Catalytic asymmetric Mannich-type reactions activated by ZnF2 chiral diamine in aqueous media

Article abstract of DOI:10.1002/chem.200500673

Catalytic asymmetric Mannich-type reactions of an α-hydrazono ester with silicon enolates in aqueous media have been developed by using ZnF ₂ and chiral diamines as catalysts. In these reactions, both Zn ²⁺ and a fluoride anion were necessary to achieve high yields and enantioselectivities. suggesting a double activation mechanism, in which Zn ²⁺ activates the α-hydrazono ester and the fluoride anion simultaneously activates the silicon enolate. When chiral diamine ligands bearing methoxy-substituted aromatic rings were employed, the reactions in aqueous THF were markedly accelerated. Furthermore, the use of these diamines facilitated the asymmetric Mannich-type reactions in water without any organic cosolvents. It is noteworthy that either syn or anti adducts were stereospecifically obtained from (E) or (Z)-silicon enolates, respectively. Interestingly, these reactions proceeded smoothly only in the presence of water. On the basis of several experimental results, it can be concluded that the reaction mechanism is likely to be a fluoride-catalyzed one, in which the ZnF₂ chiral diamine complex is regenerated from the Me₃SiF formed during the reaction.

Full text of DOI:10.1002/chem.200500673

FULL PAPER
DOI: 10.1002/chem.200500673
Catalytic Asymmetric Mannich-Type Reactions Activated by ZnF2 Chiral
Diamine in Aqueous Media
Tomoaki Hamada, Kei Manabe, and Shu Kobayashi*[a]
¯
Abstract: Catalytic asymmetric Man-
nich-type reactions of an a-hydrazono
ester with silicon enolates in aqueous
media have been developed by using
ZnF2 and chiral diamines as catalysts.
In these reactions, both Zn2+ and a
fluoride anion were necessary to ach-
ieve high yields and enantioselectivi-
gands bearing methoxy-substituted aro-
matic rings were employed, the reac-
tions in aqueous THF were markedly
accelerated. Furthermore, the use of
these diamines facilitated the asymmet-
ric Mannich-type reactions in water
without any organic cosolvents. It is
noteworthy that either syn or anti ad-
ducts were stereospecifically obtained
from (E)- or (Z)-silicon enolates, re-
spectively. Interestingly, these reactions
proceeded smoothly only in the pres-
ence of water. On the basis of several
experimental results, it can be conclud-
ed that the reaction mechanism is
likely to be a fluoride-catalyzed one, in
which the ZnF2 chiral diamine complex
is regenerated from the Me3SiF formed
during the reaction.
ties, suggesting
a double activation
mechanism, in which Zn2+ activates
the a-hydrazono ester and the fluoride
anion simultaneously activates the sili-
con enolate. When chiral diamine li-
Keywords:
aqueous media
·
asymmetric catalysis · Lewis acids ·
Mannich reaction · water chemistry
Introduction
with organic solvents, and unique reactivity and selectivity,
which cannot be obtained in organic solvents, are often ob-
served in aqueous reactions. Moreover, from a synthetic
viewpoint, these reactions have several advantages com-
pared with reactions under anhydrous conditions, which are
required in many conventional synthetic procedures. For ex-
ample, while it is necessary to dry solvents and substrates
vigorously before use for many reactions in dry organic sol-
vents, such drying is unnecessary for reactions in aqueous
media. We and others have recently reported several exam-
ples of catalytic asymmetric carbon–carbon bond-forming
reactions catalyzed by water-compatible Lewis acids[4] in
aqueous media.[5] However, it has been difficult to achieve
catalytic asymmetric Mannich-type reactions in aqueous
media, and no examples had been reported before our first
report.[6] In 2002, we reported the first catalytic asymmetric
Mannich-type reactions of an a-hydrazono ester with silicon
enolates in H2O/THF by using a combination of a stoichio-
metric amount of zinc fluoride and a catalytic amount of a
chiral diamine and trifluoromethanesulfonic acid (TfOH).[7]
Furthermore, we also found that by using ZnF2, a cationic
surfactant, and a chiral diamine, containing MeO groups on
its aromatic rings, in water without any organic cosolvents,
the above Mannich-type reactions proceeded to give high
yields and stereoselectivities.[8] Herein we describe the full
details of our studies on these Mannich-type reactions.
Asymmetric Mannich reactions provide useful routes for the
synthesis of optically active b-amino ketones and esters,
which are versatile chiral building blocks for the preparation
of many nitrogen-containing biologically important com-
pounds.[1] In the past few years, various enantioselective
Mannich reactions have been developed. Among them, cata-
lytic enantioselective additions of silicon enolates to imines
have been elaborated into one of the most powerful and ef-
ficient asymmetric Mannich-type reactions, not least because
silicon enolates can be prepared regio- and stereoselectively
from various carbonyl compounds.[2]
In recent years, organic reactions in aqueous media have
attracted a great deal of attention.[3] Water is no doubt
cheap, safe, and environmentally friendly when compared
[a] T. Hamada, Dr. K. Manabe, Prof. Dr. S. Kobayashi
Graduate School of Pharmaceutical Sciences
The University of Tokyo, The HFRE Division, ERATO
Japan Science and Technology Agency (JST)
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+81)3-5684-0634
E-mail: skobayas@mol.f.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2006, 12, 1205 – 1215
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Results and Discussion
or ZnCl2 were employed (entries 3 and 4), it was remarkable
to find that high enantioselectivity was obtained when ZnF2
was used (entry 5).[17] Although the yield was low, this high
ee prompted us to investigate the ZnF2-mediated reaction
further.
Several reaction conditions were examined in order to im-
prove the yield (Table 2). Interestingly, a stoichiometric
amount of ZnF2 led to a low yield, due to rapid hydrolysis
Imines are usually used as electrophiles in Mannich reac-
tions.[9] Although some imines are easily prepared from the
corresponding carbonyl compounds and amines, most of
them necessitate dehydrative preparation by azeotropic dis-
tillation or with dehydrating agents. In addition, imines are
generally difficult to purify by distillation or column chro-
matography and are unstable when stored for long periods.
In contrast, N-acylhydrazones[10] are readily prepared from
aldehydes and N-acylhydrazines, and are often isolated as
much more stable crystals than the corresponding imines.
Recently, we found that such electrophiles reacted smoothly
with several nucleophiles in the presence of a catalytic
amount of a Lewis acid.[11,12] It should be noted that hydra-
zines, such as the products of the Mannich reaction or allyla-
tion, are interesting compounds, not only because hydra-
zines themselves can be used as unique building blocks,[13]
Table 2. Several reaction conditions.
Entry
ZnF2 [mol%]
100
Yield [%]
ee [%]
1[a]
2100
3
19
92
89
34
17
34
90
93
50
30
10
92
89
85
–
4
À
but also because N N bond cleavage would lead to amine
5[b]
6[c]
products. Furthermore, N-acylhydrazones have been suc-
cessfully used for Sc(OTf)3-catalyzed allylation reactions in
aqueous THF,[14] indicating that they can be regarded as
imine surrogates, stable even in aqueous media. Therefore,
we decided to examine the catalytic asymmetric Mannich-
type reactions of N-acylhydrazone with silicon enolates in
aqueous media.
100
[a] Without TfOH. [b] 143 h. [c] Without 1a.
of 3, and high enantioselectivity was maintained in spite of
the use of a large excess of ZnF2, relative to the chiral dia-
mine (entry 1). Next, we examined the effect of additives. It
was exciting to find that 1 mol% of TfOH (Tf=triflate) sig-
nificantly suppressed the hydrolysis of 3, increasing the yield
dramatically (entry 2versus 1). The same level of enantiose-
lectivity was obtained when the amount of ZnF2 was low-
ered to 50 mol% (entry 3), although the yield was decreased
when the amount of ZnF2 was reduced further (entries 4
and 5). It should be noted that the presence of 1a signifi-
cantly improved the yield (entry 2versus 6), and that this
ligand effect is key to the success of the present catalytic
system.[18]
For the catalytic asymmetric Mannich-type reaction of 2
in aqueous THF with ZnF2, 1a, and TfOH, other silyl enol
ethers were tested (Table 3). Silyl enol ethers derived from
aromatic ketones gave the desired products, mostly, in high
yields and with high enantioselectivities (entries 1–4). When
using an aliphatic ketone (entry 5), high selectivity was also
obtained, but the yield of the reaction was low. Further-
more, in entries 4 and 5, the syn adducts were obtained with
high diastereo- and enantioselectivities.
