Enantioselective Strecker reaction of phosphinoyl ketoimines catalyzed by in situ prepared chiral N,N′-dioxides

Article abstract of DOI:10.1021/jo062006y

The enantioselective Strecker reaction of N-diphenylphosphinoyl ketoimines has been achieved by use of in situ prepared chiral N,N′-dioxide catalyst from L-piperidinamide 3f and m-chloroperoxybenzoic acid (m-CPBA). Excellent yields (up to 99%) and high enantioselectivities (up to 92% ee) were obtained. In particular, in situ prepared catalyst with readily available chiral material made the procedure more convenient. Moreover, the L-piperidinamide 3f-derived N,N′-dioxide 9 could be recycled and reused at least five times without any loss of either catalytic activity or enantioselectivity.

Full text of DOI:10.1021/jo062006y

Enantioselective Strecker Reaction of Phosphinoyl Ketoimines
Catalyzed by in Situ Prepared Chiral N,N′-Dioxides
Jinglun Huang,† Xiaohua Liu,† Yuehong Wen,† Bo Qin,† and Xiaoming Feng*,†,‡
Key Laboratory of Green Chemistry & Technology (Sichuan UniVersity), Ministry of Education, College of
Chemistry, Sichuan UniVersity, Chengdu 610064, China, and State Key Laboratory of Biotherapy, West
China Hospital, Sichuan UniVersity, Chengdu 610041, China
xmfeng@scu.edu.cn
ReceiVed September 28, 2006
The enantioselective Strecker reaction of N-diphenylphosphinoyl ketoimines has been achieved by use
of in situ prepared chiral N,N′-dioxide catalyst from L-piperidinamide 3f and m-chloroperoxybenzoic
acid (m-CPBA). Excellent yields (up to 99%) and high enantioselectivities (up to 92% ee) were obtained.
In particular, in situ prepared catalyst with readily available chiral material made the procedure more
convenient. Moreover, the L-piperidinamide 3f-derived N,N′-dioxide 9 could be recycled and reused at
least five times without any loss of either catalytic activity or enantioselectivity.
Introduction
catalyzed cyanations with chiral heterobimetallic complex
catalyst3 and gadolinium complex catalyst.4 Only a metal-free
chiral urea catalyst has been reported to be effective for the
aryl methyl ketoimines and t-butyl methyl ketomine.5 Then, we
expect to find another new organocatalyst, which can enanti-
oselectively catalyze the Strecker reaction of ketoimine.
Chiral N-oxide has been disclosed as having high efficiency
in many asymmetric procedures.6 We previously reported that
chiral N,N′-dioxide was a highly efficient catalyst for the
cyanation of aldimines and aldehydes with moderate to high
The Strecker reaction is one of the most attractive methods
for the synthesis of R-amino acids and their derivatives.1
Effective catalytic asymmetric cyanation of various aldimines
has been achieved, leading to efficient formation of monosub-
stituted chiral R-amino nitriles.2 However, relatively fewer
systems have been developed for catalytic asymmetric cyanation
of ketoimines, which is very useful for the generation of
quaternary R-amino acids. Reported methods include metal-
† Key Laboratory of Green Chemistry & Technology.
‡ State Key Laboratory of Biotherapy.
(3) (a) Byrne, J. J.; Chavarot, M.; Chavant, P.-Y.; Valle´e, Y. Tetrahedron
Lett. 2000, 41, 873-876. (b) Chavarot, M.; Byrne, J. J.; Chavant, P. Y.;
Valle´e, Y. Tetrahedron: Asymmetry 2001, 12, 1147-1150.
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J. Am. Chem. Soc. 2003, 125, 5634-5635. (b) Kato, N.; Suzuki, M.; Kanai,
M.; Shibasaki, M. Tetrahedron Lett. 2004, 45, 3147-3151. (c) Kato, N.;
Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2004, 45, 3153-
3155.
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Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012-10014.
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353-354. (b) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233-
4235. (c) Shimada, T.; Kina, A.; Hayashi, T. J. Org. Chem. 2003, 68, 6329-
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Lett. 2005, 7, 3151-3154. (e) Malkov, A. V.; Bell, M.; Castelluzzo, F.;
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(1) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27-45.
(2) (a) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am.
Chem. Soc. 1996, 118, 4910-4911. (b) Sigman, M. S.; Jacobsen, E. N.
