Enantioselective conjugate addition of hydrazines to α,β- unsaturated imides. Synthesis of chiral pyrazolidinones

Article abstract of DOI:10.1021/ja069312d

This manuscript describes a highly enantioselective conjugate hydrazine addition to α,β-unsaturated imides. The achiral template used has a significant impact on product enantioselectivity. Reactions at lower temperatures provide a protocol to add substit

Full text of DOI:10.1021/ja069312d

Published on Web 03/16/2007
Enantioselective Conjugate Addition of Hydrazines to r,â-Unsaturated Imides.
Synthesis of Chiral Pyrazolidinones
Mukund P. Sibi* and Takahiro Soeta
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105
Received December 27, 2006; E-mail: mukund.sibi@ndsu.edu
Scheme 1
Enantioselective conjugate addition of heteroatom nucleophiles
to electron-poor acceptors continues to attract attention from the
synthetic community.1 The addition of bisnucleophilic donors such
as hydroxylamines and hydrazines can provide direct access to
valuable small-ring heterocycles of potential medicinal interest.2
Literature suggests that enantioselective conjugate addition of
N-monosubstituted hydroxylamines proceed with good chemose-
lectivity since there is a clear differentiation of nucleophilicity
between the two donor atoms.3 Diastereoselective addition of chiral
hydrazines to achiral acceptors4 and reactions of chiral acceptors
with simple hydrazines have been reported in the literature.5 At
present, there are no reported examples of enantioselective conjugate
addition of hydrazines. In this work we report the first examples
of highly enantioselective addition of monosubstituted hydrazines
to R,â-unsaturated imides using catalytic amounts of chiral Lewis
acids (Scheme 1). Furthermore, we also demonstrate that the
conjugate addition proceeds with high chemoselectivity using
bisnucleophilic hydrazine donors (formation of 3 over 4, Scheme
1). The hydrazine addition protocol provides direct access to chiral
pyrazolidinones.6
Table 1. Reaction Conditions for Hydrazine Additiona
We began our experiments with the goal of identifying conditions
that would allow for conjugate addition of hydrazine and its
derivatives selectively.7 To this end, initial experiments were
focused on the addition of the parent hydrazine8 to oxazolidinone
crotonate 1a in the presence of a variety of Lewis acids. These
experiments proved to be not very rewarding because only
amidation products were obtained and only traces of the desired
conjugate addition product could be isolated. We then examined
the addition of monosubstituted hydrazine benzylhydrazine to
crotonate 1a in the presence of a chiral Lewis acid derived from 5
and magnesium salts (Table 1). In these reactions, after conjugate
addition, the achiral template is cleaved resulting in the formation
of the pyrazolidinone products. Magnesium iodide, triflate, and
triflimide salts gave a nearly 1:1 mixture of 3a and 4a in good
overall yield (entries 1-3) when reactions were carried out at room
temperature in the presence of triethylamine as a base.9 The
enantioselectivity for the addition products were low (entries 1-3).
In contrast, magnesium perchlorate proved to be more effective as
a Lewis acid and gave much improved levels of enantioselectivity
for both isomers (entry 4). Other Lewis acids were also examined
but did not lead to improvements in selectivity (entries 5 and 6).10
We have previously explored the effect of achiral templates on
reactivity and/or selectivity in several enantioselective transforma-
tions.11,12 Screening of alternate templates in the hydrazine addition
is straightforward. The template is cleaved during the reaction
resulting in the same products, making analysis simple. For template
evaluation, a chiral Lewis acid prepared from 5 and magnesium
perchlorate, benzylhydrazine, triethylamine, and molecular sieves
were used as standard conditions. Replacing an oxazolidinone
template (1a) with a pyrrolidinone (1b) gave a slight improvement
in selectivity for the major isomer (compare entry 7 with 4). The
temp
yield
3a ee
4a ee
b
d
d
entry
substrate
LA
°
C
%
3a/4ac
%
%
1
2
3
4
5
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1e
1e
1f
MgI2
Mg(OTf)2
room temp 74 57:43
room temp 90 63:37
Mg(NTf2)2 room temp 88 47:53
Mg(ClO4)2 room temp 92 45:55
room temp 84 63:37
room temp 62 64:36
Mg(ClO4)2 room temp 84 69:31
Mg(ClO4)2 room temp 93 70:30
Mg(ClO4)2 room temp 90 52:48
Mg(ClO4)2 room temp 86 59:41
Mg(ClO4)2 -30
Mg(ClO4)2 -50
Mg(ClO4)2 -50
Mg(ClO4)2 -50
Mg(ClO4)2 -50
6
16
9
55
0
20
12
6
56
0
Zn(OTf)2
Cu(OTf)2
6
0
0
7e
8
67
58
30
69
79
84
54
27
72
52
55
34
47
40
52
9
10
11
12
13
14
15
87 92:8
92 98:2
63 98:2
87 98:2
91 98:2
1g
1h
a For reaction conditions, see Supporting Information. Reaction times at
room temp ) 8 h and at -30 or -50 °C ) 24 h. b The yield is for isolated
product. c Isomeric ratios (3/4) were determined by H NMR (400 MHz).
