Palladium-catalyzed double alkylation of 3-aryl-2-fluoroallyl esters with malonate nucleophiles through the carbon-fluorine bond cleavage

Article abstract of DOI:10.1021/ol500121z

The alkylation of (Z)-3-aryl-2-fluoroallyl acetate with the malonate anion by the [Pd(C₃H₅)(cod)]BF₄/2,2′-bpy catalyst proceeds through the carbon-fluorine bond cleavage, and 2 equiv of the malonate nucleophile was introdu

Full text of DOI:10.1021/ol500121z

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Double Alkylation of 3‑Aryl-2-fluoroallyl Esters
with Malonate Nucleophiles through the Carbon−Fluorine Bond
Cleavage
Mitsuaki Yamamoto, Shunsuke Hayashi, Kazuki Isa, and Motoi Kawatsura*
Department of Chemistry, College of Humanities & Sciences, Nihon University, Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan
S
* Supporting Information
ABSTRACT: The alkylation of (Z)-3-aryl-2-fluoroallyl acetate with the malonate
anion by the [Pd(C3H5)(cod)]BF4/2,2′-bpy catalyst proceeds through the
carbon−fluorine bond cleavage, and 2 equiv of the malonate nucleophile was
introduced to the allyl substrate.
t is well-known that the palladium-catalyzed allylic alkylation
of allyl esters usually proceeds through π-allyl palladium
the lithium dimethyl methylmalonate, which was generated in
situ from dimethyl methylmalonate and LiHMDS. As shown in
Table 1, the reaction of (Z)-1a with 2a without palladium
catalyst did not give any substituted products (entry 1), and the
reactions of (Z)-1a by palladium acetate with PPh3 gave the
I
intermediates, and nucleophiles generally attack the terminal
carbon atom of the π-allyl group to produce the allylic alkylated
compounds.1 On the other hand, as an alternative reaction
process, nucleophilic attack at the central carbon atom of the π-
allyl moiety provides cyclopropane derivatives under the
appropriate reaction conditions.2 Furthermore, three groups
have discovered that the disubstituted products, in which
nucleophiles attack both the terminal and central carbon atoms
of the π-allyl palladium complex, were obtained from the
Table 1. Palladium Catalysts for the Alkylation of 1a with
a
2a
reaction of 2-haloallyl compounds.3−5 In 1995, Backvall
̈
reported the double alkylation of the 2-chloro-π-allyl palladium
complex with sodium dialkyl methylmalonate.3 The palladium-
catalyzed double etherification of 2,3-dibromo-1-propene with
sodium phenoxide was demonstrated by Organ’s group in
1997.4 They further succeeded in obtaining the doubly
alkylated product as a major product from the reaction with
malonate nucleophile, but the reaction required a catalytic
amount of phenoxide and detectable amount of doubly
substituted products by both the malonate and phenoxide
anions. Murai et al. also reported that the palladium-catalyzed
reaction of 2-chloroallyl compounds provides doubly sub-
stituted products with two different nucleophiles.5 Although
they previously discovered that the platinum catalyst gave a
doubly alkylated product with the malonate anion,6 to the best
our knowledge, there is no example of the selective formation
of the doubly alkylated product by palladium catalyst without
phenoxide. Furthermore, these examples of the double
substitution reactions were limited to the reaction of the 2-
bromo- or 2-chloroallyl compounds. However, during the
course of our study on the palladium-catalyzed allylic
substitutions of fluorine-contained allyl compounds,7 we
found that the double alkylation of 2-fluorocinnamyl acetate
with malonate nucleophiles proceeded through the carbon−
fluorine bond cleavage.8 We now report the [Pd(C3H5)(cod)]-
BF4/2,2′-bipyridine-catalyzed stereoselective double alkylation
of 3-aryl-2-fluoroallyl esters with malonate nucleophiles.
b
yield (%)
entry
[Pd] (mol %)
Pd(OAc)2 (10)
L (mol %)
3aa
4aa
1
0
0
0
97
44
52
<2
<2
<2
99
54
61
<2
12
41
2
PPh3 (20)
dppe (10)
dppp (10)
bpy (10)
3
Pd(OAc)2 (10)
22
18
34
46
52
0
4
Pd(OAc)2 (10)
5
Pd(OAc)2 (10)
6
Pd2(dba)3 (5)
bpy (10)
7
[PdCl(C3H5)]2 (5)
[Pd(C3H5)(cod)]BF4 (10)
[Pd(C3H5)(cod)]BF4 (10)
[Pd(C3H5)(cod)]BF4 (10)
[Pd(C3H5)(cod)]BF4 (10)
[Pd(C3H5)(cod)]BF4 (10)
Pd(dppp)2 (10)
bpy (10)
8
PPh3 (20)
dppe (10)
dppp (10)
bpy (10)
9
36
10
11
12
13
13
c
86 (90)
tmeda (10)
35
37
a
Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), [Pd] (5 or 10
mol %), L (10 or 20 mol %), LiHMDS (2.8 equiv, 1.0 M in THF),
b
c
dioxane (5.0 mL). The yields were determined by 1H NMR. Isolated
yield is shown in parentheses.
