Trihaloacetaldehyde N,O-acetals: useful building blocks for dihalomethylene compounds

Article abstract of DOI:10.1016/j.tet.2010.04.061

The reaction of trifluoroacetaldehyde N,O-acetals with more than 2 equiv of alkyllithiums at -78 °C resulted in regiospecific defluorinative alkylation with unusual regioselectivity to give α,α-difluoroketone N,O-acetals in excellent yield. In contrast, u

Full text of DOI:10.1016/j.tet.2010.04.061

Tetrahedron 66 (2010) 4530e4541
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Tetrahedron
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Trihaloacetaldehyde N,O-acetals: useful building blocks
for dihalomethylene compounds
*
Hikaru Yanai, Takeo Taguchi
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
The reaction of trifluoroacetaldehyde N,O-acetals with more than 2 equiv of alkyllithiums at ꢀ78 ꢁ
C
Article history:
Received 13 February 2010
Received in revised form 10 April 2010
Accepted 14 April 2010
resulted in regiospecific defluorinative alkylation with unusual regioselectivity to give a,a-difluoroketone
N,O-acetals in excellent yield. In contrast, under similar conditions, trichloroacetaldehyde N,O-acetals
gave simple mono-dechlorinated product without the alkyl transfer reaction from alkyllithiums to the
generated intermediates.
Available online 22 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Defluorinative alkylation
Dechlorination
Reformatsky reaction
One-pot synthesis
a,a-Dihaloketone
1. Introduction
of synthetic reactions with nucleophiles has been known.10 As
synthetic equivalents of trihaloacetaldehydes, their acetals and
Halogen-containing organic compounds are significantly in-
teresting in the fields of material sciences and of medicinal chem-
istry, because introduction of some halogen atoms to organic
molecules often results in dramatic change of physicochemical and/
or pharmacological properties of the corresponding non-haloge-
nated compounds.1 Especially, dihalomethylene structures are
widely used as key functionalities for the design of biologically
active molecules. For example, difluoromethylene group is well
recognized as a bioisosteric structure for hydroxymethylene group2
related compounds have also been used.11 With these types of
compounds, not only substitution reaction at the acetalic carbon
using various nucleophiles in the presence of acid catalysts but also
the use of dihaloketene acetal intermediates as nucleophiles, which
generated by base-induced
b
-elimination of halide, have been re-
alized (Eqs. 1 and 2).12,13
OR
CX3
OR
CX3
Nu
(1)
RO
Nu
acidic
or ethereal oxygen.3 Since
a,a-difluorinated ketones easily form
O
O
stable tetrahedral hydrates, these compounds are also used as
transition state mimic toward several hydrolases, such as HIV
protease,4 elastase,5 renin,6 and human heart chymase.7 In addi-
tion, biologically active natural products having dichloro-
methylene8 or dichloromethyl functionalities9 were recently
isolated. For these reasons, the development of effective con-
struction methods for difluoromethylene and dichloromethylene
compounds is an important task in synthetic organic chemistry.
To synthesize polyhalogenated compounds, trihaloacetaldehyde
derivatives are widely used as readily available halogen-containing
synthones. Due to the strong ꢀI effect of trihalomethyl group, these
compounds have highly reactive carbonyl group and a wide range
OR
CX2
-elimination
basic
E
;
E
E
(2)
or
RO
H
RO
H2O
X
X
X X
As an interesting synthetic application of trihaloacetaldehyde
aminal, Dolbier and co-workers reported that the reaction of
trifluoroacetaldehyde aminal [CF3CH(NMe2)2] with strongly basic
n-butyllithium (n-BuLi) gives difluoroketene aminal through
b
-elimination of fluoride (Eq. 3).14,15 Furthermore, the reaction of
the resultant ketene aminal with another 1 M equivalent of n-BuLi
results in regioselective butyl transfer toward electronically more
negative
a
-carbon of fluorine groups and the following
b
-elimina-
tion of fluoride to give the butylated
yield after acidic aqueous workup.
a-monofluoroamide in good
* Corresponding author. Tel./fax: þ81 42 676 3257; e-mail address: taguchi@
toyaku.ac.jp (T. Taguchi).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.061

H. Yanai, T. Taguchi / Tetrahedron 66 (2010) 4530e4541
4531
O
strongly suggests that, in the reaction of trichloro substrate, lith-
Me2N
Me2N
Me2N
Me2N
n-BuLi
n-BuLi;
Bu
(3)
ium-chlorine exchange is faster than the
b
-elimination of chloride.
CF3
CF2
Me2N
H+/H2O
F
However, to the best of our knowledge, the synthetic utility of
mixed acetals, e.g., N,O-acetal derivatives, derived from poly-
halogenated aldehydes have been limited.16,17 Therefore, we ex-
amined the reaction of trifluoro- and trichloroacetaldehyde N,O-
acetals, and alkyllithiums.18 In this paper, we disclose the full detail
on our work in this area. We found that the reaction of tri-
fluoroacetaldehyde N,O-acetals with more than 2 equiv of alkyl-
n-BuLi
N
N
CCl2H
H
CCl3
Et2O
O
O
-78 °C, 1 h
4a (no alkylation)
3a
n-BuLi (2.4 eq)
n-BuLi (1.2 eq)
91%
94%
Scheme 1. Dechlorination of trichloroacetaldehyde N,O-acetal 3a.
lithium proceeds via
b-elimination of fluoride by 1 equiv of
alkyllithium followed by alkyl transfer from an excess amount of
alkyllithium to the resultant ketene N,O-acetal intermediates. Ob-
served regioselectivity in alkyl transfer step is different from that of
the symmetric aminal. Meanwhile, under similar conditions, an
exclusive dechlorination without alkyl transfer by alkyllithium was
observed in the case of trichloroacetaldehyde N,O-acetals. In ad-
Since it would be expected that the dihalomethyl products 2 and
4 are derived via protonation step during the aqueous workup,20
we examined the treatment of the intermediates generated by
defluorinative alkylation of 1a with various carbonyls as electro-
philes. Results are summarized in Table 2. After the treatment of 1a
with 2.5 M equivalent of n-BuLi at ꢀ78 ꢁC for 4 h (complete con-
sumption of 1a was observed in TLC), 2.0 M equivalents of benz-
dition, we applied these dehalogenation reactions to construct
difluoro- -hydroxyketone N,O-acetals.
a,a-
b
2. Results and discussion
Table 2
Defluorinative alkylation/Reformatsky type reaction of 1a, n-BuLi and carbonyl
electrophiles
To reveal the regioselectivity in defluorinative alkylation of
trifluoroacetaldehyde N,O-acetal, we examined the reaction of N,O-
acetal 1 with 2.4 equiv of alkyllithiums. Results are summarized in
Table 1. The reaction of N-allyl substrate 1a with n-BuLi in Et2O at
ꢀ78 ꢁC gave difluoromethylketone N,O-acetal 2aa as a sole product
n-BuLi (2.5 eq)
Et2O, -78 °C, 4 h;
OH
N
O
Allyl
N
O
R1COR2 (2.0 eq)
R2
R1
CF3
n-Bu
F
F
1a
5
Table 1
Defluorinative alkylation of trifluoroacetaldehyde N,O-acetal 1
Entry R1
R2
Temp. (ꢁC) Time (h)
5
Yielda (%) drb
R1
N
R1
N
R2Li (2.4 eq)
Et2O, -78 °C
1
Ph
H
H
H
H
H
H
H
H
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ24
0
0.5
0.5
0.5
1
0.25
1
5a 85
5b 79
5c 85
5d 87
5e 87
5f 87
5g 76
5h 81
5i 89
5j 84
5k 79
1:1.5
1:1.5
1:1.7
1.2:1
3.4:1
1:1.2
11:1c
11:1c
d
CF2H
R2
2
3
4
4-MeOC6H4
4-CF3C6H4
2-Furyl
CF3
O
O
1
2
5
6
7
8
2-Pyridyl
CH]CHPh
CH2CH2Ph
c-C6H11
Entry
1
R1
R2Li
time (h)
2
Yielda (%)
3
8
1
1a
1a
1a
1b
1c
allyl
allyl
allyl
Bn
n-BuLi
MeLi
c-C3H5Li
n-BuLi
n-BuLi
3
4
4
5
4
2aa
2ab
2ac
2ba
2ca
83
81
74
73
58
2b
3
9
Me
Me rt
d
9
10
11
eCH2(CH2)3CH2
Ph
0
6
d
Me rt
9
1.8:1
4
5c
n-C3H7
a
Isolated yield.
b
c
Based on 19F NMR.
a
Isolated yield
b
c
Reaction was carried out in Et2OeTHF (2:1) at ꢀ24 ꢁC.
anti/syn Selectivity.
Difluoromethylketone of 29% was formed (based in 19F NMR).
aldehyde was added to the resultant reaction mixture. The reaction
of the intermediate with benzaldehyde rapidly completed (within
0.5 h) to give the desired a,a-difluoro-b-hydroxyketone N,O-acetal
in 83% yield.19 Although the reaction of 1a with MeLi under the
similar conditions resulted in a poor conversion due to low solu-
bility of MeLi in Et2O, synthetically useful yield of 2ab was realized
by the reaction at ꢀ24 ꢁC in Et2O/THF (2:1 v/v) mixed solvent (entry
2, 81% yield). Cyclopropyllithium was also used as a good alkyl
donor for this reaction to result in the clean formation of defluor-
inative cyclopropylation product 2ac (entry 3, 74% yield). In con-
trast, the use of less basic organolithium reagents, such as
phenyllithium and allyllithium resulted in no reaction (not shown).
These results suggest that the deprotonation at CF3-substituted
methine position is the initiation step for the present reaction. N-
Benzyl and N-propyl substrates 1b, c were also found as nice sub-
strates for this defluorinative alkylation and the corresponding
difluoromethylketone N,O-acetal products 2ba, 2ca were obtained
in 73% and 58% yield, respectively (entries 4 and 5).
5a in 85% yield with low diastereoselectivity (entry 1). 4-
Substituted benzaldehyde derivatives, such as 4-anisaldehyde and
4-trifluoromethylbenzaldehyde, and furfural also gave the corre-
sponding carbinol 5bed in excellent yield by the reaction at ꢀ78 ꢁC
(entries 2e4). Interestingly, in the reaction with 2-pyr-
idinecarbaldehyde, the reaction rate was significantly accelerated
under the same conditions and carbinol product 5e was formed in
87% yield with moderate diastereoselectivity (entry 5). The reaction
with cinnamaldehyde proceeded with perfect 1,2-selectivity to give
allylic alcohol 5f in 87% yield (entry 6). In contrast, although
somewhat low reactivity of aliphatic aldehydes was observed in
this CeC bond forming reaction, reasonable product yield was re-
alized by conducting the reaction at a higher reaction temperature
and for a prolonged reaction time (entries 7 and 8). With aliphatic
aldehyde examined, the diastereoselectivity was generally high. For
example, the reaction with cyclohexanecarbaldehyde smoothly
proceeded at 0 ꢁC for 8 h to give carbinol 5h in 81% yield as
a mixture of diastereomers in a ratio of 11:1. The stereochemistry of
On the other hand, the reaction of trichloroacetaldehyde N,O-
acetal 3a with 2.4 equiv of n-BuLi in Et2O at ꢀ78 ꢁC for 1 h provided
the simply dechlorinated product 4a in 91% yield without the for-
mation of butyl group transfer reaction (Scheme 1). The use of
1.2 equiv of n-BuLi gave the essentially same result. This finding

4532
H. Yanai, T. Taguchi / Tetrahedron 66 (2010) 4530e4541
the major diastereomer was determined as 1,3-anti relationship on
the basis of X-ray crystallographic analysis (Fig. 1). In this one-pot
BF3$OEt2 was found as a useful Lewis acid for this reaction. That is,
after complete dechlorination of 3a with n-BuLi, the resultant re-
action mixture was treated with a 1:1 mixture of benzaldehyde and
BF3$OEt2 at ꢀ78 ꢁC for 3 h to give the desired dichloromethyl car-
binol 8a in 65% yield (entry 2). The product yield was sensitive to
the amount of BF3$OEt2 and excellent yield was realized on using
6.0 equiv of BF3$OEt2 (85% yield, entry 3). Under the same condi-
tions, 2- or 4-bromobenzaldehydes could be used for this reaction
giving rise to the corresponding carbinols 8b and 8c in 72% and 80%
yield, respectively (entries 4 and 5). The reaction with cinna-
maldehyde selectively gave 1,2-adduct 8d in 75% yield with low
diastereoselectivity (entry 6). Effect of N-substituent of N,O-acetal 3
on its reactivity was little. For example, reactions of both
N-benzyl substrate 3b and N-propyl substrate 3c with 4-bromo-
benzldehyde smoothly proceeded to give 8e and 8f in good yields
(entries 7 and 8).
procedure to obtain
a,a-difluoro-b-hydroxyketone N,O-acetals, it
was also found that ketones perform as nice carbonyl components.
After defluorinative alkylation of N,O-acetal 1a by n-BuLi, the re-
action of the resultant intermediate with acetone at room tem-
perature for 9 h gave difluorinated tertiary alcohol 5i in 89% yield
(entry 9). Likewise, the reactions with cyclohexanone and with
acetophenone resulted in clean formation of 5j and 5k in 84% and
79% yield, respectively (entries 10, 11).
Table 3
n-BuLi-mediated Reformatsky type reaction of trichloroacetaldehyde N,O-acetal 3
n-BuLi (1.2 eq)
R
N
R
Et2O, -78 °C, 1 h;
N
OH
R'
CCl3
O
R'CHO (2.0 eq)
BF3·OEt2, -78 °C
O
Cl Cl
3
8
Figure 1. X-ray structure of anti-5h.
Entry
3
R0
BF3$OEt2 Time
8
Yielda drb
(%)
(eq)
(h)
As additional entries of the present defluorinative approach
toward difluoromethylene compounds, we carried out the re-
actions using other electrophiles (Scheme 2). For example, after
defluorinative alkylation reaction of 1a with n-BuLi, the one-pot
treatment of the resultant mixture by iminium salt at room tem-
1
2
3
4
5
6
7
8
3a (R¼allyl) Ph
None
2.0
6.0
6.0
6.0
1
3
1
2
1
1
1
1
8a
8a
8a
8b
8c
8d 75
8e
8f
0
65
85
72
80
d
3a (R¼allyl) Ph
2.2:1
2.0:1
2.3:1c
2.2:1
1.4:1
1.7:1
2.2:1
3a (R¼allyl) Ph
3a (R¼allyl) 2-BrC6H4
3a (R¼allyl) 4-BrC6H4
3a (R¼allyl) CH]CHPh 6.0
perature provided b-amino-a,a-difluoroketone N,O-acetal product
3b (R¼Bn)
4-BrC6H4
4-BrC6H4
6.0
6.0
78
72
6 in 77% yield. By using N-halosuccinimides (NXS) as electrophiles,
the corresponding difluorohalomethylketone N,O-acetal 7 was also
obtained in excellent yields. That is, the one-pot reaction of 1a, n-
BuLi and NCS smoothly proceeded at ꢀ78 ꢁC to give chlorinated
product 7a in 73% yield. Under similar conditions, the use of NIS
resulted in clean formation of difluoroiodomethyl ketone derivative
7b in 88% isolated yield.
3c (R¼n-Pr)
a
Isolated yirld
b
c
Determined by 1H NMR.
anti/syn Ratio.
