-Br-BINOL (0.1)
‡ (R)-3-Br-BINOL (0.1)
(R)-6-Br-BINOL (0.1)
‡ (R)-3-Br-BINOL (0.1)
toluene
93
86
toluene/C2H5CN (1/1) 91
benzene/CH2Cl2 (1/1) 97
86
83
CH2Cl2
85
71
Recently, we reported the first catalytic enantioselective
Mannich[7] and aza-Diels ± Alder reactions[8] with a chiral
zirconium catalyst. In these reactions, the zirconium catalyst
effectively activates aldimines, which leads to efficient
catalytic processes. We then used a zirconium catalyst in
aniline or 2-methoxyaniline was used under the same reaction
conditions, the corresponding a-aminonitrile derivatives were
obtained in much lower yields and with lower enantioselec-
tivities (aniline: 29% yield, 1% ee; 2-methoxyaniline: 45%
yield, 5% ee).
It was interesting that use of a mixture of (R)-6-Br-BINOL
and (R)-3-Br-BINOL gave the best results. We then carefully
examined the structure of the zirconium catalyst, and it was
indicated from NMR studies that the zirconium binuclear
[*] Prof. Dr. S. Kobayashi,[‡] Dr. H. Ishitani, S. Komiyama
Graduate School of Pharmaceutical Sciences
The University of Tokyo, CREST
Japan Science and Technology Corporation (JST)
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
and
complex
3 was formed under the reaction conditions
(Scheme 1). Complex 3 consists of two zirconium centers,
two (R)-6-Br-BINOL and two NMI units, and one (R)-3-Br-
BINOL unit. The structure of this composition is very stable
Department of Applied Chemistry
Faculty of Science, Science University of Tokyo (SUT)
Kagurazaka, Shinjuku-ku, Tokyo 162-0825 (Japan)
Fax: (‡81)3-5684-0634
E-mail: skobayas@mol.f.u-tokyo.ac.jp
‡
[ ] Present address:
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo, 113-0033 (Japan)
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture, Japan, and a SUT Special Grant for Research Promotion.
H.I. acknowledges a JSPS fellowship for Japanese Junior Scientists.
Scheme 1. Structure of the chiral zirconium catalyst 3 (L ˆ NMI).
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and is formed even with different molar ratios of Zr(OtBu)4,
(R)-6-Br-BINOL, (R)-3-Br-BINOL, and NMI; formation of 3
upon combination of 1 equiv of Zr(OtBu)4, 1 equiv of (R)-6-
Br-BINOL, 0.5 ± 1 equiv of (R)-3-Br-BINOL, and 2 ± 3 equiv
1
of NMI was confirmed by H and 13C NMR spectroscopy.[12]
We then examined several different Strecker reactions
(Table 2). Aldimines derived from aromatic aldehydes as well
Table 2. Catalytic, asymmetric Strecker reactions.
Scheme 2. Synthesis of leucinamide (5).
zirconium binuclear catalyst. High enantioselectivities in the
synthesis of a-aminonitrile derivatives with a wide range of
substrates have been achieved.
Entry
R
Yield [%]
ee [%]
1
2
3
4
5
6
1-Naphthyl
Ph
p-ClC6H4
p-MeOC6H4
o-MeC6H4
o-MeC6H4
98
92
90
97
96
93
91
91
88
76
89[a]
89 (S)[b]
Experimental Section
3: To a solution of Zr(OtBu)4 (0.04 mmol) in toluene (0.25 mL) was added
(R)-6-Br-BINOL (0.04 mmol) and (R)-3-Br-BINOL (0.04 mmol) in tol-
uene (0.5 mL) and NMI (0.12 mmol) in toluene (0.25 mL) at room
temperature. After the mixture was stirred for 1 h at the same temperature,
solvent was removed and the residue was dried for 3 h at 508C in vacuo. 1H
NMR (CD2Cl2): d ˆ 1.22 (s, tBuO), 2.60 (s, 3H, NMe), 5.59 (s, 1H, H4 or H5
of NMI), 5.65 (s, 1H, H4 or H5 of NMI), 6.02 (s, 1H, H2 of NMI), 6.33 (d,
1H, J ˆ 8.5 Hz), 6.41 (d, 1H, J ˆ 9.1 Hz), 6.52 (d, 1H, J ˆ 9.1 Hz), 6.55 (dd,
1H, J ˆ 7.0, 8.5 Hz), 6.78 (d, 1H, J ˆ 9.1 Hz), 6.82 (d, 1H, J ˆ 9.1 Hz), 6.90
(dd, 1H, J ˆ 7.0, 8.0 Hz), 7.33 (d, 1H, J ˆ 8.0 Hz), 7.67 (d, 1H, J ˆ 8.9 Hz),
7.69 (d, 1H, J ˆ 8.9 Hz), 7.72 (s, 1H), 7.78 (s, 1H), 8.03 (s, 1H), 8.08 (d, 1H,
J ˆ 8.9 Hz), 8.20 (d, 1H, J ˆ 8.9 Hz); 13C NMR (CD2Cl2): d ˆ 30.6 (tBuO),
34.0 (NMe), 114.2, 114.4, 117.6, 117.7, 118.7, 118.8, 119.1 (C4 and C5 of
NMI), 122.0, 124.6, 124.7, 125.7, 126.1, 126.5, 126.6, 126.7, 126.8, 126.9, 127.0,
127.1, 127.2, 127.6, 128.86, 128.90, 128.93, 129.0, 130.5, 132.0, 132.9 (C2 of
NMI), 155.5, 159.3, 159.9; other signals were assigned to free (R)-3-Br-
BINOL.
