A novel reaction of titanacyclopentenes and aldehydes with or without Lewis acids

Article abstract of DOI:10.1016/j.tetlet.2007.06.149

Oxatitanacyclopentenes were prepared in high yields from the reaction of aldehydes with titanacyclopenetens via substitution of ethylene. No insertion product was obtained in this reaction. The combination of alkynes and aldehydes played an important role in the successive formation of oxatitanacyclopentenes. Some oxatitanacyclopentenes are very stable and can be purified using column chromatography. The cooperation between Ti and LA led to very different results from that between Zr and LA.

Full text of DOI:10.1016/j.tetlet.2007.06.149

Tetrahedron Letters 48 (2007) 6167–6170
A novel reaction of titanacyclopentenes and aldehydes
with or without Lewis acids
Qiaoshu Hu,a Dongzhen Li,a Huijun Zhanga and Zhenfeng Xia,b,
*
aBeijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Received 28 April 2007; revised 24 June 2007; accepted 26 June 2007
Available online 4 July 2007
Abstract—Oxatitanacyclopentenes were prepared in high yields from the reaction of aldehydes with titanacyclopenetens via substi-
tution of ethylene. No insertion product was obtained in this reaction. The combination of alkynes and aldehydes played an impor-
tant role in the successive formation of oxatitanacyclopentenes. Some oxatitanacyclopentenes are very stable and can be purified
using column chromatography. The cooperation between Ti and LA led to very different results from that between Zr and LA.
Ó 2007 Elsevier Ltd. All rights reserved.
We have recently demonstrated that a combination of
transition-metal-mediated C–C bond forming reaction
with Lewis-acid-mediated organic transformation is a
powerful strategy leading to unprecedented reaction pat-
terns and synthetically useful methodologies.1–5 Thus,
zirconacyclopentenes 1, prepared in situ from Cp2ZrEt2
(Takahashi reagent) and alkynes, reacted with aldehydes
via insertion reaction to afford oxazirconacycloheptenes
2, which gave homoallylic alcohols 3 upon hydrolysis
with 3 N HCl.6,7 However, in the presence of Lewis
acids, instead of 3, homoallyl ketones 4 or tetrahydro-
furans 5 were obtained in excellent yields (Scheme
1).3,4 Prompted by these interesting results,1–5 we initi-
ated a project on reactions between titanacyclopentenes
6 and aldehydes with or without the presence of Lewis
acids, for the following reasons: (1) although Cp2Zr
and Cp2Ti are both group IV metals, their reactivity
are frequently found remarkably different, (2) compared
with many reports about the reaction of Cp2Zr–zircona-
cyclopentenes,2–8 few reports have appeared about reac-
tions of Cp2Ti–titanacyclopentenes,9–12 an immediate
analogy of zirconacyclopentenes. In this Letter, preli-
minary results about reaction of Cp2Ti–titanacyclo-
R
R
R'
ZrCp2
OH
O
1
3N HCl
AlCl3
insertion R'CHO
R
R
R
3
R
R
R'
R'CHO
ZrCp2
O
R
R
4
R'
2
R
R'
CuCl
O
3N HCl
R'
5
Scheme 1.
petenes with aldehydes in the presence and in the
absence of Lewis acids are reported.
Titanacyclopentenes 6 could be readily prepared in excel-
lent yields from Cp2TiCl2/2EtMgBr at À30 °C as dem-
onstrated by NMR and GC.9c As shown in Scheme 1,
zirconacyclopentenes 1 underwent insertion reaction of
aldehydes at 0 °C affording the corresponding seven-
Keywords: Lewis acid mediated reaction; Indene; Insertion;
Titanacyclopentene.
*
Corresponding author. Tel.: +86 10 6275 9728; fax: +86 10 6275
1708; e-mail: zfxi@pku.edu.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.149