We also found that the use of BF3$OEt2 is not necessary in the
reactions with highly electrophilic carbonyls (Scheme 3). For ex-
ample, n-BuLi-mediated reaction of 3a with chloral proceeded at
room temperature in the absence of BF3$OEt2 to give penta-
chlorinated alcohol 8g in 65% yield. Furthermore, tertiary alcohol
8h was obtained in reasonable yield by the reaction of 3a with ethyl
trifluoropyruvate at room temperature for 24 h.
n-BuLi (2.5 eq)
Et2O, -78 °C, 4 h;
1a
Allyl
N
O
[H2C=NMe2]+Cl- (2.0 eq)
rt, 24 h
n-Bu
NMe2
F
F
6 77%
n-BuLi (1.2 eq)
n-BuLi (2.5 eq)
N
OH
CCl3
Allyl
N
Et2O, -78 °C, 1 h;
Et2O, -78 °C, 4 h;
3a
O
CF2X
CCl3CHO (2.0 eq)
rt, 5 h
NXS (2.0 eq)
-78 °C, 4-7 h
Cl Cl
8g 65% (syn/anti = 1 : 1.4)
n-Bu
O
7a (X = Cl)
7b (X = I)
73%
88%
n-BuLi (1.2 eq)
THF, -78 °C, 1 h;
Scheme 2. One-pot synthesis of a,a-difluoroketone N,O-acetals 6 and 7.
N
OH
CO2Et
CF3
CF3COCO2Et (2.0 eq)
rt, 24 h
O
Next, we turned our attention to examine the CeC bond forming
reaction of the intermediate generated by dechlorination of N,O-
acetal 3. Since dechlorinative addition of masked chloro-
acetaldehyde to aldehydes should provide an alternative method
for the cross Reformatsky type reaction of chloroacetaldehyde de-
rivatives,21,22 we examined the Reformatsky-type reaction of tri-
chloroacetaldehyde N,O-acetal 3 by stepwise addition of n-BuLi and
benzaldehyde (Table 3). Although the intermediate generated by
dechlorination of 3a with 1.2 equiv of n-BuLi did not react with
benzaldehyde in the absence of catalysts at ꢀ78 ꢁC (entry 1),
Cl Cl
8h 51% (dr = 2.3 : 1)
Scheme 3. Reformatsky type reaction of 3a in the absence of BF3$OEt2.
Concerning these results, we propose the reaction mechanism
as shown in Scheme 4. In the case of trifluoroacetaldehyde N,O-
acetal 1, as the first step, b-elimination of N,O-acetal 1 by 1 equiv of
alkyllithiums rapidly gives difluoroketene N,O-acetal intermediate
A.16,23 Dolbier and co-workers reported that butyl transfer of

H. Yanai, T. Taguchi / Tetrahedron 66 (2010) 4530e4541
4533
E
R
N
R
N
R
N
F
R
R
X = F
n-BuLi
F
F
F
F
F
N
N
n-BuLi
F
O
CX3
n-Bu
O
F
O
O
O
Li
Li n-Bu
Li n-Bu
1 (X = F)
3 (X = Cl)
A
B
C
X = Cl
n-BuLi
R
N
CF2-E
E
R
N
Cl
n-Bu
R
N
O
Cl
CCl2-E
H
O
O
Li
D
Scheme 4. Proposed reaction mechanism.
difluoroketene aminal [F2C¼C(NMe2)2] by n-BuLi proceeds at
1a (4.03 g, 17.6 mmol, 88% yield). Pale yellow oil; IR (neat)
n
3064,
d 3.77
electronically more negative
a
-position of fluorine atoms to give
a
-
2983, 1487, 1291, 1156, 739 cmꢀ1; 1H NMR (400 MHz, CDCl3)
fluoroamide after aqueous workup.14 In contrast, the structure of
the products in this study clearly indicates that alkyl transfer from
an excess alkyllithium to the resultant intermediate A proceeds at
(1H, dd, J¼15.8, 6.9 Hz), 3.91 (1H, dd, J¼15.8, 5.2 Hz), 5.28 (1H, dd,
J¼8.7,1.4 Hz), 5.32 (1H, dd, J¼15.6,1.4 Hz), 5.66 (1H, q, JHeF¼4.0 Hz),
5.78e5.89 (1H, m), 6.73 (1H, d, J¼7.7 Hz), 6.78e6.83 (2H, m),
b
-position of fluorines. We attributed this unusual regioselectivity
6.84e6.91 (1H, m); 13C NMR (100 MHz, CDCl3)
d 54.2, 92.8 (q,
to the equilibrium between ketene N,O-acetal form C and zwitter-
ion form B. That is, alkyl transfer to A by an excess alkyllithium is
possibly induced by the coordination of N,O-acetal oxygen to lith-
ium center to give lithium phenoxide C via zwitterion B.24 Pro-
tonation of C or reaction of C with carbonyl electrophiles probably
proceeds with the simultaneous formation of dihydrobenzoxazole
structure via 5-exo-trig cyclization. On the other hand, the reaction
of trichloroacetaldehyde N,O-acetal 3 with n-BuLi would result in
JCeF¼35.8 Hz), 108.3, 110.4, 119.3, 121.3, 121.8 (q, JCeF¼284.5 Hz),
122.2, 136.1, 138.0, 150.2; 19F NMR (282 Hz, CDCl3)
d
ꢀ21.3 (3F, d,
JHeF¼4.0 Hz); MS (ESI-TOF) m/z 230 [MþH]þ; HRMS calcd for
C11H11F3NO [MþH]þ, 230.0793; found, 230.0804.
4.1.2. 3-Benzyl-2-(trifluoromethyl)-2,3-dihydrobenzo[d]oxazole
(1b). According to the preparation of 1a, this compound was
obtained in 87% yield (3.63 g, 13.0 mmol) from 2-(benzylamino)
phenol26 (2.99 g, 15 mmol) and TFAE (4.33 g, 30 mmol). Pale yellow
a rapid lithium-chlorine exchange prior to b-elimination of chloride
to give enamine phenoxide D. Therefore, the following butyl
transfer does not occur under the present conditions.
oil; IR (neat)
n 3065, 2888, 1601, 1488, 1292, 1254, 1153, 739,
697 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
4.35 (1H, d, J¼15.4 Hz), 4.54
(1H, d, J¼15.4 Hz), 5.68 (1H, q, JHeF¼4.0 Hz), 6.67 (1H, br d,
3. Conclusion
J¼6.9 Hz), 6.78e6.88 (3H, m), 7.28e7.40 (5H, m); 13C NMR
(100 MHz, CDCl3)
d
55.2, 93.0 (q, JCeF¼35.8 Hz), 108.3, 110.0, 121.1,
We found that the reaction of trifluoroacetaldehyde N,O-acetal with
121.8 (q, JCeF¼284.3 Hz), 122.2, 127.8, 128.0, 128.8, 136.2, 138.4,
more than 2 equiv of alkyllithium proceeded via
b-elimination of
149.9; 19F NMR (282 Hz, CDCl3)
d
ꢀ20.9 (3F, d, JHeF¼4.0 Hz); MS
fluoride with 1 equiv of alkyllithium followed by alkyl transfer from an
excess amount of alkyllithium to the resultant ketene N,O-acetal in-
termediate. Observed regioselectivity in the alkyl transfer step is dif-
ferent from that of difluoroketene aminal with symmetric structure.
Under the similar conditions, trichloroacetaldehyde N,O-acetal pro-
vided only dechlorinated intermediate without alkyl transfer by excess
alkyllithium. Moreover, we showed that, by the treatment with car-
bonyl electrophiles, the intermediates derived from the reactions of
(ESI-TOF) m/z 280 [MþH]þ; HRMS calcd for C15H13F3NO [MþH]þ,
280.0949; found, 280.0968.
4.1.3. 3-Propyl-2-(trifluoromethyl)-2,3-dihydrobenzo[d]oxazole
(1c). Under H2 atmosphere (1 atm), a mixture of 3-allyl-2-(tri-
fluoromethyl)-2,3-dihydro-1,3-benzoxazole 1a (462.2 mg, 2.0 mmol)
and 10% palladium on carbon (50% wet., 212 mg, 0.1 mmol) in EtOAc
(5.0 mL) was stirred for 6 h at room temperature. A resulting mix-
ture was filtrated through Celite pad and the filtrate was concen-
trated under reduced pressure. The residue was purified by column
chromatography on silica gel to give 1c (450.8 mg, 1.95 mmol, 97%
these N,O-acetals with alkyllithium can be converted to a,a-dihalo-b-
hydroxycarbonyl N,O-acetals in excellent yields. These findings clearly
demonstrate the synthetic utilities of trihaloacetaldehyde N,O-acetals
as dihalomethyl anion precursors through carbonefluorine or car-
bonechlorine bond cleavage.
yield). Colorless oil; IR (neat)
n
3063, 2968, 2879, 1489, 1292, 1245,
1
1154, 1058, 854, 738 cmꢀ1; H NMR (400 MHz, CDCl3)
d
0.98 (3H, t,
J¼7.4 Hz), 1.58e1.74 (2H, m), 3.13e3.26 (2H, m), 5.64 (1H, q,
JHeF¼4.2 Hz), 6.69 (1H, d, J¼7.2 Hz), 6.65e6.83 (2H, m), 6.86e6.91
4. Experimental section
(1H, m); 13C NMR (100 MHz, CDCl3)
d 11.2, 21.2, 54.2, 94.0 (q,
4.1. Preparation of trihaloacetaldehyde N,O-acetal substrates
JCeF¼35.4 Hz), 108.1, 110.0, 120.9, 121.7 (q, JCeF¼284.0 Hz), 122.2,
138.7, 150.0; 19F NMR (282 Hz, CDCl3)
d
ꢀ21.4 (3F, d, JHeF¼4.2 Hz);
4.1.1. 3-Allyl-2-(trifluoromethyl)-2,3-dihydrobenzo[d]oxazole
(1a).
MS (ESI-TOF) m/z 232 [MþH]þ; HRMS calcd for C11H13F3NO
[MþH]þ, 232.0949; found, 232.0950.
To a round-bottom flask equipped with DeaneStark apparatus, 2-
(allylamino)phenol25 (2.99 g, 20 mmol), TFAE (5.76 g, 40 mmol),
p-toluenesulfonic acid monohydrate (200 mg, 1.1 mmol), and ben-
zene (150 mL) were added. After being refluxed for 4 h, reaction
mixture was quenched with saturated NaHCO3 aqueous solution,
extracted with Et2O (30 mLꢂ3) and evaporated. The resulting res-
idue was purified by column chromatography on silica gel to give
4.1.4. 3-Allyl-2-(trichloromethyl)-2,3-dihydrobenzo[d]oxazole (3a).
To a round-bottom flask equipped with DeaneStark apparatus, 2-
(allylamino)phenol25 (1.21 g, 8.0 mmol), chloral (2.36 g, 16 mmol),
PPTS (50 mg, 0.2 mmol), and benzene (100 mL) were added. After
being refluxed for 2 h, reaction mixture was quenched with

4534
H. Yanai, T. Taguchi / Tetrahedron 66 (2010) 4530e4541
saturated NaHCO3 aqueous solution, extracted with Et2O
(30 mLꢂ3) and evaporated. The resulting residue was purified by
column chromatography on silica gel to give trichloroacetaldehyde
N,O-acetal 3a (1.75 g, 6.3 mmol, 79% yield). Pale yellow oil; IR (neat)
JHeF¼55.4 Hz); MS (ESI-TOF) m/z 268 [MþH]þ; HRMS calcd for
C15H20F2NO [MþH]þ, 268.1513; found, 268.1500.
4.2.2. 3-Allyl-2-(difluoromethyl)-2-methyl-2,3-dihydrobenzo[d]ox-
azole (2ab). This compound was obtained in 81% yield (91.1 mg,
0.40 mmol) by the reaction of trifluoroacetaldehyde N,O-acetal 1a
(114.3 mg, 0.5 mmol) and methyllithium (1.09 M in Et2O, 1.10 mL,
1.2 mmol) in Et2O/THF (3:1, 4 mL) for 4 h at ꢀ24 ꢁC. Brown oil; IR
n
;
3064, 2878, 1487, 1241, 830, 804, 738 cmꢀ1 1H NMR (400 MHz,
CDCl3)
d
3.97 (1H, dd, J¼16.2, 7.2 Hz), 4.12e4.20 (1H, m), 5.28 (1H, d,
J¼10.3, 1.2 Hz), 5.36 (1H, dd, J¼17.1, 1.2 Hz), 5.77e5.90 (1H, m), 5.83
(1H, s), 6.76 (1H, d, J¼7.4 Hz), 6.78e6.90 (3H, m); 13C NMR
(100 MHz, CDCl3)
d
56.0, 100.9, 103.0, 107.8, 110.2, 119.0, 121.3, 122.1,
(neat)
n 3064, 2986, 1599, 1494, 1394, 1302, 1227, 1096, 1074,
132.4, 138.9, 150.5; MS (ESI-TOF) m/z 278 [MþH]þ; HRMS calcd for
735 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 1.64 (3H, br s), 3.79 (1H, dd,
C11H11Cl3NO [MþH]þ, 277.9906; found, 277.9894.
J¼16.8, 5.6 Hz), 3.90e3.98 (1H, m), 5.21 (1H, dd, J¼10.3,1.5 Hz), 5.31
(1H, dd, J¼17.1, 1.5 Hz), 5.67 (1H, t, JHeF¼55.3 Hz), 5.83e8.94 (1H,
m), 6.46 (1H, d, J¼7.5 Hz), 6.61e6.70 (2H, m), 6.74e6.81 (1H, m); 13C
4.1.5. 3-Benzyl-2-(trichloromethyl)-2,3-dihydrobenzo[d]oxazole
(3b). According to the synthetic procedure for 3a, this compound
was obtained in 83% yield (4.06 g, 12.5 mmol) by the reaction of 2-
(benzylamino)phenol26 (2.99 g, 15 mmol), chloral (4.43 g,
30 mmol) in the presence of PPTS (100 mg, 0.4 mmol) in benzene
NMR (100 MHz, CDCl3)
d
15.7, 47.5, 99.4 (t, JCeF¼25.0 Hz), 106.8,
107.5, 113.7 (dd, J¼254.9, 249.6 Hz), 116.9, 118.7, 121.7, 134.2, 138.4,
148.4; 19F NMR (282 Hz, CDCl3)
d
ꢀ70.9 (1F, dd, JFeF¼287.3 Hz,
JHeF¼55.3 Hz), ꢀ66.8 (1F, dd, JFeF¼287.3 Hz, JHeF¼55.3 Hz); MS (EI)
m/z 225 [M]þ. Anal. Calcd for C12H13F2NO: C, 63.99; H, 5.82; N, 6.22.
Found: C, 63.82; H, 5.91; N, 6.40.
(200 mL). Colorless crystals; mp 84.0e85.5 ꢁC; IR (KBr)
2881,1487,1256,1175,1009, 831, 801, 763 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
4.54 (1H, d, J¼15.7 Hz), 4.79 (1H, d, J¼15.7 Hz), 5.87 (1H, s),
6.52 (1H, dd, J¼5.6, 3.2 Hz), 6.77e6.89 (3H, m), 7.28e7.39 (5H, m);
n 3063,
d
4.2.3. 3-Allyl-2-cyclopropyl-2-(difluoromethyl)-2,3-dihydrobenzo[d]
oxazole (2ac). This compound was obtained in 74% yield (92.9 mg,
0.37 mmol) by the reaction of trifluoroacetaldehyde N,O-acetal 1a
(114.6 mg, 0.5 mmol) and cyclopropyllithium (1.2 M in hexane,
1.0 mL,1.2 mmol) in Et2O (2 mL) for 4 h at ꢀ78 ꢁC. Pale yellow oil; IR
13C NMR (100 MHz, CDCl3)
d 57.3, 100.8, 103.2, 107.2, 110.1, 121.3,
122.2, 127.5, 127.8, 128.8, 136.7, 139.3, 150.3; MS (EI) m/z 327 [M]þ,
329 [Mþ2]þ, 210 [MꢀCCl3]þ. Anal. Calcd for C15H12Cl3NO: C, 54.82;
H, 3.68; N, 4.26. Found: C, 54.73; H, 3.80; N, 4.33.
