Enantioselective amination of α-phenyl-α-cyanoacetate catalyzed by chiral amines incorporating the α-phenylethyl auxiliary

Article abstract of DOI:10.1021/jo0622633

(Chemical Equation Presented) Nineteen chiral amines and their derivatives were prepared and investigated as organocatalytic Lewis bases in the α-amination of ethyl α-phenyl-α-cyanoacetate. For comparison purposes, a few natural products were also examine

Full text of DOI:10.1021/jo0622633

R- or â-amino acids,6 which play determinant roles in biology,
chemistry, and medicine. In particular, unnatural R,R-disubsti-
tuted R- and â-amino acids are of increasing importance for
the preparation of conformationally restricted peptide libraries
as well as intermediates of natural products.7
Enantioselective Amination of
r-Phenyl-r-cyanoacetate Catalyzed by Chiral
Amines Incorporating the r-Phenylethyl
Auxiliary
The application of natural products as organocatalysts con-
stitutes a relevant concept in the field of enantioselective
organocatalysis;8 nevertheless, organocatalysis with natural
products can suffer from their structural complexity, large
molecular weight, and in some cases high cost of isolation. Since
one of the challenges in asymmetric catalysis is to develop a
highly enantioselective reaction under convenient conditions
using a simple catalyst system that is as cheap as possible,9
development of synthetic structurally simpler organic molecules
for organocatalysis is highly desirable. In addition, the main
advantages of synthetic over natural molecules are that both
enantiomers are readily available and that their structure can
be easily modified.
Yongjun Liu, Roberto Melgar-Ferna´ndez, and
Eusebio Juaristi*
Departamento de Qu´ımica, Centro de InVestigacio´n y de
Estudios AVanzados del Instituto Polite´cnico Nacional,
Apartado postal 14-740, 07000 Me´xico, D.F., Mexico
juaristi@relaq.mx
ReceiVed NoVember 1, 2006
Proline is among the most famous examples of a structurally
simple natural catalyst, whose use can be traced even to the
1970s, in applications pioneered by Hajos et al.10 Although this
research then faded away for 25 years, it has reblossomed more
recently.11 In spite of its great efficiency and practicality, proline
has its own limitations, and its supremacy is being challenged
by new synthetic analogues.12 Nevertheless, relatively little new
work appears on successful enantioselective reactions catalyzed
with structurally simple compounds besides proline analogues.
Nineteen chiral amines and their derivatives were prepared
and investigated as organocatalytic Lewis bases in the
R-amination of ethyl R-phenyl-R-cyanoacetate. For com-
parison purposes, a few natural products were also examined
as catalysts in this study. Among the results obtained, (R)-
N-benzyl-N-(1-phenylethyl)-amine and (R,R)-N,N′-bis(1-phen-
ylethyl)-propane-1,3-diamine as the catalysts afforded the
amination products in excellent yields and with up to 84%
ee. By contrast, under comparable conditions the two
derivatives of natural products (DHQ)2PYR and (DHQD)2PYR
provided the product of amination with lower than 10%
enantiomeric excess.
(4) Xu, X.; Yabata, T.; Yuam, P.; Takemoto, Y. Synlett 2006, 137-
140.
(5) Review: Guillena, G.; Ramo´n, D. J. Tetrahedron: Asymmetry 2006,
17, 1465-1492.
(6) (a) Suri, J. T.; Steiner, D. D.; Barbas, C. F., III. Org. Lett. 2005, 7,
3885-3888. (b) Poulsen, T. B.; Alemparte, C.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 11614-11615.
(7) See, for example: (a) Williams, R. M.; Hendrix, J. A. Chem. ReV.
1992, 92, 889-917. (b) Cativiela, C.; D´ıaz, de Villegas, M. D. Tetrahe-
dron: Asymmetry 1998, 9, 3517-3599. (c) Cativiela, C.; D´ıaz, de Villegas,
M. D. Tetrahedron: Asymmetry 2000, 11, 645-732. (d) EnantioselectiVe
Synthesis of â-Amino Acids, 2nd ed.; Juaristi, E., Soloshonok, V., Eds.;
Wiley: New York, 2005.
Ongoing studies in our group on the enantioselective synthesis
of amino acids1 brought our attention to the very recently
reported organocatalytic enantioselective electrophilic amination
reactions of R-substituted R-cyanoacetates and R-substituted
â-ketoesters with azodicarboxylates.2-5 Indeed, the R-aminated
products thus formed have the potential to be converted to either
(8) (a) Kocovsky, P.; Malkov, A. V., Eds. Tetrahedron 2006, 62, 257-
502. (b) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis: From
Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-
VCH: Weinheim, 2005. (c) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138-5175. (d) Houk, K. N.; List, B., Eds. Acc. Chem. Res.