An important feature in the design of a chiral ligand for
Lewis acid mediated asymmetric reactions in aqueous media
is its binding affinity to metal cations. We noted the strong
binding ability of ethylenediamine to Zn2+ ion,[15] and decid-
ed to test various chiral analogues of ethylenediamine for
use in catalytic asymmetric Mannich-type reactions in aque-
ous media. After many trials, we found that the combination
of chiral diamine 1a[16] and Zn(OTf)2 gave a low but signifi-
cant enantiomeric excess (ee, 24%) in the reaction of a-hy-
drazono ester 2 with silyl enol ether 3 in H2O/THF 1:9
(Table 1, entry 1). The effect of the counteranions of Zn2+
was then examined, and it was found that the same level of
enantioselectivity was obtained when Zn(ClO4)2 was used
(entry 2). While the reaction hardly proceeded when ZnBr2
Table 1. Effect of counterions.
While the first catalytic, diastereo- and enantioselective
Mannich-type reactions in aqueous media had been devel-
oped, there were several problems that remained to be
solved. These were as follows: 1) TfOH is essential to
obtain high yields, 2) the reaction time is long, and 3) more
than 50 mol% of ZnF2 is necessary to complete the reac-
tion. Accordingly, it was clear that this Mannich-type reac-
tion left much room for improvement; therefore, we decided
Entry
ZnX2
Yield [%]
ee [%]
1
Zn(OTf)2
2
1
2
4
to investigate this reaction further.
2Zn(ClO
4)2·6H2O
2
trace
0
5
2
6
3
4
5
ZnBr2
ZnCl2
ZnF2
–
–
86
Effect of additives: As mentioned above, addition of TfOH
was essential for obtaining high yields in the reaction. We
7
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Mannich-Type Reactions
FULL PAPER
Table 3. Catalytic asymmetric Mannich-type reactions.
Entry
R1
R2
t [h]
Product
Yield [%]
syn/anti
ee [%]
1
H
4-Me-C6H4
120
72
96
72
420
4b
4c
4d
6a
6b
82–
63
88
91
30
91
–
–
96:4
90:10
2H
3[a]
4[a,b]
5[a,c]
4-MeO-C
H
Me
6H4
4-Cl-C6H4
Ph
91
89
88
91
Me
iPr
[a] 100 mol% of ZnF2 and 20 mol% of 1a were used. [b] E/Z <2:>98. [c] E/Z 4:96.
searched for effective additives other than TfOH in the re-
action of 2 with 3 in aqueous THF. First, we tested several
acids; however, no marked effect was observed. Interesting-
ly, the reactions utilizing metal triflates as additives pro-
duced better yields than the reaction conducted without any
additives (Table 4, entries 3–6 versus 1). In particular, alkali
Table 5. Effect of chiral diamines 1.
Table 4. Effect of metal triflates.
Entry
Ar (diamine)
Yield [%]
ee [%]
1
Ph (1a)
2
5
-Me-C
22
3
4
5
6
6H4 (1b)
2-MeO-C6H4 (1c)
2-EtO-C6H4 (1d)
2,5-(MeO)2-C6H3 (1e)
3,5-(MeO)2-C6H3 (1 f)
3-MeO-2-naphthyl (1g)
2-MeO-4-tBu-C6H3 (1h)
2-MeO-5-tBu-C6H3 (1i)
2-MeO-5-tBu-C6H3 (1i)
2
3
83
35
84
19
43
53
72
81
93
94
93
86
91
92
96
96
Entry
Additive (mol%)
–
Yield [%]
ee [%]
1
2
1
90
7
8
2TfOH (1)
57
90
69
73
68
48
3
4
5
6
LiOTf (1)
NaOTf (1)
KOTf (1)
90
92
91
89
9
10[a]
Zn(OTf)2 (0.5)
[a] Without NaOTf.
metal triflates produced higher yields than TfOH, and the
best yield was obtained when NaOTf was employed
(entry 4). These results indicate that TfOH acts not as a
protic acid, but as a triflate anion source. It is likely that one
fluoride anion of ZnF2 is replaced with a triflate anion, thus
generating ZnF(OTf) in the reaction system. It is noted that
ZnF(OTf) must be more Lewis acidic than ZnF2.
the aromatic rings of chiral diamine ligands plays an essen-
tial role in producing the high yields and selectivities ob-
served in these reactions.[19] When 1i was employed, Man-
nich adduct (R)-4a was obtained in a satisfactory yield, and
with the greatest enantioselectivity observed for the dia-
mines examined in Table 5 (entry 9). Furthermore, it is
worth noting that the reaction with 1i proceeded to produce
a high yield, even in the absence of NaOTf (entry 10).
One of the interesting features of the present Mannich-
type reactions is that high enantioselectivity can be obtained
in spite of the use of a large excess of ZnF2 with respect to
the chiral diamine. Thus, we investigated the use of reduced
amounts of diamine 1i in the reaction of 2 with 3 (3.0 equiv)
and ZnF2 (100 mol%). It was found that 1i could be re-
duced to only 2mol% without significant loss of enantiose-
lectivity (87% yield, 94% ee, 20 h).
Effect of chiral diamines: Next, we examined the effect of
chiral diamines on the rate of the Mannich-type reaction.
Indeed, various chiral diamines derived from (1R,2R)-1,2-di-
phenylethylenediamine were tested in the reaction of 2 with
3 (1.5 equiv) under the conditions shown in Table 5. It was
exciting to find that diamine 1c, which contains ortho-MeO
groups on its aromatic rings, afforded a much higher yield
than 1a (entry 3), although the corresponding ortho-tolyl
ligand 1b gave a comparable yield to 1a (entry 2). To our
further delight, 1c produced greater enantioselectivity than
1a. Moreover, it was found that the use of 1e resulted in
both a high yield and ee (entry 5), whereas 1 f gave a compa-
rable yield and ee to 1a (entry 6). The above results demon-
strate that the MeO groups located at the ortho position on
We also examined the effect of the diamines in the reac-
tion with propiophenone-derived silyl enol ether 5 (Table 6).
As with the reaction using 3, both diamines 1c and 1i were
found to be effective in accelerating the reaction. In contrast
to when 3 was employed, however, 1c produced greater
enantioselectivity than 1i (entry 1 versus 2). It is further
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S. Kobayashi et al.
Table 6. Effect of chiral diamines 2.
ucts. We suppose that this interesting phenomenon is due to
the different steric influences of the Et and StBu groups.[21]
Reduction of the ZnF2 loading: As mentioned earlier, one
of problems in the present reactions is that more than
50 mol% of ZnF2 is required to obtain high yields. Catalytic
use of the fluoride anion presents a significant challenge due
to the great strength of the silicon–fluorine bond
(592kJmol À1) of Me3SiF, which was generated by the activa-
tion of the silicon enolate with the fluoride anion of ZnF2.
However, the marked acceleration of the reaction observed
when using diamine 1c or 1i prompted us to re-examine the
reduction of the ZnF2 loading by using these diamines.
Entry
Diamine
t [h]
Yield [%]
syn/anti
ee[a] [%]
1
1i
1c
1c
6
16
2
6296:4
87
0
86
95:5
89
2
92
91:9
3[b]
94
[a] ee of syn adduct. [b] Without NaOTf.
It was exciting to find that when 20 mol% of ZnF2 was
used in the reaction of 2 with 3 and diamine 1i, a compara-
ble yield and enantioselectivity, compared to that found
with 100 mol% of ZnF2 were obtained (Table 8, entry 2
versus 1). The use of 1a instead of 1i resulted in a very low
yield, due to the rapid hydrolysis of 3 (entry 3). Further-
more, when NaOTf (1 mol%) was added to this reaction,
noted that the reaction using 1c proceeded to afford 6a in a
high yield with high diastereo- and enantioselectivities in
the absence of NaOTf (entry 3).
Stereospecificities: Diastereoselection in this Mannich-type
reaction is of great interest not only from a synthetic point
of view, but also from a mecha-
nistic aspect. In fact, the Z silyl
Table 7. Stereospecific, asymmetric Mannich-type reactions.
enol ethers derived from pro-
piophenone and 2-methyl-3-
pentanone afforded high syn se-
lectivities, as shown in Tables 3
and 6. Thus, we took an interest
in the relationship between the
configurations of the silicon Entry
enolates and the relative config-
Enolate
t [h]
Product
Yield [%]
80
syn/anti
ee [%] (syn/anti)
1
8
6c
97:3
87:27[b]
urations of the major products.
