Intramolecular titanium-promoted deoxygenative cyclization to 9-substituted-1,2,3,4-tetrahydrofluorene skeleton

Article abstract of DOI:10.1016/j.tetlet.2009.12.090

The Mukaiyama aldol reaction of 2-aryl-1-cyclohexene-1-carboxaldehydes with phenyl trimethylsilyl ketene acetal unexpectedly resulted in the formation of 9-substituted-1,2,3,4-tetrahydrofluorene derivatives via a novel intramolecular titanium-promoted deoxygenative cyclization. By successive treatment of the corresponding allyl alcohols with n-butyllithium and titanium tetrachloride, the cyclization products were obtained in good yields.

Full text of DOI:10.1016/j.tetlet.2009.12.090

Tetrahedron Letters 51 (2010) 1651–1653
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Tetrahedron Letters
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Intramolecular titanium-promoted deoxygenative cyclization to
9-substituted-1,2,3,4-tetrahydrofluorene skeleton
*
Syun-ichi Kiyooka , Satoshi Matsumoto, Satoshi Umezu, Ryoji Fujiyama, Daisuke Kaneno
Department of Materials Science, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The Mukaiyama aldol reaction of 2-aryl-1-cyclohexene-1-carboxaldehydes with phenyl trimethylsilyl
ketene acetal unexpectedly resulted in the formation of 9-substituted-1,2,3,4-tetrahydrofluorene deriv-
atives via a novel intramolecular titanium-promoted deoxygenative cyclization. By successive treatment
of the corresponding allyl alcohols with n-butyllithium and titanium tetrachloride, the cyclization prod-
ucts were obtained in good yields.
Received 31 October 2009
Revised 16 December 2009
Accepted 17 December 2009
Available online 23 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Titanium-promoted deoxygenation
Deoxygenative cyclization
Tetrahydrofluorenes
Tetrahydrofluorenes are ideal tricyclic precursors for the syn-
thesis of gibberellin A diterpenoid1 and are also recognized to be
effective ligands for metallocenes.2 However, direct synthetic
routes to the substituted tetrahydrofluorenes have been limited.3
We have recently reported the first asymmetric synthesis of anes-
thetic (S)-ketamine through 1,3-chirality transfer from an optically
pure (S)-alcohol, prepared by enantioselective reduction with (S)-
BINAL-H.4 An alternative synthesis introducing the chirality to
the corresponding (S)-alcohol by C–C bond formation has been
examined using the chiral oxazaborolidinone-promoted enantiose-
lective aldol reaction.5 The reaction of 2-(o-chlorophenyl)-1-cyclo-
hexene-1-carboxaldehyde (1)6 with phenyl trimethylsilyl ketene
acetal (2) gave the (S)-aldol product 3 in high enantioselectivity
(Eq. 1 in Scheme 1).7 During the process of determining the enanti-
O
O
N
OH
B
H
Cl
O
O
Cl
Ts
H
H
OTMS
OPh
COOPh
(1)
H
H
-78oC/6 h/CH2Cl2
82% yield
86% ee
3
1
2
X
X
H
H
OTMS
OPh
TiCl4
COOPh
(2)
0oC/1 h/CH2Cl2
X = Cl 1
X = H
X = Cl 5
X = H
74% yield
2
6
85% yield
4
Scheme 1.
oselectivity of the aldol reaction, the preparation of racemic 3 led
to an unexpected reaction (Eq. 2 in Scheme 1), that is, an unknown
* Corresponding author. Tel.: +81 88 844 8295; fax: +81 88 844 8359.
E-mail address: kiyooka@kochi-u.ac.jp (S. Kiyooka).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.090

