Stereoseleetive synthesis of polysubstituted alkenes through a phosphine-mediated three-component system of aldehydes, α-halo carbonyl compounds, and terminal alkenes

Article abstract of DOI:10.1002/chem.200900177

A study was conducted to demonstrate stereoselective synthesis of polysubstituted alkenes through a phosphine-mediated three-component system of aldehydes, α-halo carbonyl compounds, and terminal alkenes. Triphenylphosphine, α-halo carbonyl compounds, and methyl acrylate were added to a solution of aldehyde in chloroform or 1-propanol under nitrogen at room temperature. The resulting mixture was stirred at the specified temperature until transformation was completely observed by thin layer chromatography (TLC) analysis. The mixture was cooled to room temperature and purified by column chromatography on silica gel, eluting with petroleum ether/ethyl acetate. The study demonstrated that the first one-pot and three-component reaction of aldehydes, α-haloacetates, and terminal alkenes was developed in the presence of phenylphosphine to produce a wide range of trisubstituted alkenes with significant stereoselectivity.

Full text of DOI:10.1002/chem.200900177

DOI: 10.1002/chem.200900177
Stereoselective Synthesis of Polysubstituted Alkenes through a Phosphine-
Mediated Three-Component System of Aldehydes, a-Halo Carbonyl
Compounds, and Terminal Alkenes
Da-Neng Liu and Shi-Kai Tian*[a]
The Wittig reaction is widely employed for the stereose-
ate phosphorus ylide F. Thus, a phosphine-mediated one-
pot, three-component reaction of aldehyde 1, a-halo carbon-
yl compound 2, and an electron-deficient alkene could be
developed to afford trisubstituted alkene 4. The appropriate
choice of a phosphine and electron-deficient alkene was an-
ticipated to prevent unwanted side reactions such as the
Rauhut–Currier[6a] and Morita–Baylis–Hillman reactions.[9]
ꢀ
lective construction of carbon carbon double bonds in or-
ganic synthesis.[1] The one-pot protocol for the Wittig reac-
tion, involving the in-situ preparation of phosphonium salts
and phosphorus ylides, has already been applied to the
direct olefination of aldehydes with a-bromoacetates in the
presence of bases[2] or epoxides.[3,4] Although certain a-
bromo ketones can also serve as substrates for the one-pot
Wittig reaction, the yields are not satisfactory.[2a,3b] To the
best of our knowledge, there is no general method to effi-
ciently realize the one-pot Wittig reaction of a-halo esters,
a-halo amides, and a-halo ketones. Furthermore, the a-halo
carbonyl compounds bearing a-alkyl substituents have
hardly been explored in the one-pot Wittig reaction despite
the potential to synthesize trisubstituted alkenes.[2,3] Herein
we report a highly stereoselective one-pot Wittig reaction of
aldehydes with a-halo and a-alkyl-a-halo carbonyl com-
pounds without requiring bases, and the first one-pot, three-
component synthesis of trisubstituted alkenes with excellent
stereoselectivity from readily available aldehydes, a-haloa-
cetates, and terminal alkenes.[5]
Scheme 1. Proposed reaction pathways for the syntheses of polysubstitut-
ed alkenes 3 and 4. EWG=electron-withdrawing group. X=halogen.
