Catalytic enantioselective electrophilic α-hydrazination of β-ketoesters using bifunctional organocatalysts

Article abstract of DOI:10.1016/j.tetlet.2008.07.041

The catalytic enantioselective electrophilic α-hydrazination promoted by chiral bifunctional organocatalysts is described. Treatment of β-ketoesters with azodicarboxylates as electrophilic amination reagents under mild reaction conditions afforded the cor

Full text of DOI:10.1016/j.tetlet.2008.07.041

Tetrahedron Letters 49 (2008) 5527–5530
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Tetrahedron Letters
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Catalytic enantioselective electrophilic
a-hydrazination
of b-ketoesters using bifunctional organocatalysts
Sun Hee Jung, Dae Young Kim *
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic enantioselective electrophilic a-hydrazination promoted by chiral bifunctional organocata-
lysts is described. Treatment of b-ketoesters with azodicarboxylates as electrophilic amination reagents
Received 19 June 2008
Accepted 8 July 2008
Available online 11 July 2008
under mild reaction conditions afforded the corresponding
meric excesses (93–99% ee).
a
-amino b-ketoesters with excellent enantio-
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Bifunctional organocatalysts
Hydrazination
Asymmetric reactions
b-Ketoesters
Amino acids constitute one of the most important families of
natural products and are used as pharmaceuticals, agrochemicals,
and fundamental synthetic building blocks for preparation of an
assortment of biologically valuable molecules. The development
of stereoselective synthetic methods for the preparation of natural
chiral amine–thiourea catalysts, which show high enantioselec-
tively for a broad scope of substrates, is still in great demand.
As part of research program related to the development of
synthetic methods for the enantioselective construction of stereo-
1
1
1
genic carbon centers, we report the catalytic enantioselective
and non-natural
able attention over the past decades. The most popular methods
for the catalytic asymmetric synthesis of -amino acids are C–C
bond formation and include the catalytic hydrogenation of
a
-amino acid derivatives has attracted consider-
amination of ester derivatives promoted by chiral palladium com-
2
8f,11f
plexes.
To the best of our knowledge, there are no example of
-hydrazination of b-ketoesters using thiourea-
based organocatalysts. In this Letter, we wish to report the direct
-amination of b-ketoesters 1 catalyzed by using chiral amine–
a
the electrophilic a
3
a
-dehydroamino acids, alkylation of a tert-butyl glycinate-benzo-
a
4
phenone Schiff base using phase-transfer catalysts, and addition
to imines using Strecker and Mannich reactions with chiral Lewis
acids or organocatalysts.
thiourea bifunctional organocatalysts with azodicarboxylates 2 as
the electrophilic nitrogen source.
5
6
We envision that the assembly of a structurally well-defined
chiral 1,2-diamine and binaphthyl scaffold with a thiourea motif
could constitute a new class of bifunctional organocatalyst. The
rigid binaphthyl structure can serve as an efficient stereocontrol-
ling element. The new bifunctional organocatalysts IV–VII were
synthesized according to the reported procedure from the reaction
of 3,5-bis(trifluoromethyl)phenyl iso(thio)cyanate with chiral 1,2-
The catalytic enantioselective electrophilic amination of car-
bonyl compounds represents an efficient and the simplest proce-
dures to generate stereogenic carbon center attached to a
7
nitrogen atom. Recently, several groups presented the direct
enantioselective amination of 1,3-dicarbonyl compounds catalyzed
8
9a
9b
by chiral Lewis acids, cinchona alkaloid, chiral urea, and chiral
9
c
12,13
guanidines as organocatalysts. Bifunctional organocatalysts pos-
sessing a combination of thiourea and amine groups have been
developed for activation of both electrophilic and nucleophilic
components. They have emerged as powerful tools for the enantio-
selective formation of carbon–carbon bond and carbon–hetero-
atom bonds. Nonetheless, substrate dependence still remains
an important issue in asymmetric reactions using bifunctional
organocatalysts. Therefore, the development of highly efficient
diamines containing (R)-binaphthyl moiety.
