A one-pot palladium-catalyzed allylic alkylation and wittig reaction of phosphorus ylides

Article abstract of DOI:10.1002/chem.201000316

(Chemical equation presented) Put a(n) (y)lid(e) on it! The one-pot palladium-catalyzed allylic alkylation and Wittig reaction of phosphorus ylides with various aldehydes and ketenes has been realized, which produce skipped dienes, including trisubstituted alkenes and tetrasubstituted allenes, respectively (see scheme), in moderate to good overall yields.

Full text of DOI:10.1002/chem.201000316

DOI: 10.1002/chem.201000316
A One-Pot Palladium-Catalyzed Allylic Alkylation and Wittig Reaction of
Phosphorus Ylides
Wen-Bo Liu, Hu He, Li-Xin Dai, and Shu-Li You*[a]
Stabilized phosphorus ylides (P-ylides) are used extensive-
ly in organic synthesis, particularly since the discovery of the
Wittig reaction.[1] In addition to their reactions with carbon-
yl compounds,[2] P-ylides are used in Michael additions and
alkylation reactions, in which they act as nucleophiles.[3] An
elegant study by Chen and co-workers recently demonstrat-
ed that P-ylides can be used in an organocatalytic Mannich-
type process that, following a Wittig reaction, affords aza-
Morita–Baylis–Hillman products.[4] However, in general, the
utilization of P-ylides as nucleophiles in alkylation reactions
has been scarcely explored. To our knowledge, there are no
reports of the use of P-ylides as nucleophiles in Pd-catalyzed
Scheme 1. Possible pathway of the one-pot Tsuji–Trost/Wittig reaction.
allylic alkylation reactions (Tsuji–Trost reactions) despite
these being widely recognized as one of the most important
reactions in organic synthesis;[5] all previous reports on P-
ylides with transition-metals have been coordination stud-
ies.[6] The strong binding ability of P-ylides with transition
metals will likely impede their use in transition-metal-cata-
lyzed reactions. However, as part of our ongoing efforts in
the development of transition-metal-catalyzed allylic substi-
tution reactions,[7] we recently found that P-ylides are suita-
ble nucleophiles in Pd-catalyzed allylic alkylation reactions
which occur via functionalized P-ylide intermediates. This
intermediate then undergoes a Wittig reaction in a novel re-
action pathway (Scheme 1).[8] In this paper, we report the
results of such a one-pot reaction.
and 1,2-bis(diphenylphosphino)ethane (dppe; 11 mol%).
After all of the starting material (2b) had disappeared, an
excess of formalin was added and the mixture was stirred
for a further 24 h. To our delight, the desired product 4ab
was obtained in 30% yield (entry 1, Table 1). Encouraged
by this result, we examined a series of phosphine ligands,
such as 1,3-bis(diphenylphosphino)propane (dppp), 1,1’-bis-
(diphenylphosphino)ferrocene (dppf), 1,4-bis(diphenylphos-
phino)butane (dppb), PPh3, and PACTHNURTGENNG(U OPh)3.
Interestingly, the Trost ligand, L1, was found to provide
the optimal conditions, affording 4ab in 57% yield under
otherwise identical conditions (entry 7, Table 1). Further op-
timization of the conditions revealed that the reaction in di-
oxane at reflux gives the best yield (79%, entry 8,
Table 1).[9] Notably, intermediate 3 can be isolated in 33%
yield prior to the quenching with formalin, which provides
evidence for the reaction pathway proposed in Scheme 1.[9]
Under these optimized reaction conditions, the scope of
this one-pot Tsuji–Trost/Wittig reaction was investigated
with various P-ylides, allylic carbonates, and aldehydes, as
summarized in Table 2. Interestingly, both cinnamyl methyl
carbonate (2a) and methyl 1-(phenylallyl) carbonate (2’a)
led to the same, linear, product, 4aa, indicating that the p-
allyl–palladium intermediate shown in Scheme 1 is involved
in both cases (entries 1 and 2, Table 2). The reactions of
allyl carbonates containing para-, meta-, or ortho-methoxy-
phenyl groups (2b–d) occurred smoothly and gave the de-
sired products (4ab–ad) in 46–79% yields (entries 3–5,
We began our study by carrying out the reaction of P-
ylide 1a (1.5 equiv) with allyl carbonate 2b and Cs2CO3
(1.5 equiv) in THF, which was heated at reflux, utilizing the
catalyst generated in situ from [{PdACHTNURGTNEUNG(C3H5)Cl}2] (5 mol%)
[a] W.-B. Liu, H. He, Prof. L.-X. Dai, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
Fax : (+86)21-5492-5087
E-mail: slyou@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000316.
7376
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Chem. Eur. J. 2010, 16, 7376 – 7379

