Reaction of aldimines and difluoroenoxysilane, an unexpected protocol for the synthesis of 2,2-difluoro-3-hydroxy-1-ones

Article abstract of DOI:10.1016/j.tet.2010.07.034

An unexpected reaction of aldimines and difluoroenoxysilane promoted with Zn(OTf)₂ was disclosed. The reaction gave the unexpected Mukaiyama-aldol adducts 3 in excellent yields (up to 87%) with the addition of H₂O and the correspondi

Full text of DOI:10.1016/j.tet.2010.07.034

Tetrahedron 66 (2010) 7361e7366
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Reaction of aldimines and difluoroenoxysilane, an unexpected protocol
for the synthesis of 2,2-difluoro-3-hydroxy-1-ones
,b,
Zhi-Liang Yuan a, Yin Wei b, Min Shi a
*
a Laboratory for Advanced Materials & Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and Technology,
130 Mei Long Lu, Shanghai 200237, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032 China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 May 2010
Received in revised form 16 July 2010
Accepted 16 July 2010
Available online 22 July 2010
An unexpected reaction of aldimines and difluoroenoxysilane promoted with Zn(OTf)2 was disclosed.
The reaction gave the unexpected Mukaiyama-aldol adducts 3 in excellent yields (up to 87%) with the
addition of H2O and the corresponding Mannich-type adduct 4 was not observed in this catalytic
system.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
and difluoroenoxysilane 2 formed an unexpected Mukaiyama-al-
dol adducts 3 rather than the corresponding Mannich adduct 4,
Since the introduction of fluorine atoms into organic molecules
causes changes in physical, chemical and pharmacological proper-
ties,1 organofluorine chemistry provides stimulation in synthetic,
biomedical, and material science.2 Among some reported fluorine-
containing units, a difluoromethylene unit, which plays a significant
role in current organofluorine chemistry,3 was revealed containing
in some biologically interesting compounds, such as in phospho-
tyrosine (pTyr) mimetics,4 anticancer agent gemcitabine,5 and HIV-
1 protease inhibitors.6 Furthermore, due to the importance in
which we expected to obtain. Therefore, we wish to investigate this
novel route for the synthesis of 2,2-difluoro-3-hydroxy-1-ones via
the reaction of aldimines and difluoroenoxysilane promoted by
Lewis acids.
Previous research
Ar2
AgOAc,
Ar2
+
HN
Chiral Ligand
N
*
Ar1
*
Ar1
O
chemical biology, a,a-difluoro-b-amino acids have attracted much
OTMS
O
interest in the past decades.7 Recently, scientists have developed
a variety of methods for the preparation of difluoromethylene units
containing compounds. Among them, difluoroenolsilylanes, which
could be readily prepared by Mg(0) promoted selective defluori-
nation of trifluoromethyl ketones in the presence of TMSCl,8 are
considered as excellent building blocks for the synthesis of gem-
difluorinated compounds.
O
up to 91% yield,
up to 81% ee,
up to 99/1 dr (anti/ syn)
This research
Ar2
Ar2
Our previous research has disclosed a catalytic asymmetric
vinylogous Mannich (AVM) reaction of readily available aldimines
with trimethylsiloxyfuran promoted by silver salts.9 The catalytic
system gave the AVM products in high yields along with good
enantioselectivities (Scheme 1). We envisioned that the use of
difluoroenoxysilanes in the AVM reaction instead of trimethylsi-
loxyfuran might be a novel method to achieve chiral gem-
difluorinated compounds. To the best of our knowledge, the direct
catalytic asymmetric difluoromethylation of imines has not been
reported. However, it was found that the reaction of aldimines 1
F
OTMS
Ph
N
NH
F
O
Lewis acid
?
+
Ar1
Ar1
Ph
F
F
Scheme 1. Previously studied Lewis acid catalyzed AVM reaction and the proposal in
this research.
2. Results and discussion
We initially investigated the reaction of aldimine 1a with
difluoroenoxysilane 2 in the presence of a catalytic amount of
AgOAc. Unfortunately, the reaction could not be promoted by AgOAc
that has shown good catalytic activity in our previouslystudied AVM
* Corresponding author. E-mail address: mshi@mail.sioc.ac.cn (M. Shi).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.034

7362
Z.-L. Yuan et al. / Tetrahedron 66 (2010) 7361e7366
Ph
Ph
OH
O
NH
F
O
Ph
+
F
F
OTMS
Ph
N
AgOAc (10 mol%)
Ph
Ph
+
Ph
THF, rt, overnight
F
F
Ph
F
4
3a
1a
2
not observed
Scheme 2. Initial survey in the reaction of aldimine 1a with difluoroenoxysilane 2.
