Enantioselective direct amination of α-cyanoketones catalyzed by bifunctional organocatalysts

Article abstract of DOI:10.1055/s-0028-1083510

The catalytic enantioselective electrophilic α-amination promoted by chiral bifunctional organocatalysts is described. Treatment of α-cyanoketones with azodicarboxylates as electrophilic animation reagents under mild reaction conditions afforded the corresponding a-aminated α-cyanoketones with excellent enantiomeric excesses (87-99%).

Full text of DOI:10.1055/s-0028-1083510

LETTER
2659
Enantioselective Direct Amination of a-Cyanoketones Catalyzed by
Bifunctional Organocatalysts
Amination of
u
a
-Cyanoketo
nnes Mi Kim, Ju Hee Lee, Dae Young Kim*
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Korea
Fax +82(41)5301247; E-mail: dyoung@sch.ac.kr
Received 19 June 2008
Abstract: The catalytic enantioselective electrophilic a-amination
promoted by chiral bifunctional organocatalysts is described. Treat-
MeO
MeO
ment of a-cyanoketones with azodicarboxylates as electrophilic
N
N
amination reagents under mild reaction conditions afforded the cor-
S
CF3
CF3
S
CF3
CF3
responding a-aminated a-cyanoketones with excellent enantiomer-
ic excesses (87–99%).
N
N
H
H
HN
HN
N
N
Key words: electrophilic amination, asymmetric catalysis, bifunc-
tional organocatalyst, a-cyanoketones
I
II
MeO
CF3
One of the ultimate goal and challenges in organic synthe-
N
sis is the development of catalytic asymmetric transfor-
S
S
mation for the creation of functionalized optically active
compounds with structural diversity from simple and
readily available precursor molecules. The efficient syn-
N
H
N
N
CF3
HN
N
H
H
N
Me
Me
III
IV
NH
thetic construction of a-amino carbonyl compounds is one
of the most intensely studied areas in organic synthesis.1
Chiral a-substituted a-amino nitriles,2 since cyano group
is easily converted into other functional groups, would be
versatile synthetic intermediates for the synthesis of nitro-
N
N
gen-containing heterocycles3 and chiral 1,2-diamine de-
rivatives which are employed as medicinal agents or
chiral ligands.4 Enantioselective electrophilic amination
of active methines is one of the most attractive reaction to
HN
HN
HN
X
S
HN
generate quaternary stereocenters attached to a nitrogen
V X = S
CF3
CF3
atom.5
VII
VI X = O
F3C
F3C
Recently, several groups presented the direct enantiose-
lective amination6–8 of active methine compounds in the
Figure 1 Structures of various chiral thiourea–tertiary amine cata-
presence of chiral Lewis acid complexes or chiral organo-
catalysts such as quinidine-derived alkaloids,8a cinchona
alkaloids,6d ureas,6e and guanidines,6g but no electrophilic
amination reaction was observed with a-cyanoketones.9
Bifunctional organocatalysts possessing a combination of
thiourea and amine groups have been developed for acti-
vation of both electrophilic and nucleophilic components.
They have emerged as powerful tools for the enantioselec-
tive formation of carbon–carbon bond and carbon–het-
eroatom bonds.10
lysts
port the direct a-amination of cyclic and acyclic a-cy-
anoketones 1 catalyzed by bifunctional organocatalysts
with azodicarboxylates 2 as the electrophilic nitrogen
source (Table 1).
We envision that the assembly of a structurally well-de-
fined 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 stereocontrolling axial chiral element. The
new bifunctional organocatalysts V–VII (Figure 1) were
synthesized according to the reported procedure from the
reaction of 3,5-bis(trifluoromenthy)phenyl iso(thio)cyan-
ate with chiral 1,2-diamines containing (R)-binaphthyl
moiety.14,15
As part of research program related to the development of
synthetic methods for the enantioselective construction of
stereogenic carbon centers,11,12 we report the catalytic
enantioselective amination of cyanoketones promoted by
chiral palladium catalysts.13 In this letter, we wish to re-
SYNLETT 2008, No. 17, pp 2659–2662
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083510; Art ID: U06508ST
x
x
.x
x
.2
0
0
8
To determine suitable reaction conditions for the catalytic
enantioselective electrophilic amination of a-cyanoke-
© Georg Thieme Verlag Stuttgart · New York

2660
S. M. Kim et al.
LETTER
CO2t-Bu
Table 1 Optimization of the Reaction Conditions
HN
CO2t-Bu
CN
cat. V
N
N
O
O
N
CO2t-Bu
+
NC
Ph
cat.
