Asymmetrie hydrocyanation of hydrazones catalyzed by in situ formed O-silylated BINOL-phosphate: A convenient access to versatile α-hydrazino acids

Article abstract of DOI:10.1021/ol9025974

Chemical Equation Presented A first organocatalytic enantioselective route was developed for the conversion of readily prepared and air stable aliphatic hydrazones to synthetically valuable α- hydrazinonitriles. This BINOL-phosphate catalyzed Strecker-type reaction (see scheme, Ar = ρ-N02_-Ph) provides a new practical and direct route to α-hydrazino acids of synthetic and biological importance. The actually active catalyst is proposed to be an in situ formed O-silylated BINOL-phosphate, thus shifting the nature of catalysis from Bronsted acid to Lewis acid organocatalysis.

Full text of DOI:10.1021/ol9025974

ORGANIC
LETTERS
2010
Vol. 12, No. 1
188-191
Asymmetric Hydrocyanation of
Hydrazones Catalyzed by in Situ
Formed O-Silylated BINOL-Phosphate: A
Convenient Access to Versatile
r-Hydrazino Acids§
Alexandru Zamfir and Svetlana B. Tsogoeva*
Department of Chemistry and Pharmacy, Chair of Organic Chemistry I, UniVersity of
Erlangen-Nuremberg, Henkestrasse 42, 91054, Erlangen, Germany
tsogoeVa@chemie.uni-erlangen.de
Received November 9, 2009
ABSTRACT
A first organocatalytic enantioselective route was developed for the conversion of readily prepared and air stable aliphatic hydrazones to
synthetically valuable r-hydrazinonitriles. This BINOL-phosphate catalyzed Strecker-type reaction (see scheme, Ar ) p-NO2-Ph) provides a
new practical and direct route to r-hydrazino acids of synthetic and biological importance. The actually active catalyst is proposed to be an
in situ formed O-silylated BINOL-phosphate, thus shifting the nature of catalysis from Brønsted acid to Lewis acid organocatalysis.
Hydrazino acids and their derivates have been identified as
inhibitors of several amino acid metabolizing enzymes1 with
potential applications as antibacterial agents1a,b or even as
anti-HIV therapeutics.1c Furthermore, R-hydrazino acids have
attracted great interest in recent years, finding applications
in the design of novel non-natural peptides.2
Strecker reaction,4 the hydrazone cyanation, which enables
direct access to R-hydrazino acids, is still a rather poorly
investigated reaction. The reported few inventions have relied
on metal based catalysts.5,6a In 2004, the group of Jacobsen
reported the first asymmetric variant of the reaction, using
(2) (a) Gu¨nther, R.; Hofmann, H.-J. J. Am. Chem. Soc. 2001, 123, 247.
(b) Hannachi, J.-C.; Vidal, J.; Mulatier, J.-C.; Collet, A. J. Org. Chem.
2004, 69, 2367. (c) Bouillon, I.; Brosse, N.; Vanderesse, R.; Jamart-Gre´goire,
B. Tetrahedron Lett. 2004, 45, 3569.
Routes by which R-hydrazino acids are obtained are still
few.3 In contrast to the hydrocyanation of imines, the
§ This paper is dedicated to Professor Rolf W. Saalfrank on the occasion
of his 70th birthday.
(3) (a) Viret, J.; Gabard, J.; Collet, A. Tetrahedron 1987, 43, 891. (b)
Bonnet, D.; Samson, F.; Rommens, C.; Gras-Masse, H.; Melnyk, O. J.
Peptide Res. 1999, 54, 270. (c) Gennari, C.; Colombo, L.; Bertolini, G.
J. Am. Chem. Soc. 1986, 108, 6394. (d) Evans, D. A.; Britton, T. C.; Dorow,
R. L.; Dellaria, J. F. J. Am. Chem. Soc. 1986, 108, 6395. (e) Trimble, L. A.;
Vederas, J. C. J. Am. Chem. Soc. 1986, 108, 6397.
