T. Takeda et al. / Tetrahedron Letters 52 (2011) 4575–4578
4577
is a tendency that the compounds in which the silyl group locates
at to the titanium atom become thermodynamically favored. For
2
R X 7
6
1
a
Pd dba3 / TBAF / THF
2
example, the [2+2]cycloaddition between a 1-trimethylsilylalkyne
with a titanium vinylidene complex at room temperature forms a
mixture of 2- and 3-trimethylsilyltitanacyclobutenes and refluxing
Scheme 4.
1
3
the reaction mixture affords only the 2-trimethylsilyl derivative.
This result implies that the -silyl group substituted organotitani-
a
um species are more thermodynamically stable than other possible
regioisomers. On the basis of the above assumption, the observed
regio- and stereoselectivity of the reaction is explained by the
Table 2
Pd-catalyzed cross-coupling of d-silylhomoallylic alcohols 6
a
Yield (%)b
anti:sync
Entry
6
7
1
selective formation of
a-silylallyltitanocenes 2 with E-configura-
1
2
3
4
5
6
7
8
6g
6k
6k
6g
6k
6g
6g
6k
7a
7a
7b
7c
7c
7d
7e
7e
1a
1b
1c
1d
1e
1f
78
85
82
50
52
63
75
81
91:9
91:9
93:7
tion and their addition to carbonyl compounds 5 via the well estab-
lished chair-like six-membered transition states Ts in which the
larger group of carbonyls occupies an equatorial position
89:11
89:11
91:9
d
(Scheme 3). The E configuration of d-silylhomoallylic alcohols 6
indicates that the reaction proceeds via the transition state Ts-1,
in which the equatorial benzyldimethylsilyl group suffers only
gauche-like interactions with two Cp rings. In contrast, another
possible transition state Ts-2 is destabilized by the gauche-like
interaction between the axial silyl group and the Cp ring and the
1g
1h
90:10
89:11
MeO
I
Me-I
Hex
Ph Br
I
I
7a
7b
7c
7d
7e
1
,3-alyllic strain of allylsilane moiety.
a
The d-silylhomoallylic alcohols 6 thus obtained were readily
2 3
Condition: (3) homoallylic alcohol 6 (1 equiv), halide 7 (1 equiv), Pd dba
(
5 mol %), TBAF (2.2 equiv) in THF at 25 °C for 3 h.
transformed into b,d-disubstituted homoallylic alcohols 1 by the
palladium-catalyzed cross-coupling with aryl, alkenyl, benzyl,
and methyl halides 7 (Scheme 4).14 All the reactions proceeded
with complete retention of configuration in good yields (Table 2).
In conclusion, it should be noted that the titanocene(II)-pro-
b
Isolated yield.
Determinated by NMR analysis.
c
d
Determined by GC analysis.
moted allylation of ketones with a-silylallylic sulfides and the fol-
AcOEt = 9:1, v/v) to give 6-(benzyldimethylsilyl)-3-methyl-4-
phenyl-5-hexen-3-ol (6g) (578 mg, 85%).
lowing palladium(0)-catalyzed cross-coupling with organic halides
constitute a convenient way for the regio-, stereo-, and diastereo-
selective synthesis of highly substituted tertiary homoallylic alco-
hols. The present approach enjoys an advantage that a variety of
2 3
Pd dba (9 mg, 0.01 mmol) was added to a THF (1.2 mL) solu-
tion of 6g (68 mg, 0.2 mmol) at 25 °C and then a THF solution of
TBAF (1 M, 0.44 mL, 0.44 mmol) was added dropwise to the reac-
tion mixture. A THF (0.8 mL) solution of 4-iodoanisole (7a)
homoallylic alcohols bearing four different substituents at
a, b,
and d-positions, each of which originated from ketones, allylic sul-
fides, and organic halides, are readily accessible. Further study on
the transformation of d-silylhomoallylic alcohols is now under
investigation.
(
3
47 mg, 0.2 mmol) was added and the mixture was stirred for
h. The reaction was quenched by addition of water and the insol-
uble materials were filtrated off through Celite. The organic mate-
rials were extracted with Et O and dried over Na SO . After the
2
2
4
solvent was evaporated under reduced pressure, the residue was
purified by PTLC (hexane/AcOEt = 9:1, v/v) to give 3-methyl-6-(4-
methoxyphenyl)-4-phenyl-5-hexene-3-ol (1a) (46 mg, 78%).
Typical experimental procedure for preparation of anti-
homoallylic alcohols 1
2 2
To a THF (12 mL) suspension of Cp TiCl (996 mg, 4.0 mmol)
was added a hexane solution of BuLi (1.65 M, 4.8 mL, 8.0 mmol)
Acknowledgment
at À78 °C under argon. After 1 h, a THF (8 mL) solution of 3a
This work was supported by Grant-in-Aid for Scientific Re-
search (No. 21350026) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
(
749 mg, 2.0 mmol) was added dropwise over 5 min to the reaction
mixture. The mixture was warmed up to 0 °C and stirred for 2 h.
After stirring the mixture at À40 °C for 15 min, a THF (4 mL) solu-
tion of methyl ethyl ketone (5e) (432 mg, 6.0 mmol) was added
and the mixture was further stirred for 24 h. The reaction was
quenched by addition of a mixture of 1 M NaOH (5 mL) and THF
Supplementary data
(
5 mL), and the insoluble materials were filtered off through Celite
and washed with ether. The organic materials were extracted with
ether and dried over Na SO . After removal of the solvent, the res-
2
4
References and notes
idue was purified by column chromatography (hexane/
1.
(a) Risch, N.; Arend, M. In Stereoselective Synthesis, Methods of Organic Chemistry
Houben-Weyl); Helmchen, G., Hoffmann, R., Mulzer, J., Schaumann, E., Eds.;
(
Thieme: Stuttgart, 1996; vol. 3, p 1357; (b) Denmark, S. E.; Almstead, N. G. In
Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000. Chapter
10; (c) Chemler, S. R.; Roush, W. R. In Modern Carbonyl Chemistry; Otera, J., Ed.;
Wiley-VCH: Weinheim, 2000. Chapter 11; (d) Szymoniak, J.; Moïse, C. In
Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-VCH:
Weinheim, 2002. Chapter 13; (e) Santanilla, A. B.; Leighton, J. L. In Science of
Synthesis; De Vries, J. G., Molander, G. A., Evans, P. A., Eds.; Thieme: Stuttgart,
gauche-like
RS
interaction
SPh
H
Ti
RS
R1
RL
H
O
SPh
Ti
gauche-like
interaction
RL
H
R1
O
SiBnMe2
SiBnMe2
2011; Vol. 2, p 401.
H
2. (a) Yatsumonji, Y.; Nishimura, T.; Tsubouchi, A.; Noguchi, K.; Takeda, T. Chem.
Eur. J. 2009, 15, 2680; (b) Takeda, T.; Nishimura, T.; Yatsumonji, Y.; Noguchi, K.;
Tsubouchi, A. Chem. Eur. J. 2010, 16, 4729; Precedent works for the preparation
of allyltitanium compounds and their diastereoselective addition to carbonyls,
see: (c) Reetz, M. T. Organotitanium Reagents in Organic Synthesis; Springer:
1
,3-allylic strain
gauche-like
interaction
Ts-1
Ts-2
Scheme 3.