Lewis acid promoted carbon - Carbon double-bond formation via organozinc reagents and carbonyl compounds

Article abstract of DOI:10.1021/jo901252z

(Chemical Equation Presented) Using cheap and readily available AlCl3 as Lewis acid, functionalized aldehydes react with organozinc reagents to give (E)-alkenes stereoselectively in high yields. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901252z

pubs.acs.org/joc
related processes involving sulfur4 and silicon5 ylides have
Lewis Acid Promoted Carbon-Carbon Double-Bond
Formation via Organozinc Reagents and Carbonyl
Compounds
been developed. Furthermore, olefination of carbonyl group
using transition metals, such as titanium6 and chromium,7 or
using metal carbene complexes, including Re,8 Ru,9 Fe,10
and Rh,11 have also been reported. Organozinc reagents
have been widely used in organic synthesis.12 Compared
with organomagnesium and organolithium reagents,
organozincs are relatively stable yet active, more selective,
and tolerant to ester and amide functional groups. Gener-
ally, the reaction of organozinc reagents and aldehydes
represents one of the most reliable methods to prepare
secondary alcohols,13 while gem-dizinc species reacts with a
carbonyl group to give olefination products.14
Wang has reported a useful procedure to make alkenes by
transition-metal-catalyzed olefination of benzylzinc halides
and carbonyl compounds,15 in which Co, Ni, or Pd was used
to catalyze the reaction between organozinc reagents and
carbonyl groups. A reaction involving a transition-metal-
catalyzed formation of secondary silyl ethers, followed by
the loss of Me3SiOH to give (E)-alkenes, was proposed
(Scheme 1). One feature associated with this mechanism is
that it is well established that organozinc reagents react with
Zhi-Yong Peng,† Fang-Fang Ma,† Lv-Feng Zhu,†
Xiao-Min Xie,† and Zhaoguo Zhang*,†,‡
†School of Chemistry and Chemical Engineering,
Shanghai Jiao Tong University, Shanghai 200240,
China, and ‡Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
zhaoguo@sjtu.edu.cn
Received June 11, 2009
Using cheap and readily available AlCl3 as Lewis acid,
functionalized aldehydes react with organozinc reagents
to give (E)-alkenes stereoselectively in high yields.
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DOI: 10.1021/jo901252z
r
Published on Web 08/07/2009
J. Org. Chem. 2009, 74, 6855–6858 6855
2009 American Chemical Society

Peng et al.
JOCNote
TABLE 1. Olefination of Secondary Alcohol and Silyl Ethera
entry
1
NiCl2(PPh3)2 (mol %)
TMSCl (equiv)
ZnCl2 (equiv)
product (2a/1a/1b)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
3
3
0
0
0
0
3
3
3
3
3
3
0
0
0
0
2
2
2
2
0
0
0
0
2
2
0
0
2
2
2
2
1.5
1.5
0
58/7/35
63/3/34
0/92/8
0/0/100
0/100/0
0/0/100
0/100/0
0/0/100
0/92/8
0/0/100
0/100/0
0/0/100
69/12/19
68/6/26
100/0/0c
100/0/0c
0
1.5
1.5
0
0
0
0
1.5
1.5
1.5
1.5
1.5
1.5
a Reaction conditions: 1 (0.5 mmol), THF (2.0 mL), at 25 °C under N2 for 8 h. b Detected by GC. c Reaction temperature: 50 °C.
SCHEME 1. Transition-Metal-Involved Mechanism by Wang
difficult to obtain, as it is known that the silyl ether is labile
to hydrolysis rather than elimination.
We reinvestigated this reaction and found that transition
metal was not necessary in this reaction. Herein, we report the
Lewis acid promoted olefination of benzylzinc halides and
carbonyl compounds under transition-metal-free conditions.