(neat)
NMR (400 MHz, CDCl3)
n ;
3064, 3015, 2980, 1599, 1494, 1230, 1074, 734 cmꢀ1 1H
4.1.6. 3-Propyl-2-(trichloromethyl)-2,3-dihydrobenzo[d]oxazole
(3c). Under H2 atmosphere (1 atm), a mixture of 3-allyl-2-(tri-
chloromethyl)-2,3-dihydrobenzo[d]oxazole 3a (0.56 g, 2.0 mmol)
and 10% palladium on carbon (50% wet., 420 mg, 0.2 mmol) in
EtOAc (5.0 mL) was stirred for 3 h at room temperature. A resulting
mixture was filtrated through Celite pad, then the filtrate was
concentrated under reduced pressure. The obtained residue was
purified by column chromatography on silica gel to give 3c in 62%
d 0.48e0.55 (2H, m), 0.65e0.72 (1H, m),
0.86e0.92 (1H, m), 1.38e1.46 (1H, m), 3.91 (1H, dd, J¼16.7, 5.4 Hz),
4.14 (1H, dd, J¼16.7, 5.2 Hz), 5.23 (1H, d, J¼10.3 Hz), 5.36 (1H,
J¼17.2 Hz), 5.72 (1H, t, JHeF¼55.5 Hz), 5.91e6.03 (1H, m), 6.47 (1H,
d, J¼7.6 Hz), 6.58e6.66 (1H, m), 6.76 (1H, t, J¼7.2 Hz); 13C NMR
(100 MHz, CDCl3)
d
ꢀ0.6, 1.8, 9.9, 48.0, 99.2 (t, JCeF¼23.7 Hz), 106.26
107.0, 114.1 (dd, JCeF¼252.9, 250.9 Hz), 116.6, 118.3, 121.6, 134.6,
139.3, 148.8; 19F NMR (282 Hz, CDCl3)
d
ꢀ71.8 (1F, dd,
yield (347.9 mg, 1.24 mmol). Pale yellow oil; IR (neat)
2876, 1488, 1268, 1243, 829, 803, 737 cmꢀ1 1H NMR (400 MHz,
CDCl3)
0.94 (3H, t, J¼7.4 Hz),1.61e1.71 (2H, m), 3.33e3.49 (2H, m),
n
3061, 2965,
JFeF¼285.2 Hz, JHeF¼55.5 Hz), ꢀ67.4 (1F, dd, JFeF¼285.2 Hz,
JHeF¼55.5 Hz); MS (ESI-TOF) m/z 252 [MþH]þ; HRMS calcd for
C14H16F2NO [MþH]þ, 252.1200; found, 252.1179.
;
d
5.83 (1H, s), 6.72 (1H, d, J¼7.4 Hz), 6.76e6.84 (2H, m), 6.88 (1H, dt,
J¼7.4, 1.7 Hz); 13C NMR (100 MHz, CDCl3)
d
11.3, 20.5, 54.9, 101.0,
4.2.4. 3-Benzyl-2-butyl-2-(difluoromethyl)-2,3-dihydrobenzo[d]ox-
azole (2ba). This compound was obtained in 73% yield (115.8 mg,
0.37 mmol) by the reaction of trifluoroacetaldehyde N,O-acetal 1a
(139.8 mg, 0.5 mmol) and n-BuLi (1.55 M in hexane, 0.77 mL,
1.2 mmol) in Et2O (2 mL) for 5 h at ꢀ78 ꢁC. Pale yellow crystals; mp
103.6, 107.7, 109.9, 120.9, 122.0, 138.9, 150.5; MS (ESI-TOF) m/z 280
[MþH]þ; HRMS calcd for C11H13Cl3NO [M]þ, 280.0063; found,
280.0052.
4.2. Regiospecific defluorinative alkylation reaction of
trifluoroacetaldehyde N,O-acetal
62.5e63.0 ꢁC; IR (KBr)
1074, 732, 703 cmꢀ1
n
3063, 2959, 2872, 1645, 1600, 1494, 1235,
;
1H NMR (400 MHz, CDCl3)
d
0.93(3H, t,
J¼7.1 Hz), 1.29e1.44 (3H, m), 1.52e1.61 (1H, m), 2.01e2.07 (2H, m),
4.43 (1H, d, J¼16.1 Hz), 4.54 (1H, d, J¼16.1 Hz), 5.78 (1H, t,
JHeF¼55.3 Hz), 6.12 (1H, d, J¼7.3 Hz), 6.59e6.73 (3H, m), 7.27e7.43
4.2.1. 3-Allyl-2-butyl-2-(difluoromethyl)-2,3-dihydrobenzo[d]ox-
azole (2aa). To a solution of trifluoroacetaldehyde N,O-acetal 1a
(114.5 mg, 0.5 mmol) in Et2O (2.0 mL), n-BuLi (1.55 M in hexane,
0.77 mL, 1.2 mmol) was added at ꢀ78 ꢁC over 15 min. After being
stirred for 4 h at the same temperature, the mixture was poured
into ice water and Et2O, which was extracted with Et2O (20 mLꢂ3).
The organic phase was washed with brine, dried over MgSO4, and
evaporated. The obtained residue was purified by short column
chromatography on silica gel to give difluoroacetaldehyde N,O-ac-
(5H, m); 13C NMR (100 MHz, CDCl3)
d 13.9, 22.7, 23.6, 295, 48.7,
101.2 (t, JCeF¼23.3 Hz),106.0,106.9,114.3 (dd, JCeF¼254.5, 251.5 Hz),
118.4, 121.6, 126.8, 127.3, 128.7, 137.7, 139.4, 149.0; 19F NMR (282 Hz,
CDCl3)
d
ꢀ71.0 (1F, dd, JFeF¼285.4 Hz, JHeF¼55.3 Hz), ꢀ66.4 (1F, dd,
JFeF¼285.4 Hz, JHeF¼55.3 Hz); MS (EI) m/z 317 [M]þ, 266
[MeCHF2]þ. Anal. Calcd for C19H21F2NO: C, 71.90; H, 6.67; N, 4.41.
Found: C, 72.03; H, 6.80; N, 4.41.
etal 2aa in 83% yield (110.8 mg, 0.42 mmol). Colorless oil; IR (neat)
3064, 2959, 2873, 1599, 1456, 1398, 1311, 1235, 1201, 1116, 1073,
732 cmꢀ1 1H NMR (400 MHz, CDCl3)
n
4.2.5. 2-Butyl-2-(difluoromethyl)-3-propyl-2,3-dihydrobenzo[d]ox-
azole (2ca). This compound was obtained in 58% yield (78.1 mg,
0.29 mmol) by the reaction of trifluoroacetaldehyde N,O-acetal 1a
(115.4 mg, 0.5 mmol) and n-BuLi (1.55 M in hexane, 0.77 mL,
;
d
0.90 (3H, t, J¼7.2 Hz),
1.25e1.59 (4H, m), 1.97 (2H, t, J¼7.9 Hz), 3.76e3.95 (2H, m), 5.21
(1H, dd, J¼10.3, 1.5 Hz), 5.33 (1H, dd, J¼17.2, 1.5 Hz), 5.68 (1H, t,
JHeF¼55.4 Hz), 5.83e5.94 (1H, m), 6.39 (1H, dd, J¼7.5, 1.0 Hz),
6.54e6.62 (1H, m), 6.65 (1H, dd, J¼7.6, 1.0 Hz), 6.70e6.77 (1H, m);
1.2 mmol) in Et2O (2 mL) for 4 h at ꢀ78 ꢁC. Colorless oil; IR (neat)
n
3062, 2962, 2874, 1599, 1496, 1235, 1116, 1072, 731 cmꢀ1 1H NMR
;
13C NMR (100 MHz, CDCl3)
d
13.9, 22.6, 23.4, 28.8, 46.9, 100.9 (t,
(400 MHz, CDCl3)
d
0.90 (3H, t, J¼7.3 Hz), 0.97 (3H, t, J¼7.4 Hz),
JCeF¼23.6 Hz), 105.2, 106.8, 114.0 (dd, JCeF¼254.8, 251.0 Hz), 116.8,
117.9, 121.6, 133.9, 139.0, 148.9; 19F NMR (282 Hz, CDCl3)
ꢀ71.3 (1F,
dd, JFeF¼285.4 Hz, JHeF¼55.4 Hz), ꢀ66.7 (1F, dd, JFeF¼285.4 Hz,
1.21e1.53 (4H, m), 1.62e1.80 (2H, m), 1.93e2.00 (2H, m), 3.16 (2H, t,
J¼7.8 Hz), 5.67 (1H, t, JHeF¼55.5 Hz), 6.37 (1H, dd, J¼7.5, 1.0 Hz),
6.54e6.60 (1H, m), 6.64 (1H, dd, J¼7.6, 1.0 Hz), 6.71e6.79 (1H, m);
d

H. Yanai, T. Taguchi / Tetrahedron 66 (2010) 4530e4541
4535
13C NMR (100 MHz, CDCl3)
JCeF¼23.7 Hz), 104.2, 106.7, 114.1 (dd, JCeF¼254.8, 251.0 Hz), 117.4,
121.6, 139.6, 148.9; 19F NMR (282 Hz, CDCl3)
JFeF¼285.4 Hz, JHeF¼55.5 Hz), ꢀ66.6 (1F, dd, JFeF¼285.4 Hz,
JHeF¼55.5 Hz); MS (ESI-TOF) m/z 270 [MþH]þ; HRMS calcd for
C15H22F2NO [MþH]þ, 270.1669; found, 270.1668.
d
11.4, 13.9, 22.2, 22.7, 23.9, 46.3, 101.0 (t,
3.96e4.04 (1H, m), 5.13e5.22 (1H, m), 5.29 (1H, dd, J¼10.2, 1.3 Hz),
5.40 (1H, dd, J¼17.2, 1.3 Hz), 5.94e6.07 (1H, m), 6.51 (1H, d,
J¼7.5 Hz), 6.60e6.67 (2H, m), 6.74e6.83 (1H, m), 7.30e7.38 (3H, m),
d
ꢀ71.3 (1F, dd,
7.39e7.45 (2H, m); 13C NMR (100 MHz, CDCl3)
d 13.9, 22.6, 23.6,
30.4, 48.1, 72.7 (dd, JCeF¼28.7, 23.8 Hz), 103.7 (t, JCeF¼29.6 Hz),
105.9, 106.9, 117.6, 118.5, 118.7 (dd, JCeF¼260.9, 257.8 Hz), 121.8,
128.0, 128.2, 128.5, 133.9, 136.2, 139.1, 148.8; 19F NMR (282 Hz,
4.3. Mono-dechlorination reaction of trichloroacetaldehyde
N,O-acetal
CDCl3)
d
ꢀ63.6 (1F, dd, JFeF¼269.3 Hz, JHeF¼17.8 Hz), ꢀ51.0 (1F, d,
JFeF¼269.3 Hz); MS (ESI-TOF) m/z 396 [MþNa]þ; HRMS calcd for
C22H25F2NNaO2 [MþNa]þ, 396.1751; found, 396.1726. Anal. Calcd
for C22H25F2NO2: C, 70.76; H, 6.75; N, 3.75. Found: C, 70.75; H, 6.77;
N, 3.66.
4.3.1. 3-Allyl-2-(dichloromethyl)-2,3-dihydrobenzo[d]oxazole (4a).
To a solution of trichloroacetaldehyde N,O-acetal 3a (138.2 mg,
0.5 mmol) in Et2O (2.0 mL), n-BuLi (1.38 M solution in hexane,
0.40 mL, 0.55 mmol) was added at ꢀ78 ꢁC for 15 min. After being
stirred for 1 h at the same temperature, the mixture was poured
into ice water and Et2O, which was extracted with Et2O (20 mLꢂ3).
The organic phase was washed with brine, dried over anhydrous
MgSO4, and evaporated. The obtained residue was purified by short
column chromatography on silica gel (hexane/EtOAc¼25:1) to give
dichloroacetaldehyde N,O-acetal 4a in 91% yield (111.1 mg,
4.4.2. 2-(3-Allyl-2-butyl-2,3-dihydrobenzo[d]oxazol-2-yl)-2,2-di-
fluoro-1-(4-methoxyphenyl)ethanol (5b). This compound was
obtained in 79% yield (less 63.8 mg, 0.16 mmol; more 95.6 mg,
0.24 mmol) by the reaction of trifluoroacetaldehyde N,O-acetal 1a
(115.2 mg, 0.5 mmol), n-BuLi (1.42 M in hexane, 0.88 mL,
1.25 mmol), and p-anisaldehyde (136.4 mg, 1.0 mmol) in Et2O
(3 mL) for 30 min at ꢀ78 ꢁC. For 5b-less colorless oil; IR (neat)
n
0.46 mmol). Colorless oil; IR (neat)
1245, 1208, 1180, 929, 809, 788, 738 cmꢀ1
CDCl3)
n
3063, 2983, 2874, 1487, 1353,
3469, 3064, 2958, 2871, 1613, 1599, 1514, 1496, 1249, 1069,
;
1H NMR (400 MHz,
734 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
0.88 (3H, d, J¼7.3 Hz),
d
3.89 (1H, dd, J¼15.9, 6.7 Hz), 3.98 (1H, dd, J¼15.9, 5.1 Hz),
1.12e1.26 (1H, m), 1.26e1.51 (3H, m), 2.00e2.11 (1H, m), 2.22e2.34
(1H, m), 2.69 (1H, br s, OH), 3.74 (1H, dd, J¼16.4, 6.1 Hz), 3.76e3.84
(1H, m), 3.80 (3H, s), 5.19 (1H, dd, JHeF¼17.8, 4.2 Hz), 5.24 (1H, d,
J¼10.3 Hz), 5.33 (1H, d, J¼17.2 Hz), 5.78e5.90 (1H, m), 6.39 (1H,
m), 6.58e6.64 (1H, m), 6.69 (1H, d, J¼7.6 Hz), 6.75e6.80 (1H, m),
6.86 (2H, d, J¼8.6 Hz), 7.28 (2H, d, J¼8.6 Hz); 13C NMR (100 MHz,
5.28 (1H, dd, J¼10.2, 1.3 Hz), 5.36 (1H, dd, J¼17.2, 1.3 Hz), 5.62 (1H,
d, J¼4.2 Hz), 5.72 (1H, d, J¼4.2 Hz), 5.81e5.95 (1H, m), 6.71 (1H, d,
J¼7.4 Hz), 6.77e6.83 (2H, m), 6.83e6.90 (1H, m); 13C NMR
(100 MHz, CDCl3)
d 55.2, 72.6, 99.7, 107.9, 110.1, 118.9, 121.0, 121.9,
132.9, 138.8, 150.2; MS (EI) m/z 243 [M]þ, 245 [Mþ2]þ, 247 [Mþ4]þ.
Anal. Calcd for C11H11Cl2NO: C, 54.12; H, 4.54; N, 5.74. Found: C,
54.36; H, 4.71; N, 5.58.
CDCl3)
d
13.9, 22.6, 23.5, 30.5, 47.6 (d, JCeF¼2.5 Hz), 55.2, 71.9 (dd,
JCeF¼30.6, 22.7 Hz), 104.2 (t, JCeF¼29.5 Hz), 105.4, 106.8, 113.5,
117.1, 118.0, 119.2 (dd, JCeF¼265.6, 253.5 Hz), 122.0, 128.7, 129.3,
4.4. Three component synthesis of
a
,a
-difluoro-
b-
133.9, 139.3, 148.6, 159.8; 19F NMR (282 Hz, CDCl3)
d
ꢀ60.7 (1F, dd,
hydroxyketone N,O-acetal
JFeF¼269.3 Hz, JHeF¼17.8 Hz), ꢀ51.3 (1F, dd, JFeF¼269.5 Hz,
JHeF¼4.2 Hz); MS (ESI-TOF) m/z 426 [MþNa]þ; HRMS calcd for
C23H27F2NNaO3 [MþNa]þ, 426.1857; found, 426.1863. For 5b-more
4.4.1. 2-(3-Allyl-2-butyl-2,3-dihydrobenzo[d]oxazol-2-yl)-2,2-di-
fluoro-1-phenylethanol (5a). To a solution of trifluoroacetaldehyde
N,O-acetal 1a (114.6 mg, 0.5 mmol) in Et2O (2 mL), n-BuLi (1.55 M in
hexane, 0.81 mL, 1.25 mmol) was added at ꢀ78 ꢁC over 15 min.