The reaction of 2 with the (Z)-
ketene silyl acetal (Z)-7, de-
rived from (S)-tert-butyl thio-
propionate, and 1c afforded the
corresponding adduct with high
syn selectivity and good ee
(Table 7, entry 1). In this reac-
tion, the addition of NaOTf was
[b]
2[c]
3
(Z)-7[a]
8
6c
6c
3297:3
22
4
86:2
20
27:73
65:85[b]
88:91
4
5
72
72
6d
6d
98
65
13:87
77:23
86:81
essential for obtaining a high
yield (entry 2). To our surprise,
[a] E/Z 3:97. [b] (2R,3R):(2R,3S). [c] Without NaOTf. [d] E/Z 98:2. [e] E/Z 76:24. [f] E/Z 1:99.
the anti adduct was obtained
with good diastereoselectivity
Table 8. Reduction of ZnF2 loading.
from the reaction with the (E)-7 under the same conditions
as those of entry 1 (entry 3). We then examined the reac-
tions with the (E)- and (Z)-silyl enol ethers derived from 3-
pentanone, (E)-8 and (Z)-8. When (E)-8 was employed, the
anti adduct was obtained selectively with high diastereo-
and enantioselectivity (entry 4). In contrast, (Z)-8 afforded
good syn selectivity (entry 5). Good stereospecificity was ob-
served in the reactions of both 7 and 8. It is noted that such
stereospecificities are rare in catalytic asymmetric Mannich-
type reactions,[20] and that both syn and anti adducts can be
easily prepared by simply changing the geometry of the sili-
con enolates. Furthermore, 7 and 8 afforded the opposite re-
sults with regards to the relationships between the geometry
of the enolates and the relative configurations of the prod-
Entry Enolate ZnF2 [mol%] Diamine Yield [%] syn/anti ee [%]
1
2
3
3
3
3
3
3
5
100
20
20
20
20
20
1i
1i
1a
1a
1i
94
94
13
25
82–
95
–
–
–
–
96
96
87
79
4[a]
5[b,c]
6
96
94:6
1c
94[d]
[a] NaOTf (1 mol%) was added. t=72h. [b] Enolate (1.5 equiv).
[c] NaOTf (4 mol%) was added. [d] ee of syn adduct.
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Mannich-Type Reactions
FULL PAPER
the yield produced was still low, despite the fact that large
amounts of silicon enolate 3 remained after the reaction had
been completed (entry 4). These results clearly indicate that
1i permits catalytic turnover of the fluoride anion. In addi-
tion, 20 mol% of ZnF2 was sufficient to obtain both a high
yield and stereoselectivity in the reaction of 5 with diamine
1c (entry 6). Therefore, diamines containing ortho-methoxy
groups were effective not only for the acceleration of the re-
action, but also for the reduction of the ZnF2 loading. It is
worth noting that the use of these diamines overcame the
problems (1–3, see above) of the reaction when using 1a.
On the other hand, it was found that NaOTf suppressed
the hydrolysis of the silicon enolates for the reactions in-
volving diamines 1i and 1a, and that the reaction proceeded
smoothly with a reduced amount of the silicon enolate, with-
out a significant decrease in the yield. In fact, when
1.5 equivalents of 3 were employed, satisfactory results were
obtained (entry 5).
Scheme 1. Proposed catalytic cycle (fluoride-catalyzed mechanism).
hydrolysis of C affords the Mannich adduct and ZnF(OH)–
diamine complex D. It is considered that a catalytic amount
of the fluoride anion provides a high yield of the product
for this reaction, probably because catalytic turnover of the
fluoride anion occurs. This apparently means that D reacts
with Me3SiF, regenerating ZnF2 diamine complex A for the
next catalytic cycle (fluoride-catalyzed mechanism[25,26]).
The double activation mechanism was partly supported by
the following experiments. The reaction of 2 with 3 by using
Zn(OTf)2 (10 mol%) and 1i (12mol%) gave a much lower
ee than the reaction with ZnF2 and 1i (Table 10, entry 3
Effect of water: It was also revealed that the present Man-
nich-type reactions proceeded only in aqueous media.
Indeed, the reaction of 2 with 3 in anhydrous THF produced
only a trace amount of the product (Table 9, entry 2), and
Table 9. Effect of water.
Entry
Solvent
H2O [equiv]
Yield [%]
94
ee [%][a]
Table 10. Investigations into the proposed double activation mechanism
and catalyst turnover step.
1
H2O/THF 1:9
–
96
2THF
–
trace
nd
3
4
5
6
THF
THF
MeOH/THF 1:9
DMF
1
5
–
–
trace
10
0
nd
95
–
0
–
[a] nd=not detected.
Entry
ZnX2 (mol%)
Additive (mol%)
Yield [%]
ee [%]
1
ZnF2(100)
2 (20)
Zn(OTf)2 (10)
–
ZnF(OH) (100)
ZnF(OH) (100)
–
–
–
94
94
16
0
7
90
96
96
20
–
94
96
2ZnF
3[a]
4[b]
5
no product was obtained in anhydrous DMF (entry 6).
When one or five equivalents of water were added to the re-
action in THF, the yield was still very low (entries 3 and 4).
These results evidently indicate that a large excess of water
is required to obtain a satisfactory yield. In addition, the re-
action in MeOH/THF 1:9 did not proceed at all (entry 5).
Accordingly, it is not likely that water merely acts as a
proton source. At this stage, we speculate that water facili-
tates the dissociation of the fluoride anion from Zn2+, there-
by enhancing the catalytic activity of the chiral ZnF2 com-
plex.
TBAF (20)
–
Me3SiF (100)
6
[a] 1i (12mol%). [b] Without 1i.
versus 2). When tetrabutylammonium fluoride (TBAF) was
employed as a catalyst, no product was obtained due to the
rapid hydrolysis of 3 (entry 4). These results indicate that
both Zn2+ and the fluoride anion are required to gain high
yields and enantioselectivity.
Reaction mechanism: A proposed catalytic cycle for this
Mannich-type reaction is depicted in Scheme 1. This reac-
tion is likely to proceed with double activation, in which
Zn2+ acts as a Lewis acid to activate 2, whilst at the same
time, the fluoride anion acts as a Lewis base to attack the
silicon atom of the silicon enolate B.[22–24] In other words,
zinc amide C and Me3SiF are formed first, and subsequent
To confirm the catalytic turnover step (from D to A in
Scheme 1), we investigated the ability of Me3SiF to regener-
ate ZnF2 from ZnF(OH). First, it was confirmed that the re-
action of 2 with 3 proceeded very sluggishly in the presence
of ZnF(OH)[27] (100 mol%) and 1i (10 mol%, entry 5).
When Me3SiF (100 mol%) was added, however, the reaction
proceeded well, and (R)-4a was obtained with a similar
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S. Kobayashi et al.
yield and selectivity to that obtained for the reaction with
ZnF2 (entry 6 versus 1). These results indicate that the ex-
change of the fluoride anion between ZnF(OH) and Me3SiF
regenerates ZnF2, which is a requirement for effective catal-
ysis of this reaction.
À
Next, we investigated the stability of the Si F bond of
Me3SiF in aqueous THF. The hydrolysis of Me3SiF in D2O/
[D8]THF 1:9 was followed by 1H NMR spectroscopy. The
hydrolysis of Me3SiF proceeded[28] to afford Me3SiOD, after
25 h, in a quite low but significant yield (2.5%) that did not
change even after 69 h (Table 11). Moreover, when
Table 11. Hydrolysis of Me3SiF.[a]
Figure 1. ORTEP drawing of the [ZnCl2-1c] moiety in the X-ray crystal
structure of [ZnCl2-1c]·CH2Cl2 (all hydrogen atoms, except the NH
proton and those in solvent of crystallization have been omitted for clari-
ty).
Entry
t [h]
Me3SiOD[b] [%]
Me3SiF[b] [%]
1
2
3
0.5
25
69
0.6
2.5
2.5
93
91
89
[a] A small amount of (Me3Si)2O was observed in all cases (approxi-
mately 0.2% yield). [b] Determined by 1H NMR spectroscopy (internal
standard=benzotrifluoride or 4-fluorotoluene).
between the MeO groups of 1c and Zn2+ were not ob-
served, a finding contrary to our initial expectation. Instead,
the MeO groups proved to be located near the amino
groups, suggesting hydrogen bonding between the MeO
oxygen atom and the amino proton (N1···O1=3.028 Š;
N2···O2=3.141 Š). On the basis of this X-ray crystal struc-
ture, and that 1a and 1c produced similar enantioselectivi-
ties (Table 5), it is proposed that the MeO groups of the dia-
mine do not coordinate to Zn2+, even in the transition
states for the asymmetric reactions.[29]
Me3SiOH was treated with ZnF2 (100 mol%) and chiral dia-
mine 1i (10 mol%), Me3SiF was obtained in 60% yield
[Eq. (1)], indicating the existence of the reverse reaction
(from A to D in Scheme 1).
