Dynamic kinetic asymmetrie allylation of hydrazines and hydroxylamines

Article abstract of DOI:10.1021/ol901185d

Hydrazines and hydroxylamines have been found to be excellent nucleophiles for the palladium-catalyzed dynamic asymmetric allylic amination of vinyl epoxide, with good yields and enantioselectivities of up to 97% ee. This method is applicable to acyclic a

Full text of DOI:10.1021/ol901185d

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3258-3260
Dynamic Kinetic Asymmetric Allylation
of Hydrazines and Hydroxylamines
Ian Mangion,* Neil Strotman, Michael Drahl, Jason Imbriglio, and Erin Guidry
Merck Research Laboratories, Merck and Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065
ian_mangion@merck.com
Received May 27, 2009
ABSTRACT
Hydrazines and hydroxylamines have been found to be excellent nucleophiles for the palladium-catalyzed dynamic asymmetric allylic amination
of vinyl epoxide, with good yields and enantioselectivities of up to 97% ee. This method is applicable to acyclic and heterocyclic amines and
was applied toward a five-step synthesis of (R)-piperazic acid.
The central importance of new methods for the enantiose-
lective synthesis of chiral amines has been demonstrated
through numerous recent advances in asymmetric catalysis.1
Despite the abundance of hydrazines and hydroxylamines
in biologically active compounds, there are few general
methods for their synthesis in a stereocontrolled fashion.2
We became interested in dynamic kinetic asymmetric allylic
allylation3 as a broadly useful tool for the introduction of
C-N stereogenicity. An intriguing recent report demon-
strated the utility of imido carboxylates in the enantioselective
amination of vinyl aziridines and epoxides.4 We sought to
demonstrate that hydrazines and hydroxylamines could
display analogous reactivity, enabling access to new chiral
synthons (Scheme 1).
Scheme 1. Asymmetric Allylation of Hydrazines
(1) For recent examples, see: (a) Hsiao, Y.; Rivera, N. R.; Rosner, T.;
Krska, S. W.; Njolito, E.; Wang, F.; Sun, Y.; Armstrong, J. D.; Grabowski,
E. J. J.; Tillyer, R. D.; Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004,
126, 9918. (b) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2006, 128, 84. (c) Hashimoto, T.; Maruoka, K. J. Am.
Chem. Soc. 2007, 129, 10054.
(2) (a) Fa¨ssler, R.; Frantz, D. E.; Oetiker, J.; Carreira, E. M. Angew.
Chem., Int. Ed. 2002, 41, 3054. (b) List, B. J. Am. Chem. Soc. 2002, 124,
5656. (c) Jin, X. L.; Sugihara, H.; Daikai, K.; Tateishi, H.; Jin, Y. Z.; Furuno,
H.; Inanaga, J. Tetrahedron 2002, 58, 8321. (d) Yamagiwa, N.; Matsunaga,
S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 16178. (e) Saaby, S.; Bella,
M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. (f) Imada, Y.;
Nishida, M.; Kutsuwa, K.; Murahashi, S.-I.; Naota, T. Org. Lett. 2005, 7,
5837. (g) Miyabe, H.; Takemoto, Y. Synlett 2005, 1641.
The Trost family of ligands (such as 1 and 2) have a well-
documented ability to impart enantiodiscrimination for a
number of different reactions involving palladium π-allyl
(3) (a) Lloyd-Jones, G. C.; Pfaltz, A. Angew. Chem., Int. Ed. 1995, 34,
462. (b) Glorius, F.; Pfaltz, A. Org. Lett. 1999, 1, 141. (c) Trost, B. M.;
Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am. Chem. Soc. 2000, 122,
5968. (d) Malkov, A. V.; Spoor, P.; Vinader, V.; Kocovsky, P. Tetrahedron
Lett. 2001, 42, 509. (e) Hughes, D. L.; Palucki, M.; Yasuda, N.; Reamer,
R. A.; Reider, P. J. J. Org. Chem. 2002, 67, 2762. (f) Lueseem, B. J.; Gais,
H.-J. J. Org. Chem. 2004, 69, 4041.
(4) Trost, B. M.; Fandrick, D. R.; Brodmann, T.; Stiles, D. T. Angew.
Chem., Int. Ed. 2007, 46, 6123.
10.1021/ol901185d CCC: $40.75
Published on Web 07/09/2009
 2009 American Chemical Society

