Diastereoselective electrophilic α-amination of camphor N1-acyl N2-phenylpyrazolidinones: the metal enolate-dependent synthesis of two possible hydrazide diastereomers

Article abstract of DOI:10.1016/j.tetlet.2008.11.003

Complementary approaches under enolate amination reactions for the synthesis of both α-hydrazidoacyl diastereomers have been achieved. Both isomers are obtained with high to excellent chemical yields and high stereoselectivities (up to >95:5 dr) when aryl

Full text of DOI:10.1016/j.tetlet.2008.11.003

Tetrahedron Letters 50 (2009) 333–336
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Tetrahedron Letters
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Diastereoselective electrophilic
a
-amination of camphor N1-acyl
N2-phenylpyrazolidinones: the metal enolate-dependent synthesis
of two possible hydrazide diastereomers
*
Chin-Sheng Chao, Chung-Kai Cheng, Ssu-Hsien Li, Kwunmin Chen
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 116, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Complementary approaches under enolate amination reactions for the synthesis of both a-hydrazidoacyl
Received 10 September 2008
Revised 30 October 2008
Accepted 4 November 2008
Available online 7 November 2008
diastereomers have been achieved. Both isomers are obtained with high to excellent chemical yields and
high stereoselectivities (up to >95:5 dr) when aryl-substituted camphor N1-acyl N2-phenylpyrazolidinone
was treated with potassium hexamethyldisilylamide (KHMDS) and lithium hexamethyldisilylamide
(LHMDS), respectively, followed by the addition of di-tert-butyl azodicarboxylate. The nondestructive
removal of the chiral auxiliary, which can be carried out under mild condition, afforded the hydrazido
alcohol with high enantiomeric ratio. The facial stereoselectivity and stereochemical course of the reac-
tions are discussed.
Keywords:
Amination
Reversal of stereoselectivity
Chiral auxiliary
Ó 2008 Elsevier Ltd. All rights reserved.
The electrophilic
a
-amination of carbonyl compounds consti-
also been reported.6 On the other hand, only limited examples of
diastereoselective electrophilic amination of metal enolates have
been documented.7 The metal enolate-based methodology for the
carbon–nitrogen bond formation remained unexplored. Further,
from a practical synthetic point of view, the preparation of both
stereoisomers from the same chiral source has many synthetic
advantages and has received considerable attention in recent
years.8 The stereochemical outcomes can be influenced by several
factors such as solvent, the structure of metal-substrate complex,
and reagent components employed. We have recently developed
a novel camphor-derived auxiliary, camphor N-phenyl pyrazolidi-
none, that has proved to be effective in asymmetric synthesis.8f,j
We wish to report herein that electrophilic amination of chiral
tutes one of the fundamental challenges in modern organic synthe-
sis.1 Several asymmetric variants have been developed in recent
years for the construction of the nitrogenous molecules by using
azodicarboxylates as the nitrogen source. The resulting hydrazine
derivatives serve as versatile precursors for the preparation of
amino acids, -hydrazino acids, and other important synthetic
intermediates.2 The metal-based catalytic enantioselective
-ami-
nation of N-acyloxazolidinones,3 -keto esters,4 and b-keto esters5
provides an easy entry to optically active -amino acids and
amino-b-hydroxy esters with high to excellent enantioselectivi-
ties. More recently, the organocatalytic electrophilic -amination
a-
a
a
a
a
a-
a
of unmodified aldehydes,
a-cyanoacetate, and b-keto esters has
Me
Me
Me
Me
Me
Me
R
H
1
N
H
R
N
Boc
Boc
N
Boc
Boc
5
R
N
N
N
N
N
2
O
O
O
O
O
HN
O
HN
Ph
Ph
Ph
1
3
2
a R = C6H5
b R = 1-Naphthyl
c R = 4-MeOC6H4
d R = 3-MeC6H4
e R = 2-Thienyl
f R = t-Butyl
Figure 1.
* Corresponding author. Tel.: +886 2 89315831; fax: +886 2 29324249.