2004, 37, 488-631. (e) List, B.; Bolm, C., Eds. AdV. Synth. Catal. 2004,
346, 1023-1246. (f) Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. ReV. 2003,
103, 3401-3430.
* To whom correspondence should be addressed. Tel: +52-55 5061 3722.
Fax: +52-55 5061 3389.
(9) Blaser, H.-U. Chem. Commun. 2003, 293-296.
(1) See, for example: (a) Avila-Ortiz, C. G.; Reyes-Rangel, G.; Juaristi,
E. Tetrahedron 2005, 61, 8372-8381. (b) Castellanos, E.; Reyes-Rangel,
G.; Juaristi, E. HelV. Chim. Acta 2004, 87, 1010-1024. (c) Juaristi, E.;
Leo´n-Romo, J. L.; Ram´ırez-Quiro´s, Y. J. Org. Chem. 1999, 64, 2914-
2918. (d) Juaristi, E.; Lo´pez-Ruiz, H.; Madrigal, D.; Ram´ırez-Quiro´s, Y.;
Escalante, J. J. Org. Chem. 1998, 63, 4706-4710. (e) Juaristi, E.; Quintana,
D.; Balderas, M.; Garc´ıa-Pe´rez, E. Tetrahedron: Asymmetry 1996, 7, 2233-
2246. (f) Juaristi, E.; Escalante, J. J. Org. Chem. 1993, 58, 2282-2285.
(g) Juaristi, E.; Escalante, J.; Lamatsch, B.; Seebach, D. J. Org. Chem.
1992, 57, 2396-2398. (h) Juaristi, E.; Quintana, D.; Lamatsch, B.; Seebach,
D. J. Org. Chem. 1991, 56, 2553-2557.
(10) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971,
83, 492-493. (b) Parrish, R. D.; Hajos, Z. G. J. Org. Chem. 1974, 39,
1615-1621.
(11) (a) Northrup, A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 6798-6799. (b) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J.
Am. Chem. Soc. 2003, 125, 16-17. (c) Allemann, C.; Gordillo, R.;
Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. Acc. Chem. Res. 2004, 37,
558-569. (d) Chowdari N. S.; Barbas, C. F., III. Org. Lett. 2005, 7, 867-
870. (e) Suri, J. T.; Steiner, D. D.; Barbas, C. F., III. Org. Lett. 2005, 7,
3885-3888. (f) Vogt, H.; Vanderheiden, S.; Brase, S. Chem. Commun. 2003,
2448-2449. (g) Co´rdova, A.; Barbas, C. F., III. Tetrahedron Lett. 2003,
44, 1923-1926.
(2) (a) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790-1793. (b) List,
B. J. Am. Chem. Soc. 2002, 124, 5656-5657. (c) Marigo, M.; Juhl, K.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1367-1369. (d) Pihko,
P. M.; Pohjakallio, A. Synlett 2004, 2115-2118. (e) Saaby, S.; Bella, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120-8121.
(12) (a) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558-
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8167-8177. (d) Fache, F.; Piva, O.; Tetrahedron: Asymmetry 2003, 14,
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10.1021/jo0622633 CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/18/2007
1522
J. Org. Chem. 2007, 72, 1522-1525

SCHEME 1
Thus, development of new catalysts to meet the demand for
enantioselective synthesis is of both scientific and economic
importance. Herein we aim to search for practical and simple
organocatalysts to promote the enantioselective amination of
racemic ethyl R-phenyl-R-cyanoacetate, (()-1, with di-tert-butyl
azodicarboxylate (2), the product thus formed (3) being a
precursor of amino acids (Scheme 1).
Examination of Enantioselective Efficiency of Amination
with Selected Natural Products. So far, cinchona alkaloids2c,3
are reported to be the most efficient organocatalysts for the
enantioselective R-amination reaction. Here we further examined
the catalytic activity of other natural organocatalysts, such as
sparteine13 and DHQ derivatives,14 which owing to the structural
similarity to cinchona alkaloid and/or to their C2-symmetry were
expected to provide high enantioinduction in the asymmetric
amination reaction.
However, although the amination of ethyl R-phenyl-R-
cyanoacetate with (DHQ)2PYR (4a) and (DHQD)2PYR (4b)
(Figure 1) as catalysts at -78 °C gave high yields of the product,
it unfortunately resulted in a disappointingly poor enantiose-
lectivity (<10% ee) (Table 1, entries 1 and 2). Under the same
conditions, (-)-sparteine (5) afforded higher enantiomeric
excess (28%) of the product at -78 °C (Table 1, entry 3), but
the amination failed to occur at lower temperature (Table 1,
entry 4), at which higher enantioselectivity could be anticipated.