(1) For selected examples, see: (a) Morley, J. S.; Payne, J. W.;
Hennessey, T. D. J. Gen. Microbiol. 1983, 129, 3701. (b) Lam, L. K. P.;
Arnold, L. D.; Kalantar, T. H.; Kelland, J. G.; Lane-Bell, P. M.; Palcic,
M. M.; Pickard, M. A.; Vederas, J. C. J. Biol. Chem. 1988, 263, 11814. (c)
Chen, S.; Chrusciel, R. A.; Nakanishi, H.; Raktabutr, A.; Johnson, M. E.;
Sato, A.; Weiner, D.; Hoxie, J.; Saragovi, H. U.; Greene, M. I.; Kahn, M.
Proc. Natl. Acad. Sci. 1992, 89, 5872.
(4) (a) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27. For reviews see:
(b) Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875. (c) Gro¨ger, H. Chem.
ReV. 2003, 103, 2795. (d) Spino, C. Angew. Chem., Int. Ed. 2004, 43, 1764.
10.1021/ol9025974  2010 American Chemical Society
Published on Web 12/01/2009

lanthanide-PYBOX complexes.6a Recently, the hydrocya-
nation of chiral oxazolidinone-derived N-acylhydrazones has
also been demonstrated.6b The development of new effective
catalytic systems for the asymmetric hydrocyanation of
hydrazones with enhanced performance and application
potential, especially to aliphatic hydrazones,6 still remains
a challenging task.
Table 1. Screening of the Catalysts
In 2004, the research groups of Akiyama7a and Terada7b
independently developed BINOL-phosphates as organocata-
lysts for enantioselective C-C bond-forming reactions. Later,
several research groups,8 notably the groups of Rueping,8a
List,8b and Antilla,8c reported the application of BINOL-
phosphates in the development of various highly enantiose-
lective transformations.
entry
catalyst
t (°C)
time (h)
yielda (%)
eeb (%)
Herein we report, to the best of our knowledge, the first
organocatalytic enantioselective hydrocyanation of hydra-
zones, employing BINOL-phosphate as organocatalyst and
which allow the conversion of aliphatic hydrazones with up
to 95% yield and 93% ee.
Our studies were commenced with the screening of chiral
phosphoric acid catalysts (R)-3a-h (Table 1), easily prepared
according to known procedures.7,8
Their catalytic efficiency was examined in the hydrocya-
nation reaction of the aliphatic hydrazone 1, which is a
readily prepared and an air/moisture stable substrate.9 Easier
to handle TMSCN (trimethylsilyl cyanide) was employed
instead of HCN. The model reaction was initially carried
out at room temperature, using dichloromethane as a solvent
and 10 mol % of the catalyst 3 (Table 1, entries 1-8).
Notably, catalyst 3a, without any substituents at the 3,3′-
position on the binaphthyl backbone, showed almost no
activity (entry 1). We assume that the observed result is due
to the poor solubility of the catalyst 3a in dichloromethane.
BINOL-phosphates 3b and 3c, bearing 3,3′-SiPh3- and 3,3′-
C6H5-groups, respectively, both catalyzed the reaction, but
with almost no enantioselectivity (Table 1, entries 2 and 3).
Variations of the substituents on the 3,3′-C6H5-groups were
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3d
3e
3e
rt
rt
rt
rt
rt
rt
rt
rt
24
24
24
24
24
24
24
24
72
72
72
traces
71
99
94
91
95
93
94
37
6 (S)
1 (S)
1 (S)
67 (R)
64 (R)
59 (R)
8 (S)
24 (R)
76 (R)
90 (R)
90 (R)
-10
-10
-20
10
11
86
45
a Yield of isolated product. b Enantioselectivities were determined by
chiral-phase HPLC analysis (Daicel Chiralpak IB) in comparison with
authentic racemic material.
examined next. Introduction of the sterically demanding
ꢀ-Naph-moiety or the electron-withdrawing NO2-group into
the para-position of the 3,3′-phenyl-moieties of BINOL-
phosphate (catalysts 3d and 3e, respectively) resulted in a
positive effect on the enantioselectivity. That is, catalysts
3d and 3e gave the most promising results under the reaction
conditions with respect to yields and enantioselectivities
(94%, 67% ee and 91%, 64% ee, respectively, entries 4 and
5). Interestingly, introduction of another and/or additional
electron-withdrawing group into the 3,3′-phenyl-moieties has
not resulted in an improvement of the enantioselectivity, but
rather led to its deterioration (Table 1, entries 6-8).
