Palladium-catalyzed arylation of α,α-difluoro-allylic-β-hydroxyester

Article abstract of DOI:10.1016/j.tetlet.2006.09.111

The aryl-substituted α,α-difluoro-allylic-β-hydroxyesters and aryl-substituted α,α-difluoroketones were obtained via the coupling reaction of aryl iodides with α,α-difluoro-allylic-β-hydroxyester in the presence of Pd(OAc)₂ as the catalyst and Et₃N as the base.

Full text of DOI:10.1016/j.tetlet.2006.09.111

Tetrahedron Letters 47 (2006) 8231–8234
Palladium-catalyzed arylation of
a,a-difluoro-allylic-b-hydroxyester
a
a
a
a
Xiang Fang, Xueyan Yang, Xianjin Yang, Min Zhao,
a
a,b,
*
Guorong Chen and Fanhong Wu
a
School of Chemistry and Molecular Engineering, East China University of Science and Technology,
30 Meilong Road, Shanghai 200237, China
1
b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Received 26 June 2006; revised 21 September 2006; accepted 22 September 2006
Available online 10 October 2006
Abstract—The aryl-substituted a,a-difluoro-allylic-b-hydroxyesters and aryl-substituted a,a-difluoroketones were obtained via the
coupling reaction of aryl iodides with a,a-difluoro-allylic-b-hydroxyester in the presence of Pd(OAc) as the catalyst and Et N as the
2 3
base.
ꢀ
2006 Elsevier Ltd. All rights reserved.
The formation of carbon–carbon bond at unsubstituted
vinylic positions by the palladium-catalyzed coupling
reaction of aryl or vinyl halides with alkenes, known
as the Heck reaction, has become a powerful tool in
It provides the organic chemists with an opportunity
to study an extreme case of electronic effect in organic
6
,7
reactions. To the best of our knowledge, the palla-
dium-catalyzed arylation of a,a-difluoro-allylic-b-
hydroxyester is unprecedented. Herein, we wish to
report a Heck reaction in which a strongly electron-with-
drawing a,a-difluoroester group coordinates Pd(II) to
afford the corresponding aryl-substituted a,a-difluoro-
allylic-b-hydroxyesters and aryl-substituted a,a-
difluoroketones.
1
organic chemistry. Palladium-catalyzed arylation of
allylic alcohols with aromatic halides is a convenient
synthetic method of aromatic-substituted alkyl alde-
2
3
hydes and ketones. Jeffery reported that a highly selec-
tive formation of conjugated aromatic allylic alcohols
was achieved from aromatic halides and allylic alcohols
in the presence of silver salt, the alteration of the reac-
tion course was rationalized by assuming a four-mem-
To compare the influence of the difluoromethylene
group, the a,a-difluoro-allylic-b-hydroxyester 2a and
its non-fluorinated analogue 2b were obtained by using
the Reformastsky reactions of ethyl bromodifluoro-
acetate 1a and its non-fluorinated analogue 1b with
propenal (Scheme 1). Both of the two-step procedure
4
bered intermediate. Tamaru also utilized o-substituted
allylic alcohols to coordinate Pd(II) forming a six-mem-
bered intermediate without the elimination of proton
5
adjacent to oxygen-bearing carbon. Kang found that
the arylation of allylic diols could be highly controlled
by the choice of base in the presence of similar reaction
system. On the other hand, it is well known that the bio-
logical properties can often be influenced by the intro-
8
reported by Fried and the modified Reformatsky reac-
9
tion presented by Shen led successfully to 2 in high
yields as expected.
6
duction of fluorine atoms. The physical properties of
several electronic and optical devices also depend
immensely on the structure of fluoroorganic molecules.
O
7
OH
R
O
R
Zn
R
OC H
+
CHO
2
5
OC H
2 5
THF
Br
R
Keywords: a,a-Difluoro-allylic-b-hydroxyester; Heck reaction; Aryl-
substituted a,a-difluoro ketones.
Corresponding author. Tel.: +86 21 64253530; e-mail addresses:
fang_xiang@sohu.com; wfh@ecust.edu.cn
1
a: R=F
2a: R=F
b: R=H
b: R=H
*
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.111

