Catalytic asymmetric allylation of hydrazono esters in aqueous media by using ZnF2-chiral diamine

Article abstract of DOI:10.1002/anie.200351778

Chiral homoallylic hydrazines are synthesized by catalytic asymmetric allylation of acylhydrazono esters with allyltrimethoxysilane by using a chiral Zn catalyst (see picture). The reactions proceed smoothly in aqueous media to give the allylated products

Full text of DOI:10.1002/anie.200351778

Angewandte
Chemie
Lewis acid catalysts have been developed.[1] Among them,
enantioselective addition of allylmetal reagents to imino
compounds[2] provides a useful route to optically active
homoallylic amines, which are important building blocks in
organic synthesis as the g,d-double bonds of homoallylic
amines can be readily converted into many different func-
tional groups. In spite of the synthetic utility of optically
active homoallylic amines, however, examples of catalytic
asymmetric allylation of imino compounds are limited.
Recently, we reported catalytic asymmetric Mannich-type
reactions of acylhydrazono esters in H2O/THF by using a
combination of a stoichiometric amount of zinc fluoride and a
catalytic amount of a chiral diamine and TfOH (TfOH =
Trifluoromethanesulfonic acid).[3] Acylhydrazones are imine
surrogates more stable than imines even in aqueous media.[4]
Furthermore, hydrazines, such as the products in the Mannich
reaction or allylation are interesting compounds, not only
because hydrazines themselves can be used as unique building
blocks,[5] but also because, if the N N bond can be cleaved,
ꢀ
amines are obtained. Accordingly, asymmetric allylation of
hydrazones is considered to be a versatile methodology,
although there are no examples of a catalytic version.[6]
Herein, we describe the first catalytic asymmetric allylation
of acylhydrazones, especially acylhydrazono esters. The
reactions proceeded smoothly by using a chiral Zn catalyst
in aqueous media.
We focused on allyltrimethoxysilane as an allylating
agent,[7,8] because it can form a pentacoordinate silicate
easily,[9] and is a preferable reagent compared with allyltin
compounds from the standpoint of toxicity. As a chiral
[10]
catalyst system, we initially used the combination of ZnF2
(100 mol%), diamine 1 (10 mol%), and TfOH (1 mol%),
which was effective for the previous Mannich-type reaction.
The reaction of hydrazono ester 2 with allyltrimethoxysilane
was conducted in H2O/THF (1:9), to afford the corresponding
allylated product 3 in moderate yield with a relatively high ee
value (Table 1, entry 1). Interestingly, it was found that TfOH,
which was essential in the Mannich-type reaction, was not
needed in the allylation reaction (Table 1, entry 2). Moreover,
even when only 20 mol% of ZnF2 was used, the allylation
proceeded with a good yield (Table 1, entry 3), although more
than 50 mol% of ZnF2 was necessary to achieve high yields in
the Mannich-type reaction. These results indicate that a
catalytic amount of the fluoride anion is sufficient for the
allylation, while a stoichiometric amount of the fluoride anion
is needed in the Mannich-type reaction. The fluoride anion is
considered to be a key in this reaction, as Zn(OTf)2 gave no
product (Table 1, entry 5). Furthermore, it was found that 1
accelerated the reaction significantly[11] (Table 1, compare
entries 2and 6). From these results, it is concluded that the
reaction mechanism including the catalytic cycle of the
present asymmetric allylation may be different from that of
the previous Mannich-type reaction.
Asymmetric Allylation
Catalytic Asymmetric Allylation of Hydrazono
Esters in Aqueous Media by Using ZnF2–Chiral
Diamine**
Tomoaki Hamada, Kei Manabe, and Shu¯ Kobayashi*
Over the past several years, highly efficient methods for
enantioselective addition to C N double bonds by chiral
¼
[*] Prof. Dr. S. Kobayashi, T. Hamada, Prof. Dr. K. Manabe
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-0634
E-mail: skobayas@mol.f.u-tokyo.ac.jp
We speculate that this reaction proceeds with double
activation[12,13] in which Zn2+ acts as a Lewis acid to activate 2
and, at the same time, the fluoride anion acts as a Lewis base
to attack the silicon atom of allyltrimethoxysilane. In other
words, the zinc amide and (MeO)3SiF are formed first, and
subsequent hydrolysis of the amide affords allylated product 3
[**] This work was partially supported by CREST and SORST, Japan
Science and Technology Corporation (JST), and a Grant-in-Aid for
Scientific Research from Japan Society of the Promotion of Science.
