Copper-free defluorinative alkylation of allylic difluorides through Lewis acid-mediated C-F bond activation

Article abstract of DOI:10.1016/j.tetlet.2011.03.148

The reactions of difluorohomoallyl alcohols with trialkylaluminiums smoothly proceeded in CH₂Cl₂ at room temperature to give (Z)-fluoro-olefin products in excellent yields. On the basis of this chemistry, fluoro-olefinic dipeptide isostere of norvalinyl glycine was synthesized in stereoselective manner.

Full text of DOI:10.1016/j.tetlet.2011.03.148

Tetrahedron Letters 52 (2011) 2997–3000
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Tetrahedron Letters
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Copper-free defluorinative alkylation of allylic difluorides through Lewis
acid-mediated C–F bond activation
Hikaru Yanai a, Haruna Okada a, Azusa Sato b, Midori Okada b, Takeo Taguchi a,
⇑
a School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
b Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactions of difluorohomoallyl alcohols with trialkylaluminiums smoothly proceeded in CH2Cl2 at
room temperature to give (Z)-fluoro-olefin products in excellent yields. On the basis of this chemistry,
fluoro-olefinic dipeptide isostere of norvalinyl glycine was synthesized in stereoselective manner.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 10 March 2011
Revised 24 March 2011
Accepted 31 March 2011
Available online 7 April 2011
Keywords:
Fluoroalkene
Organoaluminium
Lewis acid
C–F bond cleavage
Peptide isostere
Me3Al (5 equiv)
additive (2.5 equiv)
OH OTBDPS
OH OTBDPS
Carbon–fluorine bonds are well known as a strong covalent
Me
bond and the bond dissociation energy D° in CH3F is measured as
472 kJ molꢀ1 1
.
Since the D° value of C–F bond is higher than that
F
THF, 0 °C, 23 h
F
F
of C–H bond (439 kJ molꢀ1 in CH4), the selective transformation
of fluoro group in organic molecule has been limited in the simple
and specific cases for a long time.2,3 On the other hand, the use of
Lewis acids as C–F bond activators would be an attractive approach
to realize C–F bond functionalization under mild conditions.4 In
fact, it was reported that the substitution reactions of relatively ac-
tive organofluorides, such as tert-alkyl fluorides and allylic fluo-
rides, are nicely promoted by aluminium, boron or silicon Lewis
acid.5–7 We also reported the Cu-mediated defluorinative alkyl-
ation reaction of difluorohomoallyl alcohols using trialkylalumini-
ums as a powerful tool to construct fluoro-olefin functionality
(Scheme 1).8,9 For example, the reaction of functionalized difluoro-
homoallyl alcohol with 5 equiv of Me3Al in the presence of
2.5 equiv of CuIꢁ2LiCl resulted in the SN20 type methylation with
mono C–F bond cleavage to give fluoro-olefin product in 97% yield
with excellent Z selectivity.10 In contrast, the reaction in the ab-
sence of Cu catalysts did not proceed.
additive: none
0%
CuI·2LiCl 97% (Z/E = >20 : 1)
Scheme 1.
lation chemistry of carbonyl compounds.13,14 However, it was a
disadvantage to use a large amount of metallic reagents such as
Me3Al, CuI and LiCl. To overcome this problem, we conducted the
re-screening to reveal more effective and atom economical condi-
tions. In this Letter, we describe that the simple change of solvent
realized this defluorinative alkylation reaction without the use of
CuIꢁ2LiCl. Furthermore, on the basis of this transformation, a
dipeptide isostere, which is depicted as Nva-
w[(Z)-CF@CH]-Gly,
was effectively synthesized.
At first, we carried out the reaction of phenylated substrate 1a
and pentylated substrate 1b with several trialkylaluminiums in
the absence of Cu catalysts. Selected results are summarized in Ta-
ble 1. As shown in entries 1 and 2, the reaction of homoallylic alco-
hol 1a with Me3Al in ethereal solvents did not give the desired
products. On the other hand, simple change of the reaction media
from ethereal solvents to CH2Cl2 dramatically improved the reac-
tion. That is, the reaction of 1a with 2.0 equiv of Me3Al in CH2Cl2
completed at room temperature for 2.5 h to give (Z)-fluoro-olefin
2a-Me in 99% yield (entry 3). These results clearly show that ethe-
real solvents perform as relatively strong Lewis bases to inhibit this
transformation. This reaction required the use of at least 2 equiv of
Since fluoro-olefin structure has been known as a biologically
isosteric structure for peptidic bonds,11,12 this transformation pro-
vides a powerful methodology to synthesize fluoro-olefinic peptide
isosteres in the stereoselective manner. In addition, the starting
difluorohomoallyl alcohols can be easily obtained by difluoroally-
⇑
Corresponding author. Tel.: +81 42 676 3257; fax: +81 426 76 3257.
E-mail address: taguchi@toyaku.ac.jp (T. Taguchi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.148

