Synthesis of tertiary 1,3-butadien-2-ylcarbinols from chromium-catalyzed addition of (4-bromobut-2-ynyl)trimethylsilane to ketones

Article abstract of DOI:10.1016/j.tetlet.2010.07.104

The synthesis of 1,3-butadien-2-ylcarbinols containing a tertiary alcohol is achieved by desilylation of (trimethylsilyl)methylallenic alcohols. The latter are obtained via a chromium-catalyzed addition of (4-bromobut-2-ynyl) trimethylsilane to aliphatic or aromatic ketones. The desired adducts are obtained in yields ranging from 21% to 67% for this two-step, one-pot process.

Full text of DOI:10.1016/j.tetlet.2010.07.104

Tetrahedron Letters 51 (2010) 5080–5082
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Tetrahedron Letters
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Synthesis of tertiary 1,3-butadien-2-ylcarbinols from chromium-catalyzed
addition of (4-bromobut-2-ynyl)trimethylsilane to ketones
*
María Durán-Galván, James R. Hemmer, Brian T. Connell
Department of Chemistry, Texas A&M University, PO Box 30012, College Station, TX 778423012, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 1,3-butadien-2-ylcarbinols containing a tertiary alcohol is achieved by desilylation of
(trimethylsilyl)methylallenic alcohols. The latter are obtained via a chromium-catalyzed addition of (4-
bromobut-2-ynyl)trimethylsilane to aliphatic or aromatic ketones. The desired adducts are obtained in
yields ranging from 21% to 67% for this two-step, one-pot process.
Received 11 June 2010
Revised 15 July 2010
Accepted 16 July 2010
Available online 22 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1,3-Butadien-2-ylcarbinols are valuable moieties that can be
used in the synthesis of more complex organic molecules.1 Several
strategies for the synthesis of 1,3-butadien-2-ylcarbinols from
additions to aldehydes to afford secondary alcohols have been
developed.2 However, methodologies for the synthesis of tertiary
1,3-butadien-2-ylcarbinols 2 from ketones are scarce, regardless
of their significance. Although the addition of a nucleophilic orga-
nometallic reagent to a carbonyl group is a common approach for
the formation of new carbon–carbon bonds,3 aldehydes are used
for this purpose much more regularly than ketones,4 presumably
due to the lower electrophilicity of ketones toward nucleophilic
additions which also increases the possibility of competitive pro-
ton transfer. Among the examples of organometallic additions to
ketones (1), the use of magnesium5 and lithium6 reagents derived
from organostannanes for the synthesis of 2 can be highlighted
(equiv 1). Unfortunately, these early methods present low regiose-
lectivity and afford mixtures of the desired diene and the corre-
sponding homoallenic alcohol 3.
nols with good yields. Nevertheless, the substrates are not commer-
cially available.
TMS
OH
OH
O
4
Br
R
TMS
R
H
cat. CrCl3
Mn0, NEt3
5
ð2Þ
R = alkyl, aryl
TBAF
R
6
In an effort to overcome some of the drawbacks presented by the
existing procedures, we recently reported the synthesis of 2°
1,3-butadien-2-ylcarbinols by the chromium-catalyzed addition of
(4-bromobut-2-ynyl)trimethylsilane (4) to aldehydes followed by
desilylation of the resulting (silylmethyl)allenic alcohols (5) to pro-
vide dienes 6 (equiv 2).9 This reaction proceeds well with a variety
of aldehydes including alkyl, aryl, electron-rich, or electron-poor
and the corresponding adducts were obtained with good yields.
Encouraged by these results with aldehydes, we aimed for the
extension of this methodology to ketone electrophiles. Even though
chromium-catalyzed additions to ketones are not common,10 it was
envisioned that the allenylation of ketones and the subsequent
desilylation of the tertiary allenic alcohol could provide a useful
approach for the regioselective synthesis of dienes 2.
The reactivity of ketones toward the chromium-catalyzed alleny-
lation was explored. 4-Phenylbutan-2-one 1a was combined with
1.1 equiv of 4 in the presence of a catalytic amount of CrCl3 and
2 equiv each of Mn0 and TMSCl in THF. After quenching with 1 M
HCl, the deprotected 3° allenic alcohol 5a was obtained in 51% con-
version (Table 1, entry 1). No regioisomers, such as the correspond-
ing propargylic alcohol 7, were observed. This is complementary to
M
R2
R1
O
R2 OH
R1
OH
ð1Þ
R1
R2
1
2
3
R1, R2 = alkyl or aryl
Due to this difficulty, alternative strategies have been developed.
Tertiary 1,3-butadien-2-ylcarbinols can be obtained by thermal ring
opening of cyclobutenyl alcohols.7 Although this method provides
the desired alcohols with good yields, the required starting materi-
als are not readily available and the substrate scope is limited. More
recently, Alcaraz et al. reported the homologation of chiral epoxy
bromides with dimethylsulfonium methylide for the synthesis of
2.8 This method provides alkyl or alkyl/aryl 1,3-butadien-2-ylcarbi-
* Corresponding author. Tel.: +1 979 845 5746; fax: +1 979 458 2969.
E-mail address: connell@chem.tamu.edu (B.T. Connell).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.104

