Chiral bisformamides as effective organocatalysts for the asymmetric one-pot, three-component strecker reaction

Article abstract of DOI:10.1021/jo701307f

(Chemical Equation Presented) C₂-symmetric chiral bisformamides have been shown to catalyze the asymmetric one-pot, three-component Strecker reaction, which produced the α-amino nitriles in excellent yields (up to 99%) with good enantioselectiv

Full text of DOI:10.1021/jo701307f

Chiral Bisformamides as Effective Organocatalysts for the
Asymmetric One-Pot, Three-Component Strecker Reaction
Yuehong Wen,† Yan Xiong,† Lu Chang,† Jinglun Huang,† Xiaohua Liu,† 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, Sichuan UniVersity, Chengdu 610041, China
xmfeng@scu.edu.cn
ReceiVed June 23, 2007
C2-symmetric chiral bisformamides have been shown to catalyze the asymmetric one-pot, three-component
Strecker reaction, which produced the R-amino nitriles in excellent yields (up to 99%) with good
enantioselectivities (up to 86% ee). Optically pure products could be obtained after a single recrystallization.
A possible transition state (TS 1) has been proposed to explain the origin of asymmetric inductivity and
reactivity according to the geometry of catalyst 2a optimized at the B3LYP/6-31G(d) level and the absolute
configuration of product 4a.
Introduction
kind of organocatalyst, C2-symmetric chiral bisformamides,
for the asymmetric one-pot, three-component Strecker re-
action.
The Strecker reaction is one of the most attractive methods
for the synthesis of R-amino acids and their derivatives.1
In recent years, considerable effort has been devoted toward
the development of asymmetric Strecker reactions.2 Several
chiral metal complexes including Al, Ti, Zr, and lanthanide have
been identified for this transformation.3 Effective metal-free
catalysts have been developed employing chiral guanidines,
ureas and thioureas, bis(N-oxides), ammonium salts, and Brøn-
sted acids.4 Nevertheless, only very recently has a single
example of organocatalytic asymmetric three-component Streck-
er reaction been reported by List et al.4f A one-pot multicom-
ponent reaction has many advantages such as its simplified
procedure, mild reaction condition, high atom economy, and
environmental friendliness. Herein, we wish to report another
(3) Al catalysts: (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc.
1998, 120, 5315-5316. (b) Takamura, M.; Hamashima, Y.; Usuda, H.;
Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650-1652.
(c) Nogami, H.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
2001, 42, 279-283. Ti catalysts: (d) 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. (e) Byrne, J. J.; Chavarot, M.;
Chavant, P. Y.; Valle´e, Y. Tetrahedron Lett. 2000, 41, 873-876. (f)
Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2001, 123, 11594-11599. (g) Porter, J. R.; Wirschun, W. G.;
Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 2657-2658. Zr catalysts: (h) Ishitani, H.; Komiyama, S.; Kobayashi,
S. Angew. Chem., Int. Ed. 1998, 37, 3186-3188. (i) Kobayashi, S.; Ishitani,
H. Chirality 2000, 12, 540-543. (j) Ishitani, H.; Komiyama, S.; Hasegawa,
Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762-766. Lanthanide
catalysts: (k) Chavarot, M.; Byrne, J. J.; Chavant, P. Y.; Valle´e, Y.
Tetrahedron: Asymmetry 2001, 12, 1147-1150. (l) Masumoto, S.; Usuda,
H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
5634-5635. (m) Kato, N.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetra-
hedron Lett. 2004, 45, 3147-3151. (n) Kato, N.; Suzuki, M.; Kanai, M.;
Shibasaki, M. Tetrahedron Lett. 2004, 45, 3153-3155. (o) Kato, N.; Mita,
T.; Kanai, M.; Therrien, B.; Kawano, M.; Yamaguchi, K.; Danjo, H.; Sei,
Y.; Sato, A.; Furusho, S.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6768-
6769.
† Key Laboratory of Green Chemistry & Technology.
‡ State Key Laboratory of Biotherapy.
(1) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27-45.
(2) For reviews, see: (a) Gro¨ger, H. Chem. ReV. 2003, 103, 2795-2827.
