A rapid and convergent synthesis of α,α-difluoro-β-hydroxyketones through regiospecific defluorinative alkylation reaction

Article abstract of DOI:10.1016/j.tetlet.2010.03.018

Both the defluorinative alkylation reaction of trifluoroacetaldehyde N,O-acetals using alkyllithiums and the following C-C bond formation with carbonyls as electrophiles were accelerated by a suitable diamine additive such as (-)-sparteine to give α,α-difluoro-β-hydroxyketone N,O-acetal products in an excellent yield. We also found that N-benzyl-N,O-acetal group of the resultant products can be removed under palladium-catalyzed hydrogenolysis conditions giving rise to the corresponding α,α-difluoro-β-hydroxyketones. The present two-step procedure is a useful and novel synthetic approach for functionalized α,α-difluoroketones.

Full text of DOI:10.1016/j.tetlet.2010.03.018

Tetrahedron Letters 51 (2010) 2625–2628
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Tetrahedron Letters
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A rapid and convergent synthesis of a,a-difluoro-b-hydroxyketones through
regiospecific defluorinative alkylation reaction
*
Hikaru Yanai, Tatsunori Ichikawa, 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
Article history:
Both the defluorinative alkylation reaction of trifluoroacetaldehyde N,O-acetals using alkyllithiums and
Received 15 February 2010
Revised 2 March 2010
Accepted 8 March 2010
Available online 11 March 2010
the following C–C bond formation with carbonyls as electrophiles were accelerated by a suitable diamine
additive such as (ꢀ)-sparteine to give
yield. We also found that N-benzyl-N,O-acetal group of the resultant products can be removed under
palladium-catalyzed hydrogenolysis conditions giving rise to the corresponding -difluoro-b-hydroxy-
ketones. The present two-step procedure is a useful and novel synthetic approach for functionalized
-difluoroketones.
a,a-difluoro-b-hydroxyketone N,O-acetal products in an excellent
a,a
a,a
Ó 2010 Published by Elsevier Ltd.
The chemical transformation of stable carbon–fluorine bond is
attracting much attention from organic chemists.1–3 In particular,
selective mono-defluorination of trifluoromethyl compounds is a
valuable transformation because the difluoromethylene struc-
ture4,5 in the products is widely used as a key functionality in
the field of drug design.6 For example, difluoromethylene group
acts as a biologically isosteric structure for hydroxymethylene
Recently, we reported that the reaction of trifluoroacetaldehyde
N,O-acetals with 2 M equiv of alkyllithium reagent smoothly gives
a,a
-difluoroketone N,O-acetal derivatives (Eq. 1).10 This reaction
probably proceeds via the b-elimination of fluoride followed by al-
kyl transfer at the b-carbon of the resultant ketene N,O-acetal
intermediate.11 Since the alkyl transfer reaction of (Me2N)2C@CF2
selectively proceeds at the electronically negative
a-carbon (Eq.
group7 or ethereal oxygen.8 Since
a,a-difluoroketones easily form
2),12 the regioselectivity of alkyl transfer step observed in the
N,O-acetal substrates is quite unique. Moreover, as a synthetic
application of this defluorinative alkylation, we developed the no-
stable tetrahedral hydrates, these compounds are also used as a
transition state mimic toward several proteases such as HIV prote-
ase.9 In addition, trifluoromethyl substrates are easily available
from commercial sources or by easy preparation in short steps.
vel and convergent synthetic methodology for
a,a-difluoro-b-
hydroxyketone derivatives through the one-pot treatment of the
reactive intermediate generated by the defluorinative alkylation
with carbonyl compounds (Eq. 3):
alkylation
R
N
R
N
R
R'Li;
R'Li
ð1Þ
N
CF2H
R'
H+/H2O
CF3
CF2
β
O
O
O
alkylation
O
Me2N
Me2N
Me2N
n-BuLi
n-BuLi;
ð2Þ
Bu
CF3
CF2
α
Me2N
H+/H2O
Me2N
F
R
N
F
R
N
R
N
R2CHO
2 R1Li
F
OH
or
CF2-Li
R1
R1
R
N
O
CF3
- LiF
ð3Þ
R1
R2
O
Li
O
O
F
F
"Defluorinative
alkylation"
"Reformatsky-type
C-C bond formation"
* Corresponding author.
E-mail address: taguchi@ps.toyaku.ac.jp (T. Taguchi).
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.03.018