1
d Determined by chiral HPLC. e Reaction with 1b at -50 °C gave 3a in
84% yield and 75% ee (3a/4a ) 98:2).
use of 3,5-dimethylpyrazole as an achiral template (1c) did not lead
to improved selectivity (entry 8). In contrast, imide templates proved
to be very effective in the conjugate additions (entries 9-15). The
benzimide 1e gave high levels of selectivity for the major isomer
at room temperature (entry 10). A significant improvement in isomer
ratio could be realized by cooling the reaction to -30 °C (entry
9
4522
J. AM. CHEM. SOC. 2007, 129, 4522-4523
10.1021/ja069312d CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Examination of Substrate and Reagent Scope
Figure 1. Stereochemical model for hydrazine addition.
rotamer of the imide substrate with magnesium in a cis-octahedral
geometry (Figure 1).14
In conclusion, we have developed a novel enantioselective
method for the preparation of pyrazolidinones in highly enantioen-
riched form. The utilization of these products as chiral auxiliaries
and ligands is being pursued in our laboratory.
yield
ee
c
entry
R1
R2
product
(%)a
3/4b
%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Me (1e)
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
c-Hex
i-Pr
Me
c-Hex
i-Pr
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
92
93
69
67
74
70
43
80
88
83
79
84
61
67
98:2
99:1
95:5
98:2
98:2
98:2
90:10
99:1
99:1
99:1
99:1
99:1
99:1
99:1
84
80
77
80
89
95
37
67
80
67
87
90
79
99
Et (1i)
i-Pr (1j)
CH2-cHex (1k)
CH2Ph (1l)
CH2OBn (1m)
Ph (1n)
CO2t-Bu (1o)
Me (1e)
Me (1e)
Me (1e)
CH2OBn (1m)
CH2OBn (1m)
CH2OBn (1m)
Acknowledgment. This work was supported by the National
Science Foundation (Grant NSF-CHE-0316203).
Supporting Information Available: Characterization data for
compounds 1-4 and experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) For reviews see: Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.
(b) Vicario, J. L.; Badia, D.; Carrillo, L.; Etxebarria, J.; Reyes, E.; Ruiz,
N. Org. Prep. Prop. Int. 2005, 376, 513.
(2) Pyrazolidinones exhibit significant biology, see: (a) Hlasta, D. J.; Casey,
F. B.; Ferguson, E. W.; Gangell, S. J.; Heimann, M. R.; Jaeger, E. P.;
Kullnig, R. K.; Gordon, R. J. J. Med. Chem. 1991, 34, 1560. (b) Perri, S.
T.; Slater, S. C.; Toske, S. G.; White, J. D. J. Org. Chem. 1990, 55, 6037.
(c) White, J. D.; Toske, S. G. Tetrahedron Lett. 1993, 34, 207. (d) Panfil,
I.; Urbanczyk-Lipkowska, Z.; Suwinska, K.; Solecka, J.; Chmielewski,
M. Tetrahedron 2002, 58, 1192.
(3) For the conjugate addition of O-protected hydroxyl amines see: (a)
Falborg, L.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1996, 2823.
(b) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc.
1998, 120, 6615. (c) Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Chem.
Commun. 2001, 1240. (d) Yamagiwa, N.; Qin, H.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13419. Carbamate addition:
(e) Palomo, C.; Oiarbide, M.; Halder, R.; Kelso, M.; Go´mez-Bengoa, E.;
Garc´ıa, J. M. J. Am. Chem. Soc. 2004, 126, 9188. For the addition of
N-substituted hydroxylamines see: (f) Niu, D.; Zhao, K. J. Am. Chem.
Soc. 1999, 121, 2456. (g) Sibi, M. P.; Liu, M. Org. Lett. 2000, 2, 3393.
(h) Sibi, M. P.; Liu, M. Org. Lett. 2001, 3, 4181. (i) Sibi, M. P.;
Prabagaran, N.; Ghorpade, S.; Jasperse, C. P. J. Am. Chem. Soc. 2003,
125, 11796.
a Isolated yield. b Isomer ratio determined by 1H NMR (400 MHz).
c Determined by chiral HPLC. The minor products were not characterized.
