Ligand-free Pd-catalyzed highly selective arylation of allylic esters with retention of the traditional leaving group

Article abstract of DOI:10.1002/anie.200800966

(Chemical Equation Presented) What leaving group? Organic halides and allylic esters undergo efficient Pd-catalyzed Heck reactions under mild conditions in air to form a new C-C bond without elimination of the β-OAc group in the intermediate palladium complex. Instead a highly regioselective β-H elimination takes place to provide substituted derivatives of allylic alcohols (see scheme).

Full text of DOI:10.1002/anie.200800966

Angewandte
Chemie
DOI: 10.1002/anie.200800966
Heck Reaction
Ligand-Free Pd-Catalyzed Highly Selective Arylation of Allylic Esters
with Retention of the Traditional Leaving Group**
Delin Pan, Anjun Chen, Yijin Su, Wang Zhou, Si Li, Wei Jia, Juan Xiao, Qingjian Liu,
Liangren Zhang, and Ning Jiao*
The Heck reaction[1] has been studied in detail as a powerful
Lautens and co-workers developed a reductive coupling of
allylic acetates that involves b-OAc elimination (Scheme 1,
path c).[11] Although products formed through b-H elimina-
tion were observed by Lautens and co-workers and oth-
ers,[11b,12] they were produced in low yield with low selectivity.
We now demonstrate an efficient and highly selective Heck
reaction of organic halides with allylic esters by avoiding
b-acetate (Scheme 1, path d) or b-carbonate elimination. The
resulting substituted allylic esters are amenable to further
functional-group transformations.
Our initial efforts focused on the Heck reaction between
PhI (1a) and allyl acetate (2a). Only a trace amount of the
expected product 3a was formed when 1a and 2a were
treated with [Pd(PPh3)4] (5 mol%; Table 1, entry 1). How-
ever, (E)-3a was produced in 7% yield when Pd(OAc)2 was
[2]
À
tool for the construction of C C bonds in organic synthesis.
Over the past several decades, the scope of the Heck reaction
has been expanded significantly to include aryl chlorides[3]
and tosylates,[4] alkyl halides,[5] and arenes (through C H
À
activation) as suitable substrates.[6] The Heck reaction can
also be carried out regioselectively with electron-rich ole-
fins.[7] However, Pd-catalyzed Heck reactions between
organic halides and allylic esters have not been well
developed. Such reactions are challenging from a mechanistic
point of view for two reasons: 1) The allylic ester could
À
readily undergo C O cleavage through oxidative addition to
Pd0 to form a p-allyl palladium species (Scheme 1, path a),
Table 1: Unexpected Pd-catalyzed Heck reaction between iodobenzene
(1a) and allyl acetate (2a).[a,b]
Entry Catalyst
Additive(s)
(equiv)
Base[c] Solvent
t
Yield
[h] [%]
1
2
3
4
5
6
7
[Pd(PPh3)4]
K2CO3 benzene 48 trace
K2CO3 benzene 48 trace
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3 DMF[d]
15
12
7
55
94
82
35
67
18
Scheme 1. Competitive processes in the Pd-catalyzed reaction of
iodobenzene and allyl acetate.
Ag2CO3 (0.6)
Ag2CO3 (0.6)
Ag2CO3 (1.0)
Ag2CO3 (0.2)
Ag2CO3 (0.6)
Ag2CO3 (2.0)
DMF[d]
benzene 10
benzene 10
benzene 48
which is the key intermediate in the Tsuji–Trost reaction.[8,9]
This process competes with the desired oxidative addition of
an aryl halide to Pd0 (Scheme 1, path b). 2) After the insertion
in path b, b-OAc elimination[10] (Scheme 1, path c) competes
with the desired b-hydride elimination (Scheme 1, path d).