To gain an insight into the structure of the catalyst in a re-
action solution, we examined the influence of the optical
purity of the chiral diamine on the enantioselectivity of the
product in the reaction of 2 with 3. When the enantiomeric
excesses of Mannich adduct (R)-4a were monitored as a
function of the ee of (R,R)-1i, a linear correlation was ob-
served (Figure 2). This result implies that the active catalyst
À
These results show that the thermodynamically stable Si
F bond is kinetically labile in aqueous THF on the timescale
of the Mannich-type reaction, and that the catalytic turnover
of the fluoride anion can occur. The results shown in
Table 11 and Equation (1) suggest that the equilibrium of
the catalytic turnover step (D to A) lies in favor of D. How-
ever, the strong Si–F interaction, resulting in the formation
of B (Scheme 1), could be the driving force that facilitates
the catalytic turnover, and indeed, the presence of a catalyt-
ic amount of the fluoride anion afforded the Mannich
adduct in high yield.
We next turned our attention to the structure of the chiral
catalyst to clarify the origin of the unique stereoselectivities.
Although crystals of the [ZnF2-1c] complex, suitable for
XRD analysis, could not be prepared due to its low solubili-
ty, a complex suitable for X-ray analysis was obtained from
ZnCl2 and 1c (Figure 1). In this X-ray structure, as expected,
the complex exhibits a tetrahedral geometry, and the asym-
metric information carried by the two asymmetric carbon
atoms on the ligand backbone is transferred to the two
benzyl moieties on the nitrogen atoms upon coordination to
the metal; this would play a key role in the production of
high stereoselectivity in catalysis. In addition, interactions
Figure 2. Plot of % ee for product (R)-4 versus % ee for diamine (R,R)-
1i.
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Mannich-Type Reactions
FULL PAPER
is the monomeric [ZnF2-1i] complex, which has a similar
structure to the ZnCl2 complex shown in Figure 1.
our disappointment, however, reduction of the ZnF2 loading
resulted in a low yield, because the hydrolysis of 3 became
predominant over the desired Mannich-type reaction
(entry 3).
We next turned our attention to the enantio- and diaster-
eoselective reactions of the silyl enol ethers derived from a-
monosubstituted carbonyl compounds. Unexpectedly, the re-
actions of 5 proceeded sluggishly, in spite of the fact that a
large amount of 5 remained after the reaction had been
completed (Table 13, entries 1 and 2). In an attempt to ac-
celerate the reaction, the addition of surfactants was then in-
As mentioned above, marked acceleration of the reaction
was observed when using diamine 1c or 1i. The origin of
this acceleration was assumed to be explained by the follow-
ing: The intramolecular hydrogen-bonding effect (see
above) or the electron-donating effect of the MeO groups
seems to increase the basicity of the amino nitrogen
atoms[30] that coordinate to Zn2+. Therefore, the use of
these diamines could facilitate the dissociation of the fluo-
ride anion from ZnF2, leading to the improved catalytic ac-
tivity of chiral ZnF2 complexes.
Table 13. Catalytic asymmetric Mannich-type reactions of 5 in water.
Catalytic asymmetric Mannich-type reactions in water:
While it was revealed that the Mannich-type reactions in
aqueous THF produce high yields and stereoselectivities in
the presence of catalytic amounts of ZnF2 and a chiral dia-
mine, it is more desirable to use only water as a solvent.
However, catalytic asymmetric carbon–carbon bond-forming
reactions in water without any organic cosolvents, are diffi-
cult to achieve due to the low solubility of most catalysts
and substrates in water, although some examples have been
reported recently.[5] Therefore, we decided to apply the pres-
ent Mannich-type reaction in aqueous THF to the reaction
in water.
It was surprising to find that the reaction of 2 with 3 in
water (direct application of the catalytic system that was
most effective in H2O/THF 1:9) produced satisfactory re-
sults. Indeed, when ZnF2 (100 mol%) and 1i (10 mol%)
were employed, Mannich adduct 4a was obtained in 91%
yield with 95% ee (Table 12, entry 1). In contrast, diamine
Entry
1
2NaOTf (1)
3
Additive (mol%)
–
t [h]
Yield [%]
6
syn/anti
ee [%, syn]
20
91:9
92
94
0
2 8
87:13
SDS (5)
Triton X-405 (5)
CTAB(5)
CTAB(2)
CTAB(5)
CTAB(5)
TBAB(5)
TBAB(5)
20
20
20
20
5
5
5
20
9
10
94
93
91:9
91:9
94:6
94:6
94:6
78
93
97
96
96
4
5
6
7
60
8[a]
9
3295:5
<289:11
24
95
92
10[b]
89:11
92
[a] Neat conditions. [b] The solvent system H2O/CH2Cl2 (1:1) was used.
vestigated.[31] While sodium dodecyl sulfate (SDS) or Triton
X-405 was not effective (entries 3 and 4), it was remarkable
that cetyltrimethylammonium bromide (CTAB) produced
an excellent yield, and that it also improved the enantiomer-
ic excess slightly (entry 5). It is worth noting that a cationic
surfactant is effective in this reaction,[32,33] while an anionic
surfactant has been reported to work well in Lewis acid cat-
alyzed aldol reactions.[34] Moreover, 2mol% of CTAB was
sufficient for producing high yields and enantioselectivities
(entry 6). The reaction under neat conditions gave a lower
yield than that in water, suggesting the importance of water
(entry 7 versus 8).[35] It was also noted that tetrabutylammo-
nium bromide (TBAB) was ineffective not only in water,
but also under biphasic conditions, which are often used for
phase-transfer catalysis[36] (entries 9 and 10).
Finally, we reduced the amount of ZnF2 to 10 mol% for
several reactions of silyl enol ethers derived from a-mono-
substituted carbonyl compounds, although unsatisfactory re-
sults were obtained in the case of 3. To our delight, the reac-
tion with 5 proceeded to give the desired adduct 6 in high
yield with high stereoselectivity, even when the amount of
1c was reduced to 5 mol% (Table 14, entry 1). However, a
further decrease in the ZnF2 loading resulted in a moderate
yield (entry 2). When the silyl enol ethers derived from 4’-
methoxypropiophenone and butyrophenone were employed,
high yields and high diastereo- and enantioselectivities were
Table 12. Catalytic asymmetric Mannich-type reactions of the silyl enol
ethers, derived from acetophenone analogues, in water.
Entry Ar
Diamine t [h] Product Yield [%] ee [%]
1
Ph, 3
Ph, 3
Ph, 3
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
1i
1a
1i
1i
1i
1i
20
72
20
20
20
36
4a
4a
4a
4b
4c
4d
91
44
35
91
93
94
95
95
96
95
91
95
2[a]
3[b]
4
5
6
[a] NaOTf (1 mol%) was added. [b] ZnF2 (10 mol%).
1a produced a moderate yield, even after 72h and despite
the addition of NaOTf (entry 2). Significantly, from these re-
sults, it is apparent that the reaction of 2 with 3 in water has
reached a practical level by using diamine 1i. We then
tested other silyl enol ethers under the same reaction condi-
tions. For 4’-substituted acetophenone-derived silyl enol
ethers, the corresponding adducts were obtained in high
yields with excellent enantioselectivities (entries 4–6). To
Chem. Eur. J. 2006, 12, 1205 – 1215
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1211

S. Kobayashi et al.
Table 14. Catalytic asymmetric Mannich-type reactions in water.
It is also noted that, in contrast
to most asymmetric Mannich-
type reactions, either syn- or
anti-adducts were stereospecifi-
cally obtained from (E)- or (Z)-
silicon enolates. As for the re-
action mechanism, some experi-
mental evidence suggests that
the ZnF2 chiral diamine com-
plex is the real catalytically
active species, and that it is re-
generated from the Me3SiF
formed during the reaction
(fluoride-catalyzed mechanism).
Finally, it should be noted that
the present reaction proceeds
smoothly only in the presence
of water, although the exact
role of water in this reaction is
Entry
Enolate[b]
1c [mol%]
t [h]
Product
Yield [%]
syn/anti
ee [%][a]
1
5
5
5
5
40
40
6a
6a
87
60
93:7
93:7
96
96
2[c]
3[d]
10
10
40
40
6e
6 f
76
74
96:4
96:4
96
96
4[d]
5
6
(E)-8
(Z)-8
10
10
155
144
6d
6d
75
63
13:87
90:10
92
98
[a] ee of the major diastereomer. [b] PMP=p-Methoxyphenyl. [c] E/Z <2:>98. [d] ZnF2 (5 mol%).
obtained (entries 3 and 4). Furthermore, stereospecific,
enantio- and diastereoselective reactions were achieved in
water by using only 10 mol% of ZnF2 and 1c. In fact, the
reactions with (E)-8 and (Z)-8 proceeded to afford anti and
syn adducts in good yields with high diastereo- and enantio-
selectivities, respectively, although a longer reaction time
was required (entries 5 and 6). It is noted that the products
obtained in the present Mannich-type reactions were often
highly crystalline, and one recrystallization afforded almost
diastereomerically and enantiomerically pure materials (en-
tries 1, 3, 4 and 6).
as yet unclear. The studies in this article will provide a
useful guide for the development of catalytic asymmetric
carbon–carbon bond-forming reactions in water.