(b) Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875-877. (c) Spino, C. Angew.
Chem., Int. Ed. 2004, 43, 1764-1766. (d) Kobayashi, S.; Ishitani, H. Chem.
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10.1021/jo701307f CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/30/2007
J. Org. Chem. 2007, 72, 7715-7719
7715

Wen et al.
Since N,N-dimethylformamide (DMF) proved to be an
effective Lewis base catalyst for some important reactions,5 the
rational design and synthesis of new chiral DMF analogues for
enantioselective synthesis have become the focus of attention.6
However, to the best of our knowledge, the chiral formamide-
based catalysts were restricted to allylation and hydrosilylation
reactions. In this context, chiral formamides have been applied
to the one-pot, three-component Strecker reaction for the first
time, and delivered good yields and enantioselectivities.
FIGURE 1. Structure of monoformamides.
Results and Discussion
Allyltrichlorosilane and trichlorosilane can be activated by
chiral formamides through formyl coordination to silicon.6d,j Our
earlier studies on bifunctional catalysis indicated that imines
could be activated through hydrogen bonding.4l,m Inspired by
those studies, we presumed that N-formyl-(L)-proline amides,
which contained both the formyl and amide moieties, might have
the ability to catalyze the asymmetric Strecker reaction.
Therefore, the one-pot Strecker reaction starting from benzal-
dehyde, (1,1-diphenyl)methylamine, and TMSCN was chosen
as the model reaction to verify our strategy. At the outset, the
monoformamide catalyst 1e derived from L-proline and (S)-1-
phenylethanamine was tested. Encouragingly, 96% yield and
44% ee were obtained employing 20 mol % 1e. Then, a series
of monoformamides 1a-g were prepared and the influence of
the substituent R on the catalytic behavior was studied (Table
FIGURE 2. Structure of bisformamides.
TABLE 1. Survey of Chiral Monoformamide Catalysts 1a-g on
the One-Pot, Three-Component Strecker Reactiona
(4) (a) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157-160. (b)
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901-4902.
(c) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2000, 39, 1279-1281. (d) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2,
867-870. (e) Pan, S. C.; Zhou, J.; List, B. Angew. Chem., Int. Ed. 2007,
46, 612-614. (f) Pan, S. C.; List, B. Org. Lett. 2007, 9, 1149-1151. (g)
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012-10014.
(h) Wenzel, A. G.; Lalonde, M. P.; Jacobsen, E. N. Synlett 2003, 1919-
1922. (i) Tsogoeva, S. B.; Yalalov, D. A.; Hateley, M. J.; Weckbecker, C.;
Huthmacher, K. Eur. J. Org. Chem. 2005, 4995-5000. (j) Liu, B.; Feng,
X. M.; Chen, F. X.; Zhang, G. L.; Cui, X.; Jiang, Y. Z. Synlett 2001, 1551-
1554. (k) Jiao, Z. G.; Feng, X. M.; Liu, B.; Chen, F. X.; Zhang, G. L.;
Jiang, Y. Z. Eur. J. Org. Chem. 2003, 3818-3826. (l) Huang, J. L.; Liu,
X. H.; Wen, Y. H.; Qin, B.; Feng, X. M. J. Org. Chem. 2007, 72, 204-
208. (m) Huang, X.; Huang, J. L.; Wen, Y. H.; Feng, X. M. AdV. Synth.
Catal. 2006, 348, 2579-2584. (n) Huang, J.; Corey, E. J. Org. Lett. 2004,
6, 5027-5029. (o) Berkessel, A.; Mukherjee, S.; Lex, J. Synlett 2006, 41-
44. (p) Ooi, T.; Uematsu, Y.; Maruoka, K. J. Am. Chem. Soc. 2006, 128,
2548-2549. (q) Rueping, M.; Sugiono, E.; Azap, C. Angew. Chem., Int.
Ed. 2006, 45, 2617-2619. (r) Rueping, M.; Sugiono, E.; Moreth, S. A.