E-mail address: kchen@ntnu.edu.tw (K. Chen).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.003

334
C.-S. Chao et al. / Tetrahedron Letters 50 (2009) 333–336
N1-acyl N2-phenylpyrazolidinones to give
with excellent chemical yield and high diastereoselectivity in the
a
-aminated derivatives
teristic C-5 methine proton (this nomenclature system) that ap-
pears at 3.49 ppm, while the carbonyl -methine proton located
a
presence of di-tert-butyl azodicarboxylate. In addition, the stereo-
at 6.01 ppm. However, two NH proton signals appear at 6.76 and
6.49 ppm, respectively, in a ratio of 1.9:1.0. High performance li-
quid chromatography (HPLC) studies indicated only one diastereo-
mer in the purified product. A 2D NMR experiment (HMQC) was
carried out, and the results indicate that both signals appearing
at 6.76 and 6.49 ppm come from the same NH proton. In addition,
variable-temperature studies of 1H NMR spectra demonstrated the
existence of structural conformers in hydrazide 2a. An equilibrium
mixture of at least two structural conformers of 2a in CDCl3 was
proposed.10 The newly generated stereogenic carbon center in
the major diastereomer 2a was assigned as an S configuration by
single crystallographic X-ray analysis.
In addition to the steric hindrance, the tautomeric equilibration
of 2a in solution may also associate with the hydrogen bonds and
the preferential disposition of the carbonyl dipoles. A close look of
the X-ray crystallographic ORTEP structure of 2a shows that the
NH forms hydrogen bonds with the nearby carbonyl groups
(Fig. 2).
To our surprise, the newly generated stereogenic center of the
aminated adduct was reversed, when LHMDS was used. Treatment
of 1a with LHMDS at ꢀ78 °C gave 3a as the major diastereomer
with 90% de (entry 4). The distinct characteristics of 1H NMR spec-
trum in 3a are worth noting. In addition to the two signals of the
hydrazide NH proton at 6.68 and 6.49 ppm, the C-5 methine proton
also appeared as a set of two signals at 4.41 and 4.31 ppm, respec-
tively, in the same ratio of 1.8:1.0, similar to that of NH signals. The
significant chemical shift difference of C-5 proton signal in 1H NMR
spectrum between hydrazides 2a (3.49 ppm) and 3a (4.41 and
4.31 ppm) can be attributed to the diamagnetic anisotropy effect
of the phenyl substituent. This represents, to the best of our knowl-
chemical course of the
a-amination is metal enolate dependent.
The facial stereoselectivity and the stereochemical course of the
reactions are discussed.
The starting camphor N1-acyl N2-phenylpyrazolidinones 1a–f
can be readily prepared from camphor N-phenylpyrazolidinone
following standard acylation conditions (Fig. 1). The phenylace-
tyl-substituted pyrazolidinone 1a was chosen as a probe substrate,
and di-tert-butyl azodicarboxylate was used as the electrophilic
nitrogen source. The desired hydrazides were obtained with low
to moderate chemical yields by treatment of 1a, when LDA, n-BuLi,
and KOtBu were used followed by the addition of di-tert-butyl azo-
dicarboxylate at ꢀ78 °C (data not shown). A reasonable chemical
yield (53%) was achieved, when 1a was treated with KHMDS in
CH2Cl2 at ꢀ78 °C followed by the addition of an electrophile (Table
1, entry 1). No reaction occurred when the reaction was carried out
in Et2O (entry 2). The chemical yield was improved to 91%, when
the same reaction was carried out in THF (entry 3). We were not
able to interpret the 1H NMR spectrum of the crude products for
the determination of stereoselectivity. This is due to the presence
of isomer and the tautomeric forms caused by the restricted rota-
tion about the Boc groups in the hydrazide, which has been docu-
mented in the literature.9 The spectrum of a purified hydrazide 2a
is interpretable, although with the presence of tautomers. A careful
analysis of 1H NMR spectrum of hydrazide 2a indicated the charac-
Table 1
Diastereoselective amination of camphor N1-acyl N2-phenylpyrazolidinones 1a–ea
Entry
R =
Solvent
Base
Yield (%)b
Dr (2:3)c
edge, the first example of a complementary electrophilic a-amination
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(1a) C6H5
(1a) C6H5
(1a) C6H5
(1a) C6H5
(1a) C6H5
(1a) C6H5
(1b) 1-Naphthyl
(1b) 1-Naphthyl
(1c) 4-MeOC6H4
(1c) 4-MeOC6H4
(1d) 3-MeC6H4
(1d) 3-MeC6H4
(1e) 2-Thienyl
(1e) 2-Thienyl
CH2Cl2
Et2O
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
KHMDS
KHMDS
KHMDS
LHMDS
53
0
87:13
—
reaction for the synthesis of both diastereomeric hydrazides by simply
changing the base.11 Having developed reaction conditions that af-
ford complementary diastereomers in the amination reactions, we
sought to test the scope and feasibility of the auxiliary architecture.
