Ti(II)-mediated domino cyclization of 2-functionalized 1-halo-2,n-enynes (n = 7, 8) to bicyclic compounds

Article abstract of DOI:10.1016/j.tetlet.2006.08.099

The reaction of 2-functionalized 1-halo-2,n-enynes (n = 7 or 8) with a divalent titanium reagent, Ti(O-i-Pr)₄/2i-PrMgCl, proceeded in a domino fashion to afford bicyclic compounds in good yields.

Full text of DOI:10.1016/j.tetlet.2006.08.099

Tetrahedron Letters 47 (2006) 7537–7540
Ti(II)-mediated domino cyclization of 2-functionalized
1-halo-2,n-enynes (n = 7,8) to bicyclic compounds
Sentaro Okamoto,a,* Hidemoto Ito,a Shogo Tanakab and Fumie Satob
aDepartment of Material and Life Chemistry, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
bGraduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho,
Midori-ku, Yokohama 226-8501, Japan
Received 21 July 2006; revised 22 August 2006; accepted 24 August 2006
Abstract—The reaction of 2-functionalized 1-halo-2,n-enynes (n = 7 or 8) with a divalent titanium reagent, Ti(O-i-Pr)4/2i-PrMgCl,
proceeded in a domino fashion to afford bicyclic compounds in good yields.
Ó 2006 Elsevier Ltd. All rights reserved.
We have recently developed a divalent titanium reagent-
mediated cyclization of 2,7- and 2,8-enyn-1-ol deriva-
tives. Thus, the reaction of enyn-1-ol derivatives 2
(G = H) with Ti(O-i-Pr)4/2i-PrMgCl (1)1 proceeded
through b-elimination of the leaving group X from a
titanacyclic intermediate 3 (G = H) to give alkenyltita-
nium compound 4 (Scheme 1).2 The resulting alkenyl-
titaniums 4 could act as a nucleophile and reacted
with various electrophiles to give 5. With these results
in hand, we thought that further intramolecular cycliza-
tion of the resulting alkenyltitaniums of the type 4 to
bicyclic compounds might occur in a domino fashion3
when the starting enynes have a functional group
(FG), which can react with the alkenyltitanium moiety,
as a substituent G at a C-2 position (Scheme 1). Herein
reported is the realization of this idea by introducing
–CO2R0 or –CH2Cl as the FG at a C-2 position of
2,7- and 2,8-enyn-1-ol derivatives, the reaction of which
produced the corresponding bicyclic products 6 and 7,
respectively.4
First, we investigated the 1-mediated reaction of 2a,
which has a methoxycarbonyl group as the substituent
G (Table 1). Thus, enynol derivative 2a was treated with
1.4 equiv of 1 at ꢀ40 to ꢀ20 °C for 2 h and the mixture
was quenched by addition of H2O. However, the ex-
pected dienone 6a was not produced but 29% of enone
compound 8 was produced with 37% of the recovered
2a (Table 1, entry 1).
Scheme 1. Plan for domino reaction.
Therefore, we carried out the reaction using 2.3 equiv of
1 and found that the reaction provided 8 [diastereomeric
ratio (dr) = 95:5] in 84% yield (Table 1, entry 2).5,6
*
Corresponding author. Tel.: +81 45 481 5661; fax: +81 45 413
9770; e-mail: okamos10@kanagawa-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.099

