Asymmetrie synthesis of (1,3-butadien-2-yl)methanols from aldehydes via [1-(Silylmethyl)allenyl]methanols

Article abstract of DOI:10.1002/ejoc.201000199

[1-(Silylmethyl)allenyl]methanols 2 were efficiently synthesized from aldehydes and (4-bromobut-2-ynyl)trimethylsilane in the presence of a catalytic amount of CrCl₂ and tridentate carbazole ligands. The desired compounds were obtained with good yields (43-88%) and enantioselectivities (55-78% ee). Alcohols 2 may be treated with TBAF or 2 M HCl in the case of aliphatic substrates, to provide (1, 3-butadien-2-yl)methanols 3 in 43-81% yields. This method allows the synthesis of dienes 3 with no regioselectivity problems, and it tolerates a large number of functionalities.

Full text of DOI:10.1002/ejoc.201000199

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000199
Asymmetric Synthesis of (1,3-Butadien-2-yl)methanols from Aldehydes via
[1-(Silylmethyl)allenyl]methanols
María Durán-Galván[a] and Brian T. Connell*[a]
Keywords: Asymmetric catalysis / Chromium / Allenylmethanols / Dienes / Regioselectivity
[1-(Silylmethyl)allenyl]methanols 2 were efficiently synthe-
sized from aldehydes and (4-bromobut-2-ynyl)trimethylsil-
ane in the presence of a catalytic amount of CrCl2 and triden-
(55–78% ee). Alcohols 2 may be treated with TBAF or 2 M
HCl in the case of aliphatic substrates, to provide (1,3-buta-
dien-2-yl)methanols 3 in 43–81% yields. This method allows
tate carbazole ligands. The desired compounds were ob- the synthesis of dienes 3 with no regioselectivity problems,
tained with good yields (43–88%) and enantioselectivities
and it tolerates a large number of functionalities.
Introduction
In addition to appearing in the structures of numerous
natural products, (1,3-butadien-2-yl)methanols 3 are versa-
tile building blocks in organic synthesis.[1] Consequently, a
number of methodologies have been developed for their
synthesis.[2] Although recent methods have overcome re-
gioselectivity problems presented by the early approaches,
there are a limited number of enantioselective procedures,
each of which is limited in some manner. Such limitations
have included the use of non-readily available organometal-
lic reagents, low functional-group tolerance, and low reac-
tivity and product yields. A recent example is Yamamoto’s
asymmetric process [Equation (1)] based on the catalytic
chromium system developed by Fürstner.[3] A complemen-
tary procedure reported by Guiry provides homoallenyl
alcohols by a related proceess in which (1,3-butadienyl)-
methanols 3 are observed only as minor byproducts
(Scheme 1).[4]
Scheme 1. Chromium-catalyzed syntheses of (butadienyl)meth-
anols.
Our work in this area focused on developing reaction
conditions that tolerate a broad range of substrates, while
avoiding issues of poor yields and poor regioselectivity. We
realized that syntheses of 3 could be facilitated by the desi-
lylation of {1-[(trimethylsilyl)methyl]allenyl}methanols 2,
which themselves may be obtained by allenylation of alde-
hydes. Because tridentate bis(oxazolinyl)carbazole ligands
developed by Nakada and co-workers have shown to be
excellent chiral ligands for chromium in catalyzed asymmet-
ric allenylations of aldehydes with propargyl bromide (Fig-
ure 1),[5] we investigated their use for the synthesis of en-
antioenriched {1-[(trimethylsilyl)methyl]allenyl}methanols.
Figure 1. Tridentate carbazole ligands.
Results and Discussion
The reaction of benzaldehyde with (4-bromobut-2-ynyl)-
trimethylsilane[6] in the presence of 10 mol-% CrCl3 and
carbazole ligand Ib was examined. After 20 h at room
temp., the reaction was complete, and the desired product
was obtained in 31% ee (Table 1, Entry 1) after acidic
workup. This result improved upon utilizing CrCl2 as the
catalyst (Table 1, Entry 2). MeCN was found to be a more
[a] Department of Chemistry, Texas A&M University,
P. O. Box 30012, College Station, TX 77842, USA
Fax: +1-979-458-2969
E-mail: connell@chem.tamu.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000199.
Eur. J. Org. Chem. 2010, 2445–2448
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Durán-Galván, B. T. Connell
SHORT COMMUNICATION
effective solvent than others (Entries 3 and 4). Additional Table 2. Asymmetric chromium-catalyzed silylallenylation reaction.
optimization showed that decreasing the percentage of
CrCl2/ligand to 5 mol-% has no effect on the ee value, but
the use of 2 equiv. of Mn0 increased the enantiomeric excess