J. Am. Chem. Soc. 1998, 120, 4901-4902. (c) Ishitani, H.; Komiyama, S.;
Kobayashi, S. Angew. Chem., Int. Ed. 1998, 37, 3186-3188. (d) Corey,
E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157-160. (e) Krueger, C. A.; Kuntz,
K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284-4285. (f) Porter,
J. R.; Wirschun, W. G.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 2657-2658. (g) Sigman, M. S.; Vachal, P.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279-1281. (h) Takamura,
M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem.,
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Tetrahedron Lett. 2003, 44, 3805-3808. (k) Nakamura, S.; Sato, N.;
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10.1021/jo062006y CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/07/2006
204
J. Org. Chem. 2007, 72, 204-208

Strecker Reaction of Phosphinoyl Ketoimines
FIGURE 1. Catalysts evaluated in this study.
TABLE 1. Asymmetric Strecker Reaction Catalyzed by Various
Catalystsa
TABLE 2. Solvent and Catalyst Loading Effects on the Strecker
Reaction of Ketoimine 7aa
catalyst
catalyst
m-CPBA
mol %
m-CPBA
(mol %)
entry
precursor (mol %)
conversion,b %
ee,c %
entry 3f (mol %)
solvent
conversion,b % ee,c %
1
2
3
4
5
6
7
8
1 (20)
2 (20)
0
28
29
56
15
45
20
50
64
28
10
95
<5
68
22
42
43
65
51
66
64
77
80
74
44
58
55
13
0
1
2
3
4
5
6
7
20
20
20
20
20
40
5
40
40
40
40
40
80
10
toluene
THF
64
60
50
<5
NR
99
38
80
65
3
40
40
40
40
40
40
40
40
40
40
40
40
40
3a (20)
3b (20)
3c (20)
3d (20)
3e (20)
3f (20)
3g (20)
3h (20)
4 (20)
CH3CN
CH2Cl2
MeOH
toluene
toluene
27
64
80
a-c See Table 1 footnotes.
9
10
11
12
13
14
5 (20)
6a (20)
6b (20)
To optimize the catalyst, various in-situ-generated chiral N,N′-
dioxides were then examined for the Strecker reaction. As shown
in Table 1, significantly higher ee values were obtained with
piperidinamide 3-derived N,N′-dioxides (Table 1, entries 3-10).
The enantioselectivity was increased to 80% ee with the bulky
1-adamantylamine-based (3f) catalyst (Table 1, entry 8). Other
changes to the catalysts, such as replacing piperidinamide (Table
1, entries 11 and 12) or decreasing or increasing the length of
carbon chain (Table 1, entries 13 and 14) resulted in lower
enantioselectivity.
Then, we selected the catalyst precursor 3f to investigate other
parameters. As shown in Table 2, the yields and enantioselec-
tivities were very much dependent on the solvent. Of the
solvents screened, toluene was the best (Table 2, entry 1).
Tetrahydrofuran (THF) and CH3CN also provided good yields,
but the enantioselectivities were notably diminished (Table 2,
entries 2 and 3). When CH2Cl2 was used, a rather low yield
was obtained (Table 2, entry 4). However, no product was
observed in MeOH as solvent, which was probably due to the
fact that the TMSCN and MeOH generated hydrogen cyanide
(Table 2, entry 5). In addition, higher catalyst loading could
result in complete conversion, but the enantioselectivity de-
creased to 64% ee (Table 2, entry 6). Fortunately, when the
catalyst loading was reduced to 5 mol %, there was no loss in
enantioselectivity (Table 2, entry 7).
a All reactions were carried out in the air; concentration of ketoimine
was 0.1 M; see Supporting Information for details. b Conversions were
determined by chiral HPLC. c Determined by HPLC on Chiralcel OD
column and the absolute configuration was determined to be R by
comparison with literature data.4
enantioselectivity.7 However, our subsequent study has shown
that the cyanation of ketones with the chiral N,N′-dioxide
required the presence of a metal.8 Herein, we report a highly
enantioselective Strecker reaction of ketoimines by a metal-
free system with a readily available chiral C2-symmetric N,N′-
dioxide as catalyst.
Results and Discussion
Reaction Condition Optimization. We initiated our search
for the Strecker reaction between N-diphenylphosphinoyl ke-
toimine 7a and trimethylsilyl cyanide (TMSCN) by using 20
mol % L-prolinamide-derived N,N′-dioxide 1 (Figure 1). As
shown in Table 1, organocatalyst 1 gave moderate enantiose-
lectivity (42% ee) (Table 1, entry 1). Interestingly, a similar
result was obtained when chiral N,N′-dioxide 1 was generated
in situ with 20 mol % prolinamide 2 and 40 mol % m-
chloroperoxybenzoic acid (m-CPBA) (Table 1, entry 2) (no
reaction was observed with prolinamide 2 as the catalyst alone).