To make it clear how the transformation of secondary silyl
ethers to alkenes occurred, 1a and 1b were employed as
substrates for the control reactions. Under standard reaction
conditions reported by Wang et al.,15a both 1a and 1b can be
converted to the desired product 2a, indicating a combina-
tion of transition metal-TMSCl-ZnCl2 is workable
(Table 1, entries 1 and 2). When we ran the reaction in the
presence of only NiCl2(PPh3)2 (3 mol %), or TMSCl (2
equiv) or ZnCl2 (1.5 equiv), no elimination product was
detected (Table 1, entries 3-8); when we ran the reaction
with a binary combination, different results were obtained:
NiCl2(PPh3)2-TMSCl or NiCl2(PPh3)2-ZnCl2 gave no pro-
ducts (Table 1, entries 9-12), while the TMSCl-ZnCl2
combination gave products with fair yields, accompanying
recovered starting material, and corresponding protection/
deprotection products (Table 1, entries 13 and 14). When the
reaction temperature was increased from 25 to 50 °C, the
starting material was completely converted to the desired
alkene (Table 1, entries 15 and 16).
aldehydes to give secondary alcohols under mild reaction
conditions. Although mechanistically this reaction does not
necessarily need a transition-metal salt, one can envision that
this reaction might be accelerated by the addition of Lewis
acids as promoters. Our recent research also proved that
Lewis acids play a profound role in asymmetric hydrogena-
tion reactions.16 Another item to note is that the conversion
of silyl ether (1) to alkene (2) without any promoters is
The results in Table 1 clearly illustrated that this olefina-
tion reaction does not need the catalysis of a transition metal;
the combination of TMSCl and ZnCl2 plays the key role. We
then repeated the reaction with or without NiCl2(PPh3)2
by reacting p-tolualdehyde and benzylzinc(II) bromide17
under the reported reaction conditions,15a and the reactions
(16) (a) Sun, Y.-H.; Wan, X.-B.; Wang, J.-P.; Meng, Q.-H.; Zhang, H.-
W.; Jiang, L.-J.; Zhang, Z.-G. Org. Lett. 2005, 7, 5425–5427. (b) Wan, X.-B.;
Meng, Q.-H.; Zhang, H.-W.; Sun, Y.-H.; Fan, W.-Z.; Zhang, Z.-G. Org.
Lett. 2007, 9, 5613–5616. (c) Meng, Q.-H.; Sun, Y.-H.; Ratovelomanana-
Vidal, V.; Genet, J. P.; Zhang, Z.-G. J. Org. Chem. 2008, 73, 3842–3847. (d)
Meng, Q.-H.; Zhu, L.-F.; Zhang, Z.-G. J. Org. Chem. 2008, 73, 7209–7212.
(17) Benzylzinc halides were prepared following Knochel’s procedure:
(a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117–2188.
(b) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 6040–6044.
6856 J. Org. Chem. Vol. 74, No. 17, 2009

Peng et al.
JOCNote
TABLE 2. Optimization of the Lewis Acid Promoted Olefination of
TABLE 3. Lewis Acid Promoted Olefination of Aldehydes with Orga-
nozinc Reagents a
Benzylzinc Bromide and p-Tolualdehyde a
entry
3 Ar
4 R’, X
product
yield (%)
entry
T (°C)
Lewis acid (equiv)
solvent
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
NMP
DMF
acetonitrile
toluene
dioxane
dioxane
yield (%)
1
2
3
4
5
6
7
8
9
25
25
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
80
TMSCl (2)
TMSCl (2)
TMSCl (2)
LiCl (2)
67b,c
61c
77
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
a
3a, p-CH3C6H4
3b, o-CH3C6H4
3c, m-CH3C6H4
3d, C6H5
3e, o-FC6H4
3f, p-ClC6H4
3g, p-BrC6H4
3h, 2,4-Di-ClC6H3
3a, p-CH3C6H4
3d, C6H5
3f, p-ClC6H4
3a, p-CH3C6H4
3d, C6H5
3f, p-ClC6H4
3a, p-CH3C6H4
3a, p-CH3C6H4
3f, p-ClC6H4
3f, p-ClC6H4
3i, p-CH3OC6H4
3d, C6H5
4a, Ph, Br
4a, Ph, Br
4a, Ph, Br
4a, Ph, Br
4a, Ph, Br
4a, Ph, Br
4a, Ph, Br
4a, Ph, Br
2a
2b
2c
2d
2e
2f
2g
2h
2a
2d
2f
2i
2f
2j
2k
2 L
2m
2n
2o
2d
89
81
83
93
94
91
90
87
88
83
80
89
78
71
76d
58d
0c
CeCl3 (2)
ZnCl2 (2)
FeCl3 (2)
Cu(OAc)2 (2)
0c
0c
BF3 Et2O (2)
56c
82
4b, Ph, Cl
4b, Ph, Cl
4b, Ph, Cl
3
10
11
12
13
14
15
16
17
18
19
a
AlCl3 (2)
AlCl3 (1)
AlCl3 (0.5)
AlCl3 (3)
AlCl3 (3)
AlCl3 (3)
AlCl3 (3)
AlCl3 (3)
AlCl3 (3)
AlCl3 (3)
38 (37)
0 (56 )
87
4c, 4-Cl-Ph, Cl
4c, 4-Cl-Ph, Cl
4c, 4-Cl-Ph, Cl
4d, n-C3H6, I
4e, n-C7H15, I
4d, n-C3H6, I
4e, n-C7H15, I
4a, Ph, Br
78d
67d
62c
74c
83
41b
44b
36b
43b
86c
77d
89
4b, Ph, Cl
Reaction conditions: aldehyde (1.0 mmol), benzylzinc
Reaction conditions: aldehyde (1.0 mmol), organozinc
reagent (1.5 mmol), AlCl3 (3.0 mmol), dioxane (3.0 mL), at
80 °C under N2. b THF (3.0 mL), reflux. c TMSCl (3.0 mmol),
THF (3.0 mL), at 65 °C. d 100 mmol of substrate was used.
