Selective carbonyl propargylation mediated by SnCl2/NiCl 2-KI in water

Article abstract of DOI:10.1071/CH05091

Propargylation of carbonyl compounds to produce homopropargylic alcohols plays a very important role in synthetic organic and pharmaceutical chemistry. A novel method that carbonyl compounds and propargyl halide were mediated by SnCl₂/NiCl

Full text of DOI:10.1071/CH05091

Short Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2005, 58, 611–614
Selective Carbonyl Propargylation Mediated by SnCl /NiCl -KI
2
2
in Water
A
A
A,B
Jun Wang, Xiao-Peng Miao, and GuYuan
A
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
Department of Chemical Biology, College of Chemistry, Peking University, Beijing 100871, China.
Corresponding author. Email: guyuan@pku.edu.cn
B
Propargylation of carbonyl compounds to produce homopropargylic alcohols plays a very important role in synthetic
organicandpharmaceuticalchemistry.Anovelmethodthatcarbonylcompoundsandpropargylhalideweremediated
by SnCl2/NiCl2-KI in water at room temperature was developed by us to successfully synthesize homopropargylic
alcohols in good yields. The reactions were carried out in an environmentally friendly solution and under mild
conditions.
Manuscript received: 20 April 2005.
Final version: 25 July 2005.
Homopropargylic alcohols are very useful intermediates in
organic synthesis and an important structural moiety in a
variety of biologically active compounds.[1] Numerous meth-
ods for the synthesis of homopropargylic alcohols have been
developed with organometallic reagents[ and the selectiv-
ity of the reactions toward yielding either homopropargylic
alcohols or allenic alcohols is an important factor. In most of
these methods, the chemoselectivity of the products is highly
dependent upon steric hindrance, solvents, and metals.
Table 1. Optimization conditions
O
OH
Br
Conditions
H ϩ
H O
2
2]
Entry
ConditionsA
SnCl2
Yield [%]B
1
2
3
4
5
6
7
8
9
0
0
0
0
0
SnCl /ZnCl (20 mol-%)
2
2
SnCl2/NiCl2 (20 mol-%)
SnCl2/CeCl3 (20 mol-%)
SnCl2/InCl3 (20 mol-%)
SnCl2/CuBr (20 mol-%)
SnCl2/KI (10 mol-%)
Recently, the synthesis of homopropargyl alcohols in
aqueous media[
3,4]
has drawn much interest because of the
0
operational simplicity and the advantages of using an envi-
ronmentally friendly solvent. Many metals have been used to
examine the propargylation of carbonyl compounds in water,
which often gives a mixture of homopropargylic alcohols and
38
53
57
63
70
65
62
59
72
SnCl /KI (30 mol-%)
2
SnCl2/KI (40 mol-%)
1
0
SnCl2/KI (30 mol-%)/ZnCl2 (20 mol-%)
SnCl2/KI (30 mol-%)/NiCl2 (20 mol-%)
SnCl2/KI (30 mol-%)/CeCl3 (20 mol-%)
SnCl2/KI (30 mol-%)/InCl3 (20 mol-%)
SnCl /KI (30 mol-%)/NiCl (10 mol-%)
[
5]
11
allenic alcohols. Among these metals, indium-mediated
1
1
2
3
propargylation has attracted considerable attention due to its
mild reaction conditions as well as high selectivity. However,
the use of zero-valent metals unavoidably causes problems
because the metal-mediated propargylation is a heteroge-
neous reaction in water. For instance, it is often difficult to
stir the reaction mixture and metal oxide or hydroxide pre-
cipitation on the surface of metal may slow or even stop the
reaction.
14
15
2
2
SnCl2/KI (30 mol-%)/NiCl2 (30 mol-%)
A
Reactions were carried out using 1 mmol of benzaldehyde and
.4 mmol of propargyl bromide at room temperature under an atmo-
sphere of air for 12 h.
1
B
Isolated yields reported.
Water-soluble reductive metal salts, such as SnCl2, can
solve these problems when the salts are applied in the aqueous
phase reaction. Stannous chloride has successfully been used
to mediate the carbonyl allylation.[ Additionally, the previ-
ous studies have shown that SnCl2 can mediate the carbonyl
propargylation.[ However, the reported reactions need to be
carried out in organic solvents or at high temperatures. Some
of these reactions need a stoichiometric excess of iodide ion,
which often results in low selectivity and yield. In this paper,
we report the selective carbonyl propargylation mediated by
SnCl /NiCl -KI under mild conditions in water to produce
homopropargylic alcohols in good yields.
2
2
6]
The investigation started with the reaction of benzalde-
hyde and propargyl bromide (Table 1). SnCl alone cannot
2
7]
mediate the coupling between propargyl bromide and a car-
bonyl compound to generate the homopropargylic alcohol
(Entry 1). When Lewis acid catalysts were added to the reac-
tion, no products were observed (Entries 2–6). With the use
of KI intended to activate propargyl bromide, the reaction
©
CSIRO 2005
10.1071/CH05091
0004-9425/05/080611