As illustrated in Scheme 1, our design of a new one-pot
Wittig reaction is based on the ability of a phosphine to un-
dergo Michael-type addition to an electron-deficient alkene
to generate zwitterion A,[6,7] which might serve as an organic
base to deprotonate phosphonium salt C, formed by the nu-
cleophilic attack of the phosphine to a-halo carbonyl com-
pound 2. The resulting phosphorus ylide D could react with
aldehyde 1 to give alkene 3. Alternatively, phosphorus ylide
D (R3 =H) might undergo Michael addition to the electron-
deficient alkene[8] and subsequent proton transfer to gener-
Triphenylphosphine in combination with an electron-defi-
cient alkene was first evaluated in mediating the reaction of
benzaldehyde (1a) with ethyl a-bromoacetate (2a) in
chloroform at 608C. To our delight, readily available methyl
acrylate, methyl vinyl ketone, acrylamide, and acrylonitrile
could mediate the one-pot Wittig reaction to give product
3a in a good yield and with an E/Z selectivity of 95:5, re-
spectively (Table 1, entries 1–4).[10,11] In contrast, the em-
ployment of either a-substituted or b-substituted methyl ac-
rylate just led to a sluggish reaction (Table 1, entries 5 and
6). The replacement of triphenylphosphine with a more nu-
cleophilic phosphine such as tributylphosphine in combina-
tion with methyl acrylate resulted in the formation of prod-
uct 3a in a poor yield (Table 1, entry 7).[12] As expected, the
use of a substoichiometric amount of either triphenylphos-
phine or methyl acrylate reduced the yield dramatically
[a] D.-N. Liu, Prof. Dr. S.-K. Tian
Department of Chemistry, University of Science
and Technology of China, Hefei, Anhui 230026 (China)
Fax : (+86)0551-3601592
E-mail: tiansk@ustc.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900177.
4538
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 4538 – 4542

COMMUNICATION
(Table 1, entries 8 and 9). Further investigations revealed
that the triphenylphosphine-mediated one-pot Wittig reac-
tion could also proceed with high stereoselectivity in many
other nonprotic solvents (Table 1, entries 10–16), but the
yields are not satisfactory except those obtained in 1,2-di-
chloroethane, acetonitrile, and N,N-dimethylformamide
(Table 1, entries 10, 14, and 16). Although excellent yields
were obtained from the reaction carried out in alcohols, the
stereoselectivity was found to decrease significantly
(Table 1, entries 17 and 18). Taken together, several elec-
tron-deficient terminal alkenes and solvents could be em-
ployed in the triphenylphosphine-mediated one-pot Wittig
reaction of aldehydes with a-halo carbonyl compounds.
Aromatic, a,b-unsaturated, and aliphatic aldehydes were
all found to be able to react well with a-bromoacetates in
the presence of triphenylphosphine and methyl acrylate to
give b-substituted acrylates with excellent E selectivity
(Table 2, entries 1–10).[13] More excitingly, a-alkyl-a-halo
esters such as ethyl a-bromopropionate and a-bromo-g-bu-
tyrolactone, previously unexplored in the one-pot Wittig re-
action, could serve as suitable substrates for the olefination
of aldehydes to synthesize trisubstituted alkenes with excel-
lent stereoselectivity (Table 2, entries 11–19). In contrast to
a-bromoacetates, higher temperature was needed to acceler-
ate the reaction with a-alkyl-a-halo esters, wherein methyl
acrylate and chloroform were replaced with acrylamide and
1-propanol, respectively.[14] To our delight, the substrate
scope with regard to a-halo carbonyl compounds was suc-
cessfully extended to a broad range of a-bromoacetamides,
a-alkyl-a-bromo amides, a-halo ketones, and a-alkyl-a-
chloro ketones, and importantly, these one-pot Wittig reac-
tions afforded the corresponding 1,2-disubstituted and tri-
substituted alkenes in good to excellent yields and with ex-
cellent stereoselectivity (Table 2, entries 20–35).
