Regioselective propargylation of carbonyl compounds with (3-bromo-prop-1-ynyl)trimethylsilane promoted by reactive barium

Article abstract of DOI:10.1055/s-2005-869874

A Barbier-type propargylation of aldehydes with (3-bromoprop-1-ynyl) trimethylsilane has been achieved using reactive barium as a low-valent metal in THF. This process is effective also for obtaining the desired homopropargylic alcohols in high yields fro

Full text of DOI:10.1055/s-2005-869874

LETTER
1679
Regioselective Propargylation of Carbonyl Compounds with (3-Bromo-
prop-1-ynyl)trimethylsilane Promoted by Reactive Barium
R
egioselective Pro
k
pargylation
i
r
onyl Com
a
pounds Yanagisawa,*a Shogo Okitsu,b Takayoshi Araia
a
Department of Chemistry, Faculty of Science, Chiba University, Inage, Chiba 263-8522, Japan
Fax +81(43)2902789; E-mail: ayanagi@scichem.s.chiba-u.ac.jp
b
Graduate School of Science and Technology, Chiba University, Inage, Chiba 263-8522, Japan
Received 18 April 2005
reactive barium, which was generated from barium iodide
and lithium biphenylide,6 and a 45:55 mixture of ho-
mopropargylic alcohol 1a and allenylic alcohol 2a was
obtained in 88% combined yield (Table 1, entry 1). Use of
Abstract: A Barbier-type propargylation of aldehydes with (3-bro-
moprop-1-ynyl)trimethylsilane has been achieved using reactive
barium as a low-valent metal in THF. This process is effective also
for obtaining the desired homopropargylic alcohols in high yields
from the corresponding ketones including enolizable ketones such a phenyl group-substituted propargyl bromide resulted in
as cyclopent-2-enone.
a similar result with g-selectivity (entry 2); however, the
homopropargylic alcohol 1c was formed almost exclu-
sively in the reaction of (3-bromoprop-1-ynyl)trimethyl-
silane (entry 3).
Key words: barium, propargylation, aldehydes, regioselectivity,
ketones
Table 1 Reactive Barium-Promoted Barbier-Type Reaction of
Various Propargylic Bromides with p-Anisaldehydea
Propargylation of carbonyl compounds is a convenient
method for introducing a carbon–carbon triple bond into
organic molecules.1 One drawback of this reaction using a
propargylic or allenylic metal reagent is the control of
regiochemistry. In general, organomagnesium and zinc
reagents generated from g-alkylated propargyl bromides
react with aldehydes preferentially at the g-position to af-
ford allenylic alcohols.2 Although the regiocontrolled
synthesis of homopropargylic alcohols has been exten-
sively studied, there are still not many satisfactory meth-
ods for the selective propargylation.1c,3 We describe
herein a new approach to a-selective reaction of a Me3Si-
substituted propargyl bromide with aldehydes and ke-
tones using reactive barium as a promoter (Scheme 1).
R
OH
OH
γ
Ba*
α
+
+
ArCHO
R
γ
α
·
THF, –78 °C
Ar
Ar
Br
1
2
Ar = 4-MeOC6H4
R
Entry
R
Time (h) Yield (%)b Products
a:gc
1
2
3
Me
1
88
89
89
1a + 2a
1b + 2b
1c + 2c
45:55
40:60
> 99:1
Ph
3.5
2.5
Me3Si
a The reaction was carried out using propargylic bromide (1 equiv),
p-anisaldehyde (0.3 equiv), and reactive barium (1.1 equiv) in dry
THF at –78 °C.
b Isolated yield.
Me3Si
OH
Ba*
c Determined by 1H NMR analysis.
Me3Si
R1COR2
+
R2
THF
Br
R1
The high a-selectivity is a specific characteristic of the
barium reagent, and other alkaline earth metal reagents
derived from the Me3Si-substituted propargyl bromide
provided a mixture of homopropargylic alcohol 1c and
allenylic alcohol 2c as shown in Table 2. Among them,
the magnesium reagent indicated the lowest 1c:2c selec-
tivity (entry 1).7
Scheme 1 Barbier-type reaction of a propargylic bromide with car-
bonyl compounds promoted by reactive barium
We have previously shown that allylic barium reagents
are readily generated from the corresponding allylic
chlorides and in situ prepared reactive Rieke barium4,5 and
react with carbonyl compounds at the least substituted
allylic terminus.4 We envisioned that if a propargylic
barium reagent is selectively formed from a propargylic
halide and the reactive barium, the targeted homopro-
pargylic alcohols could be prepared in high yield by
treatment of the barium reagent with aldehydes. First, ac-
cording to the Barbier-type technique, a mixture of p-anis-
aldehyde and 1-bromobut-2-yne was exposed to the
Then, we examined the barium-promoted regioselective
propargylation of various aldehydes and the results are
summarized in Table 3. As a consequence, not only aro-
matic aldehydes but a,b-unsaturated and aliphatic alde-
hydes were also allowed to react with the barium reagent
to give the corresponding homopropargylic alcohols in
moderate to high yields. In every case no allenylic alcohol
was observed at all. In the reaction with cinnamaldehyde,
only a 1,2-adduct was obtained (entry 6).
SYNLETT 2005, No. 11, pp 1679–1682
0
7
.0
7
.2
0
0
5
Advanced online publication: 09.06.2005
DOI: 10.1055/s-2005-869874; Art ID: U11505ST
© Georg Thieme Verlag Stuttgart · New York

