Zinc(II)-catalyzed Mannich-type reactions of hydrazones with difluoroenoxysilane and its application in the synthesis of optically active 2,2-difluoro-3-oxo-benzohydrazide

Article abstract of DOI:10.1002/cjoc.201090289

With the catalysis of Zn(OTf)₂, Mannich-type reactions of various aromatic hydrazones 1 with difluoroenoxysilane 2 proceeded smoothly to produce 2,2-difluoro-3-oxo-benzohydrazides in 27%-78% yields in THF or DCM under mild conditions. An unexpe

Full text of DOI:10.1002/cjoc.201090289

FULL PAPER
Zinc(II)-Catalyzed Mannich-type Reactions of Hydrazones with
Difluoroenoxysilane and Its Application in the Synthesis of
Optically Active 2,2-Difluoro-3-oxo-benzohydrazide†
Yuan, Zhilianga(袁之渿)
Wei, Yinb(魏音)
Shi, Min*,a,b(施敏)
a School of Chemistry & Molecular Engineering, East China University of Science and Technology,
Shanghai 200237, China
b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
With the catalysis of Zn(OTf)2, Mannich-type reactions of various aromatic hydrazones 1 with difluoroenoxysi-
lane 2 proceeded smoothly to produce 2,2-difluoro-3-oxo-benzohydrazides in 27%— 78% yields in THF or DCM
under mild conditions. An unexpected monofluorination of hydrazone 1m with difluoroenoxysilane 2 was also dis-
closed in this paper. The first example of the asymmetric Mannich-type reaction of hydrazone 1a with difluoroe-
noxysilane 2 using chiral phosphine-oxazoline ligand has been reported, giving the adduct 3a in good yields and
moderate enantioselectivities under mild conditions.
Keywords Zn(OTf)2, Mannich-type reaction, hydrazone, difluoroenoxysilane, asymmetric Mannich-type reaction,
chiral phosphine-oxazoline ligand
Introduction
presence of TMSCl,10 are considered as excellent build-
ing blocks for the synthesis of gem-difluorinated com-
pounds.
Asymmetric Mannich-type reactions, which have
been confirmed as highly efficient routes for the synthe-
sis of many nitrogen-containing biologically interesting
compounds, have been developed rapidly in the past
several years.1 Among them, Lewis acids promoted en-
antioselective additions to carbon-nitrogen double
bonds have been demonstrated as one of the most im-
portant methods to access nitrogen-containing optically
active compounds.2 Acylhydrazones, which have been
widely used as building blocks in organic synthesis,
could be synthesized by the condensation of aldehydes
or ketones and acylhydrazines.3 In addition, these inter-
esting compounds are more stable and storable than
most of imines and can be easily purified by simple re-
crystallization under ambient atomsphere.4 The suc-
cessful examples of catalytic asymmetric addition of
acylhydrazones, however, are limited.5 On the other
hand, a difluoromethylene unit, which plays a signifi-
cant role in current organofluorine chemistry,6 was re-
vealed containing in some biologically interesting
compounds, such as in phosphotyrosine (pTyr) mimet-
ics,7 anticancer agent gemcitabine,8 and HIV-1 protease
inhibitors.9 In order to introduce difluoromethylene
units into organic compounds, difluoroenolsilylanes,
which could be readily prepared by Mg(0) promoted
selective defluorination of trifluoromethyl ketones in the
Catalytic asymmetric vinylogous Mannich-type
(AVM) reactions of readily available aldimines with
trimethylsiloxyfuran promoted by silver salts have been
reported by our group recently.11 We envisioned that the
use of difluoroenoxysilanes in the Mannich-type reac-
tion of hydrazones instead of trimethylsiloxyfuran might
be a novel method to achieve chiral gem-difluorinated
compounds. Although asymmetric fluorination reactions
are attractive,12,13 there has been no report on Lewis
acids-catalyzed asymmetric difluoromethylation of hy-
drazones. Herein, we wish to report
a
novel
zinc(II)-promoted Mannich-type reaction of hydrazones
1 with difluoroenoxysilane 2. Furthermore, this paper
will disclose the investigation on the enantioselective
addition of difluoroenoxysilane 2 to hydrazone 1a and
this transformation represents the first example of
asymmetric difluoromethylation method involving the
use of a catalytic amount of zinc(II) to date.
Results and discussion
First, the reaction of hydrazone 1a (0.2 mmol),
which can be easily prepared from benzaldehyde and
benzoylhydrazine, with difluoroenoxysilane 2 (0.3
mmol) in THF (2.0 mL) was carried out in the presence
*
E-mail: mshi@mail.sioc.ac.cn
Received July 1, 2010; revised August 24, 2010; accepted August 26, 2010.
Project supported by the Shanghai Municipal Committee of Science and Technology (No. 08dj1400100-2), the National Basic Research Program of
China (973) (No. 2010CB833302), and the National Natural Science Foundation of China (Nos. 20872162, 20672127, 20821002 and 20732008).
† Dedicated to the 60th Anniversary of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.
