Dialkyltitanium-mediated titanation of conjugated 1,3-butadiynes and its coupling reactions with aldehydes: a facile synthesis of stereodefined enynes and trans-enynols

Article abstract of DOI:10.1016/j.tetlet.2008.09.042

A highly efficient and convenient method for the selective titanation of 1,3-butadiynes using Ti(OⁱPr)₄/ⁿBuLi reagent has been developed. The method provided a facile synthesis of enynes and trans-enynols in a well-stereod

Full text of DOI:10.1016/j.tetlet.2008.09.042

Tetrahedron Letters 49 (2008) 6655–6658
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Dialkyltitanium-mediated titanation of conjugated 1,3-butadiynes and
its coupling reactions with aldehydes: a facile synthesis of stereodefined
enynes and trans-enynols
*
Jingjin Chen, Yuanhong Liu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
A highly efficient and convenient method for the selective titanation of 1,3-butadiynes using Ti(OiPr)4/
nBuLi reagent has been developed. The method provided a facile synthesis of enynes and trans-enynols
in a well-stereodefined manner.
Article history:
Received 25 July 2008
Revised 1 September 2008
Accepted 9 September 2008
Available online 11 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Dialkyltitanium complex
Titanium–butadiyne complex
Coupling
Oxatitanacyclopentene
trans-Enynol
The organometallic chemistry of group 4 metal complexes with
1,3-butadiynes R(C„C)2R and polyynes R(C„C)nR has attracted
considerable attention owing to their fascinating structural fea-
tures, their unique M–C bonding, and their unusual capacity to
induce highly selective transformation reactions.1–4 Recently,
develop an efficient and convenient method for the regioselective
titanation of 1,3-butadiynes. In this Letter, we demonstrated that
Ti(II)–butadiyne complex could be readily formed and thermally
stable at room temperature using Bu2Ti(OiPr)2, and the subsequent
coupling with aldehydes could also be performed conveniently at
room temperature.
we have investigated the intermolecular cross-coupling of a-alkyn-
ylated zirconacyclopentenes5 prepared by the reaction of zircono-
cene-ethylene complex with 1,3-butadiynes with unsaturated
compounds, which afforded a regio- and stereocontrollable syn-
thesis of trans-enediynes.5a We have also shown that zirconium-
mediated coupling of 1,3-butadiynes with aldehydes or ketones
provides efficient access to cis-[3]cumulenols.5b These unusual
and interesting results prompted us to study the formation and
the reactivities of other group 4 metal complexes such as tita-
nium–butadiyne complexes. Sato et al. had reported that a site-
selective mono-titanation of coujugated 1,3-butadiynes has been
achieved through a Ti(II) alkoxide reagent (Ti(OiPr)4/2iPrMgCl).6
However, the thus formed Ti(II)–butadiyne complexes are ther-
mally unstable and can only be used below À30 °C, and the subse-
quent coupling with aldehydes also need to proceed at low
temperature of À50 °C. On the other hand, Eisch and Gitua repor-
ted7a that thermally stable Ti(II)–alkyne (only mono alkynes have
been used) complexes could be generated through a Ti(OiPr)4/
2nBuLi (or Bu2Ti(OiPr)2) reagent.7 These works prompted us to
As shown in the Scheme of Table 1, the alkoxytitanium–but-
adiyne complexes 2 and/or 3 could be successfully generated by
Ti(OiPr)4/2nBuLi system (Table 1). The procedure is operationally
convenient and practical: to a solution containing 1,3-butadiyne
1 and 1.25 equiv Ti(OiPr)4 in THF at À78 °C was added 2.5 equiv
n-BuLi, the mixture was then warmed up to room temperature
and stirred at the same temperature for 1 h. After quenching the
mixture by 3 N HCl, cis-enynes 4 and/or 5 were formed in good
yields and in high purity. The results also indicated a selective
mono-titanation that occurred under these conditions. As pro-
posed by Eisch and Gitua in Ti(II)–monoalkyne complex formation
reactions, the highly efficient titanation in this case might be due
to the strong coordination ability of the butadiynes, which
facilitates a reductive elimination of an octahedral-like transition
state,7a leading to the Ti(II)–butadiyne complex or titanacyclopro-
pene intermediates like 2 and 3. A wide range of 1,3-butadiynes,
including TMS-, TBS-(tert-butyldimethylsilyl), alkyl-, and aryl-
substituted ones, participated in this titanation reaction, furnishing
the corresponding enynes in 53–90% yields (Table 1). Moreover, in
the case of unsymmetrically substituted butadiyne 1f, titanation
selectively occurred at the acetylenic moiety substituted with an
* Corresponding author. Tel.: +86 21 54925135; fax: +86 21 64166128.
E-mail address: yhliu@mail.sioc.ac.cn (Y. Liu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.042