6168
Q. Hu et al. / Tetrahedron Letters 48 (2007) 6167–6170
R
Cp2TiEt2
Et-H
R
insertion
Pr
TiCp2
6h
Pr
Pr
TiCp2
O
Pr
Cp2Ti
PhCHO
R
- 30 oC, 3 h
>98%
R
R'
7
R'CHO
substitution
of ethylene
TiCp2
R
R
substitution
of alkyne
6
substitution
TiCp2
Pr
Pr
Pr
Pr
O
R'
TiCp2
O
91%
H+
8
Ph
9a: R = Ph, R' = Ph, 77%
H+ or D+
R
9b: R = Ph, R' =
9c: R = Ph, R' =
9d: R = Ph, R' =
9e: R = Ph, R' =
p
-Ph-Ph, 65%
-Me-Ph, 62%
-F-Ph, 84%
-Cl-Ph, 81%
8h
p
Ph
Ph
Ph
p
O
p
R
TiCp2
Ph
12: 15%
9f: R = Ph, R' = Pr, 55%
9g: R = Pr, R' = Pr, 54%
9gD: 41%, D > 80%
HO
OH
H or D
OH
10
11: 48%
R'
not observed
9h: R = Pr, R' = Ph, 0%
9
Scheme 3.
Scheme 2.
Table 1. Selected NMR data for complexes 8e–8g (unit: ppm)
Ph Ph
membered zirconacycles 2 in high yields.6,7 However,
surprisingly, titanacyclopentenes 6 did not undergo any
insertion reaction with aldehydes under a variety of reac-
tion conditions, including change of reaction tempera-
tures, reaction time, amount of reagents, etc.12 Instead,
substitution reaction of the ethylene molecule by the
aldehyde always took place at higher temperatures to
afford the five-membered oxatitanacyclopentenes 8
(Scheme 2). Hydrolysis of the reaction mixtures with
aqueous 3 N HCl gave their corresponding allylic alco-
hols 9.13 This reactivity is very different from that of its
analogous 1, although 1 could also undergo substitution
reaction with aldehydes at higher temperatures.14 The
relatively space-demanding character of Ti is proposed
to be responsible for this exclusive substitution reaction.
This substitution reaction of 6 with aldehydes affording 8
represents the first example of this kind.
1
1
Ph
Ph
Ph
1
Ph
TiCp2
TiCp2
2
2
O
O
TiCp2
2
O
Br
F
O
8g
8e
8f
8e
8f
8f
8g
1H NMR
13C NMR
Cp
CH-2
6.39, 6.38
6.18
6.40, 6.38
6.20
6.30, 6.34
6.13
8e
8g
Cp
116.4, 115.4 116.3, 115.3 116.5, 116.1
C-1
CH-2
195.8
89.8
195.5
89.9
196.1
82.1
It was interesting to find out that, probably due to the
high oxo-philic nature of Ti, several oxatitanacyclo-
pentenes 8 (Table 1. Full NMR data and spectra can
be found in the Supplementary data) are very stable,
even column chromatograph could be used to purify
them. However, they gradually decomposed with time;
thus attempts to determine their structures by single-
crystal X-ray structural analysis generally failed in
vain.17
The combination of alkynes and aldehydes was found to
be crucial for the formation of oxa-intermediates 8. For
examples, the combination between diphenylacetylene
and aromatic aldehydes afforded alcohols (9a–e) in high
to excellent isolated yields. However, the yields of
hydrolyzed products 9 were relatively lower in cases of
coupling between diphenylacetylene and aliphatic alde-
hydes (9f) or coupling between 4-octyne and aliphatic
aldehyde (9g, 9gD). The uttermost case is shown in
Scheme 3. When titanacyclopentene 6h possessing two
propyl substituents was treated with aromatic alde-
hydes, such as PhCHO, totally no coupling product 9h
was obtained. Instead, substitution of the original 4-oct-
yne was completed, regenerating 4-octyne in more than
90% recovered yield. The oxatitanacyclopentane 10 was
not obtained either. The pinacol coupling product (11)
of aldehydes and the fulvene derivative (12) formed
from an aldehyde and the Cp2Ti were isolated in 48%
and 15% yields, respectively. Although we are not sure
about the fate of Cp2Ti moiety, these results suggest that
low-valent Ti species must be formed in the reaction
mixture and the coordination mode of Cp ligands must
be also changed.15,16
Titanacyclopentenes were found to react also with
organonitriles to afford a,b-unsaturated ketones upon
hydrolysis. As demonstrated in Scheme 4, 6a reacted
with PrCN via substitution of ethylene to afford azati-
Ph
Ph
TiCp2
6a
Ph
TiCp2
1.5 equiv.
PrCN
Ph
Pr
Ph
H+
Ph
Pr
O
N
14: 72%
13
Scheme 4.