A survey of some reaction parameters was performed, and some
representative results are presented in Table 1. Our investigation
began with the catalytic enantioselective electrophilic amination
of indanone carboxylate 1a with tert-butyl azodicarboxylates 2 as
the electrophilic aminating reagent in toluene at room tempera-
ture in the presence of 10 mol % of catalysts. We surveyed chiral
thioureas containing a tertiary amine as catalysts (Fig. 1). High
yields with moderate enantioselectivities (15–67% ee) were
observed for structurally variable bifunctional catalysts (entries
1
0
*
Corresponding author. Tel.: +82 41 530 1244; fax: +82 41 530 1247.
1
–7). Under the standard reaction conditions, catalyst V exhibited
E-mail address: dyoung@sch.ac.kr (D. Y. Kim).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.041

5
528
S. H. Jung, D. Y. Kim / Tetrahedron Letters 49 (2008) 5527–5530
Table 1
Optimization of the reaction conditions
CO R2
2
O
O
O
O
cat.
(10 mol%)
N
N
OR1
*
1
OR
NCO2R2
+
2
solvent, rt
R O C
2
2
NHCO R
2
1
2
3
Entry
1, R1
2, R2
Cat.
Solvent
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1b, Et
2a, t-Bu
2a, t-Bu
2a, t-Bu
2a, t-Bu
2a, t-Bu
2a, t-Bu
2a, t-Bu
2b, i-Pr
2c, Et
2a, t-Bu
2a, t-Bu
2a, t-Bu
2a, t-Bu
2a, t-Bu
2a, t-Bu
2a, t-Bu
2a, t-Bu
I
II
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
0.5
0.3
0.5
0.5
0.3
0.5
1
0.3
0.3
2
2
24
2
0.3
0.3
4
3a, 95
3a, 94
3a, 92
3a, 91
3a, 96
3a, 90
3a, 85
3ab, 95
3ac, 94
3a, 90
3a, 93
3a, 90
3a, 91
3b, 95
3c, 93
3d, 94
3d, 93
40
15
50
51
67
55
ꢀ51
55
17
57
57
53
39
40
33
90
99
III
IV
V
VI
VII
V
V
V
V
V
1
1
1
1
1
1
1
1
CH
Cl
2 2
THF
Acetone
t-BuOH
Toluene
Toluene
Toluene
Toluene
V
V
V
V
1c, Bn
1d, t-Bu
1d, t-Bu
c
V
11
a
Yield of isolated product.
b
c
Enantiopurity of 3 was determined by HPLC analysis using Chiralpak AD-H column.
Reaction was carried out at ꢀ70 °C.
better enantioselectivity (67% ee, entry 5), where catalyst III affor-
ded product 3 in lower enantioselectivity (50% ee, entry 3). These
results represent that increasing the sterical demand of the catalyst
increases the selectivity. Compared with catalyst V, diastereomeric
catalyst VII gave desired product 3 in lower enantioselectivity with
the reversal absolute configuration as that of major enantiomer
(
ꢀ51% ee, entry 7). It suggest that chirality of (R)-binaphthyl moi-
O
N
O
N
ety and (1S,2S)-diaminocyclohexane unit in catalyst V is matched
in this reaction. Varying the structure of the azodicarboxylates
had an impact on asymmetric induction (entries 5, 8, and 9). The
best results have been obtained with tert-butyl ester of azodicarb-
oxylates. Concerning the solvent (entries 5, 10–13), there is a little
influence on the stereochemical outcome of the process but a sig-
nificant impact on the reaction time. The nature of ester group of b-
ketoesters has a significant impact on the selectivity (entries 5, 14–
N
N
S
S
CF
3
N
N
H
H
HN
HN
NH
CF3
II
I
1
6). When employing synthetically attractive, but sterically hin-
dered, tert-butyl ester of indanone carboxylate 1d, the correspond-
ing aminated adduct 3d was isolated with high enantioselectivity
of 90% ee (entry 16). Finally, we conducted the amination at low
temperature in order to improve the enantioselectivity. The
enantioselectivity was elevated at ꢀ70 °C in the reaction catalyzed
by organocatalyst V, and up to 99% ee was obtained in good iso-
lated yield (93%) after 11 h (entry 17).