Chin. J. Chem. 2010, 28, 1709— 1716
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Yuan, Wei & Shi
FULL PAPER
of various Lewis acids (10 mol%) at room temperature
(25 ℃) to examine the reaction outcome and the results
of these experiments are summarized in Table 1. It was
found that neither Ni(ClO4)2•6H2O nor copper salts
could promote this reaction (Table 1, Entries 1—4). As
shown in Table 1, the corresponding Mannich-type ad-
duct 3a was obtained in 22% yield when catalytic
amount of Sc(OTf)3 or Yb(OTf)3 was utilized (Table 1,
Entries 5 and 6). Although silver salts were successfully
applied into a catalytic asymmetric vinylogous Mannich
(AVM) reaction,11 neither AgOAc nor AgOTf could
catalyze the reaction of hydrazone 1a with difluoro-
enoxysilane 2 efficiently to give adduct 3a (Table 1,
Entries 7 and 8). Furthermore, the corresponding Man-
nich-adduct 3a could not be obtained using FeCl3,
Zr(On-Bu)4, Ti(Oi-Pr)4 and In(OTf)3 as the Lewis acids
(Table 1, Entries 13—15 and 17). Only 35% yield of
adduct 3a was achieved when Bi(OTf)2Cl was em-
ployed as a Lewis acid (Table 1, Entry 16). After sev-
eral examinations, we found that the reaction of hydra-
zone 1a with difluoroenoxysilane 2 proceeded smoothly
to give 3a in 72% yield in the presence of 10 mol% of
Zn(OTf)2 (Table 1, Entry 9). We next investigated
various zinc salts in this reaction. Unfortunately, neither
ZnCl2 nor ZnBr2 could catalyze this Mannich-type reac-
tion and the reaction was sluggish to give 3a in 19%
yield in the presence of a catalytic amount of ZnF2 (Ta-
ble 1, Entries 10—12). Subsequently, the examination
of solvents effects using Zn(OTf)2 (10 mol%) as a cata-
lyst revealed that dichloromethane (CH2Cl2) is the sol-
vent of choice, affording adduct 3a in 79% yield under
otherwise identical conditions presumably due to the
better solubility of substrate 1a in CH2Cl2 (Table 1, En-
tries 18—22).
With these optimized reaction conditions in hand,
we next turned our attention to the reaction scope using
a variety of hydrazones 1 with difluoroenoxysilane 2
under the standard conditions and the results are sum-
marized in Table 2 along with the results obtained in
THF. As for aromatic substrates 1b—1g, the reactions
proceeded smoothly to produce Mannich-type adducts
3b—3g in moderate to good yields (up to 78% yield) in
THF or CH2Cl2 (Table 2, Entries 1—6). In the case of
2-chlorobenzenealdehyde 1f, the corresponding product
3f was achieved in 45% yield (35% yield in THF), pre-
sumably due to the steric effect (Table 2, Entry 5). Us-
ing hydrazone 1h bearing a phenolic hydroxy group as
the substrate, no reaction occurred (Table 2, Entry 7). It
should be noted that in the reaction of hydrazone 1i
Table 1 Survey of reaction conditions of Lewis acids promoted
Mannich-type reaction of hydrazone 1a and difluoroenoxysilane
2a
Entry
1
Lewis acid
Solvent
THF
Yieldb/%, 3a
Ni(ClO4)2•6H2O
Cu(OTf)2
0
2
THF
0
3c
(CuOTf)2 C6H6
THF
0
.
4
Cu(CH3CN)4ClO4
Sc(OTf)3
Yb(OTf)3
AgOAc
THF
0
5
THF
20
22
0
Table 2 Survey of Zn(OTf)2 promoted Mannich-type reactions
of hydrazones 1 with difluoroenoxysilane 2a
6
THF
7
THF
8
AgOTf
THF
12
72
19
0
9
Zn(OTf)2
ZnF2
THF
10
11
12
13
14
15
16
17
18
19
20
21
THF
Entry
Hydrazone 1 (R)
4-ClC6H4 1b
4-BrC6H4 1c
4-CH3C6H4 1d
4-OCH3C6H4 1e
2-ClC6H4 1f
Yieldb/%, 3
3b, 63/(75c)
3c, 71/(78c)
3d, 76/(73c)
3e, 27/(61c)
3f, 45/(35c)
3g, 78/(67c)
3h, 0/(0c)
ZnCl2
THF
ZnBr2
THF
0
1
2
FeCl3
THF
0
Zr(On-Bu)4
Ti(Oi-Pr)4
Bi(OTf)2Cl
In(OTf)3
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
THF
0
3
THF
0
4
THF
35
0
5
THF
6
3-ClC6H4 1g
2-OHC6H4 1h
1-Naphthyl 1i
2-Furan 1j
Toluene
CH3CN
1,4-Dioxane
Et2O
Trace
51
Trace
39
79
7
8
3i, 67/(51c)
3j, 57/(63)c
3k, 0/(0c)
9
10
C6H5(CH2)2 1k
CH3(CH2)2 1l
22
CH2Cl2
11
3l, 0/(0c)
a
Reaction conditions: the reaction was carried out with 0.20
a
Experimental conditions: the reaction was carried out with 0.20
mmol of 1, 0.30 mmol of 2 and 10 mol% of Zn(OTf)2 in CH2Cl2
(2.0 mL) at room temperature. b Isolated yield. c The reaction was
carried out in THF (2.0 mL) instead of CH2Cl2.
mmol of 1a, 0.30 mmol of 2 and 10 mol% of Lewis acids in sol-
vent (2.0 mL) at room temperature. Isolated yield. 5 mol% of
(CuOTf)2•C6H6 was used as the catalyst.
b
c
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Zinc(II)-Catalyzed Mannich-type Reactions and Its Application
having a 1-naphthyl group and hydrazone 1j bearing a
furan ring with difluoroenoxysilane 2, the correspond-
ing adducts 3i and 3j could also be formed in up to 67%
yield (Table 2, Entries 8 and 9). Aliphalic hydrazones,
such as 1k [R＝C6H5(CH2)2] and 1l [R＝CH3(CH2)3],
proved to be inefficient in this Zn(OTf)2 promoted
Mannich-type reaction (Table 2, Entries 10 and 11). In
some cases, the corresponding adducts 3 were achieved
in higher yields when THF was utilized as the solvent
instead of CH2Cl2 (Table 2, Entries 1, 2, 4 and 9), pre-
sumably due to the different solubility of different hy-
drazones 1 in CH2Cl2 and THF.