(5) (a) Manabe, K.; Oyamada, H.; Sugita, K.; Kobayashi, S. J. Org.
Chem. 1999, 64, 8054. (b) Konishi, H.; Ogawa, C.; Sugiura, M.; Kobayashi,
S. AdV. Synth. Catal. 2005, 347, 1899.
(6) (a) Keith, J. M.; Jacobsen, E. N. Org. Lett. 2004, 6, 153. (b) Ding,
H.; Friestad, G. K. Heterocycles 2006, 70, 185.
(7) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
Further optimization of reaction conditions by changing
either solvent or reaction temperature was performed with
catalysts 3d and 3e. Screening studies demonstrated that the
originally chosen dichloromethane was the optimal solvent
for the reaction (see the Supporting Information). We noticed
a substantial overall improvement of the enantioselectivity
upon lowering the reaction temperature (Table 1, entries
9-11). Intriguingly, while a slight improvement of the
enantioselectivity and a drastic reduction of the obtained yield
(37%, 76% ee, entry 9 vs. entry 4) was observed when
lowering the reaction temperature to -10 °C in the presence
of catalyst 3d, an increase in the enantiomeric excess,
keeping the accompanying loss of yield minimal, was
observed at the same reaction temperature with catalyst 3e
(86%, 90% ee, entry 10 vs. entry 5). Decreasing the
temperature further from -10 to -20 °C does not lead to
2004, 126, 5356
.
(8) (a) Rueping, M.; Azap, C.; Sugiono, E.; Theissmann, T. Synlett 2005,
2367. (b) Hofmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed.
2005, 44, 7424. (c) Rowland, G. B.; Zhang, H.; Rowland, E. B.;
Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005,
127, 15696. (d) Chen, X.-H.; Xu, X.-Y.; Liu, H.; Cun, L.-F.; Gong, L.-Z.
J. Am. Chem. Soc. 2006, 128, 14802. (e) Rowland, E. B.; Rowland, G. B.;
Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 12084. (f)
Jia, Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.-L. Angew. Chem.,
Int. Ed. 2007, 46, 5565. (g) Baudequin, C.; Zamfir, A.; Tsogoeva, S. B.
Chem. Commun. 2008, 4637. (h) Sala, G. D.; Lattanzi, A. Org. Lett. 2009,
11, 3330. For reviews of chiral phosphoric acid catalysis, see: (i) Akiyama,
T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999. (j) Connon,
S. J. Angew. Chem., Int. Ed. 2006, 45, 3909
.
(9) For examples of enantioselective additions to N-acylhydrazones as
stable and readily prepared substrates, see: (a) Ogawa, C.; Sugiura, M.;
Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 6491. (b) Berger, R.; Duff,
K.; Leigton, J. L. J. Am. Chem. Soc. 2004, 126, 5686. (c) Notte, G. T.;
Leigton, J. L. J. Am. Chem. Soc. 2008, 130, 6676. (d) Yalalov, D. A.;
Tsogoeva, S. B.; Shubina, T. E.; Martynova, I. M.; Clark, T. Angew. Chem.,
Int. Ed. 2008, 47, 6624. For a review, see: (e) Sugiura, M.; Kobayashi, S.
Angew. Chem., Int. Ed. 2005, 44, 5176.
Org. Lett., Vol. 12, No. 1, 2010
189

further improvement in the enantioselectivity, but rather to
the loss of catalytic efficiency (Table 1, entry 11 vs. entry
10).
To further improve the outcome of the reaction, we
screened several additives in CH2Cl2 at -10 °C and in the
presence of catalyst 3e (Table 2).
The para-substituent at the benzoyl group of the hydra-
zones apparently plays an important role not only concerning
selectivities, but also in enhancing the reactivity of the
hydrazone (Table 2, entries 11 and 12 vs. entry 4). When X
) H, product was only obtained in traces (entry 11).