7
85
87
8
9
89
89
80
92
10
11
12
Ph(CH2)2
iBu
C8H17
55
79
72
83[c]
83[c]
74[c]
[a] When 0.05 equiv of 3 were used, a yield of 94% and 87% ee were
obtained. [b] 0.1 equiv of ent-3 were used. [c] The imine was prepared in
situ from the corresponding aldehyde and 2-amino-3-methylphenol in the
presence of 4-Š molecular sieves.
Typical experimental procedure for the catalytic enantioselective Strecker
reactions: To Zr(OtBu)4 (0.04 mmol) in toluene (0.25 mL) was added (R)-
6-Br-BINOL (0.04 mmol), (R)-3-Br-BINOL (0.04 mmol), and NMI
(0.12 mmol) in toluene (0.75 mL) at room temperature. The mixture was
stirred for 1 h at the same temperature, and then cooled to 658C. A
solution of 1 (0.4 mmol) and Bu3SnCN (0.44 mmol) in benzene (1.0 mL)
was added. The mixture was stirred and warmed from 65 to 08C over
12 h, and a saturated aqueous solution of NaHCO3 was then added to
quench the reaction. The aqueous layer was extracted with dichloro-
methane. After a usual work up, the crude product was subjected to
chromatography on silica gel to give the desired adduct. The optical purity
was determined by HPLC analysis with a chiral column (see below). Since
most of the adducts were unstable, they were characterized after
methylation of the phenolic OH group as follows: The adduct was treated
with a 20% MeI/acetone solution (5 mL) and K2CO3 (200 mg). After the
mixture was stirred at room temperature for 6 h, saturated aqueous NH4Cl
was added to quench the reaction. After extraction of the aqueous layer
with dichloromethane, the crude product was subjected to chromatography
on silica gel to afford the corresponding methylated product quantitatively.
as aliphatic and heterocyclic aldehydes reacted with Bu3SnCN
smoothly to afford the corresponding a-aminonitrile deriva-
tives in high yields and with high enantiomeric excesses. Since
both enantiomers of the chiral ligands 6-Br-BINOL and 3-Br-
BINOL are readily available, both enatiomers of a-amino-
nitrile derivatives can be easily prepared according to this
protocol. In addition, it is noteworthy that Bu3SnCN has been
successfully used as a safe cyanide source. It is stable in water
and does not react to produce HCN. This is in contrast to
trimethylsilyl cyanide (TMSCN), which is easily hydrolyzed to
form HCN even in the presence of a small amount of water.[13]
After the reaction was completed, all tin sources were quanti-
tatively recovered as bis(tributyltin) oxide, which can be con-
verted into tributyltin chloride[14] and then into Bu3SnCN.[9, 15]
a-Aminonitrile 2b was easily converted into leucinamide
according to Scheme 2. Thus, after methylation of the
phenolic OH group of 2b with methyl iodide and potassium
bicarbonate, the nitrile group was converted into an amide
moiety.[16] Treatment of 4 with cerium ammonium nitrate
(CAN)[17] gave leucinamide (5). The absolute configuration
(R) was assigned by comparison of the configuration of the
hydrochloride with that of an authentic sample.[18]
2-(2-Hydroxyphenyl)amino-2-phenylacetonitrile: HPLC (Daicel Chiral-
cel OD, hexane/iPrOH 9/1, flow rate 1.0 mLmin 1): tR ˆ 40.0 min (major
product), 49.7 min (minor product).