This protocol was demonstrated to be useful for an intra-
molecular Wittig reaction to construct a macrocycle under
high dilution conditions. The treatment of w-bromo alde-
hyde 5 with triphenylphosphine and acrylamide in 1-propa-
nol at 608C resulted in the formation of 13-membered a,b-
unsaturated macrolide 6 in 57% yield and with exclusive E
selectivity [Equation (1)].[15]
Although stable phosphorus ylides were reported to un-
dergo Michael addition to electron-deficient alkenes,[8] in
the triphenylphosphine/methyl acrylate-mediated one-pot
Wittig reaction of benzaldehyde (1a) with ethyl a-bromoa-
cetate (2a) (Table 2, entry 1) we did not obtain any product
resulting from the three-component assembly of benzalde-
hyde (1a), ethyl a-bromoacetate (2a), and methyl acrylate
according to our design shown in Scheme 1. Realizing that
the Wittig reaction of the in-situ prepared phosphorus ylide
proceeded much quicker than its Michael addition to methyl
acrylate, we postponed the incorporation of benzaldehyde
(1a) into the multicomponent system. Gratifyingly, such a
modification allowed us to
obtain product 4a (R1 =Ph,
Table 1. Survey of phosphines, electron-deficient alkenes, and solvents.[a]
R2 =OEt, EWG=CO2Me) in
88% yield and with an E/Z se-
lectivity of greater than 99:1
(Table 3, entry 1).[16] Aromatic,
Entry
Phosphine
Alkene
Solvent
t [h]
Yield[b] [%]
E/Z[c]
a,b-unsaturated, and aliphatic
aldehydes could all react well
with a-haloacetates and acryl-
ates in the presence of triphe-
nylphosphine to afford trisubsti-
tuted alkenes 4 with excellent
stereoselectivity (Table 3, en-
tries 1–12). Further investiga-
tion revealed that no desired
product was obtained from the
one-pot, three-component reac-
tion when an a-haloacetate was
replaced with either an a-haloa-
cetamide or an a-halo ketone,
and the substrate scope with
regard to terminal alkenes was
successfully extended to methyl
vinyl ketone, for which excel-
lent stereoselectivity was ach-
1
2
3
4
5
6
7
8
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
CH2=CHCO2Me
CH2=CHCOMe
CH2=CHCONH2
CH2=CHCN
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCE
PhMe
THF
EtOAc
MeCN
dioxane
DMF
5
5
5
5
10
10
10
5
89
82
86
72
7
95:5
95:5
95:5
95:5
CH2=C(Me)CO2Me
(E)-PhCH=CHCO2Me
CH2=CHCO2Me
CH2=CHCO2Me
CH2=CHCO2Me[e]
CH2=CHCO2Me
CH2=CHCO2Me
CH2=CHCO2Me
CH2=CHCO2Me
CH2=CHCO2Me
CH2=CHCO2Me
CH2=CHCO2Me
CH2=CHCO2Me
CH2=CHCO2Me
0
P
N
11
11
42
72
28
35
46
77
50
74
97
99
94:6
[d]
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
9
5
95:5
95:5
94:6
94:6
93:7
95:5
94:6
95:5
89:11
91:9
10
11
12
13
14
15
16
17
18
12
12
12
12
12
12
12
5
EtOH
nPrOH
5
[a] Reaction conditions: 1a (0.50 mmol), 2a (1.2 equiv), phosphine (2.4 equiv), alkene (1.2 equiv), solvent
(0.50 mL), 608C. [b] Isolated yield. [c] Determined by integrating the vinyl proton signals in the H NMR spec-
tra of product 3a. [d] 1.2 equiv of triphenylphosphine was used. [e] 0.5 equiv of methyl acrylate was used.
DCE=1,2-dichloroethane. THF=tetrahydrofuran. DMF=N,N-dimethylformamide.
1
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www.chemeurj.org
4539

S.-K. Tian and D.-N. Liu
Table 2. Olefination of aldehydes with a-halo and a-alkyl-a-halo carbonyl compounds.[a]
phenylphosphine to produce a
wide range of trisubstituted al-
kenes with excellent stereose-
lectivity.
Entry
R1
R2
R3
T [8C]
t [h]
Yield[b] [%]
E/Z[c]
1
2
3
4
5
6
7
8
Ph
Ph
OEt
H
H
H
H
H
H
H
H
60
60
60
60
8
60
60
8
5
8
2
18
18
3
89
86
81
88
70
89
89
77
76
97
94
85
89
76
74
90
95
77
63
62
75
97
83
68
83
74
90
95
68
84
74
93
57
67
55
95:5
94:6
94:6
96:4
91:9
92:8
93:7
>99:1
>99:1
94:6
96:4
97:3
95:5
95:5
>99:1
98:2
>99:1
96:4
94:6
97:3
O
N
Experimental Section
4-ClC6H4
4-Me2NC6H4
2-O2NC6H4
2-furyl
(E)-PhCH=CH2
Et
Me2CH
cyclohexyl
Ph
2-thienyl
3-pyridyl
1-hexyl
cyclohexyl
Ph
1-naphthyl
1-hexyl
BnO
Ph
Ph
Ph
OEt
OEt
OEt
OEt
OEt
OBn
OBn
OEt
OEt
OEt
OEt
OEt
OEt
General procedure for the olefination
of aldehydes with a-halo and a-alkyl-
a-halo carbonyl compounds (Table 2):
7
To
a
solution of aldehyde
1
24
48
6
4
9
4
4
12
8
10
8
(0.50 mmol) in chloroform or 1-propa-
nol (0.50 mL) under nitrogen at room
temperature (88C for entries 5, 8, and
9) were added triphenylphosphine
(314 mg, 1.2 mmol), a-halo or a-alkyl-
9
H
H
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
60
90
90
90
90
60
90
90
90
90
90
90
90
60
90
90
90
90
90
60
90
90
90
90
90
90
Me
Me
Me
Me
Me
a-halo
carbonyl
compound
2
(0.60 mmol), and methyl acrylate
(51.6 mg, 54 mL, 0.60 mmol) [or acryl-
amide (42.6 mg, 0.60 mmol)]. The re-
sulting mixture was stirred at the
specified temperature until no further
transformation was observed by thin
layer chromatography (TLC) analysis.
