Titanocene(ll)-promoted, one-pot, three-component coupling of thioacetals, alkynyl sulfones, and carbonyl compounds: Highly stereoselective formation of ferf-homopropargyl alcohols

Article abstract of DOI:10.1021/ol071077w

Titanocene alkylidene complexes, generated by desulfurizative titanation of thioacetals with Cp₂Ti[P(OEt)₃J₂, reacted with alkynyl methyl sulfones to produce organotitanium species, which gave tert-homopropargyl alcohols with high diastereoselectivity on treatment with aromatic and α,β-unsaturated ketones.

Full text of DOI:10.1021/ol071077w

ORGANIC
LETTERS
2
007
Vol. 9, No. 15
875-2878
Titanocene(II)-Promoted, One-Pot,
Three-Component Coupling of
Thioacetals, Alkynyl Sulfones, and
Carbonyl Compounds: Highly
Stereoselective Formation of
tert-Homopropargyl Alcohols
2
Takeshi Takeda,* Maiko Ando, Takenori Sugita, and Akira Tsubouchi
Department of Applied Chemistry, Graduate School of Engineering, Tokyo UniVersity
of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
takeda-t@cc.tuat.ac.jp
Received May 8, 2007
ABSTRACT
Titanocene alkylidene complexes, generated by desulfurizative titanation of thioacetals with Cp
to produce organotitanium species, which gave tert-homopropargyl alcohols with high diastereoselectivity on treatment with aromatic and
-unsaturated ketones.
2 3 2
Ti[P(OEt) ] , reacted with alkynyl methyl sulfones
r,â
Much attention has been paid to one-pot multistep reactions
because of their synthetic efficiency. Recently, we reported
preparation of vinylallenes by the titanocene(II)-promoted
one-pot multistep reaction utilizing alkynyl sulfones, alkenyl
Scheme 1
1
sulfones, and carbonyl compounds. This finding prompted
us to further investigate multicomponent coupling using the
titanocene(II) and alkynyl sulfones. Here we wish to describe
a new Cp Ti[P(OEt) ] 1-promoted three-component coupling
2 3 2
between thioacetals 2, alkynyl sulfones 3, and carbonyl
compounds 4 and unusual diastereoselective formation of
tert-homopropargyl alcohols 5 (Scheme 1).
reaction presumably proceeds via the formation of titana-
cyclobutenes. We anticipated that allenyltitaniums 7 would
be produced by the reaction of carbene complexes 6 with
alkynyl sulfones 3 via the formation of titanacyclobutene
intermediates 8 (Scheme 2).
Previously, we reported the formation of conjugated dienes
by the reaction of alkylidenetitanocenes 6, generated by the
2
desulfurizative titanation of thioacetals 2, with alkynes. The
(
1) Ogata, A.; Nemoto, M.; Kobayashi, K.; Tsubouchi, A.; Takeda, T.
(2) Takeda, T.; Shimokawa, H.; Miyachi, Y.; Fujiwara, T. Chem.
Commun. 1997, 1055-1056.
Chem.sEur. J. 2007, 13, 1320-1325.
1
0.1021/ol071077w CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/20/2007

yield, which suggested the formation of the intermediary
allenyltitanium compound 7. Similarly, various alkynes were
obtained by the reaction of alkynyl methyl sulfones 3 with
alkylidenetitanocenes 6 generated from thioacetals 2.
Preparation of allenylmetals has been extensively studied,3
and their reaction with carbonyl compounds provides a useful
synthetic route to homopropargyl alcohols. Therefore, the
allenyltitanium species 7 generated by the above reaction
were expected to react with carbonyl compounds 4 to
produce homopropargyl alcohols 5 (Scheme 3). Indeed,
Scheme 2
Scheme 3
Indeed, the successive treatment of the thioacetal 2a (1.5
equiv) with the titanocene(II) reagent 1 (4.5 equiv) and the
alkynyl sulfone 3a at 25 °C followed by hydrolysis produced
the internal alkyne 9a in 74% yield (Table 1, entry 1). When
treatment of aldehydes (2 equiv) with the organotitanium
species generated from thioacetals 2 (1.2 equiv), sulfones 3,
and 1 (3.6 equiv) in THF gave homopropargyl alcohols 5,
and no formation of the isomeric allenyl alcohols was
observed (Table 2, entries 1-3).
Table 1. Titanocene(II) 1-Promoted Reaction of Thioacetals 2
with Alkynyl Methyl Sulfones 3
Yamamoto et al. first reported preparation of allenyltita-
niums by lithiation of alkynes followed by transmetalation
i
4
with Ti(O Pr)
4
. Similar allenyltitaniums have been prepared
by the reaction of propargyl substrates with a titanium reagent
i
i
5
4
generated from Ti(O Pr) and PrMgBr. Although the 1,3-
disubstituted allenyltitanium reagents formed by these meth-
ods react with aldehydes at a temperature below -20 °C,
5a
ketones do not react with these reagents with the exception
5
b
of intramolecular reaction. In contrast, 7 do react with
ketones to produce tertiary alcohols 5. Considering that Ding
et al. reported that the allenyltitanium reagents generated
from propargyl acetates and a certain titanocene(II) species
6
react with acetone at 0 °C, it is reasonable to assume that
thermal stability of the allenyltitaniums bearing Cp ligands
enables them to react with ketones at a rather high temper-
ature.
(
3) (a) ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, U.K., 1991; Vol. 2. (b) Masse, C. E.; Panek, J.
S. Chem. ReV. 1995, 95, 1293-1316. (c) Marshall, J. A. Chem. ReV. 1996,
9
6, 31-47. (d) Marshall, J. A. Chem. ReV. 2000, 100, 3163-3185. (e)
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N.; G e´ rard, H.; Mangeney, P. J. Org. Chem. 2007, 72, 1770-1779 and
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(
4) (a) Ishiguro, M.; Ikeda, N.; Yamamoto, H. J. Org. Chem. 1982, 47,
225-2227. (b) Furuta, K.; Ishiguro, M.; Haruta, R.; Ikeda, N.; Yamamoto,
H. Bull. Chem. Soc. Jpn. 1984, 57, 2768-2776.
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2
(
2
886. (b) Yoshida, Y.; Nakagawa, T.; Sato, F. Synlett 1996, 437-438. (c)
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6
323-6326.
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2841.
the reaction of 2a with 3a was quenched with D
2
O, the
(
deuterated alkyne 10 (ca. 100% D) was obtained in 68%
2876
Org. Lett., Vol. 9, No. 15, 2007