After being stirred for 4 h at the same temperature, the mixture was
treated with a solution of freshly-distilled benzaldehyde (106.9 mg,
1.0 mmol) in Et2O (1 mL) for 30 min at ꢀ78 ꢁC. The resulting mix-
ture was poured into ice water and Et2O, which was extracted with
Et2O (20 mLꢂ3). The organic phase was washed with brine, dried
over anhydrous MgSO4, and evaporated. Purification of the residue
by silica gel column chromatography (hexane/EtOAc¼20:1) and
additional MPLC (hexane/EtOAc¼10:1) gave 5a-less (66.3 mg,
0.18 mmol, 36%) and 5a-more (92.4 mg, 0.25 mmol, 49%) in the
colorless oil; IR (neat)
n 3485, 3064, 2959, 2872, 1613, 1599, 1514,
1496, 1248, 1176, 1070, 1034, 734 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
0.87 (3H, d, J¼7.2 Hz), 1.14e1.50 (4H, m), 1.99e2.16 (2H, m), 3.21
(1H, br s, OH), 3.80 (3H, s), 3.83 (1H, dd, J¼16.3, 6.2 Hz), 3.96e4.03
(1H, m), 5.09e5.16 (1H, m), 5.27 (1H, dd, J¼10.2, 1.4 Hz), 5.39 (1H,
dd, J¼17.2, 1.4 Hz), 5.92e6.05 (1H, m), 6.47 (1H, d, J¼7.5 Hz),
6.59e6.64 (2H, m), 6.73e6.80 (1H, m), 6.86 (2H, d, J¼8.6 Hz), 7.32
(2H, d, J¼8.6 Hz); 13C NMR (100 MHz, CDCl3)
d 13.9, 22.6, 23.6,
30.4, 48.1, 55.2, 72.3 (dd, JCeF¼29.3, 23.2 Hz), 103.7 (t,
JCeF¼28.6 Hz), 105.9, 106.9, 113.5, 117.6, 118.5, 118.8 (dd,
JCeF¼260.6, 257.5 Hz), 121.8, 128.3 (d, JCeF¼1.2 Hz), 129.4, 133.9,
139.1, 148.8, 159.8; 19F NMR (282 Hz, CDCl3)
d
ꢀ63.7 (1F, dd,
order of elution. For 5a-less Colorless oil; IR (neat)
2959, 2872, 1599, 1495, 1401, 1317, 1239, 1031, 731, 731, 699 cmꢀ1
1H NMR (400 MHz, CDCl3)
n
3543, 3064,
JFeF¼267.3 Hz, JHeF¼17.8 Hz), ꢀ51.3 (1F, d, JFeF¼267.3 Hz); MS (ESI-
TOF) m/z 426 [MþNa]þ; HRMS calcd for C23H27F2NNaO3 [MþNa]þ,
426.1857; found, 426.1836.
;
d
0.88 (3H, t, J¼7.3 Hz), 1.12e1.26 (1H,
m), 1.26e1.52 (3H, m), 2.00e2.13 (1H, m), 2.22e2.35 (1H, m), 2.77
(1H, br s, OH), 3.70e3.82 (2H, m), 5.19e5.26 (2H, m), 5.33 (1H, d,
J¼17.2 Hz), 5.77e5.90 (1H, m), 6.40 (1H, d, 7.6 Hz), 6.62 (1H, t,
J¼7.6 Hz), 6.70 (1H, d, J¼7.6 Hz), 6.79 (1H, t, J¼7.6 Hz), 7.29e7.40
4.4.3. 2-(3-Allyl-2-butyl-2,3-dihydrobenzo[d]oxazol-2-yl)-2,2-di-
fluoro-1-(4-(trifluoromethyl)phenyl)ethanol (5c). This compound
was obtained in 85% yield (less 69.5 mg 0.16 mmol; more 118.2 mg,
0.27 mmol) by the reaction of trifluoroacetaldehyde N,O-acetal 1a
(115.2 mg, 0.5 mmol), n-BuLi (1.42 M in hexane, 0.88 mL,
(5H, m); 13C NMR (100 MHz, CDCl3)
d 13.9, 22.6, 23.5, 30.5, 47.7 (d,
JCeF¼2.7 Hz), 72.3 (dd, JCeF¼30.5, 22.4 Hz), 104.3 (t, JCeF¼29.3 Hz),
105.5, 106.8, 117.1, 118.1, 119.1 (dd, JCeF¼265.5, 254.0 Hz), 122.0,
128.05, 128.09, 128.6, 133.9, 136.5, 139.3, 148.6; 19F NMR (282 Hz,
1.25 mmol)
and
4-trifluoromethylbenzaldehyde
(174.1 mg,
1.0 mmol) in Et2O (3 mL) for 30 min at ꢀ78 ꢁC. For 5c-less colorless
CDCl3)
d
ꢀ60.4 (1F, dd, JFeF¼269.6 Hz, JHeF¼17.8 Hz), ꢀ52.0 (1F, dd,
oil; IR (neat) n 3485, 3067, 2961, 2874, 1599, 1496, 1326, 1239, 1167,
JFeF¼269.6 Hz, JHeF¼4.0 Hz); MS (ESI-TOF) m/z 396 [MþNa]þ;
HRMS calcd for C22H25F2NNaO2 [MþNa]þ, 396.1751; found,
396.1777. Anal. Calcd for C22H25F2NO2: C, 70.76; H, 6.75; N, 3.75.
Found: C, 70.58; H, 6.98; N, 3.58. For 5a-more colorless oil; IR (neat)
1127, 1068, 1018, 930, 782, 735 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
0.88 (3H, t, J¼7.2 Hz), 1.12e1.25 (1H, m), 1.26e1.50 (3H, m),
2.01e2.14 (1H, m), 2.19e2.31 (1H, m), 2.95 (1H, br, OH), 3.70e3.86
(2H, m), 5.21e5.34 (2H, m), 5.34 (1H, d, J¼16.3 Hz), 5.74e5.90 (1H,
m), 6.42 (1H, d, J¼7.5 Hz), 6.60e6.69 (1H, m), 6.42 (1H, d, J¼7.5 Hz),
6.60e6.69 (1H, m), 6.70 (1H, d, J¼7.5 Hz), 6.77e6.84 (1H, m), 7.47
(2H, d, J¼8.2 Hz), 7.59 (2H, d, J¼8.2 Hz); 13C NMR (100 MHz, CDCl3)
n
3540, 3064, 2959, 2872, 1599, 1465, 1316, 1239, 1086, 1062, 929,
732, 699 cmꢀ1 1H NMR (400 MHz, CDCl3)
0.88 (3H, t, J¼7.2 Hz),
1.16e1.52 (4H, m), 2.00e2.18 (2H, m), 3.85 (1H, dd, J¼16.2, 6.5 Hz),
;
d

4536
H. Yanai, T. Taguchi / Tetrahedron 66 (2010) 4530e4541
d
13.9, 22.6, 23.4, 30.4, 47.9 (d, JCeF¼3.0 Hz), 71.9 (dd, JCeF¼29.5,
732 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
0.91 (3H, t, J¼7.2 Hz),
23.3 Hz), 104.4 (t, JCeF¼29.4 Hz), 105.8, 107.0, 117.3, 118.5, 118.8 (dd,
JCeF¼266.2, 254.3 Hz), 122.3, 124.1 (q, JCeF¼272.0 Hz), 124.9 (q,
JCeF¼3.7 Hz), 128.5, 130.7 (q, JCeF¼32.5 Hz), 133.7, 139.2, 140.2,
1.20e1.60 (4H, m), 2.06e2.18 (1H, m), 2.53e2.66 (1H, m), 3.86 (1H,
dd, J¼16.5, 6.0 Hz), 3.94 (1H, dd, J¼16.5, 5.6 Hz), 5.06e5.60 (1H, br s,
OH), 5.20 (1H, dd, J¼10.4, 1.2 Hz), 5.25 (1H, JHeF¼21.7 Hz), 5.34 (1H,
dd, J¼17.2, 1.2 Hz), 5.84e5.97 (1H, m), 6.49 (1H, d, J¼7.5 Hz), 6.57
(1H, t, J¼7.5 Hz), 6.65 (1H, d, J¼7.5 Hz), 6.75 (1H, t, J¼7.5 Hz),
7.24e7.28 (1H, m), 7.34 (1H, dd, J¼7.8, 2.7 Hz), 7.61e7.69 (1H, m),
148.4; 19F NMR (282 Hz, CDCl3)
d
ꢀ59.7 (1F, dd, JFeF¼269.6,
JHeF¼18.0 Hz), ꢀ52.3 (1F, d, JFeF¼269.6 Hz), 0.05 (3F, s); MS (ESI-
TOF) m/z 464 [MþNa]þ; HRMS calcd for C23H24F5NNaO2 [MþNa]þ,
464.1625; found, 464.1628. For 5c-more colorless oil; IR (neat)
n
8.54 (1H, d, J¼4.9 Hz); 13C NMR (100 MHz, CDCl3)
d 14.0, 22.6, 23.8,
3500, 3067, 2961, 2874, 1599, 1494, 1326, 1239, 1166, 1127, 1067,
31.2, 47.2, 70.7 (dd, JCeF¼32.4, 24.3 Hz), 103.7 (dd, JCeF¼29.3,
24.5 Hz), 104.5, 106.4, 116.8, 117.2, 120.1 (dd, JCeF¼264.8, 255.4 Hz),
121.4, 123.47, 123.50 (t, JCeF¼5.4 Hz), 134.1, 136.4, 139.4, 147.7, 149.2,
1019, 735 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
0.89 (3H, t, J¼7.2 Hz),
1.21e1.52 (4H, m), 2.04e2.20 (2H, m), 3.54 (1H, br s, OH), 3.84 (1H,
dd, J¼16.1, 6.6 Hz), 3.96e4.04 (1H, m), 5.19e5.28 (1H, m), 5.30 (1H,
dd, J¼10.2, 1.4 Hz), 5.42 (1H, dd, J¼17.2, 1.4 Hz), 5.94e6.07 (1H, m),
6.53 (1H, d, J¼7.6 Hz), 6.57e6.68 (2H, m), 6.76e6.84 (1H, m), 7.52
(2H, d, J¼8.3 Hz), 7.58 (2H, d, J¼8.3 Hz); 13C NMR (100 MHz, CDCl3)
153.8; 19F NMR (282 Hz, CDCl3)
d
ꢀ61.8 (1F, dd, JFeF¼263.4 Hz,
JHeF¼21.7 Hz), ꢀ51.0 (1F, d, JFeF¼263.4 Hz); MS (ESI-TOF) m/z 397
[MþNa]þ; HRMS calcd for C21H24F2N2NaO2 [MþNa]þ, 397.1704;
found, 397.1714. Anal. Calcd for C21H24F2N2O2: C, 67.36; H, 6.46; N,
7.48. Found: C, 67.35; H, 6.53; N, 7.42. For 5e-more colorless oil; IR
d
13.8, 22.6, 23.5, 30.3, 48.4, 72.3 (dd, JCeF¼28.9, 23.7 Hz), 103.7 (t,
JCeF¼28.7 Hz), 106.3, 107.1, 117.9, 118.3 (t, JCeF¼260.3 Hz), 119.0,
122.0, 124.1 (q, JCeF¼272.2 Hz), 124.8 (q, JCeF¼3.6 Hz), 128.6, 130.5
(q, JCeF¼32.4 Hz),133.7,139.0,140.0,148.6; 19F NMR (282 Hz, CDCl3)
(neat)
n
3361, 2958, 2871, 1597, 1495, 1401, 1313, 1241, 1207, 1109,
0.88 (3H, t, J¼7.1 Hz),
1085, 733 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.15e1.51 (4H, m), 2.13e2.31 (2H, m), 3.87 (1H, dd, J¼16.7, 5.7 Hz),
4.03e4.12 (1H, m), 5.10 (1H, dd, JHeF¼17.8, 4.6 Hz), 5.24 (1H, dd,
J¼10.3, 1.5 Hz), 5.39 (1H, dd, J¼17.2, 1.5 Hz), 5.91e6.02 (1H, m), 6.41
(1H, d, J¼7.5 Hz), 6.47 (1H, d, J¼7.6 Hz), 6.51e6.57 (1H, m),
6.70e6.77 (1H, m), 7.26e7.31 (1H, m), 7.34 (1H, d, J¼8.0 Hz),
7.63e7.70 (1H, m), 8.58 (1H, d, J¼4.7 Hz); 13C NMR (100 MHz,
d
ꢀ63.4 (1F, dd, JFeF¼269.7, 17.9 Hz), ꢀ50.8 (1F, d, JFeF¼269.7 Hz),
0.05 (3F, s); MS (ESI-TOF) m/z 442 [MþH]þ; HRMS calcd for
C23H25F5NO2 [MþH]þ, 442.1805; found, 442.1800.
4.4.4. 2-(3-Allyl-2-butyl-2,3-dihydrobenzo[d]oxazol-2-yl)-2,2-di-
fluoro-1-(furan-2-yl)ethanol (5d). This compound was obtained in
87% yield (less 71.9 mg, 0.198 mmol; more 86.3 mg, 0.237 mmol) by
the reaction of trifluoroacetaldehyde N,O-acetal 1a (115.3 mg,
0.50 mmol), n-BuLi (1.42 M in hexane, 0.88 mL, 1.25 mmol), and
furfural (96.1 mg, 1.0 mmol) in Et2O (3 mL) for 1 h at ꢀ78 ꢁC. For 5d-
CDCl3)
d
14.0, 22.6, 23.7, 31.0, 47.6, 70.9 (dd, JCeF¼29.8, 26.2 Hz),
103.6 (t, JCeF¼26.5 Hz), 105.3, 106.3, 116.8, 117.7, 119.5 (dd,
JCeF¼263.0, 257.9 Hz), 121.4, 123.3 (br), 123.5, 134.2, 136.6, 139.6,
147.7, 149.1, 153.9; 19F NMR (282 Hz, CDCl3)
d
ꢀ60.6 (1F, dd,
JFeF¼265.6 Hz, JHeF¼17.8 Hz), ꢀ51.6 (1F, dd, JFeF¼265.6 Hz,
JHeF¼4.6 Hz); MS (ESI-TOF) m/z 397 [MþNa]þ; HRMS calcd for
C21H24F2N2NaO2 [MþNa]þ, 397.1704; found, 397.1678. Anal. Calcd
for C21H24F2N2O2: C, 67.36; H, 6.46; N, 7.48. Found: C, 67.41; H, 6.66;
N, 7.43.
