A novel preparation of methyl ketones through one-carbon homologation of aldehydes

Article abstract of DOI:10.1016/S0040-4039(03)01084-0

A novel two-step aldehyde homologation procedure for the preparation of methyl ketones has been developed, which involves the use of 1,1-dibromo-1-alkenes as precursors and zinc metal as mediator in near-critical water.

Full text of DOI:10.1016/S0040-4039(03)01084-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4685–4688
A novel preparation of methyl ketones through one-carbon
homologation of aldehydes
Lei Wang,a,b,* Pinhua Li,a Jincan Yana and Zhongzhi Wuc
aDepartment of Chemistry, Huaibei Coal Teachers College, Huaibei, Anhui 235000, PR China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, PR China
cDepartment of Chemistry, The University of Tennessee, Knoxville, TN 37996-1600, USA
Received 7 March 2003; revised 15 April 2003; accepted 25 April 2003
Abstract—A novel two-step aldehyde homologation procedure for the preparation of methyl ketones has been developed, which
involves the use of 1,1-dibromo-1-alkenes as precursors and zinc metal as mediator in near-critical water. © 2003 Elsevier Science
Ltd. All rights reserved.
Conversion of aldehydes to the homologous methyl
ketones is an important functional group transforma-
tion in organic synthesis and a variety of methods have
been recommended for this purpose. The traditional
synthetic method involves a Grignard or organolithium
reagent addition to an aldehyde followed by oxidation
of alcohol.1 On the other hand, the direct insertion of
an alkylidene unit from diazomethane to the aldehyde
CꢀH bonds is also an effective approach.2 Other meth-
ods, such as a hydride–methyl exchange reaction and
Cr(II)-mediated homologation of aldehydes using
Me3SiCBr3 have also been reported.3 However, these
methods suffer from either harsh reaction conditions
that may not be compatible with many functional
groups present in the molecules or moderate yields with
a mixture of homologous ketones, oxiranes, higher
homologs of starting aldehydes, or multi-homologation
products along with waste handling problems.
critical water research has focused on the total
oxidation of organic compounds and geochemical model-
ing,6 there are increasing numbers of papers which
suggest that near-critical water (250–325°C) can be an
excellent solvent for organic reactions because reactions
in near-critical water offer many advantages over those
in traditional organic solvents. For example, it is envi-
ronmentally benign and separation of products from
the reaction mixture is simplified.7
1,1-Dibromo-1-alkenes, easily prepared from a simple
reaction of an aldehyde with carbon tetrabromide and
triphenylphosphine,8 are important starting materials in
organic synthesis. There are a few reports on the Pd-
catalyzed cross coupling reactions of 1,1-dihalo-1-alke-
nes with boronic acids,9 organostannanes,10 alkynes
and vinylalanes,11 organozinc and Grignard reagents.12
In addition, hydrogenolysis of 1,1-dibromo-1-alkenes
with tributyltin hydride,13 reduction with hydride
anion,14 reductive debromination with indium metal15
and samarium diiodide,16 and reaction with amine17
have also been reported. However, to our knowledge,
there is no report so far on the conversion of aldehydes
to the homologous methyl ketones via 1,1-dibromo-1-
alkene. Here, we wish to report a novel method for this
conversion through the reaction of 1,1-dibromo-1-
Organic reactions carried out in water have received
considerable attention in the last decade.4 Unfortu-
nately most organic compounds are poorly soluble in
water at ambient temperature. Nonetheless, the unique
properties of water near its critical point (Tc=374°C,
Pc=221 bar) have prompted researchers to use it
instead of organic solvents or ambient temperature
water in organic synthesis.5 Although much of super-
Keywords: 1,1-dibromo-1-alkene; near-critical water; zinc metal;
homologation; methyl ketone; aldehyde.
* Corresponding author. Tel.: +86-561-380-2069; fax: +86-561-309-
0518; e-mail: leiwang@hbcnc.edu.cn
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01084-0