The mixture was cooled to room tem-
perature (if being heated), and puri-
fied by column chromatography on
silica gel, eluting with petroleum
ether/ethyl acetate 20:1 ! 1:1, to give
product 3.
-OCH2CH2-
-OCH2CH2-
-OCH2CH2-
-OCH2CH2-
N
10
12
12
4
N
N
H
H
H
>99:1
97:3
cyclohexyl
Ph
H
18
12
12
12
4
6
12
5
5
5
9
12
9
94:6
Me
Me
Me
H
H
H
H
H
H
H
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
1-hexyl
1-hexyl
Ph
NH2
NHBn
Ph
Ph
Ph
Ph
Ph
Me
Me
tBu
Me
Synthesis of macrolide 6: To a stirred
2-furyl
solution
of
triphenylphosphine
3-pyridyl
(E)-MeCH=CH2
cyclohexyl
Ph
(E)-PhCH=CH2
Ph
(39.3 mg, 0.15 mmol) and acrylamide
(5.5 mg, 0.077 mmol) in 1-propanol
(6.0 mL) under nitrogen at 608C was
slowly added a solution of w-bromo al-
dehyde 5 (22.0 mg, 0.064 mmol) in 1-
propanol (0.50 mL). After completion
of the addition (ca. 6 h), the mixture
was stirred at that temperature for
30 h, cooled to room temperature, and
concentrated. The residue was purified
by preparative TLC, developing with
petroleum ether/ethyl acetate 10:1, to
give macrolide 6 (8.9 mg, 57%, E/Z >
H
Me
Ph
[a] Reaction conditions: 1 (0.50 mmol), 2 (0.60 mmol; for entries 1-31, X=Br; for entries 32-35, X=Cl), tri-
phenylphosphine (1.2 mmol), terminal alkene (0.60 mmol; for entries 1-10, 15, 23, and 29, EWG=CO2Me; For
the other entries, EWG=CONH2), solvent (0.50 mL; For entries 1-10, chloroform; for entries 11-35, 1-propa-
nol). [b] Isolated yield. [c] Determined by integrating the vinyl proton signals in the 1H NMR spectra of the
products. Bn=benzyl.
1
99:1) as a yellow oil. H NMR (CDCl3,
ieved when the reaction was carried out in acetonitrile
(Table 3, entries 13–16).[17]
300 MHz): d
= 8.38 (d, J=16.5 Hz,
1H), 7.55 (d, J=7.5 Hz, 1H), 7.38–7.31 (m, 1H), 7.18–7.05 (m, 2H), 6.35
(d, J=16.5 Hz, 1H), 4.27 (t, J=6.0 Hz, 2H), 3.95 (t, J=4.8 Hz, 2H),
1.98–1.73 (m, 4H), 1.60–1.45 ppm (m, 4H); 13C NMR (CDCl3, 75 MHz):
d 167.9, 159.2, 142.3, 131.8, 127.1, 124.1, 121.1, 118.3, 74.3, 65.8, 29.6, 27.6,
26.4, 25.0 ppm; IR (film): n˜ = 3020, 1709, 1627, 1601, 1459 cmꢀ1; HRMS
(EI): m/z: calcd C15H18O3: 246.1256; found: 246.1255 [M]+.