less colorless oil; IR (neat)
n
3442, 3065, 2959, 2872,1599,1496,1239,
0.88 (3H, d,
1110, 1080, 924, 733 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
J¼7.2 Hz), 1.14e1.52 (4H, m), 2.00e2.12 (1H, m), 2.20e2.31 (1H, m),
2.68 (1H, br s, OH), 3.78 (1H, dd, J¼16.3, 6.3 Hz), 3.81e3.89 (1H, m),
5.19e5.30 (2H, m), 5.33 (1H, d, J¼17.2 Hz), 5.79e5.83 (1H, m),
6.28e6.36 (2H, m), 6.38 (1H, d, J¼7.6 Hz), 6.75 (1H, td, J¼7.6, 1.0 Hz),
6.65 (1H, d, J¼7.6, 1.0 Hz), 6.71e6.79 (1H, m), 7.39e7.42 (1H, m); 13C
4.4.6. (E)-1-(3-Allyl-2-butyl-2,3-dihydrobenzo[d]oxazol-2-yl)-1,1-di-
fluoro-4-phenylbut-3-en-2-ol (5f). This compound was obtained in
87% yield (less 86.5 mg, 0.236 mmol; more 72.1 mg, 0.199 mmol) by
the reaction of trifluoroacetaldehyde N,O-acetal 1a (115.5 mg,
0.50 mmol), n-BuLi (1.42 M in hexane, 0.88 mL, 1.25 mmol), and
cinnamaldehyde (132.2 mg, 1.0 mmol) in Et2O (3 mL) for 1 h at
NMR (100 MHz, CDCl3)
d 13.9, 22.6, 23.5, 30.4, 47.6, 66.9 (dd,
JCeF¼30.6, 24.4 Hz), 103.6 (t, JCeF¼28.4 Hz), 105.3, 106.7, 109.3, 110.4,
117.1,118.0,119.0 (dd, JCeF¼264.6, 256.0 Hz),121.8,134.0,139.2,142.7,
147.7, 149.7; 19F NMR (282 Hz, CDCl3)
d
ꢀ59.2 (1F, dd, JFeF¼267.3 Hz,
JHeF¼17.8 Hz), ꢀ51.3 (1F, dd, JFeF¼267.3 Hz, JHeF¼5.9 Hz); MS (ESI-
ꢀ78 ꢁC. For 5f-less colorless oil; IR (neat)
n
3417, 3061, 2959, 2871,
0.91
TOF) m/z 386 [MþNa]þ; HRMS calcd for C20H23F2NNaO3 [MþNa]þ,
1599, 1496, 1238, 1070, 732 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
386.1544; found, 386.1543. For 5d-more colorless oil; IR (neat)
n
3521,
(3H, t, J¼7.2 Hz), 1.17e1.55 (4H, m), 2.05e2.17 (1H, m), 2.22e2.34
(1H, m), 2.52 (1H, br s, OH), 3.82 (1H, dd, J¼16.3, 6.3 Hz), 3.94 (1H,
dd, J¼16.3, 5.1 Hz), 4.80 (1H, ddd, JHeF¼13.8, 9.9 Hz, JHeH¼6.9 Hz),
5.22 (1H, d, J¼10.2 Hz), 5.34 (1H, d, J¼17.2 Hz), 5.86e5.99 (1H, m),
6.28 (1H, dd, J¼15.9, 6.9 Hz), 6.37 (1H, d, J¼7.5 Hz), 6.52 (1H, d,
J¼15.9 Hz), 6.60 (1H, t, J¼7.5 Hz), 6.68 (1H, d, J¼7.5 Hz), 6.74 (1H, t,
3064, 2959, 2872, 1599, 1496, 1240, 1110, 1083, 1060, 1013, 923, 791,
734 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
0.86 (3H, t, J¼7.2 Hz),
1.13e1.25 (1H, m), 1.25e1.49 (3H, m), 1.93e2.03 (1H, m), 2.04e2.15
(1H, m), 2.98 (1H, br s, OH), 3.83 (1H, dd, J¼16.3, 6.3 Hz), 3.95e4.05
(1H, m), 5.17e5.30 (1H, m), 5.26 (1H, dd, J¼10.3,1.5 Hz), 5.38 (1H, dd,
J¼17.2, 1.5 Hz), 5.91e6.04 (1H, m), 6.32 (2H, d, J¼1.3 Hz), 6.46 (1H, d,
J¼7.2 Hz), 6.55e6.63 (2H, m), 6.71e6.79 (1H, m), 7.40 (1H, t,
J¼7.5 Hz), 7.22e7.37 (5H, m); 13C NMR (100 MHz, CDCl3)
d 13.9,
22.5, 23.4, 30.4, 47.8, 71.6 (t, JCeF¼26.4 Hz), 103.5 (t, JCeF¼29.0 Hz),
105.4, 106.7, 117.2, 118.0, 119.8 (dd, JCeF¼261.8, 257.1 Hz), 122.4,
123.5 (t, JCeF¼3.2 Hz), 126.7, 127.9, 128.4, 133.7, 133.9, 136.1, 139.2,
J¼1.3 Hz); 13C NMR (100 MHz, CDCl3)
d 13.9, 22.5, 23.5, 30.1, 48.0,
66.9 (dd, JCeF¼29.0, 24.9 Hz), 103.3 (t, JCeF¼28.0 Hz), 105.8, 106.9,
109.6, 110.4, 117.5, 118.4, 118.7 (t, JCeF¼260.0 Hz), 121.7, 133.9, 139.1,
148.7; 19F NMR (282 Hz, CDCl3)
d
ꢀ57.6 (1F, dd, JFeF¼267.6 Hz,
142.7, 148.8, 149.4 (d, JCeF¼3.0 Hz); 19F NMR (282 Hz, CDCl3)
d
ꢀ60.7
JHeF¼13.8 Hz), ꢀ56.4 (1F, dd, JFeF¼267.6 Hz, JHeF¼9.9 Hz); MS (ESI-
TOF) m/z 422 [MþNa]þ; HRMS calcd for C24H27F2NNaO2 [MþNa]þ,
422.1908; found, 422.1899. Anal. Calcd for C24H27F2NO2: C, 72.16; H,
6.81; N, 3.51. Found: C, 71.91; H, 6.83; N, 3.49. For 5f-more colorless
(1F, dd, JFeF¼267.6 Hz, JHeF¼15.8 Hz), ꢀ51.3 (1F, dd, JFeF¼267.6 Hz,
JHeF¼7.9 Hz); MS (ESI-TOF) m/z 386 [MþNa]þ; HRMS calcd for
C20H23F2NNaO3 [MþNa]þ, 386.1544; found, 386.1542.
oil; IR (neat)
n
3426, 3061, 2959, 2872, 1599, 1495, 1239, 1069,
0.87 (3H, t, J¼7.2 Hz),
4.4.5. 2-(3-Allyl-2-butyl-2,3-dihydrobenzo[d]oxazol-2-yl)-2,2-di-
fluoro-1-(pyridin-2-yl)ethanol (5e). This compound was obtained in
87% yield (less 125.8 mg, 0.34 mmol; more 37.0 mg, 0.099 mmol) by
the reaction of trifluoroacetaldehyde N,O-acetal 1a (115.6 mg,
0.5 mmol), n-BuLi (1.42 M in hexane, 0.88 mL, 1.25 mmol), and 2-
pyridinecarbaldehyde (106.9 mg, 1.0 mmol) in Et2O (3 mL) for
733 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
1.12e1.51 (4H, m), 2.05e2.21 (2H, m), 2.69 (1H, br s, OH), 3.82 (1H,
dd, J¼16.2, 6.4 Hz), 3.98 (1H, dd, J¼16.2, 4.9 Hz), 4.75 (1H, ddd,
JHeF¼23.8, 9.2 Hz, JHeH¼7.0 Hz), 5.25 (1H, d, J¼10.2 Hz), 5.36 (1H, d,
J¼17.1 Hz), 5.90e6.03 (1H, m), 6.26 (1H, dd, J¼16.0, 7.0 Hz), 6.45
(1H, d, J¼7.6 Hz), 6.50e6.58 (3H, m), 6.69e6.78 (1H, m), 7.20e7.33
15 min at ꢀ78 ꢁC. For 5e-less colorless oil; IR (neat)
n
3365, 3063,
(5H, m); 13C NMR (100 MHz, CDCl3)
d 13.9, 22.6, 23.4, 30.2, 48.1, 71.8
2958, 2871, 1597, 1496, 1402, 1315, 1239, 1206, 1110, 1085, 935, 754,
(dd, JCeF¼27.9, 24.5 Hz), 103.4 (t, JCeF¼28.6 Hz), 105.6, 107.3, 117.5,

H. Yanai, T. Taguchi / Tetrahedron 66 (2010) 4530e4541
4537
118.4, 119.4 (t, JCeF¼259.1 Hz), 121.7, 123.4 (t, JCeF¼3.3 Hz), 126.7,
J¼10.3 Hz), 5.38 (1H, d, J¼17.2 Hz), 5.91e6.06 (1H, m), 6.47 (1H, d,
J¼7.4 Hz), 6.58e6.67 (2H, m), 6.73e6.80 (1H, m); 13C NMR
127.9, 128.4, 133.9, 134.1, 136.2, 139.1, 148.7; 19F NMR (282 Hz,
CDCl3)
d
ꢀ60.8 (1F, dd, JFeF¼266.4 Hz, JHeF¼12.8 Hz), ꢀ54.9 (1F, dd,
(100 MHz, CDCl3)
d
13.9, 22.6, 23.7, 14.7 (t, JCeF¼3.2 Hz), 25.6 (t,
JFeF¼266.4 Hz, JHeF¼9.2 Hz); MS (ESI-TOF) m/z 422 [MþNa]þ;
HRMS calcd for C24H27F2NNaO2 [MþNa]þ, 422.1908; found,
422.1883. Anal. Calcd for C24H27F2NO2: C, 72.16; H, 6.81; N, 3.51.
Found: C, 71.91; H, 6.91; N, 3.32.
J¼3.3 Hz), 31.9, 48.4, 74.2 (t, JCeF¼26.4 Hz), 104.8 (dd, JCeF¼30.4,
29.6 Hz), 105.7, 106.7, 117.4, 118.3, 120.7 (t, JCeF¼260.9 Hz), 121.7,
134.0, 139.1, 148.8; 19F NMR (282 Hz, CDCl3)
J¼271.4 Hz), ꢀ53.6 (1F, d, J¼271.4 Hz); MS (ESI-TOF) m/z 326
[MþH]þ; HRMS calcd for C18H26F2NO2 [MþH]þ, 326.1964; found,
326.1964.
d
ꢀ55.9 (1F, d,
4.4.7. (R
*
)-1-((R )-3-Allyl-2-butyl-2,3-dihydrobenzo[d]oxazol-2-yl)-
*
1,1-difluoro-4-phenylbutan-2-ol (anti-5g). This compound was
obtained in 76% yield (152.6 mg, 0.38 mmol) as an inseparable anti/
syn mixture in a ratio of 11:1 by the reaction of trifluoroacetaldehyde
N,O-acetal 1a (114.9 mg, 0.5 mmol), n-BuLi (1.42 M in hexane,
0.88 mL, 1.25 mmol), and 3-phenylpropionaldehyde (137.1 mg,
1.0 mmol) in Et2O (3.0 mL) for 3 h at ꢀ24 ꢁC. Spectra date only for
4.4.10. 1-((3-Allyl-2-butyl-2,3-dihydrobenzo[d]oxazol-2-yl)di-
fluoromethyl)cyclohexanol (5j). This compound was obtained in
84% yield (153.5 mg, 0.42 mmol) by the reaction of tri-
fluoroacetaldehyde N,O-acetal 1a (115.7 mg, 0.5 mmol), n-BuLi
(1.42 M in hexane, 0.88 mL, 1.25 mmol), and cyclohexanone
(97.2 mg, 1.0 mmol) in Et2O (3 mL) for 5 h at 0 ꢁC. Colorless oil; IR
anti isomer (major isomer) are shown. Colorless oil; IR (neat)
3063, 3027, 2959, 2871, 1599, 1495, 1240, 1085, 734, 700 cmꢀ1
NMR (400 MHz, CDCl3)
n
3547,
1H
0.95 (3H, t, J¼7.2 Hz), 1.19e1.33 (1H, m),
;
(neat)
n
3548, 3064, 2936, 2864, 1599, 1496, 1239, 1086, 989,
d
731 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
0.87 (3H, t, J¼7.3 Hz),
1.34e1.59 (3H, m), 1.93e2.06 (1H, m), 2.06e2.20 (3H, m), 2.67e2.78
(2H, m), 2.89e3.00 (1H, m), 3.85 (1H, dd, J¼16.3, 6.3 Hz), 3.96e4.04
(1H, m), 4.08e4.21 (1H, m), 5.28 (1H, d, J¼10.2 Hz), 5.37 (1H, d,
J¼17.2 Hz), 5.89e6.01 (1H, m), 6.51 (1H, d, J¼7.5 Hz), 6.67e6.76 (2H,
m), 6.81e6.87 (1H, m), 7.18e7.28 (3H, m), 7.29e7.36 (2H, m); 13C
1.08e1.22 (2H, m), 1.24e1.48 (3H, m), 1.51e1.79 (8H, m), 1.91e2.00
(1H, m), 2.02e2.13 (1H, m), 2.23e2.34 (1H, m), 2.26 (1H, br s, OH),
3.81 (1H, dd, J¼16.2, 6.5 Hz), 3.94e4.03 (1H, m), 5.25 (1H, dd,
J¼10.2, 1.4 Hz), 5.37 (1H, dd, J¼17.2, 1.4 Hz), 5.91e6.03 (1H, m), 6.45
(1H, d, J¼7.5 Hz), 6.57e6.67 (2H, m), 6.75 (1H, td, J¼7.5, 1.4 Hz); 13C
NMR (100 MHz, CDCl3)
d
13.9, 22.6, 23.6, 30.3, 31.4, 48.1, 69.4 (dd,
NMR (100 MHz, CDCl3) d 14.0, 20.8, 20.9, 22.6, 23.8, 25.3, 30.6 (m),
JCeF¼29.0, 23.7 Hz), 103.6 (t, JCeF¼28.9 Hz), 105.9, 106.8, 117.4, 118.5,
31.5 (t, JCeF¼3.3 Hz), 32.2, 48.3, 75.4 (t, JCeF¼25.2 Hz), 105.2 (t,
119.5 (t, JCeF¼258.6 Hz), 121.8, 125.8, 128.3, 128.4, 133.8, 139.0, 141.4,
JCeF¼28.8 Hz), 105.6, 106.6, 117.3, 118.1, 120.7 (t, JCeF¼260.9 Hz),
148.8; 19F NMR (282 Hz, CDCl3)
d
ꢀ64.0 (1F, dd, JFeF¼267.3 Hz,
121.6, 134.1, 139.3, 148.9; 19F NMR (282 Hz, CDCl3)
d
ꢀ57.4 (1F, d,
JHeF¼17.8 Hz), ꢀ54.6 (1F, d, JFeF¼267.3 Hz); MS (ESI-TOF) m/z 424
[MþNa]þ; HRMS calcd for C24H29F2NNaO2 [MþNa]þ, 424.2064;
found, 424.2044.