COMMUNICATION
Table 1. Screening the ligands.[a]
Table 2. Substrate scope of the one-pot allylic alkylation of P-ylides/
Wittig reaction.[a]
Entry R1
R2
R3
t
Product Yield
[%][b]
[h]
1
OEt Ph
OEt Ph
OEt 4-MeO-C6H4
OEt 3-MeO-C6H4
OEt 2-MeO-C6H4
OEt 4-F-C6H4
OEt 3-Cl-C6H4
OEt 2-Cl-C6H4
OEt 4-Br-C6H4
OEt 4-CF3-C6H4
OEt 4-NO2-C6H4
OEt 1-naphthyl
OEt 2-furyl
2a
2’a
2b
2c
2d
2e
2 f
2g
2h
2i
H
H
H
H
H
H
H
H
H
H
H
H
H
14
17
16
28
32
14
14
10
12
12
5
4aa
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
86
75
79
57
46
84
82
89
82
86
84
71
45
2[c]
3
Entry
Ligand
t [h]
Yield [%][b]
1
2
3
4
dppe
dppp
dppf
dppb
PPh3
6
19
24
17
96
3
72
16
11
30
39
13
4
5
6
7
8
9
10
11
12
13
<5
5[c]
6[e,f]
7
–
[d]
P
N
50
57
79
71
L1
L1
L1
8[f]
9[f,g]
2j
2k
2l
4aj
4ak
4al
20
14
[a] [PdACHTUNGTRENNUNG(C3H5)Cl]2 (5 mol%), ligand (11 mol%), Cs2CO3 (150 mol%), 1a
(150 mol%), and 2b (100 mol%) in THF at reflux for the indicated time,
14[d,e]
OEt
OEt
2m
H
H
8
8
4am
88
27
then excess formalin was added (for a further 24 h). [b] Isolated yield
over two steps. [c] [PdACHTUNGTRENNUNG(PPh3)4] (10 mol%) was used. [d] Complex mix-
ture. [e] 4ꢁ molecular sieves were added. [f] In dioxane at reflux. [g] Per-
formed on a 1 mmol scale.
15[d,f]
2n
4an
16[d,g]
17[d,g]
18[h]
19
20
21
OEt (E)-1-propenyl
OEt n-C4H9
Me
OEt 4-MeO-C6H4
OEt 4-NO2-C6H4
OEt 4-MeO-C6H4
OEt 4-Br-C6H4
2q
2r
2b
2b
2j
H
H
H
Ph
Ph
5
3
48
16
5
4aq
4ar
4bb
5ab
5aj
25
18
23
50
47
66
58
4-MeO-C6H4
Table 2). Allylic carbonates containing aromatic electron-
withdrawing groups (p-F, m-Cl, o-Cl, p-Br, p-CF3, and p-
NO2; 2e–j) all gave the products (4ae–aj) in excellent yields
(82–89%). The reaction of 1-naphthyl- and 2-furyl-substitut-
ed allyl carbonates (2k and l) with P-ylide 1a afforded prod-
ucts 4ak and 4al in 71 and 45% yields, respectively. The
one-pot reaction of methyl 2-(phenylallyl) carbonate (2m)
led to the formation of 4am in 88% yield (entry 14,
Table 2). The allyl carbonates containing aliphatic groups
(2q and r) gave the desired products in low yields (en-
tries 16 and 17, Table 2).
2b
2h
vinyl 16
Et 12
6ab
7ah
22
[a] See the Supporting Information for details. [b] Isolated yield over two
steps. [c] 2’a was used. [d] No base was used. [e] Carbonate 2m was used.
[f] Carbonate 2n was used. [g] 4 ꢁ molecular sieves were added. [h] In
refluxed THF.
Table 3. Synthesis of allenes by using the one-pot reaction.
The P-ylide 1b, containing an acetyl group, exhibited a
lower reactivity than 1a under the current catalytic system
(entry 18, Table 2). In addition to formaldehyde, other alde-
hydes such as benzaldehyde, acrylaldehyde, and propional-
dehyde were also well tolerated (47–66% yield; entries 19–
22, Table 2), which greatly expands the range of applications
of the method. Notably, the trisubstituted alkenes were ex-
clusively formed in E configurations, as confirmed by 2D-
NOESY experiments.[9] Furthermore, a 1,3-disubstituted al-
lylic carbonate (2n) could also be used in this one-pot pro-
cess (entry 15, Table 2), which provides a basis for further
asymmetric studies into this reaction.[10]
Entry
R2
Product
Yield [%][a]
1
2
3
4
5
6
4-MeO-C6H4
3-MeO-C6H4
2-MeO-C6H4
4-NO2-C6H4
2-NO2-C6H4
2b
2c
2d
2j
2o
2p
8ab
8ac
8ad
8aj
8ao
8ap
37
40
49
33
23
39
6-MeO-2-naphthyl
[a] Isolated yield over two steps.
Interestingly, this one-pot reaction can be extended to the
synthesis of allenes,[11] which are important intermediates in
organic synthesis, by means of the olefination of ketenes.[12]
When phenylethylketene was used in place of an aldehyde,
tetrasubstituted allenes 8 were obtained in 23–49% yields
(Table 3).
ture, by-product 9 was isolated in 27% yield, possibly due to
a reaction of intermediate 3 with a second molecule of sub-
strate 2b in the presence of the palladium catalyst [Eq. (1)].
Encouraged by this result, ylide 1c was also tested under
the base free allylic alkylation conditions. As expected, the
product 10cb was obtained in 65% yield [Eq. (2)]. Further
studies into this reaction indicated that water is the proton
During the optimization of the reaction conditions,[9] we
found that, if no extra base was added to the reaction mix-
Chem. Eur. J. 2010, 16, 7376 – 7379
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www.chemeurj.org
7377