AdV. Synth. Catal. 2007, 349, 759-764.
entry
catalyst
yieldb (%)
eec (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
92
99
99
99
96
99
93
35
32
38
20
44
46
11
1g
a Reaction condition: benzaldehyde (0.2 mmol) and (1,1-diphenyl)m-
ethylamine (0.2 mmol) were stirred for 1 h at rt before catalyst 1 was added.
Then TMSCN (0.4 mmol) was added at 0 °C. b Isolated yield. c Determined
by chiral HPLC on a Chiralcel AD-H column.
(5) (a) Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993, 34, 3453-
3456. (b) Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620-6628.
(c) Wang, Z.; Wang, D.; Sui, X. J. Chem. Soc., Chem. Commun. 1996,
2261-2262. (d) Kobayashi, S.; Nishio, K. J. Am. Chem. Soc. 1995, 117,
6392-6393. (e) Saito, S.; Bunya, N.; Inaba, M.; Moriwake, T.; Torii, S.
Tetrahedron Lett. 1985, 26, 5309-5312. (f) Kobayashi, S.; Yasuda, M.;
Hachiya, I. Chem. Lett. 1996, 407-408. (g) Prakash, G. K. S.; Vaghoo,
H.; Panja, C.; Surampudi, V.; Kultyshev, R.; Mathew, T.; Olah, G. A. Proc.
Natl. Acad. Sci. U.S.A. 2007, 104, 3026-3030.
(6) (a) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron
Lett. 1998, 39, 2767-2770. (b) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi,
Y. Tetrahedron 1999, 55, 977-988. (c) Jagtap, S. B.; Tsogoeva, S. B. Chem.
Commun. 2006, 4747-4749. (d) Iwasaki, F.; Onomura, O.; Mishima, K.;
Maki, T.; Matsumura, Y. Tetrahedron Lett. 1999, 40, 7507-7511. (e) Wang,
Z. Y.; Ye, X. X.; Wei, S. Y.; Wu, P. C.; Zhang, A. J.; Sun, J. Org. Lett.
2006, 8, 999-1001. (f) Wang, Z. Y.; Cheng, M. N.; Wu, P. C.; Wei, S. Y.;
Sun, J. Org. Lett. 2006, 8, 3045-3048. (g) Malkov, A. V.; Figlus, M.;
Stoncˇius, S.; Kocˇovsky´, P. J. Org. Chem. 2007, 72, 1315-1325. (h) Malkov,
A. V.; Stoncˇius, S.; Kocˇovsky´, P. Angew. Chem., Int. Ed. 2007, 46, 3722-
3724. (i) Matsumura, Y.; Ogura, K.; Kouchi, Y.; Iwasaki, F.; Onomura, O.
Org. Lett. 2006, 8, 3789-3792. (j) Iwasaki, F.; Onomura, O.; Mishima,
K.; Kanematsu, T.; Maki, T.; Matsumura, Y. Tetrahedron Lett. 2001, 42,
2525-2527. (k) Baudequin, C.; Chaturvedi, D.; Tsogoeva, S. B. Eur. J.
Org. Chem. 2007, 2623-2629.
1). Among the aliphatic amide substituents, 1e was optimal
producing the products with 44% ee (Table 1, entry 5). Bulky
substituents, like the cyclohexyl, tert-butyl, and adamantyl
groups, gave slightly lower enantioselectivities (Table 1, entries
1-3). The phenyl substituent also resulted in a good enanti-
oselectivity of 46% ee (Table 1, entry 6). Introducing bulky
substituents onto the phenyl ring resulted in a much lower ee
value (Table 1, entry 7).
On the basis of the above studies, we confirmed that
formamides derived from the amino acid and amine could
catalyze the addition of TMSCN to in situ generated imines.