The discouraging results listed in Table 1 indicate that natural
alkaloids 4 and 5 are not efficient organocatalysts in the present
system.
Enantioselective Amination Catalyzed by Unnatural Chiral
Amines. To search for structurally simpler inexpensive orga-
nocatalysts and to gain understanding of factors affecting the
enantioselectivities for the amination, we designed and synthe-
sized a series of 19 chiral amines as the catalyst for screening.
Most catalysts investigated incorporate the R-phenylethylamine15
and include acyclic and cyclic amines, amines with nitrogen as
part of a ring, and amines with additional polar functional groups
such as hydroxy, ester, etc. The results obtained from this chiral
amine-catalyzed amination are summarized in Table 1.
FIGURE 1. Chiral amines examined as potential organocatalysts in
the enantioselective amination of ethyl R-phenyl-R-cyanoacetate.
All amines 6a-p proved to be efficient catalysts for the
amination of substrate (()-1 with electrophile 2. Remarkably,
tertiary amines 6e, 6f, and 6h, as well as urea 6g, afforded the
aminated products 3 in 90-98% yield. This observation is in
line with the pioneering work from the Jorgensen2e and Deng3
laboratories showing the efficiency of tertiary amines as
organocatalysts in the amination reaction of interest. In those
cases where both enantiomeric organocatalysts were used,
products of opposite configuration were obtained as anticipated
(cf. entries 7 and 8, 9 and 10, 9 and 11 in Table 1). For reactions
conducted at different temperature, remarkable improvement in
enantioselectivity was observed at -78 °C (cf. entries 10 and
11 in Table 1).
The highest enantioselectivity (58-68% ee) was observed
with secondary amines 6c, 6m, and 6n (entries 7, 19, and 20 in
Table 1). It is interesting that, as anticipated, replacement of
phenyl by a larger naphthyl group (6m f 6n, entries 19 and
20) leads to a higher ee value.
By contrast, when zinc triflate was added as a potential
activator,17 this failed to produce any encouraging result (entry
(13) (a) Morita, Y.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2005, 7,
4337-4340. (b) Martinez, M. M.; Hoppe, D. Org. Lett. 2004, 6, 3743-
3746. (c) Dearden, M. J.; McGrath, M. J.; O’Brien, P. J. Org. Chem. 2004,
69, 5789-5792. (d) Metallinos, C.; Snieckus, V. Org. Lett. 2002, 4, 1935-
1938.
(14) (a) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem. Soc.
2001, 123, 7001-7009. (b) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella,
M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 2896-2899. (c)
Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 5672-5673. (d)
Shibata, N.; Ishimaru, T.; Suzuki, E.; Kirk, K. L. J. Org. Chem. 2003, 68,
2494-2497.
(16) X-ray crystallographic analysis of chloro derivative A led Deng et
al.3 to conclude that the dextrorotatory enantiomer presents the (S) absolute
configuration. The positive optical rotation in analog 3 was assumed to
correspond to the (S) configured enantiomer as well.3,4 We are grateful to
Professor Yoshiji Takemoto for his advise in this matter.
(15) For reviews on the use of (R)- and (S)-R-phenyl-ethylamine in
asymmetric synthesis, see: (a) Juaristi, E.; Escalante, J.; Leo´n-Romo, J.
L.; Reyes, A. Tetrahedron: Asymmetry 1998, 9, 715-740. (b) Juaristi, E.;
Leo´n-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahedron: Asymmetry 1999,
10, 2441-2495.