to 78% ee. Use of other bis(oxazoline) ligands did not im-
prove the enantioselectivity (Entries 7 and 8). Whereas li-
gand Ia afforded the desired product in 74% ee, the pres-
ence of a bulky tert-butyl group in ligand Ic drastically de-
creased the observed ee value, while increasing the neces-
sary reaction time to 4 d.
Entry
R
Product
Yield [%][a]
ee [%][b]
1
2
3
Ph
2a
2b
2c
2d
2e
2f
88
75
60
82
77
88
67
58
78
70
74
68
59
72
68
55
p-MeC6H4
p-BrC6H4
o-BrC6H4
o-MeC6H4
p-CF3C6H4
C6H11
4
5[c]
6
Table 1. Optimization of catalytic reaction conditions.
7[d]
8[d]
2g
2h
PhCH2CH2
[a] Isolated yields. [b] Enantiomeric excess determined by chiral
HPLC. [c] (4-Bromobut-2-ynyl)trimethylsilane (3 equiv.), 50 h. [d]
Reaction time: 36 h.
Entry CrCl2 [mol-%] Mn [equiv.] Solvent Conv. [%][a] ee [%][b]
1
2
3
4
5
10[c]
10
10
10
5
5
5
5
1.5
1.5
1.5
1.5
1.5
2
THF
THF
EtCN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Ͼ 99
Ͼ 99
95
Ͼ 99
Ͼ 99
Ͼ 99
91
31
46
48
73
72
78
74
20
Table 3. Conversion of allenylmethanols to (1,3-butadien-2-yl)-
methanols.
6[d]
7[e]
8[f]
2
2
86
[a] Determined by HPLC. [b] Enantiomeric excess determined by
chiral HPLC. [c] CrCl3 was used. [d] Reaction time: 36 h. [e] Ligand
Ia was used in place of Ib. [f] Ligand Ic was used in place of Ib
with a reaction time of 4 d.
Entry
R
Product
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
Ph
3a
3b
3c
3d
3e
3f
54
86
72
82
79
59
84
43
70
65
73
77
68
69
64
48
p-MeC6H4
p-BrC6H4
o-BrC6H4
o-MeC6H4
p-CF3C6H4
C6H11
The scope of the transformation was next examined. This
allenylation is successful for both aromatic and aliphatic
substrates. Aldehydes with para substituents afforded allen-
ylmethanols 2b and 2c with high yields and enantio-
selectivities (Table 2, Entries 2 and 3). When ortho substitu-
ents are present, the products are obtained in good yields
and enantioselectivities (Entries 4 and 5). Electron-deficient
aldehyde 1f successfully provided the corresponding adduct
in 88% yield. The reaction proceeded more rapidly with
aliphatic aldehydes, which provided the desired allenyl-
methanols with moderate yields and enantioselectivities, but
in shorter reaction times (Entries 7 and 8).
Desilylation and isomerization of allenylmethanols 2 to
provide the desired (butadienyl)methanols 3 was next exam-
ined. We were aware that {1-[(trimethylsilyl)methyl]-
allenyl}methanols afford (1,3-butadien-2-yl)methanols in
moderate yield in the presence of a relatively harsh HF/
HCl mixture.[2j] In search of milder reaction conditions, we
explored the use of basic fluoride as a viable reagent for
this transformation. When tetrabutylammonium fluoride
(TBAF) was combined with 2a in THF, the desired diene
3a was obtained in 54% yield (Table 3, Entry 1). The re-
maining allenylmethanols 2b–h were successfully converted
into the desired adducts in moderate to good yields. Only a
3g
3h
PhCH2CH2
[a] Isolated yields. [b] Enantiomeric excess determined by chiral
HPLC.
The acidic workup of the mixture resulting from the Cr-
catalyzed reaction is not necessary and can be skipped in
the case of acid-sensitive products. For example, cinnamal-
dehyde was combined with (4-bromo-2-ynyl)trimethylsilane
in the presence of CrCl2, and the corresponding allene was
obtained after 16 h (Scheme 2). The crude silyl ether was
directly treated with 2 equiv. TBAF in THF to afford the
desired adduct.
Scheme 2. Synthesis of 3i from cinnamaldehyde.
On the other hand, the TBAF step can be excluded by
slight decrease in the ee value of the products was observed initial prolonged (5 h) treatment with aqueous HCl. For ex-
under these reaction conditions.[7]
ample, when intermediate [1-(silylmethyl)allenyl]methanol
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Asymmetric Synthesis of (1,3-Butadien-2-yl)methanols
silane (50 mg, 0.3 mmol) was added, and the solution was stirred
for 30 min. Next, the aldehyde (0.2 mmol) and TMSCl (24 mg,
0.22 mmol) were successively added at 0 °C. The mixture was
stirred at room temperature for 48 h or until the reaction was com-
pleted as judged by TLC. 1  HCl was added, and the obtained
green solution was stirred until the alcohol was completely depro-
tected as judged by TLC. The mixture was then extracted with
EtOAc. The mixed organic phases were washed with brine, dried
with Mg2SO4 and concentrated under reduced pressure to give a
dark orange oil. The residue was purified by flash chromatography
with EtOAc/hexanes (1:50 to 1:9) as eluent.