(10 mol%)
CO2R
toluene, r.t., 1 h
86%, 65% ee (R)
Ph
CO2Et
t-BuO2C
CN
N
N
N
*
CO2Et
+
CN
CO2R
RO2C
2d
4
5
HN
1a
2
3
CO2R
Scheme 1 Catalytic enantioselective amination of a-cyanoacetate 4
Entry 2, R
Cata- Solvent Temp Time Yield ee
lyst
(min) (%)
(%)a
37
37
41
9
catalyst in toluene at room temperature. We first exam-
ined the impact of the structure of catalysts I–VII on
enantioselectivity (Tables 1, 9–83% ee, entries 1–7). The
best results have been obtained with catalysts V. These re-
sults indicate that increasing the sterical demand of the
catalyst increases the selectivities. Varying the structure
of the azodicarboxylates had an impact on asymmetric in-
duction (Table 1, entries 5, 8–12). When employing syn-
thetically attractive, but sterically encumbered, tert-butyl
ester of azodicarboxylate 2, the corresponding aminated
adduct 3 was isolated with high enantioselectivity of 94%
ee (Table 1, entry 10). Concerning the solvent (Table 1,
entries 10, 13–23), the use of toluene gave the best results
in the yield and the enantiomeric excess (entry 10). Re-
ducing the amounts of catalyst to 1 mol% still resulted in
excellent enantioselectivity (97% ee, Table 1, entries 25,
27). Lowering the temperature to 0 to –60 °C with catalyst
V improved the enantioselectivity (97% ee, Table 1, en-
tries 25–27). In the case of –60 °C, the reaction required
longer reaction time (4 h, Table 1, entry 27).
1
2
2a, Et
2a, Et
I
Toluene r.t.
Toluene r.t.
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
30
95
93
92
94
93
92
89
40
93
93
90
88
94
95
93
92
92
91
93
93
92
91
91
94
95
92
95
II
3
2a, Et
2a, Et
2a, Et
2a, Et
2a, Et
2b, Bn
2c, i-Pr
2d, t-Bu
III Toluene r.t.
IV Toluene r.t.
4
5
V
Toluene r.t.
83
71
81
85
77
94
93
91
93
91
86
91
91
91
91
83
77
91
53
95
97
97
97
6
VI Toluene r.t.
VII Toluene r.t.
7
8
V
V
V
Toluene r.t.
Toluene r.t.
Toluene r.t.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25b
26
27b
2d, t-Bu VI Toluene r.t.
2d, t-Bu VII Toluene r.t.
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
V
V
V
V
V
V
V
V
V
V
V
V
V
V
V
Xylene r.t.
Benzene r.t.
To examine the generality of the catalytic enantioselective
amination of a-cyanoketones 1 by using new chiral bi-
functional organocatalyst V, we studied the amination of
various a-cyanoketones 1a–n.16 As can be seen by the re-
sults summarized in Table 2, the corresponding a-aminat-
ed a-cyanoketones 3a–n were obtained in excellent yields
and enantioselectivities. The cyclic a-cyanoketones 1a–h,
with cyclic aromatic ketones 1a–f, and cyclic aliphatic ke-
tones 1g and 1h, reacted with tert-butyl azodicarboxylate
(2d) to give the corresponding a-aminated a-cyanoke-
tones 3ad–hd in 77–95% yields and 94–99% ee (Table 2,
entries 1–8). Acyclic a-cyanoketones 1i–n reacted with
tert-butyl azodicarboxylate (2d) to afford the a-aminated
a-cyanoketones 3id–nd with 87–99% ee (Table 2, entries
9–14).
DCE
r.t.
CH2Cl2 r.t.
CHCl3
Et2O
r.t.
r.t.
r.t.
r.t.
MTBE
THF
Acetone r.t.
MeCN
MeOH
r.t.
r.t.
