Highly regio- and stereo-controlled Pd(0)-catalyzed nucleophilic substitution reaction for the synthesis of optically active γ-fluoroalkylated allylic alcohols

Article abstract of DOI:10.1016/S0040-4039(00)01485-4

Pd(0)-catalyzed nucleophilic substitution reaction of optically active α-(fluoroalkyl)allyl mesylates with various types of carboxylates proceeded regioselectively to afford the corresponding chiral γ-fluoroalkylated allylic alcohol derivatives in excellent yields without any loss of optical purities. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01485-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8467–8472
Highly regio- and stereo-controlled Pd(0)-catalyzed
nucleophilic substitution reaction for the synthesis of
optically active g-fluoroalkylated allylic alcohols
Tsutomu Konno,* Takashi Ishihara and Hiroki Yamanaka
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Sakyo-ku,
Kyoto 606-8585, Japan
Received 10 August 2000; revised 28 August 2000; accepted 1 September 2000
Abstract
Pd(0)-catalyzed nucleophilic substitution reaction of optically active a-(fluoroalkyl)allyl mesylates with
various types of carboxylates proceeded regioselectively to afford the corresponding chiral g-fluoroalkyla-
ted allylic alcohol derivatives in excellent yields without any loss of optical purities. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: g-fluoroalkylated allylic alcohols; palladium-catalyzed reaction.
Fluorine-containing organic molecules are well known to often exhibit unique chemical and
1
biological properties due to the electron-withdrawing effect of a fluorine atom. Practically, they
2
3
4
have widely been utilized as ferroelectric liquid crystals, pharmaceuticals, agrochemicals, and
so on. Therefore, fluorinated materials have attracted much attention from many scientists in
various fields, and much effort has been devoted to the development of general and convenient
5
methods for synthesizing such compounds.
g-Fluoroalkylated allylic alcohols 1 have frequently been employed as one of the most
valuable starting materials in the preparation of fluoroorganic compounds with a more
*
Corresponding author.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01485-4

8468
6
complicated framework, such as naturally occurring compounds. Although several synthetic
7
methods for racemic allylic alcohols are already known, only quite limited methods have been
found thus far for the preparation of their non-racemic counterparts. The enzymatic kinetic
resolution of the racemic alcohols 1 has been reported as the most convenient way to obtain
6
c,e
both enantiomers with high optical purities. However, this method suffers at least one serious
disadvantage in that the yields of the chiral alcohols are not more than 50%. On the other hand,
the asymmetric synthesis provides us with the great advantage that the transformation can be
carried out to completion, i.e. 100% maximum yield. Surprisingly, no examples of the asymmet-
ric synthesis of optically active g-fluoroalkylated allylic alcohols 1 have appeared. Herein we
wish to disclose a novel nucleophilic substitution reaction of various fluorinated allyl mesylates
2
with carboxylates under the influence of a catalytic Pd(0) complex, which can serve as a
general and efficient route to the preparation of non-racemic alcohols 1.
At first, we attempted the Pd-catalyzed reaction using racemic a-(fluoroalkyl)allyl mesylates
a–f as the starting materials, prepared readily from the corresponding perfluoroalkanoic acid
2
ethyl esters 3a–f in three steps ((1) RCꢀCLi, then RfCO Et; (2) Red–Al; (3) MsCl, Et N)
2
3
(
Scheme 1). Except for 2b–f, monofluorinated mesylate 2a was too unstable to be purified by
silica gel column chromatography. Therefore, 2a was used for the reaction without any
purification.
Rf
R
OMs
OCOR'
R
OCOR'
a
b
c
d
e
f
CFH2
n-C H
three steps
γ
R'COO -
6
13
RfCO2Et
a-f
CF H
2
+
Rf
α
R
Rf
Rf
R
CF3
3
Pd(PPh3)4
4
a-f
5
BnOCH2
n-C H
6 13
2a-f
C2F5
n-C3F7
γ-Product
α-Product
Scheme 1.
Several examinations of the reaction conditions led us to the conclusion that the best yield of
4
c was obtained by the reaction of 2c performed in the following manner: the mesylate 2c was
treated with 5 mol% of tetrakis(triphenylphosphine)palladium(0) in THF at 0°C for 5 min,
followed by the addition of 2 equiv. each of benzoic acid and triethylamine at that temperature.
After stirring for several hours at 0°C and an unusual workup, the desired g-trifluoromethylated
allylic alcohol derivative 4c (g-product) was obtained in 91% isolated yield as a sole product.
High E selectivity was observed at the newly created olefinic bond in 4c, and no regioisomer 5
8
(
a-product) was detected.
With this successful result in hand, we carried out the Pd-catalyzed reactions between various
types of the substrates 2 and carboxylic acids under the same reaction conditions. The results of
these reactions are summarized in Table 1. Although the crude mesylate 2a, as noted above, was
employed as such for the Pd-catalyzed process, the desired allylic alcohol derivative 4a was
obtained in 56% two-step yield as a single isomer (entry 1). As shown in entries 2, 3, 10, and 11,
the Rf groups of 2 did not exert any influence on the regio- and stereochemical course of the
reaction, with all the cases leading to g-products with the E configuration. A variety of
carboxylic acids, such as benzoic acid, acetic acid, propionic acid, chloro-, and methoxyacetic
acid, participated nicely in the reaction, giving rise to the corresponding g-products 4 exclusively
(
entries 3–7). It was found that the differences in the side chain R largely affected the reaction.