(8) Li, Q. H.; Liu, X. H.; Wang, J.; Shen, K.; Feng, X. M. Tetrahedron
Lett. 2006, 47, 4011-4014.
J. Org. Chem, Vol. 72, No. 1, 2007 205

Huang et al.
TABLE 3. Amount of TMSCN and m-CPBA Effects on the
SCHEME 1. Proposed Catalytic Cycle
Strecker Reaction of Ketoimine 7aa
m-CPBA
(mol %)
entry
TMSCN (equiv)
conversion,b %
ee,c %
1
2
3
4
5
6
2.0
2.0
2.0
3.0
2.5
1.5
15
5
10
10
10
10
35
17
38
75
66
34
75
73
80
79
79
80
a -cSee Table 1 footnotes.
TABLE 4. Temperature and Concentration Effects on the
Strecker Reaction of Ketoimine 7aa
ketoimine
concn, M
entry
temp, °C
time, h
conversion,b %
ee,c %
1
2
3
4
5
6
7
8
25
0
0.1
0.1
0.1
0.1
0.05
0.2
0.25
0.1
24
24
48
48
48
48
48
196
99
34
38
NR
16
68
77
>99
73
80
90
-20
-45
-20
-20
-20
-20
However, further decreasing the temperature to -45 °C led to
no product (Table 4, entry 4). With the concentration of
ketoimine increasing, the yields were improved, while the
enantioselectivities decreased from 92% to 83% ee (Table 4,
entries 3-7). When the concentration of ketoimine was 0.1 M,
the appropriate conversion and enantioselectivity were obtained
(38% conversion, 90% ee). Complete conversion could be
obtained by prolonging the reaction time and high enantiose-
lectivity remained (Table 4, entry 8).
92
84
83
90
a All reaction were performed in the air; see Supporting Information for
details. b ,cSee Table 1 footnotes.
Hence, the optimal conditions were 5 mol % 3f, 10 mol %
m-CPBA, concentration of ketoimine 0.1 M, 1.5 equiv of
TMSCN, toluene, and -20 °C.
Substrate Generality. Encouraged by these results, we
investigated a variety of N-diphenylphosphinoyl ketoimines. As
shown in Table 5, excellent yields (90-99%) were obtained
with all substrates. High enantioselectivities were obtained for
aryl methyl ketoimines (Table 5, entries 1-12). In some cases,
essentially optically pure products can be obtained by recrys-
tallization from CH2Cl2/hexane (Table 5, entries 6 and 7). The
reaction can also extend to cyclic ketoimine with 90% ee (Table
5, entry 13). Somewhat lower ee values were obtained with aryl
propyl ketoimine 7n, propiophenone-derived ketoimine 7o, and
alkyl-substituted ketoimine 7p, as well as heteroaromatic
ketoimines 7q and 7r (Table 5, entries 14-18). Most of the
products 8 in Table 5 can be directly subjected to acid hydrolysis
to produce the corresponding amino acids.4
To check the reusability of the catalyst, the chiral piperidi-
namide 3f-derived N,N′-dioxide 9 was isolated (Figure 2). From
the results in Table 6, it was clearly demonstrated that catalyst
9 could be recycled and reused at least five times without any
loss of either catalytic activity or enantioselectivity. In addition,
chiral catalyst 9 was quantitatively recovered from the reaction
mixture by using flash silica gel column chromatography.
Mechanistic Consideration. To gain preliminary insight into
the mechanism, some experiments were tested: (1) The in-situ-
FIGURE 2. N-oxides of piperidinamide 3f.
With 5 mol % 3f in toluene, we next examined the amount
of m-CPBA and TMSCN with results summarized in Table 3.
When the m-CPBA loading was increased, the yield and
enantioselectivity somewhat dropped (Table 3, entry 1 vs 3).
However, lowering the m-CPBA loading greatly decreased the
yield, which was probably due to the fact that the piperidinamide
3f was not completely oxidized into the effective N,N-dioxide
(Table 3, entry 2 vs 3). There was a tendency that higher
amounts of TMSCN resulted in higher yields (Table 3, entries
3-6). In order to use less reagent, we chose 1.5 equiv of
TMSCN in the subsequent optimization.
Under the conditions of 5 mol % 3f, 10 mol % m-CPBA,
and 1.5 equiv of TMSCN, the reaction temperature and
ketoimine concentration were investigated and the results are
presented in Table 4. The reaction temperature was found to
be the key factor in the yields and enantioselectivities. Lowering
the temperature led to a dramatic drop in reactivity (Table 4,
entries 1-4). Fortunately, the product was obtained with up to
90% ee in moderate conversion at -20 °C (Table 4, entry 3).