intermediates.5 Our initial efforts focused on the application
of these ligands to the dynamic asymmetric allylic amination
of hydrazine 3a with vinyl epoxide (Table 1). Using 1 mol
Table 2. Asymmetric Aminations of Vinyl Epoxidea
Table 1. Catalyst Optimization and Additive Survey for 4aa
conversionb eec b:lc d
,
entry solvent
additive
1
2
3
4
CH3CN none
100
95
86
89
88
89
-
5:1
5:1
5:1
-
CH3CN Et3N (0.1 equiv)
CH3CN AcOH (0.1 equiv)
CH3CN LiBr (1 equiv)
0
5
6
7
8
CH3CN Bu4NCl (1 equiv)
CH3CN Bu4NI (1 equiv)
CH3CN Bu4NBr (1 equiv)
CH3CN Bu4NBr (0.1 equiv)
CH3CN Bu4NBr (2 equiv)
CH3CN Bu4PBr (1 equiv)
CH3CN Bu4NBr (1 equiv)
CH2Cl2 Bu4NBr (1 equiv)
100
100
100
100
79
89
86
100
70
100
95
91
7:1
6:1
94 11:1
90 6:1
94 11:1
89
81
88 10:1
92
89
9
10
11e
12
13
14
9:1
1:1
THF
Bu4NBr (1 equiv)
7:1
6:1
toluene Bu4NBr (1 equiv)
a All reactions run at 0 °C for 20 h with 1.1 equiv of vinyl epoxide, 1
mol % of Pd2(dba)3 and 5 mol % of (S,S)-1 except where noted. b Conversion
of hydrazine 3a. c Determined by SFC. d Ratio of branched regioisomer to
linear regioisomer. e Run with ligand 2 in place of 1.
% of Pd2(dba)3 and 5 mol % of 1 in degassed acetonitrile at
0 °C, we obtained the desired chiral alcohol in 89% ee (entry
1, Table 1) and full conversion with respect to the hydrazine.
A notable observation was formation of the achiral (linear)
product resulting from addition of the hydrazine in an SN2′
sense to the vinyl terminus of the epoxide.6 The ratio of the
chiral, “branched” product to this “linear” byproduct was
sensitive to the reaction conditions, so a range of solvent
systems and additives were then surveyed for improved
chemoselectivty and asymmetric induction.
Acid or base additives were not observed to have ap-
preciable impact on the selectivity of the reaction and had a
slightly deleterious effect on reaction rate (entries 2 and 3,
Table 1, 88-89% ee). Further exploration revealed a marked
halide effect on selectivity. Tetrabutylammonium and phos-
phonium halide additives were the most efficient, with
tetrabutylammonium bromide (TBAB) being the best additive
for the improvement of enantio- and chemoselectivity (entries
7-9, 90-94% ee). In particular, 1 equiv of TBAB provides
the best balance of the conditions tried of conversion and
(5) (a) Trost, B. M. Acc. Chem. Res. 1996, 29, 355. (b) Trost, B. M.
Chem. ReV. 1996, 96, 395. (c) Trost, B. M.; Machacek, M. R.; Aponick,
A. Acc. Chem. Res. 2006, 39, 747.
a All reactions run at 0 °C in CH3CN with 1.1 equiv of vinyl epoxide,
1.0 equiv of Bu4NBr, 1 mol % of Pd2(dba)3 and 5 mol % of (S,S)-1 except
where noted. b Isolated yield. c Determined by HPLC or SFC, see Supporting
Information. d Isolated as a 76:24 mixture of branched and linear regioisomers.
e Reaction run with 3 mol % of (R,R)-1.
(6) This regioselectivity has been observed previously, see: (a) Trost,
B. M.; Molander, G. A. J. Am. Chem. Soc. 1981, 103, 5969. (b) Evans,
P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761.
(c) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.; Dai, L.-X. J. Am. Chem.
Soc. 2001, 123, 7471. (d) Bartels, B. G.; Yebra, C.; Helmchen, G. Eur. J.
Org. Chem. 2003, 1097.
Org. Lett., Vol. 11, No. 15, 2009
3259

