Site-selective mono-titanation of conjugated diynes with a Ti(II) alkoxide reagent. Concise preparation of stereo-defined enynes and dienynes

Article abstract of DOI:10.1039/b108444e

Conjugated diynes underwent selective mono-titanation with a Ti(II) reagent to give 1:1 diyne - titanium alkoxide complexes, which reacted with proton, aldehyde, and another acetylene to give stereo-defined enynes, enynols, and dienynes.

Full text of DOI:10.1039/b108444e

Site-selective mono-titanation of conjugated diynes with a Ti(II) alkoxide
reagent. Concise preparation of stereo-defined enynes and dienynes
Christophe Delas,a Hirokazu Urabeb and Fumie Sato*a
a Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo
Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan.
E-mail: fsato@bio.titech.ac.jp
b Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute
of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
Received (in Cambridge, UK) 24th September 2001, Accepted 3rd December 2001
First published as an Advance Article on the web 14th January 2002
Conjugated diynes underwent selective mono-titanation
with a Ti(II) reagent to give 1+1 diyne–titanium alkoxide
complexes, which reacted with proton, aldehyde, and
another acetylene to give stereo-defined enynes, enynols,
and dienynes.
mono-titanation were investigated [Eqn. (1) in Table 1)].‡ The
titanation of a couple of symmetrical diynes 8 and 9 was also
carried out for comparison. The site-selection for diynes 2–9,
which was estimated after hydrolysis of the resultant acetylene–
titanium complexes, is summarized in Table 1. All cases, except
entries 4 and 6, cleanly afforded enynes uncontaminated by the
corresponding dienes arising from exhaustive titanation, which
means that mono-titanation is an exclusive path under these
reaction conditions.9 More importantly, the complexation
occurs with excellent site-selectivity for a few unsymmetrical
diynes. Thus, diyne 2 having silyl and alkyl substituents
generated the titanium complex, in which the titanium is placed
at the alkylacetylene moiety, to give a single enyne 10 after
hydrolysis (entry 1). Another case is of 2,4-diynoate 6, for
which the triple bond bearing an ester group was selectively
titanated to give enyne 13 (entry 5). The origin of these site-
selections appears to be mainly steric in the former case, while,
in the latter case, it seems to be an electronic effect, as the
electron-deficient acetylenic bond (conjugated to ester group) is
more reactive to the electron-rich low-valent titanium complex.
Contrarily, almost no preference was observed for the reactions
with diynes 3 and 4 (entries 2 and 3), both of which involve a
phenylacetylene structure. A couple of diynes such as 5 and 7
(entries 4 and 6) did not generate the expected acetylene–
titanium complex and gave a mixture of messy products after
aqueous workup.
Conjugated enynes, dienynes, and their derivatives are useful
intermediates and/or important structural constituents in or-
ganic synthesis, natural product chemistry, and materials
science.1–3 There are already many methods available for the
synthesis of enynes. However, methods that permit the
stereoselective construction of the enyne structure and, at the
same time, facile introduction of a necessary substituent(s) to
the enyne system in correct array and in one step are notably
limited.1 We report herein such a method by taking advantage of
acetylene–titanium alkoxide complexes prepared from acet-
ylenes and Ti(OiPr)4/2 iPrMgCl reagent (1),4 which are versatile
and economical intermediates for the preparation of various
olefins.5 Thus, we theorized that, if site-selective† mono-
titanation of unsymmetrical conjugated diynes is a viable
process as well, it should serve for a concise construction of the
aforementioned enyne systems as shown in the equations and
Tables below. Although several 1+1 symmetrical diyne-group 4
metallocene complexes are known,6 their versatility in organic
synthesis has not been amply highlighted. Moreover, site-
selective generation of mono-metalated unsymmetrical diynes,
which is described below, has not been pursued.7
Having chosen diynes 2, 6, 8, and 9, which generate a single
acetylene–titanium complex, we then focused our attention on
the introduction of a substituent(s) to the enyne system based on
the electrophilic reaction to the carbon–titanium bonds.4 Thus,
First, representative unsymmetrical diynes 2–7, which are
readily available by coupling of two acetylenes,8 were chosen as
the starting material. The feasibility and site-selection of the
Table 2 Results of the addition of diyne–titanium complexes to alde-
hydes
Table 1 Generation of mono-titanated diynes estimated by their hydrolysis
to enynes1
(1)
Diyne
R1
Product (Enynes)
Yield (%)
Entry
R2
a+b
1
2
3
4
5
6
7
8
C6H13
Ph
Ph
Me3Si
Me3Si
C6H13
2
3
4
5
6
7
8
9
85
81
10
11
12
100+0
57+43
50+50
Diyne
R1
Product
65
Entry
R2
Yield (%)
a+b+c+d
t
a
Ph
CO2 Bu
t
CO2 Bu C6H13
CO2 Bu Me3Si
81
13
100+0
1
2
3
4
C6H13
Me3Si
2
6
8
9
85
57
79
61
16
17
18
19
0+100+0+0
t
a
t
CO2 Bu C6H13
55+0+0+45a
79+0+21a+—
100+0+0+—
Me3Si
C4H9
Me3Si
C4H9
85
66
14
15
—
—
Me3Si
C4H9
Me3Si
C4H9
a Intractable mixture, in which the desired enyne is a minor constituent, was
recovered.
a Obtained as a single stereoisomer, to which the structure (i.e., E or Z) has
not been assigned.
272
CHEM. COMMUN., 2002, 272–273
This journal is © The Royal Society of Chemistry 2002