We speculated that an additional formyl and the changed chiral
environment of C2-symmetric bisformamides might be more
advantageous. Therefore, a set of bisformamides 2a-e were
synthesized (Figure 2) and tested (Table 2) which were first
developed and applied to allylation of aldimines with allyl-
trichlorosilane by Tsogoeva et al.6k Indeed, the reactivity (Table
2, entries 1-5) and enantioselectivity (Table 2, entries 1 and
7716 J. Org. Chem., Vol. 72, No. 20, 2007

Organocatalysts for the Strecker Reaction
TABLE 2. Survey of Chiral Bisformamide Catalysts 2a-e on the
TABLE 4. The Catalyst Loading and Temperature Effecta
One-Pot, Three-Component Strecker Reactiona
catalyst
entry loading (mol %) temp (°C) time (h) yieldb (%) eec (%)
1
2
3
4
5
6
5
10
20
30
10
10
-20
-20
-20
-20
0
10
10
10
10
7
98
99
99
99
99
85
66
75
78
77
72
55
entry
catalyst
yieldb (%)
eec (%)
1
2
3
4
5
2a
2b
2c
2d
2e
99
97
90
97
97
61
12
17
34
51
-45
16
a Reaction condition: benzaldehyde (0.2 mmol) and (1,1-diphenyl)m-
ethylamine (0.2 mmol) were stirred together for 1 h at rt before catalyst 2a
was added. Then TMSCN (0.4 mmol) was added at -20, 0, or -45 °C.
b Isolated yield. c Determined by chiral HPLC on a Chiralcel AD-H column.
a Reaction condition: benzaldehyde (0.2 mmol) and (1,1-diphenyl)m-
ethylamine (0.2 mmol) were stirred for 1 h at rt before catalyst 2 was added.
Then TMSCN (0.4 mmol) was added at 0 °C. b Isolated yield. c Determined
by chiral HPLC on a Chiralcel AD-H column.
TABLE 5. Effect of the Molar Ratios and the Concentrationa
TABLE 3. Solvent Effect for the One-Pot, Three-Component
Strecker Reactiona
entry
solvent
THF
Et2O
PhCH3
CH2Cl2
CH2ClCH2Cl
CHCl3
time (h)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
20
20
20
10
10
7
8
37
99
94
99
99
99
7
0
ratio
concn of
entry (PhCHO:amine:TMSCN) PhCHO (M) yieldb (%) eec (%)
39
69
75
58
0
1
2
3
4
5
6
7
1:1:1.5
1:1:2
1:1:3
1:1.5:2
1:1:2
1:1:2
0.2
0.2
0.2
0.2
0.4
1
99
99
99
99
99
99
97
63
75
73
75
75
65
62
CH3OH
7
a Reaction condition: benzaldehyde (0.2 mmol) and (1,1-diphenyl)m-
ethylamine (0.2 mmol) were stirred for 1 h at rt before catalyst 2a was
added. Then TMSCN (0.4 mmol) was added at -20 °C. b Isolated yield.
c Determined by chiral HPLC on a Chiralcel AD-H column.
1:1:2
0.13
a Reaction condition: benzaldehyde (0.2 mmol) and (1,1-diphenyl)m-
ethylamine (0.2 mmol) were stirred together for 1 h at rt before catalyst
was added. Then TMSCN (0.4 mmol) was added at -20 °C and reacted
for 10-14 h. b Isolated yield. c Determined by chiral HPLC on a Chiralcel
AD-H column.
5) were greatly promoted by bisformamides compared with
monoformamides. Catalyst 2a produced the product with 61%
ee and 99% yield within 10 h (Table 2, entry 1). Any
replacement of the 1,2-diphenylethane-1,2-diamine or L-proline
led to reduced enantioselectivities (Table 2, entries 3-5). The
match between the chiral centers of diamine and proline was
very important for catalytic efficiency. The best results were
observed in the reactions with catalyst 2a, while only 12% ee
was found with 2b (Table 2, entry 1 vs 2).
Accordingly, optimization of the reaction conditions was
investigated by using 2a as the catalyst of choice. Solvent
screening showed that CH2ClCH2Cl was the best, with the
results of 99% yield and 75% ee (Table 3, entry 5). The ethereal
solvents such as THF and Et2O gave low yields and nearly
racemic products (Table 3, entries 1 and 2). Toluene provided
good yields, but the enantioselectivity was notably diminished
(Table 3, entry 3). CH2Cl2 and CHCl3 were also good solvents
for reactivity and enantioselectivity (Table 3, entries 4 and 6).
When protic solvents like CH3OH were used, high yields but
no enantioselectivities were afforded (Table 3, entry 7).