ꢀ
ꢀ
reaction (Scheme 2). Then another Lewis acid Zn(OTf)2 was tested as
a promoter. To our surprise, the reaction of aldimine 1a and
difluoroenoxysilane 2 proceeded efficiently when 10 mol % Zn(OTf)2
was used as the promoter, giving an unexpected Mukaiyama-aldol
adduct 3a in 67% yield instead of Mannich adduct 4 (Table 1, entry 1).
of MS 4 A (molecular sieves 4 A, 100 mg) affected the result of the
ꢀ
reactionofaldimine1awithdifluoroenoxysilane2. WhenMS4 A was
added into the reaction, only trace amount of adduct 3a was formed
(Table 2, entry 6). On the other hand, the addition of 1.0 equiv of H2O
could improve the yield of adduct 3a up to 87% (Table 2, entry 7).
Table 1
Reaction of aldimine 1a (1.0 equiv) with difluoroenoxysilane 2 (1.5 equiv) in the presence of Lewis acids (10 mol %) at ambient temperaturea
Ph
OH
O
Ph
NH
F
O
F
F
OTMS
Ph
N
Lewis acid (10 mol%)
THF, rt, 12 h
+
Ph
+
Ph
Ph
Ph
Ph
F
F
F
4
1a
2
3a
Entry
Lewis acid
Yield/(%)b
3a
4
1
2
Zn(OTf)2
Cu(OTf)2
(CuOTf)2$C6H6
AgOTf
Sc(OTf)3
Yb(OTf)3
67
52
60
66
30
45
0
13
0
0
29
25
3c
4
5
6
a
The reaction was carried out with 0.20 mmol of 1a, 0.30 mmol of 2, and 10 mol % of Lewis acids in THF (2.0 mL) at room temperature.
Isolated yield.
(CuOTf)2$C6H6 (5 mol %) was used.
b
c
Table 2
An extensive survey of several commonly used Lewis acids
Solvent and additive effects on the Zn(OTf)2-catalyzed reaction of aldimine 1a
(10 mol %) was carried out in the reaction of aldimine 1a
(0.20 mmol) with difluoroenoxysilane 2 (0.30 mmol) in 2 mL tetra-
hydrofuran (THF) at ambient temperature. The results are summa-
rized in Table 1. It was found that the reaction proceeded smoothly
when using (CuOTf)2$C6H6 and AgOTf as the promoters (Table 1,
entries 3 and 4), affording aldol-type adduct 3a in up to 66% yield
without forming adduct 4. When several other Lewis acids were
applied into this reaction, such as Cu(OTf)2, Sc(OTf)3, and Yb(OTf)3,
however, the reactions proceeded inefficiently (Table 1, entries 2, 5,
and 6). For example, it was found that Mannich adduct 4 was formed
in up to 29% yield along with aldol-type adduct 3a in 30% yield when
Sc(OTf)3 was used as a Lewis acid (Table 1, entry 5), and the main
product 3a was achieved in 52% yield along with 13% of adduct 4
when Cu(OTf)2 was employed as a Lewis acid (Table 1, entry 2).
Subsequently, we carried out the reaction of aldimine 1a with 2 in
different solvents and additives with 10 mol % of Zn(OTf)2, which has
been identified as the best Lewis acid in this reaction. Mannich ad-
duct 4 was not observed yet when other solvents were used. The
results are outlined in Table 2. When the reaction was carried out in
dichloromethane (DCM), aldol-type adduct 3a was obtained in 57%
yield, lower than in THF (Table 2, entry 1). Solvents, such as CH3CN
and toluene are not suitable for this reaction, providing 3a in very low
yields(Table 2, entries 3 and 4). Itwasalsoobserved thatthereactions
proceeded efficiently to give the adduct 3a in Et2O and 1,4-dioxane in
up to 62% and 66% yields, respectively (Table 2, entries 2 and 5).
Hypothetically, the water in the catalytic system may play an im-
portant role in this reaction, leading to the formation of the un-
expected adduct 3. Thus, the further studies were performed to
identify the effect of H2O in this reaction. We found that the addition
(1.0 equiv) with difluoroenoxysilane 2 (1.5 equiv)a
OH
F
O
Ph
F
F
OTMS
Ph
N
Zn(OTf)2 (10 mol%)
+
Ph
Ph
solvent, additive,
rt, 12 h
Ph
F
1a
2
3a
Entry
Solvent
Additive
Yield/(%)b
3a
1
2
3
4
DCM
Et2O
MeCN
Toluene
1,4-Dioxane
THF
None
None
None
None
None
57
66
Trace
37
62
5
6c
7d
MS 4 A
H2O
Trace
87
ꢀ
THF
a
The reaction was carried out with 0.20 mmol of 1a, 0.30 mmol of 2, and 10 mol %
of Zn(OTf)2 in solvents (2.0 mL) at room temperature.
b
Isolated yield.