J. Org. Chem, Vol. 72, No. 4, 2007 1523

TABLE 1. Amination of r-Phenyl-r-cyanoacetate with Chiral
TABLE 2. Enantioselective Amination of r-Phenyl-r-cyanoacetate
with Selected Chiral Amines as Catalysts under Optimized
Conditionsa
Amines as Catalystsa
temp
(°C)
yield
(%)
ee (major
temp
entry cat* (°C)
yield
(%)
ee (major
entry
cat*
time
erb
enantiomer)c
solvent
time
erb enantiomer)c
1
2
3
4a
4b
5
-78
-78
-78
-100d
-78
-78
-78
0e
3 h
3 h
4 h
3
3
4
53:47
48:52
64:36
6 (R)-(-)
4 (S)-(+)
28 (R)-(-)
1
2
3
4
5
6
7
8
9
6d
6f
-100 toluene
-100 toluene
10 min 95 90:10 80 (R)-(-)
2 h
1 h
2 h
94 74:24 48 (R)-(-)
95 18:82 64 (S)-(+)
96 81:19 62 (R)-(-)
6m -100 toluene
4
5
6n
6d
6f
6m
6n
6d
-100 toluene
5
6
7
6a
6b
6c
10 min
30 min
10 min
2 days
2 h
2 h
2 h
2 days
30 h
3 h
90
94
97
79
93
96
98
90
92
94
91
93
91
53:47
35:65
21:79
60:40
31:69
58:42
74:26
58:42
51:49
41:59
55:45
40:60
43:57
6 (R)-(-)
30 (S)-(+)
58 (S)-(+)
20 (R)-(-)
38 (S)-(+)
16 (R)-(-)
48 (R)-(-)
16 (R)-(-)
2 (R)-(-)
18 (S)-(+)
10 (R)-(-)
20 (S)-(+)
14 (S)-(+)
-78 tol/hexd (1:1) 30 min 91 92:8
84 (R)-(-)
-78 tol/hex (1:1)
-78 tol/hex (1:1)
-78 tol/hex (1:1)
1 h
1 h
2 h
92 78:22 56 (R)-(-)
95 13:87 74 (S)-(+)
96 88:12 76 (R)-(-)
8
6d/Zn(OTf)2
9
6e
6f
-78
-100 tol/hex (1:1) 30 min 94 88:12 76 (R)-(-)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0
10 6f
11 6m -100 tol/hex (1:1)
12 6n -100 tol/hex (1:1)
-100 tol/hex (1:1)
2 h
1 h
2 h
95 79:21 58 (R)-(-)
95 10:90 80 (S)-(+)
93 87:13 74 (R)-(-)
6f
-78
rte
6g
6h
6i
6j
6k
6l
-78
-78
-78
-78
0e
a The reaction was carried out with 0.55 mmol of substrate (()-1 and
0.5 mmol of electrophile 2 in the presence of 0.5 equiv (50 mol %) of the
chiral amine. b Enantiomeric ratios were determined by chiral HPLC. c The
assignment of the configuration was based on literature precedent.3,4,16
d Toluene/hexane.
6 h
4 h
1 day
6l
-78f
-78
-78
0
6m
6n
6o
6o
6p
1 h
1 h
2 days
94
95
86
20:80
84:16
38:62
60 (S)-(+)
68 (R)-(-)
24 (S)-(+)
TABLE 3. Examination of the Efficiency of Enantioselective
Amination with Different Amounts of Specified Catalyst under
Similar Conditionsa
-78f
-78
6 h
89
55:45
10 (R)-(-)
a The reaction was carried out with 0.55 mmol of substrate (()-1 and
0.5 mmol of electrophile 2 in the presence of 0.5 equiv (50 mol %) of the
organocatalyst. b Enantiomeric ratios were determined by chiral HPLC
analysis. c The assignment of the configuration was based on literature
precedent3,4 (see also ref 16). d Sparteine was insoluble at this temperature.
e No reaction took place at -78 °C. f Incomplete reaction.
amount of 6m
(mol %)
time
(h)
yield
(%)
ee (major
entry
erb
enantiomer)c
1
2
3
4
5
6
1
5
10
20
50
100
20
4
3
2
1
90
95
93
93
95
94
18:82
18:82
18:82
19:81
10:90
17:83
64 (S)-(+)
64 (S)-(+)
64 (S)-(+)
62 (S)-(+)
80 (S)-(+)
66 (S)-(+)
8 in Table 1). In this context, the low efficiency of catalysts 6l
and 6o (entry 17 and 21) may be attributed to steric hindrance,
which prevents effective enantioinduction.
Optimization of Reaction Conditions. The encouraging
results shown in Table 1 led us to optimize the reaction
conditions for further improvement of the enantioselectivity of
the amination protocol. Thus chiral amines 6d, 6f, 6m, and 6n,
which showed better efficiency in the asymmetric amination
reaction, were selected as the catalysts for further investigation.
It was found that the reaction temperature and the solvent used
could influence greatly the enantioselectivity of the amination
reaction (Table 2).
When the amination reaction was performed at the finally
optimized conditions for 6d and 6n (-78 °C, toluene/hexane,
Table 2, entries 5 and 8) and for 6f and 6m (-100 °C, toluene/
hexane, Table 2, entries 10 and 11), the ee of the amination
product increased up to 80%. It can also be concluded from
Table 2 that the influence of solvent and temperature on the
enantioselectivity is dramatic, allowing ee values to reach the
74-84% ee range.