2626
H. Yanai et al. / Tetrahedron Letters 51 (2010) 2625–2628
Table 1
Survey of effective diamine additives in
synthesis
a,a-difluoro-b-hydroxyketone N,O-acetal
n-BuLi (2.5 eq)
(-)-sparteine
N
N
CF2H
n-Bu
CF3
Et2O, -78 °C
O
1a
O
2a
n-BuLi (2.5 eq), amine
Et2O, -78 °C, 15 min
OH
Allyl
n
N
-Bu
O
N
CF3
(-)-sparteine (1.0 eq) 15 min 82%
(-)-sparteine (0.1 eq) 15 min 85%
none (ref. 13)
then c-C6H11CHO (2.0 eq)
-78 °C
O
F
F
1a
3 h
83%
3aa (anti/syn >10 : 1)
Yielda (%)
Scheme 1.
Entry
Diamine (equiv)
Time (h)
1
2
3
4
(ꢀ)-Sparteine (1.0)
(ꢀ)-Sparteine (0.2)
TMEDA (1.0)
Me2NCH2CH2CH2CH2NMe2 (1.0)
Me2NCH2(CH2)4CH2NMe2 (1.0)
Et3N (2.0)
1
7
1
1
1
1
8
90
56
73
78
62
49
81
However, both the defluorinative alkylation step of N,O-acetal
substrates and the following Reformatsky type C–C bond forming
step between the intermediate generated by defluorinative alkyl-
5
6
ation and less reactive carbonyl compounds such as
a-branched
7b
None
aliphatic aldehydes and ketones required relatively long reaction
time to obtain the desired products in good yield. In this Letter,
we would like to describe that suitable diamine additives such as
(ꢀ)-sparteine accelerate both the defluorinative alkylation step
and the following Reformatsky type C–C bond forming step. Fur-
thermore, although it would be easily predicted that the transfor-
mation of cyclic N,O-acetal group in the product structure to
carbonyl group under conventional hydrolytic conditions is extre-
mely difficult due to the stabilization effect of N,O-acetal group by
fluorine di-substitution, we demonstrate that N-benzyl-N,O-acetal
group can be easily converted to carbonyl group.
It has been well known that diamine additives such as N,N,N’,N’-
tetramethylethane-1,2-diamine (TMEDA) and sparteine enhance
both basicity and nucleophilicity of alkyllithium reagents through
the dissociation of aggregated structure of lithium reagents.13,14
Therefore, to accelerate the reaction rate in the defluorinative
alkylation step, we initially examined the reaction of N-allyl-N,O-
acetal 1a with 2.5 M equiv of n-BuLi in the presence of diamine
additives (Scheme 1). As shown in the previous Letter,10 the reac-
tion of 1a with n-BuLi in the absence of any diamine additives re-
quires relatively long reaction time (3 h). On the other hand, we
found that, in the presence of 1.0 M equiv of (ꢀ)-sparteine, the
same reaction at ꢀ78 °C is smoothly completed within only
15 min to give difluoroketone N,O-acetal 2a in 82% yield. Under
similar conditions, the loading of (ꢀ)-sparteine could be reduced
to 0.1 M equiv without the decrease in product yield.
a
Isolated yield.
b
c
Defluorinative butylation was completed by the reaction at ꢀ78 °C for 2 h.
The reaction was carried out at 0 °C, see: Ref. 10a.
Next, we examined the rate acceleration effect in the Reformat-
sky type C–C bond formation step between the reactive intermedi-
ates and carbonyl substrates by diamine additives (Table 1). That
is, after the defluorinative alkylation of 1a in the presence of
1.0 M equiv of (ꢀ)-sparteine, the resultant intermediate was trea-
ted with cyclohexanecarbaldehyde in a one-pot manner. In this
case, the Reformatsky type C–C bond forming step at ꢀ78 °C com-
pleted within 1 h to give a,a-difluoro-b-hydroxyketone N,O-acetal
3aa in 90% yield with excellent anti selectivity (entry 1). Unfortu-
nately, the product was obtained as a racemic mixture and the
product yield was sensitive to the amount of (ꢀ)-sparteine (entry
2). However, since we have already demonstrated that, in the ab-
sence of any diamine additives, this C–C bond forming reaction re-
quires both higher reaction temperature and prolonged reaction
time to obtain the product 3aa in good yield (entry 7, at 0 °C for
8 h),10 it is obvious that the use of (ꢀ)-sparteine accelerates not
only the defluorinative alkylation step but also the subsequent
C–C bond formation with aldehydes. By using other diamine addi-
tives such as TMEDA, carbinol product 3aa was obtained in moder-
ate yield, while the Reformatsky type C–C bond forming reaction is
slower than the reaction in the presence of sparteine (entries 3–5).
Table 2
Sparteine-mediated synthesis of b-hydroxy-
a
,a
-difluoroketone N,O-acetals
R1Li (2.5 eq),
R
N
CF3
O
(-)-sparteine (1.0 eq)
Et2O, -78 °C, 15 min
OH
R
N
O
R3
R2
R1
then R2COR3 (2.0 eq)
F
3
F
1
Entry
1
R
R1
R2
R3
Temp. (°C)
Time (h)
3
Yielda (%)
Drb
1c
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Bn
Bn
Bn
n-C3H7
Me
i-Pr
c-C6H11
c-C6H11
t-Bu
–CH2(CH2)3CH2–
Me
Ph
c-C6H11
–CH2(CH2)3CH2–
Me
H
H
H
ꢀ24
ꢀ24
ꢀ24
ꢀ24
0
4
4
4
4
1
2
2
1
2
2
3aa-Me
3aa-iPr
3ab
3ac
3ad
3ae
3ba
3bc
3bd
86
79
80
81
83
82
91
90
80
87
5.8:1
Single
15:1
—
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Me
Me
H
—
0
1.8:1
6.7:1
—
—
9.6:1
ꢀ24
0
Me
H
0
ꢀ24
10
c-C6H11
3ca
a
b
c
Isolated yield.
Determined by 19F NMR of the crude mixture.
Defluorinative methylation was carried out at ꢀ24 °C.