the acetylene complexes derived from the above diynes were
allowed to react with an aldehyde, the results of which are
summarized in Table 2. Titanium complexes derived from 2 and
9 afforded single enynols 16b and 19a (entries 1 and 4, Table 2).
It is interesting to note that the position of the reacting carbon
center was completely reversed dependent on the remote
substituents (alkyl vs. silyl) in these cases, which demonstrate a
facile, selective synthesis of stereo-defined enynols. A function-
alized diyne 6 afforded a mixture of enynol 17a and cumulenol
17d (entry 2, Table 2), the latter of which should come from
SE2A-type addition of the aldehyde to the intermediate acet-
ylene–titanium complex. Even the complex from symmetrical
diyne 8 afforded a mixture of two isomeric products, enynol
18a§ and cumulenol 18c, upon aqueous workup with dilute
hydrochloric acid (entry 3). In order to obtain a single product,
we looked for a suitable method of workup; and, eventually, we
found that iodinolysis of the same reaction mixture cleanly
afforded single iodo-enynol 20 as shown in Eqn. (2), which
demonstrates the successful double introduction of substituents
to the stereo-defined enyne structure.
disclosed. The observation described herein is informative for
further manipulation of acetylene–titanium alkoxide complexes
and provides a useful method for the construction of regio- and
stereo-defined enynes, dienynes, and their substituted or
functionalized derivatives from readily available conjugated
diynes.
We are grateful to the Japan Society for Promotion of Science
for financial support. C.D. thanks the same organization for a
postdoctoral fellowship.
Notes and references
† Site-selectivity refers to the discrimination between the two acetylenic
bonds of a diyne.
‡ General procedure. To a stirred solution of a conjugated diyne (0.579
i
mmol) and Ti(OiPr)4 (0.723 mmol) in 3 mL of Et2O was added PrMgCl
(solution in Et2O, 1.45 mmol) at 278 °C under argon to give a yellow
homogeneous solution. The solution was warmed to 250 °C over 1 h. After
stirring at 250 °C for an additional 4 h, the reaction mixture was quenched
with dilute HCl to give crude enynes. Alternatively, in place of the simple
hydrolysis, the reaction mixture was again cooled to 270 °C and
benzaldehyde or 1-octyne was added. The solution was stirred at 250 °C for
an additional 30 min. Then, aqueous workup as above and standard
purification gave the products.
§ Exhaustive or selective de-
silylation of products 18a and
23 with Bu4NF in THF af-
(2)
forded new enyne units 24 and
25 in 87 and 100% yields,
respectively.
Coupling reaction of the acetylene complexes generated from
unsymmetrical diynes 2 and 6 with an acetylene10 successfully
afforded the single dienynes 21 and 22 virtually with complete
regio- and stereoselectivities (entries 1 and 2 in Table 3). Thus,
this transformation provides one of the easiest and most
dependable methods for the concise construction of stereo-
defined dienynes. It is also noteworthy that the ester group in
diyne 6 survived the reaction conditions to allow the preparation
of a functionalized dienyne. While symmetrical diyne 9 having
alkyl substituents at both termini did not participate in the clean