91
94
92
90
90
91
90
88
75
81
90
63
93d:07
05:95
77:23
44:56
93:07
05:95
95:05
08:92
95:05
05:95
90:10
08:92
Mixed basese
Mixed basesf
KHMDS
LHMDS
KHMDS
LHMDS
KHMDS
LHMDS
KHMDS
LHMDS
a
Unless otherwise specified, all reactions were carried out in the solvent indi-
cated at ꢀ78 °C using 1 (0.81 mmol), base (0.93 mmol), and di-tert-butyl azodi-
carboxylate (0.85 mmol).
b
Total isolated yield (2+3).
c
Ratios of diastereomers were determined by 1H NMR analysis of relevant peaks
and by HPLC analyses of crude products (Agilent Technologies, ZORBAX SIL,
4.6 ꢁ 250 mm, hexanes/IPA = 96.7/3.3, flow rate = 0.5 mL/min).
d
The absolute stereochemistry of the newly generated stereogenic center in 2a
was established by single crystallographic X-ray analysis. The absolute stereo-
chemistry of 2b–e and 3b–e is assigned by 1H NMR spectra analyses (see text).
e
KHMDS (0.6 equiv) was added followed by the addition of LHMDS (0.6 equiv).
LHMDS (0.6 equiv) was added followed by the addition of KHMDS (0.6 equiv).
Figure 2. A Chem3D structural drawing of 2a regenerated from the X-ray crystal
coordinates. All hydrogens (except for C2 proton) are omitted for the sake of clarity.
f
Me
Me
Me
Me
H
Ph
H
Ph
HO
Boc
Boc
NaBH4, THF
+
N
N
Boc
Boc
NH
N
HN
N
N
O
O
O
HN
Ph
Ph
(S)-4 (65%) [α]D = +34.5 (c = 1.0 CHCl3)
(R)-4 (82%) [α]D = -39.0 (c = 1.0 CHCl3)
(84%)
(77%)
(
(
S
)-2a
)-3a
R
Scheme 1. Recovery of chiral auxiliary from hydrazides 2a and 3a.

C.-S. Chao et al. / Tetrahedron Letters 50 (2009) 333–336
335
Ph
N
Ph
N
Ph
N
Ph
N
O
O
O
O
O
N
O
N
t-BuO
N
O
N
N
N
t-BuO
N
O
N
t-BuO
t-BuO
Li
K
K
Li
O
O
O
O
N
N
N
N
H
H
H
Ph
O
Ph
O
Ph
Me
Ph
Me
H
Me
Me
t-BuO
t-BuO
O
t-BuO
Me
t-BuO
O
Me
Me
Me
E
-enolate
E
-enolate
Z-enolate
Z-enolate
Figure 3. Proposed transition state of the electrophilic amination of 1a using KHMDS and LHMDS as a base.
Me
Me
Me
Me
KHMDS, THF
Boc-N=N-Boc
n-Bu3SnH,
THF, 50 ºC
Ph
Ph
O
H
-78 ºC
0 ºC
N
Boc
N
Boc
1a
N
N
(90%)
(83%)
N
H
N
O
O
O
Ph
Ph
5
6 (70% de)
Scheme 2. Preparation of (R)-a-amino carbonyl 6.