Intriguingly, while the p-Br-substituent at the benzoyl group
led to the product formation with only 16% yield and 66%
ee (Table 2, entry 12), N-p-NO2-benzoyl-protected hydra-
zone, having encreased electrophilicity of the imino carbon,
underwent reaction to give a high yield and enantioselectivity
(95%, 93% ee, entry 4).
Table 2. Optimization of Reaction Conditions
To illustrate the scope of the reaction, a series of N-p-
NO2-benzoyl-protected aliphatic hydrazones have been syn-
thesized and subjected to these optimized reaction conditions.
To our delight, all reactions investigated can be effected in
71-93% ee, applying the catalyst at only 5 mol % loading
(Table 3). When there was a branching at the ꢀ-carbon of
catalyst
(mol %)
additive
(mol %)
yielda
(%)
entry
X
eeb (%)
1
2
3
4
5
6
7
8
9
10
5
5
5
5
5
5
5
5
5
5
5
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
H
MeOH (20)
MeOH (20)
i-PrOH (20)
t-BuOH (20)
t-BuOH (50)
t-BuOH (200)
TPM (20)
HMPA (20)
DPPO (20)
TPPO (20)
88
92
76
95
95
76
90
89
68
35
traces
16
89 (R)
93 (R)
88 (R)
93 (R)
90 (R)
89 (R)
93 (R)
91 (R)
57 (S)
59 (R)
Table 3. Scope of Substrates
10
11
12
entry
R
yielda (%)
eeb (%)
t-BuOH (20)
t-BuOH (20)
1
2
3
4
5
6
7
8c
9
(CH3)2CHCH2
CH3
CH3CH2
CH3(CH2)2
CH3(CH2)3
CH3(CH2)4
Ph(CH2)2
PhCH2
31
54
95
75
86
86
79
73
26
90
71
93
86
87
90
92
83
78
Br
66 (R)
a Yield of isolated product. b Enantiomeric excess was determined by
HPLC methods on a chiral stationary phase (Daicel Chiralpak IB). TPM )
triphenylmethanol. HMPA ) hexamethylphosphoramide. DPPO ) diphe-
nylphosphine oxide. TPPO ) triphenylphosphine oxide.
While using MeOH (20 mol %) and carrying out the
reaction with 10 and 5 mol % of catalyst 3e, respectively,
we observed that the reduction of catalyst loading has a
positive impact, increasing the yield and ee value (Table 2,
entry 1 vs. entry 2). Hence, all other additives have been
explored in the presence of 5 mol % of 3e.
CH3S(CH2)2
a Yield of isolated product. b Enantioselectivities were determined by
chiral-phase HPLC analysis (Daicel Chiralpak IB) in comparison with
authentic racemic material. The stereochemical assignment of entry 8 was
made by comparison with literature data,6a and all others were made by
analogy (see the Supporting Information). c The reaction was performed at
-5 °C, with 2.5 equiv of TMSCN.
Among the tested alcohols, t-BuOH at 20 mol % showed
the best performance (95% yield, 93% ee, entry 4). Higher
amounts of t-BuOH (e.g., 200 mol %) resulted in again
decreased yield and selectivity (Table 2, entries 5 and 6).
Interestingly, the use of TPM (triphenylmethanol) at 20 mol
% provided similarly high enantioselectivity (93% ee), albeit
slightly lower yield (90%) with respect to t-BuOH at the
same loading (Table 2, entry 7 vs. entry 4).
Besides alcohols, we screened also some Lewis bases as
additives (Table 2, entries 8-10). Interestingly, using 20 mol
% of achiral DPPO additive in combination with 3e (5 mol
%), we observed the enrichment of the opposite enantiomer
(S) of the isolated product (Table 2, entry 9), a fact that
implies that in this case the transition state structure for the
product formation might be completely different, as com-
pared to all other reactions from Table 2 (entry 9 vs. entries
1-8, 10). This potentially significant finding is under further
investigation in our laboratory and DFT calculations on the
mechanism of this catalytic system are currently underway.
the hydrazone (e.g., relatively bulky i-Bu), the product could
be isolated in high enantioselectivity, but the yield eroded
(entry 1). Hydrocyanation of hydrazones bearing different
alkyl rests (Me, Et, n-Pr, n-Bu, n-Pn) resulted in the
formation of the products in good to high yields and
enantioselectivities (Table 3, entries 2-6). The chain length
in R does not seem to affect significantly the reaction’s yield
or enantioselectivity (75-95% yields, 86-93% ee, entries
3-6).
