Asymmetric α-amination of 4-substituted pyrazolones catalyzed by a chiral Gd(OTf)3/ N,N′-dioxide complex: Highly enantioselective synthesis of 4-amino-5-pyrazolone derivatives

Article abstract of DOI:10.1021/ol102804p

The asymmetric α-amination of 4-substituted pyrazolones with azodicarboxylates was investigated for the first time, employing an N,N′-dioxide gadolinium(III) complex as the catalyst. The novel transformations exhibited high yield, and 4-amino-5-pyrazolone

Full text of DOI:10.1021/ol102804p

ORGANIC
LETTERS
2011
Vol. 13, No. 4
596–599
Asymmetric r-Amination of 4-Substituted
Pyrazolones Catalyzed by a Chiral
Gd(OTf)3/N,N0-Dioxide Complex: Highly
Enantioselective Synthesis of
4-Amino-5-pyrazolone Derivatives
Zhigang Yang, Zhen Wang, Sha Bai, Xiaohua Liu, Lili Lin, and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China
xmfeng@scu.edu.cn
Received November 18, 2010
ABSTRACT
The asymmetric R-amination of 4-substituted pyrazolones with azodicarboxylates was investigated for the first time, employing an N,N0-dioxide
gadolinium(III) complex as the catalyst. The novel transformations exhibited high yield, and 4-amino-5-pyrazolone derivatives bearing a chiral
quaternary center were obtained in excellent yields (up to 99%) and enantioselectivities (90%-97% ee) for a broad scope of 5-pyrazolones by
using 1 mol % or only 0.05 mol % of catalyst.
Pyrazolone derivatives characterized as a five-mem-
bered-ring lactam are important frameworks which exhibit
a variety of applications as pharmaceutical candidates
and biologically important structural components.1 For
example, analgin is used for the treatment of pains of
different origin and variable intensity. The development of
asymmetric methods to access pyrazolone derivatives with
a quaternary stereogenic center2 attheC4positionhasthus
given rise to considerable interest. However, relatively
fewer examples have been documented for catalytic
asymmetric transformations by using pyrazolone as a
nucleophile.3 Recently, the enantioselective R-amination
of azodicarboxylates with carbolic nucleophiles represents
(1) For selected examples; see: (a) Mariappan, G.; Saha, B. P.;
Bhuyan, N. R.; Bharti, P. R.; Kumar, D. J. Adv. Pharm. Tech. Res.
2010, 1, 260. (b) Ma, R.; Zhu, J.; Liu, J.; Chen, L.; Shen, X.; Jiang, H.; Li, J.
Molecules 2010, 15, 3593. (c) Caruso, F.; Pettinari, C.; Marchetti, F.; Natanti,
P.; Phillips, C.; Tanski, J.; Rossi, M. Inorg. Chem. 2007, 46, 7553.
(d) Kimata, A.; Nakagawa, H.; Ohyama, R.; Fukuuchi, T.; Ohta, S.; Suzuki,
T.; Miyata, N. J. Med. Chem. 2007, 50, 5053. (e) Chande, M. S.; Barve, P. A.;
Suryanarayan, V. J. Heterocycl. Chem. 2007, 44, 49. (f) Ferlin, M. G.;
Chiarelotto, G.; Acqua, S. D.; Maciocco, E.; Mascia, M. P.; Pisu, M. G.;
Biggio, G. Bioorg. Med. Chem. 2005, 13, 3531. (g) Ebner, S.; Wallfisch, B.;
Andraos, J.; Aitbaev, I.; Kiselewsky, M.; Bernhardt, P. V.; Kollenz, G.;
Wentrup, C. Org. Biomol. Chem. 2003, 1, 2550. (h) El-sonbati, A. Z.;
El-bindary, A. A.; El-mosalamy, E. H.; El-santawy, E. M. Chem. Pap. 2002,
56, 299. (i) Fryer, R. I.; Zhang, P.; Rios, R.; Gu, Z.-Q.; Basile, A. S.; Skolnick,
P. J. Med. Chem. 1993, 36, 1669. (j) Nagashima, S. Anal. Chem. 1983, 55,
2086. (k) Toth, B. Cancer Res. 1972, 32, 804. (l) Field, J. B.; Dolendo, E. C.;
Mireles, A.; Ershoff, B. H. Cancer Res. 1966, 26, 1371.