8232
X. Fang et al. / Tetrahedron Letters 47 (2006) 8231–8234
By a careful, systematic examination of the influence of
a variety of catalysts, such as PdCl (PPh ) , Pd(OAc)
2
2-iodobenzoate, only the difluoro-substituted cinnamyl
alcohol 5g was obtained, the coupling product 7g was
not found due to the influence of the steric factor (Table
1, entry 7). In the case of strong electron-deficient aryl
iodides, no desired product 5 was formed, only the cou-
pling product 7a was obtained instead (Table 1, entry 1).
When 2a reacted with aryl iodides bearing electron-
donating substituents, a mixture of cinnamyl alcohols
5 and a,a-difluoro ketones 6 was formed. For example,
in the reaction of 3d, the major product, difluoro-substi-
tuted cinnamyl alcohol 5d was separated in a 46% yield,
ketone 6d was detected instead of the minor intermedi-
ate, 2,2-difluoro-3-oxo-5-arylpentanoic acid ethyl ester
C, which was unstable and decomposed at a high tem-
2
3 2
and Pd(OAc)2 with ligands (PPh ); bases, such as
3
K CO , NaHCO , Ag CO , Et N and piperidine, and
2
3
3
2
3
3
also the reaction temperature, the optimal reaction
condition was found for the formation of the desired
cinnamyl alcohol and alkyl ketone derivatives to be
1
equiv of aryl iodide 3, 1.5 equiv of a,a-difluoro-
allylic-b-hydroxyester 2a, 0.05 equiv of Pd(OAc) and
2
4
1
.5 equiv of Et N at 80 ꢁC in DMF for 48 h. Tamaru
3
mentioned that 10 equiv of aryl iodides were important
to attain a satisfactory yield, but aryl iodides were very
expensive. Jeffery3 used 2–3 equiv of allylic alcohol.
However, the polarity of the product cinnamyl alcohol
was close to that of the starting substance, so it was dif-
ficult to isolate the product by column chromatography.
a
1
1
perature (Table 1, entry 3). The detailed results for
the arylation of a,a-difluoro-allylic-b-hydroxyester are
1
2
summarized in Table 1.
The bases showed an important effect on the reaction.
When K CO was used in a blank experiment, 2a disap-
In contrast, the reactions of non-fluorinated 2b were
tried. In the case of methyl 4-iodobenzoate, the result
was similar and major product 8b was obtained along
with coupling product 7b (Table 2, entry 1). Some re-
sults were quite different from those of 2a. For example,
iodobenzene 3e reacted with 2a to give only one prod-
uct, cinnamyl alcohol 5e (Table 1, entry 5), but when
3e reacted with 2b, the mixture of cinnamyl alcohol 8e
and keto-ester 9e was afforded under similar reaction
conditions (Table 2, entry 2). Compound 8f and keto-
ester 9f were also obtained in the reaction of 2b with
3f (Table 2, entry 3).
2
3
peared after 48 h. Because K CO might be a stronger
2
3
5
base than Et N in refluxing DMF, 2a was largely de-
3
1
0
stroyed due to alkaline hydrolysis. Best results were
obtained when Et N was used as the base.
3
Under the optimal reaction condition, iodobenzene 3e
reacted with 2a catalyzed by Pd(OAc) to give the corre-
2
sponding cinnamyl alcohol 5e in a 72% yield (Table 1,
entry 5). In the reactions of the aryl iodides bearing
the weak electron-withdrawing substituents, the prod-
ucts were cinnamyl alcohols 5 and coupling products
7
. For example, the major difluoro-substituted cinnamyl
alcohol 5b and the minor coupling product 7b were
obtained in 57% and 19% yields, respectively, in the
reaction of 2a with 3b (Table 1, entry 2). For methyl
Under similar conditions, 2-iodothiophene 3h reacted
with 2a to give the difluoro-substituted allylic alcohol
5h and coupling product 7h in 51% and 26% yields,
Table 1. Palladium-catalyzed arylation of a,a-difluoro-allylic-b-hydroxyester 2a
O
OH
O
I
H
F
Pd(OAc)
2
3
/ Et N
O
+
+
2a
DMF
F
F
F
R
1
R
2
R1
R2
R
1
R
2
3
5
6
R
2
R
1
+
R
1
R
2
7
a
b
b
b
Entry
R
1
R
2
Conversion (%)
Yield of 5 (%)
Yield of 6 (%)
Yield of 7 (%)
c
d
1
2
3
4
5
6
7
NO
COOCH
CH
2
H (3a)
H (3b)
H (3c)
H (3d)
H (3e)
0
0
57 (5b)
52 (5c)
46 (5d)
72 (5e)
50 (5f)
45 (5g)
0
0
46 (7a)
3
83
86
81
92
84
69
19 (7b)
3
24 (6c)
29 (6d)
0
27 (6f)
0
0
0
0
0
0
OCH
H
3
H
H
CH
3
(3f)
COOCH (3g)
3
a
b
c
Conversion determined by GC.
Isolated yield.
GC showed 2a did not decrease.
The reaction at 80 ꢁC for 24 h.
d