0.5
a The reaction was carried out with 0.55 mmol of substrate (()-1 and
0.5 mmol of electrophile 2 in the presence of the specified amounts of
organocatalyst 6m. b Enantiomeric ratios were determined by chiral HPLC.
c The assignment of the configuration was based on literature precedent.3,4,16
the present study, amination could be performed without
significant loss of enantioselectivity with catalyst loadings as
low as 1 mol %. Nevertheless, the use of 0.5 equiv of the
(recoverable) chiral amine organocatalyst offers the best com-
bination of enantioselectivity and short reaction times (Table
3).
In summary, this is the first attempt to search for practical
and structurally simple organocatalysts as substitutes for natural
products in the enantioselective amination of R-substituted
R-cyanoacetates with azodicarboxylates. A series of studies on
the amination reaction with various chiral amines as catalysts
were performed, and efficient optimized reaction conditions
were established. The enantioselectivity obtained with the
properly designed chiral amines under optimized conditions is
satisfactory considering its ready availability and low cost.
Furthermore, the amination reaction proceeds smoothly even
when the catalyst loading is reduced to 1 mol %. Further
exploration of this system is now under way in our laboratory.
On the other hand, a decrease in catalyst loading is highly
desirable for any catalytic reaction. Although organocatalysis
has proven successful in many respects, most of the reported
processes require 10 mol % or more of the catalyst for sufficient
product formation and maintenance of stereoselectivity.14b In
(17) Bernardi, L.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005,
127, 5772-5773.
1524 J. Org. Chem., Vol. 72, No. 4, 2007

warm to room temperature. Pure products were isolated by flash
chromatography (ethyl acetate/hexane, 1:6). H NMR (400 MHz,
Experimental Section
1
Compounds 6b,18 6c,18 6d,18 6g,19 6h,19b 6i,20a 6j,20a 6k,20b 6l,21
6m,21 and 6o22 were synthesized by literature procedures.
DMSO): δ 1.20 (t, J ) 6.9 Hz, 3H), 1.33 (s, 9H), 1.48 (s, 9H),
4.24 (q, J ) 6.9, 2H), 7.45 (s, 3H), 7.63 (s, 2H), 8.70 (br, N-H).
13C NMR (100 MHz, DMSO): δ 13.9, 28.3, 28.5, 63.7, 80.8, 80.9,
83.6, 116.3, 127.2, 128.0, 128.6, 129.1, 130.5, 130.7, 153.9, 154.9,
165.4. Enantiomeric excess determined by HPLC [tR (-) leVo
enantiomer ) 11 min; tR (+) dextro enantiomer ) 37 min). Mp:
94-96 °C. IR (CH2Cl2) ν (cm-1): 3337, 2982, 2360, 1747, 1716,
1370, 1243, 1154, 1053. [R]20D ) +48.7 (c 1, CHCl3) for 84% ee;
General Procedure for Enantioselective Amination, 3. A
mixture of ethyl R-phenyl-R-cyanoacetate (0.55 mmol) and catalyst
(0.25 mmol) in 2 mL of toluene (or 18 mL of toluene/hexane, 1:1
v/v) was stirred for 1 h at room temperature and then was cooled
to -78 °C (or -100 °C) under a nitrogen atmosphere. A solution
of di-tert-butyl azodicarboxylate (0.5 mmol) in 1 mL of toluene
(or 2 mL of toluene/hexane, 1:1 v/v) was added dropwise over a
period of 30 min. The reaction mixture was stirred until the yellow
color of the solution faded (10 min to 30 h) and then allowed to
lit.3 [R]20 ) +64.0 (c 0.175, CHCl3) for 97% ee.
D
Acknowledgment. The authors are grateful to Fred Garc´ıa
Flores and Jose´ Luis Olivares Romero (Cinvestav-IPN, Mexico)
for technical assistance, and to Conacyt, Mexico, for financial
support via grant 45157-Q.
(18) Hulst, R.; Vries, N. K.; Feringa, B. L. Tetrahedron: Asymmetry
1994, 5, 699-708.
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Mun˜oz-Mun˜iz, O.; Hayakawa, M.; Seebach, D. HelV. Chim. Acta 2002,
85, 1999-2008.
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Tetrahedron: Asymmetry 1998, 9, 2093-2099. (b) A. de Parrodi, C.;
Juaristi, E.; Quintero, L.; Clara-Sosa, A. Tetrahedron: Asymmetry 1997,
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Supporting Information Available: Experimental details for
the preparation of relevant compounds, NMR data for 3, 6e, 6f,
6n, 6p, and chromatograms for 3. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0622633
J. Org. Chem, Vol. 72, No. 4, 2007 1525