CF3
N
S
HN
HN
N
H
N
CF
3
S
H
N
CF3
To examine the generality of the catalytic enantioselective ami-
nation of b-ketoesters 3 by using new bifunctional organocatalyst
III
IV
F
3
C
14
V, we studied the amination of various b-ketoesters 1. As it can
be seen by the results summarized in Table 2, the corresponding
a-aminated b-ketoesters 3 were obtained in high to excellent
yields and excellent enantioselectivities. The cyclic b-ketoesters
1d–h, with cyclic aromatic ketones 1d–g and cyclic aliphatic ke-
tone 1h, reacted with tert-butyl azodicarboxylates 2 to give the
N
N
HN
HN
HN
corresponding
a-aminated b-ketoesters 3d–h in 85–95% yields
X
S
and 93–99% ee. In the contrast to the cyclic b-ketoesters, unfortu-
nately, the reaction of acyclic b-ketoesters with azodicarboxylate
HN
proceeded slowly even at room temperature to give the
ed products in low enantioselectivity (Scheme 1).
Although the reason for the observed enantioselectivity is still
unclear, we believe that a carbonyl group of the azodicarboxylate
is activated by a thiourea moiety through hydrogen bonding, and
a-aminat-
V : X = S
VI : X = O
CF3
CF
3
VII
F3C
F C
3
Figure 1. Structures of various chiral thiourea-tertiary amine catalysts.

S. H. Jung, D. Y. Kim / Tetrahedron Letters 49 (2008) 5527–5530
5529
Table 2
Catalytic enantioselective amination of b-ketoesters
CO2
t
-Bu
-Bu
CO2t-Bu
cat. V
O
HN
N
O
N
N
(10 mol%)
CO2t-Bu +
R1
CO2t
R1
toluene
R2
t-BuO C
2
R2 CO
t-Bu
2
1
d-1h
2
3d-3h
O
CO2
t
-Bu
O
2
CO t-Bu
CO2t-Bu
n
O
R
1
1
1
d : n = 1, R = H
e : n= 1, R = OMe
f : n= 2, R = H
1
g
1h
Entry
1
Temp. (°C)
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
1d
1d
1e
1f
1g
1h
ꢀ70
ꢀ30
ꢀ30
ꢀ70
ꢀ30
ꢀ30
11
10
7
10 d
3
3d, 93
3d, 94
3e, 95
3f, 85
3g, 92
3h, 93
99
95
97
93
93
36
97 (R)c
a
Yield of isolated product.
b
c
Enantiopurity of 3 was determined by HPLC analysis using Chiralpak AD-H (for 3d, 3f, 3g, 3h) and (S,S)-Whelk-O1 (for 3e) columns.
Absolute configuration was determined by comparison of the optical rotation and the HPLC retention time of the corresponding ester with literature value.
8g
CO t-Bu
2
CO t-Bu
cat. VI
O
O
2
HN
N
O
N
N
(10 mol%)
+
OEt
CO t-Bu
toluene, rt
2
t-BuO C
2
8
9% (25% ee)
CO Et
2
4
2
5
Scheme 1.
b-ketoester is activated by the basic nitrogen atom in tertiary
amine (Fig. 2). These interactions control the stereochemical out-
come of the reaction and accelerate the reaction rate.
acid derivatives, and the availability of these compounds should
facilitate medicinal chemical studies in various fields. Further
study of these new bifunctional organocatalysts in asymmetric
reactions is being under investigation.
In conclusion, we have developed a highly efficient catalytic
enantioselective
a-amination of cyclic b-ketoesters using new
bifunctional organocatalyst V. The desired
were obtained in good to high yields, and excellent enantioselec-
a
-aminated products
Acknowledgment
tivities (93–99% ee) were observed. We believe that this method
This research was supported by Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, Basic Research
Promotion Fund) (KRF-2006-521-C00099).
provides an efficient route for the preparation of chiral
a-amino
References and notes
1
2
3
.