(2) For reviews of catalytic enantioselective construction of quatern-
ary chiral centers, see: (a) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2006, 45, 6366. (b) Christoffers, J.; Baro, A. Adv.
Synth. Catal. 2005, 347, 1473. (c) Ramon, D. J.; Yus, M. Curr. Org. Chem.
2004, 8, 149.
(3) For selected examples, see: (a) Liao, Y.-H.; Chen, W.-B.; Wu,
Z.-J.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Adv. Synth.
Catal. 2010, 352, 827. (b) Gogoi, S.; Zhao, C.-G. Tetrahedron Lett. 2009,
50, 2252. (c) Gogoi, S.; Zhao, C.-G.; Ding, D. Org. Lett. 2009, 11, 2249.
r
10.1021/ol102804p
Published on Web 01/07/2011
2011 American Chemical Society

one of the best established strategies for the construction of
chiral C-N bonds in organic chemistry.4,5 Catalytic en-
antioselective R-amination of pyrazolone has not yet been
investigated to conduct optically active 4-amino-5-pyra-
zolones which are the core frame of numerous pharma-
ceutical compounds.
Table 1. Asymmetric R-Amination of 4-Benzyl-5-pyrazolone
Catalyzed by N,N0-Dioxide-Metal Complexesa
In asymmetric catalysis, the contribution of the chiral
complex is of leading importance. Our group is endeavor-
ing to develop chiral C2-symmetric N,N0-dioxide into a
helpful ligand which could coordinate with a series of
cations to form chiral complex catalysts.6-8 Especially, it
could give selective and flexible catalysts with lanthanide
metal salts9 which feature advantages in stability, recovery,
the electropositive properties, and high coordination abil-
ity. Herein, we wish to report the first highly enantioselec-
tive R-amination of 4-substituted 5-pyrazolones with
azodicarboxylates using a chiral N,N0-dioxide-Gd(III)
complex as the catalyst. Excellent yields (up to 99%) and
enantioselectivities (up to97% ee) were achievedfor a wide
range of pyrazolones at 0.05-1 mol % catalyst loading.
Initially, (S)-pipecolic acid derived N,N0-dioxide L1 was
complexed with various lanthanide metal salts to catalyze
the asymmetric R-amination of 4-benzyl-5-pyrazolone (1a)
rion
˚
Yield
(%)c
ee
b
(A)
Entry
Metal
Ligand
(%)d
1
La(OTf)3
Ce(OTf)3
Pr(OTf)3
Nd(OTf)3
Sm(OTf)3
Eu(OTf)3
Gd(OTf)3
Tb(OTf)3
Dy(OTf)3
Ho(OTf)3
Er(OTf)3
Tm(OTf)3
Yb(OTf)3
Lu(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
L1
L1
1.032
1.010
0.990
0.983
0.958
0.947
0.938
0.923
0.912
0.901
0.890
0.880
0.868
0.861
0.938
0.938
0.938
0.938
0.938
0.938
0.938
0.938
98
94
90
94
95
90
95
90
88
97
96
94
93
85
85
96
91
59
99
98
99
96
49
76
77
82
91
92
93
92
89
89
83
75
67
59
72
73
73
48
96
96
95
93
2
3
4
5
6
7
(4) For reviews on asymmetric R-amination reactions, see: (a) Xu,
8
ꢀ
L.-W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807. (b) Najera, C.;
9
Sansano, J. M. Chem. Rev. 2007, 107, 4584. (c) Janey, J. M. Angew. Chem.,
Int. Ed. 2005, 44, 4292. (d) Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J.