JFeF¼271.6 Hz), ꢀ55.8 (1F, d, JFeF¼271.6 Hz); MS (ESI-TOF) m/z 388
[MþNa]þ; HRMS calcd for C21H29F2NNaO2 [MþNa]þ, 388.2064;
found, 388.2071. Anal. Calcd for C21H29F2NO2: C, 69.02; H, 8.00; N,
3.83. Found: C, 68.98; H, 7.91; N, 3.73.
4.4.8. (R
*
)-2-((R )-3-Allyl-2-butyl-2,3-dihydrobenzo[d]oxazol-2-yl)-
*
1-cyclohexyl-2,2-difluoroethanol (anti-5h). This compound was
obtained in 81% yield (153.7 mg, 0.40 mmol) as an inseparable anti/
syn mixture in a ratio of 11:1 by the reaction of trifluoroacetaldehyde
N,O-acetal 1a (115.4 mg, 0.5 mmol), n-BuLi (1.42 M in hexane,
0.88 mL, 1.25 mmol), and cyclohexanecarbaldehyde (112.3 mg,
1.0 mmol) in Et2O (3.0 mL) for 8 h at 0 ꢁC. Spectra date only for anti
isomer (major isomer) are shown. Colorless crystals; mp
4.4.11. 1-(3-Allyl-2-butyl-2,3-dihydrobenzo[d]oxazol-2-yl)-1,1-di-
fluoro-2-phenylpropan-2-ol (5k). This compound were obtained in
79% yield (less 98.4 mg, 0.254 mmol; more 54.6 mg, 0.141 mmol) by
the reaction of trifluoroacetaldehyde N,O-acetal 1a (115.6 mg,
0.5 mmol), n-BuLi (1.42 M in hexane, 0.88 mL, 1.25 mmol), and
acetophenone (120.3 mg, 1.0 mmol) in Et2O (3 mL) for 9 h at room
temperature. For 5k-less Colorless oil; IR (neat)
2872, 1599, 1496, 1239, 1093, 1067, 925, 732, 700 cmꢀ1
(400 MHz, CDCl3)
1.18e1.38 (3H, m),1.76 (3H, s),1.79e1.89 (1H, m),1.89e2.00 (1H, m),
3.82 (1H, dd, J¼16.0, 6.8 Hz), 3.92e4.01 (1H, m), 4.06 (1H, br s, OH),
5.34 (1H, dd, J¼10.2, 1.4 Hz), 5.44 (1H, dd, J¼17.2, 1.4 Hz), 5.99e6.01
(1H, m), 6.33 (1H, dd, J¼7.7, 0.9 Hz), 6.52 (1H, dd, J¼7.5, 1.1 Hz),
6.55e6.60 (1H, m), 6.75e6.81 (1H, m), 7.24e7.33 (3H, m), 7.46e7.52
n
3542, 3062, 2959,
1H NMR
0.82 (3H, t, J¼7.2 Hz), 1.04e1.17 (1H, m),
49.0e50.0 ꢁC; IR (neat)
n
3564, 2929, 2854, 1599, 1496, 1240, 1089,
0.90 (3H, t, J¼7.2),
;
924, 732 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
d
1.08e1.52 (9H, m), 1.53e1.61 (1H, m), 1.62e1.70 (1H, m), 1.70e1.94
(4H, m), 2.11 (2H, t, J¼7.4 Hz), 2.51 (1H, br s, OH), 3.81 (1H, dd, J¼16.3,
6.3 Hz), 3.86e4.06 (2H, m), 5.27 (1H, dd, J¼10.3,1.4 Hz), 5.38 (1H, dd,
J¼17.1, 1.4 Hz), 5.91e6.04 (1H, m), 6.47 (1H, d, J¼7.5 Hz), 6.59e6.70
(2H, m), 6.73e6.80 (1H, td, J¼7.5, 1.3 Hz); 13C NMR (100 MHz, CDCl3)
d
for major isomer 13.9, 22.6, 23.7, 26.1, 26.2 (2C), 26.7, 30.2, 30.4, 38.4
(2H, m); 13C NMR (100 MHz, CDCl3)
d 13.7, 22.4, 23.4, 25.5 (t,
(d, JCeF¼2.5 Hz), 48.2, 73.1 (dd, JCeF¼28.2, 22.2 Hz), 103.8 (t,
JCeF¼3.7 Hz), 31.5, 48.5, 76.7e77.3 (m),105.0 (t, JCeF¼29.9 Hz),106.0,
106.9, 117.8, 118.7, 119.9 (t, JCeF¼264.0 Hz), 121.6, 125.4 (d,
JCeF¼2.4 Hz), 127.2, 127.6, 133.9, 138.8, 142.1 (d, JCeF¼3.4 Hz), 148.3;
JCeF¼28.9 Hz), 105.8, 106.7, 117.4, 118.4, 120.2 (t, JCeF¼260.4 Hz),
121.7, 134.0, 139.3, 149.0; 19F NMR (282 Hz, CDCl3)
d
ꢀ60.6 (1F, dd,
JFeF¼269.6 Hz, JHeF¼21.7 Hz), ꢀ52.6 (1F, d, JFeF¼269.6 Hz); MS (ESI-
TOF) m/z 402 [MþNa]þ; HRMS calcd for C22H31F2NNaO2 [MþNa]þ,
402.2221; found, 402.2206. Anal. Calcd for C22H31F2NO2: C, 69.63; H,
8.23; N, 3.69. Found: C, 69.82; H, 8.11; N, 3.73.
19F NMR (282 Hz, CDCl3)
d
ꢀ53.8 (1F, d, JFeF¼271.3 Hz), ꢀ48.9 (1F, d,
JFeF¼271.3 Hz); MS (ESI-TOF) m/z 410 [MþNa]þ; HRMS calcd for
C23H27F2NNaO2 [MþNa]þ, 410.1908; found, 410.1872. Anal. Calcd for
C23H27F2NO2: C, 71.30; H, 7.02; N, 3.61. Found: C, 71.32; H, 7.04; N,
3.48. For 5k-more colorless oil; IR (neat)
1599,1496,1239,1090,1074, 921, 732, 701 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
n 3548, 3062, 2959, 2872,
4.4.9. 1-(3-Allyl-2-butyl-2,3-dihydrobenzo[d]oxazol-2-yl)-1,1-di-
fluoro-2-methylpropan-2-ol (5i). This compound was obtained in
89% yield (144.8 mg, 0.45 mmol) by the reaction of tri-
fluoroacetaldehyde N,O-acetal 1a (115.7 mg, 0.5 mmol), n-BuLi
(1.42 M in hexane, 0.88 mL, 1.25 mmol), and acetone (58.2 mg,
1.0 mmol) in Et2O (3 mL) for 9 h at room temperature. Colorless oil;
d
0.86 (3H, t, J¼7.2 Hz), 1.08e1.20 (1H, m), 1.22e1.41 (3H, m),
1.74 (3H, s),1.93e2.04 (1H, m), 2.15e2.25 (1H, m), 3.23 (1H, br s, OH),
3.62 (1H, dd, J¼16.2, 5.4 Hz), 3.69 (1H, dd, J¼16.2, 6.6 Hz), 5.21 (1H,
dd, J¼10.2, 1.4 Hz), 5.30 (1H, dd, J¼17.2, 1.4 Hz), 5.81e5.94 (1H, m),
6.26 (1H, dd, J¼7.5, 1.0 Hz), 6.47 (1H, dd, J¼7.6, 1.0 Hz), 6.54e6.61
(1H, m), 6.68e6.74 (1H, m), 7.23e7.34 (3H, m), 7.42e7.49 (2H, m);
IR (neat)
n
3464, 3064, 2959, 2873, 1599, 1496, 1239, 1071,
732 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
0.88 (3H, t, J¼7.3 Hz),
13C NMR (100 MHz, CDCl3)
d
13.9, 22.5, 23.5, 26.4 (t, JCeF¼3.5 Hz),
1.11e1.25 (1H, m), 1.26e1.50 (3H, m), 1.36 (3H, s), 1.40 (3H, s),
2.03e2.16 (1H, m), 2.22e2.36 (1H, m), 2.59 (1H, br s, OH), 3.82 (1H,
dd, J¼16.1, 6.5 Hz), 3.99 (1H, dd, J¼16.1, 4.9 Hz), 5.26 (1H, d,
31.7, 47.7, 76.5e77.1 (m), 104.8 (t, JCeF¼29.8 Hz), 105.7, 106.7, 117.4,
118.0, 120.2 (t, JCeF¼263.8 Hz), 121.5, 126.1, 127.2, 127.5, 133.9, 138.6,
141.4 (d, JCeF¼2.8 Hz),148.6; 19F NMR (282 Hz, CDCl3)
ꢀ52.4 (1F, d,
d

4538
H. Yanai, T. Taguchi / Tetrahedron 66 (2010) 4530e4541
JFeF¼271.3 Hz), ꢀ50.2 (1F, d, JFeF¼271.3 Hz); MS (ESI-TOF) m/z 410
[MþNa]þ; HRMS calcd for C23H27F2NNaO2 [MþNa]þ, 410.1908;
found, 410.1889.
compound was obtained in 88% yield (172.6 mg, 0.44 mmol) by the
reaction of trifluoroacetaldehyde N,O-acetal 1a (114.0 mg, 0.5 mmol),
n-BuLi (1.48 M solution in hexane, 0.84 mL, 1.25 mmol), and N-iodo-
succinimide (223.9 mg,1.00 mmol) at ꢀ78 ꢁC for 4 h in Et2O (2.5 mL).
4.5. Three component synthesis of
b
-amino-
a,
a
-
Colorless oil; IR (neat)
n
3065, 2959, 2872,1600,1494,1237,1095,1031,
0.90 (3H, t, J¼7.2 Hz),
difluoroketone N,O-acetal
771, 732 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
1.18e1.57 (4H, m), 2.04e2.14 (1H, m), 2.14e2.25 (1H, m), 3.84 (1H, dd,
J¼16.5, 6.3 Hz), 3.92e4.01 (1H, m), 5.28 (br d, J¼10.2 Hz), 5.41 (1H, br
d, J¼17.2 Hz), 5.89e6.01 (1H, m), 6.49 (1H, d, J¼7.6 Hz), 6.61e6.68 (1H,
m), 6.74 (1H, d, J¼7.6 Hz), 6.76e6.82 (1H, m); 13C NMR (100 MHz,
4.5.1. 2-(3-Allyl-2-butyl-2,3-dihydrobenzo[d]oxazol-2-yl)-2,2-di-
fluoro-N,N-dimethylethanamine (6). To solution of tri-
a
fluoroacetaldehyde N,O-acetal 1a (113.9 mg, 0.5 mmol) in Et2O
(2.0 mL), n-BuLi (1.45 M solution in hexane, 0.86 mL, 1.25 mmol)
was added at ꢀ78 ꢁC. After being stirred for 4 h at the same tem-
perature, the resulting mixture was treated with N,N-dime-
thylmethyleneiminium chloride (93.9 mg, 1.00 mmol) at room
temperature for 24 h. The reaction mixture was poured into ice
water (15 mL) and Et2O (20 mL), which was extracted with Et2O
(20 mLꢂ3). The combined organic layer was washed with brine
(10 mL), dried over anhydrous Na2SO4, and evaporated. Purification
of the residue by column chromatography on silica gel (hexane/
CDCl3)
d
13.9, 22.6, 24.1, 28.9, 47.6,104.5 (t, JCeF¼23.2 Hz),105.5,107.0,
108.7 (dd, JCeF¼332.1, 326.6 Hz),117.5,118.4,121.8,133.6,139.0,148.8;
19F NMR (282 Hz, CDCl3)
d
6.2 (1F, d, JFeF¼188.3 Hz), 10.6 (1F, d,
JFeF¼188.3 Hz); MS (ESI-TOF) m/z 394 [MþH]þ; HRMS calcd for
C15H19F2INO [MþH]þ, 394.0479; found, 394.0495.
4.7. Reformatsky type reaction of trichloroacetaldehyde
N,O-acetal
EtOAc¼5:1) gave
yield (125.2 mg, 0.39 mmol). Colorless oil; IR (neat)
2871, 2826, 2775, 1599, 1496, 1228, 1073, 923, 731 cmꢀ1
(400 MHz, CDCl3)
b
-amino-
a
,
a
-difluroketone N,O-acetal 6 in 77%
3063, 2958,
1H NMR
0.88 (3H, t, J¼7.2 Hz), 1.10e1.22 (1H, m),
4.7.1. 2-(3-Allyl-2,3-dihydrobenzo[d]oxazol-2-yl)-2,2-dichloro-1-
phenylethanol (8a). To a solution of trichloroacetaldehyde N,O-ac-
etal 3a (138.0 mg, 0.5 mmol) in Et2O (2 mL), n-BuLi (1.38 M in
hexane, 0.40 mL, 0.55 mmol) was added at ꢀ78 ꢁC for 15 min. After
being stirred for 1 h at the same temperature, the mixture was
n
;
d
1.25e1.49 (3H, m), 2.06 (2H, t, J¼7.9 Hz), 2.35 (6H, s), 2.85 (1H, td,
J¼14.8, 9.1 Hz), 2.94 (1H, td, J¼14.8, 8.5 Hz), 3.79 (1H, dd, J¼16.3,
5.6 Hz), 3.88e3.97 (1H, m), 5.22 (1H, dd, J¼10.2, 1.4 Hz), 5.34 (1H,
dd, J¼17.2, 1.4 Hz), 5.84e5.96 (1H, m), 6.39 (1H, d, J¼7.5 Hz),
6.54e6.60 (1H, m), 6.64 (1H, d, J¼7.6 Hz), 6.70e6.76 (1H, m); 13C
treated with a mixture of freshly-distilled benzaldehyde (101 mg,
1.0 mmol) and BF3$OEt (0.3 mL, 3.0 mmol) in Et2O (1 mL) for
30 min at ꢀ78 ꢁC. The resulting mixture was poured into ice water
and Et2O, which was extracted with Et2O (20 mLꢂ3). The organic
phase was washed with brine, dried over MgSO4, and evaporated.
Purification of the residue by silica gel column chromatography
(hexane/EtOAc¼10:1) and additional MPLC (hexane/EtOAc¼6:1)
gave 8a-less (102.6 mg, 0.29 mmol, 58% yield) and 8a-more
(46.6 mg, 0.13 mmol, 27% yield). For 8a-less Pale yellow oil; IR
NMR (100 MHz, CDCl3)
d 13.9, 22.6, 23.5, 29.5, 47.2, 47.6, 57.8 (t,
JCeF¼21.9 Hz),103.0 (t, JCeF¼28.7 Hz),104.9,106.5,117.0,117.8,121.5,
122.2 (dd, JCeF¼257.1, 252.6 Hz), 133.9, 139.4, 149.1; 19F NMR
(282 Hz, CDCl3)
d
ꢀ54.8 to ꢀ53.6 (1F, m), ꢀ51.4 to ꢀ50.3 (1F, m); MS
(ESI-TOF) m/z 325 [MþH]þ; HRMS calcd for C18H27F2N2O [MþH]þ,
325.2091; found, 325.2102. Anal. Calcd for C18H26F2N2O: C, 66.64;
H, 8.08; N, 8.64. Found: C, 66.71; H, 7.99; N, 8.63.
(neat)
NMR (400 MHz, CDCl3)
n
3444, 3064, 3033, 2925, 1487, 1239, 868, 737, 700 cmꢀ1; 1H
d
2.76 (1H, br, OH), 3.94 (1H, dd, J¼16.0,
7.2 Hz), 4.08e4.16 (1H, m), 5.27 (1H, d, J¼10.3 Hz), 5.36 (1H, d,
J¼17.2 Hz), 5.43 (1H, s), 5.81e5.95 (1H, m), 6.18 (1H, s), 6.74e6.83
(3H, m), 6.83e6.91 (1H, m), 7.35e7.45 (3H, m), 7.56e7.63 (2H, m);
4.6. Three component synthesis of difluorohalomethyl
ketone N,O-acetal
13C NMR (100 MHz, CDCl3)
d 56.7, 77.3, 95.8, 99.5, 107.4, 110.4, 118.7,
4.6.1. 3-Allyl-2-butyl-2-(chlorodifluoromethyl)-2,3-dihydrobenzo[d]
oxazole (7a). To a solution of trifluoroacetaldehyde N,O-acetal 1a
(113.9 mg, 0.5 mmol) in Et2O (2.5 mL), n-BuLi (1.48 M solution in
hexane, 0.84 mL, 1.25 mmol) was added at ꢀ78 ꢁC. After being
stirred for 4 h, the resulting mixture was treated with N-chlor-
osuccinimide (134.8 mg,1.0 mmol) at the same temperature for 7 h.
The reaction mixture was quenched with saturated aqueous solu-
tion of Na2S2O3 (15 mL), and extracted with Et2O (20 mLꢂ3). The
combined organic layer was washed with brine (10 mL), dried over
anhydrous MgSO4, and evaporated. Purification of the residue by
column chromatography on silica gel (hexane/EtOAc¼100:1) gave
chlorodifluoromethylketone N,O-acetal 7a in 73% yield (109.8 mg,
120.8, 121.8, 127.7, 128.9, 129.0, 133.0, 137.2, 139.7, 151.0; MS (ESI-
TOF) m/z 350 [MþH]þ; HRMS calcd for C18H18Cl2NO2 [MþH]þ,
350.0715; found, 350.0730. Anal. Calcd for C18H17Cl2NO2: C, 61.73;
H, 4.89; N, 4.00. Found: C, 61.88; H, 4.75; N, 4.10. For 8a-more col-
orless crystals; 106.0e107.5 ꢁC; IR(KBr)
n
3434, 3062, 3033, 2925,
3.11
1488, 1241, 868, 740, 702 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
(1H, br s, OH), 3.82 (1H, dd, J¼16.1, 7.0 Hz), 3.98e4.05 (1H, m), 5.22
(1H, dd, J¼10.3, 1.5 Hz), 5.30 (1H, dd, J¼17.2, 1.5 Hz), 5.36 (1H, s),
5.64 (1H, s), 5.75e5.89 (1H, m), 6.76 (1H, d, J¼7.2 Hz), 6.79e6.89
(3H, m), 7.36e7.44 (3H, m), 7.58e7.66 (2H, m); 13C NMR (100 MHz,
CDCl3) d 56.3, 77.2, 97.2, 100.4, 107.5, 110.6, 118.6, 121.2, 121.8, 128.0,
128.7, 129.0, 132.9, 136.5, 139.5, 150.9; MS (ESI-TOF) m/z 350
[MþH]þ; HRMS calcd for C18H18Cl2NO2 [MþH]þ, 350.0715; found,
350.0718. Anal. Calcd for C18H17Cl2NO2: C, 61.73; H, 4.89; N, 4.00.
Found: C, 61.60; H, 4.93; N, 4.14.