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S. Okamoto et al. / Tetrahedron Letters 47 (2006) 7537–7540
Table 1. Reactions of 5 with 1
Entry
2
Equiv of 1
Yield (%)
Scheme 3. Formation of 6a by the reaction of 10 with I2.
8
9
Recovered 2
1
2
3
4
2a
2a
2b
2c
1.4
2.3
1.4
1.4
29
84
35
Trace
Trace
Trace
60
37
Trace
Trace
Trace
We next prepared enyne 2d as a substrate, which has a
chloromethyl moiety as the substituent G at the C-2
position, expecting that the corresponding titanium
compound 40d could undergo an intramolecular allylic
substitution giving 7d (Scheme 4). Treatment of 2d with
1.2 equiv of 1, however, resulted in the production of
mono-cyclic compound 11 after hydrolysis. The results
indicate that generated alkenyltitanium 40d could not
undergo allylic substitution. It was found that the addi-
tion of a catalytic amount of Li2Cu(CN)Cl2 to the reac-
tion mixture of 40d could effect intramolecular allylic
substitution to produce 1,2-annulated fuluvenes 7d in
80% yield.5,7
93
Enynes 2 having a more sterically demanding ester
group reacted smoothly with 1.4 equiv of 1 but afforded
mono-cyclic compounds 95 as a major product (entries 3
and 4).
The results can be explained by assuming that the
reaction of 2a with 1 provided dienone 6a via 40a as
expected, however, the resulting 6a further reacted with
1 fast to afford the corresponding oxatitanacyclic
compound 10, hydrolysis of which gave 8 (the order of
reaction rates: k2, k3 > k1) (Scheme 2). Introduction of
a cyclohexyl group into an ester moiety relatively
decreased the reaction rate from the corresponding 40
to 6a (k2) and, therefore, the reaction provided a mixture
of 8 and 9 (k1, k3 > k2). The t-Bu group may be so bulky
that the intramolecular acyl substitution reaction of the
corresponding 40 could not be undergone.
Under similar reaction conditions, analogous com-
pounds 2e–g reacted smoothly with a divalent titanium
reagent 1 and then Li2Cu(CN)Cl2 catalyst to afford the
corresponding 1,2-annulated fuluvenes 7e–g, respec-
tively, in good yield (Scheme 5). A high 1,2-diastereo-
selectivity was observed in the reaction of 2g.6
Scheme 6 illustrates the preparation of substrates 2 for
the present cyclization reactions. Thus, compounds
2a–c were synthesized by the Baylis–Hillman reaction8
of acrylic esters with 6-trimethylsilylhex-5-ynal (12) fol-
lowed by the bromination of the resulting alcohols,
where the bromination reaction proceeded stereoselec-
tively to yield the corresponding bromoesters as a Z
isomer. While, compounds 2d–f were prepared from
the known 5-bromomethylene-2,2-dimethyl-[1,3]dioxane
The presence of an intermediate 10 was confirmed by
iodolysis of the reaction mixture derived from 2a and
2.3 equiv of 1 (Scheme 3): The reaction mixture was
treated with I2 to give 6a in 62% yield.5 Thus, Ti(II)-
mediated domino cyclization could provide bicyclic
compounds 6a and 8 having a cyclopentene and methyl-
enecyclopentene structures, respectively, from the acyclic
enyne starting compound.
Scheme 4. Reaction of 2d with 1 and the following Cu-catalyzed
Scheme 2. A Possible explanation for the formation of 8 and 9.
cyclization.