MS 4 A (100 mg) was used as additive.
H2O (0.20 mmol, 1.0 equiv) was used as an additive.
c
ꢀ
d
With these optimized reaction conditions in hand, we next
turned our attention to the reactions of a variety of aldimines 1
with difluoroenoxysilane 2. The results are summarized in Table 3.
For aldimines 1def bearing electron-donating groups on the
benzene rings, the reaction proceeded smoothly to afford corre-
sponding aldol-type adducts 3a and 3d in good yields (Table 3,

Z.-L. Yuan et al. / Tetrahedron 66 (2010) 7361e7366
7363
Table 3
entries 2, 3, 7, and 8). Unfortunately, the reaction of aldimine 1i,
which containing a furan ring with difluoroenoxysilane 2 formed
the corresponding adduct 3f in only 25% yield (Table 3, entry 9).
Using aliphatic aldimine 1j as a reactant under the optimized
reaction conditions, the reaction proceeded inefficiently to form
the corresponding product 3g in low yield even 1.0 equiv of H2O
was added as an additive (Table 3, entry 10). Gratifyingly, when
1.0 equiv of H2O was added, the reaction proceeded more effi-
ciently, affording the desired aldol-type adducts 3aee in excellent
yields (up to 86%) under the optimized reaction conditions irre-
spective of the electronic properties of substrates 1 (Table 3, en-
tries 2e8) except aldimines 1i and 1j (Table 3, entries 9 and 10).
As the results described above indicated that the addition of H2O
could improve the yields of the corresponding adducts 3, another
control experiment was carried out by adding 3.0 equiv of H218O
into the reaction system instead of H2O under the optimized re-
action conditions (Scheme 3). We observed that in the presence of
3.0 equiv of H218O, the reaction proceeded efficiently, giving the
adduct 3ae18O in 91% yield along with 67% of 18O content as de-
termined by EIMS. This result indicates that H2O is involved into the
formation of the corresponding aldol adduct 3a. Some other control
experiments were also carried out in order to reveal the role of H2O
in the catalytic cycle and rationalize the reaction results. When
benzaldehyde was used as a substrate instead of aldimine 1a under
Survey of aldimine 1 (1.0 equiv) with diethyl difluoroenoxysilane 2 (1.5 equiv) in the
presence of Zn(OTf)2 (10 mol %) at room temperaturea
R2
OH
F
O
F
F
OTMS
Ph
N
Zn(OTf)2 (10 mol%)
THF, rt, 12 h
R1
Ph
+
R1
F
1
2
3
Entry
Aldimine 1 (R1/R2)
Yield/(%)b
3
1
2
3
4
5
6
7
8
9
1a (C6H5/C6H5)
3a, 67/(87)c
3b, 67/(83)c
3c, 71/(79)c
3d, 73/(79)c
3a, 68/(78)c
3a, 70/(86)c
3e, 71/(80)c
3a, 69/(78)c
3f, 25/(28)c
3g, 17/(16)c
1b (4-ClC6H4/C6H5)
1c (4-BrC6H4/4-BrC6H4)
1d (4-CH3OC6H4/C6H5)
1e (C6H5/4-CH3OC6H4)
1f (C6H5/4-CH3C6H4)
1g (4-NO2C6H4/C6H5)
1h (C6H5/4-NO2C6H4)
1i (2-Furan/C6H5)
10
1j (C6H5(CH2)2/C6H5)
a
The reaction was carried out with 0.20 mmol of 1, 0.30 mmol of 2, and 10 mol %
of Zn(OTf)2 in THF (2.0 mL) at room temperature.
b
Isolated yield.
H2O (0.20 mmol, 1.0 equiv) was used as an additive.
c
ꢀ
entries 4e6). As for aldimines bearing electron-withdrawing
groups on the benzene rings, the corresponding products 3aec
and 3e were also achieved in moderate to good yields (Table 3,
the optimized reaction conditions (MS 4 A 100 mg was added into
the reaction system), the aldol adduct 3a was achieved in very
low yield even after a prolonged reaction time [Scheme 4, Eq. 1].
18OH
Ph
O
Ph
Zn(OTf)2 (10 mol%)
H218O (3.0 equiv),
THF, rt, 12 h
F
F
OTMS
Ph
N
Ph
Ph
F
18
F
1a
2
3a- O, 91% (18O content 67%)
Scheme 3. Isotope labeling experiment of Zn(OTf)2 promoted reaction of aldimine 1a with difluoroenoxysilane 2.