0.37 mmol). Colorless oil; IR (neat)
n
3065, 2961, 2873, 1601, 1495,
0.92
1241, 1123, 1046, 911, 732 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
(3H, t, J¼7.2 Hz), 1.19e1.58 (4H, m), 2.07e2.25 (2H, m), 3.87 (1H, dd,
J¼16.7, 6.0 Hz), 3.95e4.03 (1H, m), 5.28 (1H, dd, J¼10.3,1.2 Hz), 2.39
(1H, dd, J¼17.3, 1.2 Hz), 5.86e5.98 (1H, m), 6.47 (1H, d, J¼7.5 Hz),
6.65 (1H, td, J¼7.5, 1.1 Hz), 6.74 (1H, d, J¼7.5 Hz), 6.79 (1H, dt, J¼7.5,
4.7.2. (R
*
)-2-((R
*
)-3-Allyl-2,3-dihydrobenzo[d]oxazol-2-yl)-1-(2-
)-2-((R )-3-allyl-
bromophenyl)-2,2-dichloroethanol (anti-8b) and (S
*
*
1.1 Hz); 13C NMR (100 MHz, CDCl3)
d
13.9, 22.5, 23.8, 29.7, 47.5,
2,3-dihydrobenzo[d]oxazol-2-yl)-1-(2-bromophenyl)-2,2-di-
chloroethanol (syn-8b). According to the synthetic procedure for
8a, these compounds were obtained in 72% (154.7 mg, 0.36 mmol)
as an anti/syn mixture in a ratio of 2.3:1 by the reaction of tri-
chloroacetaldehyde N,O-acetal 3a (138.8 mg, 0.5 mmol), n-BuLi
(1.52 M solution in hexane, 0.36 mL, 0.55 mmol), and 2-bromo-
benzaldehyde (185.2 mg, 1.0 mmol) in Et2O (3.0 mL) in the pres-
ence of BF3$OEt2 (0.3 mL, 3.0 mmol) at ꢀ78 ꢁC for 2 h. The
stereochemistry of these products was determined by an X-ray
103.4 (t, JCeF¼26.6 Hz), 105.5, 106.8, 117.2, 118.3, 121.7, 128.9 (dd,
JCeF¼307.6, 305.5 Hz), 133.4, 138.8, 148.9; 19F NMR (282 Hz, CDCl3)
d
ꢀ5.81 (1F, d, JFeF¼167.5 Hz), ꢀ4.71 (1F, d, JFeF¼167.5 Hz); MS (ESI-
TOF) m/z 302 [MþH]þ; HRMS calcd for C15H19ClF2NO [MþH]þ,
302.1123; found, 302.1131.
4.6.2. 3-Allyl-2-butyl-2-(difluoroiodomethyl)-2,3-dihydrobenzo[d]
oxazole (7b). According to the synthetic procedure for 7a, this

H. Yanai, T. Taguchi / Tetrahedron 66 (2010) 4530e4541
4539
crystallographic analysis of syn isomer. For syn-8b (less polar
isomer) colorless crystals; mp 115.0e118.5 ꢁC; IR (KBr)
3419,
3064, 2926, 1487, 1239, 875, 739 cmꢀ1; 1H NMR (400 MHz, CDCl3)
4.98 (0.58H, dd, J¼6.1, 1.1 Hz) and 4.89 (0.42H, dd, J¼6.1, 1.1 Hz),
5.26 (1H, br d, J¼10.3 Hz), 5.36 (1H, br d, J¼17.2 Hz), 5.80e5.94
(1H, m), 6.09 (0.58H, s) and 5.97 (0.42H, s), 6.54 (0.58H, dd,
J¼15.9, 6.1 Hz) and 6.45 (0.42H, dd, J¼15.9, 6.6 Hz), 6.72e6.89
(5H, m), 7.25e7.30 (3H, m), 7.41e7.48 (2H, m); 13C NMR (100 MHz,
n
d
3.95 (1H, dd, J¼15.9, 7.3 Hz), 4.08e4.16 (1H, m), 5,29 (1H, dd,
J¼10.3, 1.1 Hz), 5.38 (1H, dd, J¼17.2, 1.1 Hz), 5.84e5.97 (1H, m),
6.06 (1H, s), 6.13 (1H, s), 6.77e6.82 (3H, m), 6.82e6.89 (1H, m),
7.23 (1H, td, J¼7.8, 1.4 Hz), 7.35e7.43 (1H, m), 7.58 (1H, dd, J¼7.8,
1.0 Hz), 7.99 (1H, dd, J¼7.8, 1.4 Hz); 13C NMR (100 MHz, CDCl3)
CDCl3)
d for major isomer 56.6, 76.2, 96.4, 99.1, 107.4, 110.5, 118.7,
120.8, 121.8, 124.9, 126.9, 128.3, 128.7, 133.0, 135.2, 136.0, 139.7,
151.0, for minor isomer 55.9, 76.2, 96.8, 100.5, 107.6, 110.6, 118.8,
121.3, 121.7, 124.5, 126.9, 128.4, 128.7, 132.8, 135.6, 135.9, 139.5,
151.1; MS (ESI-TOF) m/z 376 [MþH]þ; HRMS calcd for
C20H20Cl2NO2 [MþH]þ, 376.0871; found, 376.0886.
d
57.1, 74.0, 95.9, 99.8, 107.5, 110.8, 119.0, 121.2, 121.8, 125.5, 127.1,
130.21, 130.24, 132.8, 132.9, 137.1, 139.5, 150.1; MS (ESI-TOF) m/z
428 [MþH]þ; HRMS calcd for C18H17BrCl2NO2 [MþH]þ, 427.9820;
found, 427.9835. Anal. Calcd for C18H16BrCl2NO2: C, 50.38; H, 3.76;
N, 3.26. Found: C, 50.10; H, 4.66; N, 3.33. For anti-8b (more polar
4.7.5. 2-(3-Benzyl-2,3-dihydrobenzo[d]oxazol-2-yl)-1-(4-bromo-
phenyl)-2,2-dichloroethanol (8e). According to the synthetic pro-
cedure for 8a, these compounds were obtained in 80% (171.2 mg,
0.40 mmol) as a mixture of diastereomers in a ratio of 2.3:1 by
the reaction of trichloroacetaldehyde N,O-acetal 3b (164.5 mg,
0.5 mmol), n-BuLi (1.52 M solution in hexane, 0.36 mL,
0.55 mmol), and 4-bromobenzaldehyde (185.3 mg, 1.0 mmol) in
Et2O (3.0 mL) in the presence of BF3$OEt2 (0.3 mL, 3.0 mmol) at
isomer) pale yellow oil; IR (neat)
n
3420, 3064, 2926, 1487, 1241,
3.64 (1H, br s,
841, 816, 740 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
OH), 3.93 (1H, dd, J¼15.9, 7.4 Hz), 4.10e4.18 (1H, m), 5.32 (1H, dd,
J¼10.3, 1.2 Hz), 5.41 (1H, dd, J¼17.1, 1.2 Hz), 5.84e5.97 (1H, m),
5.87 (1H, s), 5.98 (1H, s), 6.80e6.92 (4H, m), 7.23 (1H, td, J¼8.0,
1.6 Hz), 7.35e7.42 (1H, m), 7.58 (1H, dd, J¼8.0, 1.1 Hz), 7.92 (1H,
dd, J¼7.3, 1.6 Hz); 13C NMR (100 MHz, CDCl3)
d 56.7, 73.8, 94.7,
102.2, 107.9, 111.4, 119.5, 121.98, 122.01, 125.4, 127.2, 130.27, 130.33,
132.4, 132.7, 136.8, 139.0, 150.8; MS (ESI-TOF) m/z 428 [MþH]þ;
HRMS calcd for C18H17BrCl2NO2 [MþH]þ, 427.9820; found,
427.9845.
ꢀ78 ꢁC for 1 h. For 8e-less colorless oil; IR (neat)
n
3420, 3064,
;
3029, 2928, 2871, 1488, 1362, 1257, 1011, 808, 737 cmꢀ1
1H NMR
(400 MHz, CDCl3)
d
3.08 (1H, br s, OH), 4.38 (1H, d, J¼15.5 Hz),
4,60 (1H, d, J¼15.5 Hz), 5.29 (1H, s), 5.63 (1H, s), 6.50e6.56 (1H,
m), 6.78e6.83 (3H, m), 7.27e7.37 (5H, m), 7.44 (2H, d, J¼8.6 Hz),
4.7.3. 2-(3-Allyl-2,3-dihydrobenzo[d]oxazol-2-yl)-1-(4-bromo-
phenyl)-2,2-dichloroethanol (8c). According to the synthetic pro-
cedure for 8a, these compounds were obtained in 80% (171.2 mg,
0.40 mmol) as a mixture of diastereomers in a ratio of 2.3:1 by the
reaction of trichloroacetaldehyde N,O-acetal 3a (139.5 mg,
0.5 mmol), n-BuLi (1.52 M in hexane, 0.36 mL, 0.55 mmol), and 4-
bromobenzaldehyde (185.0 mg, 1.0 mmol) in Et2O (3.0 mL) in the
presence of BF3$OEt2 (0.3 mL, 3.0 mmol) at ꢀ78 ꢁC for 1 h. For 8c-
7.51 (2H, d, J¼8.6 Hz); 13C NMR (100 MHz, CDCl3)
d 58.2, 76.8,
97.1, 100.6, 107.7, 110.7, 121.3, 122.0, 123.3, 127.6, 127.7, 128.7,
130.4, 131.2, 135.4, 137.1, 139.9, 150.7; MS (ESI-TOF) m/z 478
[MþH]þ; HRMS calcd for C22H19BrCl2NO2 [MþH]þ, 477.9976;
found, 477.9957. For 8e-more Brown amorphous solid; mp
40.5e49.0 ꢁC; IR (neat)
n
3496, 3064, 3029, 2925, 1488, 1258,
1073, 1011, 876, 813, 738 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
2.80
(1H, br s, OH), 4.50 (1H, d, J¼15.6 Hz), 4.73 (1H, d, J¼15.6 Hz),
5.40 (1H, s), 6.19 (1H, s), 6.48e6.53 (1H, m), 6.76e6.82 (3H, m),
7.27e7.39 (5H, m), 7.44 (2H, d, J¼8.5 Hz), 7.52 (2H, d, J¼8.5 Hz);
less Pale yellow oil; IR (neat)
n
3403, 3068, 2925, 1487, 1072, 1011,
3.26 (1H, br s, OH),
874, 812, 738 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
3.82 (1H, dd, J¼16.1, 7.0 Hz), 3.97e4.07 (1H, m), 5.24 (1H, d,
J¼10.3 Hz), 5.30 (1H, d, J¼17.1 Hz), 5.31 (1H, s), 5.63 (1H, s),
5.75e5.90 (1H, m), 6.76 (1H, d, J¼7.1 Hz), 6.79e6.91 (3H, m), 7.48
(2H, d, J¼8.4 Hz), 7.52 (2H, d, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3)
13C NMR (100 MHz, CDCl3)
d 58.0, 76.7, 95.5, 99.8, 107.4, 110.3,
120.7, 121.9, 123.1, 127.6, 127.7, 128.7, 130.7, 130.9, 136.1, 137.4,
140.1, 150.7; MS (ESI-TOF) m/z 478 [MþH]þ; HRMS calcd for
C22H19BrCl2NO2 [MþH]þ, 477.9976; found, 477.9964.
d
56.4, 76.6, 96.7, 100.5, 107.6, 110.7, 118.8, 121.3, 122.0, 123.2, 130.5,
131.1, 132.7, 135.5, 139.3, 150.8; MS (ESI-TOF) m/z 428 [MþH]þ;
HRMS calcd for C18H17BrCl2NO2 [MþH]þ, 427.9820; found,
427.9835. Anal. Calcd for C18H16BrCl2NO2: C, 50.38; H, 3.76; N, 3.26.
Found: C, 50.26; H, 3.80; N, 3.15. For 8c-more Pale yellow oil; IR
4.7.6. 1-(4-Bromophenyl)-2,2-dichloro-2-(3-propyl-2,3-dihy-
drobenzo[d]oxazol-2-yl)ethanol (8f). According to the synthetic
procedure for 8a, these compounds were obtained in 72%
(154.4 mg, 0.36 mmol) as an inseparable mixture of diastereomers
in a ratio of 2.0:1 by the reaction of trichloroacetaldehyde N,O-ac-
etal 3c (140.4 mg, 0.5 mmol), n-BuLi (1.52 M solution in hexane,
0.36 mL, 0.55 mmol), and 4-bromobenzaldehyde (185.0 mg,
1.0 mmol) in Et2O (3.0 mL) in the presence of BF3$OEt2 (0.3 mL,
(neat)
NMR (400 MHz, CDCl3)
n
3404, 3063, 2924, 1487,1240, 1073, 1011, 810, 739 cmꢀ1; 1H
d
3.82 (1H, dd, J¼16.1, 7.0 Hz), 3.97e4.05
(1H, m), 5.24 (1H, dd, J¼10.2, 1.0 Hz), 5.31 (1H, dd, J¼17.0, 1.0 Hz),
5.32 (1H, s), 5.62 (1H, s), 5.75e5.82 (1H, m), 6.76 (1H, d, J¼7.3 Hz),
6.79e6.90 (3H, m), 7.48 (2H, d, J¼8.6 Hz), 7.52 (2H, d, J¼8.6 Hz); 13C
3.0 mmol) at ꢀ78 ꢁC for 1 h. Pale yellow oil; IR (neat)
n
3413, 3060,
;
NMR (100 MHz, CDCl3)
d
56.7, 76.6, 95.3, 99.5, 107.4, 110.6, 118.8,
2964, 2874, 1488, 1243, 1074, 1011, 812, 738 cmꢀ1 1H NMR
120.9, 121.9, 123.1, 130.7, 130.9, 132.9, 136.2, 139.6, 150.9; MS (ESI-
TOF) m/z 428 [MþH]þ; HRMS calcd for C18H17BrCl2NO2 [MþH]þ,
427.9820; found, 427.9840.
(400 MHz, CDCl3) d for a mixture of diastereomers 0.93 (1.98H, t,
J¼7.4 Hz) and 0.90 (1.02H, t, J¼7.4 Hz), 1.57e1.80 (2H, m), 3.18e3.42
(2H, m), 5.39 (0.66H, s) and 5.32 (0.34H, s), 6.12 (0.66H, s) and 5.56
(0.34H, s), 6.70e6.75 (1H, m), 6.75e6.82 (2H, m), 6.83e6.90 (1H,
4.7.4. (E)-1-(3-Allyl-2,3-dihydrobenzo[d]oxazol-2-yl)-1,1-dichloro-4-
phenylbut-3-en-2-ol (8d). According to the synthetic procedure
for 8a, these compounds were obtained in 75% (140.5 mg,
0.37 mmol) as an inseparable mixture of diastereomers in a ratio
of 1.4:1 (less/more) by the reaction of trichloroacetaldehyde N,O-
acetal 3a (139.3 mg, 0.5 mmol), n-BuLi (1.52 M solution in hexane,
0.36 mL, 0.55 mmol), and cinnamaldehyde (132.3 mg, 1.0 mmol)
in Et2O (3.0 mL) in the presence of BF3$OEt2 (0.3 mL, 3.0 mmol) at
m), 7.42e7.56 (4H, m); 13C NMR (100 MHz, CDCl3)
d for major iso-
mer 11.4, 20.5, 55.6, 76.7, 95.2, 100.3, 107.3, 110.2, 120.4, 121.9, 123.1,
130.7, 130.9, 136.2, 139.8, 150.8, for minor isomer 11.3, 20.5, 55.6,
76.7, 96.7, 101.1, 107.6, 110.5, 121.0, 122.0, 123.2, 130.5, 131.2, 135.5,
139.3, 150.7; MS (ESI-TOF) m/z 430 [MþH]þ; HRMS calcd for
C18H19BrCl2NO2 [MþH]þ, 429.9976; found, 429.9959.