bromide (1.5 mmol), and Lewis acid in a solvent (3.0 mL) at a
b
specified temperature under N2 for 8 h. 3 mol % of
c
NiCl2(PPh3)2 was added. Unreacted aldehyde recovered.
d 2-Phenyl-1-p-tolylethanol was obtained.
The results are summarized in Table 3 for the reactions
that were run under the optimized reaction conditions
(AlCl3 as Lewis acid, in dioxane or THF at 80 °C under
N2) where the olefination reaction was carried out with
aromatic aldehydes and organozinc halides. This reaction
has a wide scope of substrate tolerance. o, m, p-tolualde-
hyde, benzaldehyde, and halogenated benzaldehydes are all
workable substrates to react with benzylzinc bromide, good
to excellent yields were obtained, and no obvious steric
effect was observed (Table 3, entries 1-8). However, aryl
aldehydes bearing an electron-donating substituent react
faster than those bearing an electron-withdrawing substi-
tuent. Other benzylzinc reagents, such as benzylzinc chlor-
ide (4b) and 4-chlorobenzylzinc chloride (4c), worked
equally well as 4a (Table 3, entries 9-14). Likewise, without
any additive, alkylzinc iodides (4d, 4e) react very slowly
with aldehydes even in refluxing THF and at prolonged
reaction times to give the corresponding alcohols and
recovered aldehydes. Although the addition of AlCl3 greatly
improved the reactivity of alkylzinc reagents and aldehydes,
(E)-alkenes were obtained in only medium yields accom-
panied by alcohols (Table 3, entries 15-18) even at pro-
longed reaction times. When the reaction was performed
with p-anisaldehyde (3i) as substrate, very low yield was
obtained; fortunately when AlCl3 was replaced by TMSCl
as Lewis acid, olefination proceeded very well in refluxing
THF (Table 3, entry 19). The reaction can be easily per-
formed on a larger scale: when benzaldehyde (3d, 100 mmol)
was treated with benzylzinc chloride (4b) in the presence of
AlCl3, at 80 °C in dioxane for 8 h, after recrystallization
from ethanol, (E)-stilbene (2d) was obtained in 77% yield
(Table 3, entry 20).
proceeded almost equally well; (E)-alkene 2a was obtained
stereoselectively. Both of the reactions did not reach com-
pletion after 8 h at room temperature, and the secondary silyl
ether and unreacted aldehyde were detected (Table 2, entries
1 and 2). If the reaction was carried out in the absence of
NiCl2(PPh3)2 at a higher temperature (50 °C), silyl ether
disappeared and (E)-stilbene was obtained in good yield
(Table 2, entry 3). To clarify whether the elimination
occurred via silyl ether or directly via alcohol, we tried other
Lewis acids. When LiCl or CeCl3 were used as Lewis acids,
only secondary alcohol was isolated, while when ZnCl2,
FeCl3, or Cu(OAc)2 was used as Lewis acid, typically no
reaction occurred and most of the aldehyde was recovered
(Table 2, entries 4-8). Gratifyingly, when BF3 Et2O
3
or AlCl3 was employed, olefination occurred to give the
(E)-alkenes stereoselectively in fair to good yields (Table 2,
entries 9 and 10). Reducing the amount of AlCl3 to 1 molar
equiv gave a lower yield accompanied by secondary alcohol;
reducing the amount of AlCl3 to 0.5 molar equiv gave only
secondary alcohol; increasing the amount of AlCl3 to 3
molar equiv gave higher yields (Table 2, entries 11-13).