8469
Thus, a slight decrease in the stereoselectivity at the newly formed olefinic bond was observed
with the benzyloxymethyl group (entry 8). Furthermore, the t-butyl group completely prevented
the reaction from proceeding (entry 9).
Table 1
Pd(0)-catalyzed reaction of fluorinated allyl mesylates 2 with various carboxylates
a
b,c
Entry
Rf
R
RCO H
Yield (%)
2
1
2
3
4
5
6
7
8
9
CH F
n-C H
BzOH
BzOH
BzOH
56
89
91
80
74
99
96
2
6
13
13
13
13
13
13
13
CHF2
CF3
CF3
CF3
CF3
CF3
CF3
CF3
n-C H
6
n-C H
6
n-C H
CH CO H
6
3
2
n-C H
CH CH CO H
6
3 2 2
n-C H
ClCH CO H
2 2
MeOCH CO H
BzOH
BzOH
BzOH
BzOH
6
n-C H
6
2 2
d
BnOCH2
t-Bu
93
0
87
99
1
1
0
1
CF CF2
n-C H
3
6
13
CF (CF )
n-C H
3
2 2
6
13
a
b
c
All reactions were performed at 0°C by using 2 equiv. each of Et N, carboxylic acid and 5 mol% of Pd(PPh ) .
Isolated yield.
The E isomer was produced exclusively in all cases, unless otherwise noted.
The stereoisomers of E and Z forms were obtained in a ratio of 94:6.
3
3 4
d
In order to evaluate the influence of an Rf group upon the reaction, we examined the reaction
of a nonfluorinated counterpart (Scheme 2). Ethyl carbonate 6 was used as the starting ester
because the corresponding allyl mesylate was so thermally unstable that it could not be
prepared. The ester 6 was treated with 5 mol% of Pd(PPh ) and 2 equiv. of benzoic acid at
3
4
room temperature, and the reaction mixture was stirred at that temperature for 24 h. HPLC of
the reaction mixture indicated that a large amount of the substrate 6 remained unreacted, and
9
that the a- and g-products were obtained in only 16% yield in a ratio of 87:13, respectively. It
should be emphasized that the a-product was given preferentially, not g-product. This is totally
different from the results of the reaction of the fluorinated substrates 2.
Scheme 2.
The access to chiral g-fluoroalkylated allylic alcohols 1 was undertaken as outlined in Scheme
10
3
. Thus, on treating chiral (E)-substrate (S)-2c-E with benzoic acid and Et N under the same
3
conditions as described above, the optically active product (S)-4c was obtained in 91% yield.
The ester (S)-4c, after hydrolysis, was converted into the MTPA ester, whose diastereomeric
excess was measured to be 84% by gas chromatography. This clearly indicates that the reaction
proceeds without any loss of optical purity throughout the reaction. The transformation of
11
(
S)-4c into the known compound (S)-7 and comparison between their optical rotations made
it possible to determine its absolute configuration as S.