Org. Chem. 2004, 1377. (e) Duthaler, R. O. Angew. Chem., Int. Ed. 2003,
42, 975.
10
11
12
(5) For selected examples of asymmetric R-amination, see: (a) Bui, T.;
13
ꢀ
Hernandez-Torres, G.; Milite, C.; Barbas, C. F., III. Org. Lett. 2010, 12,
14
5696. (b) Han, X.; Zhong, F.; Lu, Y. Adv. Synth. Catal. 2010, 352, 2778.
(c) Mouri, S.; Chen, Z.; Mitsunuma, H.; Furutachi, M.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 1255. (d) Yang, Z. G.; Wang, Z.;
Bai, S.; Shen, K.; Chen, D. H.; Liu, X. H.; Lin, L. L.; Feng, X. M. Chem.;
Eur. J. 2010, 16, 6632. (e) Bui, T.; Borregan, M.; Barbas, C. F., III. J. Org.
Chem. 2009, 74, 8935. (f) Mashiko, T.; Kumagai, N.; Shibasaki, M. J. Am.
Chem. Soc. 2009, 131, 14990. (g) He, R.; Wang, X.; Hashimoto, T.;
Maruoka, K. Angew. Chem., Int. Ed. 2008, 47, 9466. (h) Liu, T.-Y.; Cui,
H.-L.; Zhang, Y.; Jiang, K.; Du, W.; He, Z.-Q.; Chen, Y.-C. Org. Lett. 2007,
9, 3671. (i) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai, N.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 11342. (j) Terada, M.; Nakano,
M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044. (k) Liu, X.; Li, H.; Deng,
L. Org. Lett. 2005, 7, 167. (l) Bernardi, L.; Zhuang, W.; Jørgensen, K. A.
J. Am. Chem. Soc. 2005, 127, 5772. (m) Saaby, S.; Bella, M.; Jørgensen,
K. A. J. Am. Chem. Soc. 2004, 126, 8120. (n) Vogt, H.; Vanderheiden, S.;
15
16
17
18
19e,f
20e,g,h
21e,g,h,i
22e,g,h,j
a Unless otherwise noted, all reactions were carried out with 1a
(0.1 mmol) and 2a (0.1 mmol) in CH2Cl2 (1.0 mL) with catalyst loading
of 5 mol % (metal/ligand = 1:1) under nitrogen at -20 °C for 36 h. b rion
:
3þ 9b,10 c Yield of isolated product. d Determined by
˚
ionic radii (A) of Ln
.
€
Brase, S. Chem. Commun 2003, 2448. (o) Marigo, M.; Juhl, K.; Jørgensen,
HPLC using chiral AD-H column. e 20 mg of 4 A molecular sieves (MS)
were added. f Reaction time: 2 h. g Reaction time: 4 h. h 1 mol % of
catalyst loading was used. i Performed at 0 °C. j The reaction was carried
out under an air atmosphere.
˚
K. A. Angew. Chem., Int. Ed. 2003, 42, 1367. (p) Juhl, K.; Jørgensen, K. A.
J. Am. Chem. Soc. 2002, 124, 2420. (q) List, B. J. Am. Chem. Soc. 2002,
124, 5656. (r) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595. (s) Evans,
D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452.
(6) For reviews on chiral N-oxides in asymmetric catalysis, see:
ꢁ
ꢀ
(a) Malkov, A. V.; Kocovsky, P. Eur. J. Org. Chem. 2007, 29. (b)
Chelucci, G.; Murineddu, G.; Pinna, G. A. Tetrahedron: Asymmetry
and diisopropylazodicarboxylate (2a) in CH2Cl2 at-20°C
(Table 1). The central metal ion was found to significantly
affect the enantioselectivity of the reaction. As shown in
Table 1, when changing the central metal from La(OTf)3 to
Gd(OTf)3 in a gradually diminished order of the ionic
radii, the enantioselectivity came to increase from 49% to
93% ee and the reactions completed within 36 h to give
product 3a with appropriate yields (Table 1, entries 1-7).