selectivity (entry 7, 94% ee, 11:1 b:l). Using fewer equiva-
lents of TBAB lowered the selectivity (entry 8, 90% ee),
while using more than 1 equiv led to poorer conversion (entry
9). Chloride and iodide additive sources also helped selectiv-
ity, though to a slightly lesser degree (entries 5 and 6). The
influence of added halide on enantiocontrol has been
observed previously in palladium-mediated asymmetric
allylations3a,7 with the hypothesis that the halide increases
the rate of interconversion of diastereomeric palladium
π-allyl intermediates.8 Ligand 2 exhibited diminished enan-
tioselectivity under these conditions and 1:1 chemoselectivity
(entry 11, 81% ee). The best asymmetric induction was
achieved at 0 °C with CH3CN as the preferred solvent (entry
7) though other solvents such as CH2Cl2, THF, and toluene
provided comparable results (entries 12-14, 88-92% ee).9
With highly enantioselective conditions in hand for asym-
metric allylation of hydrazine 3a, we sought to expand the
scope of this reaction and to examine the use of other
hydrazines as well as hydroxylamines. Both cyclic and
acyclic hydrazines reacted with high yield and selectivity
(entries 1-4, Table 2, 83-94% ee), including 3-pyridazinone
(entry 4, 91% yield, 87% ee). To our delight, a range of
aminoxy nucleophiles also performed successfully, with
enantioselectivity as high as 97% ee (entries 5-10, 80-97%
ee). Benzyl, allyl, and alkyl aminoxy ethers were all well
tolerated (entries 5-8, 80-88% ee). In a substrate containing
both aminoxy and amino carbamates, complete selectivity
was observed for reactivity with the aminoxy component,
consistent with relative nucleophilicity predicted from the
R-effect (entry 9, 87% ee).10 High enantioselectivity could
also be seen in the case of a cyclic hydroxylamine (entry
10, 97% ee).
Scheme 2.
Total Synthesis of (R)-Piperazic Acida
a Conditions: (a) Vinyl epoxide, 1 mol % of Pd2(dba)3, 5 mol % of
(S,S)-1, Bu4NBr, CH3CN, 0 °C, 79%; (b) 1 mol % of (H2IMes)RuCl2-
(PCy3)dCHPh, CH2Cl2, 40 °C, 91%; (c) 5 mol % of Crabtree’s catalyst,
H2, CH2Cl2, 97%; (d) PhI(OAc)2, TEMPO, CH3CN, 0 °C, 72%; (e) 5%
Pd/C, H2, CH2Cl2, TFA, 81%.
vinyl epoxide with hydrazine 3a to furnish 4a in 94% ee.
Ring-closing metathesis of 4a then provided the tetrahydro-
pyridazine 5. The olefin was selectively reduced via hydro-
genation using Crabtree’s catalyst, after which alcohol 6 was
oxidized to the corresponding acid (7). Hydrogenolysis of
the benzyl carbamates completed the synthesis of (R)-
piperazic acid in five steps from hydrazine 3a in 41% overall
yield.
For a representative application of these asymmetric vinyl
epoxide resolutions, we sought to apply the chiral hydrazine
4a toward a synthesis of piperazic acid,11 an amino acid
component of naturally occurring antibiotics (Scheme 2).12
Our synthesis began with the dynamic kinetic resolution of
The palladium-catalyzed enantioselective amination of
vinyl epoxide by hydrazines and hydroxylamines has been
demonstrated. The Trost bisphosphine ligand 1 imparts high
enantiocontrol and regiochemical control, and halide addi-
tives have been found that enhance the selectivity. This
method was used in a short synthesis of piperazic acid and
should find further utility in the asymmetric synthesis of
natural and pharmaceutical products. Efforts are currently
underway to explore mechanistic considerations of the effect
of halide additives.
(7) (a) Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc.
1998, 120, 12702. (b) Trost, B. M.; Calkins, T. L.; Oertelt, C.; Zambrano,
J. Tetrahedron Lett. 1998, 39, 1713
.
(8) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921.
(9) Over extended reaction time or at elevated temperatures in the
presence of the Pd catalyst, 4a has been observed to isomerize to its linear
regioisomer; it is recommended to purify these reactions upon completion.
See also: Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew. Chem., Int.
Ed. 2006, 45, 5546.
Acknowledgment. The authors would like to thank Prof.
Barry M. Trost (Stanford University) for helpful discussions.
(10) (a) Grekov, A. P.; Veselov, V., Ya Russ. Chem. ReV. 1978, 47,
631. (b) Fina, N. J.; Edwards, J. O. Int. J. Chem. Kinet. 1973, 5, 1.
(11) For isolation of piperazic acid, see: Bevan, K.; Davies, J. S.; Hassall,
C. H.; Morton, R. B.; Phillips, D. A. S. J. Chem. Soc. (C) 1971, 514.
(12) (a) Hale, K. J.; Cai, J.; Delisser, V.; Manariazar, S. Tetrahedron
Lett. 1992, 33, 7613. (b) Aoyagi, Y.; Saitoh, Y.; Ueno, T.; Horiguchi, M.;
Takeya, K. J. Org. Chem. 2003, 68, 6899. (c) Henmi, Y.; Makino, K.;
Yoshitomi, Y.; Osamu, H.; Hamada, Y. Tetrahedron: Asymmetry 2004, 15,
3477.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL901185D
3260
Org. Lett., Vol. 11, No. 15, 2009