2h was directly treated with acid by addition of 2  HCl to
the reaction flask, product 3h was obtained from this one-
pot procedure after 5 h in 56% yield (Scheme 3).
General Method for the Preparation of the (1,3-Butadien-2-yl)meth-
anols from the Allenylmethanols: The allene (0.11 mmol) was dis-
solved in dry THF (1.5 mL). TBAF (1  in THF, 0.1 mL,
0.1 mmol) was added, and the solution was stirred at room temp.
for 36 h. After this time, a saturated solution of NH4Cl (3 mL) was
added, and the mixture was extracted with three portions of
EtOAc. The combined organic fractions were washed with brine,
dried with Mg2SO4 and concentrated under reduced pressure. The
residue was purified by preparative thin layer chromatography with
Scheme 3. One-pot synthesis of 3h from 3-phenylpropionaldehyde.
The [1-(silylmethyl)allenyl]methanol intermediates
2
possess other useful reactivities that can be utilized for
synthesis. To illustrate the versatility of these intermediates,
2g was treated with NIS to give the iodinated adduct
4 (Scheme 4).[8] Furthermore, {1-[(trimethylsilyl)methyl]-
allenyl}methanols may be treated with other electrophiles
such as Br2 or Selectfluor® to afford the corresponding ha- EtOAc/hexanes (1:6).
logenated derivatives.[2j,9]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data.
Acknowledgments
The Norman Hackerman Advanced Research Program and the Ro-
bert A. Welch Foundation (A-1623) are acknowledged for support
of this research.
Scheme 4. Iodination of {1-[(trimethylsilyl)methyl]allenyl}meth-
anol 2g.
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Conclusions
We have developed an asymmetric synthesis (1,3-buta-
dien-2-yl)methanols. This method is valuable for the syn-
thesis of {1-[(trimethylsilyl)methyl]allenyl}methanols, valu-
able functionalized molecules that may be further converted
to a variety of nonracemic small molecules. This work also
further illustrates the utility of tridentate bis(oxazolinyl)carb-
azole ligands in chromium-catalyzed additions to aldehydes
for the synthesis of asymmetric alcohols. The present
method avoids regioselectivity problems of preceding proto-
cols and tolerates a variety of functionalities. It is comple-
mentary to previous related reports that focus on the syn-
thesis of the other regioisomers.
[3] a) A. Fürstner, N. Shi, J. Am. Chem. Soc. 1996, 118, 2533–
2534; b) M. Naodovic, G. Xia, H. Yamamoto, Org. Lett. 2008,
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Experimental Section
[4] V. Coeffard, M. Aylward, P. J. Guiry, Angew. Chem. 2009, 121,
9316; Angew. Chem. Int. Ed. 2009, 48, 9152.
General Method for the Preparation of the Allenylmethanols: Inside
a nitrogen-filled drybox, a mixture of CrCl2 (1.2 mg, 0.01 mmol),
Mn powder (325-mesh; 22 mg, 0.4 mmol), and carbazole ligand Ib
(5.5 mg, 0.01 mmol) was added to a 2-dram vial. Then, the vial was
capped with a teflon lid, and it was removed from the drybox.
Freshly distilled CH3CN (2 mL) was added through a syringe, and
a yellow suspension was formed. This was followed by addition of
diisopropyl(ethyl)amine (7.5 mg, 0.06 mmol), and the mixture was
stirred for 5 min. After this time, (4-bromo-2-butyn-1-yl)trimethyl-
[5] a) M. Inoue, M. Nakada, Angew. Chem. 2006, 118, 258; Angew.
Chem. Int. Ed. 2006, 45, 252; b) M. Inoue, M. Nakada, Org.
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cles 2007, 72, 133–138.
[6] R. Tong, J. C. Valentine, F. E. McDonald, R. Cao, X. Fang,
K. I. Hardcastle, J. Am. Chem. Soc. 2007, 129, 1050–1051.
[7] The absolute configuration was assigned by direct comparison
to known compounds or by conversion to known compounds
(see Supporting Information for details).
Eur. J. Org. Chem. 2010, 2445–2448
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2447

M. Durán-Galván, B. T. Connell
SHORT COMMUNICATION
[8] a) The synthesis of 2-iodo-1,3-dienes has also been reported
to occur by treatment of (silylmethyl)allenes with I2. See: T.
Nishiyama, T. Esumi, T. Iwabuchi, H. Irie, S. Hatakeyama, Tet-
rahedron Lett. 1998, 39, 43–46; b) during this process, half of
the alcohol was silylated in situ (by the TMSI byproduct gener-
ated), and the unpurified 1:1 mixture of free alcohol/silyl ether
was converted into the pure alcohol in 60% yield by addition
of TBAF.
M. C. Pacheco, W. Gouverneur, Org. Lett. 2005, 7, 1267–1270.
Received: February 12, 2010
[9]
Published Online: March 18, 2010
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Eur. J. Org. Chem. 2010, 2445–2448