In contrast, the enantioselectivity gradually decreased
from 93% to 59% ee when the central metal was changed
from Gd(OTf)3 toLu(OTf)3 withthe ionic radii continuing
to decrease (Table 1, entries 7-14). The results of the
influence of the metal cation suggested that Gd3þ has
relative proper ionic radii to coordinate with the ligand
ꢁ
ꢀ
2004, 15, 1373. (c) Malkov, A. V.; Kocovsky, P. Curr. Org. Chem. 2003,
7, 1737 and the references therein.
(7) For our own work in this field, see: (a) Xie, M. S.; Chen, X. H.;
Zhu, Y.; Gao, B.; Lin, L. L.; Liu, X. H.; Feng, X. M. Angew. Chem., Int.
Ed. 2010, 49, 3799. (b) Li, W.; Wang, J.; Hu, X. L.; Shen, K.; Wang, W. T.;
Chu, Y. Y.; Lin, L. L.; Liu, X. H.; Feng, X. M. J. Am. Chem. Soc. 2010, 132,
8532. (c) Wang, W. T.; Liu, X. H.; Cao, W. D.; Wang, J.; Lin, L. L.; Feng,
X. M. Chem.;Eur. J. 2010, 16, 1664. (d) Liu, Y. L.; Shang, D. J.; Zhou, X.;
Zhu, Y.; Lin, L. L.; Liu, X. H.; Feng, X. M. Org. Lett. 2010, 12, 180.
(e) Chen, D. H.; Chen, Z. L.; Xiao, X.; Yang, Z. G.; Lin, L. L.; Liu, X. H.;
Feng, X. M. Chem.;Eur. J. 2009, 15, 6807. (f) Liu, Y. L.; Shang, D. J.;
Zhou, X.; Liu, X. H.; Feng, X. M. Chem.;Eur. J. 2009, 15, 2055.
(8) (a) Kobayashi, S.; Kokubo, M.; Kawasumi, K.; Nagano, T.
Chem.;Asian J. 2010, 5, 490. (b) Kokubo, M.; Ogawa, C.; Kobayashi, S.
Angew. Chem., Int. Ed. 2008, 47, 6909.
(9) (a) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L.
Chem. Rev. 2002, 102, 2227. (b) Mikami, K.; Terada, M.; Matsuzawa, H.
Angew. Chem., Int. Ed. 2002, 41, 3554.
Org. Lett., Vol. 13, No. 4, 2011
597

Table 2. R-Amination of 4-Substituted Pyrazolones 1 with
Azodicarboxylates 2 Promoted by the Gadolinium Catalysta
t
Yield
(%)b
ee
(%)c
Entry
R1
R2
R3
(h)
1
Bn
Bn
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
iPr
Et
Bn
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
iPr
iPr
Et
Et
Et
4
1
98 (3a)
99 (3b)
99 (3c)
98 (3d)
90 (3e)
96 (3f)
94 (3g)
97 (3h)
90 (3i)
85 (3j)
98 (3k)
97 (3l)
91 (3m)
99 (3n)
85 (3o)
98 (3p)
97 (3q)
98 (3r)
92 (3s)
92 (3t)
94 (3u)
96 (3v)
98 (3w)
96
97d
94
96
96
97
96
97
96
93
94
95
93
94
94
92
94
94
90
93
92
93
94
2
3
2
4
2-MePhCH2
3-MePhCH2
4-MePhCH2
2-MeOPhCH2
3-MeOPhCH2
4-MeOPhCH2
2-ClPhCH2
3-ClPhCH2
4-ClPhCH2
4-BrPhCH2
2,4-Cl2PhCH2
2-furanylmethyl
2-thienylmethyl
1-naphthylmethyl
2-naphthylmethyl
Me
2
5
2
6
2
7
2
8
2
9
2
10
11
12
13
14
15
16
17
18
19e
20e
21
22
23
2
2
Figure 1. (a) X-ray structure of 3b with Cu KR radiation (H atoms
omitted for clarity). (b) Nonlinear effect in the amination of 1a
with 2b catalyzed by the L1-Gd(OTf)3 complex. (c) Proposed
transition-state model.