H. Yanai et al. / Tetrahedron Letters 51 (2010) 2625–2628
2627
acylsilane giving rise to 2-fluoro-1,3-diketone mono-N,O-acetal 4 or
simple adduct 3 (Scheme 2).15 After numerous attempts, we
have established that the desired reaction proceeded nicely by
0.5 M equiv of sparteine and a strict control of the reaction temper-
ature brings about the selective formation of 4 or 3. For example,
after the defluorinative alkylation of 1a with n-BuLi in the presence
of 0.5 M equiv of sparteine in Et2O, the reactive intermediate was
treated with a solution of acetyltrimethylsilane in THF. Then, the
resultant mixture was warmed to 0 °C over 7 h to give 2-fluoro-
1,3-diketone mono-N,O-acetal 4a in 68% yield as an anti/syn mixture
in a ratio of 2.2:1.16 On the other hand, the reaction with acetyltri-
methylsilane below ꢀ24 °C selectively gave simple adduct 3af in
82%yieldas asole diastereomer. Moreover, thetreatmentof 3afwith
n-BuLi at ꢀ24 °C for 6 h in Et2O/THF mixed solvent resulted in the
clean formation of 4a in 81% yield. Likewise, by one-pot procedure,
trifluoroacetaldehyde N-benzyl-N,O-acetal 1b was converted to
the corresponding mono-fluoro product 4b in 55% yield. The forma-
tion of 2-fluoro-1,3-diketone mono-N,O-acetal 4 can be a conse-
quence of the 1,2-Brook rearrangement17,18 of lithium alkoxide
intermediate followed by mono-defluorination via b-elimination.
Finally, we examined the deprotection of N,O-acetal group.
n-BuLi (2.5 eq)
R
N
(-)-sparteine (0.5 eq)
Et2O, -78 ºC, 15 min;
O
R
n-Bu
N
O
F
CF3
Me
O
then MeCOSiMe3 (2.0 eq)
THF, -78 to 0 °C, 7 h
1a R = Allyl
1b R = Bn
4a 68% (anti/syn = 2.2 : 1)
4b 55% (anti/syn = 1.9 : 1)
n-BuLi (2.5 eq)
(-)-sparteine (0.5 eq)
Et2O, -78 ºC, 15 min;
n-BuLi
OH
4a
81%
R
n-Bu
N
O
Me
SiMe3
-24 °C, 6 h
then MeCOSiMe3 (2.0 eq)
THF, -24 °C, 4 h
F
F
3af 82% (sole isomer)
3bf 81% (dr = 37 : 1)
Scheme 2.
Moreover, the use of 2.0 M equiv of triethylamine as a mono amine
additive resulted in a poor yield of 3aa under the reaction at ꢀ78 °C
(entry 6).
To reveal the scope of the present sparteine-mediated synthesis
a,a-difluoro-b-hydroxyketone N,O-acetals, we carried out the
Since several acetals derived from a,a-difluoroketones or trifluoro-
of
methyl ketones are overwhelmingly stable compared to non-fluo-
rinated ketone acetals due to the electronic and stereoelectronic
effects by fluoro groups, deprotection of these fluorinated ketone
acetals under mild conditions is considerably difficult. However,
after several attempts, we found that N-benzyl-N,O-acetal group
can be removed by catalytic hydrogenolysis giving rise to
defluorinative alkylation of trifluoroacetaldehyde N,O-acetals fol-
lowed by the Reformatsky type C–C bond formation in the pres-
ence of stoichiometric amount of (ꢀ)-sparteine (Table 2). In the
case of methyllithium, the defluorinative methylation step of 1a
smoothly completed in a mixed solvent of Et2O and THF at
ꢀ24 °C within 15 min, then the one-pot treatment of the resultant
reaction mixture by cyclohexanecarbaldehyde rapidly gave the
carbinol product 3aa-Me in 86% yield (entry 1). In the presence
of sparteine, sterically hindered isopropyllithium could be also