2-(2-Methoxyphenyl)amino-2-phenylacetonitrile: 1H NMR (CDCl3): d ˆ
3.81 (s, 3H), 4.67 (d, 1H, J ˆ 8.3 Hz), 5.43 (d, 1H, J ˆ 8.3 Hz), 6.90 ± 6.95
(m, 4H), 7.42 ± 7.47 (m, 3H), 7.59 ± 7.62 (m, 2H); 13C NMR (CDCl3): d ˆ
49.8, 55.4, 110.0, 111.6, 118.2, 119.6, 121.2, 127.2, 129.2, 129.4, 134.1, 134.5,
‡
147.4; HR-MS calcd for C15H14N2O [M ]: 238.1106, found: 238.1093.
4: The aminoamide
4 was synthesized according to the literature
precedure.[16] The methylated adduct was prepared as described above,
and the crude product (0.4 mmol) was dissolved in dichloromethane
(1.0 mL). After the solution was cooled to 08C, a catalytic amount of
Bu4NHSO4 (0.08 mmol), an excess amount of 30% aqueous hydrogen
Catalytic enantioselective Strecker reactions of aldimines
with Bu3SnCN have been developed with use of a novel chiral
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peroxide, and 20% aqueous NaOH were added successively. The mixture
was stirred for 1 h at the same temperature, and then warmed to room
temperature. The reaction was monitored by thin-layer chromatography
(TLC), and when there was no more starting material (ca. 2 h), ether was
added, and the aqueous layer was extracted with dichloromethane. The
pure N-protected leucinamide 4 was obtained in 94% yield from the
cyanation product (two steps) after isolation by column chromatography on
silica gel (CHCl3/MeOH 19/1). 1H NMR (CDCl3): d ˆ 0.85 (d, 3H, J ˆ
6.4 Hz), 0.95 (d, 3H, J ˆ 6.4 Hz), 1.58 ± 1.63 (m, 1H), 1.78 ± 1.87 (m, 2H),
2.77 (s, 3H), 3.82 (s, 3H), 3.82 (brs, 1H), 6.71 ± 6.82 (m, 3H), 6.88 (brs, 1H);
13C NMR (CDCl3): d ˆ 18.6, 21.7, 23.35, 23.38, 24.9, 55.6, 60.0, 108.9, 120.8,
124.0, 127.3, 135.6, 149.8, 178.6.
[5] M. S. Iyer, K. M. Gigstad, N. D. Namdev, M. Lipton, J. Am. Chem.
Soc. 1996, 118, 4910 ± 4911.
[6] Quite recently, Jacobsen et al. reported elegant catalytic asymmetric
Strecker reactions: a) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc.
1998, 120, 4901 ± 4902; b) M. S. Sigman, E. N. Jacobsen, J. Am. Chem.
Soc. 1998, 120, 5315 ± 5316.
[7] a) H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc. 1997, 119,
7153 ± 7154; b) S. Kobayashi, H. Ishitani, M. Ueno, J. Am. Chem. Soc.
1998, 120, 431 ± 432; see also c) H. Fujieda, M. Kanai, T. Kambara, A.
Iida, K. Tomioka, J. Am. Chem. Soc. 1997, 119, 2060 ± 2061.
[8] S. Kobayashi, S. Komiyama, H. Ishitani, Angew. Chem. 1998, 110,
1026 ± 1028; Angew. Chem. Int. Ed. 1998, 37, 979 ± 981.
[9] For the use of 6,6'-dibromo-1,1'-bi-2-naphthol, see a) M. Terada, Y.
Motoyama, K. Mikami, Tetrahedron Lett. 1994, 35, 6693 ± 6696; b) H.
Sasai, T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh, M. Shibasaki, J.
Org. Chem. 1995, 60, 7388 ± 7389.