OH
F
O
Zn(OTf)2 (10 mol%),
MS 4A (100 mg)
O
F
F
OTMS
Ph
+
(1)
(2)
Ph
Ph
Ph
THF, rt, 24 h
Ph
H
F
2
3a, 10%
OH
O
O
F
F
OTMS Zn(OTf)2 (10 mol%)
+
Ph
Ph
H2O (1.0 equiv),
THF, rt, 24 h
Ph
Ph
H
F
F
3a, 53%
2
OH
O
O
F
OTMS
Ph
TfOH (10 mol%)
THF, rt, 24 h
Ph
Ph
+
(3)
(4)
F
Ph
Ph
H
F
F
3a, 60%
2
Ph
Ph
OH
O
NH
F
O
TfOH (10 mol%),
MS 4A (100 mg)
THF, rt, 24 h
NPh
F
OTMS
Ph
+
+
Ph
+
Ph
Ph
F
F
3a
F
F
, 0%
4
, trace
1a
2
Ph
Ph
OH
O
NH
O
NPh
F
F
OTMS
Ph
TfOH (10 mol%)
H2O (1.0 equiv),
THF, rt, 24 h
+
(5)
Ph
Ph
Ph
F
F
F
F
1a
2
3a, 35%
4, 11%
Scheme 4. Control experiments of reactions of benzaldehyde or aldimine 1a with difluoroenoxysilane 2.

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Z.-L. Yuan et al. / Tetrahedron 66 (2010) 7361e7366
This result suggests that aldehydes cannot produce the corre-
sponding aldol adducts efficiently when Zn(OTf)2 was used as the
catalyst. However, the reaction of benzaldehyde with difluor-
oenoxysilane 2 could be promoted by 10 mol % Zn(OTf)2 when
1.0 equiv of H2O was added into this reaction system, and the cor-
responding product 3a was achieved in 53% yield [Scheme 4, Eq. 2].
It should be noted that when we utilized trifluoromethanesulfonic
acid CF3SO3H (TfOH) (10 mol %) as a promoter instead of zinc salt
into the reaction of benzaldehyde with difluoroenoxysilane 2
[Scheme 4, Eq. 3], this reaction proceeded efficiently, giving the
aldol-adduct 3a in 60% yield. We also found that, in the reaction of
benzaldehyde with difluoroenoxysilane 2, treatment of aldimine 1a
with difluoroenoxysilane 2 in the presence of 10 mol % TfOH and
(OTf)2, Sc(OTf)3, and Yb(OTf)3, were applied into this reaction
instead of Zn(OTf)2. On the basis of the control experiments and
18O-labeling experiment, we found that adducts 3 cannot be
achieved efficiently when Zn(OTf)2 used as a promoter in the
reaction of benzaldehyde with difluoroenoxysilane. The reaction
proceeds through an oxygen transfer from H2O, which contains
in the reaction system. As compared with these reactions to
synthesize 2,2-difluoro-3-hydroxy-1-ones utilizing 0.50 equiv of
TiCl4 or 1.0 equiv of BF3$Et2O as a promoter,12,13 herein, we
reported an unprecedented route, which could approach to these
gem-difluorinated compounds under the promotion of catalytic
amount of Zn(OTf)2 and mild reaction conditions to give the
products in higher yields.
ꢀ
MS 4 A (100 mg) could not afford aldol-adduct 3a or Mannich ad-
duct 4 (in trace) [Scheme 4, Eq. 4]. We assumed that H2O may
participate in the decomposition of aldimines in the presence of
TfOH. Therefore, we attempted to add 1.0 equiv of H2O into the
reaction of aldimine 1a with difluoroenoxysilane 2 in the presence
of 10 mol % TfOH to examine the reaction outcome. Fortunately, it
was found that not only the aldol-type product 3a was formed in
35% yield, but the Mannich adduct 4 was also obtained in 11% yield,
suggesting again that H2O and HOTf play key roles in the formation
of aldol-adduct 3a [Scheme 4, Eq. 5].
On the basis of the control experiments, a plausible mechanism
is shown in Scheme 5. Since the addition of H2O played a key role
in this reaction, we believed that Zn(OTf)2 activated aldimine 1
and generated TfOH spontaneously at the first step. After being
treated with H2O, the decomposition of activated aldimine I
generated aldehyde III with the elimination of amine II. The
protonation of aldehyde III with TfOH afforded an activated car-
bonyl compound IV, which then reacted with difluoroenoxysilane
2 in a Mukaiyama-aldol type reaction to give the corresponding
aldol-adduct 3. Generally, nitrogen containing organic bases are
considered as efficient additives to improve a lot of catalytic
processes involving silylenol ethers,11 we believed that the in situ
generated amine II acted as an efficient additive to activate the
Lewis acid and promote the elimination of silyl group to enhance
the reaction rates and the yields of the corresponding aldol-ad-
ducts 3 in this catalytic cycle. A more detailed mechanistic in-
vestigation is undergoing.