8[e]
9[e]
toluene
toluene
24
24
10[e]
Pd(OAc)2
PPh3
Ag2CO3 (0.6)
toluene
24
10
11[e]
12[e]
13[e]
14[e,f]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ag2CO3 (0.6) K2CO3 toluene
24
24
16
24
<5
0
35
32
[*] D. Pan, Y. Su, W. Zhou, S. Li, W. Jia, J. Xiao, Dr. L. Zhang, Dr. N. Jiao
State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences, Peking University
Xue Yuan Road 38, Beijing 100083 (China)
Fax: (+86)10-8280-5297
AgNO3 (1.2)
AgNO3 (1.2)
Ag2CO3 (0.6)
toluene
K2CO3 toluene
toluene
15[e,f]
Pd(OAc)2
Ag2CO3 (0.6)
H2O (4.0)
toluene
16
76
E-mail: jiaoning@bjmu.edu.cn
A. Chen, Dr. Q. Liu
Department of Chemistry, Shandong Normal University
Jinan 250014 (China)
[a] Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Pd(OAc)2
(0.025 mmol), solvent (3 mL), reflux in air. [b] Trace amounts of di-
and triphenylated products were observed for some reactions. [c] The
amount of K2CO3 used (when applicable) was 2.0 equivalents. [d] The
reaction was carried out at 1208C; DMF=N,N-dimethylformamide.
[e] PhBr (1b, 1.0 mmol) and 2a (0.5 mmol) were used as the substrates;
the reaction mixture was heated at reflux in toluene. [f] The reaction was
carried out under N2.
[**] Financial support from Peking University and the National Science
Foundation of China (No. 20742001 and No. 20702002) is greatly
appreciated.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Pd-catalyzed Heck reaction of allyl acetate (2a) with different organic halides.[a]
used as the catalyst in DMF at
1208C (Table 1, entry 3), and the
presence of Ag2CO3 in the absence
of another base led to a dramatic
improvement in the yield to 55%
(Table 1, entry 4). It seems that
Entry
1
Yield [%]
Entry
1
Yield [%]
1
2
PhI (1a)
94/(E)-3a
98/(E)-3b
86/(E)-3c
80/(E)-3d
81/(E)-3e
80/(E)-3 f
79/(E)-3g
82/(E)-3h
10[c]
11[c]
12[d,e]
13[d,f]
14
PhBr (1b)
65/(E)-3a
71/(E)-3c
65/(E)-3d
62/(E)-3e
75/(E)-3j
Ag2CO3 serves not only as
a
4-Me-C6H4-I (1c)
2-Me-C6H4-I (1d)
4-CO2Me-C6H4-I (1e)
4-NO2-C6H4-I (1 f)
4-F-C6H4-I (1g)
4-Ph-C6H4-I (1h)
4-MeCO-C6H4-I (1i)
2-Me-C6H4-Br (1k)
4-CO2Me-C6H4-Br (1l)
4-NO2-C6H4-Br (1m)
source of silver to scavenge the
halide,[13] but also as a base. Allyl-
benzene, the product of b-OAc
elimination, was not observed in
these reactions.
Further investigations indi-
cated that the desired product was
formed in the highest yield with
only 0.6 equivalents of Ag2CO3 in
the absence of an additional base
and a ligand. The yields decreased
with a higher or lower concentra-
3[b]
4
5
6
7
8
15[g]
55/(E)-3k
60/(E)-3i
9[b]
4-OMe-C6H4-I (1j)
81/(E)-3i
16[g]
[a] Reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), Pd(OAc)2 (0.025 mmol), Ag2CO3 (0.3 mmol),
benzene (3 mL), reflux in air. [b] The reaction mixture was heated at reflux in toluene. [c] The reaction
mixture was heated at reflux in toluene (1: 0.6 mmol; 2a: 0.5 mmol). [d] The reaction mixture was
heated at reflux in toluene (2a: 3.0 equiv). [e] Some of the starting material 1l (7%) was recovered.
[f] Some of the starting material 1m (19%) was recovered. [g] The amount of 2a used was
3.0 equivalents.
tion
of
Ag2CO3
(compare
entries 5–7 and entries 8 and 9 of
Table 1). An additional base
greatly inhibited the reaction
(compare entries 8 and 11 of
Table 1 and see the Supporting Information). In contrast, no
product was observed when other silver salts, such as AgNO3,
were used in the absence of an additional base (Table 1,
entry 12). However, (E)-3a was produced in 35% yield when
AgNO3 was used together with K2CO3 (2.0 equiv; compare
entries 12 and 13 of Table 1).