2998
H. Yanai et al. / Tetrahedron Letters 52 (2011) 2997–3000
Table 1
Me3Al and the reaction of 1a with 1.1 equiv of Me3Al in CH2Cl2 re-
sulted in the poor conversion of 1a (entry 4). Despite of the lower
reactivity of Et3Al compared to Me3Al, the reaction of 1a with
3.0 equiv of Et3Al rapidly gave ethylated product 2a-Et in 89% yield
as a Z/E mixture in a ratio of 19:1 (entry 5). Interestingly, the reac-
tion of 1a with 3.0 equiv of i-Bu3Al gave isobutylated product 2a-
iBu in 58% yield with the formation of a small amount (13% yield)
of the rearranged product 3a (entry 6). The formation of 3a would
be attributed to i-Bu3Al mediated generation of the stabilized flu-
oroallyl cation species. In addition, the reactions of difluorohomo-
allyl alcohol 1b equipped with alkyl side chain smoothly gave the
corresponding (Z)-fluoro-olefins 2b-Me, 2b-Et and 2b-iBu in good
to excellent yields (entries 7–9).
Next, to reveal the scope of this defluorinative allylic alkylation
chemistry, we examined the reaction of difluorohomoallyl alcohol
1 with Et3Al in CH2Cl2 (Table 2). Benzylic alcohols 1c–1f smoothly
reacted with 3.0 equiv of Et3Al at room temperature to give the
corresponding fluoro-olefin products 2c–2f in good yields with
the excellent Z selectivity (entries 1–4). Notably, trifluoromethyl
group in 1d perfectly tolerated during the reaction process. In a
case of 2-pyridyl substrate 1g, the complete consumption of 1g
within acceptable reaction time was observed by using 4.0 equiv
of Et3Al and the ethylation product 2g was obtained in 85% yield
as a Z/E mixture in a ratio of >20:1 (entry 5). This reaction can be
also applied to substrates substituted by long alkyl side chains.
For example, tridecyl and pentadecyl alcohols 1h and 1i were
smoothly converted to the fluoro-olefins 2h and 2i in 84% and
85% yields with the perfect Z selectivity, respectively (entries 6
and 7). Likewise, phenethyl derivative 2j and cyclohexyl derivative
2k were obtained in an excellent yield in a Z selective manner (en-
tries 8 and 9). From a synthetic viewpoint, it can be noted that silyl
protecting group in the substrates fully tolerated under this trans-
formation. The reactions of tert-butyldiphenylsilyl ethers 1m and
1n with Et3Al rapidly completed to give the corresponding (Z)-flu-