We examined the catalytic enantioselective electrophilic
amination of a-cyanoacetate 4 with tert-butyl azodicar-
boxylate (2d) using palladium complexes 1 and 2 at room
temperature. In the presence of 10 mol% of catalyst V, the
reaction proceeded to afford the a-aminated product 5 af-
ter one hour with 86% yield and 65% ee (Scheme 1). The
absolute configuration of 5 was determined to be R by
comparing specific rotation and chiral HPLC data with an
authentic sample.8b,c
Toluene 0 °C
Toluene –20 °C 30
Toluene –60 °C 30
Toluene –60 °C 4 h
a Enantiopurity of 3 was determined by HPLC analysis with Chiralpak
AD column.
b Reaction was carried out using 1 mol% of catalyst.
In conclusion, we have developed a highly efficient cata-
lytic enantioselective a-amination of cyclic and acyclic a-
cyanoketones using new chiral bifunctional organocata-
lysts. The desired a-aminated products were obtained in
good to high yields, and excellent enantioselectivities
tones, we initially investigated the reaction system with 2-
cyanoindanone (1a) using azodicarboxylates 2 as the elec-
trophilic aminating agent in the presence of 10 mol% of
Synlett 2008, No. 17, 2659–2662 © Thieme Stuttgart · New York

LETTER
Amination of a-Cyanoketones
2661
Table 2 Catalytic Enantioselective Amination of a-Cyanoketones
Acknowledgment
CO2t-Bu
This research was financially supported by the Ministry of Educa-
tion, Science, Technology (MEST) and Korea Industrial Technolo-
gy Foundation (KOTEF) through the Human Resource Training
Project for Regional Innovation.
O
O
HN
N
CO2t-Bu
cat. V
N
N
CN
+
*
R1
R1
CO2t-Bu
toluene
R2 CN
R2
t-BuO2C
2d
3ad–3ld
1a–1l
References and Notes
O
O
(1) For reviews on a-amino acids, see: (a) Williams, R. M.
Synthesis of Optically Active a-Amino Acids; Pergamon:
Oxford, 1989. (b) Duthaler, R. O. Tetrahedron 1994, 50,
1539. (c) Hanessian, S.; McNaughton-Smith, G.; Lombart,
H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789.
(d) Arend, M. Angew. Chem. Int. Ed. 1999, 38, 2873.
(e) Kotha, S. Acc. Chem. Res. 2003, 36, 342. (f) Maruoka,
K.; Ooi, T. Chem. Rev. 2003, 103, 3013. (g) Najera, C.;
Sansano, J. M. Chem. Rev. 2007, 107, 4584.
(2) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359.
(3) (a) Matier, W. L.; Owens, D. A.; Comer, W. T.; Dietchman,
D.; Ferguson, H. C.; Seidehamel, R. J.; Young, J. R. J. Med.
Chem. 1973, 16, 901. (b) Weinstock, L. M.; Davis, P.;
Handelsman, B.; Tull, R. J. Org. Chem. 1967, 32, 2823.
(4) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem. Int.
Ed. 1998, 37, 2580.
(5) For reviews on asymmetric a-amination reactions, see:
(a) Genet, J.-P.; Greck, C.; Lavergne, D. Modern Amination
Methods; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2000,
Chap. 3. (b) Greck, C.; Drouillat, B.; Thomassigny, C. Eur.
J. Org. Chem. 2004, 1377. (c) Erdik, E. Tetrahedron 2004,
60, 8742. (d) Janey, J. M. Angew. Chem. Int. Ed. 2005, 44,
4292.
(6) For 1,3-dicarbonyl compounds, see: (a) Juhl, K.; Jørgensen,
K. A. J. Am. Chem. Soc. 2002, 124, 2420. (b) Marigo, M.;
Juhl, K.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2003, 42,
1367. (c) Ma, S.; Jiao, N.; Zheng, Z.; Ma, Z.; Lu, Z.; Ye, L.;
Deng, Y.; Chen, G. Org. Lett. 2004, 6, 2193. (d) Pihko,
P. M.; Pohjakallio, A. Synlett 2004, 2115. (e) Xu, X.;
Yabuta, T.; Yuan, P.; Takemoto, Y. Synlett 2006, 137.
(f) Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2006, 47,
4565. (g) Terada, M.; Nakano, M.; Ube, H. J. Am. Chem.