Experimental Section
General: Melting points are uncorrected. CDCl3 was used as a solvent
for 1H and 13C NMR spectra unless otherwise noted. TMS served as an
1
internal standard (d=0 ppm) for H NMR spectra and CDCl3 as an inter-
nal standard (d=77.0 ppm) for 13C NMR spectra. For spectroscopic anal-
ysis conducted in [D6]DMSO, the methyl peak of the DMSO served as
the internal standard (2.49 ppm for 1H NMR spectra and 39.5 ppm for
13C NMR spectra). Preparative TLC was carried out by using Wakogel
B-5F. ZnF2 was purchased from Soekawa Rikagaku or Aldrich. (1R,2R)-
(+)-1,2-Diphenyl-1,2-ethanediamine was purchased from Kanto Kagaku.
Summary
Silicon enolate: All the silicon enolates (3, 5,[37a] (E)-7,[37b,c] (Z)-7,[37b,c]
(E)-8,[37b,d] (Z)-8,[37d] (Z)-(1-isopropyl-propenyloxy)-trimethylsilane, (Z)-
[1-(4-methoxy-phenyl)-propenyloxy]-trimethylsilane,[37a] and (Z)-trimeth-
Diastereo- and enantioselective Mannich-type reactions of
a-hydrazono ester 2 with silicon enolates in aqueous media
have been achieved with a ZnF2 chiral diamine complex.
This reaction seems to proceed with double activation, in
which Zn2+ acts as a Lewis acid to activate 2, and a fluoride
anion acts as a Lewis base to activate the silicon enolates.
Indeed, both Zn2+ and a fluoride anion were needed to
obtain high yields and enantioselectivities. The effect of the
diamines, which contain MeO groups on their aromatic
rings, is worth noting, and the advantages of using these dia-
mines are as follows:
yl-(1-phenyl-but-1-enyloxy)-silane[37a]
) were prepared from the corre-
sponding carbonyl compounds by using known methods.[2]
Preparation of ethyl benzoylhydrazono-acetate (2):[38] Benzoylhydrazine
(42.3 mmol) was added to a solution of ethyl glyoxylate (45–50% in tolu-
ene, 10.04 g) in EtOH (50 mL). After stirring at 808C for 15 min, the re-
action mixture was gradually allowed to cool to RT. The precipitated hy-
drazone 2 was then filtered with suction and washed successively with
EtOH (30 mL), toluene (300 mL), and hexane (500 mL). Yield: 62%;
m.p. 140–1418C; 1H NMR ([D6]DMSO, 808C): d=1.28 (t, J=7.1 Hz,
3H), 4.26 (q, J=7.1 Hz, 2H), 7.48–7.55 (m, 2H), 7.57–7.64 (m, 1H), 7.83
(s, 1H), 7.86–7.92(m, 2H), 12.07 ppm (s, 1H);
808C): d=13.6, 60.3, 127.6, 128.0, 131.7, 132.4, 137.1, 162.6, 164.3 ppm;
13C NMR ([D6]DMSO,
1) The reactions in aqueous THF were remarkably acceler-
ated.
IR (KBr): n˜ =3195, 3043, 1739, 1665, 1558, 1347, 1216, 1137, 1088 cmÀ1
;
HRMS (ESI-TOF): calcd for C11H13N2O3: 221.0926 [M+H]+; found:
221.0914; elemental analysis calcd for C11H12N2O3: C 59.99, H 5.49, N
12.72; found: C 59.95, H 5.49, N 12.73.
2) The reactions with the silicon enolates 3 or 5 proceeded
in high yield, even in the absence of TfOH or NaOTf,
which was needed in the reactions involving 1a.
3) The ZnF2 loading could be reduced to 10–20 mol%,
without loss of yield and enantioselectivity, whereas
more than 50 mol% of ZnF2 was required in the reac-
tions involving 1a.
4) The reactions in water, without any organic cosolvents,
proceeded smoothly to give high yields and stereoselec-
tivities.
A typical experimental procedure for the Mannich-type reactions in
aqueous THF (Table 2, entry 2): A solution of 1a (0.0419 mmol) in H2O/
THF (1:9, 0.83 mL), a solution of trifluoromethanesulfonic acid in H2O/
THF (1:9, 0.079m, 53 mL, 4.2 mmol), and 2 (0.419 mmol) were added to a
solution of ZnF2 (0.419 mmol) in H2O/THF (1:9, 0.27 mL). A solution of
3 (1.26 mmol) in H2O/THF (1:9, 1.19 mL) was then added, and the mix-
ture was stirred at 08C. After 72h at this temperature, the reaction was
quenched with saturated aqueous NaHCO3. The resultant mixture was
then extracted with dichloromethane (”3), and the combined organic
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Chem. Eur. J. 2006, 12, 1205 – 1215

Mannich-Type Reactions
FULL PAPER
layers were dried over anhydrous Na2SO4. Finally, the solvents were
evaporated, and the residue was purified by preparative TLC (silica gel,
CHCl3/MeOH 39:1) to give (R)-4 (93% yield). The enantiomeric excess
of the product was determined by HPLC analysis (92% ee).
7.78; N 8.44; HPLC (Daicel Chiralcel OD, hexane/iPrOH 19:1, flow
rate=1.0 mLminÀ1); syn: tR =14.2min (major), tR =17.2min (minor);
anti: tR =22.2 min (major), tR =27.0 min (minor).
A typical experimental procedure for the Mannich-type reactions with
acetophenone-derived silyl enol ether 3 in water (Table 12, entry 1):
Compound 2 (0.421 mmol) and 3 (1.26 mmol) were added to a mixture
of 1i (0.0421 mmol) and ZnF2 (0.421 mmol) in H2O (2.35 mL), and the
mixture was stirred vigorously (~1400 rpm) at 08C. After 20 h, the reac-
tion was quenched with saturated aqueous NaHCO3. The resultant mix-
ture was then extracted with dichloromethane (”3), and the combined
organic layers were dried over anhydrous Na2SO4. Finally, the solvent
was evaporated, and the residue was purified by preparative TLC (silica
gel, chloroform/MeOH 39:1 and then hexane/ethyl acetate 3:2) to give
Mannich adduct (R)-4 (91% yield, 95% ee).
Ethyl 2-(N’-benzoylhydrazino)-4-oxo-4-phenylbutyrate (4a):[7] [a]D22
=
+4.42( c=5.07 in CHCl3, 96% ee); 1H NMR (CDCl3): d=1.23 (t, J=
7.1 Hz, 3H), 3.51 (dd, J=17.9, 6.5 Hz, 1H), 3.60 (dd, J=17.9, 4.9 Hz,
1H), 4.06–4.35 (m, 3H), 5.51 (brs, 1H), 7.31–7.64 (m, 6H), 7.74 (d, J=
7.6 Hz, 2H), 7.93 (d, J=7.6 Hz, 2H), 8.50 ppm (brd, J=4.4 Hz, 1H);
13C NMR (CDCl3): d=14.0, 39.4, 59.0, 61.4, 126.9, 128.0, 128.5, 128.5,
131.7, 132.6, 133.4, 136.1, 166.9, 172.5, 197.1 ppm; IR (neat): n˜ =3289,
1735, 1681, 1536, 1216, 689 cmÀ1; MS: m/z: 340 [M]+; HRMS: calcd for
C19H20N2O4: 340.1423; found: 340.1379; HPLC (Daicel Chiralcel OD,
hexane/iPrOH 4:1, flow rate=1.0 mLminÀ1): tR =11.9 min (R), tR =
17.7 min (S).
A typical experimental procedure for the Mannich-type reactions of pro-
piophenone-derived silyl enol ether 5 in water (Table 13, entry 5): A solu-
tion of CTAB (0.0716m, 0.0200 mmol) in H2O, 2 (0.400 mmol), and 5
(1.20 mmol) were added to a mixture of ZnF2 (0.400 mmol) and 1c
(0.0400 mmol) in H2O (1.95 mL), and the mixture was stirred vigorously
(~1400 rpm) at 08C. After 20 h, the reaction was quenched with saturat-
ed aqueous NaHCO3. The resultant mixture was then extracted with di-
chloromethane (”3), and the combined organic layers were dried over
anhydrous Na2SO4. Finally, the solvent was evaporated, and the residue
was purified by preparative TLC (silica gel, hexane/ethyl acetate 2:1, ”2)
to give Mannich adduct 6 (94% yield, syn/anti 94:6, 97% ee (syn)).