Table 3 Screening of the reaction conditions in the Lewis acids
promoted unexpected monofluorination of hydrazone 1m with
difluoroenoxysilane 2a
Interestingly, an unexpected monofluoro-adduct 4
was obtained in 41% yield instead of the corresponding
Mannich-type adduct in the reaction of hydrazone 1m
with difluoroenoxysilane 2 under the optimized reaction
conditions (Scheme 1). We also investigated this unex-
pected reaction in the presence of various Lewis acids
(10 mol%) and the results of these experiments are
summarized in Table 3. Conducting the reaction of hy-
drazone 1m with difluoroenoxysilane 2 in 2.0 mL of
THF in the presence of 10 mol% of Cu(OTf)2, AgOTf
or ZnF2 did not improve the yields of 4 (up to 33%)
(Table 3, Entries 2, 5 and 6). Other Lewis acids, for in-
stance Ni(ClO4)2•6H2O, Sc(OTf)3, Yb(OTf)3, FeCl3 and
Bi(OTf)2Cl, did not promote this reaction under identi-
cal conditions (Table 3, Entries 1, 3, 4, 7 and 8). Sub-
sequently, the solvent effects have also been examined
by using Zn(OTf)2 (10 mol%) as the catalyst (Table 3,
Entries 9—12). However, the unexpected adduct 4 was
still obtained in low yields (20% in CH2Cl2, trace in
Et2O, and no reaction proceeded in CH3CN and
1,4-dioxane). A plausible mechanism for the formation
of unexpected monofluorination is the elimination of a
difluorination intermediate. The monofluorination may
occur to the difluorination intermediate only when using
hydrazone bearing a strong electron-withdrawing group
such as an alkoxycarbonyl group (—CO2R).
Entry
1
Lewis acid
Solvent
Yieldb/%, 4
Ni(ClO4)2•6H2O THF
0
2
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3
AgOTf
THF
29
0
3
THF
4
THF
0
5
THF
12
33
0
6
ZnF2
THF
7
FeCl3
THF
8
Bi(OTf)2Cl
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
THF
0
9
CH3CN
1,4-Dioxane
Et2O
0
10
11
12
0
Trace
20
CH2Cl2
a Experimental conditions: The reaction was carried out with 0.20
mmol of 1m, 0.30 mmol of 2 and 10 mol% of Lewis acids in
solvent (2.0 mL) at room temperature. b Isolated yield.
combined with L1 (11 mol%) in THF (2.0 mL) to cata-
lyze the Mannich-type reaction to examine the catalytic
ability of this system, and it was found that the corre-
sponding adduct 3a was obtained in 62% yield and 2%
ee at ambient temperature (Table 4, Entry 1). As an en-
antioselective catalytic system, we then utilized the
combination of Zn(OTf)2 (10 mol%) with chiral imine
ligands L2 or L3 (11 mol%), which was effective chiral
catalyst for the previous Friedel-Crafts reaction,14 in the
reaction of hydrazone 1a with difluoroenoxysilane 2 in
2.0 mL of THF, affording 3a in up to 45% yield with no
ee value (Table 4, Entries 2 and 3). Chiral oxazoline
ligands L4—L6 were also employed in this reaction,
but did not give good result either (Table 4, Entries 4—
6). Axially chiral ligand L7, derived from (R)-BINAM
could slightly improve the reaction outcome, giving 3a
in 78% yield and 5% ee under the standard conditions
(Table 4, Entry 7). Unfortunately, chiral phosphine-
Schiff base ligand L8, which has been successfully ap-
plied in a copper(I) catalyzed Henry reaction,15 and
chiral phosphine-Schiff base ligands L9 and L10, which
were effective for the previously reported silver cata-
lyzed asymmetric vinylogous Mannich (AVM) reaction11b
Scheme 1 An unexpected monofluorination of hydrazone 1m
with difluoroenoxysilane 2
With these optimized reaction conditions in hand,
we then attempted to examine Zn(OTf)2-catalyzed
asymmetric Mannich-type reaction of aromatic hydra-
zone 1a with difluoroenoxysilane 2 in the presence of
various chiral ligands L1—L20 (Figure 1).
Initially, we utilized Lewis acid Zn(OTf)2 (10 mol%)
Chin. J. Chem. 2010, 28, 1709— 1716
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Yuan, Wei & Shi
FULL PAPER
Figure 1 Chiral ligands L1—L20.
combined with Zn(OTf)2 afforded product 3a in good
yields but with almost no ee (Table 4, Entries 8—10).
Occasionally, it was found that when phosphine-
oxazoline ligand L11 [(R,S)-P-Oxa-I-Pr] was employed
in this Zn(OTf)2 catalyzed Mannich-type reaction, the
corresponding adduct 3a was obtained in 61% yield
along with 15% ee (Table 4, Entry 11). Since
phosphine-oxazoline ligand L11 could improve the en-
antioselectivity of adduct 3a, we then turned our atten-
tion to examine various phosphine-oxazoline ligands
L12—L18 in this reaction and the results using these
chiral ligands are outlined in Table 4, Entries 12—18. It
was found that the desired Mannich-type addition pro-
ceeded smoothly to give the desired product 3a in 69%
yield and 39% ee when L12 [(R,S)-P-Oxa-t-Bu] was
employed as a ligand in this reaction (Table 4, Entry 12).