1680
A. Yanagisawa et al.
LETTER
Table 2 Effect of Metals on the Regioselectivity of the Barbier-
Type Reaction of (3-Bromoprop-1-ynyl)trimethylsilane with p-Anis-
aldehydea
Table 4 Reactive Barium-Promoted Selective Propargylation of
Various Ketones with (3-Bromoprop-1-ynyl)trimethylsilanea
Me3Si
OH
γ
Ba*
α
R1COR2
+
Me3Si
γ
M*
α
α
R2
THF, –78 °C
+
ArCHO
Me3Si
Br
R1
THF, –78 °C
Br
Ar = 4-MeOC6H4
Entry
R1COR2
Yield (%)b,c
Me3Si
OH
OH
1
2
3
PhCOCH3
77
85
52
+
·
γ
α
Ar
Ar
4-MeOC6H4COCH3
1c
2c
SiMe3
Entry
M*
Yield (%)b
1c:2cc
53:47
74:26
88:12
> 99:1
COCH3
O
1
2
3
4
Mg*
Ca*
Sr*
34
68
87
89
4
89
O
5
6
(E)-PhCH=CHCOCH3
80d
71d
Ba*
O
a The reaction was carried out using (3-bromoprop-1-ynyl)trimethyl-
silane (1 equiv), p-anisaldehyde (0.3 equiv), and reactive metal (1.1
equiv) in dry THF at –78 °C.
7
94d
O
b Isolated yield.
c Determined by 1H NMR analysis.
a The reaction was carried out using (3-bromoprop-1-ynyl)trimethyl-
silane (1 equiv), ketone (0.3 equiv), and reactive barium (1.1 equiv)
in dry THF at –78 °C for 1–3 h.
Table 3 Reactive Barium-Promoted Selective Propargylation of
Various Aldehydes with (3-Bromoprop-1-ynyl)trimethylsilanea
b Isolated yield.
Me3Si
OH
γ
Ba*
c The a:g ratio of the product in each entry was determined to be
> 99:1 by 1H NMR analysis.
α
+
RCHO
Me3Si
α
THF, –78 °C
R
Br
d The 1,2:1,4 ratio of the a-product was determined to be > 99:1 by
1H NMR analysis.
Entry
RCHO
Yield (%)b,c
1
2
3
4
5
6
7
PhCHO
67
96
89
78
79
74
60
4-MeC6H4CHO
4-MeOC6H4CHO
1-C10H7CHO
are good Michael acceptors, still show an exclusive 1,2-
selectivity (entries 6 and 7). Noteworthy is the fact that
readily enolizable ketones gave the desired adducts in
high yield which means that the nucleophilicity of the
barium reagent predominates over its basicity (entries 4
and 7).
2-C10H7CHO
(E)-PhCH=CHCHO
Ph(CH2)2CHO
The reason for the regiochemical outcome has not yet
been fully elucidated; however, two pathways leading to
a propargylated product (a-adduct) are plausible (Scheme
2). A barium reagent generated from (3-bromoprop-1-
ynyl)trimethylsilane and reactive barium is considered to
exist at equilibrium between the allenic form A and the
acetylenic form B. The homopropargylic alcohol is ob-
tainable from both isomers in their reaction with an alde-
hyde via the transition state structure C or D. The
transition state D is, however, more favorable in view of
its less steric repulsion.9 The four-membered cyclic tran-
sition state model is also supported by the mechanism of
the reaction of allylic barium reagents with carbonyl com-
pounds.4b,c In contrast, the corresponding allenylic alcohol
(g-adduct) is conceivable to form by a SE2¢-type reaction
of B with the aldehyde via the six-membered cyclic tran-
sition state E, which is, however, destabilized by a steric
hindrance of the Me3Si group of B.
a The reaction was carried out using (3-bromoprop-1-ynyl)trimethyl-
silane (1 equiv), aldehyde (0.3 equiv), and reactive barium (1.1 equiv)
in dry THF at –78 °C for 1–3 h.
b Isolated yield.
c The a:g ratio of the product in each entry was determined to be
> 99:1 by 1H NMR analysis.
We further studied the addition of the barium reagent to
ketones with the anticipation that the selective propargyl-
ation also would occur with the bulkier and less reactive
carbonyl compounds. In fact, condensation of the barium
reagent with various ketones afforded the desired ho-
mopropargylic alcohols nearly exclusively in satisfactory
yields (Table 4).8 Cyclic a,b-unsaturated ketones, which
Synlett 2005, No. 11, 1679–1682 © Thieme Stuttgart · New York