6656
J. Chen, Y. Liu / Tetrahedron Letters 49 (2008) 6655–6658
Table 1
Regioselective mono-titanation of conjugate butadiynes
R1
R2
R1
R1
R2
R2
R1
Ti(OiPr)4/
n-BuLi
H+
R2 + R1
+
-78 oC to rt, 1 h
Ti
Ti
(OiPr)2
(OiPr)2
R2
4
5
1
2
3
R1
R2
Entry
1
Product
Yielda (%)
56
TMS
TMS
TMS
4a
TMS
TBS
1a
TBS
Ph
TBS
Ph
TBS
2
3
4b
4c
90
77
1b
1c
Ph
Ph
Bu
Bu
Bu
4
5
6
4d
4e
4f
53
Bu
1d
Ph(H2C)2
Ph(CH2)2
(CH2)2Ph
68
(CH2)2Ph
1e
TMS
Ph
TMS
Bu
72b
Bu
1f
C6H13
H
Ph
C6H13
H
+
7
4g
5g
9
C6H13
1g
Ph
H
H
55
a
Isolated yields.
b
The product was concomitant with small amount of byproduct.
alkyl group due to the less steric effect caused by alkyl group com-
pared with a trimethylsilyl group (Table 1, entry 6). However,
when phenyl, hexyl-substituted butadiyne 1g was employed,
the major product was enyne 5g derived from the coordination
of phenyl acetylenic moiety to titanium (Table 1, entry 7). This
may be due to the ability of the aryl group for the stabilization of
a Ti–Csp2 bond in the Ti(II)–butadiyne complex 3.
The Ti(II)–butadiyne complexes 2 and 3 formed in situ are valu-
able intermediates for further transformations. To demonstrate the
utility of these complexes, we first carried out the coupling reac-
tion of 1a with benzaldehyde. Thus, addition of 1 equiv of benzal-
dehyde to the reaction mixture containing titanacyclopropene
intermediate afforded oxatitanacyclopentene8,9 6a, which was
hydrolyzed to give a mixture of trans-enynol 7a and cumulenol
8a (Table 2). The structure of enynol 7 has been confirmed by 2D
NOESY spectrum of 7a and several products listed in Table 3, and
also by X-ray crystallographic analysis of the ester derivative of
compound 7g.10 It is interesting to note that the product distribu-
tion can be influenced by the quenching reagent. While 3 N HCl
afforded 7a and 8a in a ratio of 83:17, the use of H2O and saturated
NaHCO3 produced 7a in a high selectivity (P94:6).11
The coupling reaction could be applied to a variety of aldehydes.
As shown in Table 3, by quenching the reaction mixture with sat-
urated NaHCO3, the trans-enynol 7 was selectively generated in

J. Chen, Y. Liu / Tetrahedron Letters 49 (2008) 6655–6658
6657
Table 2
Optimization studies for the selective coupling of conjugated butadiyne 1a with aldehyde
TMS
TMS
TMS
TMS
TMS
Ph
i) Ti(OiPr)4/n-BuLi
TMS
TMS
Ph
H+
(iPrO)2Ti
+
H
ii) PhCHO, rt, 1h
O
Ph
HO
8a
HO
TMS
6a
7a
1a
Entry
Quenching reagent
Yield (%) of 7a and 8aa
7a:8ab
1
2
3
3 N HCl
H2O
Satd NaHCO3
64
69
68c
83:17
96:4
94:6
a
Combined NMR yields.
b
C
Determined by 1H NMR. Compound 8a was obtained as a single stereoisomer, the E or Z configuration of this compound has not been assigned.
Compound 7a was isolated in 52% yield.
Table 3
Selective coupling of conjugated 1,3-butadiynes with aldehydes
R1
R1
R1
R1
R1
R2
i) Ti(OiPr)4/n-BuLi
sat. NaHCO3
(iPrO)2Ti
R2
ii) R2CHO, rt, 1h
O
HO
R1
6
7
Entry
R1
R2CHO
Product
Yielda (%)
1
2
3
4
TMS
TBS
TBS
TBS
1a
1b
1b
1b
PhCHO
PhCHO
p-MeOC6H4CHO
p-ClC6H4CHO
7a
7b
7c
7d
52
85
85
74
5
6
TBS
TBS
1b
1b
7e
7f
81
CHO
S
81b
CHO
7
8
9
Ph
Bu
Ph(CH2)2
1c
1d
1e
PhCHO
PhCHO
PhCHO
7g
7h
7i
67
55
68
a
Isolated yields.
b
Containing two regioisomers in a ratio of 92:8 after column chromatography. Pure 7f could be obtained in 69% yield after recrystallization.
good to high yields. The aryl aldehydes bearing electron-donating
or electron-withdrawing substituent were all compatible with this
reaction, furnishing 7c and 7d in 85% and 74% yields, respectively,
(Table 3, entries 3 and 4). A heterocyclic group could also be incor-
porated into the final product, and the desired enynol 7e was
obtained in 81% yield (Table 3, entry 5).
When unsymmetrically substituted butadiynes 1f and 1g were
employed, regioselective coupling reactions have been observed.
Silylated butadiyne 1f afforded 7j as a sole product in 63% yield.
The regioselectivity in this case is in sharp contrast with Sato’s re-
sult, in which C–C bond formed at the olefinic carbon having the
alkynyl group.6 The phenylated butadiyne 1g afforded 7k as a
major isomer (Fig. 1).
C6H13
Bu
Ph
TMS
Ph
Ph
C6H13
-MeOC6H4
+
p
-MeOC6H4
p
HO
HO
HO
7j, 63%
7k, 56%
9, 5%
Figure 1.
The oxatitanacycle 6 could be further confirmed by deuterioly-
sis or iodinolysis of the metal intermediate, which provided a deu-
terated compound 7b–d in 86% yield with excellent deuterium
incorporation (D = 97%) and an iodinated product 10 in 66% yield,
respectively (Scheme 1). Interestingly, iodination of the oxatitana-
cycle derived from a silyl-butadiyne 1b did not afford the desired
iodinated enynol, instead, a butadiyne derivative 11 was formed
in good yields, presumably via a Brook rearrangement mechanism
(Scheme 2).12
In summary, we have developed an efficient and convenient
method for the selective titanation of 1,3-butadiynes using
Ti(OiPr)4/nBuLi reagent. The method provided a facile synthesis of