In summary, we have developed a highly stereoselective
synthesis of polysubstituted alkenes through a phosphine-
mediated three-component system of aldehydes, a-halo car-
bonyl compounds, and terminal alkenes. Triphenylphosphine
and methyl acrylate (or acrylamide) are able to mediate, in
an excellent stereoselective fashion, the one-pot Wittig reac-
tion of aldehydes with a-bromoacetates, a-alkyl-a-bromo
esters, a-bromoacetamides, a-alkyl-a-bromo amides, a-halo
ketones, and a-alkyl-a-chloro ketones for the synthesis of
1,2-disubstituted and trisubstituted alkenes. This protocol
has been demonstrated to be useful for an intramolecular
Wittig reaction to construct an a,b-unsaturated macrolide
with exclusive E selectivity. Furthermore, the first one-pot,
three-component reaction of aldehydes, a-haloacetates, and
terminal alkenes has been developed in the presence of tri-
General procedure for the three-component synthesis of trisubstituted al-
kenes (Table 3): To a solution of triphenylphosphine (314 mg, 1.2 mmol)
in chloroform or acetonitrile (0.50 mL) under nitrogen at room tempera-
ture were added a-haloacetate (0.60 mmol) and terminal alkene
(0.60 mmol). The resulting mixture was stirred at 608C for 3 h, cooled to
room temperature, and was added the same terminal alkene (0.90 mmol).
The mixture was stirred at 608C for 6 h (Table 3, entries 1–12) or 3 h
(Table 3, entries 13–16), cooled to room temperature, and was added al-
dehyde 1 (0.50 mmol). The resulting mixture was stirred at 608C until no
further transformation was observed by TLC analysis. The mixture was
cooled to room temperature, and purified by column chromatography on
silica gel, eluting with petroleum ether/ethyl acetate 10:1 ! 1:1, to give
product 4.
4540
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 4538 – 4542

Stereoselective Synthesis of Polysubstituted Alkenes
Table 3. Three-component synthesis of trisubstituted alkenes.[a]
COMMUNICATION
Angew. Chem. 2005, 117, 1628–
1661; Angew. Chem. Int. Ed.
2005, 44, 1602–1634; e) J. Zhu,
Eur. J. Org. Chem. 2003, 1133–
1144; f) V. Nair, C. Rajesh, A. U.
Vinod, S. Bindu, A. R. Sreekanth,
J. S. Mathen, L. Balagopal, Acc.
Chem. Res. 2003, 36, 899–907;
g) R. V. A. Orru, M. Greef, Syn-
Entry
R1
R2
EWG
t [h]
Yield[b] [%]
E/Z[c]
1
Ph
Ph
Ph
Ph
OEt
OEt
CO2Me
CO2Me
CO2Me
CO2Me
16
16
19
19
16
19
27
19
19
19
19
19
24
20
24
24
88
70
62
80
80
89
61
87
87
68
80
72
83
50
82
50
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
96:4
>99:1
>99:1
92:8
95:5
96:4
>99:1
>99:1
>99:1
2[d]
3
O
O
U
thesis 2003, 1471–1499.
4
5
6
7
8
9
10
11
12
13
14
15
16
[6] For reviews, see: a) J. L. Methot,
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
CO
N
W. R. Roush, Adv. Synth. Catal.
2004, 346, 1035–1050; b) D.
Enders, A. Saint-Dizier, M.-I.
Lannou, A. Lenzen, Eur. J. Org.
Chem. 2006, 29–49. For a review
on the Michael-type addition of
phosphines to electron-deficient
alkynes and allenes, see: c) X. Lu,
4-ClC6H4
4-MeOC6H4
2-furyl
3-pyridyl
(E)-MeCH=CH2
1-hexyl
1-hexyl
Ph
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
COMe
COMe
COMe
COMe
O
N
OEt
OEt
OEt
OEt
C. Zhang, Z. Xu, Acc. Chem. Res.
2001, 34, 535–544.