We initially examined the palladium-catalyzed allylic
alkylation of (Z)-2-fluoro-3-phenylallyl acetate ((Z)-1a) with
Received: November 21, 2013
Published: January 30, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
usual linear-type allylic alkylation product 4aa (entry 2).
However, when the phosphine ligand was changed from PPh3
to dppe or dppp, we detected the formation of the doubly
alkylated product (tetraester) (E)-3aa together with 4aa
(entries 3 and 4). The selective formation of the doubly
alkylated product (E)-3aa was attained using 2,2′-bipyridine
(bpy) as a ligand, but the yield was poor (entry 5). To improve
the yield of (E)-3aa, we screened several palladium precatalysts,
such as Pd2(dba)3, [PdCl(C3H5)]2, or [Pd (C3H5)(cod)]BF4.
The reactions using Pd2(dba)3 or [PdCl(C3H5)]2 with bpy gave
the desired product (E)-3aa in 46% and 52% yields,
respectively (entries 6 and 7). To our delight, the highest
yield (86% NMR yield, 90% isolated yield) was obtained by the
combination of [Pd(C3H5)(cod)]BF4 with bpy (entry 11). The
exact structure, including olefin geometry, of product (E)-3aa
was determined by an X-ray crystallographic analysis (Figure
1).9,10 We also examined the reaction using [Pd(C3H5)(cod)]-
Table 2. [Pd(cod)(C3H5)]BF4/bpy-Catalyzed Double
Alkylation of 1 with 2
a
entry
1
2
yield (%) of 3
1
2
3
4
1b
1c
1d
1e
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2c
2d
2e
2f
72 (3ba)
80 (3ca)
89 (3da)
37 (3ea)
78 (3ea)
67 (3fa)
80 (3ga)
10 (3ha)
b
5
6
7
1g
1h
1i
c
8
d
9
0 (3ia)
10
11
12
13
14
15
1j
76 (3ja)
69 (3ka)
60 (3la)
1k
1l
1m
1a
1a
1a’
1a’
1a’
1a
74 (3ma)
66 (3ab)
29 (3ac)
74 (3ac)
76 (3ad)
<10 (3ae)
0 (3af)
b
16
b
17
Figure 1. X-ray crystal structure of 3aa.
18
19
BF4/tmeda (N,N,N′,N′-tetramethylethylenediamine)3 or Pd-
(dppp)2,4 but both catalysts gave a mixture of 3aa and 4aa with
low yields (entries 12 and 13). We further confirmed that the
reaction of 2-chlorocinnamyl acetates (5) provide 7aa as a
major product and the reaction of 2-bromocinnamyl acetates
(6) did not gave any doubly alkylated product 3aa under
optimized conditions (Scheme 1).11 Those results indicate that
a
b
c
Isolated yield. 10 equiv of 2 was used. 4ha (61%) was obtained.
4ia (26%) was obtained.
d
Typically, the reaction was carried out as follows: 10 mol % of
[Pd(C3H5)(cod)]BF4, 10 mol % of bpy, allylic acetate 1,
malonic ester 2 (3.0 equiv), and LiHMDS (2.8 equiv) were
mixed in dioxane at 0 °C, and the reaction mixture was stirred
at 100 °C for 12 h. The reactions of the 3-aryl-2-fluoroallyl
acetates 1b−d, which contained electron-donating or -with-
drawing groups on the aromatic ring, smoothly proceeded and
gave the desired doubly alkylated product (3ba, 3ca, and 3da)
in good yield (entries 1−3). The o-tolyl-substituted 2-
fluoroallyl acetate 1e produced 3ea in poor yield (37%), but
an acceptable yield (78%) was obtained by increasing the
amount of methyl dimethylmalonate (2a) from 3 to 10 equiv
(entries 4 and 5). The reaction of the naphthyl-substituted allyl
acetates 1f and 1g also required an excess of nucleophiles to
obtain the desired products 3fa and 3ga in moderate to good
yield (entries 6 and 7). Unfortunately, the reaction of the alkyl-
substituted 2-fluoroallyl acetate 1h resulted in a 10% yield, the
monoalkylated linear type product 4ha was formed as a major
product (entry 8), and 1i did not provide any of the desired
doubly alkylated product (entry 9). On the other hand,
reactions of heteroaromatic-substituted acetates, such as 1k−m,
provided the desired products 3ka−ma over 60% yield (entries
Scheme 1. Palladium-Catalyzed Reaction of 2-Halocinnamyl
Acetates 5 and 6
the fluorine atom of 1a stabilizes positive charge at C-2 carbon
of the π-allylpalladium intermediate more strongly than
chlorine or bromine atom, and nucleophiles selectively attack
at the C-2 carbon bearing a fluorine atom.