1652
S. Kiyooka et al. / Tetrahedron Letters 51 (2010) 1651–1653
1. n-BuLi
OH
X
X
2. TiCl4
COOPh
COOPh
CH2Cl2
-78oC
rt, 30 min
68% yield
71% yield
X = Cl 3
X = Cl 5
X = H 6
X = H
7
OTiCl4- Li+
R'
OLi
R'
OTiCl3
metal exchange
or
R
R
R'
R
(A)
(B)
Scheme 2.
intramolecular cyclization was induced in the Mukaiyama aldol
reaction. We disclose herein a novel titanium-promoted deoxyge-
native cyclization.
From a mechanistic viewpoint, an effective deoxgenative pro-
cess occurs during the cyclization. The deoxygenative coupling of
titanium alkoxides, derived from allyl and benzyl alcohols, has
been reported only under radical conditions10, but that is not what
was shown in our case. A plausible electrophilic aromatic substitu-
tion (SEAr) mechanism is conceivable for the deoxygenative cycli-
zation, as shown in Scheme 3. Here, the titanium aldolate
intermediate X is converted to allyl cationic species Y and then
to Z by being assisted with steric demands.
On the basis of the cyclization method (Scheme 2), we tried cyc-
lizing allylic alcohols by the successive treatment with n-butyllith-
ium and titanium tetrachloride. The results are summarized in
Table 1. The reaction of primary allyl alcohol 8 at 0 °C gave
complex mixtures but the reaction at À78 °C gave the correspond-
ing chloride 11 in a moderate yield (entries 1 and 2). The chloride is
presumably to have been obtained via an intramolecular chloride
transfer from the titanium alkoxide intermediate.11 Steric restric-
tion allowing the efficient interaction between the aryl ortho and
the hydroxyl moieties is required for the cyclization. Actually,
the secondary alcohol 9 underwent the cyclization to product 12,
in which the double bond was migrated, at 0 °C (entry 3). The reac-
tion at À78 °C gave the normal cyclization product 13 in an excel-
lent yield (entry 4). The yield was high for tertiary alcohol 10,
probably reflecting the formation of the stable tertiary allyl cation
intermediate so as to give product 14 (entry 5).
The Mukaiyama aldol reaction of 1 with 2 in the presence of
stoichiometric titanium tetrachloride resulted in the formation of
a large amount of an unknown compound.8 The structure of the
compound was elucidated to be 9-substituted-1,2,3,4-tetrahydro-
fluorene 5, supported by comparison with the spectral data of
the unsubstituted tetrahydrofluorenes.9 The reaction of aldehyde
4 without the ortho-chloro substituent also smoothly produced
the cyclization product 6 in an 85% yield. The cyclization is consid-
ered to have taken place via a titanium aldolate intermediate in the
reaction. Apparently, the cyclization requires an unavoidable ap-
proach between the hydroxyl carbon moiety and the aryl ortho po-
sition, arisen from the Z-geometry in the titanium aldolate
intermediate. If the intermediate is formed by a different method,
the cyclization may be realized. Then, we envisaged generating the
key intermediate by treating racemic 3 with n-butyllithium and
titanium tetrachloride (Scheme 2). The sequence was expected to
form lithium alkoxide A, followed by the metal exchange reaction
to afford titanium alkoxide (or the corresponding ate complex) B. A
CH2Cl2 solution of 3 was stirred with 1 mol equiv of n-butyllithium
at À78 °C (low temperature was used to prevent a retro-aldol reac-
tion), followed by the addition of one equiv of titanium tetrachlo-
ride. The reaction mixture was allowed to warm to room
temperature and stirred for 30 min. The expected 5 was obtained
in a 68% yield. The reaction using the aldol 7 without the ortho-
chloro substituent also resulted in the formation of the corre-
sponding product 6 (71% yield), so the ortho-chloro substituent is
not essential for the cyclization.
In summary, 2-aryl-1-cyclohexene-1-carboxaldehydes under-
went an intramolecular titanium-promoted deoxygenative cycliza-
tion reaction to give 9-substituted-1,2,3,4-tetrahydrofluorenes.
The reaction seems to have proceeded via allyl cations, followed
by an intramolecular SEAr cyclization. A novel route to such tetra-
Cl
Cl
O
Cl
Cl
Cl
Ti
Cl
Ti
Cl
Me
Cl
O
O
Me
Cl
TMSCl
Si Me
Me
O
OPh
H
H
OPh
(X)
H
2
1
Cl
Cl
Cl
Ti
-
O
Cl
Cl
O
Product
O
OPh
O
Ph
(Z)
(Y)
Scheme 3. A plausible SEAr mechanism of the intramolecular titanium-promoted deoxygenative cyclization.