S. Okamoto et al. / Tetrahedron Letters 47 (2006) 7537–7540
7539
References and notes
1. Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100,
2835–2886; Kulinkovich, O. G.; de Meijere, A. Chem. Rev.
2000, 100, 2789–2834; Eisch, J. J. J. Organomet. Chem.
2001, 617–618, 148–157; Sato, F.; Okamoto, S. Adv.
Synth. Catal. 2001, 343, 759–784; Sato, F.; Urabe, H. In
Titanium and Zirconium in Organic Synthesis; Marek, I.,
Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 319–
354.
2. Takayama, Y.; Gao, Y.; Sato, F. Angew. Chem., Int. Ed.
1997, 36, 851; Takayama, Y.; Okamoto, S.; Sato, F.
Tetrahedron Lett. 1997, 38, 8351; Okamoto, S.; Taka-
yama, Y.; Gao, Y.; Sato, F. Synthesis 2000, 975; Okamoto,
S.; Subburaj, K.; Sato, F. J. Am. Chem. Soc. 2001, 123,
4857; Ohkubo, M.; Uchikawa, W.; Matsushita, H.;
Nakano, A.; Shirato, T.; Okamoto, S. Tetrahedron Lett.
2006, 47, 5181, and references cited therein.
Scheme 5. Domino Ti(II)-mediated and Cu-catalyzed bicyclization
reactions.
3. For domino reactions, see: Pellissier, H. Tetrahedron 2006,
62, 1619; Suffert, J.; Salem, B.; Klotz, P. J. Am. Chem. Soc.
2001, 123, 12107, and references cited therein; Reviews:
Bra¨se, S.; de Meijere, A. In Metal-Catalyzed Cross
Coupling Reactions; Stang, P. J., Deiderich, F., Eds.;
Wiley-VHC: Weiheim, Germany, 1997; Tietze, L. F.
Chem. Rev. 1996, 96, 115; Waldmann, H. In Organic
Synthesis Highlights II; Waldmann, H., Ed.; Wiley-VHC:
Weiheim, Germany, 1995; p 193; de Meijere, A.; Meyer, F.
E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379.
4. Other syntheses of bicyclic compounds by 1-mediated
domino reaction, see: Suzuki, K.; Urabe, H.; Sato, F. J.
Am. Chem. Soc. 1996, 118, 8729; Urabe, H.; Suzuki, K.;
Sato, F. J. Am. Chem. Soc. 1997, 119, 10014; Urabe, H.;
Narita, M.; Sato, F. Angew. Chem., Int. Ed. 1999, 38,
3516; Urabe, H.; Hideura, D.; Sato, F. Org. Lett. 2000, 2,
381; Okamoto, S.; Subburaj, K.; Sato, F. J. Am. Chem.
Soc. 2000, 122, 11244; Subburaj, K.; Okamoto, S.; Sato,
F. J. Org. Chem. 2002, 67, 1024.
5. Compound 8: To a solution of 2a (1.0 mmol) and Ti(O-i-
Pr)4 (2.3 mmol) in ether (10 mL) was added i-PrMgCl
(4.6 mmol, 0.97 M in ether) at ꢀ40 °C and the mixture was
stirred for 2 h at this temperature. After the addition of
aqueous 1 M HCl, usual extractive work-up was followed;
1H NMR (300 MHz, CDCl3): d 2.39–2.70 (m, 3H), 2.18
(dt, J = 12, 6.6 Hz, 1H), 1.83–2.11 (m, 4H), 1.19 (d,
J = 7.2 Hz, 3H), 0.18 (s, 9H). Compound 9c: 1H NMR
(300 MHz, CDCl3): d 6.12 (br s, 1H), 5.43 (br s, 1H), 5.20
(q, J = 2.1 Hz, 1H), 3.36–3.43 (m, 1H), 2.33–2.46 (m, 2H),
1.40–1.97 (m, 4H), 1.47 (s, 9H), 0.08 (s, 9H). Compound 6a:
To the reaction mixture derived from 2a (1.0 mmol) and 1
(2.3 mmol) prepared above was added a solution of I2
(2.3 mmol) in ether at ꢀ20 °C. After the addition of
aqueous 1 M HCl, usual extractive work-up was followed;
1H NMR (300 MHz, CDCl3): d 5.91 (br s, 1H), 5.26 (br s,
1H), 3.27–3.37 (m, 1H), 2.50–2.75 (m, 2H), 1.90–2.25 (m,
2H), 1.08–1.30 (m, 2H), 0.21 (s, 9H). Compound 7d: To a
solution of 2d (1.0 mmol) and Ti(O-i-Pr)4 (1.2 mmol) in
ether (10 mL) was added i-PrMgCl (2.4 mmol, 0.97 M in
ether) at ꢀ40 °C and the mixture was stirred for 3 h at
ꢀ40 °C. To the mixture was added Li2Cu(CN)Cl2
(0.1 mmol, 1.0 M in THF) and the mixture was gradually
warmed to room temperature over 2 h. After the addition
of water (0.3 mL), NaF (1 g) and Celite (1 g), the mixture
was filtered through a pad of Celite. The filtrate was
concentrated and purified by column chromatography on
silica gel; 1H NMR (300 MHz, CDCl3): d 4.80 and 4.75
(2br s, each 1H), 3.37–3.52 (m, 2H), 3.16 (d, J = 18.6 Hz,
1H), 2.16–2.25 (m, 2H), 1.90–2.05 (m, 3H), 1.08–1.25 (m,
1H), 0.08 (s, 9H). Compound 11: 1H NMR (300 MHz,
CDCl3): d 5.29 (br s, 2H), 5.05 (s, 1H), 4.04 and 3.99 (2d,
Scheme 6. Preparation of 5. Reagents and conditions: (i) PhOH
(0.2 equiv), n-Bu3P (0.2 equiv), THF, 50 °C; (ii) NBS (2 equiv), Me2S
(2 equiv), CH2Cl2, rt, 12 h; (iii) R–C„CCH2CH@CH2 (1.5 equiv),
9-BBN (1.5 equiv), THF, rt, 12 h then 13, cat. PdCl2(dppf) (0.05 equiv),
K3PO4 (3 equiv), reflux, 2 h; (iv) p-TsOH (0.05 equiv), THF–H2O, rt,
2.5 h; (v) MsCl (2.5 equiv), Et3N (5.4 equiv), CH2Cl2, rt, 12 h; (vi)
t-BuLi (2 equiv), ether, ꢀ78 °C then 12; (vii) BnBr (1.2 equiv), NaH
(1.4 equiv), THF, rt, 12 h.
(13)9 by the Suzuki–Miyaura coupling reaction and the
following cleavage of ketal and chlorination of the
resulting diols.10 Compound 2g was obtained via the
lithiation of 13 and the reaction with aldehyde 12.
In summary, we have demonstrated that a divalent tita-
nium reagent could effectively cyclize 2-functionalized
2,7- and 2,8-enyn-1-ol derivatives in a domino fashion
to provide bicyclic compounds. The synthetic applica-
tion of the present method is now underway in our
laboratory.
Acknowledgement
We thank the Ministry of Education, Culture, Sports,
Science and Technology (Japan) for financial support.