T.H. thanks the JSPS fellowship for Japanese Junior Scientists.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 3927 –3930
DOI: 10.1002/anie.200351778
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3927

Communications
Table 1: Investigation of catalyst system.
mol%) was added, however, the
reaction proceeded, and 3 was
obtained in similar yield and selec-
tivity to that of the reaction with
ZnF2 (33% yield, 76% ee, compare
with Table 1, entry 2). These
results indicate that the exchange
of the fluoride anion between
Zn(OH)F and (EtO)3SiF regener-
ates ZnF2, which is active to cata-
lyze the reaction.
Entry
ZnX2
1
TfOH
[mol%]
t
[h]
Yield
[%]
ee
Next, we examined the effect of
chiral diamines on the enantiose-
lectivity in the reaction of 4-
[mol%]
[mol%]
[%][a]
1
2
3
4
5
6
ZnF2 (100)
ZnF2 (100)
ZnF2 (20)
ZnF2 (10)
Zn(OTf)2 (10)
ZnF2 (100)
10
10
10
12
12
0
1
0
0
0
0
0
20
20
90
36
36
20
46
51
77
33
0
75
76
75
74
–
methoxybenzoylhydrazone
4.[15]
Diamine 6[16] without the methoxy
group on the aromatic ring of 1
gave lower yield and ee (Table 2,
entry 2). When 7 was employed,
the yield was low, while the same ee
value was obtained as that in the
2
–
[a] The absolute configuration is assumed to be R (see [5]).
reaction with 1 (Table 2, entry 3). Diamine 8 afforded
comparable yield and ee value to 1, although 9 gave a
disappointing result (Table 2, entries 4 and 5). The above
results indicate that the MeO group in the chiral diamine
ligand plays an essential role for attaining high yields and
selectivities. Among the diamines examined in Table 2, 12
gave the highest ee value (Table 2, entry 8).
Several examples of the allylation reactions are shown in
Table 3. The reactions were conducted in the presence of
ZnF2 (20 mol%) and a chiral diamine (10 mol%) in H2O/
THF (1:9) at 08C. When 4-methoxybenzoylhydrazone
derived from methyl glyoxylate was used as a substrate, the
ee value was slightly improved (Table 3, entries 1 and 2). An
improvement in the yield was observed when the reaction of
4-ethoxybenzoylhydrazone derived from ethyl glyoxylate was
performed (Table 3, entries 3 and 4). The reactions of 2-
substituted allylsilanes gave the desired products with mod-
erate to good yields and selectivities (Table 3, entries 5 and 6).
Scheme 1. Proposed reaction mechanism.
Table 2: Effect of chiral diamines.
and Zn(OH)F (Scheme 1). It is
considered that a catalytic amount
of the fluoride anion gives a good
yield in this reaction probably
because catalytic turnover of the
fluoride anion occurs. This appa-
ꢀ
rently means that the Si F bond of
(MeO)3SiF is hydrolyzed by
Zn(OH)F, regenerating ZnF2. To
elucidate this mechanism, we
Entry
Ar
Yield [%]
ee [%]
investigated
the
ability
of
1
2
3
4
5
6
7
8
2-MeO-C6H4 (1)
C6H5 (6)
2-Me-C6H4 (7)
2,5-(MeO)2-C6H3 (8)
3,5-(MeO)2-C6H3 (9)
2-MeO-5-tBu-C6H3 (10)
1-MeO-2-naphthyl (11)
8-MeO-2-naphthyl (12)
84
29
26
81
27
99
19
59
81
48
83
76
31
64
70
84
(MeO)3SiF to regenerate ZnF2
from Zn(OH)F. In fact, the reac-
tion of 2 with allyltriethoxysilane
did not proceed in the presence of
Zn(OH)F[14] (100 mol%) and 1 (10
mol%) in H2O/THF = 1:9 at 08C
for 20 h. When (EtO)3SiF (100
3928
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Angew. Chem. Int. Ed. 2003, 42, 3927 –3930

Angewandte
Chemie
¼
Table 3: Catalytic asymmetric allylation.
asymmetric allylation to the C N
bond in aqueous media is unprece-
dented. Further investigations
involving elucidation of the
detailed reaction mechanism are
currently in progress.
Entry
R1
R2
R3
Diamine
Yield [%]
ee [%]
Received: April 30, 2003 [Z51778]
1
Me
Me
Et
Et
Et
Me
Me
Et
Et
Et
H
H
H
H
Me
Ph
1
12
1
12
1
61
60
92
81
88
62
83
86
81
85
65
78
2[a]
3
Keywords: allylation · asymmetric
.
synthesis · fluorides · zinc
4
5
6[b]
Et
Et
1
[a] 96 h. [b] 162 h.