10
2
2
2
2
2
equilibrium for the formation of the enolate intermediate
and to accelerate the reaction.5h Notably, reducing the
catalyst loading to 1 mol % led to no loss of yield and
enantioselectivity (Table 1, entry 20). Moreover, the en-
antioselectivity was slightly decreased when the reaction
was carried out at 0 °C or under an air atmosphere.
2
12
14
2
Et
Me
Me
Me
n-propyl
allyl
2
-(CH2)4-
10
After having established the optimal reaction conditions
(Table 1, entry 20), we began to examine the scope of the R-
amination reaction. First, the effect of the ester group of
the azodicarboxylate was tested for the asymmetric R-
amination of 4-benzyl-5-pyrazolone. The ester groups
exhibiteda slight effect on both the reactivity and enantios-
electivity (Table 2, entries 1-3). Diethylazodicarboxylate
(DEAD) was the best electrophile for this reaction, and the
corresponding product 3b was obtained in 99% yield with
97% ee after 1 h (Table 2, entry 2). Next, a wide variety of
pyrazolones bearing different arylmethyl substituents were
investigated for this chiral gadolinium(III) complex cata-
lyzed R-amination reaction (Table 2, entries 4-23). In
general, the reactions took place efficiently with excellent
levels of enantioselectivity (90-97% ee) and good yields
(85-99%). The absolute configuration of 3b was deter-
mined by X- ray crystallography to be R (Figure 1a).
The catalytic synthesis of optically active chiral com-
pounds with an extremely low catalyst loading is one of the
most valuable advantages for the chemical industry.
Although the asymmetric R-amination of the other carbolic
nucleophiles with azodicarboxylates had been reported,4,5
most of these transformations required at least 5 mol % of
catalyst loading for sufficient formation of the product and
maintenance of the enantioselectivity. The reaction reported
herein could be performed without obvious influence upon
the enantioselectivity and reactivity even with a catalyst
loading of 0.05 mol %, albeit with a somewhat prolonged
a Unless otherwise noted, all reactions were carried out with 5-pyra-
˚
zolone 1 (0.1 mmol), azodicarboxylates 2 (0.1 mmol), and 4 A MS
(20 mg) in CH2Cl2 (1.0 mL) with a catalyst loading of 1 mol % L1/
Gd(OTf)3 (1:1) under nitrogen at -20 °C. b Yield of isolated product.
c Determined by chiral HPLC analysis. d The absolute configuration of
3b was determined by X-ray analysis (see Figure 1a). The other products
were assigned by analogy. e The catalyst was L4/Ho(OTf)3 and in the
˚
absence of 4 A MS.
to form the active catalyst with a strong asymmetric
inducing capability.
Further optimization of the reaction conditions was
then aimed at the efficiency of Gd(OTf)3 with other N,
N0-dioxide ligands. The results showed that the steric and
electronic effects of the amide moiety played a crucial role
on the asymmetric induction of the R-amination reaction
(Table 1, entries 15,16). Moreover, the chiral backbone of
the N,N0-dioxide had also a significant impact on the
enantioselectivity of the reaction. (S)-Pipecolic acid deri-
vative N,N0-dioxide L1 was superior to L-proline derived
L4 and L-ramipril acid derived L5 (Table 1, entry 7 vs
˚
entries 17 and 18). Remarkably, when 4 A molecular sieves
(20mg) were employed asanadditive, the reactionratewas
greatly improved with completed conversion within 2 h to
give product 3a, and the enantioselectivity slightly increased
˚
from 93% to 96% ee (Table 1, entry 19). The role of the 4 A
molecular sieves might be helpful for the promotion of the
(10) Shannon, R. D. Acta Crystallogr., Sect. A 1976, 32, 751.