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S. Okamoto et al. / Tetrahedron Letters 47 (2006) 7537–7540
each J = 12.6 Hz, each 1H), 3.26 (t, J = 6.3 Hz, 1H), 2.14–
2.54 (m, 2H), 1.51–2.03 (m, 4H), 0.08 (s, 9H).
Shipman, M. Tetrahedron Lett. 1989, 30, 7107; Binger,
Paul; Lu, Qi Hao; Wedemann, P. Angew. Chem. 1985, 97,
333.
6. Stereochemistries of compounds 8 and 7g were determined
1
by H–1H COSY and NOESY experiments. Explanation
8. Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000,
41, 2165.
of these stereoselectivities must await further study.
7. Formation of 4-methylenecyclopentenes from enyene
substrates by metal-mediated and/or—catalyzed cycliza-
tion has been reported: Van der Louw, J.; Komen, C. M.
D.; Knol, A.; De Kanter, F. J. J.; Van der Baan, J. L.;
Bickelhaupt, F.; Klumpp, G. W. Tetrahedron Lett. 1989,
30, 4453; Bapuji, S. Antony; Motherwell, William B.;
9. For preparation of 13, see: Saito, T.; Suzuki, T.; Morimoto,
M.; Akiyama, C.; Ochiai, T.; Takeuchi, K.; Matsumoto,
T.; Suzuki, K. J. Am. Chem. Soc. 1998, 120, 11633.
10. Although bromination of the intermediate diol was carried
out, the resulting dibromides were relatively unstable to be
stored.