Notably, catalyst 3e also proved to be well applicable to
hydrazones with phenylethyl and benzyl rests (entries 7 and
8). In addition, hydrazone bearing a 1-thioalkyl group
provided the desired adduct in good enantioselectivity but
with a decrease in the yield of the product (Table 3, entry 9
vs. entry 4).
Regarding the reaction mechanism, we noticed that
BINOL-phosphate 3e reacts easily with TMSCN to give
190
Org. Lett., Vol. 12, No. 1, 2010

Scheme 1. Two Plausible Mechanisms for the Strecker-Type Hydrocyanation of Hydrazones by Using BINOL-Phosphate 3e
chiral silane 3e′. New methyl group signals have been
R-hydrazino acid 5 upon refluxing 2 in 6 N HCl (Scheme
2). Notably, both the hydrolysis of the nitrile group and the
1
observed in H NMR spectra (see the SI). We also found
that the resulting O-silylated BINOL-phosphate 3e′ promoted
the hydrocyanation reaction even in the presence of 2,6-di-
tert-butyl-4-methylpyridine,10 confirming that the actual
catalyst is the in situ generated Lewis acidic 3e′. Notably,
the in situ formation of a TMS-containing compound from
BINOL-phosphate has also been reported by Antilla and co-
workers in an enantioselective desymmetrization of meso-
aziridines with use of TMS-N3.8e
Scheme 2
.
Conversion of Protected R-Hydrazinonitrile to
R-Hydrazino Acid
1
On the basis of thorough 29Si, 31P, and H NMR studies
(see the SI) we propose the following mechanism for this
reaction (Scheme 1): (1) the active catalyst 3e′ forms by
displacement of the cyanide (step A); (2) the benzoyl oxygen
becomes covalently attached to the catalyst 3e′ (steps B and
C); and (3) the resulting species undergoes attack from the
cyanide nucleophiles formed in step A, giving the silylated
product 2′ (which decomposes on silica gel to form product
2) and the reformation of 3e.
Notably, we could not confirm directly the formation of
silylhydrazone 4 in the reaction mixture. Furthermore,
measuring the 29Si NMR of two mixtures, (1) 3e + readily
prepared 4 and (2) 3e + 1 + TMSCN, we observed a signal
at about 7.36 ppm in both cases (Scheme 1 and the SI). This
observation forced us to formulate also an alternative
mechanistic pathway involving steps B′, C′, and D′ (Scheme
1). The transition state structures for both mechanistic
pathways are supposed to be additionally stabilized by
t-BuOH additive (Scheme 1).
cleavage of the N-benzoyl protecting group took place under
these reaction conditions in one step and in quantitative yield.
In summary, we have successfully developed the first
organocatalytic enantioselective hydrocyanation of aliphatic
hydrazones, providing a new convenient and direct route to
versatile R-hydrazino acids. This organocatalytic transforma-
tion provides efficient access to synthetically useful R-hy-
drazinonitriles in good to high yields and enantioselectivities
and demonstrates a rare example of the cyanation of CdN
bonds catalyzed by a Lewis acid, generated in situ from a
Brønsted acid. Further studies focusing on the full scope of
this and related systems, as well as DFT calculations on the
mechanism, are currently under investigation and will be
reported in due course.
Acknowledgment. The authors gratefully acknowledge
generous financial support from the Deutsche Forschungs-
gemeinschaft (SPP 1179 “Organocatalysis”) and BMBF.
Conversion of the hydrocyanation products to R-hy-
drazino acids proved straightforward. Thus, hydrazinoni-
trile 2 has been smoothly transformed to the corresponding
Supporting Information Available: Experimental pro-
cedures and NMR and HPLC data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) 2,6-Di-tert-butyl-4-methylpyridine has been used to differentiate
between Lewis acid and Brønsted acid catalyzed pathways: Mathieu, B.;
Ghosez, L. Tetrahedron, 2002, 58, 8219.
OL9025974
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