4.7.7. (S
*
)-1-((R
*
)-3-Allyl-2,3-dihydrobenzo[d]oxazol-2-yl)-1,1,3,3,3-
)-1-((R )-3-allyl-2,3-dihy-
ꢀ78 ꢁC for 2 h. Pale yellow oil; IR (neat)
n
3403, 3060, 3025, 2926,
;
pentachloropropan-2-ol (anti-8g) and (R
*
*
1488, 1241, 968, 860, 824, 744, 693 cmꢀ1
1H NMR (400 MHz,
drobenzo[d]oxazol-2-yl)-1,1,3,3,3-pentachloropropan-2-ol (syn-8g).
According to the synthetic procedure for 8a, these compounds were
obtained in 65% (127.8 mg, 0.33 mmol) as an anti/syn mixture in
CDCl3)
d
for a mixture of diastereomers 3.92 (0.58H, dd, J¼16.1,
7.2 Hz) and 3.88 (0.42H, dd, J¼16.5, 7.0 Hz), 4.05e4.15 (1H, m),

4540
H. Yanai, T. Taguchi / Tetrahedron 66 (2010) 4530e4541
Bioorganic Chemistry; Welch, J. T., Eswarakrishnan, S., Eds.; Wiley: New York,
NY, 1991; (d) Biomedicinal Aspects of Fluorine Chemistry; Filler, R., Kobayashi, Y.,
Eds.; Elsevier: Amsterdam, 1982.
2. (a) Hertel, L. W.; Boder, G. B.; Kroin, J. S.; Rinzel, S. M.; Poore, G. A.; Todd, G. C.;
Grindey, G. B. Cancer Res. 1990, 50, 4417e4422; (b) Szarek, M. A.; Wu, X.;
Szarek, W. A. Carbohydr. Res. 1997, 299, 165e170; (c) Wang, R.-W.; Qiu, X.-L.;
Bols, M.; Ortega-Caballero, F.; Qing, F.-L. J. Med. Chem. 2006, 49, 2989e2997.
3. (a) Halazy, S.; Ehrhard, A.; Danzin, C. J. Am. Chem. Soc. 1991, 113, 315e317; (b)
Hikishima, S.; Isobe, M.; Koyanagi, S.; Soeda, S.; Shimeno, H.; Shibuya, S.; Yo-
komatsu, T. Bioorg. Med. Chem. 2006, 14, 1660e1670.
4. (a) Schirlin, D.; Baltzer, S.; Van Dorsselaer, V.; Weber, F.; Weill, C.; Altenburger,
J. M.; Neises, B.; Flynn, G.; Remy, J. M.; Tarnus, C. Bioorg. Med. Chem. Lett. 1993, 3,
253e258; (b) Schirlin, D.; van Dorsselaer, V.; Tarnus, C.; Taylor, D. L.; Tyms, A.
S.; Baltzer, S.; Weber, F.; Remy, J. M.; Brennan, T.; Farr, R.; Janowick, D. Bioorg.
Med. Chem. Lett. 1994, 4, 241e246; (c) Sham, H. L.; Wideburg, N. E.; Spanton, S.
G.; Kohlbrenner, W. E.; Betebenner, D. A.; Kempf, D. J.; Norbeck, D. W.; Plattner,
J. J.; Erickson, J. W. J. Chem. Soc., Chem. Commun. 1991, 110e112; (d) Silva, A. M.;
Cachau, R. E.; Sham, H. L.; Erickson, J. W. J. Mol. Biol. 1996, 255, 321e346.
5. Skiles, J. W.; Miao, C.; Sorek, R.; Jacober, S.; Mui, P. W.; Chow, G.; Weldon, S. M.;
Possanza, G.; Skoog, M.; Keirns, J.; Letts, G.; Rosenthal, A. S. J. Med. Chem. 1992,
35, 4795e4808.
a ratio of 1.4:1 by the reaction of trichloroacetaldehyde N,O-acetal
3a (139.5 mg, 0.5 mmol), n-BuLi (1.52 M solution in hexane,
0.36 mL, 0.55 mmol), and chloral (147.5 mg, 1.0 mmol) in Et2O
(3.0 mL) at room temperature for 5 h. The stereochemistry of these
products was determined by an X-ray crystallographic analysis of
syn isomer. For syn-8g (less polar isomer) colorless crystals; mp
111.0e113.0 ꢁC; IR (KBr)
n
3502, 3068, 2930, 1488, 1239, 866,
3.66 (1H, br s, OH), 3.93 (1H,
738 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
dd, J¼16.2, 7.1 Hz), 4.06e4.17 (1H, m), 4.98 (1H, br s), 5.27(1H, d,
J¼10.2 Hz), 5.38 (1H, d, J¼17.1 Hz), 5.81e5.89 (1H, m), 6.12 (1H, s),
6.73e6.82 (3H, m), 6.82e6.88 (1H, m); 13C NMR (100 MHz, CDCl3)
d
57.0, 83.0, 91.4, 99.8, 100.6, 107.4, 110.4, 118.7, 120.9, 122.0, 132.9,
139.8, 150.7; MS (ESI-TOF) m/z 390 [MþH]þ; HRMS calcd for
C13H13Cl5NO2 [MþH]þ, 389.9389; found, 389.9401. For anti-8g
(more polar isomer) colorless oil; IR (neat)
n 3423, 3064, 2985,
2933, 1488, 1306, 1236, 1140, 738 cmꢀ1; 1H NMR (400 MHz, CDCl3)
6. (a) Doherty, A. M.; Sircar, I.; Kornberg, B. E.; Quin, J.; Winters, R. T.; Kaltenbronn,
J. S.; Taylor, M. D.; Batley, B. L.; Rapundalo, S. R.; Ryan, M. J.; Painchaud, C. A.
J. Med. Chem. 1992, 35, 2e14; (b) Schirlin, D.; Tarnus, C.; Baltzer, S.; Remy, J. M.
Bioorg. Med. Chem. Lett. 1992, 2, 651e654.
d
3.72 (1H, br s, OH), 3.88 (1H, dd, J¼16.1, 7.0 Hz), 4.04e4.13 (1H, m),
4.84 (1H, s), 5.30 (1H, dd, J¼10.3, 1.3 Hz), 5.48 (1H, dd, J¼17.2,
1.3 Hz), 5.79e5.91 (1H, m), 6.15 (1H, s), 6.75e6.90 (4H, m); 13C NMR
7. (a) Eda, M.; Ashimori, A.; Akahoshi, F.; Yoshimura, T.; Inoue, Y.; Fukaya, C.;
Nakajima, M.; Fukuyama, H.; Imada, T.; Nakamura, N. Bioorg. Med. Chem. Lett.
1998, 8, 913e918; (b) Eda, M.; Ashimori, A.; Akahoshi, F.; Yoshimura, T.; Inoue,
Y.; Fukaya, C.; Nakajima, M.; Fukuyama, H.; Imada, T.; Nakamura, M. Bioorg.
Med. Chem. Lett. 1998, 8, 919e924; (c) Akahoshi, F.; Ashimori, A.; Sakashita, H.;
Yoshimura, T.; Eda, M.; Imada, T.; Nakajima, M.; Mitsutomi, N.; Kuwahara, S.;
Ohtsuka, T.; Fukaya, C.; Miyazaki, M.; Nakamura, N. J. Med. Chem. 2001, 44,
1297e1304.
(100 MHz, CDCl3)
d 56.8, 82.0, 93.2, 99.1, 101.2, 107.7, 111.0, 119.0,
121.8, 121.9, 132.7, 139.6, 151.2; MS (ESI-TOF) m/z 389 [MþH]þ;
HRMS calcd for C13H13Cl5NO2 [MþH]þ, 389.9389; found, 389.9409.
4.7.8. Ethyl 3-(3-allyl-2,3-dihydrobenzo[d]oxazol-2-yl)-3,3-dichloro-
2-hydroxy-2-(trifluoromethyl)propanoate (8h). According to the
synthetic procedure for 8a, these compounds were obtained in 51%
(105.8 mg, 0.26 mmol) as an inseparable mixture of diastereomers
in a ratio of 2.3:1 by the reaction of trichloroacetaldehyde N,O-ac-
etal 3a (139.4 mg, 0.5 mmol), n-BuLi (1.52 M solution in hexane,
0.36 mL, 0.55 mmol), and chloral (147.5 mg, 1.0 mmol) in Et2O
€
8. Gerth, K.; Steinmetz, H.; Hofle, G.; Jansen, R. Angew. Chem., Int. Ed. 2008, 47,
600e602.
9. (a) Teruya, T.; Nakagawa, S.; Koyama, T.; Arimoto, H.; Kita, M.; Uemura, D.
Tetrahedron 2004, 60, 6989e6993; (b) Gao, S.; Wang, Q.; Chen, C. J. Am. Chem.
Soc. 2009, 131, 1410e1412; (c) Larsen, T. O.; Breinholt, J. J. Nat. Prod. 1999, 62,
1182e1184; (d) Fu, X.; Ferreira, M. L. G.; Schmitz, F. J.; Kelly-Borges, M. J. Nat.
Prod. 1998, 61, 1226e1231.
10. (a) Luknitskii, F. I. Chem. Rev. 1975, 75, 259e289; (b) Ishii, A.; Takeda, Y. Yuki
Gosei Kagaku Kyokaishi 1999, 57, 898e900; (c) Braid, M.; Iserson, H.; Lawlor, F. E.
J. Am. Chem. Soc. 1954, 76, 4027e4029; (d) Mikami, K.; Itoh, Y.; Yamanaka, M.
Chem. Rev. 2004, 104, 1e16; (e) Mikami, K.; Yajima, T.; Takasaki, T.; Matsukawa,
S.; Terada, M.; Uchimaru, T.; Maruta, M. Tetrahedron 1996, 52, 85e98; (f) Torii,
H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004,
43, 1983e1986; (g) Yanai, H.; Mimura, H.; Kawada, K.; Taguchi, T. Tetrahedron
2007, 63, 2153e2160.
11. (a) Bégué, J.-P.; Bonnet-Delpon, D.; Crousse, B.; Legros, J. Chem. Soc. Rev. 2005,
34, 562e572; (b) Billard, T.; Gille, S.; Ferry, A.; Barthelemy, A.; Christophe, C.;
Langlois, B. R. J. Fluorine Chem. 2005, 126, 189e196; (c) Loh, T.-P.; Li, X.-R. Chem.
Commun. 1996, 1929e1930; (d) Funabiki, K.; Nojiri, M.; Matsui, M.; Shibata, K.
Chem. Commun. 1998, 2051e2052.
12. For dichloroketene acetals, see: (a) Guseva, S. A.; Mirskova, A. N.; Levkovskaya,
G. G.; Kalikhman, I. D.; Voronkov, M. G. Zh. Org. Khim. 1988, 24, 298e307; J. Org.
Chem. USSR 1988, 24, 261e268; (b) Mamedov, S.; Lerner, G. Zh. Obshch. Khim.
1962, 32, 403e407; J. Gen. Chem. USSR 1962, 32, 395e398.
(3.0 mL) at room temperature for 24 h. Colorless oil; IR (neat)
3429, 3068, 2985, 2942, 1743, 1488, 1306, 1237, 1177, 1141,
739 cmꢀ1 1H NMR (400 MHz, CDCl3)
for a mixture of di-
n
;
d
astereomers 1.39 (1.97H, t, J¼7.1 Hz) and 1.40 (1.03H, t, J¼7.2 Hz),
3.81 (0.66H, dd, J¼15.8, 7.6 Hz) and 3.92 (0.34H, dd, J¼15.6, 7.4 Hz),
3.96e4.04 (0.66H, m) and 4.08e4.16 (0.34H, m), 4.47 (1.31H, q,
J¼7.1 Hz) and 4.42e4.57 (0.69H, m), 4.87 (0.66H, s) and 4.97 (0.34H,
s), 5.25 (1H, br d, J¼10.2 Hz), 5.30 (0.66H, br d, J¼17.1 Hz) and 5.34
(0.34H, br d, J¼17.1 Hz), 5.73e5.88 (1H, m), 6.05 (0.66H, s) and 6.07
(0.34H, s), 6.72e6.89 (3.66H, m) and 6.58 (0.34H, d, J¼7.0 Hz); 13C
NMR (100 MHz, CDCl3)
d for major isomer 13.8, 57.3, 65.1, 81.3 (q,
JCeF¼30.2 Hz), 91.6, 98.5, 107.7, 111.4, 119.4, 121.7, 121.8, 121.9 (q,
JCeF¼287.9 Hz),132.4,139.2,151.4,166.3, for minor isomer 13.8, 57.1,
65.4, 79.9 (q, JCeF¼29.6 Hz), 90.3, 98.3, 107.1, 110.9, 119.0, 121.0,
122.16,122.20 (q, JCeF¼289.4 Hz),132.6, 139.5, 150.7, 166.7; MS (ESI-
TOF) m/z 414 [MþH]þ; HRMS calcd for C16H17Cl2F3NO4 [MþH]þ,
414.0487; found, 414.0495.
13. For difluoroketene acetals, see: He, Y.; Junk, C. P.; Cawley, J. J.; Lemal, D. M. J. Am.
Chem. Soc. 2003, 125, 5590e5591.
14. (a) Xu, Y.; Dolbier, W. R., Jr.; Rong, X. X. J. Org. Chem. 1997, 62, 1576e1577; (b)
Ding, Y.; Wang, J.; Abboud, K. A.; Xu, Y.; Dolbier, W. R., Jr. J. Org. Chem. 2001, 66,
6381e6388.
15. For CeF bond cleavage reactions through
b-elimination of fluoride, see: (a)
Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119e2183; (b) Uneyama, K.;
Maeda, K.; Kato, T.; Katagiri, T. Tetrahedron Lett. 1998, 39, 3741e3744; (c) Amii,
H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem. Commun. 1999, 1323e1324;
(d) Jin, F.; Xu, Y.; Huang, W. J. Chem. Soc., Chem. Commun. 1993, 814e816; (e)
Brigaud, T.; Doussot, P.; Portella, C. J. Chem. Soc., Chem. Commun. 1994,
2117e2118.
Acknowledgements
The authors gratefully acknowledge Mr. Hideyuki Mimura and
Dr. Kosuke Kawada (TOSOH F-TECH Inc.) for supplying tri-
fluoroacetaldehyde hemiacetals. We also thank Mr. Hiroyuki
Nagashima for his technical assistance.
16. For the formation of difluoroketene N,O-acetal from trifluoroacetaldehyde N,O-
acetal and its nucleophilicity, see: Blond, G.; Billard, T.; Langlois, B. R. Chem.d
Eur. J. 2002, 8, 2917e2922.
17. Review on synthetic utility of N,O-acetal functionality, see: Yamazaki, N.; Ki-
bayashi, C. Product class 1: O,N-acetals In. Science of Synthesis, Houben-Weyl
Methods of Molecular Transformations; Otera, J., Ed.; Georg Thieme: Stuttgart,
2007; Vol. 30, pp 7e19.
18. (a) Yanai, H.; Taguchi, T. Chem. Commun. 2009, 1034e1036; (b) Yanai, H.; Ichi-
kawa, T.; Taguchi, T. Tetrahedron Lett. 2010, 51, 2625e2628.
19. Difluoromethylketone N,O-acetals were generally unstable on neutral silica gel,
while chromatographic purification by short silica gel pad resulted in the
reasonable isolated yield of these products.
20. By D2O quench of the reaction mixture of 1a and n-BuLi, deuterium in-
troduction at difluoromethinic position of 2aa was observed.
Supplementary data
Compound characterization data, 1H and 13C NMR spectra.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.061.
References and notes
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