.
.
(a) Williams, R. M. Synthesis of Optically Active a-Amino Acids; Pergamon:
Oxford, 1989; (b) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell,
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In Comprehensive Asymmetric Catalysis; Springer: Berlin, 1999; Vols. 1–3.
Reviews on synthesis of
994, 50, 1539; (b) Arend, M. Angew. Chem., Int. Ed. 1999, 38, 2873; (c) Kotha, S.
Acc. Chem. Res. 2003, 36, 342; (d) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107,
584.
a-amino acids, see: (a) Duthaler, R. O. Tetrahedron
N
1
H
R1
O
4
O
S
N
H
(a) Okuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; Wiley-VCH: New York, 2000; pp 1–110; (b) Tang, W.; Zhang, X. Chem.
Rev. 2003, 103, 3029.
H
R2
3
N
CF3
OR
N
RO C
O
2
4. (a) Corey, E. J.; Now, M. C. J. Am. Chem. Soc. 1997, 119, 12414; (b) Lygo, B.;
Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595; For review, see: (c)
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Shibassaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650; (c) Corey, E. J.; Grogan, M. J.
N
OR
CF3
Figure 2. Proposed stereochemical model.

5
530
S. H. Jung, D. Y. Kim / Tetrahedron Letters 49 (2008) 5527–5530
Org. Lett. 1999, 1, 157; (d) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi,
S. J. Am. Chem. Soc. 2000, 122, 762.
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Kim, H. R.; Joung, C. W.; Kim, D. Y. Bull. Korean Chem. Soc. 2004, 25, 1451; (e)
Kim, D. Y.; Huh, S. C. Bull. Korean Chem. Soc. 2004, 25, 347; (f) Kim, S. M.; Kim, H.
R.; Kim, D. Y. Org. Lett. 2005, 7, 2309; (g) Kim, H. R.; Kim, D. Y. Tetrahedron Lett.
2005, 46, 3115; (h) Kim, S. M.; Kang, Y. K.; Lee, K.; Mang, J. Y.; Kim, D. Y. Bull.
Korean Chem. Soc. 2006, 27, 423; (i) Kang, Y. K.; Cho, M. J.; Kim, S. M.; Kim, D. Y.
Synlett 2007, 1135; (j) Cho, M. J.; Kang, Y. K.; Lee, N. R.; Kim, D. Y. Bull. Korean
Chem. Soc. 2007, 28, 2191; (k) Kim, S. M.; Kang, Y. K.; Cho, M. J.; Mang, J. Y.; Kim,
D. Y. Bull. Korean Chem. Soc. 2007, 28, 2435.
6
.
2
002, 154, 5640; (b) Ferassis, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J.;
Ryzhkov, L.; Taggi, A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67; (c) Cordova,
A.; Watanabe, S. I.; Tanaka, F.; Notz, W.; Barbas, C. F. J. Am. Chem. Soc. 2002, 124,
1
842; (d) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F. J. Am.
Chem. Soc. 2002, 124, 1866; (e) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J.
Am. Chem. Soc. 2002, 124, 827; (f) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.
2
002, 124, 112964; (g) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Angew. Chem.,
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7
8
.
.
C.; Lavergne, D. In Modern Amination Methods; Ricci, A., Ed.; Wiley-VCH:
Weinheim, 2000. Chapter 3; (b) Greck, C.; Drouillat, B.; Thomassigng, C. Eur. J.
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Angew. Chem., Int. Ed. 2005, 44, 4292.