Q. Hu et al. / Tetrahedron Letters 48 (2007) 6167–6170
6169
References and notes
1. Wang, C. Y.; Xi, Z. Chem. Soc. Rev., in press.
2. (a) Xi, Z.; Li, P. Angew. Chem., Int. Ed. 2000, 39, 2950; (b)
Zhao, C.; Li, P.; Cao, X.; Xi, Z. Chem. Eur. J. 2002, 8,
4292.
Ph
PhCHO
Ph
Ph
without LA
3N HCl
Ph
TiCp2
6a
OH
Ph
PhCHO
9a: 71%
PhCHO
with LA
3. (a) Zhao, C.; Yu, T.; Xi, Z. Chem. Commun. 2002, 142; (b)
Zhao, C.; Yan, J.; Xi, Z. J. Org. Chem. 2003, 68, 4355.
4. (a) Zhao, C.; Lu, J.; Yan, J.; Xi, Z. Tetrahedron Lett. 2003,
44, 6895; (b) Zhao, C.; Lu, J.; Li, Z.; Xi, Z. Tetrahedron
2004, 60, 1417.
Ph
Ph
3N HCl
PhCHO
Ph
15a: 73%-86%
5. Lu, J.; Mao, G.; Zhang, W.; Xi, Z. Chem. Commun. 2004,
38, 4848.
Ph
Ph
6. (a) Takahashi, T.; Kageyama, M.; Denisov, V.; Hara, R.;
Negishi, E. Tetrahedron Lett. 1993, 34, 687; (b) Xi, Z.;
Hara, R.; Takahashi, T. J. Org. Chem. 1995, 60, 4444; (c)
Takahashi, T.; Xi, C.; Xi, Z.; Kageyama, M.; Fischer, R.;
Nakajima, K.; Negishi, E. J. Org. Chem. 1998, 63, 6802.
7. For insertion of aldehydes into zirconacyclopentenes, see:
(a) Coperet, C.; Negishi, E.; Xi, Z.; Takahashi, T.
Tetrahedron Lett. 1994, 35, 695; (b) Li, P.; Xi, Z.;
Takahashi, T. Chin. J. Chem. 2001, 19, 45.
LA
TiCp2
O
Ph
Ph
8a
16a: 28%
Scheme 5.
tanacyclopentadiene 13, which after long-time hydroly-
sis (9 h) gave product 14 in 72% isolated yield.14
8. For recent examples, see: (a) Liu, Y.; Gao, H.; Zhou, S.
Angew. Chem., Int. Ed. 2006, 45, 4163; (b) Liu, Y.; Gao,
H. Org. Lett. 2006, 8, 309; (c) Mito, S.; Zhou, L.; Xi, C.
Chem. Lett. 2006, 35, 122; (d) Quntar, A. A. A.;
Rosenthal, D.; Srebnik, M. Tetrahedron 2006, 62, 5995;
(e) Chen, C.; Xi, C.; Shi, Y.; Hong, X. Synlett 2005, 911;
(f) Liu, Y.; Liu, M.; Song, Z. J. Am. Chem. Soc. 2005, 127,
3662.
9. For the preparation method of Cp2Ti–titanacyclopent-
enes, see: (a) Maercker, A.; Groos, A. Angew. Chem., Int.
Ed. 1996, 35, 210; (b) Pellny, P. M.; Burlakov, V. V.;
Peulecke, N.; Baumann, W.; Spannenberg, A.; Kempe, R.;
Francke, V.; Rosenthal, U. J. Organomet. Chem. 1999,
578, 125; (c) Sato, K.; Nishihara, Y.; Huo, S.; Xi, Z.;
Takahashi, T. J. Organomet. Chem. 2001, 633, 18, and
references therein.
10. An oxatitanacyclopentene was synthesized from reaction
of ketones with titanacyclopropenes Burlakov, V. V.;
Peulecke, N.; Baumann, W.; Spannenberg, A.; Kempe, R.;
Rosenthal, U. J. Organomet. Chem. 1997, 536–537, 293.
11. Reaction of titanacyclopentenes with CO affording cyclo-
pentenones via Pauson-Khand type reaction: (a) Hicks, F.
A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc.
1999, 121, 5881; see also (b) Zhao, Z.; Ding, Y. J. Chem.
Soc., Perkin Trans. 1 1998, 171.
We then carried out reactions of 6a (R = Ph) with
PhCHO in the presence of a variety of Lewis acids, such
as AlCl3, EtAlCl2, BF3, and CuCl. Surprisingly, hydro-
lysis of the reaction mixtures gave 15a as the major
product in 73–86% isolated yields (Scheme 5). This
result is in contrast with the usual activity of adduct of
carbonyl compounds with Lewis acids (LA). Insertion