Ethyl 2-(N’-benzoylhydrazino)-4-oxo-4-p-tolylbutyrate (4b):[7] 1H NMR
(CDCl3): d=1.25 (t, J=7.1 Hz, 3H), 2.40 (s, 3H), 3.51 (dd, J=17.8,
6.3 Hz, 1H), 3.59 (dd, J=17.8, 4.6 Hz, 1H), 4.06–4.37 (m, 3H), 5.40–5.52
(brs, 1H), 7.16–7.56 (m, 5H), 7.73 (d, J=7.3 Hz, 2H), 7.84 (d, J=8.3 Hz,
2H), 8.27 ppm (brd, J=5.1 Hz, 1H); 13C NMR (CDCl3): d=14.1, 21.6,
39.4, 59.2, 61.5, 126.9, 128.2, 128.6, 129.3, 131.8, 132.7, 133.7, 144.4, 166.8,
172.7, 196.8 ppm; IR (neat): n˜ =3295, 2924, 1735, 1680, 1606, 1181 cmÀ1
;
HRMS: calcd for C20H22N2O4: 354.1580; found: 354.1548; HPLC (Daicel
Chiralcel OD, hexane/iPrOH 4:1, flow rate=1.0 mLminÀ1): tR =12.0 min
(R), tR =17.0 min (S).
Ethyl
2-(N’-benzoylhydrazino)-4-(4-methoxyphenyl)-4-oxobutyrate
Ethyl 2-(N’-benzoylhydrazino)-4-tert-butylthio-3-methyl-4-oxobutanoate
(6c):[8] 1H NMR (CDCl3); syn: d=1.28 (t, J=7.2Hz, 3H), 1.31 (d, J=
7.1 Hz, 3H), 1.44 (s, 9H), 3.12(dq, J=4.3, 7.1 Hz, 1H), 4.00 (dd, J=3.7,
4.3 Hz, 1H), 4.15–4.29 (m, 2H), 5.50 (dd, J=3.7, 6.3 Hz, 1H), 7.38–7.44
(m, 2H), 7.46–7.52 (m, 1H), 7.71–7.77 (m, 2H), 8.08 ppm (brd, J=
6.3 Hz, 1H); 13C NMR (CDCl3); syn: d=13.2, 14.0, 29.6, 48.3, 49.5, 61.4,
64.5, 126.9, 128.5, 131.7, 132.5, 166.7, 171.1, 201.8 ppm; 1H NMR
(CDCl3); anti: d=1.27 (t, J=7.1 Hz, 3H), 1.29 (d, J=7.1 Hz, 3H), 1.47
(s, 9H), 3.10 (dq, J=6.8, 7.1 Hz, 1H), 3.85 (dd, J=6.2, 6.8 Hz, 1H), 4.09–
4.35 (m, 2H), 5.32 (dd, J=5.4, 6.2Hz, 1H), 7.39–7.56 (m, 3H), 7.70–7.79
(m, 2H), 7.94 ppm (brd, J=5.4 Hz, 1H); 13C NMR (CDCl3); anti: d=
14.1, 14.5, 29.7, 48.4, 49.4, 61.4, 65.9, 126.9, 128.6, 131.8, 132.6, 166.9,
171.4, 201.4 ppm; IR (neat, syn/anti 8:92): n˜ =3292, 2966, 1738, 1680,
(4c):[7] 1H NMR (CDCl3): d=1.25 (t, J=7.2Hz, 3H), 3.49 (dd, J=17.6,
6.3 Hz, 1H), 3.57 (dd, J=17.6, 4.4 Hz, 1H), 3.87 (s, 3H), 4.10–4.33 (m,
3H), 5.29–5.60 (m, 1H), 6.92 (d, J=8.8 Hz, 2H), 7.36–7.46 (m, 2H), 7.50
(t, J=7.3 Hz, 1H), 7.73 (d, J=7.3 Hz, 2H), 7.93 (d, J=8.8 Hz, 2H),
8.26 ppm (brs, 1H); 13C NMR (CDCl3): d=14.1, 39.2, 55.5, 59.2, 61.5,
113.8, 126.9, 128.6, 129.3, 130.5, 131.8, 132.7, 163.8, 166.8, 172.8,
195.7 ppm; IR (neat): n˜ =3257, 1740, 1686, 1627, 1600, 1453, 1262, 1222,
1192, 1169 cmÀ1; MS: m/z: 370 [M]+; HPLC (Daicel Chiralcel OD,
hexane/iPrOH 4:1, flow rate=1.0 mLminÀ1): tR =19.6 min (R), tR =
28.2 min (S).
Ethyl 2-(N’-benzoylhydrazino)-4-(4-chlorophenyl)-4-oxobutyrate (4d):[7]
1H NMR (CDCl3): d=1.22 (t, J=7.1 Hz, 3H), 3.46 (dd, J=17.9, 6.2Hz,
1H), 3.56 (dd, J=17.9, 5.0 Hz, 1H), 4.10–4.34 (m, 3H), 5.52(brs, 1H),
7.32–7.55 (m, 5H), 7.69–7.79 (m, 2H), 7.85 (d, J=8.6 Hz, 2H), 8.55 ppm
(brd, J=5.0 Hz, 1H); 13C NMR (CDCl3): d=14.1, 39.4, 59.1, 61.6, 127.0,
128.6, 129.0, 129.5, 131.9, 132.5, 134.5, 140.0, 167.0, 172.3, 196.0 ppm; IR
(neat): n˜ =3293, 1733, 1683, 1590, 1535, 1215, 693 cmÀ1; MS: m/z: 374
[M]+; HPLC (Daicel Chiralcel OD, hexane/iPrOH 4:1, flow rate=
1.0 mLminÀ1): tR =14.0 min (R), tR =19.7 min (S).
Ethyl 2-(N’-benzoylhydrazino)-3-methyl-4-oxo-4-phenylbutyrate (6a):[7]
M.p. 120–1228C; [a]2D3 =+24.5 (c=0.40 in CHCl3, syn/anti 99.7:0.3,
>99.5% ee (syn)); 1H NMR (CDCl3); syn: d=1.23 (t, J=7.1 Hz, 3H),
1.28 (d, J=7.1 Hz, 3H), 3.88–4.37 (m, 4H), 4.83 (brs), 7.30–7.61 (m, 6H),
7.71 (d, J=7.3 Hz, 2H), 7.94 (d, J=7.1 Hz, 2H), 8.29 ppm (brs, 1H); de-
tectable peak of anti isomer: 8.14 ppm (brs, 1H); 13C NMR (CDCl3);
syn: d=13.9, 14.2, 42.5, 61.2, 65.9, 126.9, 128.3, 128.4, 128.6, 131.6, 132.5,
133.1, 136.0, 166.8, 172.1, 201.5 ppm; IR (KBr): n˜ =3269, 1732, 1682,
1628, 1551, 1194, 706 cmÀ1; MS: m/z: 354 [M]+; elemental analysis calcd
for C20H22N2O4: C 67.78, H 6.26, N 7.90; found: C 67.84, H 6.47, N 7.93;
HPLC (Daicel Chiralcel OD, hexane/iPrOH 19:1, flow rate=
1.0 mLminÀ1); syn: tR =23.5 min (major), tR =28.2 min (minor); anti: tR =
31.4 min (major), tR =32.9 min (minor).
1456, 1211, 964, 696 cmÀ1
; HRMS (FAB): calcd for C18H27N2O4S:
367.1692[ M+H]+; found: 367.1671; HPLC (Daicel Chiralpak AD-H
(double), hexane/iPrOH 4:1, flow rate=0.50 mLminÀ1); syn: tR =
34.8 min (2S,3S), tR =41.4 min (2R,3R). anti: tR =28.8 min (2S,3R), tR =
33.1 min (2R,3S).