used to give isopropyl ketone N,O-acetal 3aa-iPr in 79% by the
reaction of 1a for 4 h at ꢀ24 °C (entry 2). Interestingly, the diaste-
a,a-difluoroketones (Scheme 3). Thus, N-benzyl-N,O-acetal 3ba
was converted to the corresponding b-hydroxyketone 5a by the
reaction in a mixed solvent of MeOH and 10% aqueous HCl solution
under Pd/C-H2 conditions. In the absence of any palladium cata-
lysts, the starting material 3ba could not be converted to the ke-
tone 5a under such acidic conditions. This deprotecting
procedure could be applied to tertiary cyclohexanol 3bc and ben-
zylic alcohol 3bg without decomposition of these functionalities
reoselectivity in these three component syntheses of a,a-difluoro-
b-hydroxyketone N,O-acetals strongly depended on the steric bulk-
iness of the introduced alkyl group and the improvement of anti-
selectivity was observed by increasing the steric bulkiness of alkyl-
lithiums (entries 1, 2 and also see Table 1). Furthermore, pivalalde-
hyde performed as a nice electrophile and the corresponding
carbinol product 3ab was obtained in 80% yield (entry 3). It is
worth mentioning that the use of stoichiometric amount of sparte-
ine also resulted in the rate acceleration of the Reformatsky type
reaction using relatively low reactive ketones, which had required
both higher reaction temperature and prolonged reaction time in
the absence of sparteine. For example, the one-pot reaction of
the intermediate, which generated by defluorinative alkylation of
1a with n-BuLi, with ketones such as cyclohexanone, acetone and
acetophenone smoothly proceeded at ꢀ24 °C or at 0 °C to give
the corresponding tertiary alcohols 3ac, 3ad and 3ae in excellent
yields (entries 4–6). Likewise, this rate acceleration by sparteine
was observed in the reactions of N-benzyl and N-propyl N,O-acetal
substrates 1b and 1c (entries 7–10).
to give the corresponding
a,a-difluoro-b-hydroxyketones 5b and
5c in 81% and 86% yield, respectively.
In conclusion, we found that (ꢀ)-sparteine accelerates both the
defluorinative alkylation reaction of trifluoroacetaldehyde N,O-
acetals with alkyllithiums and the following Reformatsky type
C–C bond formation with carbonyl compounds. N-Benzyl-N,O-
acetal group of the obtained products can be removed under
palladium-catalyzed hydrogenolysis conditions to give the corre-
sponding
procedure is a useful and novel synthetic approach to functional-
ized -difluoroketones.
a,a-difluoro-b-hydroxyketones. The present two-step
a,a
Acknowledgments
The authors gratefully acknowledge Mr. Hideyuki Mimura and
Dr. Kosuke Kawada (TOSOH F-TECH Inc.) for supplying trifluoro-
acetaldehyde hemiacetals.
Next, to show the useful extension of this sparteine-mediated
conditions, we examined the reaction of reactive intermediate with
Supplementary data
Pd/C (10 mol%)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.03.018.
OH
O
H2 (1 atm)
OH
Bn
n-Bu
N
O
R2
R2
n-Bu
R1
MeOH-aq.HCl
rt, 1-3 h
R1
F
F
References and notes
F
F
3ba R1 = c-C6H11, R2 = H
5a 99%
5b 81%
5c 86%
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Scheme 3.

2628
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