6658
J. Chen, Y. Liu / Tetrahedron Letters 49 (2008) 6655–6658
R
R
R
R
i) Ti(OiPr)4/n-BuLi
ii) PhCHO
R
D2O or I2
rt
(iPrO)2Ti
E
Ph
O
Ph
HO
R
7b-
d: R= TBS, E = D, 86% yield, D= 97%
1
10: R= Ph, E = I, 66% yield
Scheme 1.
TBS
TBS
TBS
TBS
tBu
i) Ti(OiPr)4/
ii) RCHO
n-BuLi
TBS
R
Si
O
I2
rt
I
(iPrO)2Ti
O
R
TiI2(OiPr)2
R
OTBS
TiI(OiPr)2
TBS
11a, R=Ph, 66%
11b, R= 3,4,5-triMeOC6H2, 89%
1b
Scheme 2.
Wiley-VCH: Weinheim, Germany, 2004; p 139, Chapter 4; (g) Rosenthal, U.;
Pellny, P.; Kirchbauer, F. G.; Burlakov, V. V. Acc. Chem. Res. 2000, 33, 119.
enynes and enynols in a well-stereodefined manner. Further
research to explore the new synthetic utility of these titanacycle
intermediates is currently underway.
3. (a) Takahashi, T.; Aoyagi, K.; Denisov, V.; Suzuki, N.; Choueiry, D.; Negishi, E.
Tetrahedron Lett. 1993, 34, 8301; (b) Takahashi, T.; Xi, Z.; Nishihara, Y.; Huo, S.;
Kasai, K.; Aoyagi, K.; Denisov, V.; Negishi, E. Tetrahedron 1997, 53, 9123; (c) Liu,
Y.; Sun, W.; Nakajima, K.; Takahashi, T. Chem. Commun. 1998, 1133.
4. For other groups, see: (a) Bredeau, S.; Delmas, G.; Pirio, N.; Richard, P.;
Donnadieu, B.; Meunier, P. Organometallics 2000, 19, 4463; (b) Hsu, D. P.; Davis,
W. M.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 10394; (c) Temme, B.; Erker,
G.; Fröhlich, R.; Grehl, M. Angew. Chem. 1994, 106, 1570; (d) Temme, B.; Erker,
G.; Fröhlich, R.; Grehl, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 1480; (e) Ahlers,
W.; Temme, B.; Erker, G.; Fröhlich, R.; Fox, T. J. Organomet. Chem. 1997, 527,
191; (f) Erker, G.; Venne-Dunker, S.; Kehr, G.; Kleigrewe, N.; Fröhlich, R.; Mück-
Lichtenfeld, C.; Grimme, S. Organometallics 2004, 23, 4391; (g) Spies, P.; Kehr,
G.; Fröhlich, R.; Erker, G.; Grimme, S.; Mück-Lichtenfeld, C. Organometallics
2005, 24, 4742.
Acknowledgments
We thank the National Natural Science Foundation of China
(Grant Nos. 20672133 and 20732008), Chinese Academy of Sci-
ence, Science and Technology Commission of Shanghai Municipal-
ity (Grant Nos. 08QH14030 and 07JC14063), and the Major State
Basic Research Development Program (Grant No. 2006CB806105)
for financial support.
5. (a) Liu, Y.; Gao, H. Org. Lett. 2006, 8, 309; (b) Liu, Y.; Gao, H.; Zhou, S. Angew.
Chem., Int. Ed. 2006, 45, 4163.
Supplementary data
6. Delas, C.; Urabe, H.; Sato, F. Chem. Commun. 2002, 272.
7. (a) Eisch, J. J.; Gitua, J. N. Organometallics 2003, 22, 24. For related paper, see: (b)
Obora, Y.; Moriya, H.; Tokunaga, M.; Tsuji, Y. Chem. Commun. 2003, 2820.
8. For alkyne-aldehyde coupling reactions using titanium or zirconium, see: (a)