Table 2. Three-Component Coupling of Thioacetals 2, Alkynyl Sulfones 3, and Carbonyl Compounds 4
a
Isolated yield. Based on the isolated yields of the diastereomers. c 3 equiv of 4 was used. d Determined by NMR analysis. e Determined by GLC
b
f
analysis. 1.2 equiv of 4g was used.
The three-component coupling can also be applied to R,â-
unsaturated carbonyl compounds. Selective 1,2-additon of
the allenyltitanium intermediates 7 takes place in the case
of both enals and enones (Table 2, entries 3, 9, and 10-12).
Despite the extensive studies on the reactivity of allenylmetal
reagents, only a few reactions with enones have been known.
Org. Lett., Vol. 9, No. 15, 2007
2877

4
Danheiser et al. reported TiCl -promoted reaction of alle-
nylsilanes with enones which involves the 1,4-addition
process. As far as we know, there is no report on the
Scheme 4
7
selective 1,2-addition of allenylmetal species to R,â-unsatur-
ated ketones.
The diastereoselectivity is also dependent on the ligands
of allenyltitaniums. The reaction of allenyltitanium reagents
i
bearing PrO ligands with aldehydes tends to produce anti
homopropargyl alcohols with good selectivity.3 No selec-
tivity, however, was observed in the reaction of the Cp
congeners 7 with aldehydes (Table 2, see entries 1-3). In
contrast, the reaction of 7 with aliphatic ketones showed
moderate diastereoselectivity, and high stereoselectivity was
observed when R,â-unsaturated and aromatic ketones were
employed. Addition of allylmetal species to carbonyl com-
pounds has been extensively studied as a useful tool for
,6a
tion10 of 5m produced the dihydrofuran 12 in 94% yield. A
positive NOE observed between 2-CH and 3-H of 12
3
suggests that the reaction of allenyltitanium species 7 with
acetophenone (4f) proceeds with syn stereochemistry.
In summary, we have established a new three-component
coupling of thioacetals, alkynyl sulfones, and carbonyl
compounds promoted by the titanocene(II) reagent providing
access to tert-homopropargyl alcohols. Further study on the
elucidation of high diastereoselectivity observed in the
reaction of allenyltitaniums 7 with ketones is currently
underway.
3a,e,8
preparation of homoallylic alcohols.
Reactions of γ-sub-
stituted allylmetals with aldehydes generally produce second-
ary homoallylic alcohols bearing adjacent chiral centers with
high diastereoselectivity, but the selectivity tends to decrease
when ketones are employed. In this context, recently, much
attention has been paid to diastereoselective addition of
allylmetals to ketones and several highly diastereoselec-
9
tive reactions with aromatic ketones have been reported.
To the best of our knowledge, howeVer, no reaction which
produces tertiary alcohols more diastereoselectiVely than
secondary alcohols has been reported. Therefore, the
selectivity observed in the present reaction is of special
interest from the mechanistic as well as synthetic points of
view.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research (No. 18350018) and Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” (No.
1
8037017) from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
The same diastereoselective formation of tertiary alcohols
5
was also observed in the reaction of allenyltitanium species
formed by the reductive titanation of propargylic acetates
1 with 1: the reactions of 11a with 4j and 11b with 4f
Supporting Information Available: Experimental pro-
cedures and characterization data of all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
gave 5k (69%, ratio of isomers; 90:10) and 5m (67%, single
isomer), respectively (Scheme 4). The Pd-catalyzed cycliza-
OL071077W
(
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1
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2878
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