Using L13 [(R,S)-P-Oxa-Ph] as a ligand combined with
Zn(OTf)2 afforded 3a in 71% yield and 15% ee (Table 4,
Entry 13). Moreover, when a di(3,5-dimethylphenyl)-
phosphine group was introduced into the phosphine-
oxazoline ligand instead of diphenylphosphine group in
L12, both the yield and ee value of Mannich-type ad-
duct 3a were improved (77% yield and 40% ee) (Table
4, Entry 14). However, the phosphine-oxazoline ligand
L15, bearing a dicyclohexylphosphine group instead of
diphenylphosphine group in L12, combined with
Zn(OTf)2 gave 3a in 78% yield with 17% ee (Table 4,
Entry 15). As shown in Entry 16 of Table 4, L16 bear-
ing a phosphing oxide group showed similar reactivity
as that of L12 but leading to 3a in low enantioselectivity.
Encouraged by the results of L12 and L14, we then
synthesized chiral ligands L17 [(S,S)-P-Oxa-t-Bu] and
L18 [(S,S)-DMP-P-Oxa-t-Bu], which are the di-
astereomeric isomers of L12 and L14 and applied them
in the reaction of hydrazone 1a with difluoroenoxysi-
lane 2 as well. However, no improvement was observed
(Table 4, Entries 17 and 18). In addition, the combina-
tion of Zn(OTf)2 and 1,3-bis(oxazolin-2-yl)pyridine L19
(pybox type ligand) or (1S,2R)-(－)-1-amino-2-indanol
L20 gave 3a in low enantiomeric excesses either (up to
13% ee) though the yields of adduct 3a were 77% and
79% (Table 4, Entries 19 and 20).
Previous researches have disclosed that additives of-
ten played an important role in the enhancement of the
reactivity and enantioselectivity.16 We next performed
the optimization studies on the effects of different addi-
tives with the best ligand L14 being identified. When
the reaction was carried out with 1.5 equiv. of
1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), the desired
product 3a was obtained in 77% yield and 47% ee (Ta-
ble 4, Entry 21). Adding CF3CH2OH into this Man-
nich-type reaction system afforded 3a in similar yield
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Zinc(II)-Catalyzed Mannich-type Reactions and Its Application
Table 4 Screening of chiral ligands in the Zn(OTf)2-catalyzed
asymmetric Mannich-type reaction of aromatic hydrazone 1a
with difluoroenoxysilane 2a
Zn(OTf)2, 11 mol% of L14, 1.5 equiv. of HFIP as the
additive, we next examine the solvent and temperature
effects in this Mannich-type reaction. When the reaction
was carried out in CH2Cl2, 3a was attained in 86% yield
but lower ee (Table 4, Entry 25). The examination of
temperature effects revealed that the reaction proceeded
inefficiently at 0 ℃, affording adduct 3a in 39% yield
and 38% ee (Table 4, Entry 26). Reducing the reaction
temperature to －10 ℃ did not give 3a (Table 4, Entry
28). When the reaction was carried out at －5 ℃, the
enantiomeric excess of 3a could be improved to 51%
but only in 20% yield (Table 4, Entry 27). The combi-
nation of 20 mol% of Zn(OTf)2 and 22 mol% of L14 led
to 3a in 51% yield and 48% ee at －5 ℃ (Table 4,
Entry 29). Product 3a could be obtained in 51% ee
along with 20% yield at －5 ℃ and 77% yield along
with 40% ee at room temperature using L14 as a chiral
ligand combined with Zn(OTf)2.
EntryLigandSolvent Additive
t/℃ Yield b/%, 3a ee c/%, 3a
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
THF
THF
THF
THF
THF
THF
THF
THF
THF
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
r.t. 62
r.t. 45
r.t. 43
r.t. 61
r.t. 69
r.t. 70
r.t. 78
r.t. 33
r.t. 76
r.t. 71
r.t. 61
r.t. 69
r.t. 71
r.t. 77
r.t. 78
r.t. 70
r.t. 59
r.t. 50
r.t. 79
r.t. 77
r.t. 77
2
0
0
0
0
0
5
0
0
Conclusion
10 L10 THF
11 L11 THF
12 L12 THF
13 L13 THF
14 L14 THF
15 L15 THF
16 L16 THF
17 L17 THF
18 L18 THF
19 L19 THF
20 L20 THF
3
We have presented a novel catalytic reaction system
applicable to the reactions of hydrazones and difluoro-
enoxysilane using Lewis acid Zn(OTf)2 as a catalyst.
Using this new synthetic protocol, we can produce
Mannich adducts 3 in moderate to good yields under
mild conditions. An unexpected monofluorination ad-
duct 4 could be formed when hydrazone 1m was util-
ized as the substrate in this reaction. On the basis of the
optimized reaction conditions, we found that the opti-
cally active adduct 3a could be achieved in moderate
enantioselectivity and good yield when 10 mol% of
Zn(OTf)2 was used as a promoter and L14 was used as a
ligand in the reaction of hyrazone 1a with difluoroe-
noxysilane 2. Current efforts are in progress to improve
the enantioselectivity of this novel approach to the
chiral 2,2-difluoro-3-oxo-benzohydrazides in our labo-
ratory.
15
39
15
40
17
15
2
0
3
13
47
23
20
43
38
38
51
—
48
21 L14 THF HFIP
22 L14 THF CF3CH2OH r.t. 75
23 L12 THF HFIP r.t. 73
24 L12 THF CF3CH2OH r.t. 75
25 L14 CH2Cl2 HFIP
26 L14 THF HFIP
27 L14 THF HFIP
28 L14 THF HFIP
r.t. 86
39
0
Experimental section
－5 20
General procedure for the preparation of difluoroe-
noxysilane 2.10 A mixture of chlorotrimethylsilane
(TMSCl) (6.0 mmol), Mg (6.0 mmol) and THF (10 mL)
was cooled down to 0 ℃ under argon atmosphere.