LETTER
Regioselective Propargylation of Carbonyl Compounds
1681
(d, 2 H, J = 8.0 Hz, aromatic), 7.25 (d, 2 H, J = 8.0 Hz, aromatic).
13C NMR (100 MHz, CDCl3): d = 0.0 (3 C), 21.1, 31.1, 72.1, 87.7,
103.1, 125.6 (2 C), 129.0 (2 C), 137.4, 139.6. The above-mentioned
spectral data indicated good agreement with reported data.11
XBa
γ
γ
α
α
·
Me3Si
Me3Si
BaX
A
B
RCHO
R
RCHO
R
RCHO
Me3Si
H
O
α
References
BaX
H
XBa
H
O
Me3Si
O
·
α
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γ
Ba
R
Me3Si
X
C
D
E
Me3Si
OH
OH
γ
α
·
R
R
homopropargylic alcohol
Me3Si
allenylic alcohol
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Scheme 2 Plausible reaction pathways to homopropargylic
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alcohols and allenylic alcohols
In summary, we have achieved a novel Barbier-type reac-
tion of trimethylsilylpropargyl bromide with aldehydes
and ketones using reactive barium as a promoter. This
method is superior to those employing other group 2 metal
reagents from the viewpoint of regioselectivity and pro-
vides a variety of (trimethylsilyl)homopropargylic alco-
hols in satisfactory yields. The Me3Si group can be further
transformed into other useful functional groups.10 Studies
on related reactions using the organobarium reagent are
now in progress.
A Typical Experimental Procedure for the Barbier-Type Pro-
pargylation (Table 3, Entry 2).
An oven-dried, 30 mL two-necked round-bottomed flask equipped
with a Teflon®-coated magnetic stirring bar was flushed with argon.
Freshly cut lithium (15.0 mg, 2.16 mmol) and biphenyl (350 mg,
2.27 mmol) were put into the apparatus and covered with dry THF
(3 mL), and the mixture was stirred for 2 h at 20–25 °C (lithium was
completely consumed). Anhyd BaI2 (450 mg, 1.15 mmol) was
placed in a separate oven-dried, 30 mL flask also equipped with a
Teflon®-coated magnetic stirring bar under argon atmosphere; this
was covered with dry THF (5 mL), and stirred for 20 min at r.t. To
the solution of BaI2 in THF was added at r.t. a solution of the lithium
biphenylide in THF under an argon stream. The reaction mixture
was stirred for 30 min at r.t. A solution of (3-bromoprop-1-ynyl)tri-
methylsilane (191 mg, 1.00 mmol) and p-tolualdehyde (36.0 mL,
0.305 mmol) in dry THF (4 mL) was added dropwise to the result-
ing dark brown suspension of reactive barium (1.08 mmol) in THF
(8 mL) at –78 °C. After being stirred for 2.5 h at this temperature,
the mixture was treated with a sat. NH4Cl aqueous solution (10 mL)
at –78 °C and the aqueous layer was extracted with Et2O (10 mL).
The combined organic extracts were washed with 1 N Na2S2O3 so-
lution (20 mL), dried over anhyd Na2SO4, and concentrated in vac-
uo after filtration. The residual crude product was purified by
column chromatography on silica gel to give the homopropargylic
alcohol (68.3 mg, 96% yield). The a:g ratio was determined to be
>99:1 by 1H NMR analysis. Spectral data of the product: TLC Rf =
0.57 (1:3 EtOAc–hexane). 1H NMR (400 MHz, CDCl3): d = 0.15 (s,
9 H, 3 CH3), 2.34 (s, 3 H, CH3), 2.53 (d, 1 H, J = 2.7 Hz, OH), 2.62
(d, 2 H, J = 6.5 Hz, CH2), 4.79 (dt, 1 H, J = 6.5, 2.7 Hz, CH), 7.15
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Synlett 2005, No. 11, 1679–1682 © Thieme Stuttgart · New York

1682
A. Yanagisawa et al.
LETTER
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Synlett 2005, No. 11, 1679–1682 © Thieme Stuttgart · New York