Hu, Q.; Li, D.; Zhang, H.; Xi, Z. Tetrahedron Lett. 2007, 48, 6167; (b) Takahashi, T.;
Kageyama, M.; Denisov, V.; Hara, R.; Negishi, E. Tetrahedron Lett. 1993, 34, 687;
(c) Copéret, C.; Negishi, E.; Xi, Z.; Takahashi, T. Tetrahedron Lett. 1994, 35, 695;
(d) Buchwald, S. L.; Nielsen, R. B. Chem. Rev. 1988, 88, 1047; (e) Harada, K.;
Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203; (f) Zhao, C.; Yu, T.; Xi, Z.
Chem. Commun. 2002, 142; (g) Zhao, C.; Yan, J.; Xi, Z. J. Org. Chem. 2003, 68,
4355; (h) Liu, Y.; Song, F.; Cong, L. J. Org. Chem. 2005, 70, 6999; (i) Guo, S.;
Zhang, H.; Song, F.; Liu, Y. Tetrahedron 2007, 63, 2009; (j) Guo, S.; Liu, Y. Org.
Biomol. Chem. 2008, 6, 2064.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.042.
References and notes
1. For reviews, see: (a) Grotjahn, D. B. In Comprehensive Organometallic Chemistry
II; Hegedus, L. S., Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon:
Oxford, 1995; Vol. 12, p 741 (b) Titanium and Zirconium in Organic Synthesis;
Marek, I., Ed.; Wiley-VCH: Weinheim, Germany, 2002; (c) Takahashi, T.; Xi, Z.;
Hara, R. Trends Organomet. Chem. 1997, 2, 117.
2. For reviews, see: (a) Rosenthal, U.; Burlakov, V. V.; Arndt, P.; Baumann, W.;
Spannenberg, A. Organometallics 2005, 24, 456. and the references therein; (b)
Rosenthal, U.; Burlakov, V. V.; Arndt, P.; Baumann, W.; Spannenberg, A.
Organometallics 2003, 22, 884; (c) Rosenthal, U. Angew. Chem. 2003, 115, 1838; .
Angew. Chem., Int. Ed. 2003, 42, 1794; (d) Rosenthal, U. Angew. Chem. 2004, 116,
3972; Rosenthal, U. Angew. Chem., Int. Ed. 2004, 43, 3882; (e) Rosenthal, U.;
Arndt, P.; Baumann, W.; Burlakov, V. V.; Spannenberg, A. J. Organomet. Chem.
2003, 670, 84; (f) Rosenthal, U. Modern Acetylene Chemistry II-Chemistry,
Biology, and Material Science. In Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.;
9. For the formation of titanacycles, see: (a) Sato, K.; Nishihara, Y.; Huo, S.; Xi, Z.;
Takahashi, T. J. Organomet. Chem. 2001, 633, 18 and references cited therein; (b)
Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100, 2835.
10. See Supplementary data.
11. For the effect of quenching methods on the product distributions, see: (a) Fang,
H.; Song, Q.; Wang, Z.; Xi, Z. Tetrahedron Lett. 2004, 45, 5159; (b) Song, Z.; Li, Y.;
Liu, M.; Cong, Li; Liu, Y. Organometallics 2006, 25, 5035; (c) Xi, Z.; Guo, R.; Mito,
S.; Yan, H.; Kanno, K.; Nakajima, K.; Takahashi, T. J. Org. Chem. 2003, 68, 1252.
12. (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77; (b) Jankowski, P.; Raubo, P.; Wicha, J.
Synlett 1994, 985; (c) Moser, W. H. Tetrahedron 2001, 57, 2065.