6
12
J. Wang, X.-P. Miao and G. Yuan
Table 2. Propargylation of various carbonyl compounds
O
Br
OH
SnCl2/KI (30 mol-%)/NiCl2 (20 mol-%)
ϩ
R
H
H2O
R
Entry
1
Substrates
Products
Time [h]
Yield [%]A
70
O
OH
H
1
2
3
12
O
OH
2
3
H
14
16
70
65
Me
Me
O
OH
H
MeO
MeO
O
OH
4
5
H
4
5
16
12
67
66
C H O
3 5
C H O
3
5
Cl
O
Cl
OH
H
O
OH
6
7
H
6
11
57
F
F
O
OH
H
7
8
11
12
59
64
F3C
F3C
OH
CHO
8
9
OH
9
12
15
65
60
CHO
CHO
C6H13
C6H13
1
0
10
OH
(
Continued)

Selective Carbonyl Propargylation
613
Table 2. (Continued)
Entry
Substrates
Products
Time [h]
12
Yield [%]A
62
OH
11
11
12
C6H13
CHO
C6H13
OH
1
1
2
3
12
18
58
–
CHO
O
–
–
O
14
18
–
A
Isolated yields.
provided moderate yields of the desired products (Entries
–9).The addition of 0.3 eq. KI into the reaction stabilized the
electron-withdrawing group offers a moderate selectivity and
yield at ambient temperature.
7
yield but further increase of the amount of KI did not improve
the yield significantly. When Lewis acids were employed
in the system, there was an increase in the yields (Entries
Experimental
General Procedure
1
0–15). More than 20 mol-% Lewis acid was used, but the
To a mixture of carbonyl compound (1 mmol) and propargyl bro-
mide (1.4 mmol) in water (2 mL), KI (30 mmol-%), and Lewis acid
NiCl2·6H2O (20 mmol-%) were added. After the mixture was stirred
for about one minute, SnCl2·2H2O (2 mmol) was added. The mix-
ture was vigorously stirred at room temperature for several hours. The
mixture was extracted with ether (3 × 15 mL) directly. The combined
organic extract was washed with brine (2 × 10 mL), dried over anhy-
drous sodium sulfate, filtered, and then evaporated. The residue was
purified by flash chromatography over silica gel. The products were
yields did not dramatically improve (Entries 11 and 15). On
the basis of these results, the optimal conditions are shown
in Entry 11.
Subsequently, a variety of carbonyl compounds and
propargyl bromide were investigated in the synthesis of
homopropargylic alcohols under the conditions in Table 2.
The reactions of aromatic aldehydes with propargyl bro-
mide in water mainly produce homopropargylic alcohols.The
aromatic aldehydes substituted by electron-donating groups,
which need a longer time to complete the reaction, are
less reactive to propargyl bromide than those substituted by
electron-withdrawing groups. However, the aromatic alde-
hydes substituted by electron-withdrawing groups give the
relatively low yields of propargyl alcohols (Entries 1–7).
This is due mainly to the lower selectivity in propargylation
of aromatic aldehydes substituted by electron-withdrawing
groups, compared to the selectivity in propargylation of other
aromatic aldehydes. For α,β-unsaturated aldehydes, the
reaction also offers a high selectivity in the propargylation
and gives good yields (Entries 8 and 9). On the other hand, the
propargylation of aliphatic aldehydes exhibits a slightly low
selectivity and yield (Entries 10–12). Under the same condi-
tions, no propargylation products were found when ketones
were employed (Entries 13 and 14).
1
13
identified by H NMR and C NMR.
Accessory Materials
Spectroscopic characterization data for 1–12 are available
from the author or, until August 2010, the Australian Journal
of Chemistry.
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