1-naphthyl
2-furyl
1-hexyl
[7] The reversible nature of this pro-
95:5
cess has recently been demon-
[a] Reaction conditions: Triphenylphosphine (1.2 mmol), XCH2COR2 (0.60 mmol, X=Br), terminal alkene
(1.5 mmol), aldehyde 1 (0.50 mmol), solvent (0.50 mL; for entries 1-12, chloroform; for entries 13–16, acetoni-
trile), 608C. [b] Isolated yield. [c] Determined by integrating the vinyl proton signals in the 1H NMR spectra
of the products. [d] X=Cl.
strated by the deuterium-labeling
experiments with the triphenyl-
phosphine/methyl acrylate-cata-
lyzed Henry reaction. See: X.
Wang, F. Fang, C. Zhao, S.-K.
Tian, Tetrahedron Lett. 2008, 49,
6442–6444.
Acknowledgements
[8] For examples of the Michael addition of stable phosphorus ylides to
electron-deficient alkenes, see: a) H. J. Bestmann, F. Seng, Angew.
Chem. 1962, 74, 154–155; Angew. Chem. Int. Ed. Engl. 1962, 1,
116–117; b) J. Asunskis, H. Schechter, J. Org. Chem. 1968, 33,
1164–1168; c) H. J. Bestmann, A. Gross, Tetrahedron Lett. 1997, 38,
4765–4768; d) R. A. Aitken, N. A. Al-Awadi, M. E. Balkovich, H. J.
Bestmann, O. Clem, S. Gibson, A. Groß, A. Kumar, T. Rçder, Eur.
J. Org. Chem. 2003, 840–847. For examples of the Michael addition
of allylic phosphorus ylides to electron-deficient alkenes, see: e) Y.
Du, X. Lu, C. Zhang, Angew. Chem. 2003, 115, 1065–1067; Angew.
Chem. Int. Ed. 2003, 42, 1035–1037; f) L.-W. Ye, X. Han, X.-L. Sun,
Y. Tang, Tetrahedron 2008, 64, 8149–8154; g) X.-L. Sun, Y. Tang,
Acc. Chem. Res. 2008, 41, 937–948.
[9] For recent reviews, see: a) G. Masson, C. Housseman, J. Zhu,
Angew. Chem. 2007, 119, 4698–4712; Angew. Chem. Int. Ed. 2007,
46, 4614–4628; b) D. Basavaiah, A. J. Rao, T. Satyanarayana, Chem.
Rev. 2003, 103, 811–891. For recent examples, see: c) S. I. Pereira, J.
Adrio, A. M. S. Silva, J. C. Carretero, J. Org. Chem. 2005, 70, 10175–
10177; d) W.-D. Teng, R. Huang, C. K.-W. Kwong, M. Shi, P. H. Toy,
J. Org. Chem. 2006, 71, 368–371.
We are grateful for the financial support from the National Natural Sci-
ence Foundation of China (20732006 and 20672105) and the Chinese
Academy of Sciences.
Keywords: aldehydes · alkenes · macrolide · phosphanes ·
Wittig reactions
[1] For reviews, see: a) A. Maerckar, Org. React. 1965, 14, 270–490;
b) B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89, 863–927.
[2] a) J. Westman, Org. Lett. 2001, 3, 3745–3747; b) J. Wu, C. Yue,
Synth. Commun. 2006, 36, 2939–2947; c) B. M. Choudary, K. Ma-
hendar, M. L. Kantam, K. V. S. Ranganath, T. Athar, Adv. Synth.
Catal. 2006, 348, 1977–1985; d) F. Orsini, G. Sello, T. Fumagalli,
Synlett 2006, 1717–1718; e) A. El-Batta, C. Jiang, W. Zhao, R.
Anness, A. L. Cooksy, M. Bergdahl, J. Org. Chem. 2007, 72, 5244–
5259.
[3] a) J. Buddrus, Angew. Chem. 1968, 80, 535–536; Angew. Chem. Int.
Ed. Engl. 1968, 7, 536–537; b) J. Buddrus, Chem. Ber. 1974, 107,
2050–2061; c) U. Nꢁsera, A. J. Pierikb, R. Scotta, I. Cinkayab, W.