Ethyl 2-(N’-benzoylhydrazino)-3-methyl-4-oxohexanoate (6d):[8] syn (syn/
anti 98.5:1.5, >99.5% ee (syn)): m.p. 117–1198C; [a]2D5 =+8.3 (c=0.25 in
CHCl3); 1H NMR (CDCl3): d=1.06 (t, J=7.2Hz, 3H), 1.23 (d, J=
7.2Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 2.43–2.66 (m, 2H), 3.08 (dq, J=7.2,
7.2Hz, 1H), 3.87 (d, J=7.2Hz, 1H), 4.12–4.30 (m, 2H), 4.84 (brs, 1H),
7.37–7.56 (m, 3H), 7.70–7.79 (m, 2H), 8.08 ppm (s, 1H); 13C NMR
(CDCl3): d=7.6, 13.5, 14.1, 34.7, 47.1, 61.3, 65.5, 126.9, 128.6, 131.8,
132.6, 166.7, 172.0, 212.2 ppm; IR (KBr): n˜ =3251, 1730, 1711, 1626, 1556,
1452, 1205, 694 cmÀ1
; HRMS (ESI-TOF): calcd for C16H22N2O4Na:
329.1477 [M+Na]+; found: 329.1460; anti: 1H NMR (CDCl3): d=1.04 (t,
J=7.2Hz, 3H), 1.25 (d, J=7.2Hz, 3H), 1.26 (t, J=7.2Hz, 3H), 2.48–
2.70 (m, 2H), 3.11 (dq, J=4.9, 7.2Hz, 1H), 3.98 (dd, J=4.5, 4.9 Hz, 1H),
4.10–4.29 (m, 2H), 5.35 (dd, J=4.5, 5.5 Hz, 1H), 7.36–7.54 (m, 3H),
7.70–7.78 (m, 2H), 8.18 ppm (brd, J=5.5 Hz, 1H); 13C NMR (CDCl3):
d=7.5, 12.4, 14.0, 34.3, 46.9, 61.3, 64.0, 126.8, 128.5, 131.7, 132.4, 166.9,
171.7, 212.3 ppm; HPLC (Daicel Chiralpak AD-H, hexane/iPrOH 9:1,
flow rate=0.80 mLminÀ1); syn: tR =23.9 min (minor), tR =33.7 min
(major); anti: tR =26.7 min (minor), tR =44.3 min (major).
Ethyl
2-(N’-benzoylhydrazino)-3,5-dimethyl-4-oxohexanoate
(6b):[7]
1H NMR (CDCl3); syn: d=1.11 (d, J=6.8 Hz, 3H), 1.12(d, J=6.8 Hz,
3H), 1.23 (d, J=7.2Hz, 3H), 1.26 (t, J=7.1 Hz, 3H), 2.73–2.91 (m, 1H),
3.24 (quin, J=7.2Hz, 1H), 3.81 (d, J=7.2Hz, 1H), 4.21 (dq, J=7.1,
3.2Hz, 1H), 7.38–7.56 (m, 3H), 7.69–7.78 (m, 2H), 8.08 ppm (brs, 1H);
detectable peak of the anti isomer: 3.93 ppm (d, J=4.8 Hz, 1H);
13C NMR (CDCl3); syn: d=13.7, 14.1, 18.1, 18.3, 39.6, 45.7, 61.4, 65.8,
126.9, 128.6, 131.8, 132.6, 166.7, 172.4, 215.7 ppm; IR (KBr): n˜ =3253,
3228, 1731, 1707, 1625, 1204, 696 cmÀ1; MS: m/z: 32 0 M[ ]+; elemental
analysis calcd for C17H24N2O4: C 63.73, H 7.55, N 8.74; found: C 63.70, H
Ethyl 2-(N’-benzoylhydrazino)-3-methyl-4-(4-methoxyphenyl)-4-oxobuty-
rate (6e): syn: m.p. 117–1188C; [a]2D5 =+12.5 (c=0.51 in CHCl3);
1H NMR (C6D6): d=0.97 (t, J=7.1 Hz, 3H), 1.27 (d, J=6.9 Hz, 3H),
3.20 (s, 3H), 3.92–4.12 (m, 3H), 4.42 (dd, J=7.6, 7.6 Hz, 1H), 5.90 (dd,
J=7.6, 6.0 Hz, 1H), 6.65 (d, J=8.7 Hz, 2H), 6.95–7.10 (m, 3H), 7.69 (d,
J=8.2Hz, 2H), 7.97 (d, J=8.7 Hz, 2H), 8.36 ppm (d, J=6.0 Hz, 1H);
13C NMR (CDCl3): d=14.1, 14.8, 42.1, 55.5, 61.3, 66.2, 113.9, 126.9, 128.5,
Chem. Eur. J. 2006, 12, 1205 – 1215
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S. Kobayashi et al.
128.9, 130.8, 131.7, 132.6, 163.7, 166.7, 172.4, 200.0 ppm; IR (KBr): n˜ =
3267, 1728, 1665, 1620, 1601, 1176 cmÀ1; HRMS (ESI-TOF): calcd for
C21H25N2O5: 385.1763 [M+H]+; found: 385.1751; anti: 1H NMR (C6D6);
detectable peaks of the anti isomer: d=0.92(t, J=7.1 Hz, 3H), 1.46 (d,
J=6.9 Hz, 3H), 3.19 (s, 3H), 4.32(d, J=6.0 Hz, 1H), 6.61 (d, J=9.2Hz,
2H), 7.75–7.82 (m, 2H); 13C NMR (CDCl3): d=13.8, 14.0, 41.8, 55.3,
61.4, 64.8, 113.8, 126.8, 128.3, 128.4, 130.7, 131.7, 132.4, 163.6, 166.7,
171.7, 200.3 ppm; HPLC (Daicel Chiralcel OJ-H (double), hexane/iPrOH
4:1, flow rate=1.0 mLminÀ1); syn: tR =33.9 min (minor), tR =38.0 min
(major); anti: tR =46.2min (minor), tR =54.1 min (major).
Me3SiF: 1H NMR (D2O/[D8]THF 1:9, 08C): d=0.18 (d, J=6.9 Hz, 9H).
Reaction of Me3SiOH with ZnF2 [Eq. (1)]: Me3SiOH (0.499 mmol) was
added to a solution of ZnF2 (0.492mmol), 1i (0.0492mmol), and 4-fluo-
rotoluene (internal standard, 0.232 mmol) in D2O/[D8]THF (1:9,
0.97 mL) at 08C. The reaction vessel was then capped and stirred at 08C.
After 20 h, the stirring was stopped, and the mixture was allowed to
stand for 15 min. The supernatant liquid (~0.70 mL) was transferred to a
NMR tube with a gas-tight syringe. A 1H NMR spectrum was then re-
corded (600.17 MHz, D2O/[D8]THF 1:9, 08C) to measure the amounts of
Me3SiOD, (Me3Si)2O, and Me3SiF present in the reaction mixture.
Crystallization of [ZnCl2-1c]·CH2Cl2 complexes[8] (Figure 1): Crystalliza-
tion of [ZnCl2–1c]·CH2Cl2 was carried out as follows: A solution of 1c
(0.032mmol) in CH 2Cl2 (0.81 mL) was added to a suspension of ZnCl2
(0.039 mmol) in CH2Cl2 (0.81 mL), and the mixture was stirred for 16 h
at RT. The resulting clear solution was filtered, and slow vapor diffusion
of hexane into this solution at 58C produced the product as colorless
crystals. CCDC-244175 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Ethyl 2-(N’-benzoylhydrazino)-3-ethyl-4-oxo-4-phenylbutyrate (6 f):[8] syn
(syn/anti 99:1, >99.5% ee (syn)): m.p. 88–918C; [a]2D7 =+13.2( c=2.72 in
1
CHCl3); H NMR (CDCl3): d=0.97 (t, J=7.3 Hz, 3H), 1.20 (t, J=7.1 Hz,
3H), 1.75–1.90 (m, 2H), 3.93 (ddd, J=6.9, 6.9, 7.6 Hz, 1H), 4.04 (d, J=
7.6 Hz, 1H), 4.08–4.23 (m, 2H), 5.09 (brs, 1H), 7.35–7.51 (m, 5H), 7.53–
7.59 (m, 1H), 7.71 (d, J=7.3 Hz, 2H), 7.96 (d, J=7.6 Hz, 2H), 8.20 ppm
(s, 1H); 13C NMR (CDCl3): d=11.6, 14.0, 22.7, 48.9, 61.4, 64.8, 126.9,
128.3, 128.5, 128.7, 131.7, 132.6, 133.3, 137.2, 166.6, 172.5, 202.1 ppm; IR
(KBr): n˜ =3269, 1732, 1682, 1628, 1551, 1194, 706 cmÀ1; HRMS (FAB):
1
calcd for C21H25N2O4: 369.1814 [M+H]+; found: 369.1834; anti: H NMR
(CDCl3): d=0.93 (t, J=7.3 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H), 1.78–1.92
(m, 1H), 2.01–2.16 (m, 1H), 3.99 (ddd, J=5.0, 5.1, 7.8 Hz, 1H), 4.07 (d,
J=5.0 Hz, 1H), 4.17–4.28 (m, 2H), 4.96 (brs, 1H), 7.35–7.57 (m, 6H),
7.62–7.68 (m, 2H), 7.93–8.01 ppm (m, 3H); 13C NMR (CDCl3): d=11.9,
14.0, 21.7, 48.7, 61.5, 63.5, 126.8, 128.4, 128.5, 128.7, 131.8, 132.4, 133.3,
136.5, 166.8, 171.8, 201.7 ppm; HPLC (Daicel Chiralpak AD-H, hexane/
iPrOH 4:1, flow rate=0.70 mLminÀ1); syn: tR =18.3 min (major), tR =
29.4 min (minor); anti: tR =20.2 min (minor), tR =25.2 min (major).