This complementary amination process is applicable to various
aryl-substituted substrates 1b–e. Toward this end, good to high
levels of stereoselectivities of the aminating adducts with S config-
uration (except for 2e due to the priority numbering) were ob-
tained, when 1b–e were treated with KHMDS followed by the
addition of di-tert-butyl azodicarboxylate (entries 7, 9, 11, and
13). The 1H NMR signal of the corresponding C-5 methine proton
in 2b–e consistently appeared in a range of 3.50–3.62 ppm. On
the other hand, reversal of stereoselectivity of the aminated ad-
ducts 3b–e (R configuration, except for 3e) was observed when
LHMDS was used under the same conditions (entries 8, 10, 12,
and 14). The 1H NMR signal of the C-5 methine protons in 3b–e ap-
pears in a range of 4.41–4.53 ppm as expected. The characteristic
features of the 1H NMR spectra of the hydrazides 2 and 3 permitted
the assignment of the newly generated stereogenic centers. No
reaction occurred when a bulky substituent 1f (R = t-butyl) was
used. To complete one cycle of the chiral auxiliary, the aminated
adducts (S)-2a and (R)-3a were then subjected to reduction condi-
tions. Exposure of 2a to NaBH4 in THF at ambient temperature pro-
hydrazide 2a was isolated as the major product (70%), and the imi-
no intermediate 5 was obtained with 20% chemical yield. Tributyl-
tin hydride reduction of 5 in THF afforded the Boc-protected (R)-a-
amino product 6 (70% de) as the major diastereomer in a total of
83% chemical yield. The hydride attacks from the bottom si face
of the imino functionality in 5.12
In conclusion, complementary metal enolate amination of the
auxiliary-derived N-acyls was developed for the synthesis of two
possible hydrazide diastereomers. Either isomer can be obtained
with excellent chemical yield and high diastereoselectivity (up to
90% de), when aryl-substituted camphor N1-acyl N2-phenylpyrazo-
lidinones are treated with KHMDS and LHMDS, respectively, fol-
lowed by the addition of di-tert-butyl azodicarboxylate. This
extends the synthetic applications to the versatile and general util-
ity of camphor N2-phenylpyrazolidinone as a good stereocontrol-
ling element in diastereoselective reaction.
Acknowledgments
vided the desired hydrazido alcohol (S)-4 (65%) (½a D
ꢂ
+34.5 (c 1.0,
This work was supported by the National Science Council of the
Republic of China (NSC 96-2113-M-003-005-MY3) and the Na-
tional Taiwan Normal University (96TOP001). Our gratitude goes
to the Academic Paper Editing Clinic, NTNU, and we are also grate-
ful to the National Center for High-Performance Computing for
computer time and facilities.
CHCl3)), and camphor N2-phenylpyrazolidinone was recovered in
84% yield (Scheme 1). Similar conditions were applied to give
(R)-4 (½aꢂD ꢀ39.0 (c 1.0, CHCl3)) with 82% yield, when 3a was used.
The mechanistic explanation for the asymmetric amination has
not yet been elucidated at this moment and can be rationalized by
the structurally well-defined metal enolate geometries in the tran-
sition states as depicted in Figure 3.9a The hydrogen bond formed
Supplementary data
between the
a-hydrogen and the carbonyl group of di-tert-butyl
azodicarboxylate may play a role in stabilizing the favored enolate
complexes. The eight-membered potassium Z-enolate is preferen-
tially formed, when 1a is treated with KHMDS to give the corre-
sponding adduct 2a. On the other hand, the six-membered
lithium E-enolate is energetically favored, when LHMDS is used,
resulting in the formation of 3a as the major isomer. The size of
the metal counterion may also be important in forming the
eight-membered and six-membered enolates.
An interesting imino intermediate 5 was isolated, when the
amination reaction was carried out at ꢀ78 °C followed by warm
up to 0 °C gradually (Scheme 2). When phenylacetyl-substituted
pyrazolidinone 1a was treated with KHMDS and di-tert-butyl azo-
dicarboxylate at ꢀ78 °C and warmed up to 0 °C over a period of 5 h,
the imino product 5 was isolated with high chemical yield. On the
other hand, when the reaction temperature was raised to ꢀ30 °C,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.003.
References and notes
1. For recent reviews, see: (a) Erdik, E. Tetrahedron 2004, 60, 8747–8782; (b)
Genet, J. P.; Greck, C.; Lavergne, D. In Modern Amination Method; Ricci, A., Ed.;
Wiley-VCH: Wienheim, 2000; Chapter 3; (c) Boche, G.. In Stereoselective
Synthesis: Houben-Weyl; G. Thieme: Thieme: Stuttgart, 1995; Vol. E21, pp
5133–5157; (d) Dembech, P.; Seconi, G.; Ricci, A. Chem. Eur. J. 2000, 6, 1281–
1286.