With cheap and readily available AlCl3 as Lewis acid, we
tested the reaction in different solvents. When N,N-dimethyl-
formamide (DMF) or N-methyl-2-pyrrolidone (NMP) was
used as solvent, olefination did not proceed; only secondary
alcohol was separated in fair yields. Olefination product was
obtained in medium to good yield, respectively, with aceto-
nitrile, toluene, or dioxane as solvent (Table 2, entries 14-18).
When we performed the reaction in dioxane at 80 °C, a better
yield was obtained, and the reaction time was reduced from 8 to
2 h (Table 2, entry 19).
J. Org. Chem. Vol. 74, No. 17, 2009 6857

Peng et al.
JOCNote
SCHEME 2. Olefination of Cinnamaldehyde
In conclusion, a highly stereoselective carbon-carbon
double-bond-forming reaction was reported. Using cheap
and readily available AlCl3 as Lewis acid, functionalized
aldehydes react with organozinc reagents to give (E)-alkenes
stereoselectively in high yields.
Experimental Section
General Procedure for the Lewis Acid Promoted Olefination of
Aldehydes with Organozinc Reagents. AlCl3 (400 mg, 3.0 mmol)
and dry dioxane (3.0 mL) were added into an oven-dried
Schlenk tube equipped with a septum and a stirring bar under
nitrogen. The mixture was cooled with ice-water, and then
p-tolualdehyde (120 mg, 1.0 mmol) was added. The reaction
mixture was stirred for an additional 5 min before benzylzinc
bromide (1.0 mL, 1.5 mmol, 1.5 M in THF) was added via
syringe over 5 min. The reaction mixture was moved into an oil
bath and stirred at 80 °C for 2 h. The starting materials were
completely consumed as determined by GC analysis, the reac-
tion mixture was cooled with ice-water, and ether (10.0 mL)
and saturated NH4Cl solution (3.0 mL) were added. The aqu-
eous layer was separated and extracted with ether (3 ꢀ 5.0 mL),
and the combined organic extracts were dried over Na2SO4 and
evaporated. Flash chromatography with hexanes as eluent
SCHEME 3. Olefination of Aromatic Ketones
This method can be extended to unsaturated aldehydes.
When cinnamaldehyde was reacted benzylzinc bromide,
the corresponding (1E,3E)-1,4-diphenyl-1,3-butadiene (2l)
was obtained in medium isolated yields; both AlCl3
1
afforded compound 2a, which was confirmed by H and 13C
NMR.
(E)-40-Methylstilbene (Compound 2a, Table 3, Entry 1). Pre-
pared according to the general procedure using hexanes as
eluent (173.0 mg, 89%): white solid; 1H NMR (400 MHz,
CDCl3) δ 2.36 (s, 3H), 7.07 (d, J = 2.0 Hz, 2H), 7.17 (d, J =
8.0 Hz, 2H), 7.24-7.27 (m, 1H), 7.34 (m, 2H), 7.41 (m, 2H), 7.50
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.5, 126.6, 126.7,
127.6, 127.9, 128.8, 128.9, 129.6, 134.8, 137.7.
and BF3 Et2O are suitable Lewis acids for the reaction
3
(Scheme 2).
Aromatic ketones also reacted with benzylzinc bromide in
the presence of AlCl3 to give an (E)/(Z) mixture as products.
Solvents are important in this reaction. With dioxane as
solvent, medium yields was obtained with poor selectivities;
when THF was used as solvent, good selectivities but lower
yields were observed (Scheme 3).
According to our experimental results and other rela-
ted studies,13,14 Lewis acid may play multiple roles in this
reaction: (1) it activates carbonyl compound by coordina-
tion to carbonyl group; (2) it accelerates the insertion of
organozinc reagent to carbonyl compound; and (3) it facili-
tates the formation of alkene from secondary alcohol or silyl
ether.
Acknowledgment. We are grateful to the National Nat-
ural Science Foundation of China, Shanghai Municipal
Commission of Science and Technology, and the Shanghai
Municipal Commission of Education for financial support.
Supporting Information Available: Experimental procedure
and spectroscopic data for the products. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
6858 J. Org. Chem. Vol. 74, No. 17, 2009