8470
OH
OMs
OBz
R
OMTPA-(R)
R
MsCl
Et 3N
Pd(PPh3)4, BzOH
Et3N
1) NaOH, MeOH
F3C
R
F3C
R
F3C
F3C
2) (R)-MTPA,
Et 3N, DCC, DMAP
8
2% ee
(
S)-2c-E
(S)-4c
84% de
[
α]D28 = +33.8° (c 0.60 , CHCl3)
1
2
) O3, -78 °C then Me2S
) LiAlH4
ref 10
OH
CF3CO2Et
R = n-C6H13
HO
R
(
S)-7
ref 10
26
(
S) : [α]D = -14.5° (c 2.14, EtOH)
cf11 (R) [α]D = +17.5° (c 1.16, EtOH, ee>98%)
20
:
OH
OMs
OBz
OMTPA-(R)
R
MsCl
Et 3
Pd(PPh3)4, BzOH
Et N
1) NaOH, MeOH
R
R
F3C
N
F3C
S)-2c-Z
F3C
R
2) (R)-MTPA,
Et 3N, DCC, DMAP
F3C
3
(
(R)-4c
89% de
92% ee
[
α]D28 = -34.5° (c 0.88 , CHCl3)
Scheme 3.
10
Similarly, the reaction of chiral (Z)-substrate (S)-2c-Z was conducted under the same
conditions, leading to the corresponding chiral allylic alcohol derivative (R)-4c in 88% yield. The
optical rotation of the product was opposite to the (S)-enantiomer, and thereby its absolute
configuration was assigned as R. In addition, this ester was transformed into the MTPA ester,
followed by gas chromatography, which was determined to be 89% de. This fact strongly
suggests that the reaction of the (Z)-substrate takes place in an entirely stereoselective fashion.
The mechanism of the present reaction may be proposed as indicated in Fig. 1. Thus, when
the Pd complex coordinates on the face of the olefin distal to the mesyloxy group, the Pd species
Nu-
Nu-
OMs
Nu
Pd(0)L2
NuH
+
Et3N•HOMs
+
Pd(0)L2
F3C
R
F3C
R
α
γ
3
Et N
F3C
R
(S)-2c-E
L2P+d
-OMs
8
MsO-
+
+
MsO- L2Pd
MsO- PdL2
OMs
H
R
R
+
Pd(0)L2
PdL2
H
R
F3C
L2Pd
F3C
H
F3C
Nu-
R
F3C
S)-2c-Z
F3C
R
(
OMs
Nu-
10
9
NuH
Et3N
Nu
+
+
Pd(0)L2
Et3N•HOMs
F3C
R
Figure 1.

8471
displaces the mesylate with inversion to give a p-allyl complex 8. The carboxylate nucleophile
attacks complex 8 on the face opposite to that occupied by Pd. The double inversion results in
1
2
a net retention for these processes. In this case, the Pd moiety might be closer to the Rf group
13
than the R due to the electron-withdrawing effect of the Rf group. Therefore, the nucleophile
attacks preferentially at the less hindered g-carbon to give the g-fluoroalkylated allylic alcohol
derivative 4.
On the other hand, oxidative addition of Pd(0) to the (Z)-substrate generates the p-allylpalla-
1,3
dium complex 9, which is less stable than 10 due to a A strain, so that 9 could be converted
into 10 via p-s-p equilibrium with inversion. The nucleophilic attack occurs with inversion, as
mentioned in the (E)-substrate. Thus, the reaction of the (Z)-substrate involves three inversion
processes, which creates a net inversion.
Finally, we investigated the application of the present reaction combined with an Ireland–
Claisen rearrangement (Scheme 4).
Scheme 4.
Thus, the Pd-catalyzed reactions of chiral mesylates 2b,c,e with methoxyacetic acid gave the
corresponding allylic alcohol derivatives 4b,c,e in situ, which were treated successively with 6
equiv. each of trimethylsilyl chloride and lithium hexamethyldisilazide at −50°C. After stirring at
that temperature for 30 min, the whole was gradually warmed up to room temperature over 2
h and then stirred at ambient temperature for 3 h. The usual workup gave the corresponding
rearranged products, which were subjected to esterification with diazomethane to afford
a-methoxy-b-trifluoromethyl ester 11b,c,e in 85–99% overall yields as single stereoisomers.
Although the stereochemistry and enantiomeic excess of these esters have not been confirmed,
6
c
our precedent work allows us to expect that the reaction proceeds via an energetically stable
six-membered cyclic transition state, where the R group occupies the equatorial position,
without any loss of optical purities throughout the reaction.
In conclusion, we have investigated the Pd-catalyzed nucleophilic substitution reaction of
chiral a-(fluoroalkyl)allyl mesylates 2 with carboxylates affording the corresponding chiral
g-fluoroalkylated allylic alcohol derivatives 4 in excellent yields. This reaction can serve as a
general and expedient means for synthesizing optically active fluorinated allylic alcohols. We
have also demonstrated that the sequential Pd-catalyzed allylic substitution reaction and
Ireland–Claisen rearrangement leads efficiently to optically enriched a-methoxy-b-(fluoroalkyl)-
g,d-unsaturated esters in excellent yields.

8472
Further studies on the synthetic utilizations of fluorine-containing palladium complexes are
now under way in our laboratory.
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1
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1
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