4686
L. Wang et al. / Tetrahedron Letters 44 (2003) 4685–4688
alkene (generated from aldehyde) with zinc metal in
near-critical water (Scheme 1).
pounds
were
successfully
converted
to
the
corresponding aromatic methyl ketones in good to
excellent yields (except for entry 8, Table 2). The reac-
tion was carried out simply by stirring 2-aryl-1,1-
dibromo-1-alkenes with commercially available zinc
powder in water under nitrogen without any other
organics or additives at 275°C. The results are listed in
Table 2. As is evident from Table 2, electron-donating
groups (such as CH3O, CH3) or electron-withdrawing
groups (such as CO2Et, F, Cl) and their location on the
Our initial studies were directed towards exploring the
reaction conditions for the reaction of 1,1-dibromo-1-
alkenes with metallic zinc in hot water. The results are
summarized in Table 1. 1,1-Dibromo-2-phenyl-1-ethene
was chosen as a model compound for this investigation.
As can be seen from Table 1, the reaction temperature
plays a very important role in the reduction of 1,1-
dibromo-2-phenyl-1-ethene with metallic zinc in hot
water. It is evident that 1,1-dibromo-2-phenyl-1-ethene
cannot be converted to acetophenone with zinc metal in
water at T 5200°C without any additives18 and only a
small quantity of product was generated in the temper-
ature range 200 to 250°C. When the reaction tempera-
ture was at 275°C, the yield of acetophenone was
improved significantly. The ratio of zinc metal to 1,1-
dibromo-2-phenyl-1-ethene was also examined. The
results showed that when the ratio of zinc to 1,1-
dibromo-2-phenyl-1-ethene was less than 2:1, the reduc-
tion was not complete (entries 7 and 8, Table 1) and
while the ratio equals or was more than 3:1, satisfactory
results were achieved (entries 5, 9 and 10, Table 1). We
also investigated the effect of reaction time. The experi-
mental data indicate that the reaction was not com-
pleted when the reaction time was less than 3 h (entries
11 and 12, Table 1). However, no increase in yield was
observed when the reaction time was prolonged. The
optimized conditions for the reaction of 1,1-dibromo-2-
phenyl-1-ethene with zinc metal in water were found to
be 1,1-dibromo-2-phenyl-1-ethene (1 mmol), Zn (3
mmol), H2O (10 mL) at 275°C for 4 h.
Table 2. Conversion of 1,1-dibromo-1-alkenes to methyl
ketones with zinc metal in near-critical watera
A variety of 2-aryl-1,1-dibromo-1-alkenes were sub-
jected the new reaction sequence. Essentially, all com-
Table 1. Optimization reaction conditions for the conver-
sion of 1,1-dibromo-2-phenyl-1-ethene to acetophenone
with zinc metal in watera
Entry
Zn:dibromide Temp (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
3:1
3:1
3:1
3:1
3:1
3:1
1:1
2:1
4:1
5:1
3:1
3:1
3:1
3:1
175
200
225
250
275
300
275
275
275
275
275
275
275
275
4
4
4
4
4
4
4
4
4
4
1
3
5
7
0c
0
15
45
83
80
36
62
82
83
28
60
81
78
9
10
11
12
13
14
a Reaction conditions: 1,1-dibromo-2-phenyl-1-ethene (1.00 mmol),
tap water (10 mL) in a high T/p batch reactor system.
b Isolated yields.
c Starting material 1,1-dibromo-2-phenyl-1-ethene (98%) was recov-
ered.

L. Wang et al. / Tetrahedron Letters 44 (2003) 4685–4688
4687
aromatic ring had little effect on the reaction. However,
a bromo group on the aromatic ring underwent reduc-
tive elimination in a competitive process, but a chloro
group could tolerate the reaction conditions and
remained unchanged. The reactivity of halogen atoms
on the aromatic ring is Br>Cl, which is consistent with
the expected reactivity and Poliakoff’s experimental
result.19 Fortunately, 2-alkyl-1,1-dibromo-1-alkenes
also react with zinc metal under reaction conditions to
yield aliphatic methyl ketones (entries 11 and 12, Table
2). 1,1-Dichloro-1-alkenes were also examined, but they
are far less reactive, probably due to the stronger
carbonꢀchlorine bond.
tion Ministry, China (No. 2002247), and the Excellent
Young Teachers Program of MOE, China (No. 2024)
for financial support.
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Although a study of the detailed reaction mechanism
has not been undertaken, the reaction presumably pro-
ceeds through the reduction of 1,1-dibromo-1-alkene by
zinc to form the corresponding alkyne followed by
hydration in the presence of ZnBr2 formed in the
reaction and under near-critical water reaction condi-
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phenylacetylene, an 89% yield of acetophenone was
obtained from reactions with ZnBr2 in near-critical
water. Further investigation is currently underway.
General procedure for the reaction of 1,1-dibromo-1-
alkenes with metallic zinc in near-critical water: 1,1-
Dibromo-1-alkenes (1.00 mmol) and metallic zinc
powder (196 mg, 3.00 mmol) were added to a high
temperature and pressure stainless steel reactor charged
with tap water (10 mL) under nitrogen with stirring.
The reactor was heated at 275°C for 4 h. After cooling,
ether (2×10 mL) was added to extract the products. The
organic layer was dried with anhydrous sodium sulfate,
the solvents were evaporated under reduced pressure,
and the product was purified by flash chromatography
to yield the methyl ketone.
CAUTION: This procedure involves a high tempera-
ture and pressure and must only be carried out in an
apparatus with the appropriate pressure rating at the
reaction temperature. The reaction should be per-
formed in a safe place.
In conclusion, a novel, reliable, and practical two-step
aldehyde homologation procedure for the preparation
of methyl ketones has been developed, which involves
the use of 1,1-dibromo-1-alkene as precursor and zinc
metal as mediator in near-critical water. The method
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