[1] a) S. Masumoto, H. Usuda, M.
Suzuki, M. Kanai, M. Shibasaki,
J. Am. Chem. Soc. 2003, 125, 5634;
To highlight the importance of the allylated products
obtained in this reaction, 5 (84% ee) was converted into
synthetically important N-Boc (Boc = 1,1-dimethylethoxycar-
bonyl) a-amino acid 13 [Eq. (1)]; DMAP = 4-dimethylamino
pyridine. N-Boc protection of 5 afforded N-Boc hydrazine[17]
b) N. S. Josephsohn, M. L. Snapper, A. H. Hoveyda, J. Am.
Chem. Soc. 2003, 125, 4018; c) S. Kobayashi, R. Matsubara, Y.
Nakamura, H. Kitagawa, M. Sugiura, J. Am. Chem. Soc. 2003,
125, 2507; d) A. G. Wenzel, E. N. Jacobsen, J. Am. Chem. Soc.
2002, 124, 12964; e) S.-I. Murahashi, Y. Imada, T. Kawakami, K.
Harada, Y. Yonemushi, N. Tomita, J. Am. Chem. Soc. 2002, 124,
2888; f) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069, and
references therein; g) A. E. Taggi, A. M. Hafez, T. Lectka, Acc.
Chem. Res. 2003, 36, 10, and references therein.
[2] a) H. Nakamura, K. Nakamura, Y. Yamamoto, J. Am. Chem.
Soc. 1998, 120, 4242; b) D. Ferraris, T. Dudding, B. Young, W. J.
Drury III, T. Lectka, J. Org. Chem. 1999, 64, 2 168; c) K.
Nakamura, H. Nakamura, Y. Yamamoto, J. Org. Chem. 1999,
64, 2614; d) X. Fang, M. Johannsen, S. Yao, N. Gathergood, R. G.
Hazell, K. A. Jørgensen, J. Org. Chem. 1999, 64, 4844; e) T.
Gastner, H. Ishitani, R. Akiyama, S. Kobayashi, Angew. Chem.
2001, 113, 1949; Angew. Chem. Int. Ed. 2001, 40, 1896.
[3] S. Kobayashi, T. Hamada, K. Manabe, J. Am. Chem. Soc. 2002,
124, 5640.
ꢀ
in 82% yield, and the N N bond of the hydrazine was cleaved
with SmI2[18] to afford 13 in 91% yield without significant loss
of the enantiomeric purity.[19] Thus, this allylation reaction has
been shown to be a versatile method to obtain not only the
optically active a-amino ester hydrazine analogues but also
N-protected a-amino esters.
[4] a) S. Kobayashi, T. Hamada, K. Manabe, Synlett 2001, 1140;
b) H. Oyamada, S. Kobayashi, Synlett 1998, 249; c) K. Manabe,
H. Oyamada, K. Sugita, S. Kobayashi, J. Org. Chem. 1999, 64,
8054.
(DMAP = N,N-dimethyl 1,3-propanediamine). Another
important aspect of the present catalytic asymmetric allyla-
tion is that the reactions proceed smoothly in aqueous media.
Recently, organic reactions in aqueous media have attracted a
great deal of attention,[20] because water is a clean and safe
solvent. In addition, the drying of substrates and solvents by
dehydration is not required, and unique reactivities and
selectivities are often observed by using water as a solvent.
[5] Hydrazine and its Derivatives in Kirk-Othmer Encyclopedia of
Chemical Technology, Vol. 13, Wiley, New York, 4th ed., 1995.
[6] Quite recently, we have developed asymmetric allylation of
acylhydrazones with allyltrichlorosilanes using 3 equiv of chiral
sulfoxide in dichloromethane. S. Kobayashi, C. Ogawa, H.
Konishi, M. Sugiura, J. Am. Chem. Soc. 2003, 125, 6610.
[7] For early examples with allyltrimethoxysilane in organic syn-
thesis, see: a) G. Cerveau, C. Chuit, R. J. P. Corriu, C. Reye, J.
Organomet. Chem. 1987, 328, C17; b) A. Hosomi, S. Kohra, Y.