3. Experimental section
3.1. General remarks
1H, 13C, and 19F NMR spectra were recorded on a Bruker AM-
400 spectrometer for solution in CDCl3 with tetramethylsilane
(TMS) as an internal standard; J-values are in hertz. Mass spectra
were recorded by EI methods, and HRMS was measured on a Fin-
nigan MAþ mass spectrometer. THF and toluene were distilled
from sodium (Na) under argon (Ar) atmosphere. CH3CN and 1,2-
dichloromethane were distilled from CaH2 under argon (Ar) at-
mosphere. Commercially obtained reagents were used without
further purification. All reactions were monitored by TLC with
Huanghai GF254 silica gel coated plates. Flash column chroma-
tography was carried out using 300e400 mesh silica gel at in-
creased pressure.
3.2. General procedure for the preparation
of difluoroenoxysilane 210
A mixture of chlorotrimethylsilane (TMSCl) (6.0 mmol), Mg
(6.0 mmol), and THF (10 mL) was cooled down to 0 ꢀC under argon
atmosphere. Then trifluoroacetophenone (1.5 mmol) was added
dropwise and the resulting mixture was stirred for additional 1.0 h.
After the solvent was removed under vacuum, hexane (15 mL) was
added totheresidue. Theresultingsaltwasfiltered and the filtratewas
then concentrated to give the crude product of difluoroenoxysilane
2 under reduced pressure. This crude product 2 was used for the
Mukaiyama-aldol type reaction without further purification.
Ar2
OH
F
O
F
Zn(OTf)2 (10 mol%),
H2O (1.0 equiv)
N
F
F
OTMS
Ph
+
Ar1
Ph
Ar1
THF, r.t.
3.3. General procedure for the reaction of aldimine 1 with
difluoroenoxysilane 2 in the presence of 1 equiv of H2O and
catalytic amount of Zn(OTf)2
1
3
2
TMS+
Zn(OTf)2, H2O
The solution of aldimine 1a (0.20 mmol), Zn(OTf)2
(0.02 mmol) and THF (2.0 mL) was allowed to stir for 5.0 min at
ambient temperature. A freshly prepared difluoroenoxysilane 2
(0.30 mmol) was added dropwise by syringe and followed by
addition of 1.0 equiv of H2O. The reaction mixture was allowed to
stir for 12 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.
Ar2
Zn2+
H2O
Zn2+
OH
H
Si
O
Ar2
Ar1
O
O
TfOH
N
HN
F
Ar1
IV
Ar1
Ar1
Ph
F
I
III
Ar2 NH2
+
TfOH
II
Scheme 5. A plausible reaction mechanism of the reaction of aldimine
difluoroenoxysilane 2.
1 with
In summary, we have presented a new catalytic reaction
system applicable to the reactions of aldimines and difluoro-
enoxysilane using Lewis acid Zn(OTf)2 as a catalyst. On the basis
of this synthetic route, we can achieve unexpected Mukaiyama-
aldol adducts 3 in excellent yields. Adducts 4 could be formed
simultaneously in low yields when other Lewis acids, such as Cu
3.3.1. 2,2-Difluoro-3-hydroxy-1,3-diphenylpropan-1-one (3a). A pale
yellow solid. This is a known compound.8,11 1H NMR (400 MHz,
CDCl3, TMS):
d
3.13 (br, 1H, OH), 5.37 (dd, 1H, J¼18.4, 5.6 Hz, CH),
7.37e7.39 (m, 3H, ArH), 7.40e7.50 (m, 4H, ArH), 7.60e7.64 (m, 1H,

Z.-L. Yuan et al. / Tetrahedron 66 (2010) 7361e7366
7365
ArH), 8.04 (d, J¼8.4, 0.8 Hz, ArH); 19F NMR (376 MHz, CDCl3,
51 (1.7); HRMS (EI) calcd. For C17H16O2 F2 (MþHþ): 290.1123,
TMS):
d
ꢁ104.8 (dd, 1F, J¼290, 6.0 Hz), ꢁ116.3 (dd, 1F, J¼290,
found: 290.1118.
18.0 Hz).
3.3.8. 2,2-Difluoro-1,3-diphenyl-3-(phenylamino)propan-1-one (4).