oro-olefins 2m and 2n in 85% and 79% yields, respectively (entries
10 and 11).
Survey of effective reaction conditions for defluorinative allylic alkylation
OH
R'
OH
R'
R3Al
rt
R
F
F
F
2
1a (R' = Ph)
1b (R' = n-C5H11
)
Entry
1
R3Al (equiv)
Solvent
Time
(h)
2
Yielda
(%)
Z/Eb
1
2
3
4
1a
1a
1a
1a
1a
1a
1b
1b
1b
Me3Al (2.0)
Me3Al (2.0)
Me3Al (2.0)
Me3Al (1.1)
Et3Al (3.0)
i-Bu3Al (3.0)
Me3Al (2.0)
Et3Al (3.0)
THF
20
16
2.5
20
3.5
6.5
2
2a-Me
2a-Me
2a-Me
2a-Me
2a-Et
2a-iBu
2b-Me
2b-Et
0
0
—
—
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
99
<5
89
58
90
90
61
Z only
Z only
19:1
>20:1
Z only
Z only
Z only
5
6c
7
8
2
9d
i-Bu3Al (3.0)
2.5
2b-iBu
OH
3
R'
a
b
c
Isolated yield.
Determined by 19F NMR of crude mixture.
13% of 3a was obtained.
d
6% of 3b was obtained.
Table 2
Defluorinative allylic alkylation of difluorohomoallyl alcohol 1 with Et3Al
OH
OH
Et3Al (3.0 equiv)
Et
R
R
CH2Cl2, rt
F
F
F
1
2
Entry
1
R
Time (h)
2
Yielda (%)
Z/Eb
1
2
3
1c
1d
1e
1f
1g
1h
1i
4-MeC6H4
4-CF3C6H4
2-BrC6H4
4-BrC6H4
2-Pyridyl
n-C13H27
3
3
3
4
4
3
2
5
3
2
1
2c
2d
2e
2f
2g
2h
2i
82
85
97
88
85
84
85
80
80
85
79
>20:1
>20:1
Z only
>20:1
>20:1
Z only
Z only
>20:1
Z only
Z only
Z only
Regarding the reaction pathway in this reaction system, we
point out the importance of C–F bond activation via intramolecular
coordination of fluoro group to aluminium center (Fig. 1). In all
cases of the reactions using Me3Al, quantitative formation of meth-
ane gas was observed. This result suggests that the initial reaction
of substrate 1 with 1 equiv of trialkylaluminium gives aluminium
alkoxide such as intermediate A. In this intermediate, the intramo-
lecular coordination of one of the fluoro groups to aluminium cen-
ter presumably activates the C–F bond. In fact, 19F NMR of a 1:1
mixture of p-tolyl substrate 1c and Me3Al in CDCl3 at room temper-
ature showed that significant downfield shift of one fluoro group
4
5c
6
7
8
9
10
11
n-C15H31
1j
CH2CH2Ph
c-Hex
CH2OTBDPS
CH2CH2OTBDPS
2j
1k
1m
1n
2k
2m
2n
a
b
c
Isolated yield.
Determined by 19F NMR of crude mixture.
4.0 equiv of Et3Al were used.
(D
d = +7.0 ppm) compared to that of another fluoro group
Me
Me
Me
Me
Al
Al
O
Me3Al
Me3Al
F
O
1a
Me3Al
F
Me
Me
Ph
Ph
F
CH4
F
A
B
Me
Me
Me Al
Me
Al
Me
H2O
Me
O
Al
O
H
F
Me2AlF
2a-Me
Ph
H2C
F
F
C
H
Ph
TS-1
Figure 1. Proposed reaction pathway.