We next investigated the [Pd(C3H5)(cod)]BF4/bpy-cata-
lyzed double alkylation of several 2-fluoroallyl esters with
malonate anions, and the results are summarized in Table 2.
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Organic Letters
Letter
11−13). As shown in entries 14−18, the reactions with other
malonic esters (4b−e) were also examined, and we confirmed
that the reaction with 2b, which has a methyl group on the α-
carbon of the malonic ester, gave the doubly alkylated product
3ab in 66% yield (entry 14). The reaction with a dialkyl
malonate, such as 2c, resulted in a low yield (29%) under the
optimized catalyst conditions (entry 15). However, changing
the leaving group of an allyl substrate from acetate (1a) to
methyl carbonate (1a′) and using a large excess (10 equiv) of
dialkyl malonate effectively improved the yield of the desired
doubly alkylated product 3ac to 74% yield (entry 16). The
reaction with diethyl malonate (2d) also smoothly proceeded
(entry 17), but the reaction with di-tert-butyl malonate (2e)
resulted in a low yield (entry 18). We also examined the
reaction with ethyl acetoacetate (2f), but the reaction gave
furan derivatives5,6,13 in 78% yield instead of doubly alkylated
product (entry 19).
Scheme 2. Proposed Reaction Mechanism
We further examined the reaction of (E)-2-fluoro-3-phenyl-
allyl acetate ((E)-1a) and 2-fluoro-1-phenylallyl acetate (9)
with the anion of 2a. The reaction of (E)-1a produced (E)-3aa,
which is the same product from the reaction of (Z)-1a, but the
yield was slightly lower (eq 1). Again, changing the leaving
III due to the steric repulsion between two the substituents on
the C-1 and C-2 carbons of the π-allyl group. Finally, a second
nucleophile attacks the C-3 carbon of the anti-III to produce
the doubly alkylated product (E)-3.
In summary, we have demonstrated the palladium-catalyzed
alkylation of 3-aryl-2-fluorinated allyl esters with malonate
nucleophiles and found that 2 equiv of malonate nucleophiles
were introduced to the allyl substrate through the carbon−
fluorine bond cleavage. Reaction results of three regioisomeric
2-fluorinated allyl esters suggest that the reaction proceeded via
same reaction intermediates, such as 2-fluoro-π-allylpalladium,
palladacyclobutane, and 2-alkylated-π-allylpalladium. Further
studies to reveal the details of the reaction mechanism, and
reaction with other fluorinated allyl substrates and nucleophiles
are in progress.
group from acetate to methyl carbonate effectively increased
the yield to 69%, and the acetate 9 also afforded (E)-3aa in 84%
yield (eq 2). The fact that the same doubly alkylated product
was obtained in the reaction of the 2-fluoroallyl esters (E)-1,
(Z)-1 and 9 suggests that the reaction proceeds through the
same reaction intermediate, which is likely to be a 2-fluoro-π-
allyl palladium complex. Unfortunately, our several trials for
observing and/or isolating the 2-fluoro-π-allyl complexes failed,
and the details of the reaction mechanism have not yet been
clarified. However, we currently believe that the reaction
proceed with a similar pathway as the reported for the double
substitution reaction of the 2-bromo- or 2-chloroallyl esters.3−5
Based on these observations and in accordance with previous
reports, we propose a possible reaction mechanism in Scheme
2. The 2-fluoro-π-allylpalladium intermediate resulting from
(Z)-1 should be syn-2-fluoro-π-allylpalladium (syn-I), which
contains the aromatic substituent at the syn position with
respect to the fluorine atom at the 2 position of the π-allyl
group. On the other hand, (E)-1 selectively forms anti-I, and 9
forms both syn-I and anti-I in a certain ratio,14 with the
sterically more stable syn-I being predominant. After the
isomerization from anti-I to the thermodynamically more stable
syn-I occurred, the nucleophile first attacks at the central carbon
atom of the π-allyl moiety and provides palladacyclobutane
II2−5,12 followed by the C−F bond cleavage, which affords the
2-alkylated π-allypalladium complex III. In the palladium
complex III, anti-III is assumed to be more stable than syn-
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, characterization data, and X-ray crystallo-
graphic data (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: kawatsur@chs.nihon-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Japan Society for the Promotion of
Science.
REFERENCES
■
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1
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