206 J. Org. Chem., Vol. 72, No. 1, 2007

Strecker Reaction of Phosphinoyl Ketoimines
TABLE 5. Scope of the Enantioselective Strecker Reaction of Ketoimine 7a
a Unless other specified, reactions were run with 0.1 mmol of ketoimine, 0.15 mmol of TMSCN, and 5 mol % catalyst in 1 mL of toluene for 60-196
h in the air; see Supporting Information for details. b Isolated yields. c The ee values were determined by chiral HPLC. The absolute configuration of 8a was
determined by comparison with literature data4 and other configurations were compared with the Cotton effect in their CD spectra (see Supporting Information
for details). d 10 mol % 3f and 20 mol % m-CPBA were used, and the reaction was at -10 °C. e 10 mol % 3f and 20 mol % m-CPBA were used. f Product
was recrystallized from CH2Cl2/hexane.
generated 9 and isolated 9 gave the same enantioselectivities
and conversions (see Supporting Information), whereas no
product was detected with piperidinamide 3f or m-CPBA alone
as the catalyst. This result revealed that the N-oxide played the
role of actual catalyst. (2) The single N-oxide 10 derived from
L-piperidinamide 3f could not catalyze the addition of TMSCN
to ketoimine (Figure 2), which suggested that TMSCN was
likely to be activated by the two donors (N-O) of catalyst 9.9
(3) The nucleophilicity of the cyano group was enhanced, which
can be proved by simple 29Si NMR spectra. Another strong
silicon signal was found at δ ) 0.51 ppm when chiral N,N′-
dioxide 9 and TMSCN were mixed (see Supporting Informa-
tion). (4) No product was found when HCN replaced TMSCN,
which suggested that the attacking group was not CN- ion but
activated TMSCN. On the basis of these observations, we
proposed a possible catalytic cycle (Scheme 1). The chiral N,N′-
dioxide 9 was first generated from piperidinamide 3f and
m-CPBA. Then chiral N,N′-dioxide 9 coordinated with the
TMSCN to form the possible hypervalent silicate, enhancing
(9) (a) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6195-6196.
(b) Tian, S.-K.; Hong, R.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900-
9901. (c) Kato, N.; Tomita, D.; Maki, K.; Kanai, M.; Shibasaki, M. J. Org.
Chem. 2004, 69, 6128-6130. (d) Hamashima, Y.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2000, 122, 7412-7413. (e) Ryu, D. H.; Corey, E. J.
J. Am. Chem. Soc. 2005, 127, 5384-5387. (f) Knudsen, K. R.; Risgaard,
T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc.
2001, 123, 5843-5844.
J. Org. Chem, Vol. 72, No. 1, 2007 207

Huang et al.
TABLE 6. Recycling and Reuse of the Chiral N,N′-Dioxide 9 in
allowed to warm to ambient temperature and detected by thin-layer
chromatography (TLC). The mixture was washed with 1 M KHSO4,
saturated NaHCO3, and brine, dried over anhydrous MgSO4, and
concentrated. To the residue in CH2Cl2 (4 mL) was added TFA (4
mL), and the mixture was stirred until the reaction was finished.
Then the solvent was evaporated, and H2O (10 mL) was added.
The pH value of the mixture was brought into the range of 8-10
by the addition of 1 M NaOH. The aqueous phase was extracted
with CH2Cl2 (5 × 20 mL). The combined organic phase was washed
with brine, dried over anhydrous MgSO4, and evaporated in vacuo.
The residue was directly used for next step. To a solution of (S)-
1-N-Boc-piperidine-2-carbonamide in CH3CN (4 mL) were added
K2CO3 (608 mg, 4.4 mmol) and 1,3-dibromopropane (204 µL, 2
mmol) under stirring. It was kept at 80 °C and monitored by TLC.
Then K2CO3 was removed by filtration. The residue was concen-
trated and purified by silica gel column chromatography (EtOAc)
to give a white product 3f (1.060 g, 94% yield): mp 74-76 °C;
a
Strecker Reaction
cycle
1
2
3
4
5
yield,b %
ee,c %
95
87
96
90
95
89
93
88
96
89
a The reaction were performed with 5 mol % N,N’-dioxide 9 at -20 °C
for 68 h. b Isolated yield. c Determined by HPLC on Chiralcel OJ column.
[R]D ) -103.60 (c ) 0.50 in CHCl3); 1H NMR [400 MHz,
25
the nucleophilicity of TMSCN and creating a fixed chiral pocket.