X. Fang et al. / Tetrahedron Letters 47 (2006) 8231–8234
8233
Table 2. Palladium-catalyzed arylation of allylic-b-hydroxyester 2b
OH
O
O
O
I
Pd(OAc)
2
3
/ Et N
O
O
+
2b
+
DMF
R
1
R
2
R1
R2
R
1
R
2
3
8
9
R
2
R
1
+
R
1
R
2
7
a
b
b
b
Entry
R
1
R
2
Conversion (%)
Yield of 7 (%)
Yield of 8 (%)
Yield of 9 (%)
1
2
3
COOCH
H
H
3
H (3b)
H (3e)
CH (3f)
3
79
87
82
20 (7b)
0
0
53 (8b)
33 (8e)
27 (8f)
0
38 (9e)
23 (9f)
a
Conversion determined by GC.
Isolated yield.
b
OH
O
S
Pd(OAc)
/ Et N
S
S
S
2
3
O
+
I + 2a
DMF
F
F
3
h
5h
7h
Scheme 2.
respectively (Scheme 2). Besides the two-molecule cou-
pling product, four and six-molecule coupling products
were detected in the mass spectrometry. The reason
might be that the coupling reaction of 3h occurred eas-
ily. When 2-iodothiophene reacted with 2b, the products
were complicated.
tionality, which can be explained by the simultaneous
coordination of palladium with two oxygens (intermedi-
ate A), or the chelation of ester group to palladium
intermediate B. when R = F, intermediate B is more
stable than A for the strongly electron-withdrawing
a,a-difluoroester group to coordinate Pd(II) forming a
six-membered intermediate, intermediate B might be
unfavorable for syn palladium hydride elimination of
the hydrogen on the hydroxy-bearing carbon atom,
resulting in the formation of 5e rather than C; while
R = H, both intermediates A and B can exist, palladium
hydride elimination of the hydrogen on the exocyclic
phenyl-bearing methylene carbon would give 8e and
elimination of the hydrogen on the endocyclic hydr-
oxy-bearing carbon could give 9e (Fig. 1). Electron-
donating groups on the phenyl ring might decrease the
chelation of difluoroester, the equilibrium could increase
intermediate A, which would afford major products
cinnamyl alcohols 5 and the minor products a,a-difluoro
ketones 6. Electron-withdrawing groups on the phenyl
ring might increase the chelation of difluoroester, so
no products 6 were found.
A plausible mechanism for the difference between the
reactions of a,a-difluoro-allylic-b-hydroxyester 2a and
its non-fluorinated analogue 2b with iodobenzene 3e is
illustrated in Figure 1. Werner has shown that in the
presence of the strongly electron-withdrawing poly-
fluoroalkyl group, ketone was formed as the major
1
3
product along with the minor cinnamyl alcohol. We
presume that there is an important role of the ester func-
O
R
OH
R
O
O
H*
H
O
R
-
Pd
H
H
O
Pd
R
I
Ph
I
H
H
H*
B
Ph
In summary, the aryl-substituted a,a-difluoro-allylic-b-
hydroxyesters and aryl-substituted a,a-difluoroketones
were obtained via the coupling reaction of aryl iodides
with a,a-difluoro-allylic-b-hydroxyester in the presence
A
OH
O
O
O
of Pd(OAc) as the catalyst and Et N as the base in a
Ph
O
2
3
Ph
O
R
R
moderate yield under mild conditions. A plausible mech-
anism for the formation of a,a-difluoro-allylic-b-
hydroxyester 2a and its non-fluorinated analogue 2b
was proposed.
R
R
C, 9
5, 8
*
Figure 1. (H is favorable for syn b-elimination).