H. Yanai et al. / Tetrahedron Letters 52 (2011) 2997–3000
2999
(
D
d = +0.4 ppm). This fact strongly supports the electrophilic acti-
pared. Further studies on this chemistry are progressing in our
laboratory.
vation of C–F bond via the intramolecular coordination. Since the
present reaction required the use of at least 2 equiv of trialkylalu-
minium, additional 1 equiv of aluminium reagent would perform
as an alkyl donor. That is, the alkyl transfer reaction to intermedi-
ate A aggregated by Me3Al smoothly proceeds via TS-1 to give flu-
oro-olefin in Z selective manner. The alkyl transfer reaction giving
rise to intermediate B is a catalytic process by Me3Al in principle.
However, a reversible ligand exchange between intermediate B
and Me3Al would result in a formation of thermodynamically
stable Me2AlF. Therefore, the reaction requires at least of 2 equiv
of trialkylaluminium. Furthermore, since strong Lewis bases such
as ethereal solvents inhibit both the electrophilic activation of
C–F bond via the intramolecular coordination and the following
alkyl transfer reaction giving rise to intermediate B, the use of
CH2Cl2 as a solvent dramatically improve the efficiency of this
reaction.
Acknowledgement
We thank Mr. Daiki Suzuki (Tokyo University of Pharmacy and
Life Sciences) for his technical assistance.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.148.
References and notes
1. (a) Kerr, J. A.; Stocker, D. W. Strength of Chemical Bonds. In CRC Handbook of
Chemistry and Physics; Lide, D. R., Ed.; CRC Press: New York, 1999–2000; pp 51–
70. 80 Ed., Section 9; (b) Uneyama, K. Organofluorine Chemistry; Blackwell
Publishing: Oxford, 2006.
The nonequivalent downfield shifts in 19F NMR were also found
in silyl ether 1o. Thus, 19F NMR of tert-butyldimethylsilyl ether 1o
showed a large downfield shift of one fluoro group (
and a small shift of another fluoro group ( d = +0.2 ppm) com-
2. (a) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119; (b) Terao, J.; Todo, H.;
Watabe, H.; Ikumi, A.; Shinohara, Y.; Kambe, N. Pure Appl. Chem. 2008, 80, 941.
3. Our papers in relation to defluorinative alkylations under basic conditions, see:
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Dd = +3.9 ppm)
D
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tion of silyl ether 1o with only 1 equiv of Et3Al rapidly completed
to give the ethylated product 2o in 95% yield (Scheme 2).16
As a synthetic application of this defluorinative alkylation
chemistry, we carried out the synthesis of a dipeptide fluoro-ole-
finic isostere (Scheme 3). On the basis of Allmendinger’s proce-
dure,17 the ethylated compound 2n could be converted to the
corresponding trichloroimidate and the following [3,3]-sigmatrop-
ic rearrangement18 by heating in xylenes gave amide product 4 in
73% yield without the formation of (E)-isomer. After the change of
N-trichloroacetyl group to Boc group, N-fluoroallyl carbamate 5
was converted to (Z)-fluoro-olefinic isostere of norvalinyl glycine
6 by the desilylation followed by the Jones oxidation. By these four
steps from the defluorinative ethylation product 2n, Boc-Nva-
4. For the Dꢂ298 values of Al–F bond (664 kJ molꢀ1), B–F bond (757 kJ molꢀ1), and
Si–F bond (553 kJ molꢀ1), see: Ref. 1a.
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w
[(Z)-CF@CH]-Gly 6 was obtained in good overall yield and in a
highly stereoselective manner.
In summary, we found that the reactions of difluorohomoallyl
alcohols with trialkylaluminiums smoothly proceed in CH2Cl2 in
the absence of any Cu catalysts. The present defluorinative allylic
alkylation can be applied to a broad range of substrates and the
corresponding (Z)-fluoroallyl alcohol products were obtained in
good to excellent yields. In addition, on the basis of this methodol-
10. Watanabe, D.; Koura M.; Saito, A.; Yanai, H.; Nakamura, Y.; Okada, M.; Sato, A.;
Taguchi, T. J. Fluorine Chem. 2011, 132, in press (doi:10.1016/
j.jfluchem.2011.03.007).
ogy, racemic Boc-Nva-
w
[(Z)-CF@CH]-Gly isostere was easily pre-
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OTBS
OTBS
Ph
Et3Al (1.0 equiv)
CH2Cl2, rt, 1 h
Et
Ph
F
F
F
1o
2o 95% (Z/E = >20 : 1)
Scheme 2.
CH3
OH OTBDPS
a
NHR
OTBDPS
c, d
CO2H
H3C
H3C
BocHN
F
F
F
2n
4 R = COCCl3
5 R = Boc
6
b
Scheme 3. Reagents and conditions: (a) CCl3CN, DBU; xylenes, 140 °C, 73%; (b) NaOH, H2O–EtOH; Boc2O, 76%; (c) TBAF, 90%; (d) Jones reagent, acetone, 75%.

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H. Yanai et al. / Tetrahedron Letters 52 (2011) 2997–3000
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