We next observed the catalyst loading and temperature effect
(Table 4). Decreasing of the catalyst loading from 10 to 5 mol
%, the ee value was reduced from 75% to 66% (Table 4, entry
2 vs entry 1). Unfortunately, the enantioselectivity was not
notablely improved when increasing the catalyst loading to 20
and 30 mol % (Table 4, entries 3 and 4). So 10 mol % 2a was
determined to be the optimal catalyst loading. The best results
were found at -20 °C (Table 4, entry 2). Higher or lower
temperatures were not beneficial for the ee value (Table 4,
entries 5 and 6).
molar ratio of PhCHO, amine, and TMSCN was 1:1:2, 99%
yield and 75% ee were obtained (Table 5, entry 2). By
decreasing TMSCN to 1.5 equiv, the enantioselectivity was
reduced to 63% ee (Table 5, entry 1). Increasing TMSCN to 3
equiv led to a small reduction of the ee value (Table 5, entry
3). The yield and enantioselectivity were unchanged while
varying the amount of (1,1-diphenyl)methylamine (Table 5,
entry 4 vs entry 2). When the concentration of benzaldehyde
was diminished from 0.2 to 0.13 M, the enantioselectivity was
decreased remarkably (Table 5, entry 7 vs entry 2). The same
yield and ee value were produced with 0.4 M of PhCHO (Table
5, entry 5 vs entry 2). However, when further enhancing the
concentration of benzaldehyde to 1 M, only 65% ee was
observed (Table 5, entry 6). Thereafter, 0.2 M of PHCHO was
chosen to test other conditions.
To improve the enantioselectivity, some common drying
agents, such as MgSO4, Na2SO4, and 3, 4, and 5 Å MS, were
examined. The best results (81% ee and 99% yield) were
obtained when using anhydrous Na2SO4. The optimal conditions
were 0.2 mmol of benzaldehyde, 0.2 mmol of (1,1-diphenyl)-
methylamine, 100 mg of Na2SO4, 10 mol % of 2a, 0.4 mmol
of TMSCN, 1 mL of CH2ClCH2Cl and -20 °C.
With the optimal conditions, the scope of this three-
component reaction with different aldehydes was explored and
the results were summarized in Table 6. Good to high yields
(up to 99%) and good enantioselectivities (up to 86% ee; single
recrystallization, up to 99% ee) were achieved. The substrates
with para-substituted aromatic rings provided adducts in high
enantioselectivities (Table 6, entries 2, 5, 7, 10, and 11). A
slightly lower enantioselectivity was obtained for the ortho- or
The ratio of the three components and the effect of the
substrate concentration were also checked (Table 5). When the
J. Org. Chem, Vol. 72, No. 20, 2007 7717

Wen et al.
TABLE 6. Scope of the Enantioselective One-Pot,
Three-Component Strecker Reactiona
entry
RCHO (3)
time (h) yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
R ) phenyl (3a)
10
10
10
10
10
14
50
60
50
60
14
50
14
14
99
98
99
97
96
97
98
74
81
85
94
75
92
94
81 (R)d
84 (>99)e
80 (R)
76
85
76
R ) 4-methylphenyl (3b)
R ) 2-methylphenyl (3c)
R ) 3-methylphenyl (3d)
R ) 4-methoxyphenyl (3e)
R ) 3-methoxyphenyl (3f)
R ) 4-chlorophenyl (3g)
R ) 3-chlorophenyl (3h)
R ) 2-chlorophenyl (3i)
R ) 4-bromophenyl (3j)
R ) 4-phenylphenyl (3k)
R ) 2-naphthyl (3l)
83
73
75 (R)
86 (>99)
86
81 (R)
73
FIGURE 3. Optimized geometry of catalyst 2a at the B3LYP/6-31G-
(d) level.