3.3.2. 3-(4-Chlorophenyl)-2,2-difluoro-3-hydroxy-1-phenylpropan-
1-one (3b). A pale yellow solid. This is a known compound.8,11 1H
A yellow solid. This is a known compound.12 1H NMR (400 MHz,
CDCl3, TMS):
d
3.49 (br, 1H, OH), 5.52 (dd, 1H, J¼19.2, 4.0 Hz, CH),
NMR (400 MHz, CDCl3, TMS):
d
3.10 (d, 1H, J¼4.8 Hz, OH), 5.37 (dt,
7.48e7.53 (m, 2H, ArH), 7.65e7.72 (m, 3H, ArH), 8.07 (dd, 2H, J¼8.8,
1H, J¼18.8, 4.8 Hz, CH), 7.36e7.38 (m, 2H, ArH), 7.43e7.51 (m, 4H,
1.2 Hz, ArH), 8.25 (dt, 2H, J¼8.8, 2.0 Hz, ArH); 19F NMR (376 MHz,
ArH), 7.63e7.67 (m, 1H, ArH), 8.06 (dd, 2H, J¼8.0, 1.2 Hz, ArH); 19F
CDCl3, TMS):
19.0 Hz).
d
ꢁ103.4 (dd, 1F, J¼300, 5.0 Hz), ꢁ116.6 (dd, 1F, J¼300,
NMR (376 MHz, CDCl3, TMS):
d
ꢁ104.3 (dd, 1F, J¼297, 5.0 Hz),
ꢁ116.7 (dd, 1F, J¼297, 19.0 Hz).
Acknowledgements
3.3.3. 3-(4-Bromophenyl)-2,2-difluoro-3-hydroxy-1-phenylpropan-
1-one (3c). A pale yellow solid. This is a known compound.8,11 1H
Financial support from the Shanghai Municipal Committee of
Science and Technology (08dj1400100-2), National Basic Research
Program of China (973)-2009CB825300, and the National Natural
Science Foundation of China (20872162, 20672127, 20732008,
20821002 and 20702013) are greatly acknowledged.
NMR (400 MHz, CDCl3, TMS):
d 3.27 (br, 1H, OH), 5.33 (dd, 1H,
J¼18.8, 4.8 Hz, CH), 7.36 (d, 2H, J¼8.0 Hz, ArH), 7.45e7.53 (m, 4H,
ArH), 7.61e7.66 (m, 1H, ArH), 8.05 (dd, 2H, J¼8.0, 1.2 Hz, ArH); 19F
NMR (376 MHz, CDCl3, TMS):
ꢁ116.6 (dd, 1F, J¼295, 20.0 Hz).
d
ꢁ104.3 (dd, 1F, J¼295, 5.0 Hz),
Supplementary data
3.3.4. 2,2-Difluoro-3-hydroxy-3-(4-methoxyphenyl)-1-phenyl-
propan-1-one (3d). A pale yellow oil. This is a known com-
Spectroscopic data of the compounds shown in Tables 1e3,
Schemes 2e4 and the detailed descriptions of experimental pro-
cedures. Supplementary data associated with this article can be
found in online version at doi:10.1016/j.tet.2010.07.034.
pound.11,12 1H NMR (400 MHz, CDCl3, TMS):
d 3.21 (br, 1H, OH), 3.79
(s, 3H, OCH3), 5.29 (dd, 1H, J¼18.4, 6.0 Hz, CH), 6.89 (dt, 2H, J¼8.8,
2.8 Hz, ArH), 7.39 (d, 2H, J¼8.4 Hz, ArH), 7.43e7.47 (m, 2H, ArH),
7.58e7.63 (m, 1H, ArH), 8.03 (dd, 2H, J¼8.4, 1.2 Hz, ArH); 19F NMR
(376 MHz, CDCl3, TMS):
1F, J¼287, 19.0 Hz).
d
ꢁ105.2 (dd, 1F, J¼287, 7.0 Hz), ꢁ116.5 (dd,
References and notes
1. For recent reviews in the developments of organofluorine chemistry in physi-
cal, chemical and pharmacological properties, please see: (a) Smart, B. E.
J. Fluorine Chem. 2001, 109, 3e11; (b) Purser, S.; Moore, P. R.; Swallow, S.; Gou-
verneur, V. Chem. Soc. Rev. 2008, 37, 320e330; (c) Welch, J. Tetrahedron 1987, 43,
3123e3197; (d) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881e1886;
(e) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432e5446; (f) Singh, R. P.;
Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31e44; (g) Cahard, D.; Xu, X. H.; Couve-
3.3.5. 2,2-Difluoro-3-hydroxy-3-(4-nitrophenyl)-1-phenylpropan-1-
one (3e). A yellow solid. This is a known compound.8,11 1H NMR
(400 MHz, CDCl3, TMS):
d
3.49 (br, 1H, OH), 5.52 (dd, 1H, J¼19.2,
4.0 Hz, CH), 7.48e7.53 (m, 2H, ArH), 7.65e7.72 (m, 3H, ArH), 8.07
(dd, 2H, J¼8.8, 1.2 Hz, ArH), 8.25 (dt, 2H, J¼8.8, 2.0 Hz, ArH); 19F
€ €
Bonnaire, S.; Pannecoucke, X. Chem. Soc. Rev. 2010, 39, 558e568; (h) Torok, M.;
NMR (376 MHz, CDCl3, TMS):
d
ꢁ103.4 (dd, 1F, J¼300, 5.0 Hz),
€ €
Abid, M.; Mhadgut, S. C.; Torok, B. Biochemistry 2006, 45, 5377e5383; (i) Wil-
ꢁ116.6 (dd, 1F, J¼300, 19.0 Hz).