S. Kiyooka et al. / Tetrahedron Letters 51 (2010) 1651–1653
1653
Table 1
References and notes
The intramolecular titanium-promoted deoxygenative cyclization reaction starting
with alcoholsa
1. (a) House, H. O.; Melillo, D. G.; Sauter, F. J. J. Org. Chem. 1973, 38, 741; (b) Hook,
J. M.; Mander, L. N.; Urech, R. J. Org. Chem. 1984, 49, 3250.
2. Thomas, E. J.; Rausch, M. D.; Chien, J. C. W. Organometallics 2000, 19,
5744.
3. (a) Colonge, J.; Sibeud, J. Bull. Chim, Soc. Fr. 1952, 786; (b) Colonge, J.; Sibeud, J.
Bull. Chim, Soc. Fr. 1953, 75.
4. Yokoyama, R.; Matsumoto, S.; Nomura, S.; Higaki, T.; Yokoyama, T.; Kiyooka, S.-
i. Tetrahedron 2009, 65, 5181.
5. (a) Kiyooka, S.-i.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano, M. J. Org. Chem.
1991, 56, 2276; (b) Kiyooka, S.-i. Rev. Heteroat. Chem. 1997, 17, 245; (c) Kiyooka,
S.-i.; Hena, M. A. J. Org. Chem. 1999, 64, 5511; (d) Kiyooka, S.-i.; Shahid, K. A.;
Goto, F.; Okazaki, M.; Shuto, Y. J. Org. Chem. 2003, 68, 7967.
6. The starting aldehydes (1 and 4) were obtained by DIBAL-H reduction from the
corresponding nitriles, according to Fleming’s procedure: Fleming, F. F.; Funk, L.
A.; Altundas, R.; Sharief, V. J. Org. Chem. 2002, 67, 9414.
Entry Alcohols
Reaction
temperature (°C)
Product (% yield)
Complex mixtures
OH
OH
OH
OH
OH
1
0
À78
0
8
8
2
3
4
5
(57)
(68)
(89)
(95)
11
7. Yokoyama, T.; Yokoyama, R.; Nomura, S.; Matsumoto, S.; Fujiyama, R.; Kiyooka,
S.-i. Bull. Chem. Soc. Jpn. 2009, 82, 1528.
8. Synthesis of 5: To a CH2Cl2 solution of aldehyde 1 (220 mg, 1 mmol) and TiCl4
Cl
(1 mL, 1.0 M solution in CH2Cl2) was added
a CH2Cl2 solution of phenyl
trimethylsilyl ketene acetal 2 (250 mg, 1.2 mmol) at 0 °C. The reaction mixture
was stirred for 30 min and the reaction was quenched with a satd aq solution of
Na2CO3. The mixture was extracted with diethyl ether and dried over anhyd
MgSO4. The solvent was evaporated in vacuo. The crude was purified by flash
column chromatography (3% ethyl acetate/n-hexane) to give cyclization
9
12
13
14
product 5 (250 mg, 74% yield): IR 2932, 1755, 1193, 1161 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d 1.74–1.83 (m, 4H), 2.25–2.37 (m, 2H), 2.67 (dd, J = 7.8,
16.2, 1H), 2.74–2.78 (m, 2H), 2.86 (dd, J = 4.3, 16.2, 1H), 3.69 (t, J = 4.6, 1H),
6.93–6.99 (m, 3H), 7.11–7.18 (m, 2H), 7.22–7.26 (m, 1H), 7.29–7.34 (m, 2H);
13C NMR (100 MHz, CDCl3): d 22.3, 22.8, 24.5, 25.3, 35.8, 47.1, 121.2, 121.4
(Â2), 125.2, 125.9, 126.0, 128.6, 129.4 (Â2), 136.2, 141.5, 144.9, 148.1, 150.5,
170.8.
À78
9
9. (a) Kimmer Smith, W.; Hardin, J. N.; Ratideau, P. W. J. Org. Chem. 1990,
55, 5301; (b) Halterman, R. L.; Zhu, C. Tetrahedron Lett. 1999, 40, 7445.
10. van Tamelen, E. E.; Akermark, B.; Sharpless, K. B. J. Am. Chem. Soc. 1969, 91,
1552.
11. Similar chlorination of metal allylic and benzylic alkoxides using titanium
tetrachloride: (a) Kiyooka, S.-i.; Fujiyama, R.; Kawaguchi, K. Chem. Lett. 1984,
1979; (b) Fuchter, M. J.; Levy, J. N. Org. Lett. 2008, 10, 4919.
0
10
12. Synthesis of 13: The n-BuLi (0.156 mL, 0.248 mmol) was added to the solution
of alcohol 9 (50 mg, 0.248 mmol) in CH2Cl2 at À78 °C. After 10 min, the 1.0 M
solution of TiCl4 (0.25 mL) was added and the mixture was stirred for 30 min.
The reaction was quenched with satd aq Na2CO3. The mixture was extracted
with diethyl ether and dried over anhyd MgSO4. The solvent was evaporated in
vacuo. The crude was purified by flash column chromatography (3% ethyl
acetate/n-hexane) to give cyclization product 13 (41 mg, 89% yield): IR 3016,
a
Typical procedure is described in Ref. 12.
hydrofluorenes has been developed by successive treatment of sec-
ondary and tertiary allyl alcohols with n-butyllithium and titanium
tetrachloride. An expanded study on the scope and limitations of
the intramolecular titanium-promoted deoxygenative cyclization
is currently underway.
2927, 1446 cmÀ1 1H NMR (400 MHz, CDCl3): d 1.25–1.27 (d, J = 7.8, 3H), 1.79–
;
1.82 (m, 4H), 2.21–2.41 (m, 4H), 3.17–3.23 (q, J = 7.8, 1H), 7.11–7.18 (m, 2H),
7.22–7.26 (t, J = 7.8, 1H), 7.34–7.36 (d, J = 7.8, 1H); 13C NMR (100 MHz, CDCl3):
d 15.5, 22.0, 22.6, 23.1, 23.8, 45.5, 117.4, 122.2, 123.7, 126.2, 134.1, 144.9,
146.4, 148.6.