(a) Juhl, K.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 2420; (b) Marigo, M.;
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Takemoto, Y. Synlett 2006, 137; (f) Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2006,
13. Typical procedure for the preparation of ogranocatalyst V: To a stirred solution
0
0
of N-(1S,2S)-2-[(R)-3,5-dihydro-4H-dinaphth[2,1-c:1 ,2 -e]azepin-4-yl]cyclo-
hexanamine (785 mg, 2 mmol)12 in dry THF (10 mL) was added 3,5-
bis(trifluoromethyl)phenyl isothiocyanate (542 mg, 2 mmol). After the
reaction mixture was stirred for 48 h, the reaction mixture was concentrated
in vacuo. The residue was purified by column chromatography on silica gel
(hexane/ethyl acetate = 5/1) gave the desired thiourea V (862 mg, 65%) as
2
1
1
yellow solid. Mp = 151–152 °C; ½
a
ꢁ
ꢀ349 (c 1.0, CHCl
3
); H NMR (400 MHz,
D
CDCl ) d 7.97–7.77 (m, 4H), 7.62–7.38 (m, 5H), 7.35–7.15 (m, 6H), 6.72–6.15
3
4
7, 4565; (g) Comelles, J.; Pericas, A.; Moreno-Manas, M.; Vallribera, A.; Drudis-
(br s, 1H), 4.16–3.66 (m, 3H), 3.65–3.40 (m, 2H), 2.73–2.53 (m, 1H), 2.48–2.12
(br s, 1H), 2.09–1.88 (m, 1H), 1.87–1.67 (m, 3H), 1.66–1.45 (m, 1H), 1.44–1.21
Sole, G.; Lledos, A.; Parella, T.; Roglans, A.; Garcia-Grands, S.; Roces-Fernandez,
L. J. Org. Chem. 2007, 72, 2077; (h) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara,
Y.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 11342; (i) Hasegawa,
Y.; Watanabe, M.; Gridnev, I. D.; Ikariya, T. J. Am. Chem. Soc. 2008, 130, 2158.
(a) Pihko, P. M.; Pohjakallio, A. Synlett 2004, 2115; (b) Xu, X.; Yabuta, T.; Yuan,
P.; Takemoto, Y. Synlett 2006, 137; (c) Terada, M.; Nakano, M.; Ube, H. J. Am.
Chem. Soc. 2006, 128, 16044.
(m, 2H), 1.20–1.04 (m, 1H); 13C NMR (50 MHz, CDCl
3
) d 180.0, 135.09, 133.15,
132.19, 131.15, 130.89, 129.05, 128.33, 127.48, 127.34, 126.09, 125.89, 125.46,
123.07, 120.05, 117.58, 69.46, 52.30, 33.34, 28.54, 25.54, 25.35; ESI-HRMS: m/z
+
9
.
calcd for C37
14. General procedure for the
ketoester (0.2 mmol) and catalyst
(0.4 mL) was stirred at room temperature for 10 min and then was cooled to
solution of tert-butyl azodicarboxylate (46.05 mg,
H
32
F
6
N
3
S [M+H] : 664.2221; found: 664.2212.
a
-hydrazination of b-ketoesters 1: A mixture of b-
(13.24 mg, 0.02 mmol) in toluene
1
V
1
0. For selected recent reviews, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
004, 43, 5138; (b) Connon, S. J. Chem. Eur. J. 2006, 12, 5418; (c) Tylor, M. S.;
2
ꢀ70 °C (or ꢀ30 °C).
A
Jacobson, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520; (d) Connon, S. J. Angew.
Chem., Int. Ed. 2006, 45, 3909; (e) Takemoto, Y. Org. Biomol. Chem. 2005, 3,
4
0.4 mmol) in toluene (0.3 mL) was added dropwise over a period of 5 min.
The reaction mixture was stirred for indicated time in Table 2. After
completion of the reaction, the resulting solution was allowed to warm to
room temperature, concentrated in vacuo and the obtained residue was
299; (f) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999; (g)
Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516.
1
1. (a) Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545; (b) Kim, D. Y.; Choi, Y. J.; Park, H.
Y.; Joung, C. U.; Koh, K. O.; Mang, J. Y.; Jung, K.-Y. Synth. Commun. 2003, 33, 435;
purified by flash chromatography (hexane/ethyl acetate = 5/1) to give the a-
aminated products 3.