liam, R.; Dolbier, J.; Merle, A. B. Chem. Rev. 2003, 103, 1071e1098; (j) Kuroboshi,
M.; Kanie, K.; Hiyama, T. Adv. Synth. Catal. 2001, 343, 235e250; (k) Fustero, S.;
ꢁ
Sanz-Cervera, J. F.; Acena, J. L.; Sánchez-Roselló, M. Synlett 2009, 4, 525e549.
3.3.6. 2,2-Difluoro-3-(furan-2-yl)-3-hydroxy-1-phenylpropan-1-one
(3f). A pale yellow oil; IR (acetone): 3480, 2925, 1698, 1598,
1450, 1283, 1183, 1125, 1081, 795, 745 cmꢁ1 1H NMR (400 MHz,
CDCl3, TMS):
2. (a) Smart, B. E.; Hudlicky, H.; Pavlath, A. E. Chemistry of Organic Fluorine Com-
pounds II; American Chemical Society: Washington, DC, 1995, pp 979e1010; (b)
Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry; Plenum: New
York, NY, 1994, pp 57e88; (c) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organo-
fluorine Chemistry; Plenum: New York, NY, 1994, pp 501e539; (d) Lang, R. W.
Chemistry of Organic Fluorine Compounds II; American Chemical Society:
Washington, DC, 1995, pp 1143e1148; (e) Tius, M. A. Tetrahedron 1995, 51,
6605e6634.
3. (a) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214e231; (b) Martin,
S. F.; Lopez, O. D. Tetrahedron Lett. 1999, 40, 8949e8953.
4. Berkowitz, D. B.; Sloss, D. G. J. Org. Chem. 1995, 60, 7047e7050.
5. Chou, T. S.; Heath, P. C.; Patterson, L. E.; Poteet, L. M.; Lakin, R. E.; Hunt, A. H.
Synthesis 1992, 565e569.
6. (a) Sham, H. L.; Eideburg, N. E.; Spanton, S. G.; Kohlbrenner, D. W.; Betebenner,
D. A.; Kempf, D. J.; Norbeck, D. W.; Plattrer, J. J.; Erickson, J. W. J. Chem. Soc.,
Chem. Commun. 1991, 110e112; (b) Balnaves, A. S.; Gelbrich, T.; Hursthouse, M.
B.; Light, M. E.; Palmer, M. J.; Percy, J. M. J. Chem. Soc., Perkin Trans. 1 1999,
2525e2535; (c) Myers, A. G.; Barbay, J. K.; Zhong, B. Y. J. Am. Chem. Soc. 2001,
123, 7207e7219; (d) Lefebvre, O.; Brigaud, T.; Portella, C. J. Org. Chem. 2001, 66,
1941e1946; (e) Ngoc Tam, N. T.; Magueur, G.; Ourévitch, M.; Crousse, B.; Bégué,
J. P.; Bonnet-Delpon, D. J. Org. Chem. 2005, 70, 699e702.
n
;
d
3.35 (d, 1H, J¼7.6 Hz, OH), 5.41 (dt, 1H, J¼16.0,
7.8 Hz, CH), 6.36 (dd, 1H, J¼3.2, 2.4 Hz, ArH), 6.49 (d, 1H, J¼3.2 Hz,
ArH), 7.41e7.48 (m, 3H, ArH), 7.59e7.63 (m, 1H, ArH), 8.04 (dd,
2H, J¼6.0, 1.6 Hz, ArH ArH); 13C NMR (75 MHz, CDCl3, TMS):
d
68.0 (dd, JCeF¼21.5, 18.4 Hz), 110.1, 110.6, 115.5 (t,
JCeF¼192.7 Hz), 118.0, 128.6, 130.0 (t, JCeF¼1.9 Hz), 132.2, 134.6,
143.2, 148.3, 189.9 (t, JCeF¼21.3 Hz); 19F NMR (376 MHz, CDCl3,
TMS):
d
ꢁ106.3 (dd, 1F, J¼288, 7.0 Hz), ꢁ116.8 (dd, 1F, J¼288,
16.0 Hz). MS (EI) m/e 252 [Mþ] (2.2), 232 (62.8), 216 (1.7), 156
(35.0), 127 (6.6), 105 (93.3), 97 (100), 77 (66.1), 51 (21.1), 41
(11.9); HRMS (EI) calcd. For C13H10O3F2 (MþHþ): 252.0602,
found: 252.0598.