Tominaga, J. Chem. Soc. Chem. Commun. 1987, 1517; c) K. Sato,
M. Kira, H. Sakurai, J. Am. Chem. Soc. 1989, 111, 6429.
[8] For catalytic allylation by using a combination of metal fluoride
and allyltrimethoxysilane, see: a) A. Yanagisawa, H. Kageyama,
Y. Nakatsuka, K. Asakawa, Y. Matsumoto, H. Yamamoto,
Angew. Chem. 1999, 111, 3916; Angew. Chem. Int. Ed. 1999, 38,
3701; b) S. Yamasaki, K. Fujii, R. Wada, M. Kanai, M. Shibasaki,
J. Am. Chem. Soc. 2002, 124, 6536; c) N. Aoyama, T. Hamada, K.
Manabe, S. Kobayashi, Chem. Commun. 2003, 676.
ꢀ
However, catalytic asymmetric carbon carbon bond-forming
reactions in aqueous media are extremely difficult to attain,
because most chiral catalysts are not stable in the presence of
even a small amount of water.[21] However, water plays a key
role to obtain the product in the present allylation. Namely, it
was shown that the reaction of 2 with allyltrimethoxysilane
did not proceed at all in THF without water or MeOH/THF
(1:9) in the presence of ZnF2 (100 mol%) and 1 (10 mol%) at
08C for 20 h.
[9] Review: C. Chuit, R. J. P. Corriu, C. Reye, J. C. Young, Chem.
Rev. 1993, 93, 1371.
In summary, the asymmetric allylation of acylhydrazono
esters in aqueous media has been achieved by using a catalytic
amount of ZnF2 and a chiral diamine ligand. This reaction is
the first example of catalytic asymmetric allylation of
hydrazones. Furthermore, it should be noted that the catalytic
[10] The results of the reaction of 2 with allyltrimethoxysilane in the
presence of several metal fluorides (10 mol%) and 1 (12mol%)
in H2O/THF (1:9) at 08C for 48 h: ZnF2, 40% yield, 73% ee;
CdF2, 49% yield, 5% ee; AgF, 93% yield, 1% ee (20 h); No
reaction occurred with CuF2 and ScF3.
Angew. Chem. Int. Ed. 2003, 42, 3927 –3930
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Communications
[11] Quite recently, we reported that the ligand acceleration was
observed in the allylation of carbonyl compounds by using
allyltrimethoxysilane in aqueous media. See reference [8c].
[12] For a similar type of double activation, see: a) S. Kobayashi, H.
Uchiro, I. Shiina, T. Mukaiyama, J. Am. Chem. Soc. 1991, 113,
4247; b) D. R. Gauthier, Jr., E. M. Carreira, Angew. Chem. 1996,
108, 2 52 1A; ngew. Chem. Int. Ed. Engl. 1996, 35, 2363.
[13] Diastereoselective allylsilane additions to acylhydrazones with
double activation by fluoride and In(OTf)3 have been reported.
G. K. Friestad, H. Ding, Angew. Chem. 2001, 113, 4623; Angew.
Chem. Int. Ed. 2001, 40, 4491.
[14] O. K. Srivastava, E. A. Secco, Can. J. Chem. 1967, 45, 579.
[15] 4-Methoxybenzoylhydrazone derived from ethyl glyoxylate
afforded higher yield and ee (69% yield, 81% ee) than
benzoylhydrazone did (51% yield, 76% ee) in the reaction
with allyltrimethoxysilane in the presence of ZnF2 (100 mol%)
and 1 (10 mol%) in H2O/THF (1:9) at 08C for 20 h.
[16] A. Alexaxis, P. Mangeney, Advanced Asymmetric Synthesis (Ed.:
G. R. Stephenson), Chapman & Hall, London, 1996, p. 93, and
references therein.
[17] This compound was highly crystalline, and one recrystallization
from ethyl acetate/hexane afforded the enantiomerically almost
pure material (from 70% ee to 98% ee).
[18] M. J. Burk, J. E. Feaster, J. Am. Chem. Soc. 1992, 114, 6266.
[19] The absolute configuration and the ee of 13 were determined by
HPLC analysis after 13 had been converted to the corresponding
N-tosylate (81% ee), which was reported by Jørgensen et al. See
reference [2d].
[20] a) Organic Synthesis in Water (Ed.: P. A. Grieco), Blackie
Academic and Professional, London, 1998; b) C.-J. Li, T.-H.
Chan, Organic Reactions in Aqueous Media, Wiley, New York,
1997.
[21] a) D. Sinou, Adv. Synth. Catal. 2002, 344, 221; b) U. M.
Lindstrꢀm, Chem. Rev. 2002, 102, 2751; c) K. Manabe, S.
Kobayashi, Chem. Eur. J. 2002, 8, 4094.
3930
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