Then trifluoroacetophenone (1.5 mmol) was added
dropwise and the resulting mixture was stirred for addi-
tional 1.0 h. After the solvent was removed under vac-
uum, hexane (15 mL) was added to the residue. The
resulting salt was filtered and the filtrate was then con-
centrated to give the crude product of difluoroenoxysi-
lane 2 under reduced pressure. This crude product 2 was
used for the Mukaiyama-aldol type reaction without
further purification.
－10 0
29d L14 THF HFIP
a
－5 51
Experimental conditions: 1a (0.20 mmol), 2 (0.30 mmol), addi-
tive (0.30 mmol), Zn(OTf)2 (10 mol%), ligand (11 mol%), sol-
vent (2.0 mL), and the reaction was carried out at r.t. for 24 h.
b
c
d
Isolated yield. Determined by chiral HPLC analysis. 20
mol% Zn(OTf)2 and 22 mol% L14 were used in this reaction.
but less effective in ee (Table 4, Entry 22). Interestingly,
using L12 instead of L14 combined with Zn(OTf)2 pro-
duced the corresponding adduct 3a in only 20% ee
when HFIP was used as the additive (Table 4, Entry 23).
However, the combination of L12 and Zn(OTf)2 could
slightly improve the enantioselectivity of Mannich-type
adduct 3a when CF3CH2OH was used as the additive
(Table 4, Entry 24). Under the optimized reaction con-
ditions described above, that is, use of 10 mol% of
Typical procedure for the Zinc(II)-catalyzed Man-
nich-type reaction of hydrazone 1a with difluoro-
enoxysilane 2
The solution of hydrazone 1a (0.20 mmol), Zn(OTf)2
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Yuan, Wei & Shi
FULL PAPER
(0.02 mmol) and THF (2.0 mL) was allowed to stir for
5.0 min at ambient temperature. A freshly prepared di-
fluoroenoxysilane 2 (0.30 mmol) was added dropwise
by syringe. The reaction mixture was allowed to stir for
24 h at ambient temperature. The reaction was quenched
by addition of a saturated aqueous solution of NH4Cl
(5.0 mL). After stirring for 15 min at room temperature,
the mixture was extracted by DCM and washed with
brine. The organic layer was dried over anhydrous
Na2SO4. Then the solvent was removed under reduced
pressure and the residue was purified by flash column
chromatography (SiO2) to give the corresponding prod-
uct 3a.
13C NMR (CDCl3, 75 MHz, TMS) δ: 65.9 (dd, JC—
＝
F
23.6, 20.3 Hz), 116.9 (t, JC—F＝260.0 Hz), 123.4, 126.8,
128.6, 128.7, 130.0 (t, JC—F＝3.4 Hz), 131.2, 131.7,
131.9, 132.1, 132.3, 134.5, 167.6, 189.2 (t, JC—F＝28.7
Hz); 19F NMR (CDCl3, 282 MHz, TMS) δ: －111.1 (dd,
J＝279, 1F, 12 Hz), －114.5 (dd, J＝279, 1F, 14 Hz);
IR (acetone) ν: 3292, 3064, 2924, 2853,1778, 1704,
1645, 1597, 1579, 1528, 1488, 1467, 1449, 1309, 1281,
－1
1212, 1182, 1072, 1012, 925, 908 cm ; MS (ESI) m/z
(%): 460 (97) [＋M＋＋1]; HRMS (MALDI) calcd for
C22H17BrF2N2O2 1 (M＋＋1) 459.0518, found 459.0514.
N-(2,2-Difluoro-3-oxo-3-phenyl-1-p-tolylpropyl)-
benzohydrazide (3d) A pale yellow oil (76%, 60 mg);
1H NMR (CDCl3, 300 MHz, TMS) δ: 2.33 (s, 3H, CH3),
4.96 (t, J＝13.5 Hz, 1H, NH), 5.44 (d, J＝5.1 Hz, 1H,
CH), 7.15 (d, J＝7.8 Hz, 2H, ArH), 7.35—7.51 (m, 7H,
ArH), 7.57 (d, J＝6.9 Hz, 3H, ArH), 7.63 (d, J＝4.8 Hz,
1H, BzNH), 7.97 (d, J＝7.5 Hz, 2H, ArH); 13C NMR
(CDCl3, 75 MHz, TMS) δ: 21.2, 66.5 (dd, JC—F＝21.3,
2.4 Hz), 118.2 (t, JC—F＝302.0 Hz), 126.8, 128.6, 129.3
(d, JC—F＝3.2 Hz), 129.7, 130.0 (t, JC—F＝3.5 Hz), 132.0,
132.2, 132.6, 134.3, 139.1, 167.3, 189.7 (t, JC—F＝29.5
Hz); 19F NMR (CDCl3, 282 MHz, TMS) δ: －111.7 (dd,
J＝277, 13 Hz, 1F), －114.0 (dd, J＝277, 14 Hz, 1F);
IR (acetone) ν: 3294, 3061, 3030, 2923, 2860, 1779,
1706, 1648, 1598, 1579, 15－15, 1449, 1309, 1283, 1183,
N-(2,2-Difluoro-3-oxo-1,3-diphenylpropyl)benzo-
hydrazide (3a) A pale yellow oil (79%, 61 mg); H
1
NMR (CDCl3, 300 MHz, TMS) δ: 5.01 (t, J＝12.6 Hz,
1H, NH), 5.46 (br, 1H, CH), 7.34—7.60 (m, 13H, ArH),
7.69 (s, 1H, BzNH), 7.95 (d, J＝7.8 Hz, 2H, ArH); 13C
NMR (CDCl3, 75 MHz, TMS) δ: 66.5 (dd, JC—F＝23.8,
21.1 Hz), 117.3 (t, JC—F＝259.1 Hz), 126.8, 128.5, 128.6,
129.1, 129.5, 129.9 (t, JC—F＝3.6 Hz), 131.9, 132.1,
132.4 (t, JC—F＝1.9 Hz), 132.7 (d, JC—F＝2.3 Hz), 134.2,
167.5, 189.6 (t, JC—F＝28.7 Hz); 19F NMR (282 MHz,
CDCl3, TMS) δ: －111.5 (dd, J＝276, 12 Hz, 1F),
－114.0 (dd, J＝276, 14 Hz, 1F); IR (acetone) ν: 3293,
3064, 2374, 1775, 1702, 1697, 1676, 1655, 1598, 1579,
－1
1
1528, 1450, 1310, 1283, 1211, 1184, 1066, 907 cm ;
1126, 1068,＋1026, 925 cm ; MS (ESI) m/z (%): 395
MS (ESI) m/z (%): 381 (100) [M ＋ ＋ 1]; HRMS
(100) [M
＋ 1]; HRMS (MALDI) calcd for
(MALDI) calcd for C22H18F2N2O2Na ＋ (M ＋ ＋ 1)
C23H21F2N2O2 1 (M＋＋1) 395.1574, found 395.1565.