598
Org. Lett., Vol. 13, No. 4, 2011

Table 3. R-Amination of 4-Substituted Pyrazolones 1 with
Diethylazodicarboxylate 2b Using 0.05 mol % Catalyst
Loadinga
Scheme 1. Asymmetric R-Amination of 4-Substituted
Pyrazolones 1a on a Gram Scale
Entry
R1
t (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Bn
5
10
10
10
10
10
10
12
96 (3b)
97 (3d)
95 (3f)
90 (3h)
96 (3j)
95 (3k)
94 (3n)
95 (3p)
93
96
90
93
93
94
90
92
2-MePhCH2
4-MePhCH2
3-MeOPhCH2
2-ClPhCH2
of the pyrazolone would coordinate to the active L1-Gd
complex toform anenolate. The azodicarboxylate alsocan
coordinate to the central metal ion through an ester
carbonyl group. Subsequently, the Re-face attack of the
electrophilic diethylazodicarboxylate of the enolate would
afford the desired adduct 3b with an R-configuration.
In summary, we have successfully presented the first
highly stereoselective R-amination of 4-substituted pyra-
zolones with azodicarboxylates as the nitrogen fragment
source. The reactions were catalyzed by an N,N0-dioxide
gadolinium(III) complex to give the optically active 4-ami-
no-5-pyrazolones in high yields (up to 99%) and excellent
enantioselectivities (up to 97% ee). In particular, the
procedure is capable of tolerating a relatively wide range
of substrates, and excellent results (90%-96% ee) can also
be obtained, even in the presence of 0.05 mol % of catalyst
loading. Furthermore, excellent ee values and yields can
also be obtained in gram-scale, which showed the poten-
tial value of the catalyst system. Current studies are under-
way to investigate the synthetic utility of the R-amination
products.
3-ClPhCH2
2,4-Cl2PhCH2
2-thienylmethyl
a Unless otherwise noted, all reactions were carried out with 5-pyr-
azolone 1 (0.1 mmol), diethylazodicarboxylate (DEAD) 2b (0.1 mmol),
˚
and 4 A MS (5 mg) in CH2Cl2 (1.0 mL) with 0.05 mol % L1/Gd(OTf)3
(1:1) under nitrogen at -20 °C. b Yield of isolated product. c Determined
by chiral HPLC analysis.
reaction time (Table 3). And a relatively wide range of
substrates can be tolerated, affording the desired products
with 90-97% yield and 90-96% ee. It is noteworthy that
this is a rare example of an asymmetric R-amination
with azodicarboxylates with such a low amount of catalyst
(0.05 mol %).
The low catalyst loading and the inexpensive starting
materials and catalyst for this R-amination reaction of-
fered a practical way to scale-up production. As shown in
Scheme 1, the reaction proceededsmoothly and the desired
addition product 3b was obtained in 95% yield with 93%
ee using only a 0.05 mol % N,N0-dioxide L1-gadolinium-
(III) complex as the catalyst.
The relationship between the enantiomeric excess of the
ligand L1 and the product 3b was investigated. A positive
nonlinear effect was observed (Figure 1b), suggesting that
the oligomeric aggregates of L1-Gd(OTf)3 might exist in
the reaction system. On the basis of the observed absolute
configuration of enantiopure 3b and previous reports
of using N,N0-dioxide-metal complexes as catalysts,7c,f
a plausible working model by concerted activation was
proposed. As illustrated in Figure 1c, the carbonyl group
Acknowledgment. We acknowledge the National Nat-
ural Science Foundation of China (Nos. 20732003 and
21021001) and the National Basic Research Program of
China (973 Program: No. 2010CB833300) for financial
support. We also thank Sichuan University Analytical
& Testing Center for NMR and X-ray analysis.
Supporting Information Available. Experimental pro-
cedures and spectral and analytical data for the products.
This material is available free of charge via the Internet
at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 4, 2011
599