[10] Bu3SnCN is commercially available; a) J. G. A. Luijten, G. J. M.
van der Kerk, Investigations in the Field of Organotin Chemistry, Tin
Research Institute, Greenford, 1995, p. 106; b) M. Tanaka, Tetrahe-
dron Lett. 1980, 21, 2959 ± 2962; c) S. Harusawa, R. Yoneda, Y. Omori,
T. Kurihara, Tetrahedron Lett. 1987, 28, 4189 ± 4190.
5: The N-protected aminoamide 4 (0.38 mmol) was dissolved in 80% wet
MeOH (5.0 mL). CAN (2.0 mmol) was added at 08C, and the mixture was
stirred for 6 h at the same temperature. Water was added, and the acidic
solution was washed with dichloromethane. The aqueous solution was
made alkaline by adding 1n NaOH, and was then extracted with ethyl
acetate. The combined organic layers were washed with brine and dried
over Na2SO4. The solvent was removed, and the pure d-leucinamide 5 was
1
obtained without further purification. H NMR (CDCl3): d ˆ 0.93 (d, 3H,
J ˆ 6.4 Hz), 0.97 (d, 3H, J ˆ 6.4 Hz), 1.39 (ddd, 1H, J ˆ 4.9, 9.8, 13.8 Hz),
1.65 (ddd, 1H, J ˆ 4.3, 4.9, 13.8 Hz), 1.55 ± 1.80 (m, 3H), 3.76 (dd, 1H, J ˆ
4.3, 9.8 Hz), 6.37 (brs, 1H), 7.22 (brs, 1H); 13C NMR (CDCl3): d ˆ 21.0,
[11] P. J. Cox, W. Wang, V. Snieckus, Tetrahedron Lett. 1992, 33, 2253 ±
2256.
[12] This could be partially due to the lower reactivity of (R)-3-Br-BINOL
compared to (R)-6-Br-BINOL and equilibration of the coordination
of NMI to the zirconium center. After careful examination, the best
results and reproducibility were obtained when the catalyst was
prepared by combining 1 equiv of Zr(OtBu)4, 1 equiv of (R)-6-Br-
BINOL, 1 equiv of (R)-3-Br-BINOL), and 3 equiv of NMI.
[13] When TMSCN was used in this system, moderate yields and moderate
enantiomeric excesses were observed. The reaction of the aldimine
prepared from 1-naphthaldehyde and 2-aminophenol with TMSCN
led to the corresponding a-aminonitrile in 33% yield and with
63% ee; with triethylsilyl cyanide this product was obtained in 65%
yield and with 63% ee (not optimized).
‡
23.1, 24.4, 43.7, 53.1, 178.8; HR-MS calcd for C6H14N2O [M ]: 130.1107,
found: 130.1091; (R)-leucinamide hydrochloride: [a]D25
ˆ
8.2 (c ˆ 0.22 in
H2O).[18]
Received: June 29, 1998 [Z12067IE]
German version: Angew. Chem. 1998, 110, 3369 ± 3372
Keywords: amino acids ´ asymmetric catalysis ´ asymmetric
synthesis ´ Lewis acids ´ zirconium
[1] Y. M. Shafran, V. A. Bakulev, V. S. Mokrushin, Russ. Chem. Rev. 1989,
58, 148 ± 162.
[14] a) J. M. Brown, A. C. Chapman, R. Harper, D. J. Mowthorpe, A. G.
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[15] Quite recently, we developed scandium triflate catalyzed Strecker
reactions of aldehydes, amines, and Bu3SnCN (achiral methods). In
these reactions, the tin compounds were completely recovered by
environmentally friendly chemical processes: S. Kobayashi, T. Busu-
jima, S. Nagayama, Chem. Commun. 1998, 981 ± 982.
[16] S. Cacchi, D. Misiti, F. L. Torre, Synthesis 1980, 243 ± 244.
[17] D. R. Kronenthal, C. Y. Han, M. K. Taylor, J. Org. Chem. 1982, 47,
2765 ± 2768.
[18] (S)-Leucinamide hydrochloride: [a]2D5 ˆ ‡10 (c ˆ 5 in H2O) (Beilstein
4 (3), 1414). (S)-Leucinamide hydrochloride is commercially available
(Aldrich).
[3] a) I. Ojima, S. Inaba, K. Nakatsugawa, Chem. Lett. 1975, 331 ± 334;
b) K. Mai, G. Patil, Tetrahedron Lett. 1984, 25, 4583 ± 4586; c) S.
Kobayashi, H. Ishitani, M. Ueno, Synlett 1997, 115 ± 116.
[4] Reviews, a) R. M. Williams, Synthesis of Optically Active a-Amino
Acids, Pergamon, Oxford, 1989; b) R. M. Williams, J. A. Hendrix,
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50, 1539 ± 1650; see also: d) H. Kunz, K. Rück, Angew. Chem. 1993,
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3188
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Angew. Chem. Int. Ed. 1998, 37, No. 22