R ) tert-butyl (3m)
R ) 2-furyl (3n)
43
meta-substituted aldehydes (Table 6, entries 4, 6, 8, and 9). The
halogen-substituted aromatic aldehydes produced the corre-
sponding R-amino nitriles with moderate to high yields and good
enantioselectivities (Table 6, entries 7-10), but the reactivity
was not as good as that of alkyl- or alkoxyl-substituted aromatic
aldehydes. A 75% yield and 81% ee were given by 2-naph-
thaldehyde (Table 6, entry 12). Pivaldehyde also gave good
results (Table 6, entry 13). The heterocyclic aldehyde furfural
gave high yield but moderate enantioselectivity (Table 6, entry
14). Moreover, the Strecker adducts were important precursors,
which could be conveniently hydrolyzed to R-amino acids with
no loss of optical purity.3d,f,g,8
a Reaction condition: Na2SO4 (100 mg), aldehyde (0.2 mmol), and (1,1-
diphenyl)methylamine (0.2 mmol) were stirred together for 1 h at rt before
catalyst 2a was added. Then TMSCN (0.4 mmol) was added at -20 °C.
b Isolated yield. c Determined by chiral HPLC on a Chiralcel AD-H column.
d The absolute configuration was established as R by comparison of the
literature (see refs 3d, 4k, and 7). e After single recrystallization.
Mechanistic Consideration
The geometry of catalyst 2a was optimized at the B3LYP/
6-31G(d) level (Figure 3) with use of the Gaussian 03 program
package. The distances between the O on the formyl group and
the H of amide were 2.009 and 2.015 Å, which indicated two
hydrogen bonds exist in 2a. The modeling calculation also
showed that the two phenyl rings of the diamine moiety are
bent forward and backward, and the two pyrrole units are bent
upward and downward, respectively. According to the observed
absolute configuration of product 4a (Table 6, entry1) and the
optimized geometry of catalyst 2a, a possible transition state
(Figure 4, TS 1) has been proposed. In situ generated imine is
activated by hydrogen bond via the nitrogen of imine coordinat-
ing to the hydrogen of amide,4l,m while TMSCN is activated by
two oxygens in another pyrrole unit coordinated to silicon.6d,j
The Si face attack is much more accessible than the Re face, as
the increased repulsion between the phenyl group of the imine
and the pyrrole unit occurs in TS 2.
FIGURE 4. Proposed transition states.
under simple and mild conditions. It is the first example that
chiral DMF analogues have been used in asymmetric cyanosi-
lylation of imine. A possible transition state TS 1 has been
proposed according to the geometry of catalyst 2a optimized at
the B3LYP/6-31G(d) level and the absolute configuration of
product 4a. Further investigations are underway in our labora-
tory, including exploration of a relative catalyst library, detailed
mechanisms, extended substrate scope, and enhancement of
enantioselectivity.
Experimental Section
Typical Experimental Procedure for the Preparation of
Catalyst 2a.6c,e,9 To a solution of Boc L-proline (1.34 g, 6.2 mmol)
in CH2Cl2 were added Et3N (1.1 mL) and sec-butylcarbonochlo-
ridate (0.82 mL, 6.2 mmol) at 0 °C. After 15 min, (1S,2S)-1,2-
diphenylethane-1,2-diamine (637 mg, 3 mmol) was added directly.
Then the reaction mixture was stirred at room temperature for 3 h.
The solution was washed with 1 M KHSO4 (40 mL), saturated
NaHCO3 (40 mL), and brine (20 mL) and dried over anhydrous
Conclusion
C2-symmetric bisformamide has been applied to catalyze the
one-pot, three-component Strecker reaction in good enantiose-
lectivities (up to 86% ee; single recrystallization, up to 99%
ee) with high yields (up to 99%) for a range of aldehydes. This
catalysis utilizes inexpensive chemicals and can be carried out
(7) Banphavichit, V.; Mansawat, W.; Bhanthumnavin, W.; Vilaivan, T.
Tetrahedron 2004, 60, 10559-10568.
(8) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem.
Soc. 1996, 118, 4910-4911.
(9) (a) Wen, Y. H.; Huang, X.; Huang, J. L.; Xiong, Y.; Qin, B.; Feng,
X. M. Synlett 2005, 2445-2448. (b) Xiong, Y.; Huang, X.; Gou, S. H.;
Huang, J. L.; Wen, Y. H.; Feng, X. M. AdV. Synth. Catal. 2006, 348, 538-
544.