3.3.7. 2,2-Difluoro-3-hydroxy-1,5-diphenylpentan-1-one (3g). A pale
7. For reviews on
a,a-difluoro-b-amino acids, see: (a) Seebach, D.; Gardiner, J. Acc.
yellow oil; IR (acetone)
1277, 1170, 1163, 1139, 1055, 798, 750 cmꢁ1
CDCl3, TMS): 1.94e2.11 (m, 2H, CH2), 2.70e2.77 (m, 1H, CH),
n
3483, 2929, 1698, 1598, 1509, 1450, 1432,
Chem. Res. 2008, 41, 1366e1375; (b) Kimmerlin, T.; Seebach, D. J. Pept. Res. 2005,
65, 229e236; (c) Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206e243; (d)
Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodiversity 2004, 1, 1111e1239
For reviews on fluorinated amino acid, see: (e) Qiu, X. L.; Meng, W. D.; Qing, F. L.
Tetrahedron 2004, 60, 6711e6745.
;
1H NMR (400 MHz,
d
2.82 (d, 1H, J¼5.6 Hz, OH), 2.94e2.99 (m, 1H, CH), 4.20e4.27 (m,
1H, CH), 7.16e7.27 (m, 5H, ArH), 7.44 (t, 2H, J¼7.6 Hz, ArH),
7.57e7.61 (m, 1H, ArH), 8.07 (d, 2H, J¼7.6 Hz, ArH); 13C NMR
8. Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem. Commun. 1999,
1323e1324.
9. Yuan, Z. L.; Jiang, J. J.; Shi, M. Tetrahedron 2009, 65, 6001e6007.
10. Uneyama, K.; Tanaka, H.; Kobayashi, S.; Shioyama, M.; Amii, H. Org. Lett. 2004,
16, 2733e2736.
11. For some representative examples in nitrogen-containing base additives im-
proved catalytic reactions involving silylenol ethers, please see: (a) Hanamoto,
T.; Furuno, H.; Sugimoto, Y.; Inanaga, J. Synlett 1997, 77e80; (b) Kobayashi, S.;
Ishitani, H. J. Am. Chem. Soc. 1996, 116, 4083e4084; (c) Sugiura, M.; Nakai, T.
Angew. Chem., Int. Ed. 1997, 36, 2366e2368; (d) Verdaguer, X.; Lange, U. E. W.;
(75 MHz, CDCl3, TMS):
d
30.2, 30.3, 31.3, 70.4 (dd, JCeF¼20.8,
18.4 Hz), 116.5 (t, JCeF¼191.2 Hz), 126.0, 128.4, 128.6, 130.2 (t,
JCeF¼2.6 Hz), 132.1, 134.6, 141.0, 190.5 (t, JCeF¼22.3 Hz); 19F NMR
(376 MHz, CDCl3, TMS):
d
ꢁ107.4 (dd, 1F, J¼295, 6.0 Hz), ꢁ116.8
(dd, 1F, J¼295, 16.0 Hz). MS (EI) m/e 290 [Mþ] (4.0), 272 (1.0), 252
(6.6), 156 (4.7), 133 (3.5), 105 (100), 91 (20.1), 77 (28.1), 63 (1.0),

7366
Z.-L. Yuan et al. / Tetrahedron 66 (2010) 7361e7366
Buchwald, S. L. Angew. Chem., Int. Ed. 1998, 37, 1103e1107; (e) Verdaguer, X.;
yield (seven examples), for the details, please see: Hata, H.; Kobayashi, T.; Amii,
H.; Uneyama, K.; Welch, J. T. Tetrahedron Lett. 2002, 43, 6099e6102.
13. 1.0 equiv of BF3$Et2O could promote the conversion of aldimine 1a with
difluoroenoxysilane 2 in anhydrous CH2Cl2 at ꢁ78 C, giving the corresponding
Mannich adduct 4 in 63% yield, for the details about this reaction, please see:
Kobayashi, S.; Tanaka, H.; Amii, H.; Uneyama, K. Tetrahedron 2003, 59,
1547e1552.
Lange, U. E. W.; Reding, M. T.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
6784e6785; For a review on the effect of additives in asymmetric catalysis,
please see: (f) Vogl, E. M.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999,
38, 1570e1577.
12. Treatment of aldehydes and difluoroenoxysilane 2 with 50 mol % of TiCl4 in
anhydrous CH2Cl2 at ꢁ78 C gave the corresponding aldol adducts 3 in up to 72%