Buckelb, B. T. Golding, Bioorg. Chem. 2005, 34, 53–66.
[4] For a review on the phosphine/metal-mediated olefination of alde-
hydes with a-halo esters and a-halo amides, see: a) Y. Shen, Acc.
Chem. Res. 1998, 31, 584–592. For the one-pot Wittig-type reaction
involving arsenic ylides, see: b) L. Shi, W. Wang, Y. Wang, Y.-Z.
Huang, J. Org. Chem. 1989, 54, 2027–2030. For the one-pot Wittig-
type reaction involving tellurium ylides, see: c) Z.-Z. Huang, S. Ye,
W. Xia, Y. Tang, Chem. Commun. 2001, 1384–1385; d) Z.-Z. Huang,
S. Ye, W. Xia, Y.-H. Yu, Y. Tang, J. Org. Chem. 2002, 67, 3096–
3103; e) Z.-Z. Huang, Y. Tang, J. Org. Chem. 2002, 67, 5320–5326;
f) K. Li, L. Ran, Y.-H. Yu, Y. Tang, J. Org. Chem. 2004, 69, 3986–
3989.
[10] Intermediates B (R=Ph, EWG=CO2Me) and C (R=Ph, R2 =OEt,
R3 =H) could be identified by the 1H and 31P NMR analysis of the
reaction mixture of benzaldehyde (1a) with ethyl a-bromoacetate
(2a) in the presence of triphenylphosphine and methyl acrylate. In
contrast, phosphorus ylide D (R=Ph, R2 =OEt, R3 =H) could not
be observed. These results imply that the Wittig reaction proceeds
much quicker than the formation of a phosphorus ylide.
[11] No reaction was observed by 1H and 31P NMR analysis between tri-
phenylphosphine and methyl acrylate in the absence of ethyl a-bro-
moacetate (2a) under similar reaction conditions.
[12] The weaker nucleophilicity of triphenylphosphine relative to tribu-
tylphosphine is essential to prevent possible side reactions such as
the Rauhut–Currier and Morita–Baylis–Hillman reactions (ref. [6a],
[9a] and [9b]). In addition, triphenylphosphine is one of the most
often used phosphines in chemical synthesis owing to its low cost
and air-stability.
[5] For reviews of multicomponent reactions, see: a) A. Dondoni, A.
Massi, Acc. Chem. Res. 2006, 39, 451–463; b) A. Dçmling, Chem.
Rev. 2006, 106, 17–89; c) Multicomponent reactions (Eds.: J. Zhu, H.
Bienaymꢂ), Wiley-VCH, Weinheim, 2005; d) D. J. Ramꢃn, M. Yus,
[13] Most of the products shown in Table 2 are known compounds; their
stereochemistries were assigned by comparing their 1H NMR data
with that reported in literature. And the stereochemistry of a new
Chem. Eur. J. 2009, 15, 4538 – 4542
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4541

S.-K. Tian and D.-N. Liu
product was assigned by 2D NOESY analysis and/or by analogy. For
details, see the Supporting information.
[14] As judged by the H NMR spectra of the crude products, no transes-
1507–1522, and references therein. The stereochemistries for some
of the products were further confirmed by 2D NOESY analysis. For
details, see the Supporting information.
1
terification took place at 908C when 1-propanol was employed as
the solvent.
[15] For the preparation of w-bromo aldehyde 5, see the Supporting in-
formation.
[16] The stereochemistry of each product shown in Table 3 was assigned
according to the chemical shift of the vinyl proton carried by the
carbon b to the ester group. In general, the vinyl proton of an E
isomer exhibits a signal that is downfield relative to the correspond-
ing Z isomer. See:H. J. Cristau, M. Taillefer, Tetrahedron 1998, 54,
[17] The reaction of benzaldehyde (1a) with ethyl a-bromoacetate (2a)
and acrylonitrile in chloroform gave a complex mixture. In addition,
no desired product was obtained when methyl acrylate was replaced
with acrylamide, diethyl 2-(ethoxymethylene)malonate, or methyl
propiolate in the one-pot, three-component reaction.
Received: January 21, 2009
Published online: March 19, 2009
4542
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 4538 – 4542