Soc. 2006, 128, 16044. (h) Comelles, J.; Pericas, A.;
Moreno-Mañas, M.; Vallribera, A.; Drudis-Sole, G.; Lledos,
A.; Parella, T.; Roglans, A.; Garcia-Grands, S.; Roces-
Fernandez, L. J. Org. Chem. 2007, 72, 2077. (i) Mashiko,
T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai, N.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 11342.
(7) For b-ketophosphonates, see: (a) Kim, S. M.; Kim, H. R.;
Kim, D. Y. Org. Lett. 2005, 7, 2309. (b) Bernardi, L.;
Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127,
5772.
(8) For a-cyanoacetates, see: (a) Saaby, S.; Bella, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120.
(b) Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167.
(c) Liu, Y.; Melgar-Fernandez, R.; Juaristi, E. J. Org. Chem.
2007, 72, 1522. (d) Hasegawa, Y.; Watanabe, M.; Gridnev,
I. D.; Ikariya, T. J. Am. Chem. Soc. 2008, 130, 2158.
(9) For catalytic asymmetric reactions of a-cyanoketones, see:
(a) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128,
3928. (b) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L.
J. Am. Chem. Soc. 2007, 129, 768. (c) Nojiri, A.; Kumagai,
N.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 5630.
O
O
CN
CN
CN
CN
R
Ph
Ph
R
n
n
R
1a n = 0, R = H
1g n = 0
1h n = 1
1i R = Ph
1j R = 2-Naph
1k R = 4-OMe, Ph
1l R = allyl
1m R = Me
1n R = Et
1b n = 0, R = 5-Me
1c n = 0, R = 5,6-Me
1d n = 1, R = H
1e n = 1, R = 6-Me
1f n = 2, R = H
Entry
1c
2
1
Temp (°C) Time (h)
Yield (%)a ee (%)b
1a
1b
1c
1d
1e
1f
1g
1h
1i
–20
–78
–78
–35
–78
–30
–78
r.t.
0.5
20
24
21
48
8 d
3
3ad, 95
3bd, 92
3cd, 85
3dd, 94
3ed, 94
3fd, 77
3gd, 94
3hd, 95
3id, 94
3jd, 94
3kd, 93
3ld, 92
3md, 45
3nd, 93
97
97
98
99
99
99
95
94
94
93
99
87
96
90
3
4c
5
6
7
8
2
9
–30
–35
–30
–78
10 d
7 d
36
4 d
30
1.3
10
11
12
13
14
1j
1k
1l
1m –78
1n –18
a Yield of isolated product.
b Enantiopurity of 3 was determined by HPLC analysis with Chiral-
pak AD (for 3ad), AS (for 3dd,fd), AD-H (for 3ld,nd), Chiralcel
OD-H (for 3bd,cd,ed,hd,id,jd,kd,md) and (S,S)-Whelk-O1 (for 3gd)
columns.
c Reaction was carried out using 1 mol% of catalyst.
(87–99% ee) were observed for all the substrates exam-
ined in this work. To our knowledge, these results consti-
tute the first examples of the direct catalytic asymmetric
amination of a-cyanoketones using organocatalysts. We
believe that this method provides a practical entry for the
preparation of chiral a-amino-a-cyanoketone derivatives.
Further study of these new bifunctional organocatalysts in
other asymmetric reactions is under investigation.
Synlett 2008, No. 17, 2659–2662 © Thieme Stuttgart · New York

2662
S. M. Kim et al.
LETTER
(10) For selected recent reviews, see: (a) Dalko, P. I.; Moisan, L.
Angew. Chem. Int. Ed. 2004, 43, 5138. (b) Connon, S. J.
Chem. Eur. J. 2006, 12, 5418. (c) Tylor, M. S.; 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, 4299. (f) Akiyama, T.; Itoh,
J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999. (g) Yu,
X.; Wang, W. Chem. Asian J. 2008, 3, 516.
(11) (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.
(c) Park, E. J.; Kim, M. H.; Kim, D. Y. J. Org. Chem. 2004,
69, 6897. (d) Park, E. J.; 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) Kang, Y. K.; Cho, M. J.; Kim, S. M.; Kim, D. Y. Synlett
2007, 1135. (g) Cho, M. J.; Kang, Y. K.; Lee, N. R.; Kim,
D. Y. Bull. Korean Chem. Soc. 2007, 28, 2191. (h) Kim, S.
M.; Kang, Y. K.; Cho, M. J.; Mang, J. Y.; Kim, D. Y. Bull.