N-(2,2-Difluoro-1-(4-methoxyphenyl)-3-oxo-3-
phenylpropyl)benzohydrazide (3e) A pale yellow oil
＋
1
403.1234, found 403.1229. Enantiomeric excess was
determined by HPLC with a Chiralcel OJ-H column
1
(hexane/i-PrOH＝70/30, 0.6 mL/min, 230 nm, tminor
＝
(61%, 53 mg); H NMR (CDCl3, 300 MHz, TMS) δ:
34.00 min, tmajorr＝47.63 min; [α]2D0 －12.7 (c 0.55,
CH2Cl2), 51% ee).
3.78 (s, 3H, OCH3), 4.99 (dt, J＝14.4, 1.8 Hz, 1H, NH),
5.41 (d, J＝4.5 Hz, 1H, CH), 6.85 (d, J＝8.7 Hz, 2H,
ArH), 7.35—7.50 (m, 7H, ArH), 7.55—7.60 (m, 3H,
ArH), 7.69 (d, J＝6.0 Hz, 1H, BzNH), 7.96 (d, J＝7.2
Hz, 2H, ArH); 13C NMR (CDCl3, 75 MHz, TMS) δ:
55.2, 66.1 (dd, JC—F＝22.9, 21.0 Hz), 113.9, 119.2 (t,
JC—F＝130.2 Hz), 124.6 (d, JC—F＝2.7 Hz), 126.8, 128.6,
130.0 (t, JC—F＝3.4 Hz), 130.7, 131.9, 132.2, 132.5,
134.2, 160.1, 167.3, 189.7 (t, JC—F＝28.3 Hz); 19F NMR
(CDCl3, 282 MHz, TMS) δ: －112.0 (dd, J＝292, 14
Hz, 1F,), －113.9 (dd, J＝292, 13 Hz, 1F); IR (acetone)
ν: 3298, 3065, 3003, 2958, 2934, 2838, 1775, 1709,
1642, 1612, 1580, 1514, 14－49, 1363, 1306, 1253, 1179,
N-(1-(4-Chlorophenyl)-2,2-difluoro-3-oxo-3-phen-
ylpropyl)benzohydrazide (3b) A pale yellow oil
1
(75%, 62 mg); H NMR (CDCl3, 300 MHz, TMS) δ:
5.02 (t, J＝12.6 Hz, 1H,NH), 5.46 (br, 1H, CH), 7.30—
7.51 (m, 9H, ArH), 7.55—7.62 (m, 3H, ArH), 7.76 (d,
J＝4.8 Hz, 1H, BzNH), 7.98 (d, J＝7.8 Hz, 2H, ArH);
13C NMR (CDCl3, 75 MHz, TMS) δ: 65.9 (dd, JC—
＝
F
23.3, 20.9 Hz), 117.0 (t, JC—F＝261.1 Hz), 126.8, 128.6,
128.7, 128.8, 130.0 (t, JC—F＝3.5 Hz), 130.9, 131.4,
132.0, 132.1, 132.3, 134.5, 135.2, 167.6, 189.3 (t, JC—
F
＝29.0 Hz); 19F NMR (CDCl3, 282 MHz, TMS) δ:
－111.3 (dd, J＝278, 12 Hz, 1F), －114.3 (dd, J＝278,
16 Hz, 1F); IR (acetone) ν: 3293, 3064, 2925, 2854,
1777, 1703, 1649, 1598, 1579, 1527, 1492, 1467, 1449,
1
1125, 1072,＋1027, 925 cm ; MS (ESI) m/z (%): 411
(100) [M
＋ 1]; HRMS (MALDI) calcd for
C23H21F2N2O3 1 (M＋＋1) 411.1520, found 411.1515.
N-(1-(2-Chlorophenyl)-2,2-difluoro-3-oxo-3-phen-
ylpropyl)benzohydrazide (3f) A pale yellow oil
＋
－1
1310, 1282, 1211, 1184, 1091, 1016, 925, 908 cm ;
MS (ESI) m/z (%): 415 (100) [M ＋ ＋ 1]; HRMS
＋ 1
1
(MALDI) calcd for C22H17ClF2N2O2Na
437.0844, found 437.0839.