S.-L. You et al.
formed, which, after protona-
tion, gives the product. This
proposed reaction mechanism is
supported by the formation of
triphenylphosphine oxide and
the acceleration of the reaction
rate if water is added to the re-
action mixture.
In conclusion, we have dem-
onstrated for the first time that
P-ylides are suitable nucleo-
philes for allylic alkylation reac-
Figure 1. Pd-catalyzed allylic alkylation of P-ylide 1c.
tions in the presence of a Pd/
Trost ligand system. This one-
pot Tsuji–Trost/Wittig reaction
source. In the presence of D2O (4 equiv), the reaction led to
a 50:50 ratio of 10cb/11cb, in 76% yield, while with diox-
ane/D2O (1:1) as the solvent, the reaction gave the deuterat-
ed product (11cb) exclusively, in 80% yield (Figure 1). This
with various aldehydes and ketenes was accomplished, pro-
viding skipped dienes, including trisubstituted alkenes, and
tetrasubstituted allenes in moderate to good overall yields.
P-ylide 1c was also used in the allylic alkylation reaction,
À
À
reaction provides an alternative method for Csp3 Csp3 bond
providing an efficient method for Csp3 Csp3 bond formation.
formation.[13]
Experimental Section
Typical procedure for the one-pot Pd-catalyzed allylic alkylation and
Wittig reaction: [{Pd
ACHTNUGERTN(NGNU C3H5)Cl}2] (3.7 mg, 0.010 mmol) and Trost ligand
L1 (N,N’-(cyclohexane-1,2-diyl)bis[2-(diphenylphosphino)benzamide];
15.3 mg, 0.022 mmol) were dissolved in dioxane (2.0 mL) in a dry Schlenk
tube filled with argon and stirred for 20 min at room temperature. Then
allyl carbonate 2 (0.20 mmol) was added to the mixture. After stirring for
10 min, P-ylide 1 (0.30 mmol) and cesium carbonate (97.7 mg, 0.30 mmol)
were added and the mixture was heated at reflux until the allyl carbonate
was fully consumed (as monitored by TLC). After cooling to room tem-
perature, formalin (0.50 mL, 35% in water, w/w) was added and the re-
sulting reaction mixture was stirred for a further 24 h. Then water
(5.0 mL) was added and the product was extracted with dichloromethane
(5.0 mL ꢂ 3). The combined organic layers were washed with brine, sep-
arated, and dried over anhydrous Na2SO4. The solvent was evaporated
and the residue purified by silica gel column chromatography using pe-
troleum ether/ethyl acetate (20:1) as the eluent to give products 4.
Full experimental details and characterization data are given in the Sup-
porting Information.
A possible mechanism for the Pd-catalyzed allylic alkyla-
tion with 1c is depicted in Scheme 2. The P-ylide (1c) acts
as a nucleophile and attacks the p-allyl-palladium intermedi-
ate to give intermediate I. The hydroxide anion, generated
during this process from water, then reacts with intermedi-
ate I to give intermediate II. Upon the release of triphenyl-
phosphine oxide from intermediate II, intermediate III is
Acknowledgements
We thank the NSFC (20821002, 20932008, and 20923005) and the Nation-
al Basic Research Program of China (973 Program 2009CB825300) for
generous financial support.
Keywords: allenes · alkylation · allylic compounds · one-pot
reactions · palladium · ylides
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Scheme 2. A plausible mechanism for the allylation with 1c.
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Tsuji–Trost/Wittig Reaction
COMMUNICATION
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Received: February 5, 2010
Published online: May 19, 2010
Chem. Eur. J. 2010, 16, 7376 – 7379
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7379