Korean Chem. Soc. 2007, 28, 2435.
(12) (a) Kim, S. M.; Kim, H. R.; Kim, D. Y. Org. Lett. 2005, 7,
2309. (b) Kim, H. R.; Kim, D. Y. Tetrahedron Lett. 2005,
46, 3115. (c) Kim, S. M.; Kang, Y. K.; Lee, K.; Mang, J. Y.;
Kim, D. Y. Bull. Korean Chem. Soc. 2006, 27, 423.
(13) Lee, J. H.; Bang, H. T.; Kim, D. Y. Synlett 2008, 1821.
(14) (a) Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama, N.;
Yanagisawa, A. Angew. Chem. Int. Ed. 2006, 45, 6978.
(b) Arai, T.; Watanabe, M.; Yanagisawa, A. Org. Lett. 2007,
9, 3595.
reaction mixture was concentrated in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc–
hexane, 1:5) gave the desired thiourea V (862 mg, 65%) as
yellow solid; mp 151–152 °C; [a]D25 –349 (c 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3): d = 7.97–7.77 (m, 4 H), 7.62–7.38
(m, 5 H), 7.35–7.15 (m, 6 H), 6.72–6.15 (br s, 1 H), 4.16–
3.66 (m, 3 H), 3.65–3.40 (m, 2 H), 2.73–2.53 (m, 1 H), 2.48–
2.12 (br s, 1 H), 2.09–1.88 (m, 1 H), 1.87–1.67 (m, 3 H),
1.66–1.45 (m, 1 H), 1.44–1.21 (m, 2 H), 1.20–1.04 (m, 1 H).
13C NMR (50 MHz, CDCl3): 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 calcd for
C37H32F6N3S [M + H]+: 664.2221; found: 664.2212.
(16) Typical Procedure for the Amination of 2-Cyano-1-
indanone (1a)
To a stirred solution of 2-cyano-1-indanone (1a, 47.15 mg,
0.3 mmol) and catalyst V (1.99 mg, 0.003 mmol) in toluene
(0.3 mL) was added dropwise the solution of tert-butyl
azodicarboxylate (103.6 mg, 0.45 mmol) in 0.3 mL of
toluene at –20 °C. Reaction mixture was stirred for 30 min at
–20 °C. The mixture was concentrated and purified by flash
chromatography (EtOAc–hexane, 1:4) to afford the 110.4
21
mg (95%) of a-aminated 2-cyano-1-indanone 3ad; [a]D
–22.5 (c 1.38, CHCl3, 97% ee). 1H NMR (200 MHz, CDCl3):
d = 7.90–7.86 (d, J = 8.0 Hz, 1 H), 7.82–7.70 (t, J = 8.1 Hz,
1 H), 7.56–7.43 (m, 2 H), 7.09–7.01 (s, 1 H), 4.07–3.87 (q,
J = 10.0 Hz, 2 H), 1.62–1.22 (m, 18 H). 13C NMR (50 MHz,
CDCl3): d = 192.0, 155.5, 149.3, 136.9, 136.6, 132.2, 128.6,
126.5, 123.8, 115.6, 83.0, 82.6, 68.4, 40.0, 28.2, 27.8. ESI-
MS: m/z (%) = 387 [M+], 356 (10), 332 (70), 275 (32), 232
(8), 213 (12), 188 (7.5), 158 (8). ESI-HRMS: m/z [M]+ calcd
for C20H25N3O5: 387.1794; found: 387.1802. HPLC
(15) Typical Procedure for the Preparation of
Organocatalyst V
To a stirred solution of N-(1S,2S)-2-{(R)-3,5-dihydro-4H-
dinaphth[2,1-c:1¢,2¢-e]azepin-4-yl}-cyclohexanamine (785
mg, 2 mmol)14 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
(hexane–i-PrOH, 8:2, 254 nm, 1.0 mL/min, Chiralpak AD
column): tR = 5.8 min (minor), tR = 7.7 min (major).
Synlett 2008, No. 17, 2659–2662 © Thieme Stuttgart · New York

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