coupling reaction (entry 4), bis-silylated counterpart 8 afforded
the dienyne 23§ in good yield (entry 4).
1 K. Sonogashira, in Comprehensive Organic Synthesis, vol. 3, ed. B. M.
Trost and I. Fleming, Pergamon Press, Oxford, 1991, pp. 521–549; J.
Uenishi and K. Matsui, Tetrahedron Lett., 2001, 42, 4353–4355.
2 K. C. Nicolaou, D. Vourloumis, N. Winssinger and P. S. Baran, Angew.
Chem., Int. Ed., 2000, 39, 44–122 and references cited therein; J. W.
Grissom, G. U. Gunawardena, D. Klingberg and D. Huang, Tetra-
hedron, 1996, 52, 6453–6518.
3 F. Diederich, Chem. Commun., 2001, 219–227.
4 For the generation and synthetic application of (mono)acetylene–
Ti(OiPr)2 complexes and their extension to relevant conjugated enyne–
Ti(OiPr)2 complexes, see: K. Harada, H. Urabe and F. Sato, Tetrahedron
Lett., 1995, 36, 3203–3206; T. Hamada, R. Mizojiri, H. Urabe and F.
Sato, J. Am. Chem. Soc., 2000, 122, 7138–7139. ; For reviews, see: F.
Sato, H. Urabe and S. Okamoto, Pure Appl. Chem., 1999, 71,
1511–1519; F. Sato, H. Urabe and S. Okamoto, Chem. Rev., 2000, 100,
2835–2886; F. Sato, H. Urabe and S. Okamoto, Synlett, 2000, 753–775;
F. Sato and S. Okamoto, Adv. Synth. Catal., in press.
5 For other acetylene–group 4 metal complexes, see: S. L. Buchwald and
R. B. Nielsen, Chem. Rev., 1988, 88, 1047–1058; E. Negishi, in
Comprehensive Organic Synthesis, vol. 5, ed. B. M. Trost and I.
Fleming, Pergamon Press, Oxford, 1991, pp. 1163–1184; E. Negishi and
T. Takahashi, Acc. Chem. Res., 1994, 27, 124–130; E. Negishi and T.
Takahashi, Bull. Chem. Soc. Jpn., 1998, 71, 755–769.
In summary, the viability and site-selectivity of mono-
titanation of diynes as well as the regiochemistry of their
coupling reactions with an aldehyde or acetylene have been
Table 3 Coupling of diyne–titanium complexes with 1-octyne
6 A. Ohff, S. Pulst, C. Lefeber, N. Peulecke, P. Arndt, V. V. Burlakov and
U. Rosenthal, Synlett, 1996, 111–118; U. Rosenthal, P.-M. Pellny, F. G.
Kirchbauer and V. V. Burlakov, Acc. Chem. Res., 2000, 33, 119–129
and references cited therein.
7 Some relevant reactions, but not the formation of mono-metalated
diynes themselves, to dicriminate unsymmetrical diynes were recorded:
T. Takahashi, K. Aoyagi, V. Denisov, N. Suzuki, D. Choveiry and E.
Negishi, Tetrahedron Lett., 1993, 34, 8301–8304; P.-M. Pellny, F. G.
Kirchbauer, V. V. Burlakov, W. Baumann, A. Spannenberg and U.
Rosenthal, Chem. Eur. J., 2000, 6, 81–90.
8 M. J. Dabdoub, A. C. M. Baroni, E. J. Lenardão, T. R. Gianeti and G.
R. Hurtado, Tetrahedron, 2001, 57, 4271–4276; K. Sonogashira, in
Comprehensive Organic Synthesis, vol. 3, ed. B. M. Trost and I.
Fleming, Pergamon Press, Oxford, 1991, pp. 551–561.
Product
(Dienynes)
Diyne
R1
Entry
R2
Yield (%)
1
2
3
4
C6H13
Me3Si
2
6
8
9
70
75
21
22
23
t
CO2 Bu C6H13
Me3Si
C4H9
Me3Si
C4H9
70
9 Cf. N. L. Hungerford and W. Kitching, J. Chem. Soc., Perkin Trans. 1,
1998, 1839–1858.
a
10 For the coupling reaction of simple acetylenes, see: T. Hamada, D.
Suzuki, H. Urabe and F. Sato, J. Am. Chem. Soc., 1999, 121, 7342–7344.
Also see reference 4.
a Intractable mixture, in which the desired enyne is a minor constituent, was
recovered.
CHEM. COMMUN., 2002, 272–273
273