On the other hand, hydrogen bonding,10 between the amide
moiety and the ketoimine 7a, may also play a role in activating
the ketoimine and controlling the reaction conformation. The
cyano group prefered to attack the si face of the hydrogen-bond-
activated ketoimine (proposed TS-1), affording enantiomer R-8a
as major product, since the re-face attack was likely to disfavor
the steric repulsion between the phenyl group of phosphinoyl
and the bulky 1-adamantylamine of catalyst in proposed TS-2.
CDCl3, 25 °C, tetramethylsilane (TMS)] δ 6.38 (s, 2H), 3.05 (d, J
) 11.2 Hz, 2H), 2.46-2.52 (m, 4H), 2.16-2.22 (m, 2H), 2.07-
2.10 (m, 8H), 1.92-1.98 (m, 14H), 1.65-1.68 (m, 18H), 1.34-
1.45 (m, 4H), 1.22-1.28 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3, 25 °C, TMS) δ 173.7, 69.2, 54.7, 51.4, 50.9, 41.6, 36.2,
30.8, 29.3, 25.0, 24.5, 23.5 ppm; EI-HRMS calcd for C35H56N4O2
(M+) 564.4403, found 564.5426.
Typical Experimental Procedure for the Catalytic Enantio-
selective Strecker Reaction (7a). The chiral piperidinamide 3f (2.8
mg, 0.005 mmol) and m-CPBA (1.8 mg, 0.01 mmol) in toluene
(0.4 mL) were stirred in a tube at ambient temperature for 0.5 h.
Then ketoimine 7a (31.9 mg, 0.1 mmol), dissolved in toluene (0.6
mL), was added. Subsequently, TMSCN (20.2 µL, 0.15 mmol) was
added at -20 °C. When ketoimine 7a disappeared (monitored by
HPLC), the reaction mixture was directly purified by column
chromatography on silica gel eluted with ethyl acetate/petroleum
ether (1:1 v/v) to afford product 8a as an off-white solid: mp 122-
124 °C; [R]D25 ) +14.02 (c ) 0.214 in CHCl3, 90% ee); 1H NMR
(400 Hz, CDCl3, 25 °C, TMS) δ 8.01-8.07 (m, 2H), 7.81-7.86
(m, 2H), 7.73-7.76 (m, 2H), 7.33-7.60 (m, 9H), 3.68 (d, J ) 7.6
Hz, 1H, NH), 2.29 (s, 3H) ppm; HPLC (Chiralcel OD, hexane/2-
propanol ) 95/5, 0.6 mL/min), tR (minor) ) 40.63 min, tR (major)
) 45.66 min, 91% yield, 90% ee.
Conclusion
In summary, we have developed a new strategy for asym-
metric Strecker reaction of ketoimines using in-situ-formed N,N′-
dioxide catalyst. High yields and moderate to excellent enan-
tioselectivities have been obtained for a wide variety of
substrates. Attractive features of the present method include the
simple in situ catalyst preparation with readily available material,
mild reaction conditions, and convenient procedure with the
tolerance of moisture and air. Moreover, the chiral N,N′-dioxide
can be easily recovered and reused at least five times without
any loss in either catalytic activity or enantioselectivity.
Experimental Section
Acknowledgment. This work was financially supported by
the National Natural Science Foundation of China (20225206,
20390055, and 20372050) and the Ministry of Education,
People’s Republic of China (104209). We also thank Sichuan
University Analytical and Testing Center for CD spectra
analysis.
Typical Procedure for Catalyst Preparation (3f). To a solution
of (S)-1-N-Boc-piperidine-2-carboxylic acid (917 mg, 4 mmol) in
CH2Cl2 (40 mL) were added Et3N (0.62 mL, 4.4 mmol) and isobutyl
carbonochloridate (576 mg, 4.4 mmol) at 0 °C under stirring. After
15 min, amine (666 mg, 4.4 mmol) was added. The reaction was
(10) (a) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662-
9663. (b) Roitzsch, M.; Lippert, B. J. Am. Chem. Soc. 2004, 126, 2421-
2424. (c) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43, 2062-2064. (d)
Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem.
Soc. 2005, 127, 1336-1337. (e) Kim, K. M.; Park, H.; Kim, H.-J.; Chin,
J.; Nam, W. Org. Lett. 2005, 7, 3525-3527. (f) Taylor, M. S.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2006, 45, 1520-1543.
Supporting Information Available: Experimental procedures
1
and structural proofs for catalysts and racemates, CD spectra, H
NMR and 13C NMR spectra, and HPLC results. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO062006Y
208 J. Org. Chem., Vol. 72, No. 1, 2007