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Re-
search from the Japanese Society for the Promotion of Science (JSPS).
T.H. thanks the JSPS fellowship for Japanese junior scientists.
The absolute configurations of Mannich adduct 4a and the adduct ob-
tained in the reaction with 7 were determined to be 2R.[7,8] By analogy
the absolute configurations of all the other adducts were assumed to be
2R.
[1] For reviews on asymmetric Mannich reactions see: a) S. Kobayashi,
H. Ishitani, Chem. Rev. 1999, 99, 1069–1094; b) A. E. Taggi, A. M.
Hafez, T. Lectka, Acc. Chem. Res. 2003, 36, 10–19; c) S. Kobayashi,
M. Ueno in Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacob-
sen, A. Pfaltz, H. Yamamoto), Supplement 1, Springer, Berlin, 2004,
Chapter 29.5, pp. 143–159.
[2] S. Kobayashi, K. Manabe, H. Ishitani, J. Matsuo in Science of Syn-
thesis, Houben-Weyl Methods of Molecular Transformations, Vol. 4
(Eds.; D. Bellus, S. V. Ley, R. Noyori, M. Regitz, E. Schauman, I.
Shinkai, E. J. Thomas, B. M. Trost), Thieme, Stuttgart, 2002,
pp. 317–369.
The relative configurations of the Mannich adducts obtained in the reac-
tions of both (Z)-7 and (Z)-8 were determined to be syn.[8] The relative
configurations of the adducts obtained in the reactions of 5, (Z)-(1-iso-
propylpropenyloxy)trimethylsilane, (Z)-[1-(4-methoxyphenyl)propenyloxy]-
trimethylsilane, and (Z)-trimethyl(1-phenylbut-1-enyloxy)silane were as-
sumed to be syn by analogy with (Z)-8.
Reaction mechanism:
ZnF(OH): This material was prepared by a known method.[27] IR (KBr):
n˜ =3558, 3367, 1024, 908, 787, 465 cmÀ1
.
Me3SiF: This material was purchased from Aldrich and purified by distil-
lation (through K2CO3) just before use. All the experiments using
Me3SiF were conducted in a low temperature room (48C).
[3] For reviews on organic synthesis in water see: a) C.-J. Li, T.-H.
Chan, Organic Reactions in Aqueous Media, Wiley, New York, 1997;
b) Organic Synthesis in Water (Ed.: P. A. Grieco), Blackie Academic
and Professional, London, 1998.
Mannich-type reactions with ZnF(OH) and Me3SiF (Table 10, entry 6): A
[4] S. Kobayashi, K. Manabe, S. Nagayama in Modern Carbonyl
Chemistry (Ed.: J. Otera), Wiley-VCH, Weinheim, 2000; see also
reference [3b].
[5] For reviews on stereoselective organic reactions in aqueous media
see: a) D. Sinou, Adv. Synth. Catal. 2002, 344, 221–237; b) U. M.
Lindstrçm, Chem. Rev. 2002, 102, 2751–2772; c) K. Manabe, S. Ko-
bayashi, Chem. Eur. J. 2002, 8, 4094–4101.
[6] After our first report (reference [7]), some new reports on catalytic
asymmetric Mannich reactions in aqueous media appeared: a) W.
Notz, F. Tanaka, S.-i. Watanabe, N. S. Chowdari, J. M. Turner, R.
Thayumanavan, C. F. Barbas III, J. Org. Chem. 2003, 68, 9624–9634;
b) I. Ibrahem, J. Casas, A. Cꢁrdova, Angew. Chem. 2004, 116, 6690–
6693; Angew. Chem. Int. Ed. Engl. 2004, 43, 6528–6531.
[7] S. Kobayashi, T. Hamada, K. Manabe, J. Am. Chem. Soc. 2002, 124,
5640–5641.
[8] T. Hamada, K. Manabe, S. Kobayashi, J. Am. Chem. Soc. 2004, 126,
7768–7769.
[9] For review on Mannich reactions see: M. Arend, B. Westermann, N.
Risch, Angew. Chem. 1998, 110, 1096–1122; Angew. Chem. Int. Ed.
1998, 37, 1044–1070.
[10] For review on N-acylhydrazones in organic synthesis see M. Sugiura,
S. Kobayashi, Angew. Chem. 2005, 117, 5306–5317; Angew. Chem.
Int. Ed. 2005, 44, 5176–5186; Burk reported the catalytic asymmet-
solution of 1i (0.0466 mmol) in H2O/THF (1:9, 0.95 mL) and
2
(0.466 mmol) were added to a solution of ZnF(OH) (0.466 mmol) in
H2O/THF (1:9, 0.28 mL). Compound 3 (1.40 mmol) in H2O/THF (1:9,
1.35 mL) and Me3SiF (54 mL, 0.466 mmol) were then added to this mix-
ture, and the mixture was stirred at 08C. After 20 h, the reaction was
quenched with saturated aqueous NaHCO3, and the resultant mixture
was extracted with dichloromethane (”4). The combined organic layers
were then dried over anhydrous Na2SO4, and the solvents were evaporat-
ed. The resulting residue was purified by preparative TLC (silica gel,
CHCl3/MeOH (39:1) and then hexane/ethyl acetate 3:2) to give (R)-4a
(90% yield, 96% ee).
Me3SiOH: This compound was prepared by
a
known method.[39]
1H NMR (CDCl3): d=0.14 ppm (s, 9H); 13C NMR (CDCl3): d=1.3 ppm.
Hydrolysis of Me3SiF (Table 11): Me3SiF (41 mL, 0.35 mmol) and D2O/
[D8]THF (1:9, 0.70 mL) were added at 08C to a solution of benzotrifluor-
ide (internal standard, 0.183 mmol) in a NMR tube. The resulting solu-
1
tion was then stored at 08C. After 0.5 h, 25 h, and 69 h, H NMR spectra
were recorded (600.17 MHz, D2O/[D8]THF 1:9, 08C) to measure the
amounts of Me3SiOD, (Me3Si)2O, and Me3SiF present in the reaction
mixture.
Me3SiOD: 1H NMR (D2O/[D8]THF 1:9, 08C): d=0.03 ppm (s, 9H).
1
(Me3Si)2O: H NMR (D2O/[D8]THF 1:9, 08C): d=0.04 (s, 18H).
1214
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Chem. Eur. J. 2006, 12, 1205 – 1215

Mannich-Type Reactions
FULL PAPER
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[30] As for the tert-amines, the basicity of the nitrogen atom of 2’-me-
thoxybenzylamine is known to be higher than that of benzylamine
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[13] Hydrazine and its Derivatives, Kirk-Othmer Encyclopedia of Chemi-
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[16] A. Alexaxis, P. Mangeney in Advanced Asymmetric Synthesis (Ed.:
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[17] For a review on transition metal fluoride complexes in asymmetric
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[18] For effects of achiral ligands on allylation in aqueous media see: S.
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[20] Although diastereoselectivities were not as high as the present reac-
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Mannich-type reactions conducted in organic solvent see: S. Ko-
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[32] Since cationic micelles are known to catalyze anionic processes, it
seems likely that the addition of a cationic surfactant facilitates the
formation of fluorosiliconate B (Scheme 1), accelerating the Man-
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accelerated by the addition of a cationic surfactant see: a) M. T. A.
Behme, J. G. Fullington, R. Noel, E. H. Cordes, J. Am. Chem. Soc.
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[33] When CTAB (5 mol%) was used for the reaction in Table 12
(entry 1) the reaction was not remarkably accelerated, and the ee
was decreased (56% yield, 92% ee, 5 h).
[34] a) S. Kobayashi, T. Wakabayashi, S. Nagayama, H. Oyamada, Tetra-
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[21] Details are shown in the Supporting Information.
[22] For a similar type of double activation see: a) S. Kobayashi, H.
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[26] A similar fluoride-catalyzed mechanism was partly proposed for
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[29] For a possible transition state model see the Supporting Informa-
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[35] In reference [8], we reported that the reaction with 5 proceeded
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(syn)). However, further investigations have since revealed that this
reaction can produce a higher yield (32% yield, syn/anti 95:5,
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[39] L. H. Sommer, E. W. Pietrusza, F. C. Whitmore, J. Am. Chem. Soc.
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Received: June 10, 2005
Published online: November 3, 2005
Chem. Eur. J. 2006, 12, 1205 – 1215
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