A series of substituted allylic acetates 2 were investigated
as substrates (Table 3). Certain allylic acetates substituted at
the 1- or 2-position were found to be viable for the
Table 3: Pd-catalyzed Heck reaction of aryl iodides 1 with substituted
allylic acetates 2.[a]
The yield of (E)-3a decreased to 10% in the presence of
PPh3 (20 mol%; Table 1, entry 10). With other ligands, such as
dppe, the yield was even lower (see the Supporting Informa-
tion). Surprisingly, (E)-3a was obtained in only 32% yield
when the reaction was carried out in toluene under N2
(compare entries 8 and 14 of Table 1). The presence of
water (4.0 equiv) led to a dramatic improvement in the yield
of (E)-3a to 76% (compare entries 14 and 15 of Table 1).
Pd(OAc)2 was more effective than other palladium catalysts,
such as PdCl2 and Pd(O2CCF3)2 (see the Supporting Infor-
mation). After extensive screening of the other reaction
parameters (see the Supporting Information), we concluded
that the reaction proceeded most efficiently in the presence of
Pd(OAc)2 (5 mol%) and Ag2CO3 (0.6 equiv) and in the
absence of a ligand at refluxin benzene (Table 1, entry 5), or
in toluene in air when bromobenzene (1b) was used as the
substrate.
Entry
Ar (1)
2
R1
R2
t [h]
Yield [%]
1
2
3
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
4-NO2-C6H4 (1 f)
4-NO2-C6H4 (1 f)
2b
2c
2d
2e
2 f
2g
2e
Me
Et
iPr
Ph
H
H
H
H
H
Me
Ph
H
12
10
10
15
15
12
12
45/(E)-3m
87/(E)-3n
98/(E)-3o
80/(E)-3p
73[c]/3q
4[b]
5
6
7
H
Ph
92[d]/3r
87/(E)-3s
[a] Reaction conditions:
1 (0.5 mmol), 2 (1.0 mmol), Pd(OAc)2
(0.025 mmol), Ag2CO3 (0.3 mmol), benzene (3 mL), reflux in air.
[b] The amount of 1a used was 2.0 mmol; the amount of 2e used was
1.05 equivalents. [c] (E)-3q/(Z)-3q 80:20. [d] (E)-3r/(Z)-3r 19:81.
The scope of the Heck reaction was expanded to a variety
of organic halide substrates (Table 2). Substituted E-allylic
acetates (E)-3 were formed with high stereoselectivity in
these reactions. Reactions of aryl iodides with electron-
withdrawing or electron-donating groups proceeded effi-
ciently (Table 2, entries 2–9; 79–98%). The heterocyclic
iodide 2-iodothiophene (1n) was coupled with 2a to give
(E)-3j in 75% yield (Table 2, entry 14). Even vinyl iodides
reacted well with 2a to give the desired products in moderate
yields (Table 2, entries 15 and 16). The wide applicability of
this reaction is also demonstrated by the good reactivity of
aryl bromide substrates (Table 2, entries 10–13).
stereoselective construction of aryl-substituted E-allylic ace-
tates (E)-3 in good yields (Table 3, entries 2–7). When the
2-position of the substrate was substituted, the E/Z selectivity
decreased as a result of steric hindrance (Table 3, entries 5
and 6).
The allylic acetate 2h, in which the 3-position is substi-
tuted, reacted with 1a to give 3t and 4 in 65% combined yield
[3t/4 12:88; Eq. (1)].
These results inspired us to consider allylic substrates with
other leaving groups. We were pleased to find that even the
Heck reaction of relatively active allyl methyl carbonate (5)
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128.0, 126.6, 123.1, 65.1, 21.0 ppm; MS (70 eV): m/z (%): 176.2 (17)
[M+], 43 (100).
Received: February 28, 2008
Published online: May 19, 2008
Keywords: allylic compounds · Heck reaction · palladium ·
.
regioselectivity · silver
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À
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;
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4732
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