2. (a) Hannachi, J.-C.; Vidal, J.; Mulatier, J.-C.; Collet, A. J. Org. Chem. 2004, 69,
2367–2373; (b) Vicario, J. L.; Badia, D.; Carrillo, L.; Anakabe, E. Tetrahedron:
Asymmetry 2002, 13, 745–751; (c) Arya, P.; Ben, R. N.; Qin, H. Tetrahedron Lett.
1998, 39, 6131–6134; (d) Hale, K. J.; Cai, J.; Delisser, V.; Manaviazar, S.; Peak, S.
A.; Bhatia, G. S.; Collins, T. C.; Jogiya, N. Tetrahedron 1996, 52, 1047–1068; (e)
Greck, C.; Ferreira, F.; Genet, J. P. Tetrahedron Lett. 1996, 37, 2031–2034.
3. Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452–6453.

336
C.-S. Chao et al. / Tetrahedron Letters 50 (2009) 333–336
4. (a) Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2006, 47, 4565–4568; (b) Juhl, K.;
Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908–9909; (i) Adam, W.; Pastor, A.;
Peters, K.; Peters, E.-M. Org. Lett. 2000, 2, 1019–1022; (j) Yang, K.-S.; Chen, K.
Org. Lett. 2000, 2, 729–731.
Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 2420–2421.
5. Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1367–1369.
6. (a) Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044–16045;
(b) Liu, X.; Li, H.; Deng, L. Org. Lett 2005, 7, 167–169; (c) Saaby, S.; Bella, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120–8121; (d) Pihko, P.;
Pohjakallio, A. Synlett 2004, 2115–2118; (e) List, B. J. Am. Chem. Soc. 2002, 124,
5656–5657.
7. (a) Gennari, C.; Colombo, L.; Bertolini, G. J. Am. Chem. Soc. 1986, 108, 6394–
6395; (b) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F. J. Am. Chem. Soc.
1986, 108, 6395–6397; (c) Trimble, L. A.; Vederas, J. C. J. Am. Chem. Soc. 1986,
108, 6397–6399.
8. (a) Zhang, H.-H.; Hu, X.-Q.; Wang, X.; Luo, Y.-C.; Xu, P. F. J. Org. Chem. 2008, 73,
3634–3637; (b) Capriati, V.; Florio, S.; Luisi, R.; Mazzanti, A.; Musio, B. J. Org.
Chem. 2008, 73, 3197–3204; (c) Luisi, R.; Capriati, V.; Florio, S.; Musio, B. Org.
Lett. 2007, 9, 1263–1266; (d) Frolander, A.; Moberg, C. Org. Lett. 2007, 9, 1371–
1374; (e) Dambacher, J.; Bergdahl, M. Org. Lett. 2003, 5, 3539–3541; (f) Fan, C.
L.; Lee, W.-D.; Teng, N-W.; Sun, Y.-C.; Chen, K. J. Org. Chem. 2003, 68, 9816–
9818; (g) Sibi, M. P.; Liu, M. Curr. Org. Chem. 2001, 5, 719–755; (h) Yabu, K.;
Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.; Du, W.; Curran, D. P.;
9. (a) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F., Jr. Tetrahedron 1988,
44, 5525–5540; (b) Oare, D. A.; Heathcock, C. H. Tetrahedron Lett. 1986, 27,
6169–6172; (c) Heathcock, C. H.; Henderson, M. A.; Oare, D. A.; Sanner, M. A. J.
Org. Chem. 1985, 50, 3019–3022; (d) Heathcock, C. H.; Oare, D. A. J. Org. Chem.
1985, 50, 3022–3024; (e) Corey, E. J.; Peterson, R. T. Tetrahedron Lett. 1985, 26,
5025–5028.
10. Variable-temperature 1H NMR studies of 2a showed that the conformeric ratio
increases with increasing temperature. For example, the conformeric ratio of
hydrazide 2a is 1.5 when the spectrum was recorded at ꢀ15 °C. The ratio was
increased to 1.7 (at 5 °C), to 1.9 (at 25 °C) and further to 2.3 (at 55 °C).
Interestingly, a third conformer appears when the temperature was decreased
to ꢀ55 °C.
11. (a) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990,
112, 4011–4030; (b) Stork, G.; Boeckman, R. K., Jr. J. Am. Chem. Soc. 1973, 95,
2016–2017.
12. The absolute stereochemistry of the minor (S)-a-amino diastereomer 6 was
confirmed by single crystallographic X-ray analysis.