7718 J. Org. Chem., Vol. 72, No. 20, 2007

Organocatalysts for the Strecker Reaction
Na2SO4. After removal of solvents under reduced pressure, CH2-
Cl2 (20 mL) and TFA (6 mL) were added. The mixture was
concentrated under reduced pressure after 1 h. The residue was
dissolved in CH2Cl2 and the resulting solution was cooled to 0 °C.
The pH was adjusted to 10 with 2 M NaOH. The product was
extracted with CH2Cl2 (3 × 30 mL) and the filtrate was concentrated
under reduced pressure. The residue was dissolved in formic acid
(6 mL) and the resulting solution was cooled to 0 °C. Acetic
anhydride (4 mL) was added and the mixture was allowed to stir
at room temperature overnight. After removal of solvents under
reduced pressure, the residue was purified though column chro-
purified by flash chromatography on silica gel (Et2O/light petroleum
ether, 1:60 v/v) to afford the product in 99% yield as a white solid.
The chromatographed material was determined to be of 81% ee by
chiral HPLC analysis [Chiralpak AD-H, 80:20 n- hexane/iPrOH,
1.0 mL/min, tR(major) ) 6.769 min, tR(minor) ) 12.999 min]; mp
1
94-96 °C. [R]20 75.0 (c 0.10 in CHCl3). H NMR (400 MHz,
D
CDCl3) δ 7.58-7.20 (m, 15 H), 5.25 (s, 1 H), 4.60 (d, J ) 12.4
Hz, 1 H), 2.14 (d, J ) 12.0 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3) δ 142.7, 141.0, 134.9, 129.03, 129.00, 128.98, 128.8, 127.9,
127.7, 127.4, 127.2, 127.1, 118.7, 65.6, 52.4 ppm.
matography on silica gel to give 2a as a white solid in 80% yield:
1
[R]20 -136.0 (c 0.20, CHCl3); mp 132-134 °C. H NMR (400
Acknowledgment. This work was financially supported by
the National Nature Science Foundation of China (No. 20602025).
We also thank Sichuan University Analytival and Testing Center
for NMR spectra analysis.
D
MHz, CDCl3) δ 1.26-2.17 (m, 8H), 3.51-3.57 (m, 4H), 4.10-
4.62 (m, 2H), 5.11-5.13 (m, 2H), 7.01-7.06 (m, 4H), 7.15-7.17
(m, 6H), 7.68-8.21 (m, 2H), 8.22 and 8.25 (2 × s, 2H) ppm; 13C
NMR (100 MHz, CDCl3) δ 171.3, 162.4, 138.5, 128.3, 127.2, 127.0,
58.3, 58.2, 46.9, 44.2, 30.3, 27.7, 24.1, 24.0, 22.9, 21.1 ppm. HRMS
(FT-ICRMS) exact mass calcd for [C26H30N4O4 + H]+ requires
m/z 463.2345, found 463.2346.
General Procedure for the Chiral Formamide (2a)-Catalyzed
One-Pot, Three-Component Strecker Reaction. Benzaldehyde
(21 µL, 0.2 mmol), (1,1-diphenyl)methylamine (36 µL, 0.2 mmol),
and Na2SO4 (100 mg) were combined in a dry test tube. Then 0.2
mL of CH2ClCH2Cl was added to the mixture and the reaction
solution was stirred at rt for 1 h. After that, catalyst 2a (10 mol %)
and CH2ClCH2Cl (0.8 mL) were added. The test tube was cooled
to -20 °C. Then TMSCN (54 µL, 0.4 mmol) was added, and the
mixture was stirred for 10 h at -20 °C. The crude material was
Note Added after ASAP Publication. Reference 6k and its
citation in the text were not included in the version published
ASAP August 30, 2007; the corrected version was published
ASAP Septemter 13, 2007.
Supporting Information Available: Experimental procedures
1
and structural proofs for catalysts and racemates, H NMR, 13C
NMR spectra, and HPLC. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO701307F
J. Org. Chem, Vol. 72, No. 20, 2007 7719