products 7 were expected because the aldehyde was acti-
vated by forming the adduct. However, this result indi-
cated that even the substitution reaction was blocked.
With this information in hand, we first generated oxati-
tanacyclopentene 8a, followed by treatment with Lewis
acids. The result was again a surprise and gave an indene
derivative 16a in 28% isolated yields along with several
unknown products. Although the function of Lewis
acids in this reaction is not yet clear, our preliminary
results suggest that the cooperation between Cp2Ti
and LA must lead to very different results from that
between Cp2Zr and LA as we already observed.
12. Insertion of an aldehyde into (O-i-Pr)2Ti–titanacyclopent-
enes forming seven-membered ring intermediates. (a)
Urabe, H.; Sato, F. J. Org. Chem. 1996, 61, 6756; (b)
Urabe, H.; Sato, F. J. Am. Chem. Soc. 1999, 121, 1245.
13. A general procedure for the reaction of titanacyclopent-
enes 6 with aldehydes affording allylic alcohols 9. An
alkyne (2.0 mmol) was added to a THF solution of
[Cp2TiEt2] prepared in situ from Cp2TiCl2 (2.4 mmol,
598 mg) and EtMgBr (4.8 mmol, 4.8 ml, 1.0 M THF
solution) in THF (10 ml) at À78 °C. The reaction mixture
was then stirred at À30 °C for 3 h to afford titanacycl-
opentene 6. After aldehyde (2.4 mmol) was added, this
solution was warmed up to 70 °C and stirred for 2 h. The
reaction mixture was cooled down to 0 °C and quenched
with aqueous 3 N HCl and extracted with ether. The
extract was washed with saturated aqueous NaHCO3 and
brine and dried over Na2SO4. The solvent was then
evaporated in vacuo to give red-brown oil, which was
purified by column chromatograph to give the products.
14. Takahashi, T.; Xi, C.; Xi, Z.; Kageyama, M.; Fischer, R.;
Nakajima, K.; Negishi, E. J. Org. Chem. 1998, 63,
6802.
Further investigation into the reaction chemistry of
titanacycles and the Lewis acid-mediated reactions of
titanacycles with a variety of organic substrates are in
progress.
Acknowledgments
This work was supported by the National Natural Sci-
ence Foundation of China, and Peking University. The
Cheung Kong Scholars Programme, Qiu Shi Science &
Technologies Foundation, BASF, and Eli Lilly China
are gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.06.149.

6170
Q. Hu et al. / Tetrahedron Letters 48 (2007) 6167–6170
15. For recent reviews, see: (a) Zhuang, Z.; Zhang, W.; Jia, X.;
Zhai, H. Chin. J. Org. Chem. 2006, 26, 145; (b) Ladipo, F.
T. Curr. Org. Chem. 2006, 10, 965.
16. (a) Xi, Z.; Sato, K.; Gao, Y.; Lv, J.; Takahashi, T. J. Am.
Chem. Soc. 2003, 125, 9568; (b) Takahashi, T.; Kuzuba,
Y.; Kong, F.; Nakajima, K.; Xi, Z. J. Am. Chem. Soc.
2005, 127, 17188.
17. X-ray structure for a titanafuranone complex: (a) Burla-
kov, V. V.; Yanovsky, A. I.; Struchkov, Yu. T.; Rosen-
thal, U.; Spannenberg, A.; Kempe, R.; Ellert, O. G.; Shur,
V. B. J. Organomet. Chem. 1997, 542, 105; (b) Pellny, P.
M.; Kirchbauer, F. G.; Burlakov, V. V.; Baumann, W.;
Spannenberg, A.; Rosenthal, U. J. Am. Chem. Soc. 1999,
121, 8313.