(M ＋ ＋ 1)
(45%, 37 mg); H NMR (CDCl3, 300 MHz, TMS) δ:
5.52 (br, 1H, NH), 5.66 (dd, J＝18.6, 7.5 Hz, 1H, CH),
7.29—7.48 (m, 8H, ArH), 7.50—7.63 (m, 4H, ArH),
7.77 (d, J＝7.5 Hz, 1H, BzNH), 8.07 (d, J＝7.5 Hz, 2H,
ArH); 13C NMR (CDCl3, 75 MHz, TMS) δ: 62.1 (dd,
JC—F＝24.9, 20.6 Hz), 117.1 (t, JC—F＝255 Hz), 126.8,
127.0, 128.5, 128.7, 129.7, 130.0 (t, JC—F＝3.4 Hz),
130.2, 131.0, 131.9, 132.0, 132.2, 134.4, 135.5, 167.4,
N-(1-(4-Bromophenyl)-2,2-difluoro-3-oxo-3-phen-
ylpropyl)benzohydrazide (3c) A yellow oil (78%, 72
1
mg); H NMR (CDCl3, 300 MHz, TMS) δ: 4.99 (t, J＝
12.3 Hz, 1H, NH), 5.45 (d, J＝3.3 Hz, 1H, CH), 7.36—
7.51 (m, 9H, ArH), 7.55—7.63 (m, 3H, ArH), 7.73 (d,
J＝6.0 Hz, 1H, BzNH), 7.98 (d, J＝7.8 Hz, 2H, ArH);
1714
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1709— 1716

Zinc(II)-Catalyzed Mannich-type Reactions and Its Application
189.2 (t, JC—F＝27.9 Hz); 19F NMR (CDCl3, 282 MHz,
TMS) δ: －109.3 (dd, J＝276, 7.6 Hz, 1F), －116.6
(dd, J＝276, 18 Hz, 1F); IR (acetone) ν: 3291, 3065,
1968, 1901, 1818, 1780, 1703, 1648, 1598, 1579, 1528,
1475, 1449, 1362, 1308, 1282, 1181, 1128, 1070, 1028,
MHz, TMS) δ: －109.6 (dd, 1F, J＝282, 10 Hz),
－114.5 (dd, J＝282, 16 Hz, 1F); IR (acetone) ν: 3293,
3063, 2926, 2285, 1969, 1911, 1707, 1648, 1598, 1580,
1534, 1450, 1311, 1279, 1201, 1185, 1128, 1062, 1027,
－1
1001, 917, 809 cm ; MS (ESI) m/z (%): 371 (10＋0)
－1
1
1001, 926, 901 cm ; MS (ESI) m/z (%): 415 (100)
[M＋＋1]; HRMS (MALDI) calcd for C20H17F2N2O3
＋1
[M＋＋1]; HRMS (MALDI) calcd for C22H17ClF2N2O2
(M＋＋1) 371.1213, found 371.1202.
(M＋＋1) 415.1032, found 415.1019.
(E)-Ethyl 2-(2-benzoylhydrazono)-3-fluoro-4-oxo-
4-phenylbutanoate (4) A pale yellow solid, m.p. 99
N-(1-(3-Chlorophenyl)-2,2-difluoro-3-oxo-3-phen-
ylpropyl)benzohydrazide (3g) A pale yellow oil
(78%, 65 mg); H NMR (CDCl3, 300 MHz, TMS) δ:
1
—102 ℃ (33%, 23 mg); H NMR (CDCl3, 400 MHz,
1
TMS) δ: 1.34 (t, J＝6.8 Hz, 3H, CH3), 4.38 (q, J＝6.8
Hz, 2H, CH2), 5.13 (br, 1H, NH), 5.60 (d, JH－F＝52 Hz,
1H, CH), 7.35—7.40 (m, 3H, ArH), 7.45—7.49 (m, 4H,
ArH), 7.55—7.59 (m, 1H, ArH), 7.97 (d, J＝7.2 Hz, 2H,
ArH); 13C NMR (CDCl3, 100 MHz, TMS) δ: 14.0, 62.3,
95.5 (d, JC—F＝91 Hz), 96.8 (d, JC—F＝26 Hz), 124.2,
125.7 (d, JC—F＝2.7 Hz), 128.1, 128.2, 128.3, 128.5,
128.8, 129.3, 129.4, 130.4, 130.6, 131.5, 132.8 (d,
JC—F＝52 Hz), 133.0, 134.3 (d, JC—F＝3.8 Hz), 143.2 (d,
JC—F＝17 Hz), 160.1, 168.8; 19F NMR (CDCl3, 376
MHz, TMS) δ: －177.6 (d, J＝52 Hz, 1F); IR (acetone)
ν: 3448, 3066, 2975, 1741, 1720, 1665, 1578, 1450,
1389, 1－365, 1302, 1247, 1192, 1091＋, 1065, 1013, 905,
5.00 (dt, J＝11.4, 1.8 Hz, 1H, NH), 5.45 (d, J＝3.9 Hz,
1H, CH), 7.26—7.31 (m, 3H, ArH), 7.34—7.41 (m, 3H,
ArH), 7.43—7.46 (m, 2H, ArNH), 7.48—7.62 (m, 4H,
ArH), 7.77 (d, J＝5.7 Hz, 1H, BzNH), 7.98 (d, J＝7.2
Hz, 2H, ArH); 13C NMR (CDCl3, 75 MHz, TMS) δ:
66.0 (dd, JC—F＝23.5, 20.6 Hz), 116.9 (t, JC—F＝255 Hz),
126.8, 127.9, 128.6, 128.7, 129.3, 129.6, 129.8, 130.0 (t,
JC—F＝3.3 Hz), 131.9, 132.0, 132.3 (t, JC—F＝2.6 Hz),
134.4, 134.5, 134.9 (d, JC—F＝2.6 Hz), 167.6, 189.2 (t,
JC—F＝28.3 Hz); 19F NMR (CDCl3, 282 MHz, TMS) δ:
－110.8 (dd, J＝280, 11 Hz, 1F), －114.5 (dd, J＝280,
16 Hz, 1F); IR (acetone) ν: 3303, 3066, 3003, 2922,
1968, 1908, 1818, 1779, 1715, 1638, 1598, 1579, 1528,
1449, 1361, －1309, 1282, 1220, 1186, 1055, 1027,＋1001,
1
855 cm ; MS (EI) m/z (%): 356 [M ] (0.4), 283 (7.9),
251 (4.3), 232 (2.8), 219 (3.1), 175 (1.5), 130 (1.7), 105
(100), 77 (32.9). 5＋1 (5.4); HRMS (EI) calcd for
C19H17N2O4F (M＋H ): 356.1172, found 356.1171.