11), and the highest level of selectivity of 84% was obtained by
conducting the reaction at -50 °C (entry 12).13 It is interesting to
note that at lower temperature the reaction is better able to
discriminate between the nucleophilicity of the hydrazine nitrogens.
Thus the more nucleophilic and bulky nitrogen adds selectively to
the â-carbon. As can be expected, lower temperature also provides
improved enantioselectivity. Other structural changes to the imide
template did not provide improved enantioselectivity (entries 13-
15).
Having established that a highly selective method for conjugate
hydrazine addition was at hand, we explored the scope of substrate
and the reagent and these results are tabulated in Table 2. For these
reactions, the optimal benzimide template and the chiral Lewis acid
prepared from 5 and magnesium perchlorate were used. Changing
the methyl substituent in 1e to an ethyl group (1i) gave the
pyrazolidinone product with similar yields and selectivity (compare
entry 1 with 2). Reaction efficiency with a bulky isopropyl group
on the â-carbon (1j) was lowered; however, the isomer ratio and
enantioselectivity remained nearly the same (entry 3). Other
substituents on the â-carbon were also competent substrates in the
conjugate addition (entries 4-6) with a protected hydroxymethyl
substituent providing a very high level of enantioselectivity (entry
6). The reactivity of cinnamate 1n was low and gave product in
low yield and enantioselectivity (entry 7). The fumarate 1o gave
the product in good yield and moderate selectivity (entry 8). The
reaction of substrates 1e and 1m with different hydrazines was
investigated (entries 9-14). Of these, reactions with methyl and
isopropyl hydrazine were very selective. The addition of isopropyl
hydrazine 2d to 1m gave pyrazolidinone with 99% enantioselec-
tivity (entry 14). The data in Table 2 clearly demonstrates that there
is good substrate and reagent scope for the conjugate addition of
hydrazines to R,â-unsaturated imides.
(4) (a) Enders, D.; Muller, S. F.; Rassbe, G. Angew. Chem., Int. Ed. 1999,
38, 195-197. (b) Prieto, A.; Fernandez, R.; Lassaletta, J. M.; Vazquez,
J.; Alvarez, E. Tetrahedron, 2005, 61, 4609.
(5) (a) Matsuyama, H.; Itoh, N.; Matsumoto, A.; Ohira, N.; Hara, K.; Yoshida,
M.; Iyoda, M. J. Chem. Soc., Perkin Trans. 1, 2001, 2924. (b) Panfill, I.;
Mostowicz, D.; Chmielewski, M. Polish J. Chem. 1999, 73, 1099.
(6) For elegant methods for accessing enantioenriched pyrazolidinones using
cycloaddition strategies see: (a) Shintani, R.; Fu, G. C. J. Am. Chem.
Soc. 2003, 125, 10778. (b) Suarez, A.; Downey, C. W.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 11244. (c) Chen, W.; Yuan, X.-H.; Li, R.; Du,
W.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. AdV. Synth. Catal. 2006, 348, 1818.
(d) Suga, H.; Funyu, A.; Kakehi, A. Org. Lett. 2007, 9, 97.
(7) For reaction conditions and characterization of starting materials and
products see Supporting Information.
(8) Hydrazine monohydrate or a 1 M solution of hydrazine-THF in the
presence of MS 4 Å gave only the amidation product at -78 °C.
(9) The identity of the isomers was established by comparing their spectral
characteristics with known compounds and/or by spectroscopic analysis
(see Supporting Information for details).
(10) We have examined other amines and solvents in the conjugate addition.
A variety of Lewis acid/box ligand combinations have also been
investigated using both 1a and 1e. These reactions showed either low
reactivity and/or selectivity and results in Table 1 proved to be optimal.
(11) (a) Sibi, M. P.; Sausker, J. B. J. Am. Chem. Soc. 2002, 124, 984. (b) Sibi,
M. P.; Prabagaran, N. Synlett 2004, 2421. (c) Sibi, M. P.; Shay, J. J.; Ji,
J. Tetrahedron Lett. 1997, 38, 5955. (d) Sibi, M. P.; Stanley, L. M.; Soeta,
T. AdV. Synth. Catal. 2006, 2371.
(12) For related work see: Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada,
S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7559.
(13) The variation in ee for the two isomers could arise from differences in
size of the nucleophile, position of the transition state, and intramolecular
delivery.
The absolute stereochemistry for the major isomer of the
pyrazolidinone product was established by comparison of its optical
rotation with that reported in the literature.6b The R stereochemistry
for the product(s) is consistent with hydrazine addition to an s-cis
(14) For a similar model using imide templates see: (a) Sibi, M. P.; Petrovic,
G.; Zimmerman, J. J. Am. Chem. Soc. 2005, 127, 2390. (b) Reference 3i.
JA069312D
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