8234
X. Fang et al. / Tetrahedron Letters 47 (2006) 8231–8234
Acknowledgement
Series 746; American Chemical Society: Washington, DC,
000; For a review on the effect of fluorine on OH, NH,
2
and CH acidities, see (b) Schloser, M. Angew. Chem., Int.
Ed. 1998, 37, 1497.
. Fried, J.; Hallinan, E. A. Tetrahedron Lett. 1984, 25, 2301.
. Shen, Y.; Qi, M. J. Fluorine Chem. 1994, 67, 229.
This research work was supported by the National Nat-
ural Science Foundation of China and Shanghai Science
and Technology Committee (03QB14012).
8
9
1
1
1
0. Ocampo, R.; Dolbier, W. R.; Abboud, K. A.; Zuluaga, F.
J. Org. Chem. 2002, 67, 72.
1. Mcbee, E. T.; Pierce, O. R.; Kilbourne, H. W.; Wilson, E.
R. J. Am. Chem. Soc. 1953, 75, 3152.
2. Typical procedure: Under an inert atmosphere, palladium
acetate (11 mg; 0.05 mmol) was added to a solution of a,a-
difluoro-b-hydroxyester (270 mg; 1.5 mmol), p-methoxy-
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2
006.09.111.
iodobenzene (234 mg; 1 mmol) and Et N (152 mg;
3
1
.5 mmol) in dry N,N-dimethylformamide (2 mL). The
References and notes
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reaction mixture was stirred vigorously at 80 ꢁC for 48 h.
The reaction mixture was then cooled to room tempera-
ture and diluted with ethyl acetate (5 mL) and water
(10 mL). The organic layer was separated, the aqueous
layer was extracted with ethyl acetate (10 mL · 3) and the
organic layers were combined, washed with water and then
1
2379; (e) Oh, C.-H.; Jung, S.-H.; Bang, S.-Y.; Park, D.-I.
dried over anhydrous Na SO . After concentrated under
2 4
Org. Lett. 2002, 4, 3325.
. (a) Melpolder, J. B.; Heck, R. F. J. Org. Chem. 1976, 41,
reduced pressure, the residue was chromatographed on
silica gel eluting with petroleum ether–ethyl acetate (5:1)
2
2
65; (b) Frank, W. C.; Kim, Y. C.; Heck, R. F. J. Org.
to give 5d (107 mg) in 46% yield and 6d (50 mg) in 29%
1
Chem. 1978, 43, 2947; (c) Tamaru, Y.; Yamada, Y.;
Yoshida, Z.-i. J. Org. Chem. 1978, 43, 3396; (d) Tamaru,
Y.; Yamada, Y.; Yoshida, Z. Tetrahedron 1979, 35, 329;
yield. For 5d: H NMR (CDCl
3
, 500 MHz): d 1.25 (t, 3H,
J = 7.1 Hz), 2.61 (br, 1H), 3.73 (s, 3H), 4.27 (q, 2H, J =
7.1 Hz), 4.61–4.64 (m, 1H), 6.01 (dd, 1H, J = 7.1 Hz, J =
15.9 Hz), 6.65 (d, 1H, J = 15.9 Hz), 6.79 (d, 2H,
(
(
e) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287;
f) Benhaddou, R.; Czernecki, S.; Ville, G. J. Chem. Soc.,
1
9
3
J = 8.6 Hz), 7.26 (d, 2H, J = 8.6 Hz). F NMR (CDCl ,
Chem. Commun. 1988, 247; (g) Bouquillon, S.; Ganchegui,
B.; Estrine, B.; Henin, F.; Muzart, J. J. Organomet. Chem.
470 MHz): d À121.9 (dd, 1F, JF–F = 258.5 Hz, JH–F
F–F = 258.5 Hz, J
H–F
9.4 Hz). C NMR (CDCl3, 125.8 MHz): d 14.6, 56, 63.8,
73.8 (t, J = 26.5 Hz), 114.6 (t, J = 256.4 Hz), 114.8, 114.8,
119.8, 128.8, 128.8, 129.1, 136.3, 160.6, 164.1 (t, J =
=
=
14.1 Hz), À115.8 (dd, 1F,
J
1
3
2001, 634, 153.
3
. (a) Jeffery, T. Tetrahedron Lett. 1991, 32, 2121; (b) Jeffery,
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. For recent reviews see: Biomedical Frontiers of Fluorine
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ACS Symposium Series 639; American Chemical Society:
Washington, DC, 1996.
31.6 Hz). HRMS: calcd for
found: 286.1017. For 6d: H NMR (CDCl , 500 MHz): d
C
H
F
O
:
286.1017,
14
16
2
4
1
4
5
6
3
2.81 (d, 2H, J = 6.8 Hz), 2.86 (d, 2H, J = 6.8 Hz), 3.69 (s,
3H), 5.57 (t, 1H, J = 53.9 Hz), 6.74 (d, 2H, J = 7.3 Hz),
1
9
7.02 (d, 2H, J = 7.3 Hz). F NMR (CDCl
, 470 MHz): d
3
1
3
À128.5 (d, 2F, JH–F = 51.7 Hz).
C NMR (CDCl
3
125.8 MHz): d 28.2, 38.7, 55.9, 110.5 (t, J = 252.9 Hz),
114.7, 114.7, 129.9, 129.9, 132.6, 158.9, 199.6 (t,
J = 26.2 Hz). HRMS: calcd for C11H F O : 214.0805,
12 2 2
7
. (a) For recent reviews see: Asymmetric Fluoro organic
Chemistry, Ramachandran, P. V., Ed.; ACS Symposium
found: 214.0804.
13. Werner, K. V. J. Organomet. Chem. 1977, 136, 385.