1
933, 910 cm ; MS (ESI) m/z (%): 415 (100) [M ＋＋1];
＋1
HRMS (MALDI) calcd for C22H17ClF2N2O2 (M ＋1)
415.1026, found 415.1019.
N-(2,2-Difluoro-1-(naphthalen-1-yl)-3-oxo-3-
phenylpropyl)benzohydrazide (3i) A yellow oil
References
1
1
For reviews on asymmetric Mannich reactions see:
(a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
(b) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res.
2003, 36, 10.
(67%, 58 mg); H NMR (CDCl3, 300 MHz, TMS) δ:
5.56 (br, 1H, CH), 5.92 (t, J＝12.0 Hz, 1H, NH), 7.29—
7.36 (m, 4H, ArH), 7.40—7.54 (m, 7H, ArH), 7.82—
7.89 (m, 6H, ArNH), 8.15 (br, 1H, BzNH); 13C NMR
(CDCl3, 75 MHz, TMS) δ: 60.5 (dd, JC—F＝22.9, 21.2
Hz), 117.9 (t, JC—F＝258.1 Hz), 124.9, 125.7, 126.7,
(c) Kobayashi, S.; Ueno, M. In Comprehensive Asymmetric
Catalysis, Eds.: Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,
Supplement 1, Springer, Berlin, 2004, Chapter 29.5, p. 143.
(d) Arrayás, R. G.; Carretero, J. C. Chem. Soc. Rev. 2009,
38, 1940.
126.8, 128.4, 128.5, 128.7, 128.9, 129.8, 129.9 (t, JC—
F
＝3.4 Hz), 131.9, 132.0, 132.2, 132.6, 133.7, 134.2,
167.5, 189.9 (t, JC—F＝43.0 Hz); 19F NMR (CDCl3, 282
MHz, TMS) δ: －109.1 (dd, J＝274, 8 Hz, 1F),
－113.1 (dd, 1F, J＝274, 11 Hz); IR (acetone) ν: 3292,
3062, 2925, 1919, 1779, 1704, 1656, 1598, 1579, 1514,
1468, 1449, 1362, 1310, 1277, 1184, 1125, 1069, 1028,
2
(a) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shi-
basaki, M. J. Am. Chem. Soc. 2003, 125, 5634.
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＋
－1
(c) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa,
H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507.
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908 cm ; MS (ESI) m/z (%): 431 (100＋) [M ＋1];
HRMS (MALDI) calcd for C26H21F2N2O2 (M＋＋1)
1
431.1570, found 431.1565.
N-(2,2-Difluoro-1-(furan-2-yl)-3-oxo-3-phenylpro-
pyl)benzohydrazide (3j) A yellow oil (63%, 47 mg);
1H NMR (CDCl3, 300 MHz, TMS) δ: 5.15 (dt, J＝10.2,
3.0 Hz, 1H, NH), 5.59 (br, 1H, CH), 6.35 (dd, J＝3.3,
1.8 Hz, 1H, ArH), 6.50 (d, J＝3.3 Hz, 1H, ArH), 7.37—
7.52 (m, 6H, ArH), 7.59—7.76 (m, 3H, ArH), 7.77 (d,
J＝3.6 Hz, 1H, BzNH), 8.03 (d, J＝8.1 Hz, 2H, ArH);
(f) Ref. 1a and the references cited therein.
For recent reviews of the chemistry of N-acylhydrazines,
see:
(a) Licandro, E.; Perdicchia, D. Eur. J. Org. Chem. 2004,
665.
(b) Friestad, G. K. Eur. J. Org. Chem. 2005, 3157.
Sugiura, M.; Kobayashi, S. Angew. Chem., Int. Ed. 2005, 44,
5176.
3
4
13C NMR (CDCl3, 75 MHz, TMS) δ: 60.6 (dd, JC—
＝
F
24.2, 22.1 Hz), 110.7, 111.3, 120.1 (t, JC—F＝261 Hz),
126.9, 128.7, 130.0 (t, JC—F＝3.5 Hz), 132.0, 132.2 (t,
JC—F＝3.8 Hz), 134.4, 143.4, 146.3 (d, JC—F＝3.5 Hz),
167.4, 189.1 (t, JC—F＝28.7 Hz); 19F NMR (CDCl3, 282
Chin. J. Chem. 2010, 28, 1709— 1716
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1715

Yuan, Wei & Shi
FULL PAPER
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Chin. J. Chem. 2010, 28, 1709— 1716