M. Durán-Galván et al. / Tetrahedron Letters 51 (2010) 5080–5082
5081
Table 1
Table 3
Optimization of the allenylation reactiona
Scope of the reactiona
Br
TMS
Br
4
TMS
O
HO
R1
R2
4
O
CrCl3 (30 mol%), Mn0, Et3N,
HO
CH3
CrCl3 (30 mol%)
R1
R2
TMSCl; then 1 M TBAF
Ph
TMS
TMS
Ph
CH3
Mn0, Et3N, TMSCl;
then 1 M HCl
1a-g
2a-g
1a
5a
Entry
Ketone
Product
Yieldb (%)
Entry
4 (equiv)
Conversionb (%)
HO
CH3
1
2
3
4
1.1
2.2
51
61
OH
1
1a
2a
2b
2c
2d
69
41
23
45
Ph
3.0
4.0
80
50
7
Ph
HO
CH3
Not observed
2
1b
1c
1d
CrCl3 (30 mol %), Mn0 (2 equiv), TMSCl (2 equiv), rt, 24 h. Then 1 M HCl, rt,
a
30 min.
Determined by 1H NMR.
b
OH
3c
4
prior methods in which the formation of the propargylic alcohol 7 is
favored.11 Increasing the equivalents of 4 results in an increase in
conversion (entries 1–3) until 4 equiv is reached, at which point a
notable decrease in conversion is observed (entry 4).
The desired 1,3-butadien-2-ylcarbinol 2a was prepared in situ
from the unpurified allene 5a by direct treatment with TBAF. Use
of 2 equiv of TBAF resulted in only 25% conversion to the desired die-
nylalcohol (Table 2, entry 1). Use of excess TBAF greatly increased
the product yield. The required excess can be explained by the pres-
ence of excess (4-bromobut-2-ynyl)trimethylsilane 4 in the reaction
mixture, which competitively consumes the fluoride.
HO
CH3
HO
CH3
5
1e
1f
2e
2f
53
67
51
H3C
Br
HO
CH3
6c
After obtaining these optimized reaction conditions for ketone
addition followed by diene formation, the substrate scope was
evaluated. Aliphatic methyl ketone 1a is an excellent substrate
for this reaction (Table 3, entry 1). Ketone 1b, which is more steri-
HO
CH3
cally hindered due to the presence of a secondary carbon
a to the
7c
1g
2g
carbonyl group, is somewhat less reactive, but afforded the desired
product in 41% yield (entry 2). Cyclohexanone gave the corre-
sponding diene 2c, albeit in poor yield (entry 3). Aromatic ketones
including acetophenone and p-methylacetophenone afford the de-
sired diene in 45% and 53% yield, respectively (entries 4 and 5). It
was observed that the nature of the substituent in the aromatic
group affects the rate of the reaction. Allenylation of ketone 1f con-
taining a slightly electron-withdrawing group in the para position
afforded diene 2f in 67% after the starting material was consumed
(48 h). Reactions involving the electron-rich ketone 1g did not go
to completion after 48 h. Although a 50% yield of product 2g was
obtained, 40% of the starting material was also recovered (entry 7).
In an attempt at the asymmetric synthesis of 3° butadienylcar-
binols 2, ketone 1d was submitted to the reaction conditions that
MeO
CrCl3 (30 mol %), 4 (3 equiv), Mn0 (2 equiv), Et3N (1 equiv) TMSCl (2 equiv), rt,
24 h; then 1 M TBAF in THF, rt, 16 h.
Isolated yield.
a
b
c
Reaction time: 48 h.
we had previously developed for the enantioselective synthesis
of 2° 1,3-butadien-2-ylcarbinols from aldehydes.9 As shown in
Eq. (3), a racemic mixture of 2d was obtained with 17% conversion
under our standard conditions. Further optimization of the reac-
tion conditions increased the conversion to 90% when 2,6-lutidine
was used as the base, when only 1.2 equiv of 4 was utilized. This
represents a substantial increase over the yield observed in the ab-
sence of ligand (Table 2, entry 4), but no enantioselectivity was ob-
served in the product mixture. Although this is a disappointing
result on the surface, it does demonstrate that a bulky ligand does
not inhibit this already hindered C–C bond forming reaction.
Table 2
Optimization of desilylation conditionsa
Br
TMS
4
O
HO
CH3
Ph
Ph
CrCl3 (30 mol%)
Ph
Ph
CH3
Mn0, Et3N, TMSCl;
then 1 M TBAF
1a
2a
N
H
O
O
N
N
Entry
TBAF (equiv)
Conversionb (%)
8
ð3Þ
1
2
3
4
2
3
5
8
25
45
68
88
i-Pr
i-Pr
O
HO
CH3
8/CrCl3 (5 mol%), Mn0
Ph
Ph
CH3
4 (1.2 equiv), TMSCl,
THF; then TBAF
1d
CrCl3 (30 mol %), 4 (3 equiv), Mn0 (2 equiv), Et3N (1 equiv) TMSCl (2 equiv), rt,
24 h, then 1 M TBAF in THF, rt, 16 h.
a
rac-2d
17% (i-Pr2NEt)
90% (2,6-lutidine)
Determined by 1H NMR.
b

5082
M. Durán-Galván et al. / Tetrahedron Letters 51 (2010) 5080–5082
In summary, we have developed a method for the synthesis of
References and notes
3° 1,3-butadien-2-ylcarbinols 2 from the chromium-catalyzed
addition of (4-bromobut-2-ynyl)trimethylsilane to ketones. This
method overcomes some of the disadvantages of the previous ap-
proaches to this class of functionalized molecules. More impor-
tantly, this is, to the best of our knowledge, the first chromium-
catalyzed nucleophilic addition to ketones to afford 3° allenylalco-
hol products 5. These conditions strongly favor the formation of
homoallenyl alcohols over their propargylic isomers. Aliphatic as
well as aromatic ketones are suitable substrates for this reaction.
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The Norman Hackerman Advanced Research Program and the
Robert A. Welch Foundation (A-1623) are acknowledged for sup-
port of this research.
Supplementary data
Experimental procedures, characterization data, and 1H and 13
C
NMR spectra for new compounds. Supplementary data associated
with